Merional (Lyophilisate) Instructions for Use

Marketing Authorization Holder

IBSA Institut Biochimique, S.A. (Switzerland)

ATC Code

G03GA02 (Menotropins)

Active Substance

Menotropins

Dosage Forms

	Merional	Lyophilisate for preparation of solution for intramuscular and subcutaneous administration 75 IU+75 IU: vial 1 pc. in a set with solvent
		Lyophilisate for preparation of solution for intramuscular and subcutaneous administration 150 IU+150 IU: vial 1 pc. in a set with solvent

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for intramuscular and subcutaneous administration in the form of a compact mass from white to light yellow in color; the supplied solvent is a transparent, colorless liquid without odor.

Excipients: lactose monohydrate 10 mg.

Solvent sodium chloride (apyrogenic for injection) 9 mg, water for injection (up to 1 ml).

Glass vials (1) in a set with solvent (amp. 1 pc.) – cardboard packs.
Glass vials (1) in a set with solvent (amp. 1 pc.) – cardboard packs (10) – common cardboard packs.

Lyophilisate for preparation of solution for intramuscular and subcutaneous administration in the form of a compact mass, from white to light yellow in color; the supplied solvent is a transparent, colorless liquid without odor.

Excipients: lactose monohydrate 10 mg.

Solvent sodium chloride (apyrogenic for injection) 9 mg, water for injection (up to 1 ml).

Glass vials (1) in a set with solvent (amp. 1 pc.) – cardboard packs.
Glass vials (1) in a set with solvent (amp. 1 pc.) – cardboard packs (10) – common cardboard packs.

Clinical-Pharmacological Group

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

Pharmacotherapeutic Group

Gonadotropins and other ovulation stimulants

Pharmacological Action

The drug is a highly purified human menopausal gonadotropin (hMG). It belongs to the group of menotropins. The ratio of biological activity of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) is 1:1. The drug is obtained from the urine of postmenopausal women.

Specific receptors for gonadotropins are present only in the tissues of the reproductive organs. In the ovaries, LH binds to receptors on the surface of theca cells and the corpus luteum, as well as to granulosa cells of large follicles. FSH binds to receptors on the surface of granulosa cells of small follicles in the ovaries and Sertoli cells in the testes.

Receptors for LH and FSH are linked to adenylate cyclase via a guanine nucleotide-binding regulatory protein (Gs-protein). An increase in intracellular cAMP causes an increase in the amount of the mitochondrial enzymatic complex, which oxidatively cleaves the side chains of cholesterol; this reaction is the rate-limiting step in the process of converting cholesterol to pregnenolone. Although the mechanism of stimulating gametogenesis by gonadotropins is unknown, it is also mediated by cyclic AMP.

Pharmacokinetics

Absorption

After a single subcutaneous and intramuscular administration at a dose of 225 IU, the time to reach C_max of the drug in plasma is 17.9 and 27.5 hours, respectively. After multiple administrations (150 IU daily for 7 days), the time to reach C_max of the drug in plasma is 8.0 hours for subcutaneous and 9.0 hours for intramuscular administration.

With a single subcutaneous and intramuscular administration, C_max averages 8.5 and 7.8 mIU/ml, respectively. With multiple subcutaneous and intramuscular administrations, C_max averages 15.0 mIU/ml and 12.5 mIU/ml, respectively.

AUC with a single subcutaneous and intramuscular administration averages 726.2 mIU×h/ml and 656.1 mIU×h/ml, respectively. With multiple subcutaneous and intramuscular administrations, AUC averages 622.7 mIU×h/ml and 546.2 mIU×h/ml, respectively.

The bioavailability of the drug with subcutaneous administration is higher than with intramuscular administration.

Elimination

The T_1/2 of FSH with multiple administrations is approximately 11-13 hours.

Indications

In women

• Anovulation when clomiphene therapy is ineffective;
• Controlled ovarian hyperstimulation to induce the growth of multiple follicles during assisted reproductive technologies, such as in vitro fertilization, gamete intrafallopian transfer, zygote intrafallopian transfer.

In men

• Stimulation of spermatogenesis in congenital or acquired hypogonadotropic hypogonadism in combination with a human chorionic gonadotropin (hCG) preparation.

ICD codes

Dosage Regimen

Treatment with Merional should be carried out only under the supervision of a physician with appropriate specialization and experience in the treatment of infertility.

It is administered intramuscularly or subcutaneously. The solution is prepared immediately before injection using the supplied solvent. The contents of 5 vials can be dissolved in 1 ml of solvent.

Doses are given in terms of FSH.

In women with anovulation, the drug is administered daily at a dose of 75-150 IU/day for the first 7 days of the cycle in menstruating women. Injections continue until an adequate response is achieved, which can be judged by daily analysis of estrogen concentrations and determination of follicle size using ultrasound.

Follicle maturation usually occurs during a treatment cycle lasting 7-12 days. If there is no ovarian response to administration, the daily dose of the drug can be gradually increased. The maximum daily dose usually does not exceed 225 IU.

After treatment and in the presence of an adequate, but not excessive, ovarian response, determined by clinical and biochemical studies, 24-48 hours after the last administration of the drug, 5000-10,000 IU of hCG is administered once to induce ovulation, which increases LH levels and stimulates the release of a mature egg. The day of hCG injection and the following day are optimal for conception.

If ovulation occurs and pregnancy does not occur, treatment can be repeated for 2 cycles. If there is no adequate response to therapy within 4 weeks of its initiation, the drug should be discontinued and a new course started with a higher initial dose.

For “superovulation” stimulation (during assisted reproductive technologies), the drug is used daily at a dose of 150-225 IU/day, starting from the 2nd or 3rd day of the cycle. Injections continue until an adequate response is achieved, which can be judged by daily analysis of estrogen concentrations and determination of follicle size using ultrasound. The dose is selected according to the patient’s response. The maximum daily dose usually does not exceed 450 IU. Adequate follicle maturation usually occurs on day 10 of treatment (in the range from 5 to 25 days).

24-48 hours after the last injection of Merional, an injection of 5000-10,000 IU of hCG must be given to stimulate follicle maturation. In patients using a GnRH agonist to suppress pituitary gonadotropic activity, Merional is started approximately two weeks after the start of treatment with the GnRH agonist, and both drugs are continued until adequate follicle development is achieved. For example, after two weeks of using a GnRH agonist, Merional is administered at a dose of 150-225 IU for 7 days. Then the dose is adjusted according to the patient’s ovarian response. Dose adjustment should be performed no more than once every 2 days and by no more than 150 IU.

Experience with assisted reproductive technologies shows that the degree of success of treatment remains stable during the first four attempts and then gradually decreases.

In anovulation caused by severe deficiency of LH and FSH, treatment can be started at any time, since such patients have amenorrhea and very low endogenous estrogen concentration.

The drug is administered daily at a dose of 75-150 IU/day until an adequate response is achieved, which can be judged by daily analysis of estrogen concentrations and determination of follicle size using ultrasound.

If the dose needs to be increased, dose selection should preferably be done after 7-14 days and preferably with an increase of 150 IU. The duration of stimulation in one cycle can be up to 5 weeks.

After treatment and in the presence of an adequate, but not excessive, ovarian response, determined by clinical and biochemical studies, 24-48 hours after the last administration of the drug, 5000-10,000 IU of hCG is administered once to induce ovulation. The day of hCG injection and the following day are optimal for conception.

In this case, luteal support may be needed, since a deficiency of substances with luteotropic activity (LH/hCG) after ovulation can lead to premature degradation of the corpus luteum.

In men for the purpose of stimulating spermatogenesis, 1-2 thousand IU of hCG is administered 2-3 times a week until the blood testosterone concentration normalizes. Then Merional is administered at 75-150 IU 2-3 times a week for at least 3 months until any improvement in spermatogenesis appears. Available clinical experience shows that to achieve spermatogenesis, treatment can continue for 18 months.

Adverse Reactions

Adverse reactions were classified as follows: very common (> 1/10); common (from ≥ 1/100 to ≤ 1/10); uncommon (from ≥1/1000 to ≤1/100); rare (from ≥1/10,000 to ≤ 1/1000); very rare (< 1/10,000).

From the digestive system: common – abdominal pain, gastrointestinal syndrome, including nausea, vomiting, diarrhea, abdominal cramps and bloating.

From the nervous system: very common — headache.

From the reproductive system: very common – ovarian cysts; common – mild and moderate ovarian hyperstimulation syndrome; uncommon – severe ovarian hyperstimulation syndrome; rare – ovarian torsion, complication of ovarian hyperstimulation syndrome.

Allergic reactions very rare – mild erythema, rash or facial swelling.

From the body as a whole: very rare – thromboembolic disease, usually associated with severe ovarian hyperstimulation syndrome.

Local reactions very common – severe and mild reactions at the injection site (pain, redness, bruising, swelling and/or irritation).

In addition, the following adverse reactions may occur: mastalgia, significant increase in urinary estrogen excretion, lower abdominal pain, enlarged ovarian size, hypovolemia, blood thickening, water-electrolyte disturbances, ascites, hydrothorax, fever, arthralgia, oliguria, decreased blood pressure, weight gain, hemoperitoneum, multiple pregnancy.

In men using a combination of Merional with an hCG preparation, side effects such as breast swelling, acne and weight gain have been reported. These effects are mostly caused by hCG.

Occasionally, with the use of similar drugs, abdominal blood clotting (blood clotting in the vessels) has been observed, which may also occur with the use of Merional.

Contraindications

• Tumors of the hypothalamic-pituitary region;
• Hyperprolactinemia;
• Diseases of the adrenal glands and thyroid gland;
• Organic lesions of the central nervous system, for example, pituitary tumors;
• Childhood;
• Hypersensitivity to the drug.

For women

• Primary ovarian failure;
• Persistent ovarian enlargement, ovarian cyst (not due to polycystic ovary syndrome);
• Polycystic ovary syndrome;
• Developmental anomalies of the genital organs (incompatible with normal pregnancy);
• Uterine fibroids;
• Metrorrhagia (of unknown etiology);
• Estrogen-dependent tumors (ovarian cancer, uterine cancer, breast cancer);
• Primary ovarian insufficiency;
• Pregnancy;
• Lactation period.

For men

• Prostate cancer;
• Testicular tumor;
• Androgen-dependent tumors.

With caution, the drug should be prescribed in the presence of risk factors for thromboembolism, such as individual or family predisposition, severe obesity (body mass index > 30 kg/m²) or thrombophilia, since in this case there is an increased risk of venous or arterial thromboembolism during or after treatment with gonadotropins. In this case, the benefit of treatment with gonadotropins must outweigh the risk of their use.

Use in Pregnancy and Lactation

The drug is contraindicated during pregnancy and breastfeeding.

Pediatric Use

Contraindicated in childhood.

Special Precautions

Before starting treatment, a thorough gynecological and endocrinological examination is necessary, including pelvic anatomy. In patients with tubal obstruction, Merional can only be used in the case of assisted reproductive technologies. Primary ovarian failure must be ruled out. A thorough examination is necessary to rule out early pregnancy. Patients of late reproductive age have an increased predisposition to endometrial carcinoma, as well as a higher frequency of anovulatory disorders.

In patients with pathological uterine bleeding or other signs of endometrial pathologies, a thorough diagnostic examination is necessary. An assessment of the partner’s fertility should also be performed.

Before prescribing the drug, appropriate treatment should be carried out for disorders of thyroid function or adrenal cortex, hyperprolactinemia of various etiologies, tumors of the hypothalamic-pituitary region.

The result of treatment may be the onset of multiple pregnancy. If signs of ovarian hyperstimulation occur (abdominal pain and palpable by a doctor or detectable by ultrasound, enlarged formations in the lower abdomen), treatment is stopped (more often develops in women with polycystic ovary syndrome).

During therapy, daily hormonal monitoring and ultrasound of developing follicles are mandatory (ovarian response can be assessed by the cervical index).

If the urinary estrogen concentration reaches 540 nmol (150 mcg)/24 h or the plasma 17β-estradiol concentration reaches 3000 pmol/l (800 pg/ml) or an excessive increase in these values is observed, then there is an increased risk of ovarian hyperstimulation, and treatment with Merional must be stopped immediately, and the use of hCG canceled.

In case of ovarian hyperstimulation syndrome, administration of the ovulatory dose of hCG is contraindicated!

In case of pregnancy, symptoms of excessive hyperstimulation may intensify and be observed for a long time, posing a threat to the patient’s life.

The development of thromboembolic complications is likely. Intravascular thrombosis and embolism, developing in arteries and veins, can lead to reduced blood flow to vital organs and limbs.

A complication of this can be venous thrombophlebitis, pulmonary embolism, pulmonary infarction, stroke, and arterial thrombosis leading to loss of a limb.

During treatment in men with high blood FSH levels, Menotropins are ineffective.

Overdose

Symptoms ovarian hyperstimulation syndrome (enlarged ovaries, lower abdominal pain, nausea, vomiting, diarrhea, weight gain, oliguria, ascites, hydrothorax, hemoperitoneum, hemoconcentration, shortness of breath), multiple pregnancy, thromboembolic complications.

Treatment consists of 3 stages: the first stage is aimed at reducing the concentration of hormones in the blood and preventing the development of thromboembolic complications (pneumonia, acute renal failure), it consists of intravenous administration of small amounts of albumin (with constant monitoring of blood electrolyte concentrations and hematocrit). The second stage begins after the patient’s condition has stabilized and should lead to a reduction in the fluid content in the body cavities, for which small amounts of hypertonic sodium chloride solution and albumin are administered intravenously. The third stage aims to prevent the development of pulmonary edema associated with the massive flow of fluid from the body cavities into the vascular bed, and includes the use of diuretics (with constant monitoring of hematocrit and plasma electrolyte concentrations).

Drug Interactions

Pharmacodynamic

Concomitant use of Merional with other drugs used to stimulate ovulation (for example, hCG, clomiphene) may enhance the follicular response.

When used concomitantly with GnRH agonists, an increase in the dose of menotropin may be required.

Pharmaceutical

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

Storage Conditions

The drug should be stored in a place protected from light, out of the reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life of the lyophilisate is 2 years, the solvent is 5 years. The shelf life of the kit is set according to the component with the shortest shelf life.

The reconstituted solution should be used immediately.

Dispensing Status

The drug is dispensed by prescription.

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.