Pregnancy

Precautions

The active ingredient of this preparation is extracted from human urine. Therefore the risk of a transmission of a pathogen (known or unknown) can not be completely excluded.

For males and females:

Hypersensitivity reactions:

·Hypersensitivity reactions, both generalised and local; anaphylaxis; and angioedema have been reported. If a hypersensitivity reaction is suspected, discontinue Pregnyl and assess for other potential causes for the event.

General:

· Patients should be evaluated for uncontrolled non-gonadal endocrinopathies (e.g. thyroid, adrenal or pituitary disorders) and appropriate specific treatment given.

· Pregnyl should not be used for body weight reduction. HCG has no effect on fat metabolism, fat distribution or appetite.

In the female:

Multi-foetal gestation and birth:

• In pregnancies occurring after induction of ovulation with gonadotrophic preparations, there is an increased risk of multiple pregnancies Ectopic pregnancy
• Infertile women undergoing Assisted Reproductive Technologies (ART) have an increased incidence of ectopic pregnancy. Early ultrasound confirmation that a pregnancy is intrauterine is therefore important.

Pregnancy loss:

·Rates of pregnancy loss in women undergoing ART are higher than in normal population.

Congenital malformations:

·The incidence of congenital malformations after Assisted Reproductive Technologies (ART) may be slightly higher than after spontaneous conceptions. This slightly higher incidence is thought to be related to differences in parental characteristics (e.g. maternal age, sperm characteristics) and to the higher incidence of multiple gestations after ART. There are no indications that the use of gonadotrophins during ART is associated with an increased risk of congenital malformations.

Ovarian Hyperstimulation Syndrome (OHSS):
·OHSS is a medical event distinct from uncomplicated ovarian enlargement.

Clinical signs and symptoms of mild and moderate OHSS are abdominal pain, nausea, diarrhoea, mild to moderate enlargement of ovaries and ovarian

cysts. Severe OHSS may be life-threatening. Clinical signs and symptoms of severe OHSS are large ovarian cysts, acute abdominal pain, ascites, pleural effusion, hydrothorax, dyspnoea, oliguria, haematological abnormalities and weight gain. In rare instances, venous or arterial thromboembolism may occur in association with OHSS. Transient liver function test abnormalities suggestive of hepatic dysfunction with or without morphologic changes on liver biopsy have also been reported in association with OHSS.

OHSS may be caused by administration of human Chorionic Gonadotrophin (hCG) and by pregnancy (endogenous hCG). Early OHSS usually occurs within 10 days after hCG administration and may be associated with an excessive ovarian response to gonadotrophin stimulation. Late OHSS occurs more than 10 days after hCG administration, as a consequence of the hormonal changes with pregnancy. Because of the risk of developing OHSS, patients should be monitored for at least two weeks after hCG administration.

Women with known risk factors for a high ovarian response may be especially prone to the development of OHSS during or following treatment with hCG. For women having their first cycle of ovarian stimulation, for whom risk factors are only partially known, close observation for early signs and symptoms of OHSS is recommended.

To reduce the risk of OHSS, ultrasonographic assessments of follicular development should be performed prior to treatment and at regular intervals during treatment. The concurrent determination of serum estradiol levels may also be useful. In ART, there is an increased risk of OHSS with 18 or more follicles of 11 mm or more in diameter. When there are 30 or more follicles in total, it is advised to withhold hCG administration.

Depending on the ovarian response, the following measures can be considered to reduce the risk of OHSS:

Withhold further stimulation with a gonadotrophin for a maximum of 3 days (coasting);

Withhold hCG and cancel the treatment cycle;
Administer a dose lower than 10,000 IU of urinary hCG for triggering final oocyte maturation, e.g. 5,000 IU urinary hCG or 250 micrograms rec-hCG (which is equivalent to approximately 6,500 IU of urinary hCG);

Cancel the fresh embryo transfer and cryopreserve embryos;

Avoid administration of hCG for luteal phase support.

Adherence to the recommended Pregnyl dose and treatment regimen and careful monitoring of ovarian response is important to reduce the risk of OHSS. If OHSS develops, standard and appropriate management of OHSS should be implemented and followed.

Ovarian torsion:

Ovarian torsion has been reported after treatment with gonadotrophins, including hCG. Ovarian torsion may be related to other conditions, such as OHSS, pregnancy, previous abdominal surgery, past history of ovarian torsion, and previous or current ovarian cysts. Damage to the ovary due to reduced blood supply can be limited by early diagnosis and immediate detorsion.

Vascular complications

Thromboembolic events, both in association with and separate from OHSS, have been reported following treatment with gonadotrophins, including hCG. Intravascular thrombosis, which may originate in venous or arterial vessels, can result in reduced blood flow to vital organs or the extremities. Women with generally recognised risk factors for thrombosis, such as a personal or family history, severe obesity or thrombophilia, may have an increased risk of venous or arterial thromboembolic events, during or following treatment with gonadotrophins. In these women the benefits of IVF treatment need to be weighed against the risks. It should be noted, however, that pregnancy itself also carries an increased risk of thrombosis.

In the male:

Antibody formation:
·Administration of hCG can provoke the formation of antibodies against hCG.

In rare cases, this may result in an ineffective treatment.

Treatment with hCG leads to increased androgen production. Therefore:

· hCG should be used cautiously in prepubertal boys to avoid premature epiphysial closure or precocious sexual development. Skeletal maturation should be monitored regularly.

· Patients with latent or overt cardiac failure, renal dysfunction, hypertension, epilepsy or migraine (or a history of these conditions) should be kept under close medical supervision, since aggravation or recurrence may occasionally be induced as a result of increased androgen production.