Pergoveris

Uses

This injection is used for the stimulation of follicular development in adult women with severe LH and FSH deficiency. In clinical trials, these patients were defined by an endogenous serum LH level < 1.2 IU/L.
Elderly: There is no relevant indication for the use of this injection in the elderly population. Safety and effectiveness of this medicinal product in elderly patients have not been established.

Renal and hepatic impairment: Safety, efficacy, and pharmacokinetics of this medicinal product in patients with renal or hepatic impairment have not been established.

Paediatric population: There is no relevant use of this medicinal product in the paediatric population.

Pergoveris is also used to associated treatment for these conditions: Assisted Reproductive Technology therapy, Ovulation induction therapy, Stimulation of spermatogenesis therapyHypogonadism, Infertility

How Pergoveris works

Follitropin is a recombinant form of endogenous follicle stimulating hormone (FSH). FSH binds to the follicle stimulating hormone receptor which is a G-coupled transmembrane receptor. Binding of the FSH to its receptor seems to induce phosphorylation and activation of the PI3K (Phosphatidylinositol-3-kinase) and Akt signaling pathway, which is known to regulate many other metabolic and related survival/maturation functions in cells.

Luteinizing hormone binds to a receptor shared with the human chorionic gonadotropin hormone (hCG) on the ovarian theca (and granulosa) cells and testicular Leydig cells. This LH/CG transmembrane receptor is a member of the super-family of G protein-coupled receptors. Adenylate cyclase then activates many other pathways leading to steroid hormone production and other follicle maturation processes.

Dosage

Pergoveris dosage

In LH and FSH deficient women (hypogonadotrophic hypogonadism), the objective of this injection therapy is to develop a single mature Graafian follicle from which the oocyte will be liberated after the administration of human chorionic gonadotrophin (hCG). This injection should be given as a course of daily injections. Since these patients are amenorrhoeic and have low endogenous oestrogen secretion, treatment can commence at any time.

Treatment should be tailored to the individual patient's response as assessed by measuring follicle size by ultrasound and oestrogen response.

A recommended regimen commences with one vial of this injection daily. If less than one vial daily is used, the follicular response may be unsatisfactory because the amount of lutropin alfa may be insufficient.

If an FSH dose increase is deemed appropriate, dose adaptation should preferably be after 7-14 day intervals and preferably by 37.5-75 IU increments using a licensed follitropin alfa preparation. It may be acceptable to extend the duration of stimulation in any one cycle to up to 5 weeks.

When an optimal response is obtained, a single injection of 250 micrograms of r-hCG or 5,000 IU to 10,000 IU hCG should be administered 24-48 hours after the last this injection. The patient is recommended to have coitus on the day of, and on the day following, hCG administration. Alternatively, intrauterine insemination (IUI) may be performed.

Luteal phase support may be considered since lack of substances with luteotrophic activity (LH/hCG) after ovulation may lead to premature failure of the corpus luteum.

If an excessive response is obtained, treatment should be stopped and hCG withheld. Treatment should recommence in the next cycle at a dose of FSH lower than that of the previous cycle.

This injection is intended for subcutaneous administration. The first injection should be performed under direct medical supervision. The powder should be reconstituted immediately prior to use with the solvent provided. Self-administration should only be performed by patients who are well motivated, adequately trained and with access to expert advice.

Side Effects

Ovarian cysts, mild to severe inj site reactions, headache, mild to moderate OHSS, abdominal pain, GI disturbances. Rarely, severe OHSS, ovarian torsion, thromboembolism, mild systemic allergic reactions.

Toxicity

Headaches, ovarian cysts, nausea and upper respiratory tract infections occurred in more than 10% of women in clinical trials. In men, the most serious adverse events reported were testicular surgery for cryptorchidism which existed prestudy, hemoptysis, an infected pilonidal cyst, and lymphadenopathy associated with an Epstein-Barr viral infection. Other concerns include overstimulation of the ovaries, pulmonary and vascular complications and multiple births. Post-marketing reports revealed hypersensitivity reactions including anaphylactoid reactions and asthma. Follitropin is contraindicated in pregnant women. No studies have been done in nursing mothers.

Lutropin alfa is not indicated for people under 16 and over 60, pregnant and lactating women, patients with uncontrolled thyroid and adrenal failure, patients with active, untreated tumours of the hypothalamus and pituitary gland, and in any patient with a condition that makes a normal pregnancy possible such as primary ovarian failure or fibroid tumors of the uterus.

Precaution

This injection contains potent gonadotrophic substances capable of causing mild to severe adverse reactions, and should only be used by physicians who are thoroughly familiar with infertility problems and their management.

Gonadotrophin therapy requires a certain time commitment by physicians and supportive health care professionals, as well as the availability of appropriate monitoring facilities. In women, safe and effective use of this injection calls for monitoring of ovarian response with ultrasound, alone or preferably in combination with measurement of serum oestradiol levels, on a regular basis. There may be a degree of interpatient variability in response to FSH/LH administration, with a poor response to FSH/LH in some patients. The lowest effective dose in relation to the treatment objective should be used in women.

Interaction

This injection should not be administered as a mixture with other medicinal products, in the same injection, except follitropin alfa for which studies have shown that co-administration does not significantly alter the activity, stability, pharmacokinetic nor pharmacodynamic properties of the active substances.

Volume of Distribution

• 8 L [female subjects following intravenous administration of a 300 IU dose]

The steady state volume of distribution is around 10-14 L.

Elimination Route

The absorption rate is the main driving force behind the pharmokinetics of Follitropin alpha as the rate of absorption was found to be slower than the elimination rate after administration subcutaneously and intramuscularly. The bioavailability is approximately 66-76%. The time to peak after subcutaneous injection in healthy volunteers was 8-16 hours in females and 11-20 hours in males.

Mean absolute bioavailability is 56%, following sub-Q administration, maximum serum concentrations reached after 4–16 hours. Time to peak, serum: 9 hours

Half Life

Circulation half life of 3-4 hours, elimination half life of 35-40 hours

Biphasic; terminal half-life is approximately 18 hours.

Clearance

• 0.01 1*h-1kg-1 [European women with a single intramuscular dose of 300 IU]
• 0.01 1*h-1kg-1 [Japanese women with a single intramuscular dose of 300 IU]

• 2 – 3 L/h [healthy female following subcutaneous administration]

Elimination Route

Via liver and kidneys.

Total body clearance is approximately 2 to 3 L/h with less than 5 percent of the dose being excreted unchanged renally.

Pregnancy & Breastfeeding use

There is no indication for the use of this injection during pregnancy. Data on a limited number of exposed pregnancies indicate no adverse reactions of follitropin alfa and lutropin alfa on pregnancy, embryonal or foetal development, parturition or postnatal development following controlled ovarian stimulation. No teratogenic effect of such gonadotropins has been reported in animal studies. In case of exposure during pregnancy, clinical data are not sufficient to exclude a teratogenic effect of this injection. This not indicated during breast-feeding.

Contraindication

This injection is contraindicated in patients with:

• hypersensitivity to the active substances or to any of the excipients
• tumours of the hypothalamus and pituitary gland
• ovarian enlargement or ovarian cyst unrelated to polycystic ovarian disease and of unknown origin
• gynaecological haemorrhages of unknown origin
• ovarian, uterine or mammary carcinoma

• primary ovarian failure
• malformations of sexual organs incompatible with pregnancy
• fibroid tumours of the uterus incompatible with pregnancy

Acute Overdose

May lead to OHSS and multiple gestations.

Storage Condition

Do not store above 25°C. Store in the original package in order to protect from light.

Innovators Monograph

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