MENOPUR 1200 IU SOLUTION FOR INJECTION IN PRE-FILLED PEN - summary of medicine characteristics

MENOPUR 1200 IU solution for injection in pre-filled pen

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One pre-filled multidose pen delivers highly purified menotrophin (human menopausal gonadotrophin, HMG) corresponding to follicle stimulating hormone activity FSH 1200 IU and luteinizing hormone activity LH 1200 IU in 1.92 mL solution.

One mL of solution contains 625 IU FSH activity and 625 IU LH activity.

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

The active ingredient in MENOPUR is obtained from the urine of postmenopausal wo­men.

For the full list of excipients, see section 6.1.

Solution for injection in pre-filled pen (injection).

Clear solution.

4.1 Therapeutic indications

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

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

– Women undergoing controlled ovarian hyperstimulation: MENOPUR can 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.

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

Anovulatory infertility:

Menotrophin is administered to induce follicular maturation and is followed by treatment with chorionic gonadotrophin to stimulate ovulation and corpus luteum formation.

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 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 3 weeks of treatment, that 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, administration of MENOPUR is stopped. A single injection of 5,000 IU to 10,000 IU of 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. Treatment should recommence in the next treatment cycle at a dose lower than in the previous cycle.

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 5,000 IU 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 IU two to three times a week) and then menotrophin is given in a dose of 75 or 150 IU units of FSH with 75 to 150 IU units of LH two or three times weekly. Treatment should be continued for at least 3 or 4 months.

Renal/hepatic impairment

Patients with renal and hepatic impairment have not been included in clinical trials (see section 5.2).

Paediatric population

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

Elderly

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

Method of administration

MENOPUR is intended for subcutaneous (S.C.) injection, preferably in the abdominal wall. The first injection should be performed under direct medical supervision. Patients must be educated on how to use the MENOPUR injection pen and to perform injections. Self-administration should only be performed by patients who are well motivated, adequately trained and have access to expert advice.

For instructions on the administration with the pre-filled pen, see the “Instructions for Use”.

4.3 Contraindications

Woman and Men

MENOPUR is contraindicated in women and men with:

– Tumours of the pituitary gland or hypothalamus

– Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

Women

– Ovarian, uterine or mammary carcinoma

– Pregnancy and lactation

– Gynaecological haemorrhage of unknown aetiology

– Ovarian cysts or enlarged ovaries not due to polycystic ovarian disease.

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

– Primary ovarian failure

– Malformation of sexual organs incompatible with pregnancy

– Fibroid tumours of the uterus incompatible with pregnancy

– Structural abnormalities in which a satisfactory outcome cannot be expected, for example, tubal occlusion (unless superovulation is to be induced for IVF), ovarian dysgenesis, absent uterus or premature menopause.

Men

– Tumours in the testes

– Prostate carcinoma

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, and calls for monitoring of ovarian response with ultrasound, alone or preferably 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.

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, hyperprolactinemia 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 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.

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, pleural 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 hypovolaemia, haemoconcentration, electrolyte imbalances, ascites, haemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic events.

If urinary oestrogen levels exceed 540 nmol (150 micrograms)/24 hours, or if plasma 17 beta-oestradiol levels exceed 3000 pmol/L (800 picograms/ml), or if there is any steep rise in values, there is an increased risk of hyperstimulation and MENOPUR treatment should be immediately discontinued and human chorionic gonadotrophin withheld. Ultrasound will reveal any excessive follicular development and unintentional hyperstimulation.

The severe form OHSS may be life-threatening and is characterised by large ovarian cysts (prone to rupture), acute abdominal pain, ascites, very often hydrothorax and occasionally thromboembolic phenomena. Other symptoms that may be observed include: abdominal distension, severe ovarian enlargement, weight gain, dyspnoea, oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhoea. Clinical evaluation may reveal hypovolaemia, haemoconcentration, electrolyte imbalances, haemoperitoneum, pleural effusions and acute pulmonary distress.

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 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). Patients undergoing controlled ovarian hyperstimulation may be at an increased risk of developing hyperstimulation in view of the excessive oestrogen response and multiple follicular development. 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, 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.

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.

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.

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.

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 an 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.

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 lactationFertility

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

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).

MENOPUR is contraindicated in women who are breast-feeding (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 serious and frequently reported adverse drug reactions (ADR) reported during treatment with MENOPUR in clinical trials are Ovarian Hyperstimulation Syndrome OHSS, abdominal pain, headache, abdominal distension and injection site pain, with an incidence rate up to 5%.

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. Further, the ADRs seen during postmarketing experience are mentioned with unknown frequency.

Most frequently reported injection site reaction was injection site

a

pain.

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

c Musculoskeletal pain includes arthralgia, back pain, neck pain and pain in extremities. d Gastrointestinal symptoms associated with OHSS such as abdominal distension and discomfort, nausea, vomiting and 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.

e Pelvic pain includes ovarian pain and adnexa uteri pain. f 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 the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

The effect of an overdose is unknown, nevertheless one could expect ovarian hyperstimulation syndrome to occur (see section 4.4).

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Gonadotrophins, ATC code: G03G A02

Menotrophin (Human Menopausal Gonadotrophin, HMG) is a gonadotrophin extracted from the urine of postmenopausal women. It has both luteinising hormone and follicle stimulating hormone activity in a 1:1 ratio. Human Chorionic Gonadotrophin (hCG), a naturally occurring hormone in postmenopausal urine, is present in MENOPUR and is the main contributor of the LH activity.

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.

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.

In line with the action of LH activity in enhancing steroidogenesis, 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 patient’s response based on oestradiol levels.

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 the spermatozoa. However, a high concentration of androgens within the testes is necessary and can be attained by a prior treatment using hCG.

5.2 Pharmacokinetic properties

The pharmacokinetics of Menotrophin following intramuscular or subcutaneous administration shows great interindividual variability. After 7 days of repeated dosing with 150 IU MENOPUR in downregulated healthy female volunteers, 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. The area under the curve (AUCT) of FSH concentration was (mean ± SD) 180 ± 77 h.IU/L and 166 ± 67 h.IU/L for 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 halflife (T1/2) (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 postpartum 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

Phenol

Methionine

Arginine hydrochloride

Polysorbate 20

Sodium hydroxide

Hydrochloric acid, dilute

Water for injections

6.2 Incompatibilities

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

6.3 Shelf life

3 years as packed for sale.

In-Use period: 28 days.

Store below 25 °C when in-use.

6.4 Special precautions for storage

Before use:

Store in a refrigerator (2°C – 8°C).

Do not freeze.

After first use (in-use period):

Store below 25 °C for a maximum of 28 days

Always store the pen with the pen cap on, in order to protect from light.

6.5 Nature and contents of container

3 mL multidose cartridge (Type I glass) with a plunger (rubber) and a crimp cap (aluminium) with bilayer septum (rubber). Each cartridge contains 1.92 mL of solution. Pack size of 1 pre-filled pen and 21 injection needles (stainless steel).

6.6 Special precautions for disposal

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

The instructions for use of the pen must be followed. Discard used needles immediately after injection.

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

7 MARKETING AUTHORISATION HOLDER

Ferring Pharmaceuticals Ltd.

Drayton Hall

Church Road

West Drayton

UB7 7PS

United Kingdom