This injection is a preparation of recombinant human follicle stimulating hormone (follitropin alfa, r-hFSH) and recombinant human luteinising hormone (lutropin alfa, r-hLH) produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology. In clinical trials the efficacy of the combination of follitropin alfa and lutropin alfa has been demonstrated in women with hypogonadotropic hypogonadism. In the stimulation of follicular development in anovulatory women deficient in LH and FSH, the primary effect resulting from administration of lutropin alfa is an increase in oestradiol secretion by the follicles, the growth of which is stimulated by FSH.

In clinical trials, patients with severe FSH and LH deficiency were defined by an endogenous serum LH level < 1.2 IU/L as measured in a central laboratory. However, it should be taken into account that there are variations between LH measurements performed in different laboratories. In these trials the ovulation rate per cycle was 70-75%.

This injection is indicated 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.

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.

Administration

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.

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

This injection must not be used when an effective response cannot be obtained, such as:

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

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.

Use in Special Populations

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.

Pregnancy & Lactation

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.