MENOPUR 1200 IU Powder and Solvent for Solution for Injection

Each vial with powder contains highly purified menotrophin (human menopausal gonadotrophin, HMG) corresponding to follicle stimulating hormone activity FSH 1200IU and luteinizing hormone activity LH 1200IU.

After reconstitution, 1 ml of the reconstituted solution contains 600 IU of highly purified menotrophin.

For a full list of 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

MENOPUR is indicated for the treatment of infertility in the following clinical situations:

• 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).

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) injection after reconstitution with the solvent provided. The powder should be reconstituted prior to use. The reconstituted solution is for multiple injections and can be used for up to 28 days. Vigorous shaking should be avoided. The solution should not be used if it contains particles or if it is not clear.

Dosage

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.

Children:

Not recommended for use in children.

Elderly:

Not recommended for use in the elderly.

MENOPUR is contraindicated in 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)

- Ovarian, uterine or mammary cancer

- Pregnancy and lactation

- Gynaecological haemorrhage of unknown aetiology

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

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. Monitoring of ovarian response requires ultrasonography, alone or in combination with monitoring of 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.

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. In very rare cases, severe OHSS may be life-threatening.

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 the 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 is contraindicated in women who are pregnant or lactating (see Section 4.3).

To date there are no signs of risk of teratogenicity when gonadotrophins are used clinically for ovarian hyperstimulation. Data on exposed pregnancies are insufficient. Animal experiments did not reveal teratogenic effects.

No studies on the effects on the ability to drive and use machines have been performed. However, MENOPUR is unlikely to have influence on the patient's ability to drive and use machines.

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.

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

Pharmacotherapeutic group: Gonadotrophins

ATC code: G03G A02

Menotrophin, which contains both FSH and LH activity, induces ovarian follicular growth and development as well as gonadal steroid production in women who do not have primary ovarian failure. FSH is the primary driver of follicular recruitment and growth in early folliculogenesis, while LH is important for ovarian steroidogenesis and is involved in the physiological events leading to the development of a competent pre-ovulatory follicle. Follicular growth can be stimulated by FSH in the total absence of LH, but the resulting follicles develop abnormally and are associated with low oestradiol levels and inability to luteinize to a normal ovulatory stimulus. Human Chorionic Gonadotrophin (hCG), a naturally occurring hormone in postmenopausal urine, is present in MENOPUR and is the main contributor of the LH activity.

Oestradiol levels associated with treatment with MENOPUR are higher than with recombinant FSH preparations in downregulated IVF/ICSI cycles. This issue should be considered when monitoring patients´ response based on oestradiol levels. The difference in oestradiol levels is not found when using low-dose ovulation induction protocols in anovulatory patients.

The pharmacokinetic profile of the FSH in MENOPUR has been documented. After 7 days of repeated dosing with 150 IU MENOPUR in downregulated healthy female volunteers, maximum plasma FSH concentrations (baseline-corrected) (mean ± SD) were 8.9 ± 3.5 IU/L and 8.5 ± 3.2 IU/L for the SC and IM administration, respectively. Maximum FSH concentrations were reached within 7 hours for both routes of administration. After repeated administration, FSH was eliminated with a half-life (mean ± SD) of 30 ± 11 hours and 27 ± 9 hours for the SC and IM administration, respectively. Although the individual LH concentration versus time curves show an increase in the LH concentration after dosing with MENOPUR, the data available were too sparse to be subjected to a pharmacokinetic analysis.

Menotrophin is excreted primarily via the kidneys.

The pharmacokinetics of MENOPUR in patients with renal or hepatic impairment has not been investigated.

Given the extensive clinical experience with menotrophin, there have been limited preclinical safety studies with MENOPUR.

Powder

Lactose monohydrate

Polysorbate 20

Sodium phosphate dibasic heptahydrate (for pH adjustment)

Phosphoric acid (concentrated) (for pH adjustment)

Solvent

Metacresol

Water for Injections

MENOPUR should not be administered in the same injection with other products.

3 years

After reconstitution, the solution may be stored for a maximum of 28 days at not more than 25°C. Do not freeze.

The patient should write the date of first preparation of Menopur on the outer carton

Store in a refrigerator (2°C – 8°C). Do not freeze. Store in the original container in order to protect from light.

Powder: 2ml colourless glass (type 1 glass) vial with rubber stopper closed with a cap.

Solvent: 1ml pre-filled syringe (type 1 glass) with rubber tip cap and plunger rubber stopper.

The product is supplied as a pack of 1 vial of powder, 2 pre-filled syringes with solvent for reconstitution, 1 needle for reconstitution, 18 alcohol pads and 18 disposable syringes for administration graduated in FSH/LH units with pre-fixed needles.

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

Attach the reconstitution needle to the prefilled syringe. MENOPUR 1200 IU must be reconstituted with two pre-filled syringes with solvent before use. 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.

The administration syringes are graduated in FSH/LH units from 37.5 – 600 IU and supplied with needles in the MENOPUR multidose box. Draw up the reconstituted solution from the vial into the administration syringe for injection according to the prescribed dose. Each ml of reconstituted solution contains 600 IU FSH and LH.

Each reconstituted MENOPUR 1200 IU vial should be for individual patient use only. Draw up the exact dose of reconstituted solution from the vial into the syringe for injection and administer the dose 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

PA 1009/15/03

Date of first authorisation: 17^th June 2011