Menopur^® Multidose (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Ferring-Leciva, a.s. (Czech Republic)

Manufactured By

Ferring, GmbH (Germany)

Labeled By

FERRING INTERNATIONAL CENTER, S.A. (Switzerland)

ATC Code

G03GA02 (Menotropins)

Active Substance

Menotropins

Dosage Forms

	Menopur® Multidose	Lyophilisate for preparation of a solution for subcutaneous administration 600 IU+600 IU: vial 1 pc. in a set with solvent
		Lyophilisate for preparation of a solution for subcutaneous administration 1200 IU+1200 IU: vial 1 pc. in a set with solvent

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of a solution for s/c administration as a white or almost white amorphous mass; the supplied solvent is a colorless transparent solution.

* Menotropins (highly purified human menopausal gonadotropin, hMG).

Excipients : lactose monohydrate – 21 mg, polysorbate 20 – 0.005 mg, sodium hydrogen phosphate heptahydrate – 0.268 mg, phosphoric acid 1M solution – q.s., sodium hydrogen phosphate 0.5M solution – q.s.

Solvent (1 syringe with solvent) metacresol – 3.63 mg, water for injections – up to 1.1 ml.

Colorless glass vials (1) in a set with solvent (syringe 1.1 ml 1 pc.), needle for solution preparation (1 pc.) and disposable graduated syringes (9 pcs.) – cardboard packs.

Lyophilisate for preparation of a solution for s/c administration as a white or almost white amorphous mass; the supplied solvent is a colorless transparent solution.

* Menotropins (highly purified human menopausal gonadotropin, hMG).

Excipients : lactose monohydrate – 21 mg, polysorbate 20 – 0.005 mg, sodium hydrogen phosphate heptahydrate – 0.268 mg, phosphoric acid 1M solution – q.s., sodium hydrogen phosphate 0.5M solution – q.s.

Solvent (1 syringe with solvent) metacresol – 3.63 mg, water for injections – up to 1.1 ml.

Colorless glass vials (1) in a set with solvent (syringe 1.1 ml 2 pcs.), needle for solution preparation (1 pc.) and disposable graduated syringes (18 pcs.) – cardboard packs.

Clinical-Pharmacological Group

Drug of menopausal human gonadotropin (FSH:LH=1:1)

Pharmacotherapeutic Group

Gonadotropins and other ovulation stimulants

Pharmacological Action

Human menopausal gonadotropin containing FSH and LH in a 1:1 ratio. It is obtained from human postmenopausal urine. It has follicle-stimulating and luteinizing activity. In women, it stimulates the growth and maturation of ovarian follicles, increases estrogen levels, stimulates endometrial proliferation and ovulation. In men, it stimulates the development of seminiferous tubules and spermatogenesis.

FSH is a key factor in the growth and development of follicles at the stage of early folliculogenesis. LH plays an important role in the production of sex hormones by the ovaries and is involved in the physiological processes leading to the development of a full-fledged preovulatory follicle. Follicular growth stimulation under the influence of FSH, in the complete absence of LH, results in pathological follicle development associated with low estradiol concentration and inability of the non-ovulating follicle to luteinize in response to a normal ovulatory stimulus. Taking into account the effect of LH, which is to enhance the synthesis of sex hormones, the use of menotropins in IVF/ICSI cycles is associated with a higher plasma estradiol concentration than when using recombinant FSH preparations. This aspect should be taken into account when monitoring the response to menotropins by the dynamics of estradiol concentration changes. No differences in estradiol concentration were found in protocols using low doses of menotropins for ovulation induction in patients with an anovulatory cycle. The target organs for the hormonal effect of hMG in men are the testes. In the testes, FSH induces the maturation of Sertoli cells, which primarily affects the division of cells of the convoluted tubules and the development of spermatozoa. This requires a high intratesticular concentration of androgens, which is achieved by prior therapy with human chorionic gonadotropin (hCG).

Pharmacokinetics

The pharmacokinetics of menotropins after i/m and s/c administration were studied separately for each component of the product.

The pharmacokinetic profile of FSH, which is part of the product, was established. The C_max of FSH in plasma is reached 6-48 hours after i/m administration and 6-36 hours after s/c administration.

Bioavailability after s/c administration is higher than after i/m. The pharmacokinetic parameters of FSH obtained after i/m and s/c administration at a dose of 300 IU were: i/m administration: C_max = 4.15 mIU/ml, time to C_max = 18 h, AUC = 320.1 mIU/ml h; s/c administration: C_max = 5.62 mIU/ml, time to C_max= 12 h, AUC = 385.2 mIU/ml h.

It is excreted mainly by the kidneys. T_1/2 is 56 h (i/m administration) and 51 h (s/c administration).

Indications

In women: anovulation; controlled ovarian hyperstimulation for the induction of multiple follicle growth during the following assisted reproductive technologies (ART): in vitro fertilization with embryo transfer (IVF/ET), gamete intrafallopian transfer (GIFT) and intracytoplasmic sperm injection (ICSI).

In men: impaired spermatogenesis due to hypogonadotropic hypogonadism.

ICD codes

Dosage Regimen

Administered s/c and i/m. The dose, method and regimen of administration, duration of therapy are determined individually, depending on the indications and effectiveness of therapy – in women – depending on the ovarian response; in men – on the state of spermatogenesis. In women, it is used as monotherapy or in combination with agonists or antagonists of gonadotropin-releasing hormone (GnRH). In men, it is usually used in combination with hCG.

Adverse Reactions

Immune system disorders: frequency unknown – local or general allergic reactions, including anaphylactic reactions.

Nervous system disorders often – headache; infrequently – dizziness.

Eye disorders transient blindness, diplopia, mydriasis, scotoma, photopsia, transient vitreous opacities, decreased visual acuity.

Gastrointestinal disorders often – abdominal pain, nausea, abdominal distension; infrequently – vomiting, abdominal discomfort, diarrhea.

Cardiovascular disorders: infrequently – hot flushes, thromboembolic disorders.

Skin and subcutaneous tissue disorders: rarely – acne, skin rashes; frequency unknown – skin itching, urticaria.

Musculoskeletal and connective tissue disorders: joint pain, back and neck pain, limb pain.

Reproductive system and breast disorders often – ovarian hyperstimulation syndrome, pelvic pain, in men – gynecomastia; infrequently – ovarian cysts, breast pain and discomfort, breast engorgement and swelling, nipple pain; frequency unknown – ovarian torsion.

Injection site reactions very often – pain at the injection site; frequency unknown – hyperthermia at the injection site.

General disorders and administration site conditions often – flu-like symptoms; infrequently – increased body temperature, increased fatigue, malaise, increased body weight.

The likelihood of spontaneous abortion in a pregnancy resulting from treatment with gonadotropins is higher than in a pregnancy in a healthy woman.

Contraindications

Hypersensitivity to menotropins; tumors of the pituitary gland and hypothalamus (for s/c administration); age under 18 years; impaired liver or kidney function.

In women: cancer of the ovaries, uterus or breast; pregnancy; breastfeeding period; vaginal bleeding of unknown etiology; presence of cysts or enlargement of the ovaries not associated with PCOS; primary ovarian failure; developmental abnormalities of the genital organs incompatible with pregnancy; uterine fibroids incompatible with pregnancy.

In men: prostate cancer; testicular tumor; primary testicular failure.

In case of a history of thyroid and adrenal diseases, hyperprolactinemia, tumors of the hypothalamic-pituitary region, appropriate treatment should be carried out before starting hMG therapy.

With caution in women – presence of risk factors for the development of thromboembolic complications (individual or family predisposition, obesity with body mass index (BMI) > 30 kg/m²), thrombophilia); history of fallopian tube diseases.

Use in Pregnancy and Lactation

Menotropins are contraindicated for use during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Contraindicated in patients with impaired liver function.

Use in Renal Impairment

Contraindicated in patients with impaired kidney function.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Not applicable.

Special Precautions

This product has pronounced gonadotropic activity, therefore, adverse events of varying severity may develop during its use. Treatment should be carried out under the supervision of a physician experienced in the diagnosis and treatment of infertility.

The use of gonadotropins requires the presence of qualified medical personnel and appropriate equipment. Before starting therapy with menotropins and during treatment, the condition of the ovaries should be monitored (ultrasound and plasma estradiol concentration). The product should be used at the lowest effective dose that meets the treatment goals.

The first injection should be performed under the direct supervision of a physician.

Before starting the use of menotropins in women, it is recommended to diagnose the causes of infertility in both the woman and her partner, and to establish possible contraindications to pregnancy. Before starting treatment, women should be examined for hypothyroidism, adrenal insufficiency, hyperprolactinemia, tumors of the hypothalamus and pituitary gland; if necessary, appropriate treatment should be prescribed.

Controlled stimulation of follicle growth, regardless of the indication for use in women, may lead to enlargement of the ovaries with the development of their hyperstimulation.

By following the dosage regimen and method of administration of menotropins in combination with therapy monitoring, it is possible to minimize the risk of the above reactions.

Assessment of follicle development should be carried out by a physician with appropriate experience.

Ovarian hyperstimulation syndrome (OHSS) is a syndrome distinct from uncomplicated ovarian enlargement, the manifestations of which depend on the severity. It includes significant ovarian enlargement, high plasma estrogen concentration, and increased vascular permeability, which can lead to fluid accumulation in the abdominal, pleural and, less commonly, pericardial cavities.

In severe cases of OHSS, the following symptoms are possible: abdominal pain, abdominal distension, significant ovarian enlargement, weight gain, shortness of breath, oliguria and gastrointestinal symptoms, including nausea, vomiting and diarrhea. Clinical examination may reveal hypovolemia, hemoconcentration, electrolyte disturbances, ascites, hemoperitoneum, exudative pleurisy, hydrothorax, acute respiratory distress syndrome and thromboembolic complications.

Excessive ovarian response to gonadotropin administration rarely leads to the development of OHSS if hCG is not used to stimulate ovulation. Therefore, in case of ovarian hyperstimulation, hCG should not be administered, and the patient should be warned to refrain from sexual intercourse or use barrier methods of contraception for at least 4 days. OHSS can progress rapidly (within 24 hours to several days), becoming a serious medical complication, so careful monitoring of patients is necessary for at least 2 weeks after hCG administration.

Adherence to recommended doses and regimens and careful therapy monitoring can minimize cases of ovarian hyperstimulation and multiple pregnancy. When performing assisted reproductive technologies (ART), aspiration of the contents of all follicles before ovulation may reduce the risk of developing OHSS.

OHSS may be more severe and prolonged if pregnancy occurs. Most often, OHSS develops after discontinuation of gonadotropin treatment and reaches maximum severity 7-10 days after the end of treatment. OHSS usually resolves spontaneously after the onset of menstruation.

If severe OHSS develops, treatment is discontinued, the patient is hospitalized and specific therapy is initiated.

The development of OHSS is more typical for patients with PCOS.

In multiple pregnancies, there is an increased risk of adverse maternal and perinatal outcomes.

When using menotropins, multiple pregnancies occur more often than with natural conception. The highest frequency of twin births is noted. To reduce the risk of multiple pregnancy, careful monitoring of the ovarian response to stimulation is recommended.

In the case of ART, the likelihood of multiple pregnancy depends on the number of embryos transferred, their quality and the age of the patient.

The patient should be warned about the potential risk of multiple pregnancy before starting treatment.

The frequency of spontaneous abortions and premature births in pregnancies occurring after treatment with menotropins is higher than in healthy women.

In patients with a history of fallopian tube diseases, both with natural conception and with infertility treatment, there is a high risk of ectopic pregnancy.

There are reports of neoplasms of the ovaries and other organs of the reproductive system, both benign and malignant, in women who have undergone several regimens of menotropin administration for infertility treatment. It has not yet been established whether treatment with gonadotropins increases the baseline risk of these tumors in women with infertility.

The prevalence of congenital malformations of the fetus when using ART is somewhat higher than with natural conception. It is believed that this may be associated with individual characteristics of the parents (maternal age, sperm characteristics) and multiple pregnancy.

Women with known risk factors for the development of thromboembolic complications, such as individual or family predisposition, obesity (BMI > 30 kg/m²) or thrombophilia, may have an increased risk of venous or arterial thromboembolic complications during or after treatment with gonadotropins. In such cases, the benefit of their use should be weighed against the possible risk. It should be taken into account that pregnancy itself also increases the risk of developing thromboembolic complications.

The use of menotropins in men with high blood FSH levels is ineffective. To evaluate the effectiveness of treatment, a semen analysis is performed 4-6 months after the start of treatment.

Drug Interactions

In women with symptoms of excessive ovarian stimulation due to the use of menotropins, the administration of drugs with LH activity increases the risk of developing ovarian hyperstimulation syndrome.

Concomitant use of menotropins with clomiphene may enhance follicle growth stimulation.

Concomitant use with GnRH agonists may require an increase in the dose of menotropins to achieve an optimal ovarian response.

This product should not be mixed in the same syringe with other drugs.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.