Menopur 75 IU/600 IU/1200 IU Solution

Female: MENOPUR u00ae is indicated for the treatment of infertility in the following clinical situations: WHO group II anovulation infertility, 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).

Male: MENOPUR u00ae has been used for oligospermia, some types of azoospermia, hypogonadism, eunuchoidism.

Treatment with MENOPUR u00ae should be initiated under the supervision of a medical practitioner experienced in the treatment of fertility problems.

Posology

MENOPUR u00ae 75 IU: Dosage regimens described below are identical for subcutaneous (S.C.) and intramuscular (I.M). administration. MENOPUR u00ae 600 IU and MENOPUR u00ae 1200 IU: For subcutaneous use only (see u2018Method of administrationu2019) 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 (sonographic visualisation of a follicle u2265 10 mm). MENOPUR u00ae 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 objective of MENOPUR u00ae therapy is to develop a single Graafian follicle from which the oocyte will be liberated after the administration of human chorionic gonadotrophin (hCG). MENOPUR u00ae therapy should start within the initial 7 days of the menstrual cycle. The recommended initial dose of MENOPUR u00ae is 75 to 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. Adjustment in dose should not be made more frequently than every 7 days. The recommended dose increment is 37,5 IU per dose 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, 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, a single injection of 5 000 IU to 10 000 IU hCG should be given 1 day after the last MENOPUR u00ae injection. The patient is recommended to have coitus on the day of and the day following hCG administration. Alternatively intra-uterine insemination (IUI) may be performed. If an excessive response to MENOPUR u00ae 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 u00ae that involved downregulation with GnRH agonists, MENOPUR u00ae therapy should start approximately 2 weeks after the start of agonist treatment. The recommended initial dose of MENOPUR u00ae 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 dosing beyond 20 days is not recommended. In a protocol using down-regulation with a GnRH antagonist, MENOPUR u00ae 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 administrated 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 u00ae 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.

Dosage for men: The recommended treatment consists of 75 IU of MENOPUR u00ae every other day for at least 90 to 120 days. Should semen volume remain lower than 1,5 mL, it is advisable to add 2500 IU of hCG once or twice weekly, particularly towards the end of treatment. Maintenance treatment should be 75 IU to 150 IU of MENOPUR u00ae every week. Prior to starting treatment, an assay of urinary gonadotrophins will be useful for discharging those cases which present above average results. In cases of oligospermia, a complete semen examination is sufficient, whereas for azoospermia cases, testicular biopsy is quite useful in order to eliminate from treatment those patients, most of whose seminiferous tubules contain only Sertoliu2019s cells, which do not seem to respond favourably.

Special populations

Elderly There is no relevant use of MENOPUR u00ae in the elderly population.

Paediatric population There is no relevant use of MENOPUR u00ae in the paediatric population.

Method of administration MENOPUR u00ae 75 IU is intended for S.C. or I.M. injection after reconstitution with the solvent provided. The powder should be reconstituted prior to use (see section 6.6). In order to avoid the injection of large volumes up to 3 vials of the powder may be dissolved in 1 mL of the solvent provided. Shaking should be avoided. The solution should not be used if it contains particles or if it not clear. MENOPUR u00ae 600 IU and 1200 IU are intended for S.C. injection, as the syringe provided is for S.C. administration only. The powder should be reconstituted prior to use (see section 6.6). 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 For instructions on reconstitution and other handling, see section 6.6.

• Hypersensitivity to the active substance, menotrophin, or to any of the excipients listed in section 6.1.
• Pregnancy and lactation.
• Tumours in the uterus, ovaries, breasts, testes, prostate, pituitary gland or hypothalamus.
• Gynaecological bleeding of unknown origin.
• Patients presenting with polycystic ovaries, or who are capable of ovulating with human chorionic gonadotrophic (hCG) administration alone.
• Ovarian cysts or enlarged ovaries not due to polycystic ovarian disease.
• Primary ovarian failure.
• Malformation of sexual organs incompatible with pregnancy.
• Fibroid tumours of the uterus incompatible with pregnancy.

MENOPUR u00ae should only be used by medical practitioners who are thoroughly familiar with infertility problems and their management. MENOPUR u00ae requires a certain time commitment by medical practitioners 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 MENOPUR u00ae administration, with a poor response to MENOPUR u00ae in some patients. The lowest effective dose in relation to the treatment objective should be used. The first injection of MENOPUR u00ae should be performed under direct medical supervision. Before starting treatment, the coupleu2019s 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 lesions, 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 u00ae dosage and regimen of administration and careful monitoring of therapy will minimise the incidence of such events.

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 of 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, less frequently, in the pericardial cavities. Patients who have ovarian enlargement are at risk of rupture. Pelvic examinations should be avoided or carried out with care. 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. 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 u00ae dosage, regimen of administration and careful monitoring of therapy will minimise the incidence of ovarian hyperstimulation and multiple pregnancy (see section 4.2). 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 medicine regimens for infertility treatment. It is not yet established if treatment with gonadotrophins, including MENOPUR u00ae , 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/m 2 ) or thrombophilia may have an increased risk of venous or arterial thromboembolic events, during or following treatment with MENOPUR u00ae . In these women, the benefits of MENOPUR u00ae administration need to be weighed against the risks.

Excipients MENOPUR u00ae contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially u2018sodium-freeu2019.

No interaction studies have been conducted with MENOPUR u00ae in humans. Although there is no controlled clinical experience, it is expected that the concomitant use of MENOPUR u00ae and clomiphene citrate may enhance the follicular response. When using GnRH agonist for pituitary desensitisation, a higher dose of MENOPUR u00ae may be necessary to achieve adequate follicular response. In women who show evidence of excessive ovarian stimulation while receiving MENOPUR u00ae , the administration of medicines with luteinising hormone (LH) activity increases the risk of ovarian hyperstimulation syndrome.

Pregnancy MENOPUR u00ae is contraindicated in women who are pregnant (see section 4.3).

Breastfeeding MENOPUR u00ae is contraindicated in women who are breastfeeding (see section 4.3).

Fertility MENOPUR u00ae is indicated for use in infertility (see section 4.1).

No studies on the effects on the ability to drive and use machines have been performed. However, MENOPUR u00ae may cause dizziness and this may affect the patientu2019s ability to drive and use machines.

a. Summary of the safety profile The most frequently reported adverse drug reactions (ADR) during treatment with MENOPUR u00ae in clinical trials are Ovarian Hyperstimulation Syndrome (OHSS), headache, abdominal pain, abdominal distension and injection site pain. Men : With regard to the gonadotrophin treatment, gynaecomastia, acne and weight gain have been reported. Additionally, administration site reactions and hypersensitivity could also be expected in the male population.

b. Tabulated list of adverse reactions The table below displays the main ADRs in women treated with MENOPUR u00ae in clinical trials distributed by system organ classes (SOCs) and frequency. Further, the ADRs seen during post marketing experience are mentioned with unknown frequency. Side effects are classified according to the following frequency classes: System Organ class Common u2265 1/100 to < 1/10 Uncommon u2265 1/1 000 to < 1/100 Rare u2265 1/10 000 to < 1/1 000 1 Unknown Eye disorders Visual disorders a Gastro-intestinal disorders Abdominal pain, Abdominal distension, Nausea Vomiting, Abdominal discomfort, Diarrhoea General disorders Injection site Fatigue Pyrexia, Malaise and administration site conditions reactions Immune system disorders Hyper-sensitivity reactions b Investigations Weight increased Musculo-skeletal & connective tissue disorders Musculo-skeletal pain c Nervous system disorders Headache Dizziness Reproductive system and breast disorders Ovarian hyperstimulation syndrome (OHSS) d , pelvic pain Ovarian cyst, Breast complaints Ovarian torsion d Skin and subcutaneous tissue disorders Acne, Rash Pruritus, Urticaria Vascular disorders Hot flush Thrombo- embolism d c. Description of selected adverse reactions 1 The ADRs seen during post-marketing experience are listed with unknown frequency. a Individual cases of temporary amaurosis, diplopia, mydriasis, scotoma, photopsia, vitreous floaters, vision blurred and vision impairment have been reported. b Cases of localised or generalised allergic reactions, including anaphylactic reaction, along with associated symptomatology have been reported. c Musculoskeletal pain includes arthralgia, back pain, neck pain and pain in extremities. d In cases of severe OHSS, ascites and pelvic fluid collection, pleural effusion, dyspnoea, oliguria, thromboembolic events and ovarian torsion have been reported.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/documents/adverse-drug-reactions-and-quality-problem- reporting-form.

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