Menopur 75IU Powder and Solvent for Solution for Injection. Menotrophin (HMG)

MENOPUR^® 75 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 75 IU and luteinizing hormone activity LH 75 IU.

Human Chorionic Gonadotrophin (hCG), a naturally occurring hormone in postmenopausal urine, is present in MENOPUR and is the main contributor of the LH activity.

For the 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

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.

Posology

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 a protocol using down-regulation with a GnRH agonist MENOPUR therapy should start approximately 2 weeks after the start of agonist treatment. In a protocol using down-regulation with a GnRH antagonist, MENOPUR therapy should start on day 2 or 3 of the menstrual cycle. 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.

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 retrieval. 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.

Paediatric population

There is no relevant use of MENOPUR in the paediatric population.

Method of Administration:

MENOPUR 75IU 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 powder may be dissolved in 1 ml of solvent provided. Shaking should be avoided. The solution should not be used if it contains particles or if it is not clear.

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 listed in 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 evaluated. In particular, patients should be evaluated 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 evaluation 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 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 prevalence 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 prevalence 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 interaction studies have been performed 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.

Fertility

MENOPUR is indicated for use in infertility (see section 4.1).

Pregnancy

MENOPUR is contraindicated in women who are pregnant (see section 4.3).

There are no or limited amount of data from the use of menotrophins in pregnant women. No animal studies have been carried out to evaluate the effects of MENOPUR during pregnancy (see section 5.3).

Lactation

MENOPUR is contraindicated in women who are lactating (see section 4.3)

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 (ADRs) reported during treatment with MENOPUR in clinical trials are ovarian hyperstimulation syndrome (OHSS), headache, abdominal pain, abdominal distension and injection site pain. None of these ADRs have been reported with an incidence rate of more than 5%.

The table below displays the main ADRs in women treated with MENOPUR in clinical trials distributed by system organ classes (SOCs) and frequency. Further, the ADRs seen during post-marketing experience are mentioned with unknown frequency.

System Organ Class	Common (>1/100 to < 1/10)	Uncommon (>1/1,000 to < 1/100)	Rare (>1/10,000 to < 1/1,000)	Unknown
Eye disorders				Visual disordersa
Gastrointestinal disorders	Abdominal pain, Abdominal distension, Nausea	Vomiting, Abdominal discomfort, Diarrhoea
General disorders and administration site condition	Injection site reactionsb	Fatigue		Pyrexia, Malaise
Immune system disorders				Hypersensitivity reactionsc
Investigations				Weight increased
Musculoskeletal & connective tissue disorders				Musculoskeletal paind
Nervous system disorders	Headache	Dizziness
Reproductive system disorders	OHSSe, Pelvic painf	Ovarian cyst, Breast complaintsg		Ovarian torsione
Skin and subcutaneous tissue disorders			Acne, Rash	Pruritus, Urticaria
Vascular Disorders		Hot flush		Thromboembolisme

^a Individual cases of temporary amaurosis, diplopia, mydiasis, scotoma, photopsia, vitreous floaters, vision blurred and vision impairment have been reported as visual disorders during the post-marketing period

^b Most frequently reported injection site reaction was injection site pain.

^c Cases of localised or generalised allergic reactions, including anaphylactic reaction, along with associated symptomatology have been reported rarely.

^d Musculoskeletal pain includes arthralgia, back pain, neck pain and pain in extremities.

^e Gastrointestinal symptoms associated with OHSS such as abdominal distension and discomfort, nausea, vomiting, diarrhoea have been reported with MENOPUR in clinical trials. In cases of severe OHSS ascites and pelvic fluid collection, pleural effusion, dyspnoea, oliguria, thromboembolic events and ovarian torsion have been reported as rare complications.

^f Pelvic pain includes ovarian pain and adnexa uteri pain.

^g Breast complaints include breast pain, breast tenderness, breast discomfort, nipple pain and breast swelling.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2. Tel: +353 1 6764971; Fax: +353 1 6762517; Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

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 Cmax (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 (Tmax) 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.

Non-clinical data reveal no special hazard for humans, which is not known from the extensive clinical experience.

Reproduction toxicity studies have not been carried out to evaluate the effects of MENOPUR during pregnancy or post partum as MENOPUR is not indicated during these periods.

MENOPUR consists of naturally occurring hormones and should be expected to be non-genotoxic. Carcinogenicity studies have not been carried out as the indication is for short term treatment.

Powder for solution for injection

Lactose monohydrate

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.

2 years.

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

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

Powder for solution for injection :	2ml glass vial
Solvent:	1ml glass ampoule

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. 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

PA 1009/15/1

4^th May 2001/4^th May 2006

July 2015