INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
PREGNYL®

                RA 2400 ZA S1 (ref 1.0).

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

PREGNYL^®

Pregnyl^® 1 500 IU powder for solution for injection, provided with Solvent for Pregnyl
Pregnyl^® 5 000 IU powder for solution for injection, provided with Solvent for Pregnyl

COMPOSITION
PREGNYL contains 1 500 and 5 000 I.U. Chorionic Gonadotrophin per ampoule
Each 1 mL ampoule of Solvent for Pregnyl contains 0,9% m/v sodium chloride in water for injection

PHARMACOLOGICAL CLASSIFICATION
A/21.10/Trophic hormones

PHARMACOLOGICAL ACTION
Pharmacodynamics
Pregnyl contains human Chorionic Gonadotrophin (hCG) which has luteotrophic (LH) activity.
In the female Pregnyl substitutes the endogenous mid-cycle LH surge to induce the final phase of follicular maturation, leading to ovulation.
In the male Pregnyl stimulates Leydig cells to promote the production of testosterone.
Pharmacokinetics
Maximal plasma hCG levels will be reached in males approximately 6 and 16 hours after a single intramuscular or subcutaneous injection of hCG, respectively and in females after approximately 20 hours. HCG is approximately 80 per cent metabolized, predominantly in the kidneys. Intramuscular and subcutaneous 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.
Preclinical safety data
No particulars.

INDICATIONS
In the female as part of a regimen to induce:

-	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 the male:

-	Hypogonadotrophic hypogonadism. Cases of idiopathic dysspermias have also shown a positive response to gonadotrophins.
-	Delayed puberty associated with insufficient gonadotrophic pituitary function.
-	Cryptorchidism, not due to anatomical obstruction.

CONTRA-INDICATIONS

-	Hypersensitivity to human gonadotrophins or any of the substances of Pregnyl.
-	Known or suspected androgen-dependent tumours, such as prostatic carcinoma or breast carcinoma in the male.
-	Pregnancy and lactation: Pregnyl may be used for luteal phase support. It must not be used during lactation.

WARNINGS
In the female:

-	In pregnancies occurring after induction of ovulation with gonadotrophic preparations, there is an increased risk of multiplets.
-	Since infertile women undergoing assisted reproduction, and particularly IVF (in vitro fertilisation), 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 Assisted Reproductive Technologies (ART) are higher than in the normal population.
-	The presence of uncontrolled non-gonadal endocrinopathies (e.g. thyroid, adrenal or pituitary disorders) should be ruled out.
-	Unwanted ovarian hyperstimulation:
	In patients treated for subfertility due to anovulation or impaired follicular ripening, the prior administration of an FSH-containing preparation may lead to unwanted ovarian hyperstimulation. Therefore ultrasonic assessment of follicular development and determinations of oestradiol levels should be performed prior to FSH-treatment and at regular intervals during FSH-treatment. Oestradiol levels may rise very rapidly, e.g. more than a daily doubling for two or three consecutive days, and possibly reach excessively high values. The diagnosis of unwanted 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 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 are gastro-intestinal problems (pain, nausea and diarrhoea), painful breasts and mild to moderate enlargement of ovaries and ovarian cysts. In rare cases severe ovarian hyperstimulation syndrome occurs, which may be life-threatening. This is characterized by large ovarian cysts (prone to rupture), ascites, weight gain, often hydrothorax and occasionally thrombo-embolic phenomena.
-	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.
-	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 warned and 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.

Interactions
Interaction with other medicaments and other forms of interaction:
No interactions of clinical relevance are known.

PREGNANCY AND LACTATION
Pregnyl may be used for luteal phase support. It must not be used during lactation. See Contra-indications.

DOSAGE AND DIRECTIONS FOR USE
Dosage in the female:
Ovulation induction or preparation of follicles for puncture
Usually, one injection of 5 000-10 000 I.U. Pregnyl, to complete treatment with an FSH-containing preparation.
Luteal phase support
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:
Hypogonadotrophic hypogonadism
1000-2000 I.U. Pregnyl, two to three times per week. If the main complaint is subfertility, additional doses of an FSH-containing preparation (75 I.U. FSH) daily or two to three times a week, may be given. 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.
Delayed puberty
1500 I.U. two to three times a week for at least six months.
Cryptorchidism:

-	under 2 years of age:	250 I.U. twice weekly for six weeks
-	under 6 years of age:	500-1000 I.U. twice weekly for six weeks
-	over 6 years of age:	1500 I.U. twice weekly for six weeks

If necessary, this treatment can be repeated.
See Warnings.

Method of administration:
After addition of the solvent to the freeze-dried substance, the reconstituted Pregnyl solution should be slowly administered intramuscularly or subcutaneously.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Reactions at the site of injection, such as bruising, pain, redness, swelling and itching, have been reported with the use of urinary gonadotrophin preparations. Occasionally allergic reactions have been reported, mostly manifesting as pain and/or rash at the injection site. In rare cases generalized rash or fever may occur.
In the female:
Unwanted ovarian hyperstimulation, ovarian hyperstimulation syndrome. Characteristic symptoms of unwanted ovarian hyperstimulation and the ovarian hyperstimulation syndrome are included above, under "Warnings".
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.

Effects on ability to drive and use machines:
As far as known this medicine has no influence on alertness and concentration.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
The acute toxicity of urinary gonadotrophin preparations has been shown to be very low. There are no symptoms of an acute parenteral overdose known in humans.

IDENTIFICATION
PREGNYL 1500 IU: 2-mL ampoules, marked in the neck with two blue rings and containing a white to almost white dry cake or powder.
PREGNYL 5000 IU: 2-mL ampoules, marked in the neck with one yellow ring and containing a white to almost white dry cake or powder.
Solvent for Pregnyl: 1-mL ampoules, marked in the neck with one green ring and containing a clear, colourless, aqueous solvent (9 mg sodium chloride in 1 mL water for injection).

PRESENTATION
PREGNYL 1500 IU: 3 x 2-mL ampoules and 3 x 1-mL ampoules of Solvent for Pregnyl containing 0,9% m/v sodium chloride in water for injection, packed in a ply-carton box.
PREGNYL 5000 IU: 3 x 2-mL ampoules and 3 x 1-mL ampoules of Solvent for Pregnyl containing 0,9% m/v sodium chloride in water for injection, packed in a ply-carton box.

STORAGE INSTRUCTIONS
Store in a refrigerator between 2°-8°C. Protect from light. Keep out of reach of children.

REFERENCE NUMBERS
Pregnyl 1500 I.U. & Solvent for Pregnyl.: G 3202 (Act 101/1965)
Pregnyl 5000 I.U. & Solvent for Pregnyl: G 3203 (Act 101/1965)

NAME AND BUSINESS ADDRESS OF THE APPLICANT
Donmed Pharmaceuticals (Pty) Limited
Donmed House
Cambridge Place
cnr Kirkby & Oxford Roads
Bedfordview 2007

DATE OF PUBLICATION OF THE PACKAGE INSERT
4 November 2003

        Under license of NV Organon, The Netherlands

                RA 2400 ZA S1 (ref 1.0).

Updated on this site: March 2004
Source: Pharmaceutical Industry
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