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 <2—8% (vs. 6%) of patients receiving Niaspan compared to placebo.(2)
Vitamin E Acetate
Bleeding complications have been reported in adults receiving high dose vitamin E supplementation due to vitamin E inhibition of platelet aggregation and vitamin K clotting factors.(54)(55) In very-low-birth-weight infants, the use of intravenous, high dose vitamin E supplementation has been associated with an increased risk in parenchymal cerebral hemorrhage (intracranial bleeding). Factors contributing to these toxicities in premature neonates include alpha-tocopherol serum concentrations more than 3.5 mg/dL and the composition of the injectable formulation.(56)
Nausea, diarrhea, and rash have been reported with the use of oral vitamin E; the oral solution, in particular, has a high osmolality that may contribute to GI intolerances such as diarrhea. Administration of the solution with food or feedings may reduce GI intolerance.(57) Prolonged use of large systemic doses of vitamin E (e.g., 533 mg/day or more [800 International Units/day or more] in adults) has, in rare instances, caused breast enlargement, fatigue, intestinal cramps, weakness; blurred vision, headache, gonadal dysfunction, increased serum cholesterol and triglycerides, increased urinary estrogens and androgens, creatinuria, and decreased serum thyroxine and triiodothyronine. These effects are reversible following discontinuance of the drug.
In preterm and very low birth weight infants, vitamin E supplementation has been associated with an increased incidence of infection and/or sepsis, especially with serum alpha-tocopherol concentrations more than 3.5 mg/dL.(56) High serum alpha-tocopherol concentrations are also associated with an increased risk of necrotizing enterocolitis in very-low-birth-weight infants treated with vitamin E for more than 1 week.(56) Initial data reported to the FDA suggests a 30% incidence of necrotizing enterocolitis in infants with serum vitamin E concentrations more than 3.5 mg/dL compared to 4% in infants with serum alpha-tocopherol concentrations of 3.5 mg/dL or less. However, this data is limited by a low number of patients studied and disparate studies.(58) Monitor serum vitamin E concentrations in these infants and also for signs and symptoms of infection or for feeding intolerance or other gastrointestinal symptoms.
Topical vitamin E products have been reported to cause contact dermatitis and other rashes; patients should report skin irritation, burning, or other unusual effects and discontinue use of the topical product if these occur.
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