In the Female:

• Ovulation Induction: FSH administered IM or SC with HCG in a sequential manner, which is indicated for ovulation induction in patients who have previously received pituitary suppression.

• Multi-follicular Development: During ART, FSH administered IM in conjunction with HCG is indicated for multiple follicular developments (controlled ovarian stimulation) during ART cycles in patients who have previously received pituitary suppression.

• Polycystic Ovarian Syndrome (PCOS): Used to treat Polycystic Ovarian Syndrome (PCOS) related infertility.

In the Male: Male infertility treatment in combination with HCG – Induction of spermatogenesis in men with deficient spermatogenesis due to hypogonadotrophic-hypogonadism.

FSH is a product containing a highly purified preparation of human follicle stimulating hormone (FSH-HP) extracted from the urine of postmenopausal women. Third generation of urinary gonadotrophins FSH-HP; use of monoclonal antibodies specific to FSH resulted in further refinements in manufacture, and the production of highly purified (HP) urinary FSH. The presence of LH is less than 0.1% per 75 IU of FSH, and unidentified urinary proteins are less than 5% in Human FSH-HP. FSH consists of two non-covalently linked glycoproteins designated as the alpha and beta subunits. The alpha subunit has 92 amino acids, of which two are modified by attachment of carbohydrates. The beta subunit has 111 amino acids, of which two are modified by attachment of carbohydrates. FSH is a sterile, lyophilized powder intended for subcutaneous (SC) or intramuscular (IM) injection after reconstitution with sterile 0.9% Sodium Chloride Injection. Each vial of FSH contains 75 International Units (IU) of Follicle Stimulating Hormone (FSH), which is reconstituted with diluents. The in vivo biological activity of Urofollitropin (FSH) for injection, purified, is determined by using reference standards calibrated against the First International Standard for follicle-stimulating hormone (FSH, Urofollitropin), Urinary, and Human for Bioassay, National Institute for Biological Standards and Control (NIBSC) at its 46th meeting in 1995. FSH is a glycoprotein that is acidic and water-soluble.

There are great inter- and intra-individual variations in the response of the ovaries to exogenous gonadotrophins. This makes it impossible to set a uniform dosage scheme. The dosage should, therefore, be adjusted individually depending on the ovarian response. This requires ultrasonography and monitoring of oestradiol levels. There should be consideration to minimize the risk of unwanted ovarian hyperstimulation. FSH can be given either alone, or in combination with a GnRH analogue to prevent premature luteinisation. In the latter case, especially when using a GnRH agonist, a higher total treatment dose of FSH may be required to achieve an adequate follicular response. Clinical experience with FSH is based on up to three treatment cycles in both indications. Overall experience with IVF indicates that in general the treatment success rate remains stable during the first four attempts and gradually declines thereafter.

Ovulation Induction in Women: Starting daily dose of 50 international units (IU) of FSH is administered subcutaneously or intramuscularly for at least the first 7 days. The dose is increased by 25 or 50 international units (IU) at weekly intervals until follicular growth and/or serum oestradiol levels indicate an adequate response. When an acceptable pre-ovulatory state is achieved, final oocyte maturation is achieved with 5000 to 10,000 international units (IU) of human chorionic gonadotropin (HCG). The woman and her partner should have intercourse daily, beginning on the day prior to the administration of HCG and until ovulation becomes apparent.

Assisted Reproductive Technology (ART): In Women: Starting dose of 150 to 225 international units (IU) of FSH is administered intramuscularly for at least the first 4 days of treatment. Subsequent doses are adjusted based upon ovarian response as determined by ultrasound evaluation of follicular growth and serum oestradiol levels. Final oocyte maturation is induced with a dose of 5000-10,000 international units of HCG. Oocyte (egg) retrieval is performed 34 to 36 hours later.

Polycystic Ovarian Syndrome (PCOS): FSH injections are therefore given each morning as an intramuscular injection. It is best to start with the lowest dose of FSH per day (using 50 IU per day). These doses are used for 4 to 6 days at a time. The ovarian response is determined by measuring oestrogen levels in the blood. When the oestrogen begins to rise, the FSH is successfully growing an egg or eggs. If there is no response to a dose of FSH in 5-6 days of injections, the dose will be increased. The normal dose increments are 75 units, 112 units, 150 units and 225 units per day. Most patients respond with 75 to 150 IU per day. However, it is very important that increments are made only cautiously.

Dosage in Male: Induction of Spermatogenesis in Men: Pre-treatment with HCG alone (1500 international units (IU) twice weekly) is required. If serum testosterone levels have not normalized after 8 weeks of HCG treatment, the dose may be increased to 3000 international units (IU) twice a week. After normalization of serum testosterone levels, administer 450 international units (IU) per week (225 international units twice weekly or 150 international units (IU) three times weekly) of FSH subcutaneously with the same pre-treatment HCG dose used to normalize testosterone level.

Administration

To prevent painful injections and minimize leakage from the injection site, FSH should be slowly administered intramuscularly or subcutaneously. The subcutaneous injection site should be alternated to prevent lipoatrophy. Any unused solution should be discarded. Subcutaneous injection of FSH may be carried out by the patient or partner, provided that proper instructions are given by the physician. Self-administration of FSH should only be performed by patients who are well-motivated, adequately trained, and have access to expert advice.

No drug/drug interaction studies have been conducted for Urofollitropin in humans.

• Tumours of the ovary, breast, uterus, pituitary or hypothalamus
• Pregnancy or lactation
• Undiagnosed vaginal bleeding
• Hypersensitivity to the active substance or to any of the excipients
• Primary ovarian failure
• Fibroid tumours of the uterus incompatible with pregnancy
• Primary testicular failure

FSH sometimes excites the ovaries too much. This may cause pelvic pain or breathing problems. It may also make you urinate less. In rare cases, patients with this problem have had serious lung problems, including fluid in the lungs, trouble breathing, and worsening of asthma, blood clots and strokes, severe pelvic pain, chest pain, or abdominal pain, nausea, vomiting, sudden weight gain, bloating, and trouble breathing. FSH may cause twins or multiple births. The most common side effects with FSH are headache, vaginal bleeding, nausea, and hot flashes. Sometimes there is a reaction at the spot where you give yourself the injection. This can include bruising, pain, or redness.

Pregnancy Category X. FSH must not be used during pregnancy and lactation.

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

• In pregnancies occurring after induction of ovulation with gonadotrophin preparations, there is an increased risk of multiple gestations (multiple birth).
• There have been no reports of hypersensitivity to FSH, but there remains the possibility of anaphylactic responses.
• The first injection of FSH should be performed under direct medical supervision.
• 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.
• Rates of pregnancy loss in women undergoing assisted reproduction techniques are higher than in the normal population.
• Unwanted ovarian hyperstimulation in the treatment of female patients: ultrasonographic assessment of follicular development and determination of oestradiol levels should be performed prior to treatment and at regular intervals during treatment. Apart from the development of a high number of follicles, oestradiol levels may rise very rapidly, e.g., more than a daily doubling for two or three consecutive days, and possibly reaching excessively 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 controlled ovarian hyperstimulation in medically assisted reproduction programs), the administration of FSH should be discontinued. In that case, pregnancy should be avoided and HCG must be withheld, because it may induce, in addition to multiple ovulation, the ovarian hyperstimulation syndrome (OHSS).
• In men, semen analysis is recommended 4 to 6 months after the beginning of treatment in assessing the response.

No data on acute toxicity of FSH in humans is available, but the acute toxicity of FSH and of urinary gonadotrophin preparations in animal studies has been shown to be very low. Too high a dosage of FSH may lead to hyperstimulation of the ovaries.

 Drugs for Infertility, Trophic Hormones & Related Synthetic Drugs

Store at 2°C to 8°C (in a refrigerator). Do not keep in deep freeze. Can be stored below 25°C for a maximum of 3 months. Protect from light and keep in a dry place.