1. NAME OF THE MEDICINAL PRODUCT

Pregnyl ® 5000 I.U.powder for solution for injection.

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Pregnyl consists of a freeze-dried powder for injection.    The    active ingredient [human chorionic

gonadotrophin (hCG)] which is obtained from the urine of pregnant women, has luteinizing hormone (LH) activity.

An ampoule contains 5000 I.U. hCG.

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Powder for solution for injection. The powder is a white, dry powder or cake.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

In the female

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

In combination with FSH or HMG, promotion of controlled superovulation in medically assisted reproduction programmes.

In the male

Hypogonadotrophic hypogonadism.

Delayed puberty associated with insufficient gonadotrophic pituitary function.

Sterility in selected cases of deficient spermatogenesis.

4.2 Posology and method of administration

Posology

In the female

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

5.000- 10,000 IU hCG to induce ovulation, following treatment with an FSH (Follicle Stimulating

Hormone) or HMG (Human Menopausal Gonadotrophins) preparation.

In combination with FSH or HMG, promotion of controlled superovulation in medically assisted reproduction programmes.

5.000- 10,000 IU hCG 30 - 40 hours after the last FSH or HMG injection. Pregnyl should not

be

administered if the following criteria have not been met: at least 3 follicles greater than 17mm in diameter are present with 17B estradiol levels of at least 3500 pmol/L (920 picogram/ml). Oocyte collection is carried out 32 - 36 hours after the hCG injection.

As luteal phase support, two to three injections of 1,000 to 3,000 IU hCG each may be given within nine days of ovulation or embryo transfer, for example on day 3, 6 and 9 after ovulation induction or embryo transfer.

In the male

Hypogonadotrophic hypogonadism.

500-1,000 IU hCG 2-3 times weekly.

Delayed puberty associated with insufficient gonadotrophic pituitary function.

1,500 IU hCG twice weekly for at least 6 months.

Sterility in selected cases of deficient spermatogenesis.

Usually, 3,000 IU hCG per week in combination with an FSH or HMG preparation.

This treatment should be continued for at least three months before any improvement in spermatogenesis can be expected. During this treatment testosterone replacement therapy should be suspended. Once achieved, the improvement may sometimes be maintained by hCG alone.

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 is 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.

4.3    Contraindications

□    Hypersensitivity to human gonadotrophins or any of the excipients listed in section 6.1.

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

□    Breast, uterine, ovarian tumours.

□    Vaginal bleeding of unknown cause.

□    Known or suspected androgen-dependent tumours such as testicular tumours, carcinoma of the prostate or mammary carcinoma in males.

□    Malformations of the sexual organs incompatible with pregnancy.

□    Fibroid tumours of the uterus incompatible with pregnancy.

4.4    Special warnings and precautions for use

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 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.

•    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 FSH or 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.

Clinical symptoms of mild ovarian hyperstimulation syndrome include gastro-intestinal problems (pain, nausea, diarrhoea, abdominal discomfort and bloating), painful breasts, and mild to moderate enlargement of ovaries and ovarian cysts. Transient liver function test abnormalities suggestive of hepatic dysfunction, which may be accompanied by morphologic changes on liver biopsy, have been reported in association with ovarian hyperstimulation syndrome.

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, weight gain, very often

hydrothrax and occasionally thrombo-embolic phenomena.

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

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.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed; interactions with commonly used medicinal products can therefore not be excluded.

Following administration, Pregnyl may interfere for up to ten days with the immunological determination of serum/urinary hCG, leading to a false positive pregnancy test.

4.6 Fertility, Pregnancy and lactation

Not applicable.

4.7 Effects on ability to drive and use machines

As far as known Pregnyl has no influence on the ability to drive and use machines.

4.8 Undesirable effects

Frequency is unknown for all undesirable effects described below (cannot be determined with available data).

Immune system disorders

In rare cases generalized rash or fever may occur.

General disorders and administrative site conditions

Local site reactions such as bruising, pain, redness, swelling and itching. Oedema. Occasionally allergic reactions have been reported, mostly manifesting as pain and/or rash at the injection site. Tiredness.

Nervous system disorders

Headache.

Psychiatric disorders

Mood changes.

In the female

Reproductive system and breast disorders

Unwanted ovarian hyperstimulation, mild or severe ovarian hyperstimulation syndrome (OHSS, see section 4.4):

Mild OHSS: Painful breasts

Mild to moderate enlargement of ovaries

Ovarian cysts

Abdominal pain

Abdominal

discomfort

Gastrointestinal symptoms such as nausea, diarrhoea and bloating Severe OHSS: Large ovarian cysts (prone to

rupture), Acute abdominal pain

Ascites

Weight gain

Hydrothorax

In rare instances, thromboembolism has been associated with FSH/hCG therapy

Not all symptoms described are always associated to OHSS.

In the male

Metabolism and nutrition disorders

Water and sodium retention is occasionally seen after administration of high dosages; this is regarded

as a result of excessive androgen production.

Reproduction system and breast disorders

HCG treatment may sporadically cause gynaecomastia.

Skin and subcutaneous tissue disorders

Acne may occur occasionally during hCG therapy.

Reporting of suspect adverse reactions

Reporting suspect adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspect adverse reactions via the Yellow Card scheme, at www.mhra.gov.uk/yellowcard.

4.9 Overdose

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").

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: gonadotrophins: ATC code G03G A01

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.

5.2 Pharmacokinetic properties

In a study performed in healthy male subjects, maximal hCG plasma levels were reached after a single IM or SC injection of hCG at approximately six and sixteen hours respectively; in addition, maximum concentrations and areas under the concentration curves were higher after the IM than after the SC injection. However, these differences did not translate into significant differences in terms of testicular steroidogenic response.

In a study performed in female subjects under oral contraceptives, 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; maximal hCG plasma levels were reached after approximately 20 hours regardless of the route of administration. Although high intersubject variability was observed, the difference related to gender after IM injection may be caused by gluteal fat thickness in women which exceeds that in men. In another study performed in female patients in the early follicular phase of their menstrual cycle, the bioavailability of a single dose of hCG was higher with the IM route than with the SC route and lower in obese women than in non-obese women.

HCG is approximately 80 per cent metabolized, predominantly in the kidneys.

On basis of the recommended dose regimens and elimination half-life, accumulation is not expected to occur.

5.3 Preclinical safety data

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

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Powder for injection contains:

Carmellose sodium Mannitol (E421)

Disodium phosphate (anhydrous)

Sodium dihydrogen phosphate (anhydrous)

6.2    Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products

6.3    Shelf life

36 months

6.4 Special precautions for storage

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

6.5 Nature and contents of container

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

Pregnyl is available in packs of 1, 3 or 10 ampoules of powder and solvent. Not all pack sizes may be marketed.

In correspondence please quote batch number.

Special precautions for disposal

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.

Any unused product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Organon Laboratories Limited

Cambridge Science Park

Milton Road

Cambridge CB4 0FL

UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 00065/5079R

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

25/02/1991    / 24/03/2003

10    DATE OF REVISION OF THE TEXT

21/07/2015