It is recommended that you also refer to http://www.medicines.ie as the Summary of Product Characteristics may have been updated since this copy was printed.

Ferring Ireland Limited

Ferring Ireland Limited

Summary of Product Characteristics last updated on medicines.ie: 27/1/2016

Menopur 600IU powder and solvent for solution for injection

1. NAME OF THE MEDICINAL PRODUCT

MENOPUR 600 IU Powder and Solvent for Solution for Injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial with powder contains highly purified menotrophin (human menopausal gonadotrophin, HMG) corresponding to follicle stimulating hormone activity FSH 600IU and luteinizing hormone activity LH 600IU.

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

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 a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder and solvent for solution for injection.

Appearance of powder: white to off-white lyophilisation cake

Appearance of solvent: clear colourless solution

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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).

4.2 Posology and method of administration

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

Posology

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.

Paediatric population

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

Method of Administration:

After reconstitution with the solvent provided, MENOPUR 600IU is intended for subcutaneous (S.C.) injection, as the syringe provided is for S.C. administration only.

The powder should be reconstituted prior to use. The reconstituted solution is for multiple injections and can be used for up to 28 days. Shaking should be avoided. The solution should not be used if it contains particles or if it is not clear.

4.3 Contraindications

MENOPUR is contraindicated in women who have:

- Tumours of the pituitary gland or hypothalamus

- Hypersensitivity to the active substance or any of the excipients listed in 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

4.4 Special warnings and precautions for use

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 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.

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 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 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.

4.5 Interaction with other medicinal products and other forms of interaction

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.

4.6 Fertility, pregnancy and lactation

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)

4.7 Effects on ability to drive and use machines

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.

4.8 Undesirable effects

The most frequently reported adverse drug reactions (ADR) 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.

4.9 Overdose

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

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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.

5.2 Pharmacokinetic properties

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.

5.3 Preclinical safety data

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 consist 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.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder

Lactose monohydrate

Polysorbate 20

Sodium phosphate dibasic heptahydrate (for pH adjustment)

Phosphoric acid (concentrated) (for pH adjustment)

Solvent

Metacresol

Water for Injections

6.2 Incompatibilities

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

6.3 Shelf life

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.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C). Do not freeze.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

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, 1 pre-filled syringe with solvent for reconstitution, 1 needle for reconstitution, 9 alcohol pads and 9 disposable syringes for administration graduated in FSH/LH units with pre-fixed needles.

6.6 Special precautions for disposal and other handling

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

Attach the reconstitution needle to the prefilled syringe. MENOPUR 600 IU must be reconstituted with one pre-filled syringe 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. Shaking should be avoided.

The single use administration syringes with pre-fixed needle are graduated in FSH/LH units from 37.5 – 600 IU.

Draw up the reconstituted solution from the vial into the administration syringe for injection according to the prescribed dose and administer the dose immediately. Each ml of reconstituted solution contains 600 IU FSH and LH.

Each reconstituted MENOPUR 600 IU vial should be for individual patient use only.

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.

7. MARKETING AUTHORISATION HOLDER

Ferring Ireland Ltd

United Drug House

Magna Drive

Magna Business Park

Citywest Road

Dublin 24

8. MARKETING AUTHORISATION NUMBER(S)

PA 1009/15/02

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 17th June 2011

Date of last renewal: 17th June 2016

10. DATE OF REVISION OF THE TEXT

January 2016

It is recommended that you also refer to http://www.medicines.ie as the Summary of Product Characteristics may have been updated since this copy was printed.