Therapeutic indications

In the female:

·        Ovulation induction in subfertility due to anovulation or impaired follicle-ripening.

·        Preparation of follicles for puncture in controlled ovarian hyperstimulation programs (for medically assisted reproductive techniques).

·        Luteal phase support in women undergoing controlled ovarian hyperstimulation (in medically assisted reproductive programs) using GnRH analogs or after ovulation induction in cases of infertility due to anovulation in the absence of endogenous estrogenous activity (WHO group I).

In the male:

·       Hypogonadotropic hypogonadism.

·       Subfertility associated with idiopathic impaired spermatogenesis.

Male pediatric patients:

·       Delayed puberty associated with insufficient gonadotropic pituitary function.

·       Cryptorchidism, not due to anatomical obstruction.

Posology and method of administration

Treatment with Pregnyl should be initiated under the supervision of a physician experienced in the treatment of fertility problems.

The first injection of Pregnyl should be performed under direct medical supervision.

Dosage in the female:

·        Ovulation induction associated with subfertility due to impaired follicle ripening or  anovulation:
Usually one injection of 5000-10,000 I.U. following treatment with an FSH or hMG preparation.

·        Preparation of follicles for puncture in controlled ovarian hyperstimulation programs:

Usually one injection of 5000 or 10,000 I.U. following treatment with a FSH- or hMG- preparation.

·        Luteal phase support, as part of controlled ovarian hyperstimulation programs:
Two to three repeat injections of 1000 to 3000 I.U. each may be given within nine days following ovulation or embryo transfer (for example on day 3, 6 and 9 after ovulation induction).

Dosage in the male:

The dosages given below are indicative and have to be adjusted individually, guided by the clinical response.

·        Hypogonadotropic hypogonadism and idiopathic impaired spermatogenesis:
1000-2000 I.U., two to three times per week. If the main complaint is subfertility associated with impaired spermatogenesis, Pregnyl may be given two to three times a week with a follitropin (FSH)- containing 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 can sometimes be maintained by hCG alone.

Dosage in male pediatric patients:

·        Delayed puberty associated with insufficient gonadotropin pituitary function:
1500 I.U. two to three times a week for at least six months.

·        Cryptorchidism, not due to an anatomical obstruction:
- under 2 years of age: 250 I.U. twice weekly for six weeks (see section 6.6 Pediatric dilution for instructions on how to prepare 250 I.U. from Pregnyl 1500 I.U.);
- under 6 years of age: 500-1000 I.U. twice weekly for six weeks (see section 6.6 Pediatric dilution for instructions on how to prepare 500 I.U. from Pregnyl 1500 I.U.);
- over 6 years of age: 1500 I.U. twice weekly for six weeks.
If necessary, this treatment can be repeated.

Method of administration

Pregnyl should be reconstituted with the solvent included. The reconstituted solution should be administered immediately. It should be checked visually whether all freeze-dried material has dissolved completely. The reconstituted solution should not be used if it contains particles or is not clear.

To prevent painful injections and minimise leakage from the injection site, the Pregnyl solution should be slowly administered intramuscularly or subcutaneously. Any unused solution should be discarded.

Subcutaneous injection of Pregnyl may be carried out by patient or partner, provided that proper instructions 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.

Special warnings and precautions for use

For males and females:

·       The presence of uncontrolled non-gonadal endocrinopathies (e.g. thyroid, adrenal or pituitary disorders) should be excluded.

·       The active ingredient of this preparation is extracted from human urine. Therefore, the risk of a transmission of a pathogen (known or unknown) cannot be excluded. No cases of viral contamination associated with administration of gonadotropin extracted from human urine have been reported.

·       Patients on a controlled sodium diet: This medicinal product contains less than 1 mmol sodium (23 mg) per daily dose, i.e. essentially “sodium-free”.

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

Additionally for females:

·        In pregnancies occurring after induction of ovulation with gonadotropic preparations, there is an increased risk of a multiple birth.

·        Since infertile women undergoing Assisted Reproduction Techniques (ART), 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.

·        Rates of pregnancy loss in women undergoing ART  as well as in anovulatory patients are higher than in the normal population.

·        The incidence of congenital malformations after ART as well as in anovulatory patients may be slightly higher than after spontaneous conceptions. This is thought to be due to differences in parental characteristics (e.g., maternal age, sperm characteristics) and a higher chance of multiple gestations. There are no signs that the use of gonadotropins in ART is associated with an increased risk of congenital defects.

·        Unwanted ovarian hyperstimulation
In patients treated for subfertility due to anovulation or impaired follicular ripening, prior administration of an FSH-preparation may lead to unwanted ovarian hyperstimulation. Therefore, ultrasonic assessment of follicular development and determinations of estradiol levels should be performed prior to FSH-treatment and at regular intervals during FSH-treatment. Apart from the possible development of a high number of follicles at the same time, estradiol levels may rise very rapidly, e.g. more than a daily doubling for two or three consecutive days, which can result in extremely high values. The diagnosis of ovarian hyperstimulation may be confirmed by ultrasound examination. If this unwanted ovarian hyperstimulation occurs (i.e. not as part of a treatment preparing for IVF/ET, GIFT or ICSI), the administration of the FSH-containing preparation should be discontinued immediately. In that case pregnancy should be avoided and Pregnyl must not be given, because the administration of an LH-active gonadotropin at this stage may induce, in addition to multiple ovulations, the ovarian hyperstimulation syndrome (OHSS). This warning is particularly important with respect to patients with polycystic ovary syndrome (PCOS). Clinical symptoms of mild ovarian hyperstimulation syndrome are gastro-intestinal problems (abdominal pain, nausea, diarrhoea), painful breasts and mild to moderate enlargement of ovaries and ovarian cysts. Transient liver function test abnormalities suggesting hepatic dysfunction, which may be accompanied by morphologic changes in liver biopsies, have been reported in connection with OHSS. In rare cases severe ovarian hyperstimulation syndrome occurs, which may be life-threatening. This is characterized by large ovarian cysts (prone to rupture), ascites, often hydrothorax and weight gain, and occasionally thrombo-embolic phenomena.

·        Women with generally recognised risk factors for thrombosis, such as a personal or family history, 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 treatment with gonadotropins need to be weighed against the risks. It should be noted, however, that pregnancy itself also carries an increased risk of thrombosis.

·        Until 10 days after administration, Pregnyl may interfere with an hCG pregnancy test, leading to a false-positive pregnancy test.

Additionally for males:

·            The formation of antibodies against hCG after administration of hCG has been described in the literature. In rare cases, this can result in ineffective treatment in males.

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.

Male pediatric patients:

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

Interaction with other medicinal products and other forms of interaction

No interaction studies have been carried out in the adult and pediatric population. Therefore, interactions with other commonly used medicines cannot be excluded.

Fertility, pregnancy and lactation

Fertility

Pregnyl can promote fertility.

Pregnyl is used for the treatment of women undergoing ovarian induction or controlled ovarian hyperstimulation in assisted reproduction programs. In males, Pregnyl is used in the treatment of deficient spermatogenesis due to hypogonadotrophic hypogonadism.

Pregnancy

Pregnyl is not indicated for use during pregnancy. There are no data on the use of chorionic gonadotropin during human pregnancy. Animal studies have shown reproduction toxicity as a result of hCG use (see section 5.3). The possible risk for humans is unknown. Pregnyl can be used at the beginning of pregnancy for luteal phase support, but should not be used at later stages of pregnancy.

Lactation

There is no information available from clinical or animal studies on the excretion of hCG in milk. It is unlikely that hCG is excreted in human milk due to its high molecular weight. If hCG were to be excreted in human milk, it would be degraded in the gastrointestinal tract of the child.

The use of Pregnyl during lactation may be considered.

Effects on ability to drive and use machines

As far as is known, this medicine has no influence on the ability to drive and use machines.

Undesirable effects

Intramuscular or subcutaneous administration of Pregnyl may lead to local reactions at the site of injection. The majority of these local reactions are mild and transient in nature. Generalised hypersensitivity reactions have been observed rarely. Unwanted ovarian hyperstimulation syndrome (OHSS) is a potential serious side effect of Pregnyl.

Drug-related adverse events are listed below by body/organ system and frequency. The frequencies are defined as follows: very common (>1/10), common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10,000, <1/1000); and very rare (<1/10,000).

Immune system disorders

Rare: generalized hypersensitivity reactions (e.g. generalized rash or fever).

General disorders and administration site conditions

Rare: allergic reactions at the injection site (pain and/or rash).

Unknown frequency: local reactions at the site of injection (bruising, pain, redness, swelling or itching).

In the female:

Blood vessel disorders

Rare: thromboembolism associated with FSH/hCG therapy, generally associated with severe OHSS.

Respiratory, thoracic and mediastinal disorders

Unknown frequency: hydrothorax as a sign of severe OHSS.

Gastrointestinal disorders

Common: abdominal and stomach disorders (such as nausea and diarrhea) as symptoms of mild OHSS.

Unknown frequency: ascites as a complication of severe OHSS.

Reproductive system and breast disorders

Unwanted ovarian hyperstimulation, mild (common) to severe (rare) 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, diarrhea 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 with OHSS.

Investigations

Unknown frequency: weight increase as a sign of severe OHSS.

In the male:

Metabolism and nutrition disorders

Uncommon: water and sodium retention after administration of high dosages; this is regarded as a result of excessive androgen production.

Reproductive system and breast disorders

Rare: hCG treatment may cause gynecomastia.

          To report any side effect(s):

·       Saudi Arabia:

The National Pharmacovigilance and Drug Safety Centre (NPC). SFDA

o Fax: +966-11-205-7662

o Call NPC at +966-11-20382222, Exts: 2317-2356-2353-2354-2334-2340.

o Toll free phone: 8002490000

o E-mail: npc.drug@sfda.gov.sa

o Website: www.sfda.gov.sa/npc

·       Other GCC States:

Please contact the relevant competent authority.

The acute toxicity of urinary gonadotropin preparations has been shown to be very low. Nevertheless there is a chance that too high a hCG dose may cause ovarian hyperstimulation syndrome (OHSS, see section 4.4).

          Pharmacodynamic properties

Pharmacotherapeutic group: gonadotropins; ATC code G03G A01.

Pregnyl contains hCG, which has LH activity. LH is indispensible for normal female and male gamete growth and maturation and gonadal steroid production.

In the female:

Pregnyl is given as a substitute for the endogenous mid-cycle LH surge to induce the final phase of follicular maturation, leading to ovulation. Pregnyl is also given as a substitute for endogenous LH during the luteal phase.

In the male:

Pregnyl is given to stimulate Leydig cells to promote the production of testosterone.

Pharmacokinetic properties

Absorption and distribution

Maximal hCG plasma levels after a single IM or SC injection will be reached after approximately 6 and 16 hours, respectively, in males, and in females in both cases after approximately 20 hours. 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.

Biotransformation

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

Elimination

IM and SC administration of hCG were found to be bioequivalent with regard to the extent of absorption and the apparent elimination half-life of approximately 33 hours. Based on the recommended dose regimens and elimination half-life, cumulation is not expected to occur.

Preclinical safety data

Safety pharmacology, repeated dose toxicity and genotoxicity studies do not indicate a special risk for humans. HCG has been shown to induce embryonic and fetal toxicity in mice.

          List of excipients

The powder for injection contains mannitol, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate anhydrous and sodium carboxymethylcellulose.
The ampoule with the solvent contains sodium chloride (9 mg) and water for injections (1 ml).

Incompatibilities

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

Special precautions for storage

Store at 2-15°C, Store in the original package, in order to protect from light. Don’t Freeze.

Nature and contents of container

Pregnyl 1500

-    One pack contains 3, 6 or 10 ampoules of 2 ml with powder for injection corresponding to 1500 I.U. hCG and 3, 6 or 10 ampoules, respectively, each containing 1 ml solvent.

Pregnyl 5000

-    One pack contains 1, 3 or 10 ampoules of 2 ml with powder for injection corresponding to 5000 I.U. hCG and 1, 3 or 10 ampoules, respectively, each containing 1 ml solvent.

Not all pack sizes may be marketed.

Special precautions for disposal and other handling

The powder for injection is reconstituted by adding the solvent (Pregnyl 1500 I.U. solution).

Pediatric dilution:

1.      take an empty sterile vial

2.      add the 1 ml Pregnyl 1500 I.U. solution

3.      add 2 ml sterile 0.9% NaCl solution

4.      gently swirl until the contents have mixed

5.      take 0.5 ml solution for the injection of 250 I.U. or 1 ml solution for the injection of 500 I.U. and use the diluted Pregnyl solution immediately

6.      discard the remaining diluted Pregnyl solution.

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