Highly purified menotrophin.
MENOPUR 75 IU: Each vial with powder contains highly purified menotrophin (human menopausal) gonadotrophin, HMG) corresponding to 75 IU FSH (Follicle Stimulating Hormone) and 75 IU LH (Luteinizing Hormone).
MENOPUR multidose 600 IU: Each vial with powder contains highly purified menotrophin (human menopausal gonadotrophin, HMG) corresponding to follicle stimulating hormone activity FSH 600 IU and luteinizing hormone activity LH 600 IU.
MENOPUR multidose 1200 IU: Each vial with powder contains highly purified menotrophin (human menopausal gonadotrophin, HMG) corresponding to follicle stimulating hormone activity FSH 1200 IU and luteinizing hormone activity LH 1200 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.
Excipients/Inactive Ingredients: MENOPUR 75 IU: Powder: Lactose and sodium hydroxide for pH-adjustment as other ingredients.
Solvent: Isotonic sodium chloride solution and dilute hydrochloric acid for pH-adjustment.
MENOPUR multidose 600, 1200 IU: Powder: Lactose monohydrate, polysorbate 20, sodium phosphate dibasic heptahydrate, phosphoric acid (concentrated).
Solvent: Metacresol, water for injection.
Pharmacotherapeutic Group: Gonadotrophins. ATC Code: G03G A02.
Pharmacology: Pharmacodynamics: 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, 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.
In line with the action of LH activity in enhancing stereoidogenesis, 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.
Pharmacokinetics: 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.
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).
Stimulation of follicular development in women with hypogonadotrophic hypogonadism.
Treatment with MENOPUR should be initiated under the supervision of a physician experienced in the treatment of fertility problems.
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 objective 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 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, 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 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 Precautions) 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 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 Precautions) and the patient should use a barrier method of contraception or refrain from having coitus until the next menstrual bleeding has started.
Administration: MENOPUR is intended for subcutaneous (S.C.) or intramuscular (I.M.) 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.
The effects of an overdose is unknown, nevertheless one could expect ovarian hyperstimulation syndrome to occur.
MENOPUR is contraindicated in women who have: Tumours of the pituitary gland or hypothalamus. Ovarian, uterine or mammary carcinoma. Pregnancy and lactation. Gynaecological haemorrhage of unknown aetiology. Hypersensitivity to the active substance or any of the excipients used in the formulation (see Incompatibilities under Cautions for Usage). 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 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 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, 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.
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 Dosage & Administration and Adverse Reactions). 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 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.
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.
MENOPUR is contraindicated in women who are pregnant or lactating (see Contraindications).
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.
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 as follows displays the main adverse drug reactions in women treated with MENOPUR in clinical trials distributed by system organ classes (SOCs) and frequency. (See table.)
Click on icon to see table/diagram/image
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.
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.
Instructions for Use and Handling:The powder should only be reconstituted with the solvent provided in the package.
Attach the reconstitution needle to the prefilled syringe. Inject the total contents of solvent 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. 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 multidose 600 IU or 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 return to hospital for further destruction.
Incompatibilities: MENOPUR should not be administered in the same injection with other products, except Ferring's urofollitrophin (FSH) BRAVELLE. Studies have shown that co-administration of BRAVELLE and MENOPUR does not significantly alter the expected bioactivity.
Store in a refrigerator (2°C-8°C). Do not freeze. Store in the original container.
After reconstitution, the solution may be stored for a maximum of 28 days at not more than 30°C. Do not freeze.
Shelf-Life: 3 years.
G03GA02 - human menopausal gonadotrophin ; Belongs to the class of gonadotropins. Used as ovulation stimulants.
Inj (vial + pre-filled syringe solvent) 75 IU x 1 mL x 10's. 600 IU x 1 mL x 1's. 1,200 IU X 1 mL x 1's.