Menopur 75 IU

Powder and Solvent for Solution for Injection

Menotrophin (HMG)

Active ingredient:

1ml solution contains:

Highly purified menotrophin (human menopausal gonadotrophin, HMG) corresponding to 75 IU FSH and 75 IU LH.

For excipients see Section 6.1

Powder and solvent for solution for injection.

Appearance of powder: white to off-white lyophilisation cake

Appearance of solvent: clear colourless solution

Treatment of female and male infertility in the following groups of patients:

Anovulation, including polycystic ovarian disease (PCOD), in women who have been unresponsive to treatment with clomiphene citrate.

Controlled ovarian hyperstimulation to induce the development of multiple follicles for assisted reproductive technologies (ART) (e.g in vitro fertilisation/embryo transfer (IVF/ET), gamete intra-fallopian transfer (GIFT) and intracytoplasmic sperm injection (ICSI).

Hypogonadotrophic hypogonadism in men: Menopur may be given in combination with human chorionic gonadotrophin (e.g. Choragon) for the stimulation of spermatogenesis.

Patients with primary testicular failure are usually unresponsive.

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

Method of Administration:

MENOPUR is intended for subcutaneous (S.C) or intramuscular (I.M) injection after reconstitution with the solvent provided. The powder should be reconstituted immediately prior to use. In order to avoid the injection of large volumes, up to 3 vials of the powder may be dissolved in 1ml of the solvent provided. Vigorous shaking should be avoided. The solution should not be used if it contains particles or if it is not clear.

Dosage

Dosage regimens described below are identical for S.C and I.M administration.

There are great inter-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. Menopur can be given alone or in combination with a gonadotrophin-releasing hormone (GnRH) agonist or antagonist.

Recommendations about dosage and duration of treatment may change depending on the actual treatment protocol.

Women with anovulation (including PCOD)

The object of Menopur therapy is to develop a single Graafian follicle from which the oocyte will be liberated after the administration of human chorionic gonadotrophin (hCG)

Menopur therapy should start within the initial 7 days of the menstrual cycle. The recommended initial dose of Menopur is 75-150 IU daily, which should be maintained for at least 7 days. Based on clinical monitoring (including ovarian ultrasound alone or in combination with measurement of oestradiol levels) subsequent dosing should be adjusted according to the individual patient response. Adjustments in dose should not be made more frequently than every 7 days. The recommended dose increment is 37.5 IU per adjustment, and should not exceed 75 IU. The maximum daily dose should not be higher than 225 IU. If a patient fails to respond adequately after 4 weeks of treatment, the cycle should be abandoned and the patient should recommence treatment at a higher starting dose than in the abandoned cycle.

When an optimal response is obtained, a single injection of 5,000 IU to 10,000 IU hCG should be given 1 day after the last Menopur injection. The patient is recommended to have coitus on the day of and the day following hCG administration. Alternatively intrauterine insemination (IUI) may be performed. If an excessive response to Menopur is obtained, treatment should be stopped and hCG withheld (see section 4.4) and the patient should use a barrier method of contraception or refrain from having coitus until the next menstrual bleeding has started.

Women undergoing controlled ovarian hyperstimulation for multiple follicular development for assisted reproductive technologies (ART):

In line with clinical trials with Menopur that involved downregulation with GnRH agonists Menopur therapy should start approximately 2 weeks after the start of agonist treatment. The recommended initial dose of Menopur is 150-225 IU daily for at least the first 5 days of treatment. Based on clinical monitoring (including ovarian ultrasound alone or in combination with measurement of oestradiol levels) subsequent dosing should be adjusted according to individual patient response, and should not exceed more than 150 IU per adjustment. The maximum daily dose given should not be higher than 450 IU daily and in most cases dosing beyond 20 days is not recommended.

In protocols not involving downregulation with GnRH agonist, Menopur therapy should start on day 2 or 3 of the menstrual cycle. It is recommended to use the dose ranges and regimen of administration suggested above for protocols with downregulation with GnRH agonists.

When a suitable number of follicles have reached an appropriate size, a single injection of up to 10,000 IU hCG should be administered to induce final follicular maturation in preparation for oocyte retrieva l. Patients should be followed closely for at least 2 weeks after hCG administration.

If an excessive response to Menopur is obtained, treatment should be stopped and hCG withheld (see section 4.4) and the patient should use a barrier method of contraception or refrain from having coitus until the next menstrual bleeding has started.

Male infertility:

Spermatogenesis is stimulated with chorionic gonadotrophin (1000 - 2000 I.U. two to three times a week) and then Menopur is given in a dose of 75 or 150 units of FSH with 75 or 150 units of LH two or three times weekly. Treatment should be continued for at least 3 or 4 months.

Children:

Not recommended for use in children.

Elderly:

Not recommended for use in the elderly.

Menopur is contra-indicated in both men and women who have:

- Tumours of the pituitary gland or hypothalamus

- Hypersensitivity to the active substance or any of the excipients used in the formulation. (see section 6.1)

Menopur is contraindicated in women who have:

- Ovarian, uterine or mammary cancer.

- Pregnancy and lactation

- Gynaecological haemorrhage of unknown aetiology

- Ovarian cysts or enlarged ovaries not due to polycystic ovary disease.

Menopur is contraindicated in men who have:

- Tumours of the testes.

- Carcinoma of the prostate

In the following situations treatment outcome is unlikely to be favourable, and therefore Menopur should not be administered:

- Primary ovarian failure

- Malformation of sexual organs incompatible with pregnancy

- Fibroid tumours of the uterus incompatible with pregnancy

Menopur is a potent gonadotrophic substance 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 professionals, and calls for monitoring of ovarian response with ultrasound, alone or in combination with measurement of serum oestradiol levels, on a regular basis. There is considerable inter-patient variability in response to menotrophin administration, with a poor response to menotrophin in some patients. The lowest effective dose in relation to the treatment objective should be used.

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

Before starting treatment, the couple's infertility should be assessed as appropriate and putative contraindications for pregnancy eva luated. In particular, patients should be eva luated for hypothyroidism, adrenocortical deficiency, hyperprolactinaemia and pituitary or hypothalamic tumours, and appropriate specific treatment given.

Patients undergoing stimulation of follicular growth, whether in the frame of a treatment for anovulatory infertility or ART procedures may experience ovarian enlargement or develop hyperstimulation. Adherence to the recommended Menopur dosage and regimen of administration and careful monitoring of therapy will minimise the incidence of such events. Acute interpretation of the indices of follicle development and maturation requires a physician who is experienced in the interpretation of the relevant tests.

In males, elevated gonadotrophin levels indicate primary testicular failure and such cases do not usually respond to this therapy.

Ovarian Hyperstimulation Syndrome (OHSS)

OHSS is a medical event distinct from uncomplicated ovarian enlargement. OHSS is a syndrome that can manifest itself with increasing degrees of severity. It comprises marked ovarian enlargement, high serum sex steroids, and an increase in vascular permeability which can result in an accumulation of fluid in the peritoneal, plural and, rarely, in the pericardial cavities.

The following symptoms may be observed in severe cases of OHSS: abdominal pain, abdominal distension, severe ovarian enlargement, weight gain, dyspnoea, oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhoea. Clinical eva luation may reveal hypovolemia, haemoconcentration, electrolyte imbalances, ascites, haemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress and thromboembolic events.

Excessive ovarian response to gonadotrophin treatment seldom gives rise to OHSS unless hCG is administered to trigger ovulation. Therefore, in cases of ovarian hyperstimulation it is prudent to withhold hCG and advise the patient to refrain from coitus or to use barrier methods for at least 4 days. OHSS may progress rapidly (within 24 hours to several days) to become a serious medical event, therefore patients should be followed up for at least two weeks after the hCG administration.

Adherence to recommended MENOPUR dosage, regimen of administration and careful monitoring of therapy will minimise the incidence of ovarian hyperstimulation and multiple pregnancy (see sections 4.2 and 4.8). In ART, aspiration of all follicles prior to ovulation may reduce the occurrence of hyperstimulation.

OHSS may be more severe and more protracted if pregnancy occurs. Most often, OHSS occurs after hormonal treatment has been discontinued and reaches its maximum severity at about seven to ten days following treatment. Usually, OHSS resolves spontaneously with the onset of menses.

If severe OHSS occurs, gonadotrophin treatment should be stopped if still ongoing, the patient hospitalised and specific therapy for OHSS started.

This syndrome occurs with higher incidence in patients with polycystic ovarian disease.

Multiple pregnancy

Multiple pregnancy, especially high order, carries an increased risk of adverse maternal and perinatal outcomes.

In patients undergoing ovulation induction with gonadotrophins, the incidence of multiple pregnancies is increased compared with natural conception. The majority of multiple conceptions are twins. To minimise the risk of multiple pregnancy, careful monitoring of ovarian response is recommended.

In patients undergoing ART procedures the risk of multiple pregnancy is related mainly to the number of embryos replaced, their quality and the age of the patient.

The patient should be advised of the potential risk of multiple births before starting treatment.

Pregnancy wastage

The incidence of pregnancy wastage by miscarriage or abortion is higher in patients undergoing stimulation of follicular growth for ART procedures than in normal population.

Ectopic pregnancy

Women with a history of tubal disease are at risk of ectopic pregnancy, whether the pregnancy is obtained by spontaneous conception or with fertility treatment. The preva lence of ectopic pregnancy after IVF has been reported to be 2 to 5 %, as compared to 1 to 1.5% in the general population.

Reproductive system neoplasms

There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for infertility treatment. It is not yet established if treatment with gonadotrophins increases the baseline risk of these tumours in infertile women.

Congenital malformation

The preva lence of congenital malformations after ART 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 multiple pregnancies.

Thromboembolic events

Women with generally recognised risk factors for thromboembolic events, such as personal or family history, severe obesity (Body Mass Index > 30 kg/m²) or thrombophilia may have increased risk of venous or arterial thromboembolic events, during or following treatment with gonadotrophins. In these women, the benefits of gonadotrophin administration need to be weighed against the risks. It should be noted however, that pregnancy itself also carries an increased risk of thromboembolic events.

This product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medication.

No drug/drug interaction studies have been conducted with Menopur in humans.

Although there is no controlled clinical experience, it is expected that the concomitant use of MENOPUR and clomiphene citrate may enhance the follicular response. When using GnRH agonist for pituitary desensitisation, a higher dose of Menopur may be necessary to achieve adequate follicular response.

Menopur should not be given if pregnancy is suspected or to lactating mothers.

None known.

The most frequently reported adverse drug reactions reported during treatment with MENOPUR in clinical trials are abdominal pain, headache, injection site reactions and injection site pain, with an incidence rate up to 10%. The table below displays the main adverse drug reactions in women treated with MENOPUR in clinical trials distributed by system organ classes (SOCs) and frequency

Gastrointestinal symptoms associated with OHSS such as abdominal distension and discomfort, nausea, vomiting and diarrhoea have been reported with MENOPUR in clinical trials. As rare complications of OHSS, venous thromboembolic events and ovarian torsion might occur.

Very rare cases of allergic reactions, localised or generalised, including anaphylactic reaction, have been reported after injection of MENOPUR.

In very rare cases, long term use of menotrophin can lead to the formation of antibodies making the treatment ineffectual.

The effect of an overdose is unknown, nevertheless one could expect ovarian hyperstimulation syndrome to occur.

Pharmacotherapeutic group: Gonadotrophins

ATC code: G03G A02

Menotrophin is a gonadotrophin extracted from the urine of postmenopausal women and having both luteinising hormone and follicle-stimulating hormone activity. It is given by intramuscular or subcutaneous injection in the treatment of male and female infertility.

Menotrophin (HMG) directly affects the ovaries and the testes. HMG has a gametropic and steroidogenic effect.

In the ovaries, the FSH-component in HMG induces an increase in the number of growing follicles and stimulates their development. FSH increases the production of oestradiol in the granulosa cells by aromatising androgens that originate in the Theca cells under the influence of the LH-component.

In the testes, FSH induces the transformation of premature to mature Sertoli cells. It mainly causes the maturation of the seminal canals and the development of spermatozoa. However, a high concentration of androgens within the testes is necessary and can be attained by a prior treatment using HCG.

HMG is not effective when taken orally and is injected either intramuscularly or subcutaneously. The biological effectiveness of HMG is mainly due to its FSH content. The pharmacokinetics of HMG following intramuscular or subcutaneous administration show great individual variation. The maximum serum level of FSH is reached within 7 hours after injection for both routes of administration. After that, the serum level decreases by a half-life (mean +/-SD) of 30+/-11 hours and 27+/-9 hours for the SC and IM administration respectively.

Excretion of HMG, following administration, is predominantly renal.

Toxic effects caused by HMG are unknown in humans.

There is no evidence of teratogenic, mutagenic or carcinogenic activity of HMG. Antibodies against HMG can be built up in single cases following repeated cyclical administration of HMG, causing the treatment to be ineffectual.

Powder for solution for injection

Lactose

Polysorbate 20

Sodium hydroxide

Hydrochloric acid

Solvent

Sodium chloride

Water for Injections

Dilute Hydrochloric acid

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

3 years.

The reconstituted product should be used immediately and any remaining solution should be discarded.

To be stored protected from light at temperatures not exceeding 25^°C

Supplied in packs of 10 vials of powder for solution for injection with 10 ampoules of solvent.

The powder should only be reconstituted with the solvent provided in the package.

Attach the reconstitution needle to the syringe. Withdraw the entire content from the ampoule with solvent and inject the total contents into the vial containing the powder. The powder should dissolve quickly to a clear solution. If not, roll the vial gently between the hands until the solution is clear. Vigorous shaking should be avoided.

If needed, the solution can be drawn up into the syringe again to transfer it to the next vial with powder until the prescribed dose has been reached. Up to three powder vials can be dissolved with one ampoule of solvent. When the prescribed dose has been reached, draw up the mixed solution from the vial into the syringe, change to the hypodermic needle and administer immediately.

The reconstituted solution should not be administered if it contains particles or is not clear.

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

Ferring Ireland Ltd

United Drug House

Magna Drive

Magna Business Park

Citywest Road

Dublin 24

Ireland

PA 1009/15/1

4^th May 2001/4^th May 2006

February 2011