Q: Indications

Treatment of erection problems in men and pulmonary hypertension.

Question 1

General Information

Accepted Answer

Vardenafil belongs to the phosphodiesterase type 5 (PDE5) inhibitors drug class, a class of drugs commonly indicated for treatment of dysfunction (ED). It is a selective phosphodiesterase (PDE) type 5 inhibitor similar to sildenafil and tadalafil. This class of drugs does not inhibit prostaglandins as do some agents for treating ED (e.g., alprostadil). Vardenafil and tadalafil are more selective for PDE5 than PDE6, which is present in the retina. This leads to less visual adverse effects such as those reported in sildenafil-treated patients. The advantage of vardenafil may be that it achieves maximum plasma concentration sooner than sildenafil and tadalafil which may result in a faster onset of action. In an analysis of 580 patients, erections improved in 80% of men, and the ability to complete sexual intercourse with ejaculation was increased. Efficacy in treating diabetics and radical prostectomy patients has also been demonstrated. According to ED treatment guidelines, oral phosphodiesterase type 5 inhibitors (PDE5 inhibitor) are considered first-line therapy.1 Vardenafil was approved by the FDA in August 2003 for dysfunction. An orally disintegrating tablet was approved by the FDA in June 2010.

Question 2

Mechanism of Action

Accepted Answer

Vardenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cGMP. Cyclic guanosine monophosphate causes smooth muscle relaxation in the corpus cavernosum thereby allowing inflow of blood; the exact mechanism by which cGMP stimulates relaxation of smooth muscles has not been determined. Phosphodiesterase type 5 is responsible for degradation of cGMP in the corpus cavernosum. Vardenafil enhances the effect of NO by inhibiting PDE5, thereby raising concentrations of cGMP in the corpus cavernosum. Vardenafil has no direct relaxant effect on isolated human corpus cavernosum and, at recommended doses, has no effect in the absence of sexual stimulation. Vardenafil has a greater selectivity for PDE5 versus PDE6, an enzyme found in the retina and involved in phototransduction. Sildenafil, another PDE inhibitor, has a lower selectivity for PDE5 vs PDE6 and is associated with abnormalities related to color vision with higher doses or plasma concentrations of the drug.
Phosphodiesterase type 5 is also abundant in lung tissue and esophageal smooth muscle. Inhibition of PDE5 in lung tissue results in pulmonary vasodilation which can be effective in treating pulmonary hypertension. Inhibition of esophageal smooth muscle PDE5 can cause a marked reduction in esophageal motility as well as in lower esophageal sphincter (LES) tone. These effects may be beneficial in certain motor disorders involving the esophagus such as diffuse spasm, nutcracker esophagus, and hypertensive LES. However, the reduction in LES tone can worsen the symptoms of gastroesophageal reflux disease (GERD). Dyspepsia is one of the more common adverse reactions associated with PDE inhibitor therapy.

Question 3

Pharmacokinetics

Accepted Answer

Vardenafil is extensively distributed throughout the body. Protein binding is approximately 95%. Clearance is primarily via the hepatic cytochrome P450 isoenzyme CYP3A4 with minor metabolism by CYP3A5 and CYP2C. The major metabolite, designated M1, is the result of desethylation at the piperazine moiety of vardenafil and is further metabolized. M1 has phosphodiesterase selectivity similar to that of vardenafil and an in vitro inhibitory potency for phosphodiesterase 5 (PDE5) that is 28% of that of vardenafil. M1 also accounts for about 7% of the total pharmacological activity. Vardenafil is excreted as metabolites predominantly in the feces (approximately 91—95% of an oral dose) and to a lesser extent in the urine (about 2—6% of an oral dose). The elimination half-life of vardenafil and M1 is about 4—5 hours with the use of the film-coated tablets. The elimination half-life of vardenafil is 4—6 hours and the elimination half-life of MI is 3—5 hours with the use of the orally disintegrating tablets.23

Specific Pharmacokinetics

Sublingual Administration: Orally disintegrating vardenafil tablets provide a higher systemic exposure than the film-coated tablets. In a study of patients with dysfunction, the mean AUC was increased by 21—29% and the mean Cmax was decreased by 19% in elderly patients (>=65) and 8% in younger patients (18—45 years) as compared to the 10 mg film-coated tablets. In a study of healthy male volunteers (18—50 years), the mean Cmax was 15% higher and the mean AUC was 44% higher as compared to the 10 mg film-coated tablets. The median time to reach Cmax in a fasted stated was 1.5 h. High fat meals had no effect on vardenafil AUC or Tmax in healthy volunteers, but reduced the Cmax by 35%. When the orally disintegrating vardenafil tablets were administered with water, the vardenafil AUC was reduced by 29% and the median Tmax was shortened by 60 minutes, while Cmax was not affected.3

Special Populations

Hepatic Impairment: Volunteers with mild hepatic impairment (Child-Pugh class A) showed an increase in vardenafil Cmax and AUC of 22% and 17%, respectively, following a 10 mg oral dose. In volunteers with moderate hepatic impairment (Child-Pugh class B), the Cmax and AUC following a 10 mg vardenafil dose were increased by 130% and 160%, respectively, compared to healthy control subjects. Reduced doses are recommended for patients with moderate hepatic impairment (see Dosage). Vardenafil has not been studied in patients with severe (Child-Pugh class C) hepatic impairment.
Renal Impairment: In volunteers with mild renal impairment (CrCl 50—80 ml/min), vardenafil pharmacokinetics were similar to those observed in a control group with normal renal function. In those with moderate (CrCl 30—50 ml/min) or severe (CrCl = 65 years) and younger males (18—45 years), mean Cmax and AUC were 34% and 52% higher for vardenafil film-coated tablets, respectively, in the elderly males; lower starting doses of the film-coated tablets should be considered for patients >= 65 years of age (see Dosage).2 In a study of patients with dysfunction using the 10 mg orally disintegrating tablets, the mean AUC was increased by 21—29% in elderly and young patients and the mean Cmax was decreased by 19% in elderly patients (>=65) as compared to the 10 mg film-coated tablets. In trials with the orally disintegrating tablets, the AUC of vardenafil in elderly patients (>= 65 years) was increased by 39% and the Cmax was increased by 21% as compared to patients

Question 4

Contraindications/Precautions:

Accepted Answer

Your health care provider needs to know if you have any of these conditions: bleeding disorders, eye or vision problems, including a rare inherited eye disease called retinitis pigmentosa, anatomical deformation of the penis, Peyronie’s disease, or history of priapism (painful and prolonged erection), heart disease, angina, a history of heart attack, irregular heartbeats, or other heart problems, high or low blood pressure, history of blood diseases, like sickle cell anemia or leukemia, history of stomach bleeding, kidney disease, liver disease, stroke, an unusual or allergic reaction to vardenafil, other medicines, foods, dyes, or preservatives, pregnant or trying to get pregnant, breast-feeding.
Vardenafil is contraindicated in patients with a known hypersensitivity to any component of the tablet. The safety and efficacy of combinations of vardenafil with other treatments for dysfunction have not been studied. Therefore, the use of such combinations is not recommended.
The safe and effective use of vardenafil in combination with other agents for treating dysfunction has not been studied. Therefore, the use of such combinations is not recommended.
Vardenafil is contraindicated in patients who are currently on nitrate/nitrite therapy. Consistent with its known effects on the nitric oxide/cGMP pathway, vardenafil may potentiate the hypotensive effects of organic nitrates and nitrites. Patients receiving nitrates in any form are not to receive vardenafil. This includes any patient who receives intermittent nitrate therapies. It is unknown if it is safe for patients to receive nitrates once vardenafil has been administered. A suitable time interval following vardenafil dosing for safe administration of nitrates or nitric oxide donors has not been determined.
Vardenafil tablets are not recommended in patients with severe hepatic disease (Child-Pugh class C) or end stage renal disease requiring dialysis (severe renal impairment or renal failure). There are no controlled clinical studies on the safety and efficacy of vardenafil in these patients; therefore, vardenafil use is not recommended until further information is available. Patients with moderate hepatic impairment require a reduction in the starting dose of the regular tablets and a lower maximum dosage (see Indications/Dosage). Patients with mild hepatic impairment or mild to moderate renal impairment do not require adjustments in the vardenafil regular tablet dosage. The concomitant use of certain potent hepatic cytochrome P450 3A4 inhibitors may result in a requirement to adjust the vardenafil dosage (see Dosage and Drug Interactions).2 Vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, the orally disintegrating tablets should not be used in patients with moderate or severe hepatic disease (Child-Pugh class B or C) or in patients on hemodialysis. Patients who require lower doses of vardenafil should use the regular tablets.3
Lower starting doses of vardenafil regular tablets should be considered for geriatric patients (>= 65 years) because elderly patients have higher plasma concentrations than younger males (18—45 years) (see Indications/Dosage).2 In phase III clinical trials of the regular tablets, 834 elderly patients participated and there was no difference in safety or effectiveness compared to younger patients.2 In trials with the orally disintegrating tablets, the vardenafil AUC in elderly patients (>= 65 years) was increased by 39% and the Cmax was increased by 21% as compared to patients  170/110); patients with cardiac disease, severe heart failure or coronary artery disease (CAD) which causes unstable angina including those with left ventricular outflow obstruction (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis). Based on recommendations for sildenafil by the American College of Cardiology, it is recommended that vardenafil be used with caution in the following: patients with active coronary ischemia who are not taking nitrates (e.g., positive exercise test for ischemia); patients with congestive heart failure and borderline low blood pressure and borderline low volume status; patients on a complicated, multidrug, antihypertensive program; and patients taking drugs that can prolong the half-life of vardenafil. Vardenafil is contraindicated in patients currently onnitrate/nitrite therapy. In a double-blind, crossover, single-dose study of patients with stable CAD, vardenafil did not cause any impairment in exercise capabilities at levels equivalent to or greater than that achieved during sexual intercourse.4 The effects of vardenafil on QT prolongation were evaluated in 59 healthy males using moxifloxacin (400 mg) as an active control. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produced similar increases in QTc interval (e.g., 4—6 msec calculated by individual QT correction) as moxifloxacin. When vardenafil (10 mg) was given with gatifloxacin (400 mg), an additive effect on the QT interval was observed.2 The effect of vardenafil on the QT interval should be considered when prescribing the drug. The manufacturer recommends that vardenafil not be used in patients with congenital long QT syndrome and those taking Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic drugs. Further, use vardenafil with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, geriatric patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation.5678910
Prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been associated with PDE5 inhibitor administration. Priapism, if not treated promptly, can result in irreversible damage to the tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention. Vardenafil and other agents for the treatment of dysfunction should be used with caution in patients with penile structural abnormality (such as angulation, cavernosal fibrosis or Peyronie’s disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell disease, leukemia, multiple myeloma, polycythemia, or history of priapism).211
Patients should be reminded that vardenafil offers no protection against sexually transmitted disease. Counseling of patients about protective measures, including the prevention of transmission of human immunodeficiency virus (HIV) infection, should be considered.
Use vardenafil cautiously in patients with pre-existing visual disturbance. Post-marketing reports of sudden vision loss have occurred with phosphodiesterase inhibitors, including vardenafil. Vision loss is attributed to a condition known as non-arteritic anterior ischemic optic neuropathy (NAION), where blood flow is blocked to the optic nerve. This can cause permanent loss of vision. Vardenafil use should be discontinued in the event of sudden loss of vision in one or both eyes. Vardenafil use is not recommended in patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa. A minority of patients with the inherited condition retinitis pigmentosa have genetic disorders of retinal phosphodiesterases. Vardenafil use is not recommended in these patients until further information is available.23
Vardenafil is not indicated for use in females. Vardenafil is classified as FDA pregnancy risk category B. There are no adequate and well-controlled trials of vardenafil in humans during pregnancy.23
Vardenafil is not indicated for use in females and is therefore not recommended during breast-feeding. It is not known if vardenafil is excreted in human breast milk; however, it is known that the drug is excreted into the milk of lactating rats at concentrations approximately 10-fold greater than found in the plasma.23
There is no known indication for the use of vardenafil in neonates, infants, or children. Vardenafil should not be prescribed to these populations.
Vardenafil should be used cautiously in patients with gastroesophageal reflux disease (GERD) or hiatal hernia associated with reflux esophagitis. Like sildenafil, vardenafil can possibly decrease the tone of the lower esophageal sphincter and inhibit esophageal motility.12
Vardenafil should be administered to patients with coagulopathy only after careful benefit vs. risk assessment. Vardenafil alone does not prolong the bleeding time nor does its use in combination with aspirin cause any additive prolongation of the bleeding time. However, vardenafil has not been studied or administered to patients with bleeding disorders or significant active peptic ulcer disease. Therefore administer to these patients after careful benefit-risk assessment.2
Patients with a sudden decrease or loss of hearing (hearing impairment) should stop taking vardenafil and seek prompt medical attention. Hearing loss, which may be accompanied by tinnitus and dizziness, has been reported in temporal association with the intake of PDE5 inhibitors, including vardenafil; however, it is unknown if the hearing loss is directly related to PDE5 inhibitors or to other factors.23
The vardenafil orally disintegrating tablets contain aspartame, which is a source of phenylalanine. This may be harmful for people with phenylketonuria. Each tablet contains 1.01 mg of phenylalanine.3
The vardenafil orally disintegrating tablets contain sorbitol. Patients with hereditary fructose intolerance should not take the orally disintegrating tablets.3
This list may not include all possible contraindications.

Question 5

Pregnancy

Accepted Answer

Vardenafil is not indicated for use in females. Vardenafil is classified as FDA pregnancy risk category B. There are no adequate and well-controlled trials of vardenafil in humans during pregnancy.23

Question 6

Breast-feeding

Accepted Answer

Vardenafil is not indicated for use in females and is therefore not recommended during breast-feeding. It is not known if vardenafil is excreted in human breast milk; however, it is known that the drug is excreted into the milk of lactating rats at concentrations approximately 10-fold greater than found in the plasma.23

Question 7

Adverse Reations/Side Effects

Accepted Answer

Side effects that you should report to your doctor or health care professional as soon as possible: allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue, breathing problems, changes in hearing, changes in vision, chest pain, fast, irregular heartbeat, prolonged or painful erection, seizures. Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome): back pain, dizziness, flushing, headache, indigestion, muscle aches, nausea, stuffy or runny nose.
Flushing occurred in 11% of those receiving vardenafil film-coated tablets and in 7.6% of patients receiving orally disintegrating tablets. The incidence of flushing appears to increase as the dose increases. Anaphylactoid reactions (including laryngeal edema) occurred in less than 2% of patients. Other events occurring in < 2% of patients include allergic edema, facial edema (angioedema), pruritus, photosensitivity reaction, sweating (hyperhidrosis), erythema, and rash (unspecified). The discontinuation rate due to adverse reactions in placebo-controlled trials was 3.4% for vardenafil and 1.1% for placebo.23
Headache occurred in 15% of those receiving vardenafil film-coated tablets and in 14.4% of those receiving the orally-disintegrating tablets. The incidence of headache appears to increase as the dose increases. Neurologic effects that occurred in less than 2% of patients included asthenia, hypertonia, hypesthesia, dysesthesia, sleep disorders, amnesia, seizures, and paresthesias. The discontinuation rate due to adverse reactions in placebo-controlled trials was 3.4% for vardenafil and 1.1% for placebo. Postmarketing reports indicate that seizures and seizure recurrence have occurred in temporal association with vardenafil use. The incidence of these adverse events is unknown. Transient global amnesia has been reported during post-marketing use of the drug.23
Gastrointestinal (GI) adverse reactions occurring in at least 2% of patients taking vardenafil film-coated tablets and more frequently than placebo included dyspepsia (4% vs 1%) and nausea/vomiting (2% vs 1%). Dyspepsia also occurred in 2.8% of patients receiving the orally disintegrating tablets. GI effects that occurred in less than 2% of patients included abdominal pain, diarrhea, dysphagia, esophagitis, gastritis, gastroesophageal reflux, vomiting, and xerostomia. Dyspepsia and nausea appear to increase as the dose increases. The discontinuation rate due to adverse reactions in placebo-controlled trials was 3.4% for vardenafil and 1.1% for placebo.23 Arthralgia, myalgia, increased creatine phosphokinase (CPK), and increased muscle tone and cramping (muscle cramps) have been reported in less than 2% of patients receiving vardenafil during clinical trials. Neck pain has been reported with similar frequency. During controlled and uncontrolled clinical trials, back pain was reported in 2% of patients receiving vardenafil. The discontinuation rate due to adverse reactions in placebo-controlled trials was 3.4% for vardenafil and 1.1% for placebo.23
Dizziness occurred in 2% of those receiving vardenafil film-coated tablets and 2.3% of patients receiving orally disintegrating tablets. Dizziness has been associated with a sudden decrease in hearing. Centrally-mediated effects occurring in less than 2% of patients included insomnia, somnolence (drowsiness), and vertigo. The discontinuation rate due to adverse reactions in placebo-controlled trials was 3.4% for vardenafil and 1.1% for placebo.23 During clinical trials, cardiovascular adverse reactions that occurred in less than 2% of patients treated with vardenafil included angina pectoris, chest pain (unspecified), hypertension, hypotension, myocardial ischemia, myocardial infarction, orthostatic hypotension, palpitations, syncope, ventricular tachyarrhythmias (ventricular tachycardia), and sinus tachycardia. The effects of vardenafil on blood pressure were evaluated using single 20 mg doses of vardenafil in patients with dysfunction. Vardenafil caused a mean maximum decrease in supine blood pressure of 7 mm Hg systolic and 8 mm Hg diastolic (compared to placebo), accompanied by a mean maximum increase in heart rate of 4 beats per minute. The maximum decrease in blood pressure occurred between 1 and 4 hours after dosing. After multiple dosing, the effects of vardenafil on blood pressure were similar on Day 31 as on Day 1. Vardenafil may add to the hypotensive effects of antihypertensive agents.23
Respiratory conditions occurring in at least 2% of patients taking vardenafil film-coated tablets and more frequently than placebo included rhinitis (9% vs 3%), sinusitis (3% vs 1%), and flu-like syndrome (3% vs 2%). The incidence of rhinitis appears to increase as the dose increases. Nasal congestion occurred in 3.1% of patients receiving the orally disintegrating tablets. Respiratory-related effects which occurred in less than 2% of patients included dyspnea, sinus congestion, and pharyngitis. The discontinuation rate due to adverse reactions in placebo-controlled trials was 3.4% for vardenafil and 1.1% for placebo.23
During clinical trials, ejaculation dysfunction occurred in less than 2% of patients treated with vardenafil. Prolonged erections greater than 4 hours and priapism have been reported rarely with PDE5 inhibitors, including vardenafil.
Epistaxis occurred in less than 2% of patients receiving vardenafil in clinical trials.23
Phosphodiesterase inhibitors, such as vardenafil, inhibit PDE6 in retinal rods and cones, which are involved in phototransduction in the retina. Changes in color vision were reported in < 2% of patients and occurred as a result of PDE6 inhibition. In single dose studies, dose-related impairment of color discrimination (blue/green) as well as reductions in electroretinogram (ERG) b-wave amplitudes were noted; peak effects were noted near the time of peak plasma levels (approximately 1 hour after dosing). These effects diminished but were still present 6 hours after administration. In a single dose study of 25 healthy males, vardenafil 40 mg did not alter visual acuity, intraocular pressure, or funduscopic and slit lamp findings.2 In an 8-week, multiple-dose, placebo-controlled clinical trial, clinically significant changes in retinal function did not occur as assessed by ERG amplitudes or the Farnsworth-Munsell 100-hue test. The trial was designed to detect retinal function changes that might occur in more than 10% of patients. Of 52 enrollees, 32 subjects completed the study. Two patients in the vardenafil group reported transient cyanopsia (objects appear blue). Other ophthalmic adverse reactions occurring in < 2% of patients receiving vardenafil include blurred vision, chromatopsia, conjunctivitis (increased redness of the eye), dim vision, glaucoma, ocular pain, photophobia, visual impairment, ocular hyperemia, increased intraocular pressure, and watery eyes (lacrimation). Post-marketing reports have included cases of visual disturbances including retinal vein occlusion, visual field defects, reduced visual acuity, and loss of vision (temporary or permanent).23 Non-arteritic anterior ischemic optic neuropathy (NAION) has also been reported rarely in patients using phosphodiesterase type 5 (PDE5) inhibitors.164165166167 It is thought that the vasoconstrictive effect of phosphodiesterase inhibitors may decrease blood flow to the optic nerve, especially in patients with a low cup to disk ratio. Symptoms, such as blurred vision and loss of visual field in one or both eyes, are usually reported within 24 hours of use. Most, but not all, of these patients who reported this adverse effect had underlying anatomic or vascular risk factors for development of NAION. These risk factors include, but are not limited to: low cup to disc ratio (‘crowded disc’), age over 50 years, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. Additionally, two patients had retinal detachment and one patient had hypoplastic optic neuropathy.164 It is not yet possible to determine if these adverse events are related directly to the use of PDE5 inhibitors, to the patient’s underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors.
Adverse reactions affecting hearing or otic special senses and occurring in < 2% of patients in controlled clinical trials of vardenafil include hearing loss and tinnitus. In addition, 29 reports of sudden changes in hearing including hearing loss or decrease in hearing, usually in 1 ear only, have been reported to the FDA during post-marketing surveillance in patients taking sildenafil, tadalafil, or vardenafil; the reports are associated with a strong temporal relationship to the dosing of these agents. Many times, the hearing changes are accompanied by vestibular effects including dizziness, tinnitus, and vertigo. Follow-up has been limited in many of the reports; however, in approximately one-third of the patients, the hearing loss was temporary. Concomitant medical conditions or patient factors may play a role, although risk factors for the onset of sudden hearing loss have not been identified. Patients should be instructed to promptly contact their physician if they experience changes in hearing.23
The effects of vardenafil on QT prolongation were evaluated in 59 healthy males using moxifloxacin (400 mg) as an active control. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produced similar increases in QTc interval (e.g., 4—6 msec calculated by individual QT correction) as moxifloxacin (7 msec). The potential effect of vardenafil on the QT interval should be considered when prescribing the drug; the manufacturer recommends against drug use in certain patient groups with risk factors for QT prolongation (see Precautions).23 Changes in laboratory values have occurred infrequently. During controlled and uncontrolled clinical trials of vardenafil in over 4430 men (mean age 56, range 18—89 years), increased creatine kinase was reported in 2% of those receiving vardenafil versus 1% of those in the placebo group. Increased GGTP and elevated hepatic enzymes (e.g., abnormal liver function tests) were reported in less than 2% of patients.23 This list may not include all possible adverse reactions or side effects. Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue, blue tint to skin, chest tightness, pain, difficulty breathing, wheezing, dizziness, red, a swollen painful area/areas on the leg.

Question 8

Pharmacokinetics

Accepted Answer

Tadalafil is administered orally. The pharmacokinetics of tadalafil were evaluated in healthy young volunteers. Once absorbed, tadalafil is distributed into the tissues. Protein binding is 94% at therapeutic concentrations. Less than 0.0005% of the administered dose appeared in the semen of healthy subjects. The primary route of elimination for tadalfil is via the hepatic cytochrome P450 isoenzyme CYP3A4, which metabolizes the drug to a catechol metabolite. The catechol metabolite undergoes extensive methylation to form the methylcatechol metabolite and then glucuronidation to the form the methylcatechol glucuronide conjugate. The major circulating metabolite is the methylcatechol glucuronide, which is 13,000 times less potent for PDE5 than tadalafil. Methylcatechol concentrations are less than 10% of glucuronide concentrations. Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose). The mean elimination half-life is 17.5 hours in healthy subjects. 
Special Populations: 
Hepatic Impairment: In patients with mild to moderate hepatic impairment (Child-Pugh class A or B), the AUC following a 10 mg tadalafil dose was comparable to that of healthy subjects. There are no data available for doses higher than 10 mg of tadalafil in patients with hepatic impairment. Tadalafil has not been studied in patients with severe hepatic impairment (Child-Pugh class C). 
Renal Impairment: In clinical pharmacology studies involving persons with mild (CrCl 51—80 ml/min) or moderate renal impairment (CrCl 31—50 ml/min), tadalafil AUC was doubled after single doses of 5 to 10 mg compared to persons with normal renal function. In those with end-stage renal disease on hemodialysis, there was a two-fold increase in Cmax and 2.7- to 4.1-fold increase in AUC following single-dose administration of 10 or 20 mg tadalafil. Exposure to total methylcatechol (unconjugated plus glucuronide) was 2- to 4-fold higher in patients with renal impairment, compared to those with normal renal function. Hemodialysis (performed between 24 and 30 hours post-dose) had negligible effects on tadalafil or metabolite clearance. 
Pediatrics: Tadalafil has not been studied in persons less than 18 years of age. 
Geriatric: In a healthy volunteer study of elderly males (>= 65 years) and younger males (19—45 years), the AUC of tadalafil was 25% higher in the elderly males with no effect on Cmax. In patients with benign prostatic hyperplasia (BPH) receiving single and multiple doses of tadalafil 20 mg, there were no statistically significant differences in AUC and Cmax in elderly (70—85 years of age) patients compared to younger patients (

Question 9

Indications

Accepted Answer

Male dysfunction, benign prostatic hyperplasia, and pulmonary arterial hypertension (PAH).

Question 10

Contraindications/Precautions

Accepted Answer

Your health care provider needs to know if you have any of these conditions: bleeding disorders; eye or vision problems, including retinitis pigmentosa; Peyronie’s disease, or history of priapism (painful and prolonged erection); heart disease, angina, a history of heart attack, irregular heart beats; high or low blood pressure; history of blood diseases; history of stomach bleeding; kidney disease; liver disease; stroke; an unusual or allergic reaction to tadalafil. If you notice any changes in your vision while taking this drug, call your doctor or health care professional as soon as possible. Stop using this medicine and call your healthcare provider right away if you have a loss of sight in one or both eyes. Contact your healthcare provider right away if the erection lasts longer than 4 hours or if it becomes painful. If you experience symptoms of nausea, dizziness, chest pain or arm pain upon initiation of sexual activity after taking this medicine, you should refrain from further activity and call your healthcare provider immediately. Do not drink alcohol when taking this medicine as alcohol can increase your chances of getting a headache or getting dizzy, increasing your heart rate or lowering your blood pressure. Using this medicine does not protect you or your partner against HIV infection or other sexually transmitted infections. 
Tadalafil is contraindicated in patients with a known hypersensitivity to the drug or any component of the tablet.32 
The safety and efficacy of combinations of tadalafil with other treatments for dysfunction have not been studied. Therefore, the use of such combinations is not recommended.2
Because the efficacy of concurrent use of tadalafil and alpha-blockers in the treatment of benign prostatic hyperplasia (BPH) has not been adequately studied, and due to the potential vasodilatory effects of such combination treatment, tadalafil is not recommended for use with alpha-blockers when treating BPH (see Drug Interactions).2 
Tadalafil is contraindicated in patients who are currently on nitrate/nitrite therapy. Consistent with its known effects on the nitric oxide/cGMP pathway, tadalafil may potentiate the hypotensive effects of organic nitrates and nitrites. Patients receiving nitrates in any form are not to receive tadalafil. This includes any patient who receives intermittent nitrate therapies. It is unknown if it is safe for patients to receive nitrates once tadalafil has been administered. 
Use tadalafil cautiously in patients with renal impairment. Dosing recommendations vary depending upon the severity of renal impairment, indication, and the dosing regimen being used (see Dosage in renal impairment). Tadalafil is not recommended in patients receiving the drug on a once daily basis for dysfunction, benign prostatic hyperplasia, or pulmonary arterial hypertension when the creatinine clearance is less than 30 ml/min or the patient has renal failure or is receiving dialysis.2 
Use tadalafil with caution in patients with altered hepatic function secondary to hepatic disease and/or drug-induced inhibition. Dosage modifications are needed in patients with mild to moderate hepatic impairment (see Dosage). In patients with severe hepatic impairment, use of tadalafil is not recommended because of insufficient data. Additionally, tadalafil is metabolized by CYP3A4 in the liver. Dosage adjustments are necessary in patients taking potent CYP3A4 inhibitors such as ritonavir, ketoconazole, and itraconazole (see Dosage and Drug Interactions). 
There is a degree of cardiac risk associated with sexual activity; therefore, prescribers should evaluate the cardiovascular status of their patients prior to initiating any treatment for dysfunction. Tadalafil and other PDE5 inhibitors have mild systemic vasodilatory properties that may result in transient decreases in blood pressure. Health care professionals should consider whether the individual would be adversely affected by vasodilatory events. The following groups of patients with cardiac disease were excluded from clinical safety and efficacy trials for tadalafil, and, therefore, the manufacturer does not recommend the use of tadalafil in these groups until more data are available: myocardial infarction within the last 90 days; coronary artery disease resulting in unstable angina or angina occurring during sexual intercourse; NYHA Class II or greater heart failure in the last 6 months; uncontrolled cardiac arrhythmias; hypotension ( 170/100 mmHg); or a stroke within the last 6 months. Based on recommendations for sildenafil by the American College of Cardiology, it is recommended that tadalafil be used with caution in the following: patients with active coronary ischemia (angina) who are not taking nitrates (e.g., positive exercise test for ischemia); patients with congestive heart failure and borderline low blood pressure and borderline low volume status (hypovolemia); patients on a complicated, multidrug, antihypertensive program; and patients taking drugs that can prolong the half-life of tadalafil. Tadalafil is contraindicated in patients who are currently on nitrate/nitrite therapy. Also, patients with left ventricular outflow obstruction (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis) or severely impaired autonomic control of blood pressure can be sensitive to the action of vasodilators, including PDE5 inhibitors. Due to the pulmonary vasodilation caused by tadalafil, patients with pulmonary veno-occlusive disease (PVOD) may experience significant worsening in cardiovascular status. Due to a lack of clinical data on administration of tadalafil to patients with veno-occlusive disease, administration of tadalafil to such patients is not recommended. The possibility of associated PVOD should be considered should signs of pulmonary edema occur when tadalafil is administered. 
Prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been associated with PDE5 inhibitor administration. Priapism, if not treated promptly, can result in irreversible damage to the tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention. Use tadalafil, and other agents for the treatment of dysfunction, with caution in patients with penile structural abnormality (such as angulation, cavernosal fibrosis, or Peyronie’s disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell disease, leukemia, multiple myeloma, polycythemia, or history of priapism).24 
Educate patients that tadalafil, when used for dysfunction, offers no protection against sexually transmitted disease. Counsel patients about protective measures, including the prevention of transmission of human immunodeficiency virus (HIV) infection, as appropriate to the individual circumstances.
Use tadalafil cautiously in patients with pre-existing visual disturbance. Post-marketing reports of sudden vision loss have occurred with phosphodiesterase inhibitors. Vision loss is attributed to a condition known as non-arteritic anterior ischemic optic neuropathy (NAION), where blood flow is blocked to the optic nerve. Although visual disturbances have been reported rarely with tadalafil, there is no safety information on the administration of tadalafil to patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa. A minority of patients with the inherited condition retinitis pigmentosa have genetic disorders of retinal phosphodiesterases. Therefore, it is recommended that tadalafil not be administered to these patients until further data are available. 
Geriatric patients (>= 65 years) made up approximately 25% of patients in the primary efficacy and safety studies of tadalafil for the treatment of dysfunction and 28% of patients in the clinical study of tadalafil for pulmonary arterial hypertension. In clinical trials for benign prostatic hyperplasia, geriatric patients greater than 65 years of age accounted for 40% of study participants and those 75 years of age and older accounted for 10% of study participants. No overall differences in efficacy and safety were observed between older and younger patients for these indications. No dose adjustment is warranted based on age alone. However, greater sensitivity to medications in some older individuals should be considered.23 
Prior to initiating treatment with tadalafil for benign prostatic hyperplasia (BPH), consideration should be given to other urological conditions that may cause similar symptoms. Prostate cancer and benign prostatic hyperplasia (BPH) cause many of the same symptoms and frequently they coexist. Prior to starting tadalafil therapy for BPH, patients should be evaluated to rule out the presence of prostate cancer.2
Tadalafil is classified as FDA pregnancy risk category B. There are no adequate and well-controlled studies of tadalafil in pregnant women. According to the manufacturer, Adcirca should be used during pregnancy only if clearly needed;3 Tadalafil is not indicated for use in women.2 
Use tadalafil cautiously in patients with gastroesophageal reflux disease (GERD) or hiatal hernia associated with reflux esophagitis. Like sildenafil, tadalafil can possibly decrease the tone of the lower esophageal sphincter and inhibit esophageal motility.5 Additionally, tadalafil is an inhibitor of phosphodiesterase type 5 (PDE5), which is found in platelets. Some data indicate that tadalafil does not potentiate the increase in bleeding time caused by aspirin. However, the manufacturer recommends caution when administering tadalafil to patients with significant active peptic ulcer disease (PUD) since the effects of the drug in this patient population have not been formally studied.2 
It is not known if tadalafil is excreted in breast milk. Adcirca should be used with caution in breast-feeding women;3 Tadalafil is not indicated for use in women.2 Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA. 
Tadalafil is an inhibitor of phosphodiesterase type 5 (PDE5), which is found in platelets. Some data indicate that tadalafil does not potentiate the increase in bleeding time caused by aspirin. However, the manufacturer recommends caution when administering tadalafil to patients with significant hematological disease (e.g., bleeding disorders) since the effects of the drug in this patient population have not been formally studied.2
This list may not include all possible contraindications.

Question 11

Pregnancy

Accepted Answer

Tadalafil is classified as FDA pregnancy risk category B. There are no adequate and well-controlled studies of tadalafil in pregnant women. According to the manufacturer, Adcirca should be used during pregnancy only if clearly needed;3 Tadalafil is not indicated for use in women.2

Question 12

Breast-feeding

Accepted Answer

It is not known if tadalafil is excreted in breast milk. Adcirca should be used with caution in breast-feeding women;3 Tadalafil is not indicated for use in women.2 Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated coAnchorndition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Question 13

Interactions

Accepted Answer

Possible interactions include certain drugs for high blood pressure; certain drugs for the treatment of HIV infection or AIDS; certain drugs used for fungal or yeast infections, like fluconazole, ketoconazole, and voriconazole; certain drugs used for seizures like carbamazepine, phenytoin, and phenobarbital; grapefruit juice; macrolide antibiotics; medicines for prostate problems; rifabutin, rifampin or rifapentine. This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.
The safety and efficacy of tadalafil administered concurrently with any other phosphodiesterase inhibitors (e.g., vardenafil and sildenafil) has not been studied. The manufacturer of tadalafil recommends to avoid the use of tadalafil with any other phosphodiesterase inhibitors.2
Tadalafil has been shown to potentiate the hypotensive effects of nitrates. This interaction is consistent with tadalafil’s known effects on the nitric oxide/cGMP pathway. Deaths have been reported in men who were using a similar agent, sildenafil, while taking nitrate or nitrite therapy for angina. Tadalafil administration to patients who are concurrently using organic nitrates or nitrites in any form is contraindicated.6 It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with other medications such as nitrates.6
Concurrent use of phosphodiesterase (PDE5) inhibitors and alpha-blockers may lead to symptomatic hypotension in some patients. Tadalafil, other PDE5 inhibitors, and alpha-blockers are systemic vasodilators which can lower blood pressure. If vasodilators are used in combination, an additive effect on blood pressure is anticipated. Because the efficacy of concurrent use of tadalafil and alpha-blockers in the treatment of benign prostatic hyperplasia (BPH) has not been adequately studied, and due to the potential vasodilatory effects of combination treatment, tadalafil is not recommended for use with alpha-blockers when treating BPH. Patients receiving alpha-blocker therapy for BPH prior to tadalafil initiation should discontinue the alpha-blocker at least one day prior to beginning tadalafil treatment. When tadalafil is co-administered with an alpha-blocker in a patient receiving tadalafil for dysfunction (ED), the patient should be stable on alpha-blocker therapy before starting PDE5 inhibitor therapy. If hemodynamic instability is evident on alpha-blocker therapy alone, there is an increased risk of symptomatic hypotension with concomitant PDE5 inhibitor therapy. For patients with ED who are stable on alpha-blocker therapy, PDE5 inhibitors should be started at the lowest recommended dose. If a patient with ED is currently receiving an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increases in the alpha-blocker dose may be associated with further hypotension when taking a PDE5 inhibitor. Other variables, such as intravascular volume depletion and other antihypertensive drugs, may affect the safety of concomitant use of PDE5 inhibitors and alpha-blockers. Studies have been conducted to determine the effects of tadalafil on the potentiation of the blood-pressure-lowering effects of the alpha-blockers doxazosin and tamsulosin. When tadalafil 20 mg was administered to healthy subjects taking doxazosin (8 mg daily), an alpha-1-blocker, there was significant augmentation of the hypotensive effects of doxazosin. In contrast, coadministration of a single 20-mg dose of tadalafil to healthy subjects taking either 0.4 mg tamsulosin once-daily or 10 mg alfuzosin once daily, both of which are selective alpha-1A-blockers, resulted in no significant decreases in blood pressure. It should be noted that during once daily administration of tadalafil for ED or other indications, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with medications such as alpha-blockers.6
Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors, such as tadalafil, to patients receiving certain protease inhibitors such as atazanavir, darunavir, ritonavir, amprenavir, fosamprenavir, indinavir, tipranavir, nelfinavir, or saquinavir.2
Tadalafil is metabolized predominantly by CYP3A4. Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme.76 Similar precautions apply to combination products containing efavirenz such as efavirenz; emtricitabine; tenofovir.
Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving delavirdine. Coadministration of delavirdine with these drugs is expected to substantially increase their plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. The manufacturer of tadalafil recommends that in patients receiving concomitant potent CYP3A4 inhibitors, the ‘as needed’ dose for dysfunction should not exceed 10 mg within a 72 hour time period, and the ‘once-daily’ dose for dysfunction or benign prostatic hyperplasia should not exceed 2.5 mg (see Dosage).6 It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4. When used for pulmonary arterial hypertension, tadalafil should not be co-administered with potent CYP3A inhibitors.6
Tadalafil is metabolized predominantly by CYP3A4. Inhibitors of CYP3A4 may reduce tadalafil clearance. In theory, CYP3A4 inhibitors which may interact with tadalafil include amiodarone, cimetidine, clarithomycin or products containing clarithomycin, conivaptan, diltiazem, erythromycin or products containing erythromycin, fluconazole, fluoxetine or combination products with fluoxetine, fluvoxamine, ketoconazole, imatinib, STI-571, itraconazole, mibefradil, nefazodone, quinidine or combination products with quinidine, troleandomycin, voriconazole, zafirlukast, and zileuton. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. The manufacturer of tadalafil recommends that in patients receiving concomitant potent CYP3A4 inhibitors, the ‘as needed’ dose for dysfunction should not exceed 10 mg within a 72 hour time period, and the ‘once-daily’ dose for dysfunction or benign prostatic hyperplasia should not exceed 2.5 mg (see Dosage).6
Etravirine is an inducer of CYP3A4; coadministration may result in decreased tadalafil concentrations. Dosage adjustments may be needed based on clinical efficacy.8
Tadalafil is metabolized via the CYP3A4 isozyme. Grapefruit juice (food) has been reported to decrease the metabolism of drugs metabolized via this enzyme. Grapefruit juice contains a furano-coumarin compound, 6,7—dihydroxybergamottin that inhibits CYP3A4 in enterocytes in the GI tract. Tadalafil levels may increase; it is possible that tadalafil-induced side effects could also be increased in some individuals.6
Although specific interaction studies have not been performed, CYP3A4 inducers such as barbiturates, bosentan, carbamazepine, dexamethasone, phenytoin or fosphenytoin, nevirapine, rifabutin, troglitazone, rifampin, or isoniazid would likely decrease tadalafil AUC since tadalafil is primarily metabolized by CYP3A4.6 Patients should be monitored for loss of efficacy of tadalafil during concurrent use
Mifepristone, RU-486 inhibits CYP3A4 in vitro.910 Coadministration of mifepristone may lead to an increase in serum levels of drugs metabolized via CYP3A4, such as tadalafil. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration.
The combination of tadalafil and substantial consumption of ethanol can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache. Ethanol and PDE5 inhibitors, including tadalafil, are mild systemic vasodilators. As reported by the manufacturer, the interaction of tadalafil with ethanol was evaluated in 3 clinical pharmacology studies. In 2 of the studies, ethanol was administered at a dose of 0.7 g/kg, which is equivalent to approximately 6 ounces of 80-proof vodka in an 80-kg male, and tadalafil was administered at a dose of 10 mg in 1 study and 20 mg in another. In both of these studies, all patients consumed the entire ethanol dose within 10 minutes of starting. In one of these studies, blood ethanol concentrations of 0.08% were confirmed. In these two studies, more patients had clinically significant decreases in blood pressure on the combination of tadalafil and ethanol as compared to ethanol alone. Some subjects reported postural dizziness, and orthostatic hypotension was observed in some subjects. When tadalafil 20 mg was administered with a lower dose of ethanol (0.6 g/kg, which is equivalent to approximately 4 ounces of 80-proof vodka, administered in less than 10 minutes), orthostatic hypotension was not observed, dizziness occurred with similar frequency to ethanol alone, and hypotensive effects of ethanol were not potentiated. Tadalafil did not affect ethanol plasma concentrations and ethanol did not affect tadalafil plasma concentrations. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for an interaction when a substantial amount of ethanol is consumed.6
Nilotinib is a competitive inhibitor of CYP3A4, and tadalafil is a CYP3A4 substrate.1112 Concurrent administration of the CYP3A4 substrate midazolam with nilotinib increased midazolam exposure by 30%. Caution should be exercised when coadministering nilotinib with CYP3A4 substrates, especially substrates with a narrow therapeutic index.12
Sapropterin acts as a cofactor in the synthesis of nitric oxide and may cause vasorelaxation. Caution should be exercised when administering sapropterin in combination with drugs that affect nitric oxide-mediated vasorelaxation such as tadalafil. When given together these agents may produce an additive reduction in blood pressure. The combination of sapropterin and a phosphodiesterase inhibitor did not significantly reduce blood pressure when administered concomitantly in animal studies. The additive effect of these agents has not studied been in humans.13
Nifedipine can have additive hypotensive effects when administered with phosphodiesterase inhibitors (PDE 5 inhibitors).14 The patient should be monitored carefully and the dosage should be adjusted based on clinical response. Vardenafil (20 mg) did not affect the AUC or Cmax of slow-release nifedipine (30 or 60 mg daily), which is metabolized by CYP3A4.15 Nifedipine did not alter plasma levels of vardenafil.15 In patients whose hypertension was controlled with nifedipine, vardenafil produced mean additional supine systolic/diastolic blood pressure reductions of 6/5 mm Hg compared to placebo.15
Potent inhibitors of CYP3A4, such as telithromycin, may reduce tadalafil clearance; tadalafil is metabolized predominantly by CYP3A4. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. The manufacturer of tadalafil recommends that in patients receiving concomitant potent CYP3A4 inhibitors, the ‘as needed’ dose for dysfunction should not exceed 10 mg within a 72 hour time period, and the ‘once-daily’ dose for dysfunction or benign prostatic hyperplasia should not exceed 2.5 mg (see Dosage). It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4. When used for pulmonary arterial hypertension, tadalafil should not be co-administered with potent CYP3A inhibitors.616
Tadalafil, when used for pulmonary arterial hypertension (PAH), is contraindicated with telaprevir. Coadministration of telaprevir with phosphodiesterase type 5 (PDE5) inhibitors is expected to substantially increase their plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Telaprevir can be used cautiously with tadalafil for dysfunction; use tadalafil at a reduced dose of 10 mg no more frequently than every 72 hours with increased monitoring for adverse reactions.317
Studies have shown that tadalafil does not inhibit or induce cytochrome P450 (CYP) enzymes 1A2, 3A4, 2C9, 2C19, 2D6, and 2E1. Therefore, tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by CYP enzymes. When tadalafil was administered with theophylline, a CYP1A2 substrate, a small augmentation (3 beats per minute) of the increase in heart rate associated with theophylline was observed. However, tadalafil had no clinically significant effect on the pharmacokinetics of theophylline. Tadalafil had no clinically significant on the AUCs of the CYP3A4 substrates midazolam or lovastatin. Additionally, no clinically significant effect was observed on S-warfarin and R-warfarin AUC when coadministered with tadalafil; prothrombin time changes induced by warfarin were not affected by tadalafil.6
Tadalafil and other PDE5 inhibitors are mild systemic vasodilators. Studies were conducted to assess the interaction of tadalafil 10 mg and sustained-release metoprolol (25 to 200 mg daily), bendroflumethiazide (2.5 mg daily), or enalapril (10 to 20 mg daily). Following dosing of tadalafil with metoprolol, the mean reduction in supine systolic/diastolic blood pressure was 5/3 mmHg, compared to placebo. After dosing of tadalafil with bendroflumethiazide, the mean reduction in supine systolic/diastolic blood pressure was 6/4 mmHg, compared to placebo. Following dosing of tadalafil with enalapril, the mean reduction in supine systolic/diastolic blood pressure was 4/1 mmHg, compared to placebo.6
Tadalafil and other PDE5 inhibitors are mild systemic vasodilators. A study was conducted to assess the interaction of tadalafil 20 mg and angiotensin II receptor blockers. Study subjects were taking any marketed angiotensin II receptor blocker, either alone, as a component of a combination product, or as part of a multiple antihypertensive regimen. Following dosing, ambulatory measurements of blood pressure revealed differences between tadalafil and placebo of 8/4 mmHg in systolic/diastolic blood pressure.6
The increase in pH associated with nizatidine administration had no significant effect on tadalafil pharmacokinetics. Additionally, simultaneous administration of an antacid (magnesium hydroxide; aluminum hydroxide) and tadalafil reduced the apparent rate of absorption of tadalafil without altering the AUC of tadalafil.6

Question 14

Adverse Reations/Side Effects

Accepted Answer

Back pain; dizziness; flushing; headache; indigestion; muscle aches; nausea; stuffy or runny nose. This list may not describe all possible side effects. Call your healthcare provider immediate if you experience signs of an allergic reaction like skin rash, itching or hives, swelling of the face, lips, or tongue; breathing problems; changes in hearing; changes in vision; chest pain; erection lasting more than 4 hours; fast, irregular heartbeat; seizures.
Adverse reactions to tadalafil for the treatment of dysfunction (ED) were evaluated based on worldwide clinical trials of tadalafil involving over 5700 men (mean age 59, range 22 to 88 years). Over 100 patients were treated for 1 year or longer and over 1300 were treated for 6 months or more. During placebo-controlled trials, the discontinuation rate for patients treated with tadalafil (10 or 20 mg) was 3.1% compared to 1.4% in placebo-treated patients. In the treatment of patients with elevated pulmonary arterial pressures (PAH), adverse reactions to tadalafil were evaluated based on worldwide clinical trials involving 398 patients; 311 patients were treated for at least 182 days and 251 patients were treated for at least 360 days. During placebo-controlled trials, the overall rate of discontinuation due to an adverse event was higher in placebo-treated patients than in patients treated with tadalafil 40 mg/day (15% vs. 9%, respectively). In addition, the rate of discontinuation due to an adverse event not related to worsening of PAH was 5% in placebo-treated patients compared to 4% in patients treated with tadalafil 40 mg/day. During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and dysfunction, the rate of discontinuation due to an adverse effect was 3.6% of tadalafil-treated patients versus 1.6% of placebo-treated patients, and the mean age of study participants was 63 years.23
During clinical trials, hypotension was reported in < 2% and hypertension was reported in 1—3% of all tadalafil recipients. The risk for serious hypotension is augmented by the use of nitrates; therefore, the use of tadalafil in patients receiving nitrate therapy is contraindicated. Other cardiac effects reported in less than 2% of patients during clinical trials include angina, chest pain (unspecified), myocardial infarction, orthostatic hypotension, palpitations, syncope, and sinus tachycardia. Sudden cardiac death, stroke, chest pain, palpitations, and sinus tachycardia have all been noted in post-marketing experience with tadalafil. Most of the affected patients had pre-existing cardiovascular risk factors. Many of these events occurred during or shortly after sexual activity. In some cases, the symptoms occurred hours to days after the use of tadalafil and sexual activity.23 The effects of tadalafil on cardiac function, hemodynamics, and exercise tolerance were investigated in a single clinical pharmacology study. In this blinded crossover trial, 23 subjects with stable coronary artery disease and evidence of exercise-induced cardiac ischemia were enrolled. The primary endpoint was time to cardiac ischemia. The mean difference in total exercise time was 3 seconds (tadalafil 10 mg minus placebo), which represented no clinically meaningful difference. Further statistical analysis demonstrated that tadalafil was non-inferior to placebo with respect to time to ischemia. Of note, in this study, in some subjects who received tadalafil followed by sublingual nitroglycerin in the post-exercise period, clinically significant reductions in blood pressure (hypotension) were observed, consistent with the augmentation by tadalafil of the blood-pressure-lowering effects of nitrates. In addition, tadalafil (20 mg) had no significant effect on supine or standing systolic and diastolic blood pressure in healthy male subjects compared to placebo; there was also no significant effect on heart rate.
The effect of a single 100-mg dose of tadalafil on QT prolongation was evaluated at the time of peak tadalafil concentration in a randomized, double-blinded, placebo, and active (intravenous ibutilide)-controlled crossover study in 90 healthy males aged 18 to 53 years. The mean change in QTc for tadalafil, relative to placebo, was 2.8 milliseconds using Individual QT correction and 3.5 milliseconds using Fridericia QT correction. A 100-mg dose of tadalafil (5 times the highest recommended dose) was chosen because this dose yields exposures covering those observed upon coadministration of tadalafil with potent CYP3A4 inhibitors or those observed in renal impairment. In this study, the mean increase in heart rate associated with a 100-mg dose of tadalafil compared to placebo was 3.1 beats per minute.23
During clinical trials, adverse reactions occurring >= 2% of patients with dysfunction, >= 9% of patients with pulmonary arterial hypertension, and more frequently in the tadalafil-treated groups than placebo included back pain (2—12%), myalgia (1—14%), and pain in limb (1—3%). Adverse musculoskeletal reactions reported in < 2% of tadalafil recipients included arthralgia and neck pain. During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and dysfunction, the following musculoskeletal effects occurred in at least 1% of tadalafil-treated patients and more frequently than in placebo-treated patients: back pain (2.4% vs 1.4%), extremity musculoskeletal pain (1.4% vs 0%), and myalgia (1.2% vs 0.3%). Adverse musculoskeletal effects reported in less than 1% of patients included arthralgia and muscle spasms. Myalgia lead to treatment discontinuation in at least 2 patients during clinical trials for BPH or BPH/ dysfunction. In tadalafil clinical pharmacology trials, back pain or myalgia generally occurred 12 to 24 hours after dosing and typically resolved within 48 hours. The back pain/myalgia was described as diffuse bilateral lower lumbar, gluteal, thigh, or thoracolumbar muscular discomfort and was exacerbated by recumbency. Generally, pain was reported as mild or moderate in severity and resolved without medical treatment; severe back pain was reported infrequently. When medical treatment was needed, acetaminophen or NSAIDs were generally effective; however, in a small number of patients who required treatment, a mild narcotic (e.g., codeine) was used. Overall, approximately 0.5% of all tadalafil-treated patients discontinued treatment due to back pain/myalgia. Diagnostic testing, including measures for inflammation, muscle injury, or renal damage revealed no medically significant underlying pathology.23
Headache occurred in 3—15% of patients during dysfunction clinical trials and in 32—42% of patients during pulmonary arterial hypertension clinical trials; headache was reported more frequently in the tadalafil-treated groups than placebo. During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and dysfunction, the following centrally-mediated effects occurred in at least 1% of tadalafil-treated patients and more frequently than in placebo-treated patients: headache (4.1% vs 2.3%) and dizziness (1% vs 0.5%). Headache lead to treatment discontinuation in at least 2 patients during clinical trials for BPH or BPH/ dysfunction. Adverse reactions reported in < 2% of tadalafil recipients during clinical trials and affecting the nervous system included hypoesthesia, insomnia, dizziness, paresthesias, vertigo, and somnolence or drowsiness. Migraine, transient global amnesia, seizures, and seizure recurrence have been reported during post-marketing use of tadalafil; due to the voluntary nature of the reports, the frequency of post-marketing adverse reactions is unknown and causality to the drug has not been established.23
Dyspepsia occurred in 1—10% of patients during dysfunction (ED) clinical trials and in 10—13% of patients in pulmonary arterial hypertension clinical trials; dyspepsia was reported more frequently in the tadalafil-treated groups than placebo. Other gastrointestinal/digestive adverse reactions reported by tadalafil recipients and more frequently than placebo included nausea (1—11%), viral gastroenteritis (3—5%), gastroesophageal reflux (1—3%), abdominal pain (1—2%), and diarrhea (1—2%). During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and dysfunction, the following gastrointestinal effects occurred in at least 1% of tadalafil-treated patients and more frequently than in placebo-treated patients: dyspepsia (2.4% vs 0.2%) and diarrhea (1.4% vs 1%). Adverse GI reactions reported in less than 1% of patients included gastroesophageal reflux disease, upper abdominal pain, nausea, and vomiting. Upper abdominal pain lead to treatment discontinuation in at least 2 patients during clinical trials for BPH or BPH/ dysfunction. Dysphagia, elevated hepatic enzymes, esophagitis, gastritis, vomiting, increased GGTP, loose stools, upper abdominal pain, hemorrhoidal hemorrhage, rectal hemorrhage, and xerostomia were reported in < 2% of patients treated with tadalafil during clinical trials.23
Nasal congestion occurred in 2—4% of patients during dysfunction clinical trials and in 9% of patients during pulmonary arterial hypertension clinical trials; nasal congestion was reported more frequently in the tadalafil-treated groups than placebo. In addition, pharyngitis (reported as nasopharyngitis, 1—13%), upper and lower respiratory tract infection (3—13%), influenza (2—5%), cough (2—4%), bronchitis (2%), and urinary tract infection (2%) were reported in tadalafil-treated patients during clinical trials. During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and dysfunction, nasopharyngitis occurred more frequently in tadalafil-treated patients (2.1%) than placebo-treated patients (1.6%). Dyspnea, epistaxis, and pharyngitis were reported in less than 2% of patients in clinical trials.23 Flushing occurred in 1—3% of patients during dysfunction clinical trials and in 6—13% of patients during pulmonary arterial hypertension clinical trials; flushing was reported more frequently in the tadalafil-treated groups than those groups receiving placebo.23
During clinical trials, blepharedema or swelling of the eyelids, conjunctivitis, increased lacrimation, and ocular pain were reported in < 2% of tadalafil recipients.182 Single oral doses of phosphodiesterase inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green), using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. In a study to assess the effects of a single dose of tadalafil 40 mg on vision (n=59), no effects were observed on visual acuity, intraocular pressure, or pupillometry. Across all clinical studies with tadalafil, reports of changes in color vision were rare (< 0.1% of patients). Post-marketing reports have included cases of visual impairment such as retinal vein occlusion and visual field defects. Non-arteritic anterior ischemic optic neuropathy (NAION) has also been reported rarely in patients using phosphodiesterase type 5 (PDE5) inhibitors.19202122 It is thought that the vasoconstrictive effect of phosphodiesterase inhibitors may decrease blood flow to the optic nerve, especially in patients with a low cup to disk ratio. Symptoms, such as blurred vision (< 2%) and loss of visual field in one or both eyes, are usually reported within 24 hours of use. Most, but not all, of these patients who reported this adverse effect had underlying anatomic or vascular risk factors for development of NAION. These risk factors include, but are not limited to: low cup to disc ratio (‘crowded disc’), age over 50 years, diabetes, high blood pressure, coronary artery disease, hyperlipidemia, and smoking. Additionally, two patients had retinal detachment and one patient had hypoplastic optic neuropathy.19 It is not yet possible to determine if these adverse events are related directly to the use of PDE5 inhibitors, to the patient’s underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors.23
Adverse reactions affecting hearing or otic special senses and occurring in < 2% of patients in controlled clinical trials of tadalafil include hearing loss and tinnitus. In addition, 29 reports of sudden changes in hearing including hearing loss or decrease in hearing, usually in 1 ear only, have been reported to the FDA during post-marketing surveillance in patients taking sildenafil, tadalafil, or vardenafil; the reports are associated with a strong temporal relationship to the dosing of these agents. Many times, the hearing changes are accompanied by vestibular effects including dizziness, tinnitus, and vertigo. Follow-up has been limited in many of the reports; however, in approximately one-third of the patients, the hearing loss was temporary. Concomitant medical conditions or patient factors may play a role, although risk factors for the onset of sudden hearing loss have not been identified. Patients should be instructed to promptly contact their physician if they experience changes in hearing.23
There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for PDE5 inhibitors, such as tadalafil. Priapism, if not treated promptly, can result in irreversible damage to the tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention. During clinical trial evaluation of tadalafil, genitourinary effects including increased erection, spontaneous penile erection, and renal impairment (unspecified) were reported in less than 2% of study patients receiving the drug.23 During clinical trial evaluation of tadalafil, the following general adverse events were reported in less than 2% of patients receiving tadalafil: asthenia, facial edema, fatigue, and pain (unspecified).23 During clinical trial evaluation of tadalafil, the following dermatologic effects were reported in less than 2% of study patients: pruritus, rash (unspecified), and hyperhidrosis. Stevens-Johnson syndrome, exfoliative dermatitis, and urticaria have all been noted in post-marketing experience with tadalafil. Due to the uncontrolled and voluntary nature of post-marketing reports, neither the frequency nor a definitive causal relationship to tadalafil can be established.23
This list may not include all possible adverse reactions or side effects. Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue, blue tint to skin, chest tightness, pain, difficulty breathing, wheezing, dizziness, red, a swollen painful area/areas on the leg.

Question 15

Pharmacokinetics

Accepted Answer

Sildenafil is administered sublingually, orally or intravenously. The mean steady state volume of distribution (Vss) is 105 L, indicating widespread tissue distribution. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations. Based upon measurements of sildenafil in semen of healthy volunteers 90 minutes after dosing, less than 0.001% of the administered dose may appear in the semen of patients.

Sildenafil is predominantly metabolized by hepatic cytochrome P450 (CYP) enzymes. CYP3A4 is the major metabolizing enzyme and CYP2C9 the minor one. One active metabolite with properties similar to the parent drug has been identified and is formed by N-desmethylation of sildenafil. This metabolite has a PDE selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil and accounts for about 20% of the pharmacologic effects of sildenafil. The metabolite is further metabolized to inactive compounds.

Sildenafil is excreted as metabolites primarily in the feces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Both sildenafil and its active metabolite have terminal half-lives of about 4 hours. Sildenafil levels at 24 hours post a single 100 mg oral dose average 2 ng/ml (compared to peak plasma levels of approximately 440 ng/ml).

Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2C9

Sildenafil is metabolized principally by the hepatic cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) isoenzymes.(10) Inhibitors of these isoenzymes may reduce sildenafil clearance. Increased systemic exposure may result in an increase in sildenafil-induced adverse effects. The manufacturer recommends dosage reduction in patients receiving potent cytochrome CYP3A4 inhibitors.(11)

Route-Specific Pharmacokinetics:

Sublingual Route: Sildenafil is rapidly absorbed after sublingual administration. Its pharmacokinetics are dose-proportional over the recommended dose range.

Special Populations:

Hepatic Impairment: In volunteers with hepatic cirrhosis (Child-Pugh A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and Cmax (47%) compared to age-matched volunteers with no hepatic impairment.

Renal Impairment: In volunteers with mild (CrCl = 50-80 ml/min) and moderate (CrCl = 30-49 ml/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) were not altered. In volunteers with severe renal impairment (CrCl

Question 16

Indications

Accepted Answer

Treatment of erection problems in men and pulmonary hypertension.

Question 17

Contraindications/Precautions

Accepted Answer

Who should not take this medication? Do not take this medicine with any of the following medications: cisapride; methscopolamine nitrate; nitrates like amyl nitrite, isosorbide dinitrate, isosorbide mononitrate, nitroglycerin; nitroprusside; other medicines for dysfunction like tadalafil, vardenafil; other sildenafil products. Your health care provider needs to know if you have any of these conditions: bleeding disorders; eye or vision problems, including retinitis pigmentosa; Peyronie’s disease, or history of priapism; heart disease, angina, a history of heart attack, irregular heartbeats, or other heart problems; high or low blood pressure; history of blood diseases; history of stomach bleeding; kidney disease; liver disease; stroke; an unusual or allergic reaction to sildenafil or other products. If you notice any changes in your vision while taking this drug, call your healthcare provider immediately. If you experience symptoms of nausea, dizziness, chest pain or arm pain upon initiation of sexual activity after taking this medicine, you should refrain from further activity and call your healthcare provider immediately. Do not use alcohol while using this medicine. Using this medicine does not protect you or your partner against HIV infection or other sexually transmitted infections..

Sildenafil is contraindicated in patients with a known hypersensitivity to any component of the tablet or injection. The safety and efficacy of combinations of sildenafil with other treatments for dysfunction have not been studied. Therefore, the use of such combinations is not recommended.

The use of sildenafil is not recommended in patients with pulmonary veno-occlusive disease (PVOD). Administration of sildenafil in this population may significantly worsen cardiovascular status. In addition, if signs of pulmonary edema occur during sildenafil administration, the possibility of associated PVOD should be considered.

Sildenafil is contraindicated in patients who are currently on nitrate/nitrite therapy (see Drug Interactions). Consistent with its known effects on the nitric oxide/cGMP pathway, sildenafil was shown to potentiate the hypotensive effects of organic nitrates and nitrites. Patients receiving nitrates in any form are not to receive sildenafil. This includes any patient who receives intermittent nitrate therapies. It is unknown if it is safe for patients to receive nitrates once sildenafil has been administered.

The following factors are associated with up to an eight time increase in plasma concentrations of sildenafil compared with healthy subjects: geriatric patients (40% increase in sildenafil AUC), hepatic disease (e.g., cirrhosis, 80% increase), severe renal impairment (i.e., CrCl < 30 ml/min, 100% increase), concomitant use of potent cytochrome P450 3A4 inhibitors (erythromycin (182% increase), itraconazole, ketoconazole, saquinavir (210% increase)). Because higher plasma concentrations may increase the incidence of adverse reactions, the sildenafil starting dose should be 25 mg in these patients. Additionally, ritonavir greatly increased the systemic concentrations of sildenafil in a study of healthy, non-HIV infected volunteers (11-fold increase in AUC). Based on these pharmacokinetic data, it is recommended not to exceed a maximum single dose of 25 mg sildenafil in a 48 hour period.

There is a degree of cardiac risk associated with sexual activity; therefore, prescribers should evaluate the cardiovascular status of their patients prior to initiating any treatment for dysfunction. Over 75 deaths due to cardiovascular events have been reported in association with sildenafil use. In a study conducted at the Mayo Clinic, sildenafil was shown to have limited cardiovascular effects during exercise in men with known or probable coronary artery disease. The study reported that sildenafil had no effect on exercise capacity or the hemodynamic response to exercise. Systolic blood pressure was reduced an average of 7 mmHg compared to baseline.(12) Another study showed that sildenafil inhibited beta-adrenergic-stimulated systolic function. Using dobutamine in healthy volunteers, investigators reported that sildenafil suppressed the cardiac response to dobutamine but had minimal effect under resting conditions. It was also reported that the effects of sildenafil were independent of cardiac afterload or preload changes.(13) Health care professionals should consider whether the individual would be adversely affected by vasodilatory events. In particular, caution should be used if sildenafil is prescribed in the following patient groups: patients who have suffered a myocardial infarction, stroke, or life-threatening cardiac arrhythmias in the last 6 months; patients with resting hypotension (BP  170/100); patients with fluid depletion; patients with cardiac disease, heart failure or coronary artery disease which causes unstable angina. The American College of Cardiology recommends that sildenafil be used with caution in the following: patients with active coronary ischemia who are not taking nitrates (e.g., positive exercise test for ischemia); patients with congestive heart failure and borderline low blood pressure and borderline low volume status; patients on a complicated, multidrug, antihypertensive program; and patients taking drugs that can prolong the half-life of sildenafil (see Drug Interactions). However, one study reported that sildenafil was effective and well tolerated in patients on multidrug antihypertensive regimens and was not associated with additional safety risks in these patients.Patients with left ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure can be particularly sensitive to the actions of sildenafil and other vasodilators. Doses of sildenafil above 25 mg should not be given within 4 hours of an alpha-blocker (e.g., doxazosin, see Drug Interactions).

Prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been associated with PDE5 inhibitor administration. Priapism, if not treated promptly, can result in irreversible damage to the tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention. Sildenafil and other agents for the treatment of dysfunction should be used with caution in patients with penile structural abnormality (such as angulation, cavernosal fibrosis or Peyronie’s disease), or in patients who have conditions which may predispose them to priapism (such as such as sickle cell anemia, leukemia, multiple myeloma, polycythemia, or a history of priapism).(11)(14) However, in one retrospective study, treatment with sildenafil did not cause any worsening deformity or progression of Peyronie’s disease.(15)

Patients should be reminded that sildenafil, when used for dysfunction, offers no protection against sexually transmitted disease. Counseling of patients about protective measures, including the prevention of transmission of human immunodeficiency virus (HIV) infection, should be considered.

Sildenafil has no effect on bleeding time when taken alone or with aspirin. In vitro studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside (a nitric oxide donor). There is no safety information on the administration of sildenafil to patients with a coagulopathy or active peptic ulcer disease. Therefore, sildenafil should be administered with caution to these patients.

Use sildenafil cautiously in patients with preexisting visual disturbance. Post-marketing reports of sudden vision loss have occurred with phosphodiesterase inhibitors. Vision loss is attributed to a condition known as non-arteritic anterior ischemic optic neuropathy (NAION), where blood flow is blocked to the optic nerve. Patients with a history of NAION are at increased risk for recurrence. Only use a PDE5 inhibitor in these individuals if the anticipated benefit outweighs the risk. Patients with low cup to disc ratio (‘crowded disc’) are also at increased risk; however, this condition is uncommon, and there is insufficient evidence to support screening of prospective users of a PDE5 inhibitor. There is no safety information on the administration of sildenafil to patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa. A minority of patients with the inherited condition retinitis pigmentosa have genetic disorders of retinal phosphodiesterases. Therefore, sildenafil should be used with caution in these patients.(11)(16)

Sildenafil is classified as FDA pregnancy risk category B. There are no adequate and well-controlled studies of sildenafil in pregnant women. According to the manufacturers, Revatio should be used during pregnancy only if clearly needed;(16) Sildenafil is not indicated for use in women.(11)

It is not known if sildenafil or its metabolites are excreted in human breast milk. The prescribing information for Revatio recommends caution when the drug is administered to a nursing mother;(16) Sildenafil is not indicated for use in women.(11) Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

In 2012, the FDA recommended against the use of sildenafil for the treatment of pulmonary hypertension in neonates, infants, children, or adolescents based on the results of a long-term pediatric clinical trial showing an increased risk of death in pediatric patients receiving a high dose of sildenafil compared to those receiving a low dose (HR 3.9, p = 0.007).(16)(17) The FDA has since clarified its recommendation stating that there may be patients in which the benefits of sildenafil therapy outweigh the risks, such as when other treatment options are limited and when close monitoring is available, and advises health care providers to weigh the risk-benefit profile for individual patients when deciding whether to initiate sildenafil.(18) Despite the FDA’s caution against use, The Pediatric Pulmonary Hypertension Network (PPHNet) recommends cautious initiation and titration of sildenafil, avoidance of high doses (> 20 mg PO 3 times daily), and consultation and/or referral to providers experienced in the treatment of pulmonary hypertension in pediatric patients. PPHNet also recommends against the abrupt discontinuation of sildenafil in pediatric patients currently receiving it as this could lead to clinical worsening or death. The FDA warning is based on chronic use of sildenafil as monotherapy and, therefore, does not apply to short-term use in critically ill patients.(19)

Sildenafil should be used cautiously in patients with gastroesophageal reflux disease (GERD) or hiatal hernia associated with reflux esophagitis. Sildenafil can decrease the tone of the lower esophageal sphincter and inhibit esophageal motility.(9)

Safety and efficacy of sildenafil has not been established in the treatment of pulmonary hypertension secondary to sickle cell disease. Vaso-occlusive crisis (sickle-cell crisis) requiring hospitalization has been reported more frequently in patients with pulmonary hypertension secondary to sickle cell disease who received sildenafil than by those who received placebo. Also, when using for dysfunction, use sildenafil with caution in patients with sickle cell disease because the risk of priapism may be increased.(16)(11)

This list may not include all contraindications.

Question 18

Breast-feeding

Accepted Answer

It is not known if sildenafil or its metabolites are excreted in human breast milk. The prescribing information for Revatio recommends caution when the drug is administered to a nursing mother;(16) Sildenafil is not indicated for use in women.(11) Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Question 19

Adverse Reations/Side Effects

Accepted Answer

During the marketing of sildenafil from late March through November 1998, more than 6 million outpatient prescriptions were dispensed. As of November 1998, 128 deaths had been reported to the FDA in association with sildenafil use. The cause of death was unknown for 48 patients. Three patients experienced a stroke and 77 patients had cardiovascular events. Cardiovascular events related to sildenafil included myocardial infarction, cardiac arrest, angina, ventricular tachycardia, hypertension, and other cardiac symptoms. Sixteen patients had received nitroglycerin or a nitrate, which is contraindicated with the use of sildenafil. Twenty-seven of these patients had died during or immediately after sexual intercourse. Other events were reported hours to days after use of sildenafil and participation in sexual activity. Larger but similarly transient effects on blood pressure were recorded among patients receiving concomitant nitrates. These effects are possibly related to the effects of sildenafil on PDE5 in vascular smooth muscle. In a study conducted at the Mayo Clinic, sildenafil was shown to have limited cardiovascular effects during exercise in men with known or probable coronary artery disease. The study reported that sildenafil had no effect on exercise capacity or the hemodynamic response to exercise. Systolic blood pressure was reduced an average of 7 mmHg compared to baseline.(12) After chronic dosing (80 mg PO TID) in healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9 mmHg and 8.4 mmHg, respectively. Post-marketing serious cardiovascular, cerebrovascular, and vascular adverse events were reported in temporal association with sildenafil use and include myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, subarachnoid and intracerebral hemorrhages or intracranial bleeding, and pulmonary hemorrhage.(11)(16)

The following adverse reactions affecting the hemic, lymphatic, metabolic, and nutritional systems occurred in < 2% of patients in controlled clinical trials of sildenafil: anemia, gout, hyperglycemia, hyperuricemia, hypoglycemia, hypernatremia, leukopenia, thirst or dipsia, and unstable diabetes mellitus. Additionally, cases of edema and peripheral edema were reported by"}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1863","name":"Interactions","acceptedAnswer":{"@type":"Answer","text":"Possible interactions include: certain drugs for high blood pressure; certain drugs for the treatment of HIV infection or AIDS; certain drugs used for fungal or yeast infections, like fluconazole, ketoconazole, and voriconazole; cimetidine; erythromycin; rifampin. This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Some items may interact with your medicine.

NOTE: Sildenafil is metabolized principally by the hepatic cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) isoenzymes.(20) Inhibitors of these isoenzymes may reduce sildenafil clearance. Increased systemic exposure to sildenafil may result in an increase in sildenafil-induced adverse effects. The manufacturer recommends dosage reduction in patients receiving potent cytochrome CYP3A4 inhibitors.(21)

Consistent with its known effects on the nitric oxide/cGMP pathway, sildenafil was shown to potentiate the hypotensive effects of nitrates. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina. Sildenafil administration to patients who are concurrently using organic nitrates or nitrites in any form is contraindicated.(21)

The safety and efficacy of tadalafil administered concurrently with any other phosphodiesterase (PDE5) inhibitors, such as sildenafil, has not been studied. The manufacturer of tadalafil recommends to avoid the use of tadalafil with any other PDE5 inhibitors.(22)

Coadministration of sildenafil, tadalafil or vardenafil and other organic nitrates has been shown to potentiate the hypotensive effects of nitrates; concomitant administration of these drugs for dysfunction with nitrates is contraindicated.(21)(23)(24)Many methscopolamine-containing products list methscopolamine nitrate as the ingredient. Therefore, the concomitant use of sildenafil, tadalafil or vardenafil and products which contain methscopolamine nitrate is not recommended.

Sildenafil is metabolized principally by cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) isoenzymes. Cimetidine is a known inhibitor of hepatic CYP enzymes and reduces the metabolism of sildenafil. Cimetidine (800 mg) caused a 56% increase in plasma sildenafil concentrations when coadministered with sildenafil 50 mg to healthy volunteers. Population data from patients in clinical trials also indicate a reduction in sildenafil clearance when it was coadministered with cimetidine. If possible, cimetidine use should be avoided in patients who take sildenafil.(21)

Etravirine is an inducer of CYP3A4; coadministration may result in decreased sildenafil concentrations. Dosage adjustments may be needed based on clinical efficacy.(25)

 

Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving ritonavir. Coadministration of ritonavir with sildenafil results in an 11-fold increase of sildenafil AUC; one death has been reported in a patient who received sildenafil in combination with ritonavir and Fortovase.(26) Substantially increased sildenafil plasma concentrations may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. If coadministered when sildenafil is used for dysfunction, a reduced dose of sildenafil 25 mg every 48 hours with increased monitoring for adverse reactions is recommended.(27)(28) When sildenafil is used for the treatment of pulmonary arterial hypertension (PAH), the use of ritonavir is contraindicated because a safe and effective dose has not been established.(27)

Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving saquinavir. Sildenafil is contraindicated for use with the anti-retroviral protease inhibitors when used for pulmonary arterial hypertension (PAH).(29) If sildenafil is coadministered with saquinavir and used for dysfunction, use sildenafil at reduced doses of 25 mg every 48 hours with increased monitoring for adverse reactions.(29)(28) Coadministration of saquinavir, especially when ‘boosted’ with ritonavir, with PDE5 inhibitors is expected to substantially increase their plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. One death has been reported in a patient who received sildenafil in combination with ritonavir and saquinavir (Fortovase).(26)

Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving amprenavir. Coadministration with sildenafil results in a 210% increase in sildenafil AUC. Sildenafil is contraindicated for use with the anti-retroviral protease inhibitors when used for pulmonary arterial hypertension (PAH).(30) If sildenafil is coadministered with amprenavir and used for dysfunction, use sildenafil at reduced doses of 25 mg every 48 hours with increased monitoring for adverse reactions.(31)(28) Substantially increased sildenafil plasma concentrations may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.(31)(28)

Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving fosamprenavir. Sildenafil is contraindicated for use with the anti-retroviral protease inhibitors when used for pulmonary arterial hypertension (PAH).(30) If sildenafil is coadministered with fosamprenavir and used for dysfunction, use sildenafil at reduced doses of 25 mg every 48 hours with increased monitoring for adverse reactions.(30)(28) Coadministration with sildenafil results in a 210% increase in sildenafil AUC. Substantially increased sildenafil plasma concentrations may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.(30)(28)

Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving atazanavir. Sildenafil is contraindicated for use with the anti-retroviral protease inhibitors when used for pulmonary arterial hypertension (PAH).(32) If sildenafil is coadministered with atazanavir and used for dysfunction, use sildenafil at reduced doses of 25 mg every 48 hours with increased monitoring for adverse reactions.(32)(28) Coadministration of atazanavir with PDE5 inhibitors is expected to substantially increase their plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.(32)(28)

Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving darunavir. Sildenafil is contraindicated for use with the anti-retroviral protease inhibitors when used for pulmonary arterial hypertension (PAH).(33) When sildenafil is coadministered with darunavir and used for dysfunction, use sildenafil at reduced doses of 25 mg every 48 hours with increased monitoring for adverse reactions.(33)(28) Coadministration of darunavir with PDE5 inhibitors is expected to substantially increase their plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.(33)(28)

Sildenafil is contraindicated for use with cobicistat when used for pulmonary arterial hypertension (PAH). If used for dysfunction, the dose of sildenafil should not exceed 25 mg every 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use is expected to substantially increase the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.(34)

Sildenafil is contraindicated for use with atazanavir; cobicistat when used for pulmonary arterial hypertension (PAH). If used for dysfunction, the dose of sildenafil should not exceed 25 mg every 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use is expected to substantially increase the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.(35)

Sildenafil is contraindicated for use with darunavir; cobicistat when used for pulmonary arterial hypertension (PAH). If used for dysfunction, the dose of sildenafil should not exceed 25 mg every 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use is expected to substantially increase the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.(36)

Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving indinavir. Altered indinavir plasma concentrations may result. Additionally, sildenafil is contraindicated for use with the anti-retroviral protease inhibitors when used for pulmonary arterial hypertension (PAH).28731 When sildenafil is coadminstered with indinavir and used for dysfunction, use sildenafil at reduced doses of 25 mg every 48 hours with increased monitoring for adverse reactions.(28) Substantially increased PDE5 inhibitor plasma concentrations are seen and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. In a small pharmacokinetic study, the coadministration of a single dose of sildenafil (25 mg) to patients receiving indinavir (800 mg every 8 hours) resulted in markedly increased sildenafil AUC values (340% increase), as compared to historical controls. The Cmax for indinavir was increased by 48% and the 8-hour AUC was increased 11% following concurrent administration. In two of the six subjects, prolonged clinical effects of sildenafil were noted for 72 hours after a single dose of sildenafil.(37)

Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving lopinavir; ritonavir (Kaletra). Coadministration of lopinavir; ritonavir (Kaletra) with these drugs is expected to substantially increase their plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Lopinavir; ritonavir is contraindicated for use with sildenafil when sildenafil is used for the treatment of pulmonary arterial hypertension (PAH).(38) If coadministered when sildenafil is used for dysfunction, use sildenafil at reduced doses of 25 mg every 48 hours with increased monitoring for adverse reactions.(28)(38)

Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving nelfinavir. Sildenafil is contraindicated for use with the anti-retroviral protease inhibitors when used for pulmonary arterial hypertension (PAH).(39) When sildenafil is coadministered with nelfinavir and used for dysfunction, use sildenafil at reduced doses of 25 mg every 48 hours with increased monitoring for adverse reactions.(39)(28) Coadministration of nelfinavir with PDE5 inhibitors is expected to substantially increase their plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.

Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving tipranavir. Sildenafil is contraindicated for use with the anti-retroviral protease inhibitors when used for pulmonary arterial hypertension (PAH).(29) When sildenafil is coadministered with tipranavir and used for dysfunction, use sildenafil at reduced doses of 25 mg every 48 hours with increased monitoring for adverse reactions.(29)(28) Coadministration is expected to substantially increase the PDE5 inhibitor plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.

Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving delavirdine. Coadministration of delavirdine with these drugs is expected to substantially increase their plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Use sildenafil at reduced doses of 25 mg every 48 hours with increased monitoring for adverse reactions.(40(28)

Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as sildenafil.(41)(20)

Sildenafil is metabolized principally by cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) isoenzymes. Fluvoxamine is a known inhibitor of both CYP3A4 and CYP2C9.(20)(42) In healthy subjects who received fluvoxamine for 10 days, the AUC of sildenafil was increased by 40% after a single 50 mg dose of sildenafil was given.(43) One case of fluvoxamine-induced dysfunction has been reported to have been treated with sildenafil.(44)A starting dose of sildenafil 25 mg is suggested for patients on fluvoxamine therapy; doses should be increased only if 25 mg is not sufficient. Fluvoxamine is likely to have an interaction with similar agents such as tadalafil and vardenafil since they are also metabolized by CYP3A4. Other selective serotonin reuptake inhibitors such as citalopram, escitalopram, paroxetine, sertraline, and venlafaxine have no significant effects on CYP3A4 and are not likely to affect sildenafil pharmacokinetics.

Aprepitant, fosaprepitant is a moderate inhibitor and inducer of CYP3A4 and is an inducer of CYP2C9.(45) Sildenafil is a substrate of CYP3A4 and CYP2C9.(21) Coadminister these drugs with caution. Altered sildenafil serum concentrations may occur, leading to either an increased risk of sildenafil-related adverse reactions or a risk of decreased sildenafil efficacy.

Sildenafil is metabolized principally by the hepatic cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) isoenzymes. Inhibitors of these isoenzymes may reduce sildenafil clearance. Increased systemic exposure to sildenafil may result in an increase in sildenafil-induced adverse effects. The manufacturer recommends dosage reduction in patients receiving potent cytochrome CYP3A4 inhibitors such as erythromycin (see Dosage).(21) When a single 100 mg dose of sildenafil is administered with erythromycin (500 mg bid for 5 days), a specific CYP3A4 inhibitor, at steady state, there is a 182% increase in sildenafil systemic exposure (AUC).(21) In vivo studies of healthy male volunteers show no clinically significant effect of azithromycin (500 mg PO daily for 3 days) on the systemic exposure of sildenafil or its major circulating metabolite.(46)

Sildenafil is metabolized principally by the hepatic cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) isoenzymes. Inhibitors of these isoenzymes may reduce sildenafil clearance. Increased systemic exposure to sildenafil may result in an increase in sildenafil-induced adverse effects. The manufacturer recommends dosage reduction in patients receiving potent cytochrome CYP3A4 inhibitors such as ketoconazole (see Dosage).(21) Population data from patients in clinical trials did indicate a reduction in sildenafil clearance when it was coadministered with CYP3A4 inhibitors.(21)

Sildenafil is metabolized principally by the hepatic cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) isoenzymes. Inhibitors of these isoenzymes may reduce sildenafil clearance. Increased systemic exposure to sildenafil may result in an increase in sildenafil-induced adverse effects. The manufacturer recommends dosage reduction in patients receiving potent cytochrome CYP3A4 inhibitors such as itraconazole (see Dosage).(21)Population data from patients in clinical trials did indicate a reduction in sildenafil clearance when it was coadministered with CYP3A4 inhibitors.(21)

Sildenafil is metabolized principally by the hepatic cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) isoenzymes. Inhibitors of these isoenzymes may reduce sildenafil clearance. Increased systemic exposure to sildenafil may result in an increase in sildenafil-induced adverse effects. The manufacturer recommends dosage reduction in patients receiving potent cytochrome CYP3A4 inhibitors such as mibefradil (see Dosage).(21) Population data from patients in clinical trials did indicate a reduction in sildenafil clearance when it was coadministered with CYP3A4 inhibitors.(21)

The use of clarithromycin and sildenafil is not recommended due to the potential increased sildenafil concentrations due to the CYP3A4 inhibition of clarithromycin.(47)

Sildenafil is metabolized principally by the hepatic cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) isoenzymes. Inhibitors of these isoenzymes may reduce sildenafil clearance. Increased systemic exposure to sildenafil may result in an increase in sildenafil-induced adverse effects. The manufacturer recommends dosage reduction in patients receiving potent cytochrome CYP3A4 inhibitors (see Dosage).(21) Population data from patients in clinical trials did indicate a reduction in sildenafil clearance when it was coadministered with CYP3A4 inhibitors.(21) CYP3A4 inhibitors include: conivaptan,(48) diltiazem,(49) imatinib, STI-571,(50) fluconazole,(51) fluoxetine,(52) fluvoxamine,(42)nefazodone,(53)troleandomycin, quinidine,(54)ranolazine,(55)sparfloxacin,(56)verapamil,(57)voriconazole,(58)zafirlukast,(59)and zileuton.(60)This list is not inclusive of all medications that may inhibit CYP3A4.

Sildenafil is metabolized principally by cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) enzymes.(21)In healthy subjects, coadministration of multiple doses of 125 mg twice daily bosentan with 80 mg three times daily sildenafil has resulted in a reduction of sildenafil plasma concentrations by 63% and increased bosentan plasma concentrations by 50%.(61)Dosage adjustment for this interaction is not needed for bosentan or sildenafil (including when used to treat pulmonary arterial hypertension or dysfunction).(61)

Sildenafil is metabolized principally by cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) enzymes.(21) It can be expected that concomitant administration of sildenafil with CYP3A4 enzyme inducers, such as barbiturates,(20) carbamazepine,(62)dexamethasone, (20)phenytoin,(63)fosphenytoin,(64) nevirapine,(65) rifabutin,(66)(67) rifampin,(66)(68)(69) troglitazone,(70)cisapride,(71)(72) Mifepristone, RU-486 in vitro,(73)(74) tacrolimus,(75) tolbutamide or warfarin.(21)

Sildenafil 50 mg did not potentiate the increase in bleeding time caused by aspirin, ASA 150 mg. In vitro studies with human platelets indicate, however, that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside (a nitric oxide donor).(21)

Healthy patients with BPH were stabilized on doxazosin for at least 14 days before receiving sildenafil or placebo. Patients receiving the combination of sildenafil and doxazosin had greater decreases in blood pressure than those receiving doxazosin and placebo. No episodes of syncope were reported in these studies. In one published study, sildenafil and doxazosin were used together in patients with non-organic dysfunction refractory to sildenafil monotherapy; blood pressure was not significantly altered in this study.(78) The safety of using PDE5 inhibitors and alpha-blockers together may also be affected by other factors, such as intravascular volume depletion and coadministration of other antihypertensive medications.

Grapefruit juice (food) has been reported to decrease the metabolism of drugs metabolized by the CYP 3A4 isozyme. Sildenafil levels may increase; it is possible that sildenafil-induced side effects could also be increased in some individuals. One study has confirmed a potential interaction; sildenafil’s AUC increased 23% with coadministration of grapefruit juice.(77)

Prolonged erections have been reported in two patients taking sildenafil with dihydrocodeine. In both cases, patients reported erections subsided immediately after orgasm when taking sildenafil alone. Although more data are needed, use caution when prescribing opiate agonists and sildenafil concomitantly.(78)

Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with medications with hypotensive properties.(79)(80) Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with medications which cause vasodilation.

A study of 12 healthy volunteers showed a 110% increase in the AUC and 117% increase in the Cmax of sildenafil with the coadministration of ciprofloxacin as compared to sildenafil alone.(81)

Nifedipine can have additive hypotensive effects when administered with phosphodiesterase inhibitors (PDE 5 inhibitors) such as si3174ldenafil.(82)

Use caution when coadministering sildenafil and telithromycin.(21)

Sildenafil, when used for pulmonary arterial hypertension (PAH), is contraindicated with telaprevir.(21)

Sildenafil is contraindicated for use with cobicistat; elvitegravir; emtricitabine; tenofovir when used for pulmonary arterial hypertension (PAH). If used for dysfunction, the dose of sildenafil should not exceed 25 mg every 48 hours with increased monitoring for adverse reactions during times of coadministration.(83)"}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1862","name":"Storage","acceptedAnswer":{"@type":"Answer","text":"Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain."}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1861","name":"References","acceptedAnswer":{"@type":"Answer","text":"Basu A, Ryder REJ. New treatment options for dysfunction in patients with diabetes mellitus. Drugs 2004;64:2667-88.
2.Shenfeld OZ, Gofrit ON, Gdor Y, et al. The role of sildenafil in the treatment of dysfunction in patients with pelvic fracture urethral disruption. J Urol 2004;172:2350-2.
3.Pickering TG, Shepherd AM, Puddey I, et al. Sildenafil citrate for dysfunction in men receiving multiple antihypertensive agents: A randomized controlled trial. Am J Hypertens 2004;17:1135-42.
4.Montague DK, Jarow JP, Broderick GA, et al. Chapter 1: The management of dysfunction: an AUA update. J Urol 2005;174:230-9.
5.Abrams D, Schulze-Neick I, Magee AG. Sildenafil as a selective pulmonary vasodilator in childhood primary pulmonary hypertension. Heart 2000;84:E4.
6.Hossein AG, Wiedemann R, Rose F, et al. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med 2002;136:515-522.
7.Michelakis E, Tymchak W, Lien D, et al. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension. Circulation 2002;105:2398-2403.
8.Richalet JP, Gratadour P, Robach P, et al. Sildenafil Inhibits the altitude-induced hypoxemia and pulmonary hypertension. Am J Respir Crit Care Med 2005;171(3):275-81. Epub 2004 Oct 29
9.Bortolotti M, Mari C, Giovannini M, et al. Effects of sildenafil on esophageal motility of normal subjects. Dig Dis Sci 2001;46:2301-2306.
10.Hansten PD, Horn JR. Cytochrome P450 Enzymes and Drug Interactions, Table of Cytochrome P450 Substrates, Inhibitors, Inducers and P-glycoprotein, with Footnotes. In: The Top 100 Drug Interactions – A guide to Patient Management. 2008 Edition. Freeland, WA
11.Viagra (sildenafil citrate) package insert. New York, NY: Pfizer; 2014 Mar.
12.Arruda-Olson AM, Mahoney DW, Nehra A, et al. Cardiovascular effects of sildenafil during exercise in men with known or probable coronary artery disease. JAMA 2002;287:719-725.
13.Borlaug BA, Melenovsky V, Marhin T, et al. Sildenafil inhibits β-adrenergic-stimulated cardiac contractility in humans. Circulation 2005;112:2642-49.
14.Burnett AL, Bivalacqua TJ. Priapism: current principles and practice. Urol Clin N Am 2007;34:631-642.
15.Levine LA, Latchamsetty KC. Treatment of dysfunction in patients with Peyronie’s disease using sildenafil citrate. Int J Impot Res 2002;14:478-482.
16.Revatio (sildenafil citrate) package insert. New York, NY: Pfizer; 2014 Mar.
17.Food and Drug Administration (US FDA) News Release. FDA recommends against use of Revatio in children with pulmonary hypertension. Retrieved August 31, 2012. Available on the World Wide Web at: http://www.fda.gov/Drugs/default.htm
18.Food and Drug Administration (US FDA) Drug Safety Communication. Revatio (sildenafil)-FDA clarifies warning about pediatric use for pulmonary arterial hypertension. Retrieved March 31, 2014. Available on the World Wide Web at: http://www.fda.gov/Drugs/default.htm
19.Abman SH, Kinsella JP, Rosenzweig EB, et al. Implications of the U.S. Food and Drug Administration Warning against the use of sildenafil for the treatment of pediatric pulmonary hypertension. Am J Respir Crit Care Med 2013;187:572-5.
20.Hansten P, Horn J. The Top 100 Drug Interactions: A Guide to Patient Management. includes table of CYP450 and drug transporter substrates and modifiers (appendices). H & H Publications, LLP 2014 edition.
21.Viagra (sildenafil citrate) package insert. New York, NY: Pfizer; 2006 Oct.
22.Cialis (tadalafil) package insert. Indianapolis, IN: Lilly ICOS, LLC; 2011 Oct.
23.Levitra (vardenafil) package insert. Kenilworth, NJ: Schering-Plough; 2007 Mar.
24.Cialis (tadalafil) package insert. Indianapolis, IN: Lilly ICOS, LLC; 2007 Jan.
25.Intelence (etravirine) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2014 Aug.
26.Hall MCS, Ahmad S. Interaction between sildenafil and HIV-1 combination therapy. Lancet 1999;353;2071-2.
27.Norvir (ritonavir capsules) package insert. Chicago, IL: AbbVie Inc; 2013 Nov.
28.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/ContentFiles/AdultandAdo
29.Invirase (saquinavir) package insert. South San Francisco, CA: Genentech Inc.; 2012 Nov.
30.Lexiva (fosamprenavir calcium) package insert. Research Triangle Park, NC: ViiV Healthcare; 2013 Apr.
31.Agenerase (amprenavir) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2005 Nov.
32.Reyataz (atazanavir) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2014 Jun.
33.Prezista (darunavir) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2014 Apr.
34.Tybost (cobicistat) package insert. Foster City, CA: Gilead Sciences, Inc; 2014 Sept.
35.Evotaz (atazanavir and cobicistat) tablet package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2015 Jan.
36.Prezcobix (darunavir and cobicistat) tablets package insert. Titusville, NJ: Janssen Therapeutics; 2015 Jan.
37.Merry C, Barry MG, Ryan M, et al. Interaction of sildenafil and indinavir when co-administered to HIV-patients. AIDS 1999;13:F101-7.
38.Kaletra (lopinavir; ritonavir) tablet and solution package insert. North Chicago, IL: AbbVie Inc; 2015 Jan.
39.Viracept (nelfinavir mesylate) package insert. Research Triangle Park, NC: ViiV Healthcare Company; 2013 May.
40.Rescriptor (delavirdine) package insert. La Jolla, CA: Agouron Pharmaceuticals; 2006 Feb.
41.Sustiva (efavirenz) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2014 May.
42.Walters JS, Woodring JH, Stelling CB, Rosenbaum HD: Salicylate-induced pulmonary edema. Radiology 1983;146:289-293.
43.Hesse C, Siedler H, Burhenne J, et al. Fluvoxamine affects sildenafil kinetics and dynamics. J Clin Psychopharmacol 2005;25:589-92.
44.Balon R. Fluvoxamine-induced dysfunction responding to sildenafil. J Sex Marital Ther 1998;24(4):313-7.
45.Emend capsules (aprepitant) package insert. Whitehouse Station, NJ: Merck & Co., Inc.; 2007 Nov.
46.Zithromax (azithromycin tablets and azithromycin oral suspension) package insert. New York, NY: Pfizer Inc.; 2004 Jan.
47.Biaxin (clarithromycin) package insert. North Chicago, IL: AbbVie, Inc.; 2015 Jan.
48.Vaprisol (conivaptan hydrochloride injection). Deerfield, IL: Astellas Pharma US, Inc.; 2007 Feb.
49.Cardizem LA (diltiazem) package insert. Mississauga, ON: Biovail Corporation; 2006 Apr.
50.Gleevec (imatinib mesylate) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2008 Dec.
51.Diflucan (fluconazole) package insert. New York, NY. Pfizer; 2004 Aug.
52.ProzacR (fluoxetine hydrochloride). Indianapolis, IN: Eli Lilly and Company; 2003 Nov.
53.Serzone (nefazodone) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2003 Sep.
54.Quinidex Extentabs (quinidine sulfate extended-release tablets) package insert. Richmond, VA: A.H. Robbins Company; 2000 Sept.
55.Ranexa (ranolazine extended-release tablets) package insert. Foster City, CA: Gilead Sciences, Inc. 2013 Dec.
56.Zagam (sparfloxacin) package insert. Research Triangle Park, NC: Bertek Pharmaceuticals; 2003 Feb.
57.Calan (verapamil tablets) package insert. Chicago, IL: GD Searle LLC; 2003 Jul.
58.VFEND (voriconazole) package insert. New York,NY: Pfizer Inc; 2008 Mar.
59.Accolate (zafirlukast) package insert. Wilmington, DE: AstraZeneca; 2004 Jul.
60.ZyfloT Filmtab (zileuton) package insert. Chicago, IL: Abbott Laboratories; 1998 Mar.
61.Tracleer (bosentan) package insert. South San Francisco, CA: Actelion Pharmaceuticals US, Inc.; 2007 Feb.
62.Tegretol (carbamazepine) package insert. East Hanover, NJ. Novartis Pharmaceuticals; 2003 Sept.
63.Phenytoin package insert. Morgantown, WV: Mylan Pharmaceuticals; 1998 Sep.
64.Cerebyx (fosphenytoin sodium) package insert. New York, NY: Parke-Davis; 2002 Jun.
65.Viramune (nevirapine) package insert. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2008 Jun.
66.Finch CK, Chrisman CR, Baciewicz AM, et al. Rifampin and rifabutin drug interactions: an update. Arch Intern Med 2002;162:985-92.
67.Mycobutin (rifabutin) package insert. Kalamazoo, MI:Pharmacia & Upjohn, Co.; 2001 Nov.
68.Rifampin Injection package insert. Bedford, OH: Bedford Laboratories; 2000 Nov.
69.Niemi M, Backman JT, Fromm MF, et al. Pharmacokinetic interactions with rifampicin . Clin Pharmacokinet 2003;42:819-50.
70.Rezulin (troglitazone) package insert. Morris Plains, NJ: Parke-Davis; 1999 June. NOTE: Troglitazone was removed from the US market in response to FDA concerns in March 2000.
71.Propulsid (cisapride) package insert. Titusville, NJ; Janssen Pharmaceutica; 2000 Jan. NOTE: As of May 2000; Propulsid has only been available in the United States via an investigational limited access program to ensure proper patient screening and pres
72.Michalets EL, Williams CR. Drug interactions with cisapride: clinical implications. Clin Pharmacokinet 2000;39:49-75.
73.Mifeprex (mifepristone, RU-486) package insert. New York, NY: Danco Laboratories, LLC; 2009 Apr.
74.Korlym (mifepristone) tablet package insert. Menlo Park, CA: Corcept Therapeutics Incorporated; 2013 Jun.
75.Christ B, Brockmeier D, Hauck EW, et al. Interactions of sildenafil and tacrolimus in men with dysfunction after kidney transplantation. Urology. 2001 Oct;58(4):589-93.
76.De Rose AF, Giglio M, Traverso P, et al. Combined oral therapy with sildenafil and doxazosin for the treatment of non-organic dysfunction refractory to sildenafil monotherapy. Int J Impot Res 2002;14:50-3.
77.Jetter A, Kinzig-Schippers M, Walchner-Bonjean M, et al. Effects of grapefruit juice on the pharmacokinetics of sildenafil. Clin Pharmacol Ther 2002;71:21-9.
78.Goldmeier D. Prolonged erections produced by dihydrocodeine and sildenafil. Br Med J 2002;324:1555. Letter.
79.NardilR (phenelzine) package insert. New York, NY: Pfizer; 2003.
80.ParnateR (tranylcypromine) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2001 Aug.
81.Casper F, Petri E. Local treatment of urogenital atrophy with an estrodiol-releasing vaginal ring: a comparative and a placebo-controlled multicenter study. Vaginal Ring Study Group. Int Urogynecol J Pelvic Floor Dysfunct 1999;10:171-6
82.Adalat CC (nifedipine extended-release tablets) package insert. West Haven, CT: Bayer Pharmaceuticals Corporation; 2010 Aug.
83.Stribild (elvitegravir; cobicistat; emtricitabine; tenofovir) package insert. Foster City, CA: Gilead Sciences, Inc; 2014 Dec.
84.Milman HA, Arnold SB. Neurologic, psychological, and aggressive disturbances with sildenafil. Ann Pharmacother 2002;36:1129-1134.
85.Gilad R, Lampl Y, Eshel Y, Sadeh M. Tonic-clonic seizures in patients taking sildenafil. BMJ 2002;325-869.
86.Pomeranz HD, Bhavsar AR. Nonarteritic ischemic optic neuropathy developing soon after use of sildenafil: a report of seven new cases. J Neuroophthalmol 2005;25:9-13.
87.Escaravage GK Jr, Wright JD Jr, Givre SJ. Tadalafil associated with anterior ischemic optic neuropathy. Arch Ophthalmol 2005;123(3):399-400.
88.Bollinger K, Lee MS. Recurrent visual field defect and ischemic optic neuropathy associated with tadalafil rechallenge. Arch Ophthalmol 2005;123(3):400-1.
89.Peter NM, Singh MV, Fox PD. Tadalafil-associated anterior ischaemic optic neuropathy. Eye 2005;19(6):715-7."}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1859","name":"General Information","acceptedAnswer":{"@type":"Answer","text":"Testosterone undecanoate is a white or off white crystalline substance. It is practically insoluble in water and soluble in methanol and ethanol and has a melting point of 58 – 64°C.

Reandron 1000 is a clear, yellowish oily solution for injection. Each glass ampoule/vial contains 1000 mg testosterone undecanoate and the excipients: benzyl benzoate and castor oil.

Each 5 mL glass ampoule or 6 mL glass vial contains 4 mL oily solution with 1000 mg testosterone undecanoate. Not all presentations may be marketed."}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1856","name":"Indications","acceptedAnswer":{"@type":"Answer","text":"Reandron 1000 is a hormonal preparation that contains 1000 mg testosterone undecanoate. The chemical name for testosterone undecanoate is (17β)-17--androst-4- en-3-one

Male hypogonadism is the condition in which there are low levels of testosterone in the body.

Reandron is used to replace the body’s natural hormone testosterone when not enough is made by the body.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason."}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1855","name":"Contraindications/Precautions","acceptedAnswer":{"@type":"Answer","text":"The use of Reandron 1000 is contraindicated in men with:
androgen-dependent carcinoma of the prostate or of the male mammary gland; § hypercalcaemia accompanying malignant tumours;
hypersensitivity to the active substance or to any of the excipients;
past or present liver tumours

The use of Reandron 1000 in women is contraindicated."}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1850","name":"Mechanism of Action","acceptedAnswer":{"@type":"Answer","text":"Reandron contains testosterone undecanoate as the active ingredient. Reandron is injected into a location in your body (buttock muscle) where it can be stored and gradually released over a period of time.

Testosterone is a natural male hormone, known as an androgen, which controls normal sexual development in men.

Testosterone is essential for the development and maintenance of the male reproductive organs as well as other male characteristics, such as hair growth, deep voice, sexual drive, muscle mass and body fat distribution.

Reandron 1000 contains 1000 mg of the active ingredient testosterone undecanoate per ampoule/vial.

It also contains the inactive ingredients benzyl benzoate and castor oil."}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1849","name":"Pharmacokinetics","acceptedAnswer":{"@type":"Answer","text":"Endogenous androgens, principally testosterone, secreted by the testes and its major metabolite dihydrotestosterone (DHT), are responsible for the development of the external and internal genital organs and for maintaining the secondary sexual characteristics (stimulating hair growth, deepening of the voice, development of the libido); for a general effect on protein anabolism; for development of skeletal muscle and body fat distribution; for a reduction in urinary nitrogen, sodium, potassium, chloride, phosphate and water excretion.

Testosterone does not produce testicular development: it reduces the pituitary secretion of gonadotropins.

The effects of testosterone in some target organs arise after peripheral conversion of testosterone to estradiol, which binds to estrogen receptors in the target cell nucleus e.g. the pituitary, fat, brain, bone and testicular Leydig cells.

Testosterone undecanoate is an ester of the naturally occurring androgen, testosterone. The active form, testosterone, is formed by cleavage of the side chain.

Pharmacokinetics

Absorption

Reandron 1000 is an intramuscularly administered depot preparation of testosterone undecanoate and thus circumvents the first-pass effect. Following intramuscular injection of testosterone undecanoate as an oily solution, the compound is gradually released from the depot and is almost completely cleaved by serum esterases into testosterone and undecanoic acid. An increase of serum levels of testosterone above basal values can already be measured one day after administration.

Distribution

In two separate studies, mean maximum concentrations of testosterone of 45 and 24 nmol/L were measured about 7 and 14 days, respectively, after single i.m. administration of 1000 mg of testosterone undecanoate to hypogonadal men. Post-maximum testosterone levels declined with an estimated half-life of about 53 days.

In serum of men, about 98% of the circulating testosterone is bound to sex hormone binding globulin (SHBG) and albumin. Only the free fraction of testosterone is considered as biologically active. Following intravenous infusion of testosterone to elderly men, an apparent volume of distribution of about 1.0 L/kg was determined.

Metabolism

Testosterone which is generated by ester cleavage from testosterone undecanoate is metabolised and excreted the same way as endogenous testosterone. The undecanoic acid is metabolised by ß-oxidation in the same way as other aliphatic carboxylic acids.

Elimination

Testosterone undergoes extensive hepatic and extrahepatic metabolism. After the administration of radiolabelled testosterone, about 90% of the radioactivity appears in the urine as glucuronic and sulphuric acid conjugates and 6% appears in the faeces after undergoing enterohepatic circulation. Urinary products include androsterone and etiocholanolone."}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1848","name":"Adverse Reations/Side Effects","acceptedAnswer":{"@type":"Answer","text":"Carcinogenicity and Mutagenicity

The potential carcinogenicity of testosterone has been tested by subcutaneous injection and implantation in mice and rats. In mice, the implant induced cervical uterine tumours, which metastasised in some cases. There is suggestive evidence that injection of testosterone in some strains of female mice increases their susceptibility to hepatoma. Testosterone is known to act as a tumour promoter and has been shown to increase carcinomas in the liver of rats. There are rare reports of hepatocellular carcinoma in patients receiving long term therapy with androgens in high doses. Chronic androgen deficiency is a protective factor for prostatic disease and hypogonadal men receiving androgen replacement therapy require surveillance for prostate disease similar to that recommended for eugonadal men of comparable age. Elderly patients treated with androgens may be at an increased risk for the development of prostatic hyperplasia and prostatic cancer.

Testosterone undecanoate was not genotoxic, as assessed in vitro for reverse gene mutations and chromosomal aberrations. An in vivo assay of chromosomal damage (micronucleus test in mice) was also negative.

Pulmonary microembolism of oily solutions can in rare cases lead to signs and symptoms such as cough, dyspnoea, malaise, hyperhidrosis, chest pain, dizziness, paraesthesia, or syncope. These reactions may occur during or immediately after the injections and are reversible. Cases suspected by the company or the reporter to represent pulmonary oily microembolism have been reported rarely in clinical trials (in ≥ 1/10,000 and < 1/1,000 injections) as well as from postmarketing experience (see PRECAUTIONS).

Suspected anaphylactic reactions after Reandron 1000 injection have been reported.

In addition to the above mentioned ADRs, nervousness, hostility, sleep apnoea, various skin reactions including seborrhoea, increased hair growth, increased frequency of erections and in very rare cases jaundice have been reported under treatment with testosterone containing preparations.

Therapy with high doses of testosterone preparations commonly reversibly interrupts or reduces spermatogenesis, thereby reducing the size of the testicles; testosterone replacement therapy of hypogonadism can in rare cases cause persistent, painful erections (priapism). High-dosed or long-term administration of testosterone occasionally increases the occurrences of water retention and oedema.

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using Reandron.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the list of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

High doses of Reandron may affect sperm cell development (spermatogenesis), which reduces the size of the testes. This is reversible once treatment is stopped.

Tell your doctor if you notice any of the following and they worry you:

-Weight gain;

-Acne;

-Enlarged prostate;

-Hot flushes;

Injection site reactions such as pain or discomfort, itching, bruising, redness or irritation.

These are the most common side effects of Reandron.

Tell your doctor as soon as possible if you notice any of the following:

Depression, irritability or aggression.

The above list includes serious side effects that may require urgent medical attention.

Tell your doctor immediately, or go to the Accident and Emergency department at your nearest hospital if you notice any of the following:

Weakness, tiredness, headache, light-headedness;
Signs of allergy such as rash, swelling of the face, lips, mouth, throat or other parts of the body, shortness of breath, wheezing or trouble breathing;
Coughing, increased sweating, chest pain, feeling that you’re about to faint;
Yellowing of the skin and eyes, also called jaundice;
Unwanted frequent or prolonged and painful erections;
Severe stomach pain or tenderness which does not disappear within a short time.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell. Other side effects not listed above may also occur in some people."}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1841","name":"Interactions","acceptedAnswer":{"@type":"Answer","text":"Androgens may enhance blood sugar levels reducing the effects of insulin. The dosage of the hypoglycaemic agent may need to be lowered.

Interactions can occur with drugs that induce microsomal enzymes, which can result in increased clearance of testosterone (e.g. barbiturates).

Androgens may interfere with the metabolism of other drugs. Accordingly, plasma and tissue concentrations may be affected e.g. increased oxyphenbutazone serum levels have been reported. The metabolism of cyclosporin might be slowed.

Moreover, testosterone and derivatives have been reported to increase the activity of coumarin- derived oral anticoagulants, possibly requiring dose adjustment. Independently of this finding, the use of intramuscular injections in patients with acquired or inherited bleeding disorders is not recommended due to the risk of bleeding (see PRECAUTIONS).

Theoretically, any substance which affects liver function should not be taken with testosterone. Examples of herbal products include: angelica dahurica, chapparal, comfrey, eucalyptus, germander tea, Jin Bu Huan, kava, penny royal oil, skullcap, and valerian."}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1838","name":"Interactions","acceptedAnswer":{"@type":"Answer","text":"Reandron 1000 should be used only if hypogonadism (hyper- and hypogonadotrophic) has been demonstrated and if other aetiologies responsible for the symptoms have been excluded before treatment is started. Testosterone insufficiency should be clearly demonstrated by clinical features (regression of secondary sexual characteristics, change in body composition, asthenia, reduced libido, dysfunction etc.), confirmed by biochemical tests (2 separate blood testosterone measurements) and according to contemporary diagnostic criteria established by endocrine societies. Currently, there is no consensus about age specific testosterone reference values. However, it should be taken into account that physiologically testosterone serum levels fall with increasing age.

Due to variability in laboratory values, all measures of testosterone should be carried out in the same laboratory.

Prior to testosterone initiation, all patients must undergo a detailed examination in order to exclude the risk of pre-existing prostatic cancer. Careful and regular monitoring of the prostate gland and breast must be performed in accordance with recommended methods (digital rectal examination and estimation of serum PSA) in patients receiving testosterone therapy at least once yearly and twice yearly in elderly patients and at risk patients (those with clinical or familial factors).

Androgens may accelerate the progression of sub-clinical prostatic cancer and benign prostatic hyperplasia.

Improved insulin sensitivity may occur in patients treated with androgens who achieve normal testosterone plasma concentrations following replacement therapy.

Haemoglobin and haematocrit should be checked periodically in patients on long-term androgen therapy to detect cases of polycythaemia (see ADVERSE EFFECTS).

In general, the use of intramuscular injections in patients with acquired or inherited bleeding disorders is not recommended due to the risk of bleeding. Testosterone and its derivatives have been reported to increase the activity of coumarin-derived oral anticoagulants (see also INTERACTIONS WITH OTHER MEDICINES).

Testosterone should be used with caution in patients with thrombophilia, as there have been post-marketing studies and reports of thrombotic events in these patients during testosterone therapy.

Deep intramuscular injection of testosterone undecanoate is not advisable in men with any form of bleeding or coagulation disorder, including those using anti-coagulants because of the risk of haematoma. Either alternative non-injectable testosterone products should be used or expert advice sought from a haematologist (see “Interactions with other medicines”).

Cases of benign and malignant liver tumours have been reported in users of hormonal substances, such as androgen compounds. A hepatic tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra- abdominal haemorrhage occur in men using Reandron 1000.

Caution should be exercised in patients predisposed to oedema. e.g. in case of severe cardiac, hepatic, or renal insufficiency or ischaemic heart disease, as treatment with androgens may result in increased retention of sodium and water. In case of severe complications characterised by oedema with or without congestive heart failure, treatment must be stopped immediately (see ADVERSE EFFECTS).

Caution must be taken in patients who have had elevated blood pressure, disturbance in renal function, epilepsy or migraine. The product may elevate blood pressure. The product is not recommended for patients with cardiac insufficiency.

Pre-existing sleep apnoea may be potentiated.

Androgens are not suitable for enhancing muscular development in healthy individuals or for increasing physical ability.

Using Reandron 1000 might result in a positive finding in doping tests.

As with all oily solutions, Reandron 1000 must be injected strictly intramuscularly and very slowly. Pulmonary microembolism of oily solutions can in rare cases lead to signs and symptoms such as cough, dyspnoea, malaise, hyperhydrosis, chest pain, dizziness, paraesthesia, or syncope. These reactions may occur during or immediately after the injection and are reversible. Treatment is usually supportive, e.g. by administration of supplemental oxygen.

Suspected anaphylactic reactions after Reandron 1000 injection have been reported.

Certain clinical signs: irritability, nervousness, weight gain, prolonged or frequent erections may indicate excessive androgen exposure requiring dosage adjustment. Periodic testosterone measurements should be made during treatment, particularly when considering dose adjustment.

Use in Pregnancy (Category D)

Reandron 1000 is for use in men only and must not be used in women. Androgenic substances may have a virilising effect on the female fetus and are contraindicated during pregnancy (see CONTRAINDICATIONS).

Use in Lactation

Reandron 1000 must not be used in women and is contraindicated during lactation (see CONTRAINDICATIONS).

Paediatric use

Clinical trials with Reandron 1000 have not been conducted in children or adolescents under the age of 18 and use in this population is not recommended.

In addition to causing masculinisation in children, testosterone can cause accelerated growth, bone maturation, and premature epiphyseal closure, thereby reducing the final height. The appearance of common acne is also expected.

Use in the Elderly

Limited data does not suggest the need for a dosage adjustment in elderly patients.

Use in Patients with Hepatic Impairment

No formal studies have been performed in patients with hepatic impairment. The use of Reandron 1000 is contraindicated in men with past or present liver tumours.

Use in Patients with Renal Impairment

No formal studies have been performed in patients with renal impairment."}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1835","name":"Dosage & Administration","acceptedAnswer":{"@type":"Answer","text":"Reandron 1000 (1 ampoule/vial corresponding to 1000 mg testosterone undecanoate) is injected every 10 to 14 weeks for testosterone replacement, where testosterone deficiency has been confirmed by clinical features and biochemical tests. Injections with this frequency are capable of maintaining sufficient testosterone levels and do not lead to accumulation.

The injections must be administered very slowly. Care should be taken to inject Reandron 1000 deeply into the gluteal muscle (the only site for which clinical experience has been obtained) following the usual precautions for intramuscular administration. Reandron 1000 is strictly for intramuscular injection. Special care must be taken to avoid intravenous injection and injections must not be given subcutaneously. See Instructions for use/handling to avoid injury when opening.

Start of Treatment

Serum testosterone levels should be measured before start of treatment and during initiation of treatment. Depending on serum testosterone levels and clinical symptoms, the first injection interval may be reduced to a minimum of 6 weeks as compared to the recommended range of 10 to 14 weeks for maintenance. With this loading dose, sufficient steady-state testosterone levels may be achieved more rapidly.

 

 

Individualisation of Treatment

The injection interval should remain within the recommended range of 10 to 14 weeks. It is advisable to measure and monitor testosterone serum levels regularly, particularly if the dosage regimen is changed or if there is clinical concern about the adequacy or excessiveness of testosterone replacement. Measurements should be performed at the end of an injection interval and clinical symptoms considered. Serum levels below normal range would indicate the need for a shorter injection interval. In case of high serum levels an extension of the injection interval may be considered or administration of a smaller volume could also be considered (i.e. could result in a shorter injection interval).

Reandron 1000 contains no antimicrobial agent. Reandron 1000 is for single use in one patient only. Discard any residue.

OVERDOSAGE

No special therapeutic measure apart from termination of therapy with the drug or dose reduction is necessary after overdosage."}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1837","name":"Precautions","acceptedAnswer":{"@type":"Answer","text":"Reandron 1000 should be used only if hypogonadism (hyper- and hypogonadotrophic) has been demonstrated and if other aetiologies responsible for the symptoms have been excluded before treatment is started. Testosterone insufficiency should be clearly demonstrated by clinical features (regression of secondary sexual characteristics, change in body composition, asthenia, reduced libido, dysfunction etc.), confirmed by biochemical tests (2 separate blood testosterone measurements) and according to contemporary diagnostic criteria established by endocrine societies. Currently, there is no consensus about age specific testosterone reference values. However, it should be taken into account that physiologically testosterone serum levels fall with increasing age.

Due to variability in laboratory values, all measures of testosterone should be carried out in the same laboratory.

Prior to testosterone initiation, all patients must undergo a detailed examination in order to exclude the risk of pre-existing prostatic cancer. Careful and regular monitoring of the prostate gland and breast must be performed in accordance with recommended methods (digital rectal examination and estimation of serum PSA) in patients receiving testosterone therapy at least once yearly and twice yearly in elderly patients and at risk patients (those with clinical or familial factors).

Androgens may accelerate the progression of sub-clinical prostatic cancer and benign prostatic hyperplasia.

Improved insulin sensitivity may occur in patients treated with androgens who achieve normal testosterone plasma concentrations following replacement therapy.

Haemoglobin and haematocrit should be checked periodically in patients on long-term androgen therapy to detect cases of polycythaemia (see ADVERSE EFFECTS).

In general, the use of intramuscular injections in patients with acquired or inherited bleeding disorders is not recommended due to the risk of bleeding. Testosterone and its derivatives have been reported to increase the activity of coumarin-derived oral anticoagulants (see also INTERACTIONS WITH OTHER MEDICINES).

Testosterone should be used with caution in patients with thrombophilia, as there have been post-marketing studies and reports of thrombotic events in these patients during testosterone therapy.

Deep intramuscular injection of testosterone undecanoate is not advisable in men with any form of bleeding or coagulation disorder, including those using anti-coagulants because of the risk of haematoma. Either alternative non-injectable testosterone products should be used or expert advice sought from a haematologist (see “Interactions with other medicines”).

Cases of benign and malignant liver tumours have been reported in users of hormonal substances, such as androgen compounds. A hepatic tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra- abdominal haemorrhage occur in men using Reandron 1000.

Caution should be exercised in patients predisposed to oedema. e.g. in case of severe cardiac, hepatic, or renal insufficiency or ischaemic heart disease, as treatment with androgens may result in increased retention of sodium and water. In case of severe complications characterised by oedema with or without congestive heart failure, treatment must be stopped immediately (see ADVERSE EFFECTS).

Caution must be taken in patients who have had elevated blood pressure, disturbance in renal function, epilepsy or migraine. The product may elevate blood pressure. The product is not recommended for patients with cardiac insufficiency.

Pre-existing sleep apnoea may be potentiated.

Androgens are not suitable for enhancing muscular development in healthy individuals or for increasing physical ability.

Using Reandron 1000 might result in a positive finding in doping tests.

As with all oily solutions, Reandron 1000 must be injected strictly intramuscularly and very slowly. Pulmonary microembolism of oily solutions can in rare cases lead to signs and symptoms such as cough, dyspnoea, malaise, hyperhydrosis, chest pain, dizziness, paraesthesia, or syncope. These reactions may occur during or immediately after the injection and are reversible. Treatment is usually supportive, e.g. by administration of supplemental oxygen.

Suspected anaphylactic reactions after Reandron 1000 injection have been reported.

Certain clinical signs: irritability, nervousness, weight gain, prolonged or frequent erections may indicate excessive androgen exposure requiring dosage adjustment. Periodic testosterone measurements should be made during treatment, particularly when considering dose adjustment.

Use in Pregnancy (Category D)

Reandron 1000 is for use in men only and must not be used in women. Androgenic substances may have a virilising effect on the female fetus and are contraindicated during pregnancy (see CONTRAINDICATIONS).

Use in Lactation

Reandron 1000 must not be used in women and is contraindicated during lactation (see CONTRAINDICATIONS).

Paediatric use

Clinical trials with Reandron 1000 have not been conducted in children or adolescents under the age of 18 and use in this population is not recommended.

In addition to causing masculinisation in children, testosterone can cause accelerated growth, bone maturation, and premature epiphyseal closure, thereby reducing the final height. The appearance of common acne is also expected.

Use in the Elderly

Limited data does not suggest the need for a dosage adjustment in elderly patients.

Use in Patients with Hepatic Impairment

No formal studies have been performed in patients with hepatic impairment. The use of Reandron 1000 is contraindicated in men with past or present liver tumours.

Use in Patients with Renal Impairment

No formal studies have been performed in patients with renal impairment."}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1834","name":"Storage","acceptedAnswer":{"@type":"Answer","text":"Store Reandron 1000 below 30C and keep out of reach of children

For further information talk to your doctor."}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1831","name":"General Information","acceptedAnswer":{"@type":"Answer","text":"Testosterone was the first ever synthesized anabolic steroid. Testosterone enanthate is a slow-acting, long-ester, oil-based injectable testosterone compound that is commonly prescribed for the treatment of hypogonadism – low testosterone levels and various related symptoms in males.

Testosterone enanthate first appeared in the U.S. prescription drug market during the early 1950’s, as Delatestryl by Squibb.  It changed hands several times over the years, most notably to Mead Johnson, BTG, Savient, and in December 2005, Indevus.  Testosterone enanthate’s was most prominently featured in a hybrid blend with testosterone propionate under the brand Testoviron, a drug that has seen uninterrupted production by Schering AG of Germany for more than 50 years.

Testosterone is the primary androgen found in the body. Endogenous testosterone is synthesized by cells in the testis, ovary, and adrenal cortex. Therapeutically, testosterone is used in the management of hypogonadism, either congenital or acquired. Testosterone is also the most effective exogenous androgen for the palliative treatment of carcinoma of the breast in postmenopausal women. Testosterone was in use in 1938 and approved by the FDA in 1939. Anabolic steroids, derivatives of testosterone, have been used illicitly and are now controlled substances. Testosterone, like many anabolic steroids, was classified as a controlled substance in 1991. Testosterone is administered parenterally in regular and delayed-release (depot) dosage forms. In September 1995, the FDA initially approved testosterone transdermal patches (Androderm); many transdermal forms and brands are now available including implants, gels, and topical solutions. A testosterone buccal system, Striant, was FDA approved in July 2003; the system is a mucoadhesive product that adheres to the buccal mucosa and provides a controlled and sustained release of testosterone. In May 2014, the FDA approved an intranasal gel formulation (Natesto). A transdermal patch (Intrinsa) for hormone replacement in women is under investigation; the daily dosages used in women are much lower than for products used in males. The FDA ruled in late 2004 that it would delay the approval of Intrinsa women’s testosterone patch and has required more data regarding safety, especially in relation to cardiovascular and breast health.

The Enanthate Ester: An ester is any of a class of organic compounds that react with water to produce alcohols and organic or inorganic acids.  Most esters are derived from carboxylic acids, and injectable testosterone is typically administered along with one or multiple esters.  The addition of a carbon chain (ester) attached to the testosterone molecule controls how soluble it will be once inside the bloodstream.  The smaller the carbon chain, the shorter the ester, and the more soluble the medication.  A small/short ester will have a shorter half life – a repeating cycle of a medication’s time and activity within the body.  The inverse is true of long carbon chains, like enanthate, which both act slowly upon the body and evacuates the body at a similar rate. Specifically, testosterone enanthate contains the carboxylic acid ester (enanthoic acid), and a half-life is approximately 8-9 days; the longest half-life of all common ester based testosterones.  An uncommon testosterone such as Nebido (testosterone undecanoate) has a very long 3-month half-life.

For more information please click onto https://www.nps.org.au/medicine-finder/primoteston-depot-solution-for-injection"}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1827","name":"Mechanism of Action","acceptedAnswer":{"@type":"Answer","text":"Endogenous testosterone is responsible for sexual maturation at all stages of development throughout life. Synthetically, it is prepared from cholesterol. The function of androgens in male development begins in the fetus, is crucial during puberty, and continues to play an important role in the adult male. Women also secrete small amounts of testosterone from the ovaries. The secretion of androgens from the adrenal cortex is insufficient to maintain male sexuality.

Increased androgen plasma concentrations suppress gonadotropin-releasing hormone (reducing endogenous testosterone), luteinizing hormone, and follicle-stimulating hormone by a negative-feedback mechanism. Testosterone also affects the formation of erythropoietin, the balance of calcium, and blood glucose. Androgens have a high lipid solubility, enabling them to rapidly enter cells of target tissues. Within the cells, testosterone undergoes enzymatic conversion to 5-alpha-dihydrotestosterone and forms a loosely bound complex with cystolic receptors. Androgen action arises from the initiation of transcription and cellular changes in the nucleus brought about by this steroid-receptor complex.

Normally, endogenous androgens stimulate RNA polymerase, resulting in an increased protein production.These proteins are responsible for normal male sexual development, including the growth and maturation of the prostate, seminal vesicle, penis, and scrotum. During puberty, androgens cause a sudden increase in growth and development of muscle, with redistribution of body fat. Changes also take place in the larynx and vocal cords, deepening the voice. Puberty is completed with beard development and growth of body hair. Fusion of the epiphyses and termination of growth is also governed by the androgens, as is the maintenance of spermatogenesis. When endogenous androgens are unavailable, use of exogenous androgens are necessary for normal male growth and development."}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1826","name":"Pharmacokinetics","acceptedAnswer":{"@type":"Answer","text":"Testosterone is administered intramuscularly (IM); via subcutaneous injection; to the skin as a topical gel, solution, ointment or transdermal systems for transdermal absorption; by implantation of long-acting pellets, or; via buccal systems.

In serum, testosterone is bound to protein. It has a high affinity for sex hormone binding globulin (SHBG) and a low affinity for albumin. The albumin-bound portion freely dissociates. The affinity for SHBG changes throughout life. It is high during prepuberty, declines during adolescence and adult life, then rises again in old age. The active metabolite DHT has a greater affinity for SHBG than testosterone. Elimination half-life is 10—100 minutes and is dependent on the amount of free testosterone in the plasma.

Testosterone is metabolized primarily in the liver to various 17-keto steroids. It is a substrate for hepatic cytochrome P450 (CYP) 3A4 isoenzyme.(1) Estradiol and dihydrotestosterone (DHT) are the major active metabolites, and DHT undergoes further metabolism. Testosterone activity appears to depend on formation of DHT, which binds to cytosol receptor proteins. Further metabolism of DHT takes place in reproductive tissues. About 90% of an intramuscular testosterone dose is excreted in the urine as conjugates of glucuronic and sulfuric acids. About 6% is excreted in the feces, largely unconjugated. There is considerable variation in the half-life of testosterone as reported in the literature, ranging from 10 to 100 minutes.(2)

Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-gp

Testosterone is a substrate for CYP3A4 and is also both transported by and an inhibitor of P-glycoprotein (P-gp) transport.(13)

Route-Specific Pharmacokinetics
Intramuscular Route: Parenteral testosterone formulations have been developed that reduce the rate of testosterone secretion, with esters being less polar and slowly absorbed from intramuscular sites. Esters have a duration of action of 2—4 weeks following IM administration. The esters are hydrolyzed to free testosterone, which is inactivated in the liver."}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1825","name":"Indications","acceptedAnswer":{"@type":"Answer","text":"Testosterone injections are primarily used in men who do not make enough testosterone naturally (hypogonadism), as well as in specific adolescent cases to induce puberty in those with delayed puberty."}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1817","name":"Contraindications/Precautions","acceptedAnswer":{"@type":"Answer","text":"Your health care provider needs to know if you have any of these conditions: breast cancer; breathing problems while sleeping; diabetes; heart disease; if a female partner is pregnant or trying to get pregnant; kidney disease; liver disease; lung disease; prostate cancer, enlargement; any unusual or allergic reactions to testosterone or other products; pregnant or trying to get pregnant; breast-feeding. Your healthcare provider will need to have regular bloodwork drawn while on testosterone. This medication is banned from use in athletes by most athletic organizations.

The manufacturers of AndroGel and Striant state that their products are contraindicated in patients with soybean, soy, or soya lecithin hypersensitivity because they are derived partially from soy plants. Topical gels and solutions are typically flammable, therefore exposure to fire, flame, and tobacco smoking should be avoided while using any topical gel or solution formulation of testosterone. Testosterone undecanoate (Aveed) oil for injection contains benzyl benzoate, the ester of benzyl alcohol and benzoic acid, and refined castor oil. Therefore, testosterone undecanoate use is contraindicated in patients with polyoxyethylated castor oil hypersensitivity, benzoic acid hypersensitivity, or benzyl alcohol hypersensitivity.(4)

Because some testosterone transdermal systems (e.g., Androderm) contain aluminum or other metal components, patients should be instructed to remove the patch before undergoing magnetic resonance imaging (MRI). Metal components contained in the backing of some transdermal systems can overheat during an MRI scan and cause skin burns in the area where the patch is adhered.

Testosterone injections are administered intramuscularly. Do not inject via intravenous administration. Respiratory adverse events have been reported immediately after intramuscular administration of testosterone enanthate and testosterone undecanoate. Care should be taken to ensure slow and deep gluteal muscle injection of testosterone.(4)

Testosterone can stimulate the growth of cancerous tissue and is contraindicated in male patients with prostate cancer or breast cancer. Patients with prostatic hypertrophy should be treated with caution because androgen therapy may cause a worsening of the signs and symptoms of benign prostatic hypertrophy and may increase the risk for development of malignancy. Elderly patients and other patients with clinical or demographic characteristics that are recognized to be associated with an increased risk of prostate cancer should be evaluated for the presence of prostate cancer prior to initiation of testosterone replacement therapy. In patients receiving testosterone therapy, surveillance for prostate cancer should be consistent with current practices for eugonadal men. Testosterone replacement is not indicated in geriatric patients who have age-related hypogonadism only or andropause because there is insufficient safety and efficacy information to support such use.(5) Additionally, the efficacy and long-term safety of testosterone topical solution in patients over 65 years of age has not been determined due to an insufficient number of geriatric patients involved in controlled trials.(6) According to the Beers Criteria, testosterone is considered a potentially inappropriate medication (PIM) for use in geriatric patients and should be avoided due to the potential for cardiac problems and its contraindication in prostate cancer. The Beers expert panel considers use for moderate to severe hypogonadism to be acceptable.(7)

Because of reduced drug clearance and an increased risk of drug accumulation, patients with hepatic disease or hepatic dysfunction should be prescribed testosterone with caution. In addition, edema secondary to water and sodium retention may occur during treatment with androgens. Use testosterone with caution in patients with hepatic disease; renal disease, including nephritis and nephrosis; preexisting edema; or cardiac disease, including heart failure, coronary artery disease, and myocardial infarction (MI), as fluid retention may aggravate these conditions. Further, the possible association between testosterone use and the increased risk of severe cardiovascular events, irrespective of pre-existing cardiac disease, is currently under investigation. An observational study in the U.S. Veteran Affairs health system included adult male patients of an average age of 60 years. Patients (n = 8709) undergoing coronary angiography with a recorded low serum testosterone concentration of  35 kg/m2 has not been established.(6)(11)

Patients receiving high doses of testosterone are at risk for polycythemia. Periodically, patients receiving testosterone should have their hemoglobin and hematocrit concentrations measured to detect polycythemia.

Testosterone is contraindicated during pregnancy because of probable adverse effects on the fetus (FDA pregnancy risk category X). Women of childbearing potential who are receiving testosterone treatments should utilize adequate contraception. Because testosterone is not used during pregnancy, there should be no particular reason to administer the products to women during labor or obstetric delivery; safety and efficacy in these settings have not been established.(6)

Testim testosterone gel is specifically contraindicated in females; the drug is for males only; the dosage form supplies testosterone in excess of what should be prescribed to females under certain endocrine situations.(12) In addition, Androgel, Androderm, Aveed, Fortesta, and Striant brand products are not indicated for use in females due to lack of controlled evaluations and/or the potential for virilizing effects. (2)(13)(14)(15)(4) Female patients receiving other forms of testosterone therapy should be closely monitored for signs of virilization (deepening of the voice, hirsutism, acne, clitoromegaly, and menstrual irregularities). At high doses, virilization is common and is not prevented by concomitant use of estrogens. Some virilization may be judged to be acceptable during treatment for breast carcinoma; however, if mild virilism is evident, discontinuation of drug therapy is necessary to prevent long term virilization.(5) Females should be aware that accidental exposure to some testosterone dosage forms (i.e., ointments, solutions, and gels) may occur if they come into direct contact with a treated patient. In clinical studies, within 2—12 hours of gel application by male subjects, 15-minute sessions of vigorous skin-to-skin contact with a female partner resulted in serum female testosterone levels > 2 times the female baseline values. When clothing covered the treated site on the male, the transfer of testosterone to the female was avoided. Accidental exposure to topical testosterone gel has also occurred in pediatric patients after contact between the child and the application site in treated individuals. The adverse events reported include genitalia enlargement, development of pubic hair, advanced bone age, increased libido, and aggressive behavior. Symptoms resolved in most patients when exposure to the product stopped. However, in a few patients, the genitalia enlargement and advanced bone age did not fully return to expected measurements. The FDA recommends taking precautions to minimize the potential for accidental exposure of topical testosterone products by washing hands with soap and warm water after each application, covering application site with clothing, and removing medication with soap and water when contact with another person is anticipated. In the case of direct skin-to-skin contact with the site of testosterone application, the non-treated person should wash the area with soap and water as soon as possible.(6)

Testosterone topical solution, transdermal patches, and gels are contraindicated in lactating women who are breast-feeding.(6)(2) It is recommended that other testosterone formulations be avoided during breast-feeding as well.(16)(5) Testosterone distribution into breast milk has not been determined; it is unclear if exposure would increase above levels normally found in human milk. Significant exposure to this androgen via breast-feeding may have adverse androgenic effects on the infant and the drug may also interfere with proper establishment of lactation in the mother.(17) Historically, testosterone/androgens have been used adjunctively for lactation suppression.(17) Alternative methods to breast-feeding are recommended in lactating women receiving testosterone therapy.

Androgen therapy, such as testosterone, can result in loss of diabetic control and should be used with caution in patients with diabetes mellitus. Close monitoring of blood glucose is recommended.

Testosterone has induced osteolysis and should be used with caution in patients with hypercalcemia, which can be exacerbated in patients with metastatic breast cancer.

Administration of testosterone undecanoate has been associated with cases of serious pulmonary oil microembolism (POME) reactions as well anaphylactoid reactions. Reported cases of POME reactions occurred during or immediately after a 1000 mg intramuscular injection of testosterone undecanoate. Symptoms included: cough, urge to cough, dyspnea, hyperhidrosis, throat tightening, chest pain, dizziness, and syncope. Most cases lasted a few minutes and resolved with supportive measures; however, some lasted up to several hours, and some required emergency care and/or hospitalization. When administering testosterone undecanoate, clinicians should take care to inject deeply into the gluteal muscle, avoiding intravascular injection. In addition to POME reactions, episodes of anaphylaxis, including life-threatening reactions, have also been reported following the intramuscular injection of testosterone undecanoate. Patients with suspected hypersensitivity reactions should not be retreated with testosterone undecanoate. After every administration, monitor patient for 30 minutes and provide appropriate medical treatment in the event of serious POME or anaphylactoid reactions. Due to the risk of serious POME and anaphylaxis reactions, testosterone undecanoate (Aveed) is only available through a restricted program called the Aveed REMS Program. Clinicians wanting to prescribe Aveed, must be certified with the REMS Program for purposes of ordering or dispensing the product. Healthcare settings must also be certified with the REMS Program and must have the resources to provide emergency medical treatment in cases of serious POME and anaphylaxis. Further information is available at www.AveedREMS.com or call 1—855—755—0494 (4)

Intranasal formulations of testosterone (e.g., Natesto) are not recommended for individuals with a history of nasal disorders such as nasal polyps; nasal septal perforation; nasal surgery; nasal trauma resulting in nasal fracture within the previous 6 months or nasal fracture that caused a deviated anterior nasal septum; sinus surgery or sinus disease. In addition, the safety and efficacy of intranasal testosterone has not been evaluated in individuals with mucosal inflammatory disorders such as Sjogren’s syndrome. Patients with rhinorrhea (rhinitis) who are receiving intranasal formulations of testosterone may experience decreased medication absorption secondary to nasal discharge. These patients may experience a blunted or impeded response to the intranasal medication. In clinical evaluation, serum total testosterone concentrations were decreased by 21—24% in males with symptomatic allergic rhinitis, whether treated with nasal decongestants or left untreated. Treatment with intranasal testosterone should be delayed until symptoms resolve in patients with nasal congestion, allergic rhinitis, or upper respiratory infection. If severe rhinitis symptoms persist, an alternative testosterone replacement therapy is advised.(11)

The safety and efficacy of testosterone topical products Androgel, Axiron, Fortesta, and Testim as well as Striant buccal tablets, Natesto intranasal gel, and Aveed injectable testosterone undecenoate have not been established in neonates, infants, children, and adolescents < 18 years old. (13)(6)(12)(14)(15)(4)(11)In addition, the safety and efficacy Depo-Testosterone injection has not be established in children < 12 years,(16) and Androdem patches have not been evaluated in pediatric patients < 15 years.(2) Generally, the use of testosterone in children should be undertaken only with extreme caution. Testosterone may accelerate bone maturation without stimulating compensatory linear growth, sometimes resulting in compromised adult stature. If testosterone is administered to prepubertal males, radiographic examinations of the hand and wrist should be performed every 6 months to assess the rate of bone maturation and the effect of the drug on epiphyseal centers. Once the epiphyses have closed, growth is terminated. Even after discontinuation of treatment, epiphyseal closure can be enhanced for several months. Accidental exposure to topical testosterone gel has also occurred in pediatric patients after skin to skin contact between the child and the application site in treated individuals. The adverse events reported include genitalia enlargement, development of pubic hair, advanced bone age, increased libido, and aggressive behavior. Symptoms resolved in most patients when exposure to the product stopped. However, in a few patients, the genitalia enlargement and advanced bone age did not fully return to expected measurements. The FDA recommends taking precautions to minimize the potential for accidental exposure by washing hands with soap and warm water after each application, covering application site with clothing, and removing medication with soap and water when contact with another person is anticipated. In the case of direct skin-to-skin contact with the site of testosterone application, the non-treated person should wash the area with soap and water as soon as possible."}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1816","name":"Pregnancy","acceptedAnswer":{"@type":"Answer","text":"Testosterone is contraindicated during pregnancy because of probable adverse effects on the fetus (FDA pregnancy risk category X). Women of childbearing potential who are receiving testosterone treatments should utilize adequate contraception. Because testosterone is not used during pregnancy, there should be no particular reason to administer the products to women during labor or obstetric delivery; safety and efficacy in these settings have not been established.(6)"}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1815","name":"Breast-feeding","acceptedAnswer":{"@type":"Answer","text":"Testosterone topical solution, transdermal patches, and gels are contraindicated in lactating women who are breast-feeding.(6)(2) It is recommended that other testosterone formulations be avoided during breast-feeding as well.(16)(5) Testosterone distribution into breast milk has not been determined; it is unclear if exposure would increase above levels normally found in human milk. Significant exposure to this androgen via breast-feeding may have adverse androgenic effects on the infant and the drug may also interfere with proper establishment of lactation in the mother.(17) Historically, testosterone/androgens have been used adjunctively for lactation suppression.(17)  Alternative methods to breast-feeding are recommended in lactating women receiving testosterone therapy."}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1814","name":"Adverse Reations/Side Effects","acceptedAnswer":{"@type":"Answer","text":"Possible interactions include: certain medicines for diabetes; certain medicines that treat or prevent blood clots like warfarin; oxyphenbutazone; propranolol; steroid medicines like prednisone or cortisone. This list may not describe all possible interactions.

NOTE: Testosterone is a substrate for hepatic cytochrome P450 (CYP) 3A4 isoenzyme.(18) Testosterone is also both transported by and an inhibitor of P-glycoprotein transport.(19)

Testosterone can increase the anticoagulant action of warfarin.(20) Serious bleeding has been reported in some patients with this drug-drug interaction. Although the mechanism is unclear, testosterone may reduce procoagulant factors. Reduction of warfarin dosage may be necessary if testosterone therapy is coadministered. More frequent monitoring of INR and prothrombin time in patients taking such oral anticoagulants is recommneded, especially at the initiation and termination of androgen therapy.(2) It is unclear if testosterone can augment the anticoagulant response to heparin therapy or if testosterone alters the effect of other non-coumarin oral anticoagulants in a similar manner.

Based on case reports with methyltestosterone and danazol, androgens may increase plasma concentrations of cyclosporine, leading to a greater risk of nephrotoxicity.(21)(22)(23)(24)

Coadministration of corticosteroids and testoterone may increase the risk of edema, especially in patients with underlying cardiac or hepatic disease. Corticosteroids with greater mineralocorticoid activity, such as fludrocortisone, may be more likely to cause edema. Administer these drugs in combination with caution.(25)

Goserelin (26) and leuprolide (27)  inhibit steroidogenesis. Concomitant use of androgens with goserelin or leuprolide is relatively contraindicated and would defeat the purpose of goserelin or leuprolide therapy.

Androgens can increase the risk of hepatotoxicity and therefore should be used with caution when administered concomitantly with other hepatotoxic medications. Patients should be monitored closely for signs of liver damage, especially those with a history of liver disease.

Androgens may be necessary to assist in the growth response to human growth hormone, but excessive doses of androgens in prepubescent males can accelerate epiphyseal maturation.(28)

Androgens are known to stimulate erythropoiesis.(29) Despite the fact that endogenous generation of erythropoietin is depressed in patients with chronic renal failure, other tissues besides the kidney can synthesize erythropoietin, albeit in small amounts. Concurrent administration of androgens can increase the patient’s response to epoetin alfa, reducing the amount required to treat anemia. Because adverse reactions have been associated with an abrupt increase in blood viscosity, this drug combination should be avoided, if possible. Further evaluation of this combination needs to be made.

The antiandrogenic effects of the 5-alpha reductase inhibitors (i.e., dutasteride, finasteride) are antagonistic to the actions of androgens; it would be illogical for patients taking androgens to use these antiandrogenic drugs.(30)(31)

Drug interactions with Saw palmetto, Serenoa repens have not been specifically studied or reported. Saw palmetto extracts appear to have antiandrogenic effects.(32)(33) The antiandrogenic effects of Saw palmetto, Serenoa repens would be expected to antagonize the actions of androgens; it would seem illogical for patients taking androgens to use this herbal supplement.

Limited data suggest that testosterone concentrations increase during fluconazole administration. It appears that fluconazole doses of 200 mg/day or greater are more likely to produce this effect than doses of 25—50 mg/day.(34)  The clinical significance of this interaction is unclear at this time. Although data are not available, a similar reaction may occur with voriconazole. Both fluconazole and voriconazole are inhibitors of CYP3A4, the hepatic microsomal isoenzyme responsible for metabolism of testosterone. (35)

Exogenously administered androgens (testosterone derivatives or anabolic steroids) have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance. Further, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. In one study in men with diabetes, testosterone undecenoate 120 mg PO/day for 3 months decreased HbA1c concentrations from a baseline of 10.4% to 8.6% (p < 0.05); fasting plasma glucose concentrations decreased from 8 mmol/l at baseline to 6 mmol/l (p < 0.05). Significant reductions in HbA1c and fasting plasma glucose concentrations did not occur in patients taking placebo.(36) Similar results have been demonstrated with intramuscular testosterone 200 mg administered every 2 weeks for 3 months in hypogonadal men with diabetes.(37) In healthy men, testosterone enanthate 300 mg IM/week for 6 weeks or nandrolone 300 mg/week IM for 6 weeks did not adversely affect glycemic control; however, nandrolone improved non-insulin mediated glucose disposal.(38) It should be noted that some studies have shown that testosterone supplementation in hypogonadal men has no effect on glycemic control.(39)(40) Conversely, the administration of large doses of anabolic steroids in power lifters decreased glucose tolerance, possibly through inducing insulin resistance.(41) While data are conflicting, it would be prudent to monitor all patients with type 2 diabetes on antidiabetic agents receiving androgens for changes in glycemic control, regardless of endogenous testosterone concentrations. Hypoglycemia or hyperglycemia can occur; dosage adjustments of the antidiabetic agent may be necessary.

In vitro, both genistein and daidzein inhibit 5 alpha-reductase isoenzyme II, resulting in decreased conversion of testosterone to the potent androgen 5-alpha-dihydrotestosterone (DHT) and a subsequent reduction in testosterone-dependent tissue proliferation.(42) The action is similar to that of finasteride, but is thought to be less potent. Theoretically, because the soy isoflavones appear to inhibit type II 5-alpha-reductase, the soy isoflavones may counteract the activity of the androgens.

Conivaptan is a potent inhibitor of CYP3A4 and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A4. Testosterone is a substrate for CYP3A4 isoenzymes.(35) The clinical significance of this theoretical interaction is not known.

Testosterone is an inhibitor of P-glycoprotein transport.(35) Ranolazine is a substrate of P-glycoprotein, and inhibitors of P-glycoprotein may increase the absorption of ranolazine.(43) In addition, ranolazine inhibits CYP3A and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A4 such as testosterone.(35)

Ambrisentan is a substrate for P-glycoprotein transport, an energy-dependent drug efflux pump.(44) The inhibition of P-glycoprotein, by drugs such as testosterone,(35) may lead to a decrease in the intestinal metabolism and an increase in the oral absorption of ambrisentan. If ambrisentan is coadministered with a P-glycoprotein inhibitor, patients should be monitored closely for adverse effects.

Coadministration of oxyphenbutazone and testosterone may lead to elevated concentrations of oxyphenbutazone. Monitor patients for adverse effects when coadministering these drugs together.(25)

Testosterone cypionate has been shown to increase the clearance of propranolol in one study. Monitor patients taking testosterone and propranolol together for decreased therapeutic efficacy of propranolol.(25)

Coadministration of dabigatran and testosterone may result in increased dabigatran serum concentrations, and, therefore, an increased risk of adverse effects. Coadministration of dabigatran and testosterone should be avoided in patients with severe renal impairment (CrCl 15—30 ml/min). Dabigatran is a substrate of P-gp; testosterone is a P-gp inhibitor.(19) P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.(45)

Concomitant use of testosterone, a P-glycoprotein (P-gp) inhibitor,(19) and afatinib, a P-gp substrate, may increase the exposure of afatinib. If the use of both agents is necessary, consider reducing the afatinib dose if the original dose is not tolerated.(46)

Concomitant use of intranasal testosterone (e.g., Natesto) and other intranasally administered drugs in not recommended; the drug interaction potential between these agents is unknown.(11) Eighteen males with seasonal allergic rhinitis were treated with intranasal testosterone and randomized to receive oxymetazoline (30 minutes prior to intranasal testosterone) or no treatment. In general, serum total testosterone concentrations were decreased by 21—24% in males with symptomatic allergic rhinitis, due to the underlying condition. A mean decrease in AUC and Cmax (2.6% and 3.6%, respectively) for total testosterone was observed in males with symptomatic seasonal rhinitis when treated with oxymetazoline compared to untreated patients. Concomitant use of oxymetazoline does not impact the absorption of testosterone.(11)

This list may not include all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine."}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1813","name":"Interactions","acceptedAnswer":{"@type":"Answer","text":"Possible interactions include: certain medicines for diabetes; certain medicines that treat or prevent blood clots like warfarin; oxyphenbutazone; propranolol; steroid medicines like prednisone or cortisone. This list may not describe all possible interactions.

NOTE: Testosterone is a substrate for hepatic cytochrome P450 (CYP) 3A4 isoenzyme.(18) Testosterone is also both transported by and an inhibitor of P-glycoprotein transport.(19)

Testosterone can increase the anticoagulant action of warfarin.(20) Serious bleeding has been reported in some patients with this drug-drug interaction. Although the mechanism is unclear, testosterone may reduce procoagulant factors. Reduction of warfarin dosage may be necessary if testosterone therapy is coadministered. More frequent monitoring of INR and prothrombin time in patients taking such oral anticoagulants is recommneded, especially at the initiation and termination of androgen therapy.(2) It is unclear if testosterone can augment the anticoagulant response to heparin therapy or if testosterone alters the effect of other non-coumarin oral anticoagulants in a similar manner.

Based on case reports with methyltestosterone and danazol, androgens may increase plasma concentrations of cyclosporine, leading to a greater risk of nephrotoxicity.(21)(22)(23)(24)

Coadministration of corticosteroids and testoterone may increase the risk of edema, especially in patients with underlying cardiac or hepatic disease. Corticosteroids with greater mineralocorticoid activity, such as fludrocortisone, may be more likely to cause edema. Administer these drugs in combination with caution.(25)

Goserelin (26) and leuprolide (27)  inhibit steroidogenesis. Concomitant use of androgens with goserelin or leuprolide is relatively contraindicated and would defeat the purpose of goserelin or leuprolide therapy.

Androgens can increase the risk of hepatotoxicity and therefore should be used with caution when administered concomitantly with other hepatotoxic medications. Patients should be monitored closely for signs of liver damage, especially those with a history of liver disease.

Androgens may be necessary to assist in the growth response to human growth hormone, but excessive doses of androgens in prepubescent males can accelerate epiphyseal maturation.(28)

Androgens are known to stimulate erythropoiesis.(29) Despite the fact that endogenous generation of erythropoietin is depressed in patients with chronic renal failure, other tissues besides the kidney can synthesize erythropoietin, albeit in small amounts. Concurrent administration of androgens can increase the patient’s response to epoetin alfa, reducing the amount required to treat anemia. Because adverse reactions have been associated with an abrupt increase in blood viscosity, this drug combination should be avoided, if possible. Further evaluation of this combination needs to be made.

The antiandrogenic effects of the 5-alpha reductase inhibitors (i.e., dutasteride, finasteride) are antagonistic to the actions of androgens; it would be illogical for patients taking androgens to use these antiandrogenic drugs.(30)(31)

Drug interactions with Saw palmetto, Serenoa repens have not been specifically studied or reported. Saw palmetto extracts appear to have antiandrogenic effects.(32)(33) The antiandrogenic effects of Saw palmetto, Serenoa repens would be expected to antagonize the actions of androgens; it would seem illogical for patients taking androgens to use this herbal supplement.

Limited data suggest that testosterone concentrations increase during fluconazole administration. It appears that fluconazole doses of 200 mg/day or greater are more likely to produce this effect than doses of 25—50 mg/day.(34)  The clinical significance of this interaction is unclear at this time. Although data are not available, a similar reaction may occur with voriconazole. Both fluconazole and voriconazole are inhibitors of CYP3A4, the hepatic microsomal isoenzyme responsible for metabolism of testosterone. (35)

Exogenously administered androgens (testosterone derivatives or anabolic steroids) have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance. Further, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. In one study in men with diabetes, testosterone undecenoate 120 mg PO/day for 3 months decreased HbA1c concentrations from a baseline of 10.4% to 8.6% (p < 0.05); fasting plasma glucose concentrations decreased from 8 mmol/l at baseline to 6 mmol/l (p 100 h, steady‐state is expected to be achieved much later than day 8. The long t1/2 probably also accounted for the measurable concentrations in subjects while receiving 0 mg GSK2881078 preceded by an active dosing regimen 5 days earlier in Part A. A washout period longer than 5 days is needed in future studies of this molecule. Given the long t1/2 of GSK2881078 and the objective of emulating steady‐state exposure profiles over the 14‐day course of the study, a loading regimen was devised based on the Part A data, which would elevate plasma exposures rapidly and maintain them over the study period. As a result, direct comparison of PK results to address accumulation of GSK2881078 from day 1 to day 14 is not possible using standard PK approaches but will be addressed in future analyses making use of population PK modelling.

Following repeat dosing, there was an apparent 38% difference in t1/2 between genders for the 0.24 mg BID then 0.24 mg QD treatment, which was probably attributable to tlast occurring much earlier for some of the male subjects. As the quantifiable concentrations with placebo or 0 mg GSK2881078 following single‐dose administration in Part A were included in the analysis for the preceding treatment dose to better characterize GSK2881078 elimination, tlast exceeded the last scheduled sampling time for the corresponding treatment, accounting for the high variability of AUC(0–t) (CVb ranging from 43% to 96%) and the apparent lack of dose proportionality in contrast to Part B, where additional samples permitted improved characterization of the long t1/2.

Consistent with other oral androgens and other SARMs under investigation, GSK2881078 (doses of 0.2 mg BID then 0.08 mg QD and higher) was associated with reductions in HDL, ApoA1, triglycerides and VLDL relative to baseline and placebo in male and female subjects. This was an expected result because androgen receptor agonists are known to affect hepatic metabolism. There were no apparent changes in total cholesterol, LDL or ApoB. The clinical implications of androgen‐associated lipid alterations are not clear.

Reductions in testosterone, DHT, SHBG and FSH were observed relative to baseline and placebo in male subjects, and reductions in SHBG in female subjects receiving GSK2881078. The accompanying decrease in SHBG in both males and females is consistent with hepatic effects observed with other SARMs. Free testosterone did not change in either males or females, consistent with the decrease in SHBG. No clinically meaningful changes were observed in other reproductive hormones. Androgen receptor agonists can act centrally on the hypothalamic–pituitary–gonadal axis, to suppress the signals for gonadal hormonal secretion, LH and FSH. In the present study, neither free testosterone nor LH levels declined, suggesting that the decrease in total testosterone was not due to hypothalamic inhibition. Thus, in men, total testosterone levels can fall, as observed. Effects in the postmenopausal women were minimal. In addition, androgen receptor agonists also suppress production of binding globulins such as SHBG in the liver, leading to lower levels of endogenous sex steroids (testosterone and oestradiol), typically without significant effect on free hormone levels. All hormonal levels were returning to baseline values by the end of the study.

There were no consistent, clinically meaningful changes in adrenal hormones in the male or female subjects. In male and female subjects, TBG was reduced relative to baseline and placebo. As noted, androgen receptor agonists act on the liver to reduce the levels of binding globulins, such as TBG and SHBG. Free hormone levels typically are unaffected, although here, men and women alike showed increases in free T4 at the higher doses. The clinical significance of this is unclear, although there was no evidence of a clinical response to this, such as an increased heart rate. There were no clinically meaningful changes in any other metabolic biomarkers. Monitoring of BNP and troponin showed no evidence of myocardial injury.

Comparison of our results with those from longer duration studies of other SARMs in development reveals modest differences. Our high‐dose male cohort (0.75 mg) yielded approximately similar levels of SHBG and total testosterone suppression as those seen in high‐dose cohorts of enobosarm and LGD‐4033, suggesting similar levels of androgen receptor agonism. Adverse effects were generally not different between SARMs. Of note were elevations in ALT seen with enobosarm, leading to study discontinuation in one subject receiving the highest dose examined, 3 mg QD. One possible differentiating feature of GSK2881078 is the long t1/2 of the compound. GSK2881078 has a terminal t1/2 of 7.5 days, considerably longer than enobosarm or LGD, which may limit peak : trough compound excursion. While daily testosterone concentrations are diurnal, a more static exposure may offer more sustained anabolic stimulation of muscle.

Currently, there are no approved therapies for the prevention or treatment of deleterious muscle wasting, although there is a clinical need for safe anabolic compounds such as SARMs. GSK2881078 has demonstrated clear target engagement shown by significant reductions in SHBG, TBG and HDL. Good safety and tolerability were also demonstrated and are consistent with the broad safety margin shown in preclinical toxicology studies (unpublished data on file, GlaxoSmithKline, King of Prussia, PA, USA). These data, combined with the dose‐proportional plasma levels and predictable biomarker profiles of GSK2881078, provide a pharmacological rationale for further clinical study of this novel SARM for the treatment of muscle wasting.

Question 20

Indications

Accepted Answer

Indications

Muscle-wasting disorders

SARMs could be used in diseases where steroidal androgens have been proposed as therapeutics. The initial focus of SARM clinical development was their use for muscle wasting conditions. However, the use of SARMs is now expanding to other diseases such as breast cancer.

Adults over 40 years of age lose about 1% muscle mass each year. With life expectancy increasing around the globe, the number of people with compromised muscle mass and accordingly deficits in physical function has increased in the last decade. Age-related muscle wasting or sarcopenia and muscle wasting due to cancer, also called cancer cachexia, are two serious muscle wasting disorders with no treatment options. Sarcopenia is a major cause of frailty and carries with it an increase in physical disability as well as morbidity and mortality. The demographic that is widely affected by cancer is adults over 60 years of age. This age-group, already at higher risk to be deficient in muscle due to age-related decline, is then at high risk to lose additional muscle due as their cancer progresses and they receive anti-cancer therapy. Advanced cancer patients lose up to 1.5 kg of lean mass per year. Studies have also demonstrated that muscle mass directly correlates with survival in cancer patients. Androgens are important for building and maintaining skeletal muscle, and due to their anabolic effects on muscle are considered front-runners in the potential treatment of cancer cachexia and sarcopenia. SARMs are particularly relevant in this regard due to their tissue-selectivity and potential to provide therapeutic increases in muscle mass with reduced side-effects.

With wide-spread use of corticosteroids to combat inflammation and allergies, even children are susceptible to corticosteroid-induced muscle wasting. Although non-steroidal SGRMs that spare muscle and bone, but have significant anti-inflammatory effects, have been preclinically developed and tested, they have not successfully entered clinical trials, making steroidal corticosteroids the only available option for a number of indications. SARMs have been shown to be effective in ameliorating multiple preclinical models of muscle wasting including glucocorticoid mediated muscle atrophy.

Osteoporosis
The ability of SARMs to increase both muscle and bone strength in animal models suggests that they may provide a unique dual approach to osteoporosis therapy. Currently osteoporosis is primarily treated with anti-resorptive agents that prevent further breakdown of bone by the body. Anti-resorptive agents potentially prevent further bone turn-over, but will be unable to increase bone mass. In preclinical models, AR agonists such as DHT and SARMs have prevented bone loss in both castrated male rats and ovariectomized female rats. They also increased cortical and trabecular bone mineral density above baseline in these experimental conditions. SARMs have been shown not only to prevent loss of bone (i.e., treatment begins at time of surgery) in ovariectomized and castrated rats, but also to increase bone strength.

Duchenne muscular dystrophy (DMD)

DMD is a genetic disorder that arises due to mutations in the cytoskeletal protein dystrophin. The dystrophin gene is located in the X chromosome and a number of its mutations cause truncated proteins that manifest clinically in the form of muscular dystrophy. Boys with DMD suffer from progressive muscle wasting and weakness and will become wheel-chair-bound often before reaching puberty. Boys with DMD suffer from cardiac and respiratory failures due to weakness in the heart and lung muscles, respectively, resulting in premature death. Recently, therapies to correct mutations using exon-skipping strategies have been developed with one of these molecules receiving approval from the Food and Drug Administration (FDA). Although corticosteroids are the standard of care to combat inflammation in DMD, with the exception of the novel exon skipping drug there are currently no disease-modifying therapeutic agents, available to treat DMD. Regrettably prolonged use of corticosteroids results in undesirable side-effects such as muscle wasting.

Question 21

Contraindications/Precautions

Accepted Answer

Contraindication and Precaution

Ostarine may cause liver damage has been reported in some people taking ostarine. Other uncommon side effects of ostartine include, constipation, diarrhoea, nausea, heart attack and stroke. It should only be considered in conjunction with the supervision of your treating physician when all other medical treatments have failed. In high does it may cause negative feedback inhibition to hypothalamic gonadal hormone.

Question 22

Pregnancy

Accepted Answer

Pregnancy

There isn’t enough reliable information to know if ostarine is safe to use when pregnant or breast-feeding. It is not recommended to take this if trying to fall pregnant, are pregnant or breast feeding

Question 23

Breast-feeding

Accepted Answer

Breast Feeding

Do not take this medication while breast feeding

Question 24

Adverse Reations/Side Effects

Accepted Answer

Side Effects

Compared with steroidal androgens, SARMs appear to be much better tolerated with few incidences of severe adverse effects. In addition, many of these pre-clinical agents can be administered as oral therapies. This helps to reduce the risk of accidental exposure, as can be seen with topical testosterone, and can significantly improve ease of administration compared to currently available forms of TTh. Enobosarm treatment led to small increases in hemoglobin in certain subjects, increases in ALT, and decreased serum HDL levels. Other early clinical studies have investigated the safety profiles and pharmacodynamics and kinetics of several candidate SARMs.

SARM being investigated by GlaxoSmithKline for muscle growth and strength in subjects with muscle wasting, was tested in a two part, randomized, double-blind, placebo-controlled dose-escalation Phase 1 study to assess safety, pharmacokinetics and pharmacological effects in a small cohort of young men and postmenopausal women.Overall the treatment was well tolerated, with the most common adverse events being constipation, dyspepsia, and nausea (3 of 89). One female subject developed a maculopapular rash with biopsy consistent with a drug reactions, two female subjects developed elevated ALT values 2–2.5 time the upper limit of normal during treatment, and two male subjects experienced muscle soreness and elevated CK levels weeks into the follow up period.GSK2881078 was also associated with reductions in HDL.

Clinical testing has shown SARMs to be well tolerated with mild and infrequent adverse effects. Several of the trials showed no increases in AEs compared to placebo. The most consistent biological alteration shared between most of the tested compounds were decreases in HDL levels and transient increases in ALT. Anabolic androgenic steroids (AAS) like testosterone are known to increase liver transaminase levels, and there have been reports of peliosis hepatis, cholestasic jaundice, and liver malignancies associated with their use. None of the subjects in the above trials had alterations in their bilirubin levels to suggest cholestasis, but several had elevations in ALT, suggesting hepatocellular injury. Liver damage from AAS was initially thought to be due to an idiosyncratic hypersensitivity reaction, but has been shown to be due to intrinsic direct hepatotoxicity of AASs depending on individual susceptibility with genetics playing a role. Thus, it remains to be seen if SARMs may pose a risk of significant hepatotoxicity and further studies are needed to examine the relationship between theses transient ALT elevations and pathologic hepatic changes.

Continued investigation and development of these agents is called for given their novel mechanisms of action and potential to address and complement conditions with a lack of effective therapies or therapies with unacceptable side effects. Additionally, to date SARMs have consistently been shown to be well tolerated, easily administered via an oral route, and overall lacking in significant drug interactions which can only further increase their future applicability. Like the SERMs before them, the next decades could herald the approval and widespread use of SARMs for an array of indications. However, further studies are currently needed to determine the safety and efficacy of these medications before they are approved for clinical use.

Question 25

Storage

Accepted Answer

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

Question 26

Interactions

Accepted Answer

Tsai MJ, O’Malley BW. Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu Rev Biochem. 1994;63:451–486.
Evans RM. The steroid and thyroid hormone receptor superfamily. Science. 1988;240:889–895.
Power RF, Conneely OM, O’Malley BW. New insights into activation of the steroid hormone receptor superfamily. Trends Pharmacol Sci. 1992;13:318–323
Mani SK, Allen JM, Lydon JP, Mulac-Jericevic B, Blaustein JD, DeMayo FJ, Conneely O, O’Malley BW. Dopamine requires the unoccupied progesterone receptor to induce sexual behavior in mice. Mol Endocrinol. 1996;10:1728–173
Nazareth LV, Weigel NL. Activation of the human androgen receptor through a protein kinase A signaling pathway. J Biol Chem. 1996;271:19900
Penning TM, Burczynski ME, Jez JM, Hung CF, Lin HK, Ma H, Moore M, Palackal N, Ratnam K. Human 3alpha-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones. Biochem J. 2000;351:67–77.
Imperato-McGinley J, Guerrero L, Gautier T, German JL, Peterson RE. Steroid 5alpha-reductase deficiency in man. An inherited form of male pseudohermaphroditism. Birth Defects Orig Artic Ser. 1975;11:91–103.
 Schindler AE. Metabolism of androstenedione and testosterone in human fetal brain. Prog Brain Res. 1975;42:330.
Liao G, Chen LY, Zhang A, Godavarthy A, Xia F, Ghosh JC, Li H, Chen JD. Regulation of androgen receptor activity by the nuclear receptor corepressor SMRT. J Biol Chem. 2003;278:5052–5061
Shang Y, Myers M, Brown M. Formation of the androgen receptor transcription complex. Mol Cell. 2002;9:601–610.
Hall JM, Couse JF, Korach KS. The multifaceted mechanisms of estradiol and estrogen receptor signaling. J Biol Chem. 2001;276:36869–36872.
Rodan GA, Martin TJ. Therapeutic approaches to bone diseases. Science. 2000;289:1508–1514.
 Dhandapani KM, Brann DW. Protective effects of estrogen and selective estrogen receptor modulators in the brain. Biol Reprod. 2002;67:1379–1385
Burns KA, Korach KS. Estrogen receptors and human disease: an update. Arch Toxicol. 2012;86:1491–1504.
Charles D, Barr W, Bell ET, Brown JB, Fotherby K, Loraine JA. Clomiphene in the Treatment of Oligomenorrhea and Amenorrhea. Am J Obstet Gynecol. 1963;86:913–922.
Kedar RP, Bourne TH, Powles TJ, Collins WP, Ashley SE, Cosgrove DO, Campbell S. Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial. Lancet. 1994;343:1318–1321
Lahti E, Blanco G, Kauppila A, Apaja-Sarkkinen M, Taskinen PJ, Laatikainen T. Endometrial changes in postmenopausal breast cancer patients receiving tamoxifen. Obstet Gynecol. 1993;81:660–664.
 Deligdisch L, Kalir T, Cohen CJ, de Latour M, Le Bouedec G, Penault-Llorca F. Endometrial histopathology in 700 patients treated with tamoxifen for breast cancer. Gynecol Oncol. 2000;78:181–186.
Mincey BA, Moraghan TJ, Perez EA. Prevention and treatment of osteoporosis in women with breast cancer. Mayo Clin Proc. 2000;75:821–829.
Dalton JT, Mukherjee A, Zhu Z, Kirkovsky L, Miller DD. Discovery of nonsteroidal androgens. Biochem Biophys Res Commun. 1998;244:1–4
Link JT, Sorensen B, Patel J, Grynfarb M, Goos-Nilsson A, Wang J, Fung S, Wilcox D, Zinker B, Nguyen P, Hickman B, Schmidt JM, Swanson S, Tian Z, Reisch TJ, Rotert G, Du J, Lane B, von Geldern TW, Jacobson PB. Antidiabetic activity of passive nonsteroidal glucocorticoid receptor modulators. J Med Chem. 2005;48:5295–5304.
Tabata Y, Iizuka Y, Shinei R, Kurihara K, Okonogi T, Hoshiko S, Kurata Y. CP8668, a novel orally active nonsteroidal progesterone receptor modulator with tetrahydrobenzindolone skeleton. Eur J Pharmacol. 2003;461:73–78.
Fang S, Suh JM, Reilly SM, Yu E, Osborn O, Lackey D, Yoshihara E, Perino A, Jacinto S, Lukasheva Y, Atkins AR, Khvat A, Schnabl B, Yu RT, Brenner DA, Coulter S, Liddle C, Schoonjans K, Olefsky JM, Saltiel AR, Downes M, Evans RM. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med. 2015;21:159–165.
 Lubahn DB, Joseph DR, Sar M, Tan J, Higgs HN, Larson RE, French FS, Wilson EM. The human androgen receptor: complementary deoxyribonucleic acid cloning, sequence analysis and gene expression in prostate. Mol Endocrinol. 1988;2:1265–1275. 
Yin D, He Y, Perera MA, Hong SS, Marhefka C, Stourman N, Kirkovsky L, Miller DD, Dalton JT. Key structural features of nonsteroidal ligands for binding and activation of the androgen receptor. Mol Pharmacol. 2003;63:211–223
Gao W, Reiser PJ, Coss CC, Phelps MA, Kearbey JD, Miller DD, Dalton JT. Selective androgen receptor modulator treatment improves muscle strength and body composition and prevents bone loss in orchidectomized rats. Endocrinology. 2005;146:4887–4897.
 Srinath R, Dobs A. Enobosarm (GTx-024, S-22): a potential treatment for cachexia. Future Oncol. 2014;10:187–194.
 Kearbey JD, Gao W, Narayanan R, Fisher SJ, Wu D, Miller DD, Dalton JT. Selective Androgen Receptor Modulator (SARM) treatment prevents bone loss and reduces body fat in ovariectomized rats. Pharm Res. 2007;24:328–335.
 Crawford J, Prado CM, Johnston MA, Gralla RJ, Taylor RP, Hancock ML, Dalton JT. Study Design and Rationale for the Phase 3 Clinical Development Program of Enobosarm, a Selective Androgen Receptor Modulator, for the Prevention and Treatment of Muscle Wasting in Cancer Patients (POWER Trials) Curr Oncol Rep. 2016;18:37.
 Dobs AS, Boccia RV, Croot CC, Gabrail NY, Dalton JT, Hancock ML, Johnston MA, Steiner MS. Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial. Lancet Oncol. 2013;14:335–345.
 Dalton JT, Barnette KG, Bohl CE, Hancock ML, Rodriguez D, Dodson ST, Morton RA, Steiner MS. The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial. J Cachexia Sarcopenia Muscle. 2011;2:153–161.
 Edwards JP, West SJ, Pooley CL, Marschke KB, Farmer LJ, Jones TK. New nonsteroidal androgen receptor modulators based on 4-(trifluoromethyl)-2(1H)-pyrrolidino quinolinone. Bioorg Med Chem Lett. 1998;8:745–750.
Higuchi RI, Edwards JP, Caferro TR, Ringgenberg JD, Kong JW, Hamann LG, Arienti KL, Marschke KB, Davis RL, Farmer LJ, Jones TK. 4-Alkyl- and 3,4-dialkyl-1,2,3,4-tetrahydro-8-pyridonoquinolines: potent, nonsteroidal androgen receptor agonists. Bioorg Med Chem Lett. 1999;9:1335–1340
Miner JN, Chang W, Chapman MS, Finn PD, Hong MH, Lopez FJ, Marschke KB, Rosen J, Schrader W, Turner R, van Oeveren A, Viveros H, Zhi L, Negro-Vilar A. An orally active selective androgen receptor modulator is efficacious on bone, muscle, and sex function with reduced impact on prostate. Endocrinology. 2007;148:363–373.
 Schmidt A, Kimmel DB, Bai C, Scafonas A, Rutledge S, Vogel RL, McElwee-Witmer S, Chen F, Nantermet PV, Kasparcova V, Leu CT, Zhang HZ, Duggan ME, Gentile MA, Hodor P, Pennypacker B, Masarachia P, Opas EE, Adamski SA, Cusick TE, Wang J, Mitchell HJ, Kim Y, Prueksaritanont T, Perkins JJ, Meissner RS, Hartman GD, Freedman LP, Harada S, Ray WJ. Discovery of the selective androgen receptor modulator MK-0773 using a rational development strategy based on differential transcriptional requirements for androgenic anabolism versus reproductive physiology. J Biol Chem. 2010;285:17054–17064.
 Smith CL, O’Malley BW. Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev. 2004;25:45–71.
 Smith CL, Nawaz Z, O’Malley BW. Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen. Mol Endocrinol. 1997;11:657–666
Madeira M, Mattar A, Logullo AF, Soares FA, Gebrim LH. Estrogen receptor alpha/beta ratio and estrogen receptor beta as predictors of endocrine therapy responsiveness-a randomized neoadjuvant trial comparison between anastrozole and tamoxifen for the treatment of postmenopausal breast cancer. BMC Cancer. 2013;13:425.
 Gao W, Dalton JT. Ockham’s Razor and Selective Androgen Receptor Modulators (SARMs): Are We Overlooking the Role of 5{alpha}-Reductase? Mol Interv. 2007;7:10–13.
 Blouin K, Richard C, Brochu G, Hould FS, Lebel S, Marceau S, Biron S, Luu-The V, Tchernof A. Androgen inactivation and steroid-converting enzyme expression in abdominal adipose tissue in men. J Endocrinol. 2006;191:637–649.
 Labrie F, Luu-The V, Lin SX, Labrie C, Simard J, Breton R, Belanger A. The key role of 17 beta-hydroxysteroid dehydrogenases in sex steroid biology. Steroids. 1997;62:148–158
Penning TM, Byrns MC. Steroid hormone transforming aldo-keto reductases and cancer. Ann N Y Acad Sci. 2009;1155:33–42
Chang CY, McDonnell DP. Androgen receptor-cofactor interactions as targets for new drug discovery. Trends Pharmacol Sci. 2005;26:225–228.
 Heinlein CA, Chang C. Androgen receptor (AR) coregulators: an overview. Endocr Rev. 2002;23:175–200.
Fujimoto N, Yeh S, Kang HY, Inui S, Chang HC, Mizokami A, Chang C. Cloning and characterization of androgen receptor coactivator, ARA55, in human prostate. J Biol Chem. 1999;274:8316–8321
Kang HY, Yeh S, Fujimoto N, Chang C. Cloning and characterization of human prostate coactivator ARA54, a novel protein that associates with the androgen receptor. J Biol Chem. 1999;274:8570–8576
Heery DM, Kalkhoven E, Hoare S, Parker MG. A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature. 1997;387:733–736.
 Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell. 1998;95:927–937.
 He B, Minges JT, Lee LW, Wilson EM. The FXXLF motif mediates androgen receptor-specific interactions with coregulators. J Biol Chem. 2002;277:10226–10235.
 Chang CY, McDonnell DP. Evaluation of ligand-dependent changes in AR structure using peptide probes. Mol Endocrinol. 2002;16:647–660.
 Chang C, Norris JD, Gron H, Paige LA, Hamilton PT, Kenan DJ, Fowlkes D, McDonnell DP. Dissection of the LXXLL nuclear receptor-coactivator interaction motif using combinatorial peptide libraries: discovery of peptide antagonists of estrogen receptors alpha and beta. Mol Cell Biol. 1999;19:8226–8239.
 Kazmin D, Prytkova T, Cook CE, Wolfinger R, Chu TM, Beratan D, Norris JD, Chang CY, McDonnell DP. Linking ligand-induced alterations in androgen receptor structure to differential gene expression: a first step in the rational design of selective androgen receptor modulators. Mol Endocrinol. 2006;20:1201–1217
Baek SH, Ohgi KA, Nelson CA, Welsbie D, Chen C, Sawyers CL, Rose DW, Rosenfeld MG. Ligand-specific allosteric regulation of coactivator functions of androgen receptor in prostate cancer cells. Proceedings of the National Academy of Sciences of the United States of America. 2006;103:3100–3105
Liu Z, Auboeuf D, Wong J, Chen JD, Tsai SY, Tsai MJ, O’Malley BW. Coactivator/corepressor ratios modulate PR-mediated transcription by the selective receptor modulator RU486. Proc Natl Acad Sci U S A. 2002;99:7940–7944
Feng Q, O’Malley BW. Nuclear receptor modulation–role of coregulators in selective estrogen receptor modulator (SERM) actions. Steroids. 2014;90:39–43.
 Narayanan R, Yepuru M, Szafran AT, Szwarc M, Bohl CE, Young NL, Miller DD, Mancini MA, Dalton JT. Discovery and mechanistic characterization of a novel selective nuclear androgen receptor exporter for the treatment of prostate cancer. Cancer Res. 2010;70:842–851.
 Guo D, Zhang H, Liu L, Wang L, Cheng Y, Qiao Z. Testosterone influenced the expression of Notch1, Notch2 and Jagged1 induced by lipopolysaccharide in macrophages. Exp Toxicol Pathol. 2004;56:173–179.
Kang HY, Cho CL, Huang KL, Wang JC, Hu YC, Lin HK, Chang C, Huang KE. Nongenomic androgen activation of phosphatidylinositol 3-kinase/Akt signaling pathway in MC3T3-E1 osteoblasts. J Bone Miner Res. 2004;19:1181–1190.
Liu L, Wang L, Zhao Y, Wang Y, Wang Z, Qiao Z. Testosterone attenuates p38 MAPK pathway during Leishmania donovani infection of macrophages. Parasitol Res. 2006;99:189–193.
Huber DM, Bendixen AC, Pathrose P, Srivastava S, Dienger KM, Shevde NK, Pike JW. Androgens suppress osteoclast formation induced by RANKL and macrophage-colony stimulating factor. Endocrinology. 2001;142:3800–3808.
Dehm SM, Tindall DJ. Ligand-independent androgen receptor activity is activation function-2-independent and resistant to antiandrogens in androgen refractory prostate cancer cells. J Biol Chem. 2006;281:27882–27893. [
Kousteni S, Bellido T, Plotkin LI, O’Brien CA, Bodenner DL, Han L, Han K, DiGregorio GB, Katzenellenbogen JA, Katzenellenbogen BS, Roberson PK, Weinstein RS, Jilka RL, Manolagas SC. Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell. 2001;104:719–730.
Lutz LB, Jamnongjit M, Yang WH, Jahani D, Gill A, Hammes SR. Selective modulation of genomic and nongenomic androgen responses by androgen receptor ligands. Mol Endocrinol. 2003;17:1106–1116.
 Lutz LB, Cole LM, Gupta MK, Kwist KW, Auchus RJ, Hammes SR. Evidence that androgens are the primary steroids produced by Xenopus laevis ovaries and may signal through the classical androgen receptor to promote oocyte maturation. Proc Natl Acad Sci U S A. 2001;98:13728–13733.
Lutz LB, Kim B, Jahani D, Hammes SR. G protein beta gamma subunits inhibit nongenomic progesterone-induced signaling and maturation in Xenopus laevis oocytes. Evidence for a release of inhibition mechanism for cell cycle progression. J Biol Chem. 2000;275:41512–41520.
Narayanan R, Coss CC, Yepuru M, Kearbey JD, Miller DD, Dalton JT. Steroidal androgens and nonsteroidal, tissue-selective androgen receptor modulator, S-22, regulate androgen receptor function through distinct genomic and nongenomic signaling pathways. Mol Endocrinol. 2008;22:2448–2465.
Carmeli E, Coleman R, Reznick AZ. The biochemistry of aging muscle. Exp Gerontol. 2002;37:477–480
Bosy-Westphal A, Eichhorn C, Kutzner D, Illner K, Heller M, Muller MJ. The age-related decline in resting energy expenditure in humans is due to the loss of fat-free mass and to alterations in its metabolically active components. J Nutr. 2003;133:2356–2362.
Muhlberg W, Sieber C. Sarcopenia and frailty in geriatric patients: implications for training and prevention. Z Gerontol Geriatr. 2004;37:2–8.
Wallengren O, Iresjo BM, Lundholm K, Bosaeus I. Loss of muscle mass in the end of life in patients with advanced cancer. Support Care Cancer. 2015;23:79–86.  Liu J, Motoyama S, Sato Y, Wakita A, Kawakita Y, Saito H, Minamiya Y. Decreased Skeletal Muscle Mass After Neoadjuvant Therapy Correlates with Poor Prognosis in Patients with Esophageal Cancer. Anticancer Res. 2016;36:6677–6685.
Chu MP, Lieffers J, Ghosh S, Belch A, Chua NS, Fontaine A, Sangha R, Turner RA, Baracos VE, Sawyer MB. Skeletal muscle density is an independent predictor of diffuse large B-cell lymphoma outcomes treated with rituximab-based chemoimmunotherapy. J Cachexia Sarcopenia Muscle. 2016
van Lierop MJ, Alkema W, Laskewitz AJ, Dijkema R, van der Maaden HM, Smit MJ, Plate R, Conti PG, Jans CG, Timmers CM, van Boeckel CA, Lusher SJ, McGuire R, van Schaik RC, de Vlieg J, Smeets RL, Hofstra CL, Boots AM, van Duin M, Ingelse BA, Schoonen WG, Grefhorst A, van Dijk TH, Kuipers F, Dokter WH. Org 214007-0: a novel non-steroidal selective glucocorticoid receptor modulator with full anti-inflammatory properties and improved therapeutic index. PLoS One. 2012;7:e48385.
Jones A, Hwang DJ, Narayanan R, Miller DD, Dalton JT. Effects of a novel selective androgen receptor modulator on dexamethasone-induced and hypogonadism-induced muscle atrophy. Endocrinology. 2010;151:3706–3719
Emery AE. Population frequencies of inherited neuromuscular diseases–a world survey. Neuromuscul Disord. 1991;1:19–29.
Rahimov F, Kunkel LM. The cell biology of disease: cellular and molecular mechanisms underlying muscular dystrophy. J Cell Biol. 2013;201:499–510.
Frankel KA, Rosser RJ. The pathology of the heart in progressive muscular dystrophy: epimyocardial fibrosis. Hum Pathol. 1976;7:375–386.
Politano L, Nigro V, Nigro G, Petretta VR, Passamano L, Papparella S, Di Somma S, Comi LI. Development of cardiomyopathy in female carriers of Duchenne and Becker muscular dystrophies. JAMA. 1996;275:1335–1338.
Lim KR, Maruyama R, Yokota T. Eteplirsen in the treatment of Duchenne muscular dystrophy. Drug Des Devel Ther. 2017;11:533–545.
 Cozzoli A, Capogrosso RF, Sblendorio VT, Dinardo MM, Jagerschmidt C, Namour F, Camerino GM, De Luca A. GLPG0492, a novel selective androgen receptor modulator, improves muscle performance in the exercised-mdx mouse model of muscular dystrophy. Pharmacol Res. 2013;72:9–24.
 Ponnusamy S, Sullivan RD, Thiyagarajan T, Tillmann H, Getzenberg RH, Narayanan R. Tissue Selective Androgen Receptor Modulators (SARMs) Increase Pelvic Floor Muscle Mass in Ovariectomized Mice. J Cell Biochem. 2016
Mohler ML, Nair VA, Hwang DJ, Rakov IM, Patil R, Miller DD. Nonsteroidal Tissue Selective Androgen Receptor Modulators: A Promising Class of Clinical Candidates. Expert Opinion in Therapeutic Patents. 2005;15(11):1565–1585.
Hanada K, Furuya K, Yamamoto N, Nejishima H, Ichikawa K, Nakamura T, Miyakawa M, Amano S, Sumita Y, Oguro N. Bone anabolic effects of S-40503, a novel nonsteroidal selective androgen receptor modulator (SARM), in rat models of osteoporosis. Biol Pharm Bull. 2003;26:1563–1569.
 Hamann LG. Discovery and Preclinical Profile of a Highly Potent and Muscle Selective Androgen Receptor Modulator (SARM). Abstract MEDI 11 from the 227th National American Chemical Society Meeting; Anaheim, CA. March 2004.
 Mason RA, Morris HA. Effects of dihydrotestosterone on bone biochemical markers in sham and oophorectomized rats. J Bone Miner Res. 1997;12:1431–1437.
Coss CC, Jones A, Dalton JT. Selective androgen receptor modulators as improved androgen therapy for advanced breast cancer. Steroids. 2014;90:94–100.
GTx Reports Results from Ongoing Enobosarm Phase 2 Clinical Trial in ER+/AR+ Breast Cancer. 2016
Schwartzberg LS, Yardley D, Elias A, Patel M, LoRusso PM, Burris HA, Gucalp A, Peterson A, Blaney M, Steinberg J, Gibbons J, Traina TA. A Phase I/Ib Study of Enzalutamide Alone and in Combination with Endocrine Therapies in Women with Advanced Breast Cancer. Clin Cancer Res. 2017
Narayanan R, Dalton JT. Androgen Receptor: A Complex Therapeutic Target for Breast Cancer. Cancers (Basel) 2016:8. [
Temel JS, Abernethy AP, Currow DC, Friend J, Duus EM, Yan Y, Fearon KC. Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials. Lancet Oncol. 2016;17:519–531.
Fearon K, Argiles JM, Baracos VE, Bernabei R, Coats A, Crawford J, Deutz NE, Doehner W, Evans WJ, Ferrucci L, Garcia JM, Gralla RJ, Jatoi A, Kalantar-Zadeh K, Lainscak M, Morley JE, Muscaritoli M, Polkey MI, Rosano G, Rossi-Fanelli F, Schols AM, Strasser F, Vellas B, von Haehling S, Anker SD. Request for regulatory guidance for cancer cachexia intervention trials. J Cachexia Sarcopenia Muscle. 2015;6:272–274.
Mohler  ML, Bohl  CE, Jones  A, et al. . Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit. J Med Chem. 2009;52:3597–3617.
Dobs  AS, Boccia  RV, Croot  CC, et al. . Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial. Lancet Oncol. 2013;14:335–345.

Question 27

References

Accepted Answer

Tsai MJ, O’Malley BW. Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu Rev Biochem. 1994;63:451–486.
Evans RM. The steroid and thyroid hormone receptor superfamily. Science. 1988;240:889–895.
Power RF, Conneely OM, O’Malley BW. New insights into activation of the steroid hormone receptor superfamily. Trends Pharmacol Sci. 1992;13:318–323
Mani SK, Allen JM, Lydon JP, Mulac-Jericevic B, Blaustein JD, DeMayo FJ, Conneely O, O’Malley BW. Dopamine requires the unoccupied progesterone receptor to induce sexual behavior in mice. Mol Endocrinol. 1996;10:1728–173
Nazareth LV, Weigel NL. Activation of the human androgen receptor through a protein kinase A signaling pathway. J Biol Chem. 1996;271:19900
Penning TM, Burczynski ME, Jez JM, Hung CF, Lin HK, Ma H, Moore M, Palackal N, Ratnam K. Human 3alpha-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones. Biochem J. 2000;351:67–77.
Imperato-McGinley J, Guerrero L, Gautier T, German JL, Peterson RE. Steroid 5alpha-reductase deficiency in man. An inherited form of male pseudohermaphroditism. Birth Defects Orig Artic Ser. 1975;11:91–103.
 Schindler AE. Metabolism of androstenedione and testosterone in human fetal brain. Prog Brain Res. 1975;42:330.
Liao G, Chen LY, Zhang A, Godavarthy A, Xia F, Ghosh JC, Li H, Chen JD. Regulation of androgen receptor activity by the nuclear receptor corepressor SMRT. J Biol Chem. 2003;278:5052–5061
Shang Y, Myers M, Brown M. Formation of the androgen receptor transcription complex. Mol Cell. 2002;9:601–610.
Hall JM, Couse JF, Korach KS. The multifaceted mechanisms of estradiol and estrogen receptor signaling. J Biol Chem. 2001;276:36869–36872.
Rodan GA, Martin TJ. Therapeutic approaches to bone diseases. Science. 2000;289:1508–1514.
 Dhandapani KM, Brann DW. Protective effects of estrogen and selective estrogen receptor modulators in the brain. Biol Reprod. 2002;67:1379–1385
Burns KA, Korach KS. Estrogen receptors and human disease: an update. Arch Toxicol. 2012;86:1491–1504.
Charles D, Barr W, Bell ET, Brown JB, Fotherby K, Loraine JA. Clomiphene in the Treatment of Oligomenorrhea and Amenorrhea. Am J Obstet Gynecol. 1963;86:913–922.
Kedar RP, Bourne TH, Powles TJ, Collins WP, Ashley SE, Cosgrove DO, Campbell S. Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial. Lancet. 1994;343:1318–1321
Lahti E, Blanco G, Kauppila A, Apaja-Sarkkinen M, Taskinen PJ, Laatikainen T. Endometrial changes in postmenopausal breast cancer patients receiving tamoxifen. Obstet Gynecol. 1993;81:660–664.
 Deligdisch L, Kalir T, Cohen CJ, de Latour M, Le Bouedec G, Penault-Llorca F. Endometrial histopathology in 700 patients treated with tamoxifen for breast cancer. Gynecol Oncol. 2000;78:181–186.
Mincey BA, Moraghan TJ, Perez EA. Prevention and treatment of osteoporosis in women with breast cancer. Mayo Clin Proc. 2000;75:821–829.
Dalton JT, Mukherjee A, Zhu Z, Kirkovsky L, Miller DD. Discovery of nonsteroidal androgens. Biochem Biophys Res Commun. 1998;244:1–4
Link JT, Sorensen B, Patel J, Grynfarb M, Goos-Nilsson A, Wang J, Fung S, Wilcox D, Zinker B, Nguyen P, Hickman B, Schmidt JM, Swanson S, Tian Z, Reisch TJ, Rotert G, Du J, Lane B, von Geldern TW, Jacobson PB. Antidiabetic activity of passive nonsteroidal glucocorticoid receptor modulators. J Med Chem. 2005;48:5295–5304.
Tabata Y, Iizuka Y, Shinei R, Kurihara K, Okonogi T, Hoshiko S, Kurata Y. CP8668, a novel orally active nonsteroidal progesterone receptor modulator with tetrahydrobenzindolone skeleton. Eur J Pharmacol. 2003;461:73–78.
Fang S, Suh JM, Reilly SM, Yu E, Osborn O, Lackey D, Yoshihara E, Perino A, Jacinto S, Lukasheva Y, Atkins AR, Khvat A, Schnabl B, Yu RT, Brenner DA, Coulter S, Liddle C, Schoonjans K, Olefsky JM, Saltiel AR, Downes M, Evans RM. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med. 2015;21:159–165.
 Lubahn DB, Joseph DR, Sar M, Tan J, Higgs HN, Larson RE, French FS, Wilson EM. The human androgen receptor: complementary deoxyribonucleic acid cloning, sequence analysis and gene expression in prostate. Mol Endocrinol. 1988;2:1265–1275. 
Yin D, He Y, Perera MA, Hong SS, Marhefka C, Stourman N, Kirkovsky L, Miller DD, Dalton JT. Key structural features of nonsteroidal ligands for binding and activation of the androgen receptor. Mol Pharmacol. 2003;63:211–223
Gao W, Reiser PJ, Coss CC, Phelps MA, Kearbey JD, Miller DD, Dalton JT. Selective androgen receptor modulator treatment improves muscle strength and body composition and prevents bone loss in orchidectomized rats. Endocrinology. 2005;146:4887–4897.
 Srinath R, Dobs A. Enobosarm (GTx-024, S-22): a potential treatment for cachexia. Future Oncol. 2014;10:187–194.
 Kearbey JD, Gao W, Narayanan R, Fisher SJ, Wu D, Miller DD, Dalton JT. Selective Androgen Receptor Modulator (SARM) treatment prevents bone loss and reduces body fat in ovariectomized rats. Pharm Res. 2007;24:328–335.
 Crawford J, Prado CM, Johnston MA, Gralla RJ, Taylor RP, Hancock ML, Dalton JT. Study Design and Rationale for the Phase 3 Clinical Development Program of Enobosarm, a Selective Androgen Receptor Modulator, for the Prevention and Treatment of Muscle Wasting in Cancer Patients (POWER Trials) Curr Oncol Rep. 2016;18:37.
 Dobs AS, Boccia RV, Croot CC, Gabrail NY, Dalton JT, Hancock ML, Johnston MA, Steiner MS. Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial. Lancet Oncol. 2013;14:335–345.
 Dalton JT, Barnette KG, Bohl CE, Hancock ML, Rodriguez D, Dodson ST, Morton RA, Steiner MS. The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial. J Cachexia Sarcopenia Muscle. 2011;2:153–161.
 Edwards JP, West SJ, Pooley CL, Marschke KB, Farmer LJ, Jones TK. New nonsteroidal androgen receptor modulators based on 4-(trifluoromethyl)-2(1H)-pyrrolidino quinolinone. Bioorg Med Chem Lett. 1998;8:745–750.
Higuchi RI, Edwards JP, Caferro TR, Ringgenberg JD, Kong JW, Hamann LG, Arienti KL, Marschke KB, Davis RL, Farmer LJ, Jones TK. 4-Alkyl- and 3,4-dialkyl-1,2,3,4-tetrahydro-8-pyridonoquinolines: potent, nonsteroidal androgen receptor agonists. Bioorg Med Chem Lett. 1999;9:1335–1340
Miner JN, Chang W, Chapman MS, Finn PD, Hong MH, Lopez FJ, Marschke KB, Rosen J, Schrader W, Turner R, van Oeveren A, Viveros H, Zhi L, Negro-Vilar A. An orally active selective androgen receptor modulator is efficacious on bone, muscle, and sex function with reduced impact on prostate. Endocrinology. 2007;148:363–373.
 Schmidt A, Kimmel DB, Bai C, Scafonas A, Rutledge S, Vogel RL, McElwee-Witmer S, Chen F, Nantermet PV, Kasparcova V, Leu CT, Zhang HZ, Duggan ME, Gentile MA, Hodor P, Pennypacker B, Masarachia P, Opas EE, Adamski SA, Cusick TE, Wang J, Mitchell HJ, Kim Y, Prueksaritanont T, Perkins JJ, Meissner RS, Hartman GD, Freedman LP, Harada S, Ray WJ. Discovery of the selective androgen receptor modulator MK-0773 using a rational development strategy based on differential transcriptional requirements for androgenic anabolism versus reproductive physiology. J Biol Chem. 2010;285:17054–17064.
 Smith CL, O’Malley BW. Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev. 2004;25:45–71.
 Smith CL, Nawaz Z, O’Malley BW. Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen. Mol Endocrinol. 1997;11:657–666
Madeira M, Mattar A, Logullo AF, Soares FA, Gebrim LH. Estrogen receptor alpha/beta ratio and estrogen receptor beta as predictors of endocrine therapy responsiveness-a randomized neoadjuvant trial comparison between anastrozole and tamoxifen for the treatment of postmenopausal breast cancer. BMC Cancer. 2013;13:425.
 Gao W, Dalton JT. Ockham’s Razor and Selective Androgen Receptor Modulators (SARMs): Are We Overlooking the Role of 5{alpha}-Reductase? Mol Interv. 2007;7:10–13.
 Blouin K, Richard C, Brochu G, Hould FS, Lebel S, Marceau S, Biron S, Luu-The V, Tchernof A. Androgen inactivation and steroid-converting enzyme expression in abdominal adipose tissue in men. J Endocrinol. 2006;191:637–649.
 Labrie F, Luu-The V, Lin SX, Labrie C, Simard J, Breton R, Belanger A. The key role of 17 beta-hydroxysteroid dehydrogenases in sex steroid biology. Steroids. 1997;62:148–158
Penning TM, Byrns MC. Steroid hormone transforming aldo-keto reductases and cancer. Ann N Y Acad Sci. 2009;1155:33–42
Chang CY, McDonnell DP. Androgen receptor-cofactor interactions as targets for new drug discovery. Trends Pharmacol Sci. 2005;26:225–228.
 Heinlein CA, Chang C. Androgen receptor (AR) coregulators: an overview. Endocr Rev. 2002;23:175–200.
Fujimoto N, Yeh S, Kang HY, Inui S, Chang HC, Mizokami A, Chang C. Cloning and characterization of androgen receptor coactivator, ARA55, in human prostate. J Biol Chem. 1999;274:8316–8321
Kang HY, Yeh S, Fujimoto N, Chang C. Cloning and characterization of human prostate coactivator ARA54, a novel protein that associates with the androgen receptor. J Biol Chem. 1999;274:8570–8576
Heery DM, Kalkhoven E, Hoare S, Parker MG. A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature. 1997;387:733–736.
 Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell. 1998;95:927–937.
 He B, Minges JT, Lee LW, Wilson EM. The FXXLF motif mediates androgen receptor-specific interactions with coregulators. J Biol Chem. 2002;277:10226–10235.
 Chang CY, McDonnell DP. Evaluation of ligand-dependent changes in AR structure using peptide probes. Mol Endocrinol. 2002;16:647–660.
 Chang C, Norris JD, Gron H, Paige LA, Hamilton PT, Kenan DJ, Fowlkes D, McDonnell DP. Dissection of the LXXLL nuclear receptor-coactivator interaction motif using combinatorial peptide libraries: discovery of peptide antagonists of estrogen receptors alpha and beta. Mol Cell Biol. 1999;19:8226–8239.
 Kazmin D, Prytkova T, Cook CE, Wolfinger R, Chu TM, Beratan D, Norris JD, Chang CY, McDonnell DP. Linking ligand-induced alterations in androgen receptor structure to differential gene expression: a first step in the rational design of selective androgen receptor modulators. Mol Endocrinol. 2006;20:1201–1217
Baek SH, Ohgi KA, Nelson CA, Welsbie D, Chen C, Sawyers CL, Rose DW, Rosenfeld MG. Ligand-specific allosteric regulation of coactivator functions of androgen receptor in prostate cancer cells. Proceedings of the National Academy of Sciences of the United States of America. 2006;103:3100–3105
Liu Z, Auboeuf D, Wong J, Chen JD, Tsai SY, Tsai MJ, O’Malley BW. Coactivator/corepressor ratios modulate PR-mediated transcription by the selective receptor modulator RU486. Proc Natl Acad Sci U S A. 2002;99:7940–7944
Feng Q, O’Malley BW. Nuclear receptor modulation–role of coregulators in selective estrogen receptor modulator (SERM) actions. Steroids. 2014;90:39–43.
 Narayanan R, Yepuru M, Szafran AT, Szwarc M, Bohl CE, Young NL, Miller DD, Mancini MA, Dalton JT. Discovery and mechanistic characterization of a novel selective nuclear androgen receptor exporter for the treatment of prostate cancer. Cancer Res. 2010;70:842–851.
 Guo D, Zhang H, Liu L, Wang L, Cheng Y, Qiao Z. Testosterone influenced the expression of Notch1, Notch2 and Jagged1 induced by lipopolysaccharide in macrophages. Exp Toxicol Pathol. 2004;56:173–179.
Kang HY, Cho CL, Huang KL, Wang JC, Hu YC, Lin HK, Chang C, Huang KE. Nongenomic androgen activation of phosphatidylinositol 3-kinase/Akt signaling pathway in MC3T3-E1 osteoblasts. J Bone Miner Res. 2004;19:1181–1190.
Liu L, Wang L, Zhao Y, Wang Y, Wang Z, Qiao Z. Testosterone attenuates p38 MAPK pathway during Leishmania donovani infection of macrophages. Parasitol Res. 2006;99:189–193.
Huber DM, Bendixen AC, Pathrose P, Srivastava S, Dienger KM, Shevde NK, Pike JW. Androgens suppress osteoclast formation induced by RANKL and macrophage-colony stimulating factor. Endocrinology. 2001;142:3800–3808.
Dehm SM, Tindall DJ. Ligand-independent androgen receptor activity is activation function-2-independent and resistant to antiandrogens in androgen refractory prostate cancer cells. J Biol Chem. 2006;281:27882–27893. [
Kousteni S, Bellido T, Plotkin LI, O’Brien CA, Bodenner DL, Han L, Han K, DiGregorio GB, Katzenellenbogen JA, Katzenellenbogen BS, Roberson PK, Weinstein RS, Jilka RL, Manolagas SC. Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell. 2001;104:719–730.
Lutz LB, Jamnongjit M, Yang WH, Jahani D, Gill A, Hammes SR. Selective modulation of genomic and nongenomic androgen responses by androgen receptor ligands. Mol Endocrinol. 2003;17:1106–1116.
 Lutz LB, Cole LM, Gupta MK, Kwist KW, Auchus RJ, Hammes SR. Evidence that androgens are the primary steroids produced by Xenopus laevis ovaries and may signal through the classical androgen receptor to promote oocyte maturation. Proc Natl Acad Sci U S A. 2001;98:13728–13733.
Lutz LB, Kim B, Jahani D, Hammes SR. G protein beta gamma subunits inhibit nongenomic progesterone-induced signaling and maturation in Xenopus laevis oocytes. Evidence for a release of inhibition mechanism for cell cycle progression. J Biol Chem. 2000;275:41512–41520.
Narayanan R, Coss CC, Yepuru M, Kearbey JD, Miller DD, Dalton JT. Steroidal androgens and nonsteroidal, tissue-selective androgen receptor modulator, S-22, regulate androgen receptor function through distinct genomic and nongenomic signaling pathways. Mol Endocrinol. 2008;22:2448–2465.
Carmeli E, Coleman R, Reznick AZ. The biochemistry of aging muscle. Exp Gerontol. 2002;37:477–480
Bosy-Westphal A, Eichhorn C, Kutzner D, Illner K, Heller M, Muller MJ. The age-related decline in resting energy expenditure in humans is due to the loss of fat-free mass and to alterations in its metabolically active components. J Nutr. 2003;133:2356–2362.
Muhlberg W, Sieber C. Sarcopenia and frailty in geriatric patients: implications for training and prevention. Z Gerontol Geriatr. 2004;37:2–8.
Wallengren O, Iresjo BM, Lundholm K, Bosaeus I. Loss of muscle mass in the end of life in patients with advanced cancer. Support Care Cancer. 2015;23:79–86.  Liu J, Motoyama S, Sato Y, Wakita A, Kawakita Y, Saito H, Minamiya Y. Decreased Skeletal Muscle Mass After Neoadjuvant Therapy Correlates with Poor Prognosis in Patients with Esophageal Cancer. Anticancer Res. 2016;36:6677–6685.
Chu MP, Lieffers J, Ghosh S, Belch A, Chua NS, Fontaine A, Sangha R, Turner RA, Baracos VE, Sawyer MB. Skeletal muscle density is an independent predictor of diffuse large B-cell lymphoma outcomes treated with rituximab-based chemoimmunotherapy. J Cachexia Sarcopenia Muscle. 2016
van Lierop MJ, Alkema W, Laskewitz AJ, Dijkema R, van der Maaden HM, Smit MJ, Plate R, Conti PG, Jans CG, Timmers CM, van Boeckel CA, Lusher SJ, McGuire R, van Schaik RC, de Vlieg J, Smeets RL, Hofstra CL, Boots AM, van Duin M, Ingelse BA, Schoonen WG, Grefhorst A, van Dijk TH, Kuipers F, Dokter WH. Org 214007-0: a novel non-steroidal selective glucocorticoid receptor modulator with full anti-inflammatory properties and improved therapeutic index. PLoS One. 2012;7:e48385.
Jones A, Hwang DJ, Narayanan R, Miller DD, Dalton JT. Effects of a novel selective androgen receptor modulator on dexamethasone-induced and hypogonadism-induced muscle atrophy. Endocrinology. 2010;151:3706–3719
Emery AE. Population frequencies of inherited neuromuscular diseases–a world survey. Neuromuscul Disord. 1991;1:19–29.
Rahimov F, Kunkel LM. The cell biology of disease: cellular and molecular mechanisms underlying muscular dystrophy. J Cell Biol. 2013;201:499–510.
Frankel KA, Rosser RJ. The pathology of the heart in progressive muscular dystrophy: epimyocardial fibrosis. Hum Pathol. 1976;7:375–386.
Politano L, Nigro V, Nigro G, Petretta VR, Passamano L, Papparella S, Di Somma S, Comi LI. Development of cardiomyopathy in female carriers of Duchenne and Becker muscular dystrophies. JAMA. 1996;275:1335–1338.
Lim KR, Maruyama R, Yokota T. Eteplirsen in the treatment of Duchenne muscular dystrophy. Drug Des Devel Ther. 2017;11:533–545.
 Cozzoli A, Capogrosso RF, Sblendorio VT, Dinardo MM, Jagerschmidt C, Namour F, Camerino GM, De Luca A. GLPG0492, a novel selective androgen receptor modulator, improves muscle performance in the exercised-mdx mouse model of muscular dystrophy. Pharmacol Res. 2013;72:9–24.
 Ponnusamy S, Sullivan RD, Thiyagarajan T, Tillmann H, Getzenberg RH, Narayanan R. Tissue Selective Androgen Receptor Modulators (SARMs) Increase Pelvic Floor Muscle Mass in Ovariectomized Mice. J Cell Biochem. 2016
Mohler ML, Nair VA, Hwang DJ, Rakov IM, Patil R, Miller DD. Nonsteroidal Tissue Selective Androgen Receptor Modulators: A Promising Class of Clinical Candidates. Expert Opinion in Therapeutic Patents. 2005;15(11):1565–1585.
Hanada K, Furuya K, Yamamoto N, Nejishima H, Ichikawa K, Nakamura T, Miyakawa M, Amano S, Sumita Y, Oguro N. Bone anabolic effects of S-40503, a novel nonsteroidal selective androgen receptor modulator (SARM), in rat models of osteoporosis. Biol Pharm Bull. 2003;26:1563–1569.
 Hamann LG. Discovery and Preclinical Profile of a Highly Potent and Muscle Selective Androgen Receptor Modulator (SARM). Abstract MEDI 11 from the 227th National American Chemical Society Meeting; Anaheim, CA. March 2004.
 Mason RA, Morris HA. Effects of dihydrotestosterone on bone biochemical markers in sham and oophorectomized rats. J Bone Miner Res. 1997;12:1431–1437.
Coss CC, Jones A, Dalton JT. Selective androgen receptor modulators as improved androgen therapy for advanced breast cancer. Steroids. 2014;90:94–100.
GTx Reports Results from Ongoing Enobosarm Phase 2 Clinical Trial in ER+/AR+ Breast Cancer. 2016
Schwartzberg LS, Yardley D, Elias A, Patel M, LoRusso PM, Burris HA, Gucalp A, Peterson A, Blaney M, Steinberg J, Gibbons J, Traina TA. A Phase I/Ib Study of Enzalutamide Alone and in Combination with Endocrine Therapies in Women with Advanced Breast Cancer. Clin Cancer Res. 2017
Narayanan R, Dalton JT. Androgen Receptor: A Complex Therapeutic Target for Breast Cancer. Cancers (Basel) 2016:8. [
Temel JS, Abernethy AP, Currow DC, Friend J, Duus EM, Yan Y, Fearon KC. Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials. Lancet Oncol. 2016;17:519–531.
Fearon K, Argiles JM, Baracos VE, Bernabei R, Coats A, Crawford J, Deutz NE, Doehner W, Evans WJ, Ferrucci L, Garcia JM, Gralla RJ, Jatoi A, Kalantar-Zadeh K, Lainscak M, Morley JE, Muscaritoli M, Polkey MI, Rosano G, Rossi-Fanelli F, Schols AM, Strasser F, Vellas B, von Haehling S, Anker SD. Request for regulatory guidance for cancer cachexia intervention trials. J Cachexia Sarcopenia Muscle. 2015;6:272–274.
Mohler  ML, Bohl  CE, Jones  A, et al. . Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit. J Med Chem. 2009;52:3597–3617.
Dobs  AS, Boccia  RV, Croot  CC, et al. . Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial. Lancet Oncol. 2013;14:335–345.

Question 28

General Information

Accepted Answer

PEPTIDES

Peptides are essentially fragmented portions of proteins. So when they’re used in skincare, the objective is for those fragments of collagen to stimulate collagen growth. When used in cosmetic skin products, peptides fall into three main categories: signal peptides, carrier peptides, and those that inhibit nerve signals. By acting as messengers, signal peptides can trigger collagen synthesis, which then increases skin firmness.

By stimulating collagen production, peptides can give your skin the impression of being plumper. Peptides help to rebuild collagen and preserve skin’s youthful appearance. As you age, collagen production decreases, which also causes dehydration. When peptides help boost collagen production, it also boosts hydration.

When collagen breaks down, the peptides send a signal to our skin’s cells, informing them to make more collagen to replace what we lose naturally as we get older. With every year, collagen production decreases, which causes wrinkles, dehydration, discolouration, loss of firmness, and a dull complexion. Antioxidants found in peptides help calm and soothe your skin, leading to less inflammation. Carrier peptides work to heal your skin from the inside out.

PATHOPYSIOLOGY

The dermal-epidermal junction (DEJ) provides a physical and biological interface between the epidermis and the dermis. In addition to providing a structural integrity, the DEJ also acts as a passageway for molecular transport. Based on the recently reported importance of the DEJ in skin aging, novel peptide derivatives have been tested for their effects on basement membrane (BM) protein expressions in cultured human epidermal keratinocytes. As a result, protein expressions of collagen XVII, laminin and nidogen were stimulated by the test peptide and peptides complex. Further ex vivo evaluation using excised human skin, confirmed that the topical application of the peptides complex significantly increased dermal collagen expression, as well as expressions of collagen XVII and laminin. Interestingly, while the origin of the laminin protein is epidermal keratinocytes, the immunohistochemical staining of skin showed that laminin was only detected in the uppermost layer of the dermis, which suggests a tight assembly of laminin protein onto the dermal side of the DEJ. These results suggest that a peptide complex could improve the structural properties of the DEJ through its ability to stimulate BM proteins. In order to evaluate the anti-wrinkle benefits of the peptide complex in vivo, a clinical study was performed on 22 healthy Asian female volunteers older than 40 years. As a result, significant improvements in skin wrinkles for all of the five sites were observed after two weeks, as assessed by skin topographic measurements. Collectively, these results demonstrate the anti-aging efficacy of the peptides complex.

Tretinoin

Tretinoin, also known as all-trans-retinoic acid (ATRA), is a naturally occurring derivative of vitamin A. As vitamin A (retinol) derivatives, retinoids are important regulators of cell reproduction, and cell proliferation and differentiation; however, unlike vitamin A, retinoids are not converted into rhodopsin, which is needed for night vision. Topical tretinoin is indicated in the treatment of mild to moderate acne (e.g., grades I-III) and photodamaged skin. Topical tretinoin has also been used in the symptomatic management of keratinization disorders such as ichthyosis and keratosis follicularis. Tretinoin represents a new class of anticancer drugs, differentiating agents. Oral tretinoin is used in the treatment of acute promyelocytic leukemia (APL) and is undergoing phase III investigation in the treatment of Kaposi’s sarcoma. In the treatment of APL, tretinoin offers a less toxic means to induce complete remission than conventional chemotherapy; however, approximately 25% of patients who receive tretinoin for the treatment of APL have experienced acute promyelocytic leukemia differentiation syndrome.(1)

Niacinamide

Niacin (nicotinic acid or 3-pyridinecarboxylic acid) is a B-complex vitamin. Good dietary sources of niacin are animal proteins, beans, green vegetables, liver, mushrooms, peanuts, whole wheat, and unpolished rice. Niacin is also present in cereal grains but is largely bound to plant proteins, and thus is poorly absorbed after ingestion. Niacin is one of the substances used in the enrichment of refined flour, and our dietary intake of pre-formed niacin comes primarily from enriched grains. However, the body’s niacin requirement is also met by the biosynthesis of niacin from tryptophan, an amino acid. For example, milk and eggs do not contain niacin, but do contain large amounts of tryptophan from which niacin is derived. Each 60 mg of excess tryptophan (after protein synthesis) is converted to approximately 1 mg of niacin. Synthesis of the vitamin from tryptophan in proteins supplies roughly half the niacin requirement in man. Iron-deficiency or inadequate pyridoxine or riboflavin status will decrease the conversion of tryptophan to niacin and may contribute to deficiency, due to an interdependence of coenzymes in the niacin production pathway. A late and serious manifestation of niacin deficiency is pellagra, a clinical symptom complex principally affecting the GI tract, skin, and CNS, producing symptoms of diarrhea, dermatitis, and dementia, respectively. Pellagra may result from a niacin- and protein-deficient diet, isoniazid therapy, or certain diseases that result in poor utilization of tryptophan. Pellagra was the only vitamin-deficiency disease to ever reach epidemic proportions in the US; pellagra is rare today in industrialized countries due to the enrichment of refined flours.

Several synonyms for niacin and niacinamide exist. Synthetic niacin could be produced by the oxidation of nicotine, and the term ‘nicotinic acid’ evolved. Scientists also coined the terms ‘nicotinamide’ and ‘niacinamide’ for the amide form of nicotinic acid. The term ‘niacin’ has been used generically since the 1940’s to label foods and to avoid association of the vitamins with the nicotine alkaloid from tobacco. Thus the name ‘niacin’ has been used to denote both chemical forms, which are equivalent as vitamins on a weight basis. Both nicotinic acid and nicotinamide are synthesized for inclusion in nutritional supplements. However, since nicotinic acid and nicotinamide have different pharmacologic properties outside of their use as vitamins, it is important to distinguish between the two forms in pharmaceutical products.

In clinical medicine, nicotinic acid is used as an antilipemic, but nicotinamide (niacinamide) is not effective for this purpose. Nicotinic acid was the first hypolipidemic agent shown to decrease the incidence of secondary myocardial infarction (MI) and reduce total mortality in MI patients. However, no incremental benefit of coadministration of extended-release niacin with lovastatin or simvastatin on cardiovascular morbidity and mortality over and above that demonstrated for extended-release niacin, simvastatin, or lovastatin monotherapy has been established. In addition, the AIM-HIGH trial demonstrated that the concurrent use of extended-release niacin (1500—2000 mg/day PO) and simvastatin does not result in a greater reduction in the incidence of cardiovascular events than simvastatin alone.(2) These results are consistent with those of the larger HPS2-THRIVE trial in which the addition of extended-release niacin to effective statin-based therapy did not result in a greater reduction in the incidence of cardiovascular events. Furthermore, there was an increased risk of serious adverse events including an increased incidence of disturbances in diabetes control and diabetes diagnoses, as well as serious gastrointestinal, musculoskeletal, dermatological, infectious, and bleeding adverse events. There was also a statistically insignificant 9% proportional increase in the incidence of death from any cause in the niacin group.(3) The ARBITER 6-HALTS trial demonstrated that the addition of extended-release niacin 2000 mg/day to statins results in significant regression in atherosclerosis as measured by carotid intima-media thickness, and is superior to the combination of ezetimibe and a statin.(4) In an MRI study, the addition of extended-release niacin 2000 mg/day to statin therapy resulted in a significant reduction in carotid wall area compared to placebo.(5) However, the NIA Plaque study, which was presented at the American Heart Association (AHA) 2009 Scientific Sessions, did not find a significant reduction in the progression of atherosclerosis associated with the addition of niacin to statin therapy as compared to statin monotherapy. Additionally, nicotinic acid has been used as a therapy for tinnitus, but efficacy data are scant. Some sustained-release nicotinic acid formulations have a lower incidence of flushing but a higher incidence of hepatotoxicity when compared to immediate-release forms.(6) Some dosage forms are available without prescription. The FDA officially approved niacin in 1938.

Vitamin E Acetate

Vitamin E is a fat-soluble vitamin found in many foods including vegetable oils, wheat germ, cereal grains, fruits, green vegetables, meat, eggs, and certain types of fish. The term ‘vitamin E’ actually represents a group of 8 different tocopherols, lipid-soluble compounds that are synthesized by plants and required by most animals, including humans. Of these, d-alpha-tocopherol is the naturally occurring form with the greatest vitamin activity. The synthetic form is dl-alpha-tocopherol. Commercial vitamin E preparations are formulated primarily from synthetic dl-alpha-tocopheryl acetate. This acetate ester confers stability to the compound but is less active than the natural form. Vitamin E deficiency is rare given the amounts found in normal dietary foods. Supplementation may be required in patients who suffer from malabsorptive disorders such as fat malabsorption syndrome, cystic fibrosis, chronic bowel disease (e.g., Crohn’s, Celiac, and Whipple’s disease), or who have undergone certain gastrointestinal surgeries (e.g., gastrectomy or gastric bypass). In children, the use of vitamin E is primarily in the form of supplementation to maintain adequate intakes to prevent deficiency.(7) Pure vitamin E was first isolated from wheat germ oil in 1936, and its chemical structure was defined and synthesis achieved in 1938. The first time vitamin E was recognized by the Food and Nutrition Board of the National Research Council was in 1968. Systemic vitamin E was approved by the FDA in 1941. In addition to oral vitamin E formulations used for supplementation, several topical formulations of vitamin E are also available. Topical vitamin E formulations have been used off-label with claims of protective antioxidant effects against photoaging. The FDA has not evaluated these claims, and the ability of topical Vitamin E products to aid in the healing of minor burns and sunburns has not been substantiated.

Although early evidence had suggested the potential for vitamin E to reduce cardiovascular disease (CVD),(8)(9)(10)(11)(12) more recent outcome studies have not shown benefits for vitamin E. The HOPE study has shown no effect of vitamin E on cardiac outcomes in high-risk patients with diabetes or vascular disease.(13) The Women’s Health Study (WHS), a study of approximately 40 thousand women receiving a daily dose of 400 mg (600 International Units), has shown no overall benefit for major cardiovascular events.(14) The American Heart Association guidelines do not recommend vitamin E therapy for women as a preventative measure for CVD.(15) As for males, results of the SU.VI.MAX study, which included a total of 13,017 subjects (including 5,141 men aged 45 to 60 years) followed for 7.5 years, has reported that supplementation with a multivitamin (containing 30 mg of vitamin E) did not reduce the incidence of ischemic CVD incidence in men.(16)

The results of studies addressing the off-label use of vitamin E in cancer have been inconsistent and inconclusive. Results of the HOPE-TOO trial showed that vitamin E supplementation does not prevent cancer, including prostate cancer. High-risk patients (e.g., diabetes, vascular disease) enrolled in this trial were administered a dose of 268 mg (400 International Units) daily and were followed for a median of 7 years.(17) A post-interventional followup of the ATBC Study reported that the initial beneficial effects of alpha-tocopherol disappeared during postinterventional followup.(18) Some studies have reported the potential benefits of vitamin E supplementation for prostate cancer. A cohort study suggested an inverse association between supplemental vitamin E use and the risk of metastatic or fatal prostate cancer among current smokers or smokers who stopped smoking.(19) In the SU.VI.MAX study, vitamin E (30 mg) provided protection in men but not women, resulting in a significant reduction in total cancer incidence.(16) In this trial, researchers concluded that supplementation may be effective in men due to lower baseline levels of antioxidants. A prior controlled clinical trial reported a 32% decrease in the incidence of prostate cancer among subjects receiving alpha-tocopherol compared to those not receiving alpha-tocopherol.(20) The reduction was seen for clinical prostate cancer, but not for latent cancer. In this study, alpha-tocopherol and beta-carotene supplementation were given either separately or together, to 29,133 prostate cancer patients who were smokers for 5-8 years. In contrast, in the Selenium and Vitamin E Cancer Prevention Trial (SELECT), which was a long-term, multi-center, placebo-controlled trial, more than 35,000 men 50 years of age and older were randomized to receive either selenium 200 mcg and vitamin E 400 mg, selenium and placebo, vitamin E and placebo, or placebo. The trial was stopped after about 7 years when interim results found that neither drug prevented prostate cancer. Further, 2 preliminary trends of vitamin E slightly increasing the risk of prostate cancer and selenium slightly increasing the risk of diabetes were found. Follow-up data collection is ongoing.(21)

Question 29

Mechanism of Action

Accepted Answer

Tretinoin 

Retinoids are intracrine and paracrine mediators of cell differentiation and proliferation, apoptosis (programmed cell death), and reproduction. Cells regulate the formation of specific retinoid isomers depending upon the cellular action required. The numerous effects of retinoids reflect the complex biology of the nuclear receptors that mediate retinoid activity. Retinoid receptors are divided into retinoid X receptors (RXRs) and retinoic acid receptors (RARs); both types can be further divided into 3 subtypes: Alpha, beta, and gamma. These receptor subtypes are further divided into many isoforms. Retinoid receptors are structurally similar but have different affinities for different types of retinoids and distribution varies throughout the body resulting in a wide range of actions. Tretinoin binds to all three RARs, but does not bind to RXRs except at very high concentrations. RAR-alpha and RAR-beta have been associated with the development of acute promyelocytic leukemia and squamous cell cancers, respectively. RAR-gamma is associated with retinoid effects on mucocutaneous tissues and bone.

•Skin Disorders: By binding to RARs, tretinoin modifies gene expression, subsequent protein synthesis, and epithelial cell growth and differentiation. It has not been established whether the clinical effects of tretinoin are mediated through activation of RARs, other mechanisms such as irritation, or both. Tretinoin appears to prevent horny cell cohesion and to increase epidermal cell turnover and mitotic activity. Subsequently, in patients with acne, expulsion of existing comedones occurs, and formation of new comedones is prevented through sloughing and expulsion of horny cells from the follicle. Tretinoin reduces the cell layers of the stratum corneum. The bacterium involved in acne, Propionibacterium acnes, and sebum production are unaffected. An additional action of tretinoin may involve keratinization inhibition, which would explain its effectiveness in treating keratinization disorders.

•Photodamage: Topical tretinoin is effective in reducing fine wrinkling, mottled hyperpigmentation, roughness, and laxity associated with photodamaged skin. Ultraviolet irradiation induces three metalloproteinases in human skin: collagenase, 92-kd gelatinase, and stromelysin-1. The combined actions of these enzymes can fully degrade skin collagen. Pretreatment of skin with tretinoin inhibits the induction of these skin matrix metalloproteinase proteins and activity by 70—80% in both connective tissue and outer layers of irradiated skin.(22)

•Acute Promyelocytic Leukemia: Similar to other retinoids, tretinoin induces cellular differentiation in malignant cells. Acute promyelocytic leukemia (APL) is caused by a genetic lesion that disrupts the alpha retinoic acid receptor (RAR-alpha) gene found on the long arm of chromosome 17 and the PML gene found on chromosome 15. The fusion protein that is formed, PML-RAR-alpha, inhibits apoptotic pathways and blocks myeloid differentiation when present in levels greater than those of the normal RAR-alpha protein. The presence of this gene translocation  is used for diagnosis of APL and as a marker of response following treatment with either cytotoxic agents or tretinoin. During tretinoin treatment, cells expressing PML/RAR-alpha undergo cellular differentiation at a rate higher than normal cells. At therapeutic doses of tretinoin, the activity of the fusion protein on differentiation converts from inhibitory to stimulatory. Terminal differentiation of APL cells as the mechanism of tretinoin therapy is supported by 1) the absence of bone marrow aplasia during treatment; 2) the appearance of cells during treatment with the morphologic characteristics of maturation stages intermediate between promyelocytes and neutrophils; 3) the presence, during treatment, of PML and RAR-alpha rearrangements in peripheral blood neutrophils that disappear after treatment.(23) Treatment with tretinoin reverses the bleeding diathesis seen in APL, before any morphologic response is noted. A retinoic acid syndrome, similar to capillary leak syndrome, may be seen in some patients (see Adverse Reactions). The etiology of this syndrome is unknown, but may be due to decreases in leukocyte adhesion protein activity. Resistance to tretinoin may develop due to pharmacokinetic reasons (decreased bioavailability) and/or changes in proteins involved in the cellular activity of tretinoin.

Niacinamide 

Dietary requirements for niacin can be met by the ingestion of either nicotinic acid or nicotinamide; as vitamins, both have identical biochemical functions. As pharmacologic agents, however, they differ markedly. Nicotinic acid is not directly converted into nicotinamide by the body; nicotinamide is only formed as a result of coenzyme metabolism. Nicotinic acid is incorporated into a coenzyme known as nicotinamide adenine dinucleotide (NAD) in erythrocytes and other tissues. A second coenzyme, nicotinamide adenine dinucleotide phosphate (NADP), is synthesized from NAD. These two coenzymes function in at least 200 different redox reactions in cellular metabolic pathways. Nicotinamide is released from NAD by hydrolysis in the liver and intestines and is transported to other tissues; these tissues use nicotinamide to produce more NAD as needed. Together with riboflavin and other micronutrients, the NAD and NADP coenzymes work to convert fats and proteins to glucose and assist in the oxidation of glucose.

In addition to its role as a vitamin, niacin (nicotinic acid) has other dose-related pharmacologic properties. Nicotinic acid, when used for therapeutic purposes, acts on the peripheral circulation, producing dilation of cutaneous blood vessels and increasing blood flow, mainly in the face, neck, and chest. This action produces the characteristic “niacin-flush”. Nicotinic acid-induced vasodilation may be related to release of histamine and/or prostacyclin. Histamine secretion can increase gastric motility and acid secretion. Flushing may result in concurrent pruritus, headaches, or pain. The flushing effects of nicotinic acid appear to be related to the 3-carboxyl radical on its pyridine ring. Nicotinamide (niacinamide), in contrast to nicotinic acid, does not contain a carboxyl radical in the 3 position on the pyridine ring and does not appear to produce flushing.

Nicotinic acid may be used as an antilipemic agent, but nicotinamide does not exhibit hypolipidemic activity. Niacin reduces total serum cholesterol, LDL, VLDL, and triglycerides, and increases HDL cholesterol. The mechanism of nicotinic acid’s antilipemic effect is unknown but is unrelated to its biochemical role as a vitamin. One of nicotinic acid’s primary actions is decreased hepatic synthesis of VLDL. Several mechanisms have been proposed, including inhibition of free fatty acid release from adipose tissue, increased lipoprotein lipase activity, decreased triglyceride synthesis, decreased VLDL-triglyceride transport, and an inhibition of lipolysis. This last mechanism may be due to niacin’s inhibitory action on lipolytic hormones. Nicotinic acid possibly reduces LDL secondary to decreased VLDL production or enhanced hepatic clearance of LDL precursors. Nicotinic acid elevates total HDL by an unknown mechanism, but is associated with an increase in serum levels of Apo A-I and lipoprotein A-I, and a decrease in serum levels of Apo-B. Nicotinic acid is effective at elevating HDL even in patients whose only lipid abnormality is a low-HDL value. Niacin does not appear to affect the fecal excretion of fats, sterols, or bile acids. Clinical trial data suggest that women have a greater hypolipidemic response to niacin therapy than men at equivalent doses.

Vitamin E Acetate  

Vitamin E (alpha-tocopherol) is a lipid soluble vitamin with actions related to its antioxidant properties. Vitamin E can be found naturally in cellular membranes where it plays an important role in the suppression of free radical-induced lipid peroxidation. A free radical is an oxygen molecule which roams the body in search of an electron, sometimes damaging healthy tissue in a process called oxidation. Free radicals are known to initiate peroxidative chain reactions of unsaturated cell membrane lipids. This reaction between the membrane-bound lipid and free radicals disrupts cell membrane integrity. As a free radical scavenger, vitamin E protects membrane-bound polyunsaturated fatty acids and other oxygen-sensitive substances from oxidation. Vitamin E is hypothesized to reduce atherosclerosis and subsequent cardiovascular disease (CVD) by preventing oxidative changes to low-density lipoproteins (LDL). Oxidized LDL particles are taken up more readily by macrophages than by native LDLs, which leads to the formation of cholesterol-laden foam cells found in fatty streak or early atherosclerosis. Alpha tocopherol is the predominant lipophilic antioxidant for LDL. Antioxidants protect LDL from oxidative modification and therefore may contribute to the reduction of CVD. Although the clinical benefits of vitamin E supplementation were demonstrated in patients with documented CVD in early studies, more recent trials including the Heart Outcomes Prevention Evaluation and the Women’s Health Study failed to confirm the efficacy of vitamin E in reducing CVD.(24)(25)(26)(27)

Oxidative injury has also been implicated in cancer; many carcinogens create free radicals that damage DNA and other cellular structures, initiating and promoting tumor development.(28) Therefore, it is attractive to consider vitamin E as an agent to inhibit the development of neoplasms. Alpha tocopherol may prevent cancer by inhibiting proliferation and angiogeneses, inducing apoptosis, and enhancing immune function. Unfortunately, human trials that have evaluated the association between vitamin E intake and the incidence of cancer have been generally inconclusive. Contrary to earlier findings, recent trials have shown a lack of benefit after prolonged periods of treatment and observation.(29)(30)

Although vitamin E is most commonly noted for its antioxidant activity, vitamin E may also act through several other mechanisms including immunomodulation and antiplatelet effects. Vitamin E appears to enhance lymphocyte proliferation, decrease production of immunosuppressive prostaglandins E2, and decrease levels of immunosuppressive serum lipid peroxides. The antiplatelet effects of Vitamin E have been confirmed repeatedly during in vitro studies; however, the antiplatelet effects have not been consistently demonstrated during in vivo studies. One study reports that alpha-tocopherol markedly reduces the sensitivity of platelets to activation in normal subjects when administered at daily doses of 267 to 800 mg (400 to 1,200 International Units) for 2 weeks. This effect is related to inhibition of protein kinase C stimulation as opposed to the vitamin’s antioxidant properties.(31) Finally, vitamin E may decrease the incidence of red blood cell hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.

The purported mechanisms of topically applied vitamin E involve antioxidant effects and purported effects against photoaging; the FDA has not evaluated these claims, and the ability of topical vitamin E products to aid in the healing of minor burns and sunburns has not been substantiated. Vitamin E is found in the skin and increases from childhood to maturity and then decreases significantly in old age. Vitamin E and coenzyme Q10 have been found to synergistically inhibit the ultraviolet (UV) deletion of squalene, cholesterol, and unsaturated fatty acids in skin surface lipids.(32) Topically applied vitamin E may result in antioxidant effects in the skin. Vitamin E absorbs UV light in the region of the solar spectrum, which is responsible for sun-induced effects on the skin. In animal models, vitamin E has been shown to prevent oxidative stress and cutaneous and systemic immunosuppression caused by UV light.(33) In addition, in animal models, topical vitamin E application has been shown to decrease the incidence of UV-induced skin cancer.

Question 30

Pharmacokinetics

Accepted Answer

Tretinoin 

Systemic tretinoin is greater than 95% bound to plasma proteins, primarily albumin. The distribution of tretinoin has not been determined. Tretinoin is metabolized by the cytochrome P450 hepatic enzyme system. The metabolites include 13-cis retinoic acid, 4-oxo trans retinoic acid, 4-oxo cis retinoic acid, and 4-oxo trans retinoic acid glucuronide. Tretinoin appears to induce its own metabolism. An approximately 10-fold increase in the urinary excretion of 4-oxo trans retinoic acid glucuronide is observed after 2—6 weeks of continuous dosing when compared with baseline.

Topical Route: Following topical application, a minimal amount of drug is absorbed systemically. There is no expected difference in the systemic absorption of tretinoin from the microsphere formulation. Prolonged treatment or application to large body surface areas can enhance systemic absorption.

Niacinamide 

Nicotinic acid may be administered by the oral or parenteral routes. Nicotinamide is administered orally. Niacin is widely distributed throughout the body and it concentrates in the liver, spleen, and adipose tissue. Niacin undergoes rapid and extensive first-pass metabolism that is dose-rate specific and, at the doses used to treat dyslipidemia, saturable. Niacin is conjugated with glycine to form nicotinuric acid (NUA), which is then excreted in the urine. Some reversible metabolism from NUA back to niacin may occur in small amounts. The other pathway results in the formation of NAD. Nicotinamide is most likely released after the formation of NAD. Nicotinamide does not have hypolipidemic activity, and is further metabolized in the liver to produce N-methylnicotinamide (MNA) and nicotinamide-N-oxide (NNO). MNA is metabolized to two other N-methylated compounds known as 2PY and 4PY, which are excreted in the urine. The formation of 2PY predominates over 4PY in humans. Roughly 12% of nicotinic acid is excreted unchanged in the urine with normal dosages. Greater proportions of niacin are renally excreted unchanged as dosages exceed 1000 mg/day and metabolic pathways become saturated.

Vitamin E Acetate  

Vitamin E is usually administered orally but may be given parenterally as part of a multivitamin injection in parenteral nutrition. Topical products are also available. Absorption of vitamin E from the GI tract is dependent upon biliary and pancreatic secretions, micelle formation and uptake into enterocytes and chylomicron secretion.(7) Systemically absorbed Vitamin E is bound to plasma beta-lipoproteins and is widely distributed, particularly in fat tissues. Vitamin E also crosses the placenta and is distributed to breast milk. Total body stores in adults are estimated to be 3 to 8 grams, which appear adequate for greater than 4 years of a vitamin E-deficient diet. The plasma half-life of alpha-tocopherol is 48 to 60 hours, while the synthetic form has a half-life of 15 hours. Alpha-tocopherol undergoes recirculation from the liver to the plasma and this recirculation plays a role in its long half-life. The liver-plasma recirculation is dependent upon alpha-tocopherol transfer protein (alpha-TTP) and results in almost the daily replacement of nearly the entire circulating alpha-tocopherol pool.(34) The different forms of vitamin E have differing affinities for alpha-TTP, which leads to the differing serum concentrations. Due to its low absorption from the intestine, the major route of elimination of vitamin E is fecal elimination. Excess alpha-tocopherol and other forms of vitamin E are probably excreted unchanged in the bile. Small amounts of other vitamin E metabolites are eliminated in the urine.(7)

Following topical application of vitamin E, vitamin E is substantially absorbed in the skin, with no evidence of conversion within the skin to free alpha-tocopherol. In one study, there was no evidence of systemic availability or biotransformation of topically applied alpha-tocopherol acetate.(35)

Question 31

Contraindications/Precautions

Accepted Answer

Tretinoin 

Tretinoin is contraindicated in patients who experience retinoid hypersensitivity reactions to vitamin A or other retinoids because cross-sensitivity between agents is possible. True contact allergy to tretinoin is rare.

The Atralin brand of tretinoin gel and Altreno brand of tretinoin lotion contain soluble fish proteins and should be used with caution in patients with known fish hypersensitivity. Patients should be instructed to contact their health care provider if they develop pruritus or urticaria following application.(36)

Approximately 25% of patients who receive tretinoin for the treatment of acute promyelocytic leukemia have experienced acute promyelocytic leukemia differentiation syndrome. When seen in association with the use of tretinoin, this syndrome is also known as retinoic acid-acute promyelocytic leukemia (RA-APL) syndrome (see Adverse Reactions for more detailed description of RA-APL syndrome). Patients must be carefully monitored for any signs or symptoms of this syndrome.

In the treatment of acute promyelocytic leukemia, approximately 40% of patients will develop rapidly evolving leukocytosis, and these patients have a higher risk of life-threatening complications. High initial leukocyte counts or rapidly increasing leukocyte counts during treatment may be predictive of retinoic acid-acute promyelocytic leukemia (RA-APL) syndrome (see Adverse Reactions). However, RA-APL syndrome has been observed with or without concomitant leukocytosis. The manufacturer recommends the immediate initiation of high-dose steroids if signs and symptoms of RA-APL are present together with leukocytosis. Some clinicians routinely add chemotherapy to oral tretinoin therapy when patients present with a WBC count > 5000/mm3 or in the case of a rapid increase in WBC count in leukopenic patients at the start of treatment. Consideration could be given to adding chemotherapy (usually cytarabine and an anthracycline, if not contraindicated) to tretinoin therapy on day 1 or 2 for patients presenting with a WBC count > 5000/mm3 or immediately, for patients presenting with a WBC count of = 6000/mm3 by day 5, >= 10,000/mm3 by day 10, or >= 15,000/mm3 by day 28. The majority of patients do not require discontinuation of tretinoin therapy during RA-APL syndrome.

Retinoids may cause photosensitivity.(37) Treatment with topical tretinoin should be postponed until sunburn has resolved to avoid exacerbation of the irritation, inflammation, and dryness associated with sunburned skin. Patients with a skin photosensitivity disorder should be closely evaluated prior to receiving tretinoin therapy. If sun exposure cannot be avoided during topical tretinoin therapy, sunscreen products and physical sun blocks (protective clothing, hats) are recommended for protection of treated areas. Sunlight (UV) exposure potentiates the inflammatory effects of tretinoin. Patients who may have considerable sun exposure due to their occupation and those patients with inherent sensitivity to sunlight should exercise particular caution when using topical tretinoin. Weather extremes, such as wind or cold, also may be irritating to patients receiving tretinoin.

Topical tretinoin should be avoided, if possible, in patients with eczema because severe irritation of eczematous skin is likely.

With the exception of the 0.05% lotion (approved for use in children 9 years and older) and 0.05% gel (approved for use in children 10 years and older) formulations, safety and efficacy of topical tretinoin have not been established in neonates, infants and children under 12 years of age. Children are prone to developing severe headache and pseudotumor cerebri while receiving oral tretinoin. For relief, some patients may require treatment with analgesics or lumbar puncture. The safety and efficacy of oral tretinoin in infants have not been established.(36)

Tretinoin cream, gel, lotion, and liquid are for external use only. Avoid ocular exposure, including eyelids, and contact with the mouth, angles of the nose, and mucous membranes. If eye contact occurs, rinse thoroughly with large amounts of water. Apply only to affected areas; accidental exposure to unaffected skin may cause irritation. Topical tretinoin is flammable; do not use near heat, open flame, or while smoking.(36)

Niacinamide 

Patients who have a known hypersensitivity to niacin or any product component should not be given the drug.

While steady state plasma concentrations of niacin are generally higher in women than in men, the absorption, metabolism, and excretion of niacin appears to be similar in both genders. Women have been reported to have greater response to the lipid-lowering effects of nicotinic acid (niacin) when compared to men.

No overall differences in safety and efficacy were observed between geriatric and younger individuals receiving niacin. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity for some older individuals cannot be ruled out.

Niacin is contraindicated in patients who have significant or unexplained hepatic disease. Patients who consume large quantities of ethanol (alcoholism), who have risk factors for hepatic disease, or who have a past-history of gallbladder disease, jaundice, or hepatic dysfunction may receive niacin with close clinical observation. Elevations in liver function tests (LFTs) appear to be dose-related. Some sustained-release nicotinic acid (niacin) formulations have a higher incidence of hepatotoxicity when compared to immediate-release dosage forms. Extended-release nicotinic acid preparations (e.g., Niaspan, Slo-Niacin) should not be substituted for equivalent dosages of immediate-release (crystalline) niacin (e.g., Niacor and others). Follow the manufacturer-recommended initial dosage titration schedules for extended-release products, regardless of previous therapy with other niacin formulations. Monitor LFTs in all patients during therapy at roughly 6-month intervals or when clinically indicated. If transaminase levels (i.e., ALT or AST) rise to 3 times the upper limit of normal, or clinical symptoms of hepatic dysfunction are present, niacin should be discontinued.

Nicotinic acid (niacin) can stimulate histamine release, which, in turn, can stimulate gastric acid output. Niacin is contraindicated in patients with active peptic ulcer disease (PUD) because it can exacerbate PUD symptoms. Use niacin with caution in patients with a past history of peptic ulcer disease or in those on maintenance therapy to prevent PUD recurrence.

Due to its vasodilatory action, nicotinic acid (niacin) should be used with caution in those patients with uncorrected hypotension (or predisposition to orthostatic hypotension), acute myocardial infarction, or unstable angina, particularly when vasodilator medications such as nitrates, calcium channel blockers, or adrenergic blocking agents are coadministered (see Drug Interactions). Because the vasodilatory response to niacin may be more dramatic at the initiation of treatment, activities requiring mental alertness (e.g., driving or operating machinery) should not be undertaken until the response to niacin is known.

Niacin, especially in high doses, can cause hyperuricemia. Niacin should be prescribed cautiously to patients with gout (or predisposed to gout). These individuals should be advised not to purchase OTC forms of niacin without the guidance of a physician.

Niacin, especially in high doses, can cause hypophosphatemia. Although the reductions in phosphorus levels are usually transient, clinicians should monitor serum phosphorus periodically in those at risk for this electrolyte imbalance.

Rare cases of rhabdomyolysis have been reported in patients taking lipid-altering dosages of nicotinic acid (niacin) and statin-type agents concurrently (see Drug Interactions). Patients undergoing combined therapy should be carefully monitored for muscle pain, tenderness, or weakness, particularly in the early months of treatment or during periods of upward dose titration of either drug. While periodic CPK and potassium determinations may be considered, there is no evidence that these tests will prevent the occurrence of severe myopathy. If rhabdomyolysis occurs, the offending therapies should be discontinued.

Niacin, especially in high doses, may cause hyperglycemia. Niacin should be prescribed cautiously to patients with diabetes mellitus. These individuals should be advised not to purchase OTC forms of niacin without the guidance of a physician. Niacin has also been reported to cause false-positive results in urine glucose tests that contain cupric sulfate solution (e.g., Benedict’s reagent, Clinitest).

Niacin therapy has been used safely in children for the treatment of nutritional niacin deficiency. However, the safety and effectiveness of nicotinic acid for the treatment of dyslipidemias have not been established in neonates, infants and children

Question 32

Pregnancy

Accepted Answer

Tretinoin 

Adequate and well-controlled trials have not been performed in humans, but increased spontaneous abortions and major human fetal abnormalities have occurred when pregnant women received other retinoids. There have been 30 case reports of temporally-associated, congenital malformations during 25 years of clinical use of Retin-A. The significance of these spontaneous reports in terms of risk to the fetus is not known. Avoid use of topical tretinoin over large areas of skin or for prolonged periods. The benefit-risk profile should be considered before prescribing. Reproductive risk should be discussed. There is a high risk of birth defects if oral tretinoin is administered during pregnancy. Females of childbearing potential must use two reliable forms of contraception simultaneously during oral tretinoin therapy and for one month following discontinuation of therapy, unless abstinence is the chosen method. Contraception requirements must be followed even when there is a history of infertility or menopause, unless a hysterectomy has been performed. Within one week of beginning tretinoin oral therapy, the patient should have a negative pregnancy test; if possible, treatment with tretinoin should be delayed until pregnancy testing results are known. Pregnancy testing and counseling should occur monthly during oral tretinoin therapy.(48)(49)(36)

Niacinamide  

Since niacin is an essential nutrient, one would expect it to be safe when administered during pregnancy at doses meeting the recommended daily allowance (RDA). Niacin is categorized as pregnancy category A under these conditions. However, when used in doses greater than the RDA for dyslipidemia, or when used parenterally for the treatment of pellagra, niacin is categorized as pregnancy category C. Most manufacturers recommend against the use of niacin in dosages greater than the RDA during pregnancy. The potential benefits of high-dose niacin therapy should be weighed against risks, since toxicological studies have not been performed.(2)

Vitamin E Acetate  

Oral supplementation of Vitamin E in amounts exceeding the RDA during pregnancy should be approached with caution. Vitamin E deficiency is rare and supplementation of vitamin E specifically during pregnancy is not necessary for females with normal fat absorption. Adverse effects have not been reported with the normal daily intake of vitamin E within the recommended dietary daily intakes for a pregnant female.(44) The use of vitamin E in excess of the recommended dietary allowance during normal pregnancy should be avoided unless, in the judgment of the physician, potential benefits in a specific, unique case outweigh the significant hazards involved.

Question 33

Breast-feeding

Accepted Answer

Tretinoin

According to the manufacturers, breast-feeding should be discontinued prior to receiving oral tretinoin and caution should be used with topical tretinoin.(50)(49) It is unknown whether oral or topical tretinoin is distributed into breast milk. Systemic absorption of tretinoin after topical application is low (49), and therefore it is unlikely that a significant amount of the drug is excreted into breast-milk. However, consideration for the use of an alternative topical agent (e.g., azelaic acid, benzoyl peroxide, clindamycin, erythromycin) may be appropriate for some patients. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Niacinamide  

According to a manufacturer of niacin (Niaspan), although no studies have been conducted in nursing mothers, excretion into human milk is expected. The manufacturer recommends the discontinuation of nursing or the drug due to serious adverse reactions that may occur in nursing infants from lipid-altering doses of nicotinic acid.(2) Niacin, in the form of niacinamide, is excreted in breast milk in proportion to maternal intake. Niacin supplementation is only needed in those lactating women who do not have adequate dietary intake. The Recommended Daily Allowance (RDA) of the National Academy of Science for niacin during lactation is 20 mg.(40) There are no safety data regarding the use of nicotinic acid in doses above the RDA during breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Vitamin E Acetate 

Vitamin E crosses the placenta and is distributed into breast milk. The amount of vitamin E that crosses the placenta appears to be less than the amount transferred to the infant via breast milk. Vitamin E concentrations in human colostrum range from 0.13 to 3.6 mg per 100 mL. The amounts in human milk range from 0.1 to 0.48 per 100 mL. Use of vitamin E within the recommended daily dietary intake for lactating women is generally recognized as safe. Oral supplementation of vitamin E during breast-feeding should be approached with caution. Vitamin E deficiency is rare, and supplementation of vitamin E specifically during lactation is not necessary for females with normal fat absorption. Topically applying vitamin E to the breasts should be avoided as it could theoretically expose the infant to additional oral vitamin E.(7)(45) Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Question 34

Adverse Reations/Side Effects

Accepted Answer

Tretinoin 

Skin changes can occur with both topical and oral tretinoin, but are more common with topical therapy. Almost all patients report a local inflammatory response, which is reversible following discontinuance of topical treatment. Almost all patients using topical tretinoin reported skin irritation such as peeling, xerosis (dry skin), burning, stinging, erythema, and pruritus. In 32% of all study patients, severe skin irritation led to temporary discontinuation of topical tretinoin 0.02% (about 7%), or led to use of a mild topical corticosteroid. About 7% of patients using tretinoin 0.02%, compared to less than 1% of the control patients, had sufficiently severe local irritation to warrant short-term use of mild topical corticosteroids to alleviate local irritation. About 4% of patients had to discontinue use of topical tretinoin because of adverse reactions. If severe erythema, edema, vesicle formation (e.g., vesicular rash), or crusting develops, topical tretinoin should be discontinued until skin integrity is restored. Therapy may be reinitiated with less frequent application or a lower concentration. Skin hyperpigmentation and skin hypopigmentation have been reported in about 2% of patients with topical tretinoin therapy, with resolution following discontinuation of tretinoin. Some patients experience increased photosensitivity during topical or oral tretinoin therapy; patients should use sunscreen (minimum SPF 15) and protective clothing. Patients with sunburn should not use topical tretinoin until fully recovered.(51)(52) Dry skin/mucous membranes were reported in the majority of patients (77%) receiving oral tretinoin. Other dermatologic adverse reactions reported with oral tretinoin include rash (unspecified) (54%), pruritus (20%), alopecia (14%), unspecified skin changes (14%), cellulitis (8%), facial edema (6%), and pallor (6%). Isolated cases of erythema nodosum and Sweet’s syndrome have also been reported with oral tretinoin.(51)

Niacinamide 

Niacin (nicotinic acid), when administered in doses equivalent to the RDA, is generally nontoxic. Niacinamide also rarely causes adverse reactions. Larger doses of nicotinic acid (i.e., >= 1 g/day PO), can cause adverse reactions more frequently. Differences in adverse reaction profiles can be explained by the fact that nicotinic acid has pharmacologic properties that are different from niacinamide.

Peripheral vasodilation is a well-known adverse reaction to niacin. It is characterized by flushing; warmth; and burning or tingling of the skin, especially in the face, neck, and chest. Hypotension can be caused by this vasodilation. Patients should avoid sudden changes in posture to prevent symptomatic or orthostatic hypotension. Dizziness and/or headache, including migraine, can occur. Cutaneous flushing is more likely to occur with immediate-release preparations as opposed to sustained-release ones and also increases in incidence with higher doses.(6) Following 4-weeks of maintenance therapy of 1500 mg daily, patients receiving immediate release niacin averaged 8.6 flushing events compared to 1.9 events in the Niaspan group. In placebo-controlled studies of Niaspan, flushing occurred in 55—69% of patients compared to 19% of patients receiving placebo. Flushing was described as the reason for discontinuing therapy for 6% of patients receiving Niaspan in pivotal studies.(2) These reactions usually improve after the initial 2 weeks of therapy. Some patients develop generalized pruritus as a result of peripheral flushing. In placebo controlled trials, pruritus was reported in 0—8% of patients receiving Niaspan compared to 2% of patients taking placebo. Rash (unspecified) was reported in 0—5% of patients in the Niaspan group compared to no patients in the placebo group.(2) Patients should avoid ethanol or hot drinks that can precipitate flushing. Flushing can be minimized by taking niacin with meals, using low initial doses, and increasing doses gradually. If necessary, taking one aspirin (e.g., 325 mg) 30 minutes before each dose can help prevent or reduce flushing. Spontaneous reports with niacin suggest that flushing may also be accompanied by symptoms of dizziness or syncope, sinus tachycardia, palpitations, atrial fibrillation, dyspnea, diaphoresis, chills, edema, or exacerbations of angina. On rare occasions, cardiac arrhythmias or syncope has occurred. Hypersensitivity or anaphylactoid reactions have been reported rarely during niacin therapy; episodes have included one or more of the following features: anaphylaxis, angioedema, urticaria, flushing, dyspnea, tongue edema, laryngeal edema, face edema, peripheral edema, laryngospasm, maculopapular rash, and vesiculobullous rash (vesicular rash, bullous rash).

Niacin can produce a variety of GI effects, such as nausea/vomiting, abdominal pain, diarrhea, bloating, dyspepsia, or flatulence, when taken in large doses. Eructation and peptic ulcer has been reported with post-marketing experience of Niaspan. Compared to placebo, diarrhea was reported in 7—14% (vs. 13%), nausea in 4—11% (vs. 7%), and vomiting in 0—9% (vs. 4%) of patients receiving Niaspan.(2) These effects are attributed to increased GI motility and may disappear after the first 2 weeks of therapy. Administering niacin with meals can reduce these adverse reactions.

Jaundice can result from chronic liver damage caused by niacin. It has been shown that elevated hepatic enzymes occur more frequently with some sustained-release niacin than with immediate-release products.(6) However, in a study of 245 patients receiving Niaspan (doses ranging from 500—3000 mg/day for a mean of 17 weeks) no patients with normal serum transaminases at baseline experienced elevations to > 3x the upper limit of normal. Sustained-release products have been associated with post-marketing reports of hepatitis and jaundice, including Niaspan. Regular liver-function tests should be performed periodically. The changes in liver function induced by niacin are typically reversible with drug discontinuation. However, rare cases of fulminant hepatic necrosis and hepatic failure have been reported. Some cases have occurred after the substitution of sustained-release dosage forms for immediate-release products at directly equivalent doses; these dosage forms are not bioequivalent. Dosage titration schedules must be observed for any patient switched to a sustained-release niacin product, even if the patient was previously taking immediate-release therapy.(2)

Niacin interferes with glucose metabolism and can result in hyperglycemia.(2) This effect is dose-related. During clinical anti-lipemic trials, increases in fasting blood glucose above normal occurred frequently (e.g., 50%) during niacin therapy. Some patients have required drug discontinuation due to hyperglycemia or exacerbation of diabetes. In the AIM-HIGH trial of patients with stable cardiovascular disease, the incidence of hyperglycemia (6.4% vs. 4.5%) and diabetes mellitus (3.6% vs. 2.2%) was higher in niacin plus simvastatin-treated patients compared to the simvastatin plus placebo group. Close blood glucose monitoring is advised for diabetic or potentially diabetic patients during treatment with niacin; adjustment of diet and/or antidiabetic therapy may be necessary.(2)

Niacin, especially in high doses, can cause hyperuricemia. Gout has been reported in post-marketing surveillance of Niaspan.(2) Therefore, patients predisposed to gout should be treated with caution.

Niacin, especially in high doses (>= 2 g/day PO), can cause hypophosphatemia (mean decrease 13%). Serum phosphorus concentrations should be monitored periodically in patients at risk for hypophosphatemia.(2)

Nicotinic acid (niacin) occasionally causes slight decreases in platelet counts (mean reduction 11%) or increased prothrombin times (mean increase 4%), especially in high doses (>= 2 g/day PO). Rarely do these reactions result in coagulopathy or thrombocytopenia, but clinically significant effects might occur in patients with other risk factors or who are predisposed to these conditions.(2)

Asthenia, nervousness, insomnia, and paresthesias have been reported during niacin therapy. Rare cases of rhabdomyolysis have been reported in patients taking niacin (nicotinic acid) in doses >=1 g/day PO and HMG-CoA reductase inhibitors (i.e., ‘statins’) concurrently. In the AIM-HIGH trial, 4 cases (0.2%) of rhabdomyolysis were reported in the niacin; simvastatin group compared with 1 case in the simvastatin plus placebo group. Rhabdomyolysis may present as myopathy (myalgia, myasthenia, muscle cramps, muscle weakness, muscle tenderness, fatigue), elevations in creatinine phosphokinase (CPK), or renal dysfunction (renal tubular obstruction). Toxicity to the skeletal muscle occurs infrequently but can be a serious adverse reaction. This toxicity appears to be reversible after discontinuation of therapy.(2)

Niacin also has been associated with a variety of ophthalmic adverse effects including blurred vision and macular edema.(2)

Although uncommon, niacin may be associated with skin hyperpigmentation or acanthosis nigricans. Dry skin (xerosis) also has been reported during post-marketing surveillance of Niaspan.(2)(53)

During clinical trials, increased cough was reported in

Question 35

Storage

Accepted Answer

Store this medication in its original container at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

Question 36

References

Accepted Answer

1. Anti-Wrinkle Benefits of Peptides Complex Stimulating Skin Basement Membrane Proteins Expression International Journal of Molecular Science, 2020 Jan; 21(1):73
Vesanoid (tretinoin) capsules package insert. Nutley, NJ: Roche Laboratories Inc.; 2004 Oct.

2.Niaspan (niacin extended-release) tablet package insert. North Chicago, IL: Abbott Laboratories; 2015 Apr.

3.HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014;371:203-12.

4.Taylor AJ, Villines TC, Stanck EJ, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med 2009. Epub ahead of print, doi:10.1056/NEJMoa907569.

5.Lee JMS, Robson MD, Yu LM, et al. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function: A randomized, placebo-controlled, magnetic resonance imaging study. J Am Coll Cardiol 2009;54:1787—94.

6.McKenney JM, et al. A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients. JAMA 1994;271:672-7.

7.Standing Committee on the Scientific Evaluation of Dietary Reference Intakes – Panel on Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids and the Subcommittee on Upper Reference Levels of Nutrients, Food and Nutrition Board, Institute of Medicine (IOM). Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. 2000.The National Academy of Sciences Press, Washington DC.

8.Stampfer MJ, Hennekens CH, Manson JE, et al. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med 1993;328:1444-9.

9.Rimm EB, Stampfer MJ, Ascherio A, et al. Vitamin E consumption and the risk of coronary disease in men. N Engl J Med 1993;328:1450-6.

10.Stephens NG, Parsons A, Schofield PM, et al. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996;347:781-6.

11.Hodis HN, Mack WJ, LaBree L, et al. Serial coronary angiographic evidence that antioxidant vitamin intake reduces progression of coronary artery atherosclerosis. JAMA 1995;273:1849-54.

12.Rapola JM, Virtamo J, Haukka JK, et al. Effect of vitamin E and beta carotene on the incidence of angina pectoris. JAMA 1996;275:693-8.

13.Yusuf S, Dagenais G, Pogue J, et al. The Heart Outcomes Prevention Evaluation Study Investigators. Vitamin E supplementation and cardiovascular events in high-risk patients. N Engl J Med 2000;342:154-160.

14.Lee MI, Cook NR, Gaziano JM, et al. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women’s Health Study: A randomized controlled trial. JAMA 2005; 294:56-65.

15.Mosca L, Women’s LJ, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women. Circulation 2004;109:672-93.

16.Hercberg S, Galan P, Preziosi P, et al. The SU.VI.MAX Study: a randomized, placebo controlled trial of the health effects of antioxidant vitamins and minerals. JAMA 2004;164:2335-42.

17.Lonn E, Bosch J, Yusuf S, et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 2005;293:1338-47.

18.Virtamo J, Pietinen P, Huttunen JK, et al. Incidence of cancer and mortality following alpha-tocopherol and beta-carotene supplementation: a postintervention follow-up. JAMA 2003;290:476-85.

19.Chan JM, Stampfer MJ, Ma J, et al. Supplemental vitamin E intake and prostate cancer risk in a large cohort of men in the United States. Cancer Epidemiol Biomarkers Prev 1999;8:893-9.

20.Heinomen OP, Albanes D, Virtamo J, et al. Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst 1998;18:440-6.

21.National Cancer Institute news release. October 27, 2008. Review of prostate cancer prevention study shows no benefit for use of selenium and vitamin E supplements. Accessed November 17, 2008. Available on the World Wide Web at www.cancer.gov/newscenter/pressreleases/SELECTresults2008.

22.Fisher GJ, Wang Z, Datta SC, et al. Pathophysiology of premature skin aging induced by ultraviolet light. N Engl J Med 1997;337:1419-28.

23.Grignani F, Fagioli M, Alcalay M, et al. Acute promyelocytic leukemia: from genetics to treatment. Blood 1994;83:10-25.

24.Stephens NG, Parsons A, Schofield PM, et al. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996;347:781-6.

25.Hodis HN, Mack WJ, LaBree L, et al. Serial coronary angiographic evidence that antioxidant vitamin intake reduces progression of coronary artery atherosclerosis. JAMA 1995;273:1849-54.

26.Yusuf S, Dagenais G, Pogue J, et al. The Heart Outcomes Prevention Evaluation Study Investigators. Vitamin E supplementation and cardiovascular events in high-risk patients. N Engl J Med 2000;342:154-160.

27.Lee MI, Cook NR, Gaziano JM, et al. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women’s Health Study: A randomized controlled trial. JAMA 2005; 294:56-65.

28.Prasad KN, Edwards-Prasad J. Vitamin E and cancer prevention: recent advances and future potentials. J Am Coll Nutr 1992;11:487-500.

29.Klatte ET, Scharre DW, Nagaraja HN, et al. Combination therapy of donepezil and vitamin E in Alzheimer’s disease. Alzheimer Dis Assoc Disord 2003;17:113-16.

30.Lonn E, Bosch J, Yusuf S, et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 2005;293:1338-47.

31.Diaz MN, Frei B, Vita JA, et al. Antioxidants and atherosclerotic heart disease. N Engl J Med 1997;337:408-16.

32.Passi S, De Pita O, Puddu P, et al. Lipophilic antioxidants in human sebum and aging. Free Radic Res 2002;36:471-7.

33.Sorg O, Tran C, Saurat JH. Cutaneous vitamins A and E in the context of ultraviolet- or chemically-induced oxidative stress. Skin Pharmacol Appl Skin Physiol 2001:14:363-72.

34.Traber MG, Stevens JF. Vitamins C and E: Beneficial effects from a mechanistic perspective. Free Radic Biol Med 2011;51:1000-1013.

35.Alberts DS, Goldman R, Xu MJ, et al. Disposition and metabolism of topically administered alpha-tocopherol acetate: a common ingredient of commercially available sunscreens and cosmetics. Nutr Cancer 1996;26:193-201.

36.Altreno (tretinoin lotion) package insert; Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; 2018 Aug.

37.Moore DE. Drug-induced cutaneous photosensitivity: incidence, mechanism, prevention and management. Drug Saf 2002;25:345-72.

38.Colletti RB, Neufeld EJ, Roff NK, et al. Niacin treatment of hypercholesterolemia in children. Pediatrics 1993;92:78-82.

39.Expert Panel: National Cholesterol Education Program. Report of the expert panel on blood cholesterol levels in children and adolescents. Pediatrics 1992;89(suppl 2):525-84.

40.Niacinamide. In: Drugs in Pregnancy and Lactation. A Reference Guide to Fetal and Neonatal Risk. Briggs GG, Freeman RK, Yaffe SJ, (eds.) 7th ed., Philadelphia PA: Lippincott Williams and Wilkins; 2005:1140-1

41.Health Care Financing Administration. Interpretive Guidelines for Long-term Care Facilities. Title 42 CFR 483.25(l) F329: Unnecessary Drugs. Revised 2015.

42.Booth SL, Golly I, Sacheck JM, et al. Effect of vitamin E supplementation on vitamin K status in adults with normal coagulation status. Am J Clin Nutr 2004;80:143-148.

43.Freedman JE, Keaney JF. Vitamin E inhibition of platelet aggregation is independent of antioxidant activity. J Nutr 2001;131:374S-377S.

44.Standing Committee on the Scientific Evaluation of Dietary Reference Intakes – Panel on Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids and the Subcommittee on Upper Reference Levels of Nutrients, Food and Nutrition Board, Institute of Medicine (IOM). Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. 2000.The National Academy of Sciences Press, Washington DC.

45.Lawrence RA. Chapter 9: Diet and dietary supplements for the mother and infant. In: Breastfeeding- A Guide for the Medical Profession. 5th ed. St. Louis MO: Mosby, Inc.; 1999.

46.Brion LP, Bell EF, Raghuveer TS. Vitamin E supplementation for prevention of morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2003;(4).

47.Brion LP, Bell EF, Raghuveer TS, et al. What is the appropriate intravenous dose of vitamin E for very-low-birth-weight infants? J Perinatol 2004;24:205-207

48.Tretinoin capsules package insert. Sellersville, PA: Teva Pharmaceuticals; 2009 Jun.

49.Retin-A Micro (tretinoin gel) package insert. Quebec, Canada: Valeant Pharmaceuticals North America, LLC; 2017 Oct.

50.Tretinoin capsules package insert. Sellersville, PA: Teva Pharmaceuticals; 2009 Jun.
51.Tretinoin capsules package insert. Chestnut Ridge, NY: Par Pharmaceutical; 2017 Jan
52.Renova 0.02% (tretinoin cream) package insert; Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; 2013 Jun.
53.Niacor (Niacin tablets) package insert. Minneapolis, MN: Upsher-Smith Laboratories, Inc.; 2000 Feb.
54.Booth SL, Golly I, Sacheck JM, et al. Effect of vitamin E supplementation on vitamin K status in adults with normal coagulation status. Am J Clin Nutr 2004;80:143-148.
55.Freedman JE, Keaney JF. Vitamin E inhibition of platelet aggregation is independent of antioxidant activity. J Nutr 2001;131:374S-377S.
56.Brion LP, Bell EF, Raghuveer TS. Vitamin E supplementation for prevention of morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2003;(4).
57.Zenk KE, Sills JH, Koeppel RM. Neonatal medications and nutrition. A comprehensive guide. 3rd ed. Santa Rosa: NICU Ink Book Publishers; 2003.
58.Brion LP, Bell EF, Raghuveer TS, et al. What is the appropriate intravenous dose of vitamin E for very-low-birth-weight infants? J Perinatol 2004;24:205-207

Question 37

General Information

Accepted Answer

Dehydroepiandrosterone (DHEA) is a C19 steroid also known as 5-androsten-3 beta-ol-17-one. DHEA and DHEAS (an active, sulfated form of DHEA), are endogenous hormones secreted by the adrenal cortex in primates and a few non-primate species in response to ACTH. DHEA is a steroid precursor of both androgens and estrogens, and thus is often called ‘the mother hormone’. Endogenous DHEA is thought to be important in several endocrine processes, but current medical use of DHEA is limited to controlled clinical trials. In 1997, Pharmadigm, Inc. received an orphan drug designation to enroll patients with thermal burns who require skin-grafting into trials using injectable DHEAS, known as PB-005. Researchers continue to investigate the role of both endogenous and exogenous DHEA in CNS, psychiatric, endocrine, gynecologic and obstetric, immune, and cardiovascular functions.(1) GeneLabs Technologies, Inc., submitted an NDA in September 2000 for its proprietary DHEA product, called prasterone (Prestara™, formerly known Aslera™ or GL-701). Prasterone appears to attentuate some symptoms of mild-to-moderate systemic lupus erythematosus (SLE) and may increase bone density based on evidence from two phase III studies in women; studies in men with SLE are ongoing. The FDA placed Prestara™ under a 6-month priority review status in October 2000; on April 19, 2001 the FDA stated that although the drug showed advantages over placebo in one study, the advantages were not statistically significant. Additional data were submitted to the FDA following a ‘not approvable’ letter on June 26, 2001. On September 2, 2002, the FDA issued an ‘approvable’ letter for the Prestara™ product, but the agency has asked for additional clinical trial data regarding the drug’s effects on bone mineral density before granting final approval for SLE. The manufacturer began a confirmatory phase III trial in early 2003; the primary endpoint will be measurement of bone mineral density of the lumbar spine; the trial is targeted for completion at the end of 2003. In October 2004, the manufacturer released information that Prestara™ therapy did not meet the primary end point in the confirmatory trial. In August 2003, Paladin Labs Inc., received orphan drug designation from the FDA for prasterone, dehydroepiandrosterone, DHEA, under the brand name Fidelin™, for adrenal insufficiency.

Exogenously administered DHEA is sold as a nutritional supplement in health and drug stores and many older individuals are using it to ‘maintain the vitality of their youth’. There is currently no objective, well-controlled, large-scale, scientific evidence to back claims that taking DHEA combats the signs or symptoms of aging, diabetes, neurologic disease, sexual dysfunction, or heart disease.(2) Some athletes abuse DHEA believing that it can enhance the body’s synthesis of testosterone; the potential action of DHEA as an anabolic steroid has lead to the prohibition of supplementation in competitive sport, even though evidence of anabolic effects in athletes is lacking.3 DHEA is also abused by athletes in an attempt to normalize the testosterone:epitestosterone ratio. However, the sensitivity and specificity of currently available testing for athletic ‘doping’ can readily identify the presence of banned substances, including testosterone. Because of DHEA’s complex physiologic actions, more than 500 scientific articles investigating it have been published since 1993. Many of the short-term trials of DHEA to date have lacked the rigor and statistical applications needed to support therapeutic claims. Most claims will need to be confirmed by large-scale, properly conducted, and controlled studies. In 1984, the FDA banned the non-prescription (OTC) sale of exogenous DHEA due to concern over hepatotoxicity (hepatitis and hepatic tumors) as noted in animal studies. The FDA formally relegated DHEA to a Category II OTC ingredient at that time (i.e., not generally recognized as safe and effective). However in 1994, the passage of the US Dietary Supplement Health and Education Act (DSHEA) allowed DHEA to be marketed as a nutritional or dietary supplement.

Question 38

Mechanism of Action

Accepted Answer

Endogenous DHEA is a complex hormone, and researchers still have much to discover in regards to its physiologic effects in males and females. Less is known regarding the mechanisms of action of exogenously administered DHEA.

CNS actions: Both DHEA and DHEAS may be synthesized de-novo by the central nervous system, and concentrations of DHEA and DHEAS are higher in the brain than in other organs. The two neurohormones appear to have excitatory activity at both GABA and NMDA receptors.(1)

Dermatologic actions after burn injury: Animal studies have suggested that DHEA and DHEAS expedite the re-epithelialization of donor skin-graft sites.(4)

Endocrine actions: Endogenous DHEA is synthesized by the conversion of cholesterol via CYP11A1 to pregnenolone, followed by CYP17 conversion to DHEA and then to DHEAS via dehydroepiandrosterone sulfatransferase. The synthesis of DHEA occurs exclusively in the adrenal cortex in women, while in men 10—25% of DHEA is synthesized by the testes and roughly 80% of the DHEA comes from the adrenal glands. DHEA is converted via hydrosteroid dehydrogenases and aromatase into androstenedione, testosterone, and estradiol by peripheral tissues. DHEA is of only minor importance as an androgenic substance itself. The production rate of DHEA by the body changes dramatically throughout life, typically peaking at adrenarche, the adrenal contribution to the onset of puberty. In males, DHEA serum levels are high in neonates right after birth, rapidly fall within 5 months, then begin to rise at the age of 9 years. Endogenous DHEA concentration then peaks again in males at roughly the 20th—30th years of life. In females, DHEA serum levels are high in neonates right after birth, rapidly fall within 5 months, then begin to rise at the age of 7 years. Endogenous DHEA concentration then peaks again in females at roughly the 20th and 40th year of life. DHEA levels decline steadily after the fifth decade in both males and females. DHEAS concentrations in males and females follow similar patterns. The administration of DHEA supplements results in different hormonal concentration changes in males and females; the actions are dependent on the dose, formulation and route of administration, and age of the person receiving the DHEA.(1)

Hemostasis: Inhibition of platelet aggregation by exogenous DHEA has been demonstrated in vivo in humans; DHEA either prolonged or completely inhibited the rate of arachidonate-stimulated platelet aggregation after 14 days of administration. The degree of inhibition of platelet aggregation was noted to be time and dose dependent.(5)

Immunologic actions: Because SLE occurs more frequently in women than men and because SLE is known to worsen during pregnancy, a hormonal etiology is suspected for this disease. DHEA up-regulates interleukin-2 (IL-2) production by T-lymphocytes in murine lupus models and reverses the clinical autoimmune disease. Lower endogenous levels of DHEA and DHEAS have been noted in both male and female patients with lupus at the time of diagnosis. Chronic corticosteroid treatment, which may cause adrenal atrophy, contributes to reduced DHEA levels in these patients. Supplementation of DHEA in SLE may augment immune system activity and potentially offset the undesired effects of chronic corticosteroid use in these patients.(6) Exact mechanisms of DHEA on immune function are not yet clear. DHEA has been shown to increase the numbers of natural killer cells in aging women. Serum DHEA levels are observed to be reduced in patients with AIDS or age-related immunodeficiency, suggesting that DHEA may serve as a marker of the integrity of the immune system. No studies to date have shown that DHEA supplementation augments currently available therapies for AIDS.(1)

Question 39

Pharmacokinetics

Accepted Answer

As a nutritional supplement, DHEA is most commonly administered by the oral route. Many DHEA products available as nutritional supplements contain varied amounts of DHEA and do not appear to be manufactured according to good manufacturing processes (GMP). Using HPLC techniques, one study found that only 7 out of the 16 assayed products contained DHEA within a 10% variation of the labeled content.(7) Some products contained no detectable DHEA.(7)

The literature is lacking in pharmacokinetic studies using serial serum sampling of DHEA after supplementation. In the body, DHEA and DHEAS are widely distributed, converted to the sex hormones in peripheral tissues, and appear to cross the blood-brain barrier. The serum pharmacokinetic parameters and metabolism of DHEA and DHEAS following administration may vary among persons of different sex and age groups and the dose or route of administration. Quantification of DHEA to aide in detection of abuse by athletes may soon be accomplished. Gas chromatography-mass spectrometry (GC-MS) can evidently detect DHEA metabolites in the urine within 8 hours of a single oral dose of 50 mg. Within 24 hours, 50—75% of an oral DHEA dose is recovered as glucuronide and sulfate conjugates, androsterone, and etiocholanone in the urine.

Route-Specific Pharmacokinetics:

Oral Route: Micronization appears to enhance oral absorption and may influence the metabolic conversion of DHEA to the various sex hormones in men and women. After oral dosing, elevations in serum concentrations of DHEA and DHEAS, above endogenous levels, persist for 12 hours.

Question 40

Contraindications/Precautions

Accepted Answer

Your health care provider needs to know if you have any of these conditions: breast cancer (men or women); cancer of the lining of the uterus (endometrial cancer); diabetes or high blood sugar; immune system problems; infertility; liver disease; post-menopause; prostate cancer or an enlarged prostate gland; rheumatoid arthritis; uterine cancer; vaginal bleeding or menstrual problems; vaginal cancer; an unusual or allergic reaction to progesterone, DHEA, soy, other medicines, foods, dyes, or preservatives; pregnant or trying to get pregnant; breast-feeding. Visit your doctor or health care professional for regular checks on your progress. Women should inform their doctor if they wish to become pregnant or think they might be pregnant. There is a potential for serious side effects to an unborn child. DHEA use is banned in competitive sports. Both college (NCAA) and olympic (USOC) committees do not allow DHEA use among athletes.

NOTE: DHEA has not yet been evaluated by the Food and Drug Administration. Nutritional supplement products containing DHEA are not intended to diagnose, treat, cure, or prevent any disease. Consumers should also be informed that rigid quality control standards are not required for nutraceuticals and substantial variability can occur in both the potency and the purity of these products.

Dehydroepiandrosterone (free and sulfate) test systems measure dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) in urine, serum, plasma, and amniotic fluid. These measurements are used in the diagnosis and treatment of DHEA-secreting adrenal cancers. It is unclear at this time if supplementation with DHEA would result in false-positives of these tests.

The effect of DHEA on hormone-dependent tumors in males and females is unknown. Many hormonal agents with androgenic or estrogenic activity are contraindicated for use in persons with various hormonally-dependent neoplasms. Some data suggests an association between elevated endogenous DHEA and DHEAS serum concentrations and the development of breast cancer andovarian cancer in women. As with other hormones, DHEA supplementation in a woman with undiagnosed abnormal vaginal bleeding, endometrial cancer, endometrial hyperplasia, uterine cancer, or vaginal cancer is not recommended. DHEA may stimulate the growth of cancerous tissue and should not be used in male patients with either breast or prostate cancer. Male patients with symptoms of prostatic hypertrophy or dysfunction that have not been medically evaluated should not take DHEA supplements. Because the incidence of some hormonally-dependent cancers naturally increases with age, “andropausal” men and post-menopausal women should approach DHEA supplementation with caution. It is recommended that a qualified healthcare prescriber’s recommendations be sought prior to DHEA supplementation.(8) Benefit versus risk should be determined individually. Women taking DHEA should receive an annual clinical breast examination and pelvic examination and regular mammograms as recommended by their healthcare professional. Men taking DHEA should receive annual physical examinations, including prostate examination or PSA levels, as recommended by their healthcare provider.

Dehydroepiandrosterone, DHEA is contraindicated for use in children

Question 41

Pregnancy

Accepted Answer

DHEA should be considered a pregnancy category X drug, similar to other androgenic hormones. Studies of the role of endogenous fetal and maternal DHEA in pregnancy indicate that the ratio of DHEA or DHEAS to other hormones in the serum or placenta may influence the processes of fetal development, parturition, and labor. Endogenous DHEA and DHEAS appear to be important in the functional development of the adrenal cortex and other endocrine activities in the fetus; it is assumed that exogenous DHEA supplementation to a pregnant woman could potentially have deleterious effects on fetal development or viability. The androgenic effects of DHEA could potentially result in masculinization of a female fetus. No controlled trials of DHEA in primate or human gestation exist. Do not administer DHEA to a pregnant woman.

Question 42

Breast-feeding

Accepted Answer

DHEA is a hormone and should not be supplemented in a lactating woman who is breast-feeding her infant. Most hormones are excreted in breast milk. Like other androgenic hormones, it is possible that DHEA could inhibit lactation. It is unknown what effect DHEA would have on the breast-feeding infant.

Question 43

Adverse Reations/Side Effects

Accepted Answer

NOTE: Some prasterone, dehydroepiandrosterone, DHEA preparations are a combination of several hormones and/or herbs, and each individual component may need to be evaluated in the presence of adverse reactions. Only adverse reactions pertaining to DHEA are discussed in this monograph. Human side-effect data to date have been collected in non-systematic fashion via the FDA special nutritional adverse effect monitoring system (SNAEMS) or relatively small clinical trials.

DHEA has been observed to cause reversible reductions in HDL cholesterol and total cholesterol in some clinical trials; other trials have not noted changes in the serum lipid profile. DHEA may also exhibit anti-platelet effects. The influence of these changes on the development of side effects, atherosclerosis, or other cardiac-related endpoints is unknown.

In one 3-month study of 28 women with SLE, the following ADRs were noted in the females receiving DHEA: acneiform rash (57%), hirsutism (14%), weight gain (14%), menstrual irregularity (7%), and emotional lability (7%). The statistical significance of these side effects relative to placebo was not determined.(22) Some events commonly associated with SLE and reported as adverse events in clinical trials were less frequent in patients treated with prasterone (GL701) compared with placebo, including muscle pain, nasal and oral ulceration, and hair loss.

Prasterone, DHEA is a hormone with androgenic actions, however, the incidence of androgenic side effects is not known. When androgens are given to women, they may cause virilization, manifested by clitoromegaly, reduced breast size, and deepening of the voice or voice hoarseness. If treatment is discontinued when these symptoms first appear, they usually subside. Prolonged treatment with androgenic substances can lead to irreversible masculinity, so the benefit of DHEA treatment should be offset against the risk of androgen-like side effects.

The effect of prasterone or DHEA supplementation on normal endocrine processes in women is not clear. Women should report any menstrual changes, including amenorrhea, unusual vaginal bleeding, dysmenorrhea, or abdominal bloating to their health care providers. Breast changes, including breast discharge, breast enlargement, breast tenderness, or galactorrhea should also be reported.

Prasterone (DHEA) has androgenic actions, and it is not clear what effect prasterone may have in male patients. Similar to female patients, male patients may experience worsening of acne vulgaris. Male patients may theoretically experience feminization during prolonged therapy with DHEA resulting from inhibition of gonadotropin secretion and conversion of testosterone to estrogens. Feminizing effects in males might include gynecomastia. Feminizing effects secondary to androgens are generally reversible. It is not clear if DHEA would affect testicular function or prostatic function. Symptoms of urinary retention or urinary urgency, prostate pain, or signs of an enlarged prostate in a male patient should prompt clinical evaluation.

Mild peripheral edema can occur with DHEA use as the result of increased fluid retention (in association with sodium retention) and may be associated with mild weight gain.

Prasterone (DHEA) may cause emotional lability. At least one case of possible DHEA-induced mania has been reported in the literature, in a patient predisposed to bipolar illness who was consuming doses >= 300 mg/day PO on a routine basis. There was a temporal association between the time of drug use and the appearance of manic symptoms. Clinicians should be alert to possible alterations in psychiatric status in patients taking this medication for supplemental or medicinal purposes.

Hepatic dysfunction can occur from use of androgenic steroids, especially the oral 17-alpha-alkylandrogens (e.g., methyltestosterone). DHEA does not contain the 17-alkyl group in its structure, however, transient cases of drug-induced hepatitis in humans have been reported in association with DHEA use; these have included a few reports to the FDA Special Nutritionals Adverse Event Monitoring System (SN/AEMS). Liver toxicity has not been reported in human studies, but elevated hepatic transaminases have been reported and confirmed upon rechallenge in some trials. In 1984, the FDA banned the non-prescription (OTC) sale of DHEA due to concern over hepatitis. Clastogenesis has been noted in hepatic tissues of animals exposed to DHEA. DHEA appears to act as a perisoxome proliferator, resulting in liver tumors and nodules in the periportal areas of the liver lobule in rats. DHEA should be discontinued in any patient developing signs or symptoms of potential liver problems, including elevated hepatic enzymes, continued nausea and vomiting, fatigue, jaundice, or severe abdominal pain; the patient should be evaluated.

In studies of male patients with HIV virus infection, side effects attributed to DHEA treatments and confirmed upon rechallenge included nasal congestion, fatigue, headache, and mild insomnia.(1)

Prasterone (DHEA) therapy is reported to cause libido increase. No objective evidence of this side effect exists at this time.

The effect of DHEA on the progression of hormonally-dependent tumors in males or females, or the risk of secondary malignancy, such as breast cancer, is not known. One case-control study of women with ovarian cancer demonstrated higher serum androstenedione and DHEA/DHEAS levels in patients with ovarian tumors versus controls.(23) Whether DHEA supplementation would be associated with similar the serum hormonal profiles is unknown. Male breast cancer, prostate cancer and prostatic hypertrophy can develop due to endocrine epithelial cell growth during therapy with androgens. One case report has been published of a patient with advanced prostate cancer who was symptomatically treated with DHEA. The patient experienced a “flare” of his cancer during the treatment period.(24) A causal relationship has not been established. Widespread use of DHEA supplements in men or women should be discouraged until more is known about potential secondary malignancy risks.

Prasterone, dehydroepiandrosterone (DHEA) is an androgenic hormone and may potentially cause teratogenesis or changes the ability to conceive or carry a viable pregnancy. Dehydroepiandrosterone, DHEA should be considered contraindicated in pregnancy, similar to other androgenic hormones. It is assumed that exogenous DHEA supplementation to a pregnant woman could potentially have deleterious effects on fetal development or viability. No controlled trials of DHEA in primate or human gestation exist. If pregnancy is suspected, pregnancy should be ruled out before continuing DHEA use.

Question 44

Storage

Accepted Answer

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

Question 45

Interactions

Accepted Answer

NOTE: Many prasterone, dehydroepiandrosterone, DHEA preparations contain a variety of other ingredients, including minerals, vitamins, hormones and/or herbs, and each individual component may need to be evaluated for the presence of drug interactions. Only drug interactions pertaining to DHEA are discussed in this monograph.

Prasterone, dehydroepiandrosterone, DHEA is converted via hydrosteroid dehydrogenases and aromatase into androstenedione, testosterone, and estradiol by peripheral tissues.(12) DHEA is a weak androgen that has complex hormonal effects. It is unclear what actions prasterone, dehydroepiandrosterone, DHEA would have on other exogenous hormonal regimens (e.g., androgens, estrogens, oral contraceptives, or progestins). Either additive or antagonistic effects could potentially occur. The mechanisms or results of interactions with DHEA and other hormones may be multifactorial and dependent on the sex and age of the individual being treated, the indication for hormone use, the route by which DHEA is given, and the length of concomitant use. Concurrent use of DHEA with any of these hormonal regimens is not recommended at this time.

Prasterone, dehydroepiandrosterone, DHEA is converted via hydrosteroid dehydrogenases and aromatase into androstenedione, testosterone, and estradiol by peripheral tissues.(12) DHEA is a weak androgen that has complex hormonal effects. It is unclear what actions prasterone, dehydroepiandrosterone, DHEA would have on other exogenous hormonal regimens. It would seem prudent to not administer DHEA with infertility or hormonal cancer treatments such as GnRH analogs (cetrorelix, ganirelix, goserelin, histrelin, leuprolide, or triptorelin) since DHEA may theoretically interfere with these therapies.

Prasterone, dehydroepiandrosterone, DHEA is converted via hydrosteroid dehydrogenases and aromatase into androstenedione, testosterone, and estradiol by peripheral tissues.(12) DHEA is a weak androgen that has complex hormonal effects. The action of 5-alpha reductase inhibitors (i.e., dutasteride, finasteride) could potentially be antagonized by DHEA administration. 5-alpha-reductase inhibitors have anti-androgenic effects on the prostate gland that may be antagonized by the androgenic effects of DHEA on these tissues. Avoid concurrent use.

Drug interactions with Saw palmetto, Serenoa repens have not been specifically studied or reported. Saw palmetto extracts appear to have antiandrogenic effects.(13)(14) The antiandrogenic effects of Saw palmetto, Serenoa repens would be expected to antagonize the actions of androgens; it would seem illogical for patients taking androgens to use this herbal supplement.

Corticosteroids blunt the adrenal secretion of endogenous DHEA and DHEAS, resulting in reduced DHEA and DHEAS serum concentrations. The impact of exogenous prasterone, dehydroepiandrosterone, DHEA administration on the safety or efficacy of chronic corticosteroid treatment regimens is not yet clear. The administration of DHEA to patients on corticosteroids should only be done under the observation of a qualified health care professional.(15)

Prasterone, dehydroepiandrosterone, DHEA appears to have anti-platelet effects,(16) which may prolong bleeding times. Inhibition of platelet aggregation by DHEA has been demonstrated in vivo in humans; the rate of arachidonate-stimulated platelet aggregation was prolonged or completely inhibited.(16) In addition, DHEA is converted to androgens and estrogens within the human body and thus may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X.(17) Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of these potential, varied effects on coagulation, patients receiving DHEA concurrently with anticoagulants (e.g., warfarin or heparin) or other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.

Concurrent use of antidiabetic agents with prasterone, dehydroepiandrosterone, DHEA is currently not warranted. The role of endogenous DHEA in relationship to insulin action or glucose intolerance is not clear. Endogenous levels of DHEA and DHEAS may be regulated by insulin and may not mediate insulin action. It is unclear what effect DHEA supplementation would have on glycemic control. Trials evaluating the effectiveness and safety of exogenous DHEA supplementation in combination with antidiabetic agents are currently unavailable.(18)

Prasterone, dehydroepiandrosterone, DHEA is converted via hydrosteroid dehydrogenases and aromatase into androstenedione, testosterone, and estradiol by peripheral tissues.(12) Prasterone or DHEA supplements should not be given concurrently with any aromatase inhibitors, as DHEA could interfere with the pharmacologic action of the aromatase inhibitor and compromise aromatase inhibitor effectiveness. Conversely, aromatase inhibitors (e.g., aminoglutethimide, anastrozole, exemestane, letrozole, testolactone, vorozole) could interfere with biotransformation of DHEA.

Prasterone, dehydroepiandrosterone, DHEA may inhibit the metabolism of triazolam, and other benzodiazepines (e.g., alprazolam, estazolam, midazolam) which undergo CYP3A4-mediated metabolism. In one study of elderly volunteers, half of the patients received DHEA 200 mg/day PO for 2 weeks, followed by a single dose of triazolam 0.25 mg. Triazolam clearance was reduced by close to 30% in the DHEA-pretreated patients vs. the control group; however, the effect of DHEA on CYP3A4 metabolism appeared to vary widely among subjects.(19) While more study is needed, benzodiazepine-induced CNS sedation and other adverse effects might be increased in some individuals if DHEA is co-administered.

Prasterone, dehydroepiandrosterone, DHEA is a weak androgen that has complex hormonal effects.(12) Androgens are known to stimulate erythropoiesis.(20) Despite the fact that endogenous generation of erythropoietin is depressed in patients with chronic renal failure, other tissues besides the kidney can synthesize erythropoietin, albeit in small amounts. Concurrent administration of androgens can increase the patient’s response to epoetin alfa, reducing the amount required to treat anemia. Because adverse reactions have been associated with an abrupt increase in blood viscosity, this drug combination should be avoided, if possible. Further evaluation of this combination needs to be made.

In vitro, both genistein and daidzein inhibit 5 alpha-reductase isoenzyme II, resulting in decreased conversion of testosterone to the potent androgen 5-alpha-dihydrotestosterone (DHT) and a subsequent reduction in testosterone-dependent tissue proliferation.(21) The action is similar to that of finasteride, but is thought to be less potent. Theoretically, because the soy isoflavones appear to inhibit type II 5-alpha-reductase, the soy isoflavones may counteract the activity of the androgens.

Question 46

General Information

Accepted Answer

1.Kroboth PD, Slalek FS, Pittenger AL et al. DHEA and DHEA-S: a review. J Clin Pharmacol 1999;39:327-348.

2.Skolnick AA. Medical news and perspectives-scientific verdict still out on DHEA. JAMA 1996;276:1365-1367.

3.Kreider RB. Dietary supplements and the promotion of muscle growth with resistance exercise. Sports Med 1999;27:97-110.

4.Araneo BA, Ryu SY, Barton S, et al. Dehydroepiandrosterone reduces progressive dermal ischemia caused by thermal injury. J Surg Res 1995;59:250-262.

5.Jesse Rl, Loesser K, Eich DM, et al. Dehydroepiandrosterone inhibits human platelet aggregation in vitro and in vivo. Ann N Y Acad Sci 1995;774:281-290.

6.25801

7.Parasrampuria J, Schwartz K, Petesch R. Quality control of dehydroepiandrosterone dietary supplement products. JAMA 1998;280:1565.

8.Katz S, Morales AJ. Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DS) as therapeutic options in menopause. Semin Reprod Endocrinol 1998;16:161-170.

9.Rosenfield RL. Ovarian and adrenal function in polycystic ovary syndrome. Endocrinol Metab Clin North Am 1999;28:265-293.

10.Wellman M, Shane-McWhorter L, Orlando PL et al. The role of dehydroepiandrosterone in diabetes mellitus. Pharmacotherapy 1999;19:582-591.

11.Centurelli MA, Abate MA. The role of dehydroepiandrosterone in AIDS. Ann Pharmacother 1997;31:639-642.

12.Kroboth PD, Slalek FS, Pittenger AL et al. DHEA and DHEA-S: a review. J Clin Pharmacol 1999;39:327—48.
13.Robbers JE, Tyler VE. Tyler’s Herbs of Choice: the Therapeutic Use of Phytomedicinals. Binghamton NY: Haworth Herbal Press, Inc.; 1999.

14.German Commission E. Saw Palmetto berry, Sabal fructus, monograph Published March 2, 1989 and revised January 
17, 1991. In: Blumenthal, M et al ., eds. The complete German Commission E Monographs -Therapeutic Guide to Alternative Medicines. Boston MA: Int

15.Robinson B, Cutolo M. Should dehydroepiandrosterone replacement therapy be provided with chronic glucocorticoids? Rheumatology 1999;38:488—95.

16.Jesse Rl, Loesser K, Eich DM et al. Dehydroepiandrosterone inhibits human platelet aggregation in vitro and in vivo. Ann NY Acad Sci 1995;774:281—90.

17.Premarin® (conjugated estrogens, equine) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2003 Jul.

18.Wellman M, Shane-McWhorter L, Orlando PL et al. The role of dehydroepiandrosterone in diabetes mellitus. Pharmacotherapy 1999;19:582—91.

19.Frye RF, Kroboth PD, Folan MM, et al. Effect of DHEA on CYP3A4-mediated metabolism of triazolam (Abstract PI-82). Clin Pharmacol Ther 2000;67:109.

20.Androderm® (testosterone transdermal system) package insert. Corona, CA: Watson Pharma, Inc.; 1999 Jan.

21.Aldercreutz H, Mazur W. Phyto-estrogens and western diseases. Annals of Medicine 1997;29:95—120.

22.VanVollenhoven RF, Engleman EG, McGuire JL. Dehydroepiandrosterone in systemic lupus erythematosus. Arthritis Rheum 1995;38:1826-1831.

23.Helzlsouer KJ, Alberg AJ, Gordon GB, et al. Serum gonadotropins and steroid hormones and the development of ovarian cancer. JAMA 1995;274:1926-1930.

24.Jones JA, Nguyen A, Straub M, et al. Use of DHEA in a patient with advanced prostate cancer: a case report and a review. Urology 1997;50:784-788.

Question 47

General Information

Accepted Answer

Because of problems with the pituitary or testis, the production of testosterone by the body may decrease. Andriol Testocaps is used in adult men for testosterone replacement to treat various health problems caused by a lack of testosterone (male hypogonadism). Your doctor will confirm this by blood testosterone measurements and also clinical symptoms such as inability to get or maintain an erection (impotence), infertility, low sex drive, tiredness, depressive moods, or bone loss caused by low hormone levels. Testosterone is a natural male hormone known as an androgen, a type of sex hormone necessary for the normal sexual development of males.

In men testosterone is produced by the testicles. It is necessary for the normal growth, development and function of the male sex organs and for secondary male sex characteristics. It is necessary for the growth of body hair, the development of bones and muscles, and it stimulates the production of red blood cells. It also makes men’s voices deepen.

Men may suffer from complaints such as depression, loss of motivation or concentration, and loss of sexual desire. Andriol Testocaps can relieve these complaints. It can also relieve these symptoms in men who have had their testis removed. Relief of symptoms usually starts within a few days, but optimal results are obtained after weeks to months of treatment.

What it looks like

Each capsule contains 40 mg of the active ingredient called testosterone undecanoate. Testosterone undecanoate is turned into testosterone by your body.

Andriol Testocaps packs are available in 3, 6# or 12 sachets, each containing a blister pack with 10 capsules. Andriol Testocaps capsules are soft oval, glossy, transparent orange coloured capsules marked with ORG DV3 printed in white. They contain a yellow oil.

What it looks like
Each capsule contains 40 mg of the active ingredient called testosterone undecanoate. Testosterone undecanoate is turned into testosterone by your body.

Andriol Testocaps packs are available in 3, 6# or 12 sachets, each containing a blister pack with 10 capsules. Andriol Testocaps capsules are soft oval, glossy, transparent orange coloured capsules marked with ORG DV3 printed in white. They contain a yellow oil.

Ingredients
Each Andriol Testocap capsule consists of 40 mg of testosterone undecanoate (equivalent to 25.3 mg testosterone) in hydrogenated castor oil and propylene glycol monolaurate. The capsule shells contain the following inactive ingredients: gelatin, glycerol, medium chain triglycerides, lecithin, sunset yellow FCF and printed with Opacode WB water based monogramming ink NSP-78- 18022 White.

If you have any further questions or require the full prescribing information for this medicine, please consult your doctor or pharmacist.

Question 48

Dosage and Administration

Accepted Answer

Dosage and Administration

Take Andriol Testocaps exactly as directed by your doctor. You should also read the instructions on the label of your medicine. If you are not sure how to take Andriol Testocaps, ask your doctor or pharmacist.

How and when to take it

Take the capsules daily, as directed by your doctor. Andriol Testocaps are to be swallowed after the morning and evening meal.

Swallow the capsules whole with some water or other drink. Do not chew them.

If you are taking an uneven number of capsules, the larger dose should be taken in the morning.

Food allows testosterone undecanoate, the active substance of this medicine, to be taken up by your body. Therefore, Andriol Testocaps must be taken with a meal.

If you have the impression that the effect of this medicine is too strong or too weak, talk to your doctor or pharmacist immediately.

These symptoms usually go away when treatment is stopped for a short while. Your doctor will then probably advise you to start at a lower dosage. In a few patients diarrhoea and stomach pain or discomfort have been reported during the use of this medicine.

Children and adolescents

The following side effects have been reported in pre-pubertal children using androgens:

early sexual development;
penis enlargement;
an increased frequency of erections;
growth limitation (limited body height)


Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything else that is making you feel unwell.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Stop taking Andriol Testocaps if you develop jaundice (yellowing of the eyes or skin).

Treatment with male hormones like testosterone may increase the size of the prostate gland, especially in elderly men. Therefore your doctor will examine your prostate gland at regular intervals by digital rectal examination (DRE) and blood tests for prostate-specific antigen (PSA).

Additionally, at regular intervals, blood tests will be done to check the oxygen-carrying substance in your red blood cells (haemoglobin). In very rare cases the number of red blood cells will increase too much leading to complications.

Your doctor will measure testosterone blood levels before and during your treatment. Based on the blood test results, your doctor may adjust the dose of Andriol Testocaps.

Question 49

Pharmacokinetics

Accepted Answer

Pharmacokinetics

Question 50

Precautions and Contraindications

Accepted Answer

Do not use Andriol Testocaps if:

you have or have had a tumour of your prostate or breast or are suspected to have one of these tumours.
you have or have had severe kidney disease
you are allergic to testosterone undecanoate or any of the ingredients listed Do not use Andriol Testocaps if the packaging is torn or shows signs of tampering.

Before you start to take it Andriol:

Andriol Testocaps may not be suitable for you if you suffer from certain medical conditions. Tell your doctor or pharmacist before you start using this medicine if you ever had, still have, or are suspected to have (particularly if you are elderly):

heart disease, high blood pressure or blood vessel problems
Diabetes mellitus, Kidney disease
Kidney or lung cancer;
 Liver disease;
Breast cancer which has spread to the bones
Epilepsy
Migraine, headaches
Psychiatric or emotional illness
Prostatic complaints, such as problems with passing urine.
Any unusual or allergic reactions to androgens or anabolic steroids
Sleep apnoea (temporarily stopping breathing during your sleep), this may get worse if you are using testosterone- containing products. Let your doctor know if you are worried about this. Extra supervision by your doctor may be necessary in case you are overweight or suffer from chronic lung disease.

Improper use

If you are a patient who participates in competitions governed by the World Anti-Doping Agency (WADA), then you should consult the WADA-code before using this medicine as Andriol Testocaps can interfere with anti-doping testing. The misuse of this medicine to enhance ability in sports carries serious health risks and is to be discouraged.

Caution: During long-term treatment with Andriol Testocaps regular medical checks, including prostate examination, are recommended.

Children and adolescents

The safety and efficacy of this medicine has not been adequately determined in children and adolescents. Extra supervision by a doctor is necessary in the treatment of young boys and adolescents since testosterone administration in general may cause early sexual development and limits growth.

Elderly people

There is limited experience on the safety and efficacy of the use of Andriol Testocaps in patients over 65 years of age.

Interactions

Tell your treating physician if you are taking:


Ciclosporin
Barbiturates, (medicines for epilepsy or sleeplessness)
 Insulin and/or other medicines
to control your blood sugar
levels (antidiabetic drugs)*
Medicines to reduce the clotting of your blood (anti-coagulants)*
the hormone ACTH or corticosteroids (used to treat various conditions such as rheumatism, arthritis, allergic conditions and asthma).

Question 51

Contraindications/Precautions

Accepted Answer

Adverse Reactions and Side Effects

The use of androgens like Andriol Testocaps may increase the risk of water retention especially if your heart and liver are not working properly. Andriol Testocaps may interfere with some laboratory tests (e.g for glucose tolerance, thyroid function and clotting factors).

Abuse of testosterone, especially if you take too much of this medicine alone or with other anabolic androgenic steroids, can cause serious health problems to your heart and blood vessels (that can lead to death), mental health and/or the liver. Individuals who have abused testosterone may become dependent and may experience withdrawal symptoms when the dosage changes significantly or is stopped immediately. You should not abuse this medicine alone or with other anabolic androgenic steroids because it carries serious health risks.

Andriol Testocaps are generally well tolerated.

In general side effects which are reported with testosterone therapy include:

stomach or bowel complaints: oily bowel motions, abdominal or stomach pain, black, tarry or light coloured stools or dark coloured urine, vomiting, nausea, diarrhoea
acne, itching (pruritus) skin irritation: pimply spotty rash, hives
sleeplessness, chills, generalised tingling, unusual tiredness
• headache, anxiety, mental
depression, excitation, confusion, dizziness, nervousness, mood alterations
muscle pain (myalgia)
• prolonged abnormal, painful
irreversible erection, inflamed
testis, bladder irritability
sexual dysfunction, changes in sexual desire, disturbed sperm formation
Feminization (gynecomastia) • prostatic growth to a size
representative for the concerned
age group
high blood pressure (hypertension)
blood disorders, increase in the number of red blood cells (the cells which carry the oxygen in your blood),
increase in percentage of red blood cells relative to the total blood volume (haematocrit);
increased concentration of the red blood cell component that carries oxygen (haemoglobin);
increased levels of a blood marker which is associated with prostate cancer (PSA increased)
changes in cholesterol levels (changes in lipid metabolism)
shortness of breath
fluid retention in the tissues,
usually marked by swelling of ankles, feet or lower legs (oedema)
breast enlargement
increased growth of a small prostate cancer which had not been detected yet (progression of a sub-clinical prostatic cancer)
changes in liver function tests


Use in children and adolescents

The safety and efficacy of this medicine have not been adequately determined in children and adolescents. Pre-pubertal children using this medicine will be monitored by your doctor

If you forget to take it

If you forget to take a capsule, take it as soon as you remember. If you do not remember to take the dose until the next dose is due, then just take one dose, do not double up.

If you stop taking Andriol Testocaps

When treatment with this medicine is stopped, complaints such as those experienced before treatment may re-occur within a few weeks.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Question 52

Adverse Reactions and Side Effect

Accepted Answer

Andriol should not be used during pregnancy

Question 53

Pregnancy and Breast Feeding

Accepted Answer

Pregnancy

Andriol Testocaps are not intended for use in female patients. Therefore this medicine must not be taken by women who are pregnant or think that they are pregnant, or by women who are breast-feeding.

In men, treatment with Andriol Testocaps can lead to fertility disorders by repressing sperm formation.

If you are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Question 54

Adverse Reations/Side Effects:

Accepted Answer

IN CASE OF OVERDOSE

It is not a medical emergency if someone has taken several capsules at once. However, you should consult a doctor, or your nearest accident and emergency department if you think you or anyone else may have taken too much Andriol Testocaps. Symptoms that may arise are nausea and vomiting and oily bowel motions. The oily substance in the capsule may cause diarrhoea.

Question 55

In Case of Overdose

Accepted Answer

Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

Store Andriol Testocaps below

30°C. Do not refrigerate or freeze.

Store in the original package and keep the blister in the outer carton in order to protect from light.

Keep this medicine out of reach and sight of children

Do not use this medicine after the expiry date stated on the carton or label after the term “Expiry date”. The expiry date refers to the last day of that month.

Question 56

Storage

Accepted Answer

Interactions

Question 57

References

Accepted Answer

References

Question 58

General Information

Accepted Answer

Anastrozole is a nonsteroidal aromatase inhibitor. Anastrozole is highly potent and specific for aromatase, and represents the fourth generation of aromatase inhibitors. Anastrozole significantly suppresses serum estradiol levels, and it offers an alternative to tamoxifen in postmenopausal women with breast cancer. Unlike aminoglutethimide, an early aromatase inhibitor, anastrozole does not inhibit adrenal steroid synthesis. Patients taking anastrozole, therefore, do not require glucocorticoid or mineralocorticoid replacement therapy. Anastrozole causes less weight gain than megestrol and may offer a survival advantage over megestrol in women with advanced breast cancer. Aromatase inhibitors are considered to be a standard of therapy and drug class of choice for the treatment of early breast cancer in postmenopausal women with hormone-receptor positive disease. The American Society of Clinical Oncology recommends that all postmenopausal women with hormone receptor-positive early breast cancer receive adjuvant aromatase inhibitor therapy. Options include 5 years of an aromatase inhibitor or sequential therapy with 2—3 years or 5 years of tamoxifen followed by 2—3 years or 5 years of an aromatase inhibitor.(1) Long-term data indicate that the improvements in disease-free survival persist for the 5 years during treatment and after drug discontinuation (see Dosage)(2)(3). Although not FDA-approved, several studies have shown that anastrozole further improves disease-free survival when used sequentially after 2—3 years of tamoxifen when compared to patients taking tamoxifen for 5 years.(4)5). Anastrozole was initially FDA-approved for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed during tamoxifen therapy in December 1995. In September 2000, the FDA approved anastrozole for the first-line treatment of postmenopausal women with advanced or metastatic breast cancer. Approval for the adjuvant treatment of early breast cancer in postmenopausal women with hormone receptor positive disease was received in September 2002.

Question 59

Mechanism of Action

Accepted Answer

Anastrozole inhibits aromatase, the enzyme that catalyzes the final step in estrogen production. Anastrozole is an oral, competitive, non-steroidal inhibitor of aromatase and is less likely to exhibit agonist or antagonist steroidal properties.(6) The formation of adrenal corticosteroids or aldosterone is not affected by anastrozole; only serum estradiol concentrations are affected by anastrozole. In postmenopausal women, the principal source of circulating estrogens is from the conversion of adrenal and ovarian androgens (androstenedione and testosterone) to estrogens (estrone and estradiol) by aromatase in peripheral tissues. Inhibition of aromatase may result in a more complete estrogen block than surgical ablation. Extraglandular sites are more amenable to aromatase inhibition by anastrozole than are premenopausal ovaries. Inhibiting the biosynthesis of estrogens is one way to deprive the tumor of estrogens and to restrict tumor growth. Estradiol plasma concentrations decrease about 80% from the baseline with continued dosing of anastrozole.(7) Aromatase inhibitors might also inhibit estrogen production at the tumor cell. However, tumor production of estradiol may be insignificant because aromatase activity appears to be low.(8) Anastrozole has little or no effect on CNS, autonomic, or neuromuscular function.

Question 60

Pharmacokinetics

Accepted Answer

Anastrozole is administered orally. Pharmacokinetics are linear, even with repeated dosing. Hepatic metabolism accounts for approximately 85% of elimination. Within 72 hours, about 60% of a dose is excreted in the urine as metabolites and only 10% as unchanged drug. Three metabolites have been identified in plasma and urine, and there are several unidentified minor metabolites. No pharmacological activity has been attributed to triazole, the main circulating metabolite. The other known metabolites are a glucuronide conjugate of hydroxy-anastrozole and a glucuronide conjugate of anastrozole. Anastrozole has a terminal elimination half-life of about 50 hours.

Per the manufacturer, it is unlikely that anastrozole administered at the recommended dose will inhibit the metabolism of cytochrome P450-mediated drugs given concomitantly. High concentrations inhibited metabolic reactions catalyzed by cytochromes P450 (CYP) 1A2, 2C8/9, and 3A4. It did not inhibit CYP2A6 or the polymorphic CYP2D6 in human liver microsomes.(9)

Route-Specific Pharmacokinetics:

Oral Route: Anastrozole is well absorbed and distributed throughout the systemic circulation (85% bioavailability). Maximum plasma concentrations occur within 2 hours.(7) Plasma concentrations approach steady-state levels by about the seventh day of once-daily dosing.

Special Populations:

Hepatic Impairment: Although hepatic cirrhosis reduces apparent oral clearance of anastrozole, no dosage adjustments are needed because plasma concentrations remain within the same range as for patients without hepatic disease.

Renal Impairment: Renal clearance of anastrozole does decrease proportionally with creatinine clearance, but overall this has very little effect on total body clearance. No dosage adjustments are therefore necessary for patients with impaired renal function.

Question 61

Indications

Accepted Answer

Anastrozole is commonly indicated and prescribed for:  treatment of advanced or metastatic carcinoma in the breast of postmenopausal women; adjunctive therapy in the treatment of early carcinoma in the breast of postmenopausal women; and treatment of excessive estrogen production in men.  It is typically found in capsule or tablet forms of .25 mg, .5 mg, and 1 mg.  The effects of Anastrozole can be very substantial, with a daily dose of 1 mg (commonly one tablet).

Question 62

Contraindications/Precautions:

Accepted Answer

Your health care provider needs to know if you have any of these conditions:  heart disease, circulation problems, a history of stroke or blood clot, severe liver disease, high cholesterol, osteoporosis, or low bone mineral density. Anastrozole may not work as well if you take it together with tamoxifen or an estrogen medication (such as hormone replacement therapy, estrogen creams, or birth control pills, injections, implants, skin patches, and vaginal rings). You may need to keep taking anastrozole for up to 5 years. In general, anastrozole should not be used in premenopausal females; anastrozole may not be able to inhibit the formation of estrogen from the ovaries and therefore is not expected to be effective, although it has been used successfully in the treatment of uterine leiomyomata in premenopausal women.(10) Hormone replacement therapy (i.e., exogenous estrogens) should not be administered concurrently with anastrozole. Hepatic cirrhosis due to alcohol abuse reduces apparent oral clearance of anastrozole by about 30%. Anastrozole should be used with caution in patients with mild to moderate hepatic impairment, and patients should be closely monitored for adverse effects. However, no dosage adjustments are recommended for patients with hepatic disease because plasma anastrozole concentrations remain within the range of those seen in normal patients. No studies have been conducted in patients with severe hepatic impairment. Consideration should be given to monitoring patients for signs and symptoms of osteoporosis, including decreased bone mineral density (BMD), during treatment with anastrozole, especially in patients with pre-existing osteoporosis, osteopenia, or risk factors for the development of osteoporosis. After a median follow-up of 68 months in the ATAC trial, the odds of bone fractures in patients taking anastrozole were significantly increased compared to patients taking tamoxifen (11% for anastrozole vs. 7.7% for tamoxifen, OR 1.49, 95% CI 1.25—1.77, P < 0.0001).(2) Similarly, in the combined analysis of the ABCSG trial 8 and the ARNO 95 trials, after a median follow-up of 36 months, the odds of bone fractures in patients taking anastrozole were significantly increased (2% for anastrozole vs. 1% for tamoxifen, OR 2.14, 95% CI 1.14—4.17, P = 0.015)(11). Anastrozole should be used with caution in women with pre-existing ischemic cardiac disease. In the ATAC trial, women with pre-existing ischemic heart disease had an increased incidence of ischemic cardiovascular events (17% of patients receiving anastrozole versus 4% of patients in the overall study population). Safety and efficacy of anastrozole in children have not been established. Anastrozole is classified as FDA pregnancy risk category X.(12) It is contraindicated for use in women who are pregnant or may become pregnant. Anastrozole may cause fetal harm when administered to pregnant women and offers no clinical benefit when administered to premenopausal women with breast cancer. Animal studies indicate that anastrozole increases pregnancy loss, both pre- and postimplantation. It crosses the placenta and causes fetal harm, including delayed fetal development, but there has been no evidence of teratogenicity. There have been no adequate studies in pregnant women, and anastrozole is only approved for the treatment of postmenopausal women, and should generally not be used in females of childbearing potential. If pregnancy occurs, however, while the patient is receiving anastrozole, she should be warned about the possible risk to the fetus and possible loss of pregnancy. It is not known whether anastrozole is excreted into breast milk. Because many drugs are excreted in human milk and because of the tumorigenicity shown for anastrozole in animal studies, or the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue breast-feeding or to discontinue the drug, taking into account the importance of the drug to the mother. Anastrozole is contraindicated in pre-menopausal females, so use during lactation would not be expected.(12) This list may not include all possible contraindications."}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1604","name":"Pregnancy","acceptedAnswer":{"@type":"Answer","text":"Anastrozole is classified as FDA pregnancy risk category X.(12) It is contraindicated for use in women who are pregnant or may become pregnant. Anastrozole may cause fetal harm when administered to pregnant women and offers no clinical benefit when administered to premenopausal women with breast cancer. Animal studies indicate that anastrozole increases pregnancy loss, both pre- and postimplantation. It crosses the placenta and causes fetal harm, including delayed fetal development, but there has been no evidence of teratogenicity. There have been no adequate studies in pregnant women, and anastrozole is only approved for the treatment of postmenopausal women, and should generally not be used in females of childbearing potential. If pregnancy occurs, however, while the patient is receiving anastrozole, she should be warned about the possible risk to the fetus and possible loss of pregnancy."}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1603","name":"Breast-feeding","acceptedAnswer":{"@type":"Answer","text":"It is not known whether anastrozole is excreted into breast milk. Because many drugs are excreted in human milk and because of the tumorigenicity shown for anastrozole in animal studies, or the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue breast-feeding or to discontinue the drug, taking into account the importance of the drug to the mother. Anastrozole is contraindicated in pre-menopausal females, so use during lactation would not be expected.(12)"}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1602","name":"Adverse Reations/Side Effects","acceptedAnswer":{"@type":"Answer","text":"Numbness; tingling; cold feeling; or weakness in your hand or wrist; problems with your fingers while gripping; hot flashes; joint pain or stiffness; depression; mood changes; sleep problems (insomnia); cough; sore throat; thinning hair; mild nausea; vomiting; back pain; bone pain. Hot flashes (11—36%) were the most commonly reported adverse reaction associated with anastrozole during clinical trials. Other commonly reported adverse reactions during controlled trials included vaginal irritation (i.e., dryness) (1—2%), vaginal bleeding (1—5%), vaginal discharge (4%), vaginitis (4%), and vulvovaginitis (6%). Vaginal bleeding occurs primarily during the first few weeks after changing from existing hormonal therapy to treatment with anastrozole. If bleeding persists, further evaluation should be considered(12). Gastrointestinal/digestive adverse reactions occurred in up to one-third of patients receiving anastrozole during clinical trials. These reactions included abdominal pain (6—9%), anorexia (5—8%), constipation (7—9%), diarrhea (7—9%), dyspepsia (7%), nausea (11—20%), vomiting (8—13%), and xerostomia or dry mouth (4—6%). Weight gain was reported in 2—9% of patients taking anastrozole, but occurred less frequently than with megestrol (12%). Additionally, 2—5% of anastrozole recipients also experienced weight loss and elevated hepatic enzymes, with or without jaundice (= 0.1% to < 1%. Due to the voluntary nature of post-market reports, neither a definitive incidence nor causal relationship can be established(12). Nervous system adverse reactions associated with the use of anastrozole during clinical trials include anxiety (2—6%), confusion (2—5%), depression (2—13%), dizziness (5—8%), drowsiness (2—5%), headache (7—18%), hypertonia (3%), insomnia (2—10%), lethargy (1%), malaise (2—5%), nervousness (2—5%), and paresthesias (5—7%)(12). Administration of anastrozole has been associated with the development of thromboembolic events. Thromboembolism was reported in 2—4% of patients treated with anastrozole during clinical trials. The incidence of anastrozole-associated thrombosis was less than that reported with tamoxifen (2—6%) or megestrol (5%). Specific cases included angina (2.3—11.6%), cerebrovascular accident (stroke) specifically cerebral ischemia and cerebral infarct (2%), myocardial infarction (0.9—1.2%), myocardial ischemia (< 4%), pulmonary embolism (< 4%), retinal thrombosis (< 4%), and thrombo-phlebitis (2—5%). In the ATAC trial, women with pre-existing ischemic cardiac disease had a 17% incidence of ischemic cardiac events. In this patient population, angina occurred in 11.6% and myocardial infarction in 0.9%.(12). Musculoskeletal reactions are some of the more common adverse events experienced by recipients of anastrozole therapy (36%). During clinical trials, patients receiving anastrozole reported symptoms including arthralgia (2—15%), arthritis (17%), arthrosis (7%), asthenia (13—19%), back pain (10—12%), bone pain (6—11%), breast pain (2—8%), carpal tunnel syndrome (2.5%), chest pain (unspecified) (5—7%), fatigue (19%), myalgia (2—6%), neck pain (2—5%), and pelvic pain (5%). Additionally, episodes of trigger finger have been reported during post-marketing use by 0.1—1% of anastrozole recipients. Due to the voluntary nature of post-market reports, neither a definitive incidence nor causal relationship with anastrozole can be established.(12). Osteoporosis has been reported as an adverse event to anastrozole, but causality has not been determined. Data from clinical trials indicate that musculoskeletal events and bone fractures are significantly more common in patients receiving anastrozole (36% and 10%, respectively) versus tamoxifen (29% and 7%, respectively). The anatomical sites with the greatest increase in fracture incidence were wrist fractures (2%), spine fractures (1%), and hip fractures (1%). Of note, long-term data indicate that fracture rates were not different after anastrozole or tamoxifen discontinuation (median follow-up 100 months).(3) Similarly, in the combined analysis of the ABCSG trial 8 and the ARNO 95 trials, after a median follow-up of 36 months, the odds of bone fractures in patients taking anastrozole were significantly increased (2% for anastrozole vs. 1% for tamoxifen, OR 2.14, 95% CI 1.14—4.17, P=0.015).(11) Health care professionals are advised to consider bone mineral density testing prior to and during anastrozole therapy in those patients at risk of developing osteoporosis.(12). During the ATAC trial, more patients receiving anastrozole were reported to have hypercholesterolemia compared to those receiving tamoxifen (9% vs. 3.5%, respectively).(14) Other anastrozole-associated adverse events affecting the cardiovascular system included edema (7—11%), hypertension (2—13%), peripheral edema (5—10%), and peripheral vasodilation (25—36%).(12). Dermatologic adverse events have been associated with anastrozole therapy. During clinical trials, patients treated with anastrozole experiences symptoms including alopecia (2—5%), diaphoresis (1—5%), pruritus (2—5%), and rash (unspecified) (6—11%). Additionally, rare cases (< 1 in 10,000 patients or < 0.01%) of serious anastrozole-induced skin reactions (e.g., skin lesion, skin ulcer, and skin blister) have also occurred. During post-market use, anaphylaxis, angioedema, erythema multiforme, Stevens-Johnson syndrome and urticaria were reported by anastrozole recipients. Due to the voluntary nature of post-market reports, neither a frequency nor a definitive causal relationship to anastrozole can be established (12). During clinical trials, the incidence of infections in patients receiving treatment with anastrozole was 2—9%. Reports identified the specific infection sites as bronchitis (2—5%), influenza (2—7%), pharyngitis (6—14%), sinusitis (2—6%), and urinary tract infections (2—8%). Symptoms reported by anastrozole recipients and potentially related to an infection included cough (7—11%), dyspnea (8—11%), fever (2—5%), leukorrhea (2—3%), and rhinitis (2—5%).(12). Hematologic and lymphatic adverse events reported by recipients of anastrozole during clinical trials included anemia (2—5%), leukopenia (2—5%), and lymphedema (10%).(12). There are currently no studies in pregnant humans; however, use of anastrozole in rats and rabbits has resulted in pregnancy failure, increased fetal abortion, and signs of delayed fetal development or teratogenesis. In both rats and rabbits, increased pregnancy loss was described as an increase in pre- and post-implantation loss, increased resorption, and decreased number of live fetuses. Additionally, adverse fetal effects associated with anastrozole included incomplete ossification and decreased fetal body weight. Use of anastrozole is contraindicated in pregnant women(12). Other adverse events associated with the use of anastrozole during clinical trials include accidental injury (2—10%), cataracts (6%), development of a cyst or neoplasm (5%), and tumor flare (3%)(12). Hypercalcemia (with or without an increase in parathyroid hormone) has been reported in post-marketing use. Due to the voluntary nature of post-market reports, neither a definitive incidence nor causal relationship with anastrozole can be established(9). This list may not include all possible adverse reactions or side effects. Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue, blue tint to skin, chest tightness, pain, difficulty breathing, wheezing, dizziness, red, a swollen painful area/areas on the leg."}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1601","name":"Storage","acceptedAnswer":{"@type":"Answer","text":"Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain."}},{"@type":"Question","url":"https://medlabglobal.com/all_helpie_faq_page/#hfaq-post-1600","name":"Interactions:","acceptedAnswer":{"@type":"Answer","text":"NOTE: High concentrations of anastrozole inhibited metabolic reactions catalyzed by cytochromes P450 (CYP) 1A2, 2C8/9, and 3A4. Anastrozole did not inhibit CYP2A6 or the polymorphic CYP2D6 in human liver microsomes. Per the manufacturer, it is unlikely that anastrozole administered at the recommended dose will inhibit the metabolism of cytochrome P450-mediated drugs given concomitantly (13). In a study in male volunteers (n=16), anastrozole did not alter the warfarin pharmacokinetics (Cmax or AUC), and did not alter warfarin anticoagulant activity as measured by prothrombin time, activated partial thromboplastin time, and thrombin time of both R- and S-warfarin (13). Anastrozole and tamoxifen should not be administered together. Clinical and pharmacokinetic results from the ATAC study (14) demonstrate that concurrent administration of anastrozole and tamoxifen results in a reduction of anastrozole plasma levels by 27% compared to those achieved with anastrozole alone.(13) However, coadministration did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen.(13).  The goal of anastrozole therapy is to decrease circulating estrogen concentrations and inhibit the growth of hormonally-responsive cancers.(13) Anastrozole should not be given concurrently with any estrogens or estrogen-containing products, including combined oral contraceptives, as these could interfere with the pharmacologic action of anastrozole. In addition, in women receiving long-term aromatase inhibitor therapy, atrophic vaginitis due to estrogen suppression is common; atrophic vaginitis due to aromatase inhibitor therapy is sometimes treated with vaginal estrogen as the systemic exposure of estrogen from vaginal preparations is thought to be low. In a recent study of 7 women on aromatase inhibitor therapy, estrogen concentrations rose significantly after the addition of vaginally administered estrogen for atrophic vaginitis. Estrogen concentrations increased from a mean baseline level of < 5 pmol/l to 72 pmol/l at 2 weeks and to  1 mcg/l persist for approximately 11—14 days following single doses of 0.75 or 1.5 mg/kg.

Special Populations:

Pediatrics: It appears that the clearance of somatropin in children and adults is similar; however, no pharmacokinetic studies have been conducted in children with short bowel syndrome.

Gender Differences: Biomedical literature indicates males may clear somatropin more quickly than females, although no gender-based analysis is available.

Question 63

Indications:

Accepted Answer

For the treatment of growth hormone deficiency, growth failure, or short stature:

NOTE: The response to somatropin therapy in pediatric patients tends to decline with time. However, the failure to increase growth rate, especially during the first year of therapy, necessitates close assessment of compliance and evaluation for underlying causes of growth failure, such as hypothyroidism, undernutrition, advanced bone age, and antibodies to recombinant human growth hormone.

For replacement therapy in adults with growth hormone deficiency (GHD) for either childhood onset (secondary to congenital, genetic, acquired, or idiopathic causes) or adult onset (endogenous or associated with multiple hormone deficiencies, i.e., hypopituitarism, as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma):

NOTE: In general, the diagnosis of both adult or childhood onset growth hormone deficiency should be confirmed by an appropriate growth hormone stimulation test. Stimulation testing may not be necessary in patients with congenital/genetic growth hormone deficiency or multiple pituitary hormone deficiencies due to organic disease.

NOTE: Clinical response, side effects, and age- and gender-adjusted serum IGF-I levels may be used to guide dose titration. This approach will tend to result in larger doses for women compared to men, smaller doses for adult-onset GHD patients compared with childhood-onset GHD patients, and smaller doses for older and obese patients.
NOTE: Patients with childhood onset growth hormone deficiency whose epiphyses are closed should be reevaluated before continuation of somatropin therapy.

Geriatric: See adult dosage. Consider giving a lower starting dose and smaller dose increments to minimize adverse events.

Subcutaneous dosage: Adults: Initially, not more than 0.004 mg/kg SC per day. After 6 weeks, the dose may be increased, as tolerated, to a maximum of 0.016 mg/kg per day. Alternatively, the following non-weight based approach may be used: initially, 0.2 mg SC per day (0.15—0.30 mg SC per day); increase dose gradually by increments of approximately 0.1—0.2 mg/day every 1—2 months based on clinical response and serum insulin-like growth factor I (IGF-I) concentrations. Decrease the dose as necessary based on the adverse events and/or serum IGF-I concentrations above the age- and gender-specific normal range. Maintenance dosages vary considerably from person to person and between male and female patients. NOTE: Obese patients are more likely to experience adverse effects when dosed by weight.
Geriatric: See adult dosage. Consider giving a lower initial dose and smaller dose increments to minimize adverse events.

For the long-term treatment of growth failure in children who have growth hormone deficiency due to inadequate growth hormone secretion:

Subcutaneous dosage: Children: 0.024—0.034 mg/kg/dose SC given 6 to 7 times a week. Dosage should be individualized for each patient.

For growth failure due to Prader-Willi syndrome:

Subcutaneous dosage: NOTE: Genotropin or Omnitrope should only be used in Prader-Willi syndrome patients who have a diagnosis of growth hormone deficiency; Genotropin and Omnitrope are contraindicated in Prader-Willi syndrome patients who are severely obese or who have severe respiratory impairment.

Children: Generally, 0.24 mg/kg SC per week divided into 6 or 7 equal daily injections.12

For the long-term treatment of growth failure in children born small for gestational age (SGA) who fail to manifest catch-up growth by age 2-4:

Subcutaneous dosage: Children: Up to 0.067 mg/kg/day SC (0.47 mg/kg/week) is recommended. Recent data suggest that for younger children with a baseline HSDS between -2 and -3, the initial dose is 0.033 mg/kg/day SC with upwards titration as needed. For children with a baseline HSDS  1 mcg/l persist for approximately 11—14 days following single doses of 0.75 or 1.5 mg/kg.

Special Populations:

Pediatrics: It appears that the clearance of somatropin in children and adults is similar; however, no pharmacokinetic studies have been conducted in children with short bowel syndrome.

Gender Differences: Biomedical literature indicates males may clear somatropin more quickly than females, although no gender-based analysis is available.

Question 64

General Information

Accepted Answer

Somatropin, rh-GH is a purified recombinant growth hormone prepared by using either Escherichia coli or mammalian-cells. Endogenous human growth hormone (hGH) is produced in the pituitary gland. Growth hormone was first isolated in 1956, and its structure was identified in 1972. Prior to 1985, growth hormone (GH) was derived from human cadavers; however, the use of human derived GH was stopped due to contamination of the product with Creutzfeldt-Jakob virus. Somatropin is approved for treating growth hormone deficiency (GHD), growth failure, or short stature and for treating cachexia and AIDS wasting; it is also approved for adults with short bowel syndrome. Somatropin has been studied in the treatment of HIV-associated adipose redistribution syndrome (HARS); limited short-term data indicate use may decrease visceral adipose tissue. Several somatropin products are available, all with varying indications and dosage regimens. Care should be taken in product selection as products may not be considered interchangeable. Somatropin was originally approved by the FDA in 1987.

All FAQs (Helpie FAQ)

Information

Arrange a

TeleHeaLth consultation with one of our doctors

A NEXT GENERATION LIFE SCIENCES COMPANY

Quick links

Our Policy

Products

Contact