Pregnyl 5000 I.U.

Injection containing human chorionic gonadotrophin 5000 IU.

Freeze dried powder for injection

In the male

Hypogonadotrophic hypogonadism.

Delayed puberty associated with insufficient gonadotrophic pituitary function.

Sterility in selected cases of deficient spermatogenesis.

In the female

Sterility due to the absence of follicle-ripening or ovulation.

In conjunction with HMG, in the promotion of controlled superovulation in medically assisted reproduction programmes.

Dosage

In the male

Hypogonadotrophic hypogonadism:

500 - 1,000 Units 2-3 times weekly.

Delayed puberty associated with insufficient gonadotrophic pituitary function:

1,500 Units twice weekly for at least 6 months.

Sterility in selected cases of deficient spermatogenesis:

Usually, 3,000 Units per week in combination with an HMG preparation.

In the female

Sterility due to the absence of follicle-ripening or ovulation:

5000 - 10 000 Units hCG to induce ovulation, following treatment with an HMG (human menopausal gonadotrophins) preparation. Up to 3 repeat injections of up to 5000 Units hCG each, may be given within the following 9 days to prevent insufficiency of the corpus luteum.

In conjunction with HMG, in the promotion of controlled superovulation in medically assisted reproduction programmes:

5000 - 10 000 Units hCG 30 - 40 hours after the last HMG injection. Pregnyl should not be administered if the following criteria have not been met: It is recommended that at least 3 follicles greater than 17mm in diameter are present with 17 oestradiol levels of at least 3500 pmol/L (920 picogram/ml). Oocyte collection is carried out 32 - 36 hours after the hCG injection.

Method of Administration

After addition of the solvent to the freeze-dried substance, the solution should be given immediately by intramuscular or subcutaneous injection. Any unused solution should be discarded. Subcutaneous injection may be carried out by patient or partner, provided that proper instruction are given by the physician. Self administration of Pregnyl should only be performed by patients who are well-motivated, adequately trained and with access to expert advice.

• Hypersensitivity to human gonadotropins or any of the substances of Pregnyl.

• Presence of uncontrolled non-gonadal endocrinopathies (e.g. thyroid, adrenal or pituitary disorders)

• Breast, uterine, ovarian, testicular tumours

• Vaginal bleeding of unknown cause

• Known or suspected androgen-dependent tumours, carcinoma of the prostate or mammary carcinoma in males.

In the female:

• Since infertile women undergoing assisted reproduction, and particularly IVF, often have tubal abnormalities the incidence of ectopic pregnancies might be increased. Early ultrasound confirmation that a pregnancy is intrauterine is therefore important.

• Prior to treating patients for inadequate endogenous stimulation of the gonads, an examination should be performed to exclude anatomical abnormalities of the genital organs or nongonadal endocrinopathies (e.g. thyroid or adrenal disorders, diabetes). Primary ovarian failure should be excluded by the determination of gonadotrophin levels.

• In the pregnancies occurring after induction of ovulation with gonadotrophic preparations, there is an increased risk of abortion and multiplets. Multiple pregnancy, especially high order, carries an increased risk in adverse maternal and perinatal outcomes. The parents should be advised of the potential risks of multiple births before starting treatment.

• The incidence of congenital malformations after Assisted Reproductive Technologies (ART) may be higher than after spontaneous conceptions. This is thought to be due to differences in parental characteristics (e.g. maternal age, sperm characteristics) and an increased incidence of multiple gestations.

• Women with generally recognised risk factors for thrombosis, such as a personal or family history, severe obesity (Body Mass Index > 30 kg/m2) or thrombophilia, may have an increased risk of venous or arterial thromboembolic events, during or following treatment with gonadotropins. 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.

• There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for infertility treatment. It is not yet established whether or not treatment with gonadotrophins increases the baseline risk of these tumours in infertile women.

Unwanted Hyperstimulation

During treatment of female patients, determinations of oestrogen levels and assessment of ovarian size and if possible, ultrasonography should be performed prior to treatment and at regular intervals during treatment. High dosages may cause oestrogen levels to rise excessively rapidly, e.g. more than doubling on 2 or 3 consecutive days, and possibly reaching excessively high pre-ovulatory values. The diagnosis of unwanted ovarian hyperstimulation may be confirmed by ultrasound examination.

If unwanted hyperstimulation occurs (i.e. not as part of a treatment preparing for IVF/ET or GIFT or other assisted reproduction techniques), the administration of HMG should be discontinued immediately. hCG must not be given, because the administration of an hLH - active gonadotrophin at this stage may induce, in addition to multiple ovulations, the ovarian hyperstimulation syndrome. This warning is particularly important with respect to patients with polycystic ovarian disease.

The severe form of ovarian hyperstimulation syndrome may be life-threatening and is characterised by large ovarian cysts (prone to rupture), acute abdominal pain, ascites, very often hydrothrax and occasionally thrombo-embolic phenomena.

In the male:

Treatment with hCG leads to increased androgen production. Therefore:

• 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.

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

None known.

Not applicable.

Not applicable.

Oedema, headache, tiredness, mood changes, gynaecomastia and local site reactions.

Skin rashes have occasionally been reported. In rare cases generalized rash or fever may occur.

In the female:

• Unwanted ovarian hyperstimulation, ovarian hyperstimulation syndrome (OHSS). Characteristic symptoms of unwanted ovarian hyperstimulation and OHSS are included under “Special Warnings and Special Precautions for Use” in Section 4.4.

• In rare instances, thromboembolism has been associated with FSH/hCG therapy (see Section 4.4)

In the male:

• Water and sodium retention is occasionally seen after administration of high dosages; this is regarded as a result of excessive androgen production.

• HCG treatment may sporadically cause gynaecomastia.

• Acne may occur occasionally during hCG therapy.

The toxicity of human chorionic gonadotrophic hormone is very low. However, too high a dose may lead to hyperstimulation of the ovaries. (See "Unwanted Hyperstimulation").

Pregnyl is a preparation of human chorionic gonadotrophin obtained from the urine of pregnant women. It stimulates the steroidogenesis in the gonads by virtue of a biological effect similar to that of LH (Luteinizing hormone, which is the same as interstitial cell stimulating hormone). In the male it promotes the production of testosterone and in the female the production of estrogens and particularly of progesterone after ovulation. In certain cases, this preparation is used in combination with human menopausal gonadotrophin (HMG).

Because HCG is of human origin, no antibody formation is to be expected.

Maximal hCG plasma levels will be reached in males after a single IM or SC injection of hCG at approximately six and sixteen hours respectively, and in females after approximately 20 hours. hCG is approximately 80 per cent metabolized, predominantly in the kidneys. IM and SC administration of hCG were found to be bioequivalent regarding the extent of absorption and the apparent elimination half-lives of approximately 33 hours. On basis of the recommended dose regimens and elimination half-life, cumulation is not expected to occur.

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

Powder for injection contains:

Solvent contains:

None stated.

36 months.

Store at 2 to 8°C. Do not freeze. Keep the ampoules in the outer carton to protect from light.

2ml ampoule containing freeze-dried powder with 1ml ampoule of solvent sodium chloride 9mg/ml.

Pregnyl should be reconstituted with the solvent provided. Do not use if the solution contains particles or if the solution is not clear. Since an opened ampoule cannot be resealed in such a way to further guarantee the sterility of the contents, the solution should be used immediately after reconstitution. Discard any remaining solution after single use.

Organon Laboratories Limited, Cambridge Science Park, Milton Road, Cambridge, CB4 0FL, U.K.

PL0065/5079R

25th February 1991/25th March 2003

September 2004

REF: USPreg5000 v7.1