Merional

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MEPRIONAL (MERIONAL®)

Composition:

Active substance: human menopausal gonadotropin;

1 vial of dry preparation contains the active substance menotropin (human menopausal gonadotropin, HMG), equivalent to 75 IU or 150 IU of FSH (follicle-stimulating hormone) and 75 IU or 150 IU of LH (luteinizing hormone);

Excipient: lactose monohydrate;

Solvent: 1 ampoule contains 1 ml of 0.9% sodium chloride solution.

Pharmaceutical form. Lyophilized powder for solution for injection.

Main physicochemical properties:

1 vial with active substance contains a lyophilized mass or white powder;

1 ampoule with solvent contains a clear, colorless, odorless liquid free of foreign particles.

Pharmacotherapeutic group.

Gonadotropic hormones. Human menopausal gonadotropin.

ATC code G03G A02.

Pharmacological Properties

Pharmacodynamics

The active ingredient of Merional is highly purified human menopausal gonadotropin. The drug contains follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which are produced by the human pituitary gland. The active substance in Merional is derived from the urine of postmenopausal women. The preparation is characterized by follicle-stimulating and luteinizing activity. In women, Merional induces an increase in estrogen levels in the blood, promotes growth and maturation of follicles, and stimulates endometrial proliferation and ovulation.

Specific gonadotropic receptors are present only in gonadal tissues. Merional acts on the surface of cells in the theca interna and corpus luteum, as well as on large granulosa cells of the follicle. FSH acts on the surface of small granulosa cells of the ovarian follicle. LH and FSH receptors are linked to adenylate cyclase via a guanine nucleotide-regulatory protein (Gs). Increased intracellular cyclic AMP leads to activation of the mitochondrial enzyme complex responsible for oxidation of the side chain of cholesterol. This reaction is the rate-limiting step that stimulates gonadogenesis.

FSH and LH are essential for normal gamete maturation (folliculogenesis in women) and sex hormone synthesis. In certain cases of impaired gonadal function, Merional is used to stimulate these processes. Additionally, the drug may be used to stimulate the development of more than one follicle in assisted reproductive technology programs.

Pharmacokinetics

Gonadotropins are effective only when administered intramuscularly or subcutaneously. The decline in FSH and LH concentrations occurs in a biphasic manner. The half-life of the first phase is 4 hours for FSH and 20 minutes for LH; the half-life of the second phase is 70 hours for FSH and 4 hours for LH. Elimination of metabolites from the body occurs via glomerular filtration into urine.

Clinical characteristics.

Indications.

Stimulation of follicular maturation in infertile women. Anovulatory cycle (including polycystic ovary syndrome) in women who are unresponsive to clomiphene citrate treatment; use in assisted reproductive technologies (ART), such as IVF (in vitro fertilization), GIFT (gamete intrafallopian transfer), to achieve fertilization (stimulation of multiple follicles).

Contraindications.

Hypersensitivity to the components of the drug. Premature menopause; infertility associated with impaired normal follicular maturation; infertility due to abnormalities preventing normal follicular development (e.g., tubal or cervical pathology), except in cases participating in assisted reproductive technology programs; hypergonadotropic ovarian insufficiency; uterine fibroids incompatible with pregnancy; ovarian cysts or ovarian enlargement not related to polycystic ovary syndrome; primary ovarian insufficiency; congenital or acquired genital tract abnormalities incompatible with pregnancy; uterine myomas; gynecological bleeding of unknown etiology; hyperprolactinemia; thyroid or adrenal endocrinopathy; pituitary or hypothalamic tumors; tumors of the uterus, ovaries, or breasts. Pregnancy or lactation period.

Hypersensitivity to gonadotropin or other components of the drug in medical history.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of Merional and clomiphene citrate may potentiate the follicular response. Concurrent use with gonadotropin-releasing hormone (GnRH) agonists may induce pituitary desensitization (increased dose of Merional may be required) to achieve an adequate ovarian response.

Special precautions for use.

Treatment of infertility with Merional should be initiated only under the supervision of a physician. Causes of infertility such as mechanical, immunological, or androgenic factors must be excluded. Before treatment with the drug, both the patient and her partner should undergo appropriate examinations to rule out contraindications. Patients must be informed about the specifics of treatment with the drug and the potential risks associated with its use. Prior to initiating infertility treatment in women, ovarian function should be assessed (by ultrasound and plasma estradiol levels). During treatment, these evaluations should be performed daily or every other day until a response is observed, which can be assessed by the cervical index. Close monitoring of the patient's condition is required throughout the entire course of treatment.

Prior to treatment with Merional, diagnostic evaluation should be performed to exclude pathologies of the reproductive organs or nongonadal endocrine disorders.

Ovarian hyperstimulation syndrome (OHSS).

OHSS is a condition distinct from uncomplicated ovarian enlargement. OHSS is a self-limiting syndrome, the severity of which may progressively increase. It is characterized by significant enlargement of the ovaries, elevated levels of sex steroid hormones, and increased vascular permeability, which may lead to fluid accumulation in the abdominal cavity, pleural space, and, in rare cases, pericardial cavity.

In severe cases, OHSS may present with symptoms such as abdominal pain, abdominal distension, large ovarian cysts, weight gain, dyspnea, oliguria; gastrointestinal disturbances including nausea, vomiting, and diarrhea; hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusion, hydrothorax, acute respiratory distress, and thromboembolic events.

Ovarian hyperresponse to gonadotropin therapy rarely leads to OHSS, except when human chorionic gonadotropin (hCG) is used to trigger ovulation. Therefore, if OHSS develops, administration of hCG for ovulation induction should be avoided. Patients should be advised to abstain from sexual intercourse or use barrier contraception for at least 4 days. OHSS may have a rapid onset (within one day to several days) and is a serious adverse effect; thus, patients should remain under close medical supervision for at least 2 weeks following hCG administration.

To minimize the risk of OHSS or multiple pregnancy, monitoring of serum estradiol levels and ovarian ultrasound are recommended. In anovulatory patients, the risk of OHSS or multiple pregnancy increases when serum estradiol exceeds 900 pg/mL (3300 pmol/L) and more than 3 follicles ≥14 mm in diameter are present. In assisted reproductive technology (ART) cycles involving multifollicular stimulation, the risk increases when plasma estradiol exceeds 3000 pg/mL (11,000 pmol/L) with at least 20 follicles ≥12 mm in diameter. When plasma estradiol exceeds 5500 pg/mL (20,200 pmol/L) or there are 40 or more follicles, hCG should not be administered.

Adherence to the recommended dosage regimen, administration schedule, and therapeutic monitoring will reduce the incidence of ovarian hyperstimulation and multiple pregnancy (see sections "Administration and dosage" and "Adverse reactions").

In assisted reproductive technology (ART) programs, aspiration of all follicles prior to ovulation may help reduce the risk of hyperstimulation.

OHSS may be more severe and prolonged if pregnancy occurs. OHSS most commonly occurs approximately 7–10 days after discontinuation of hormonal therapy. Typically, OHSS resolves spontaneously with the onset of menstruation.

Patients with polycystic ovary syndrome (PCOS) have a higher incidence of OHSS.

To exclude this syndrome, the patient should undergo clinical and endocrinological evaluation during the treatment course and for 2 weeks after its completion.

High doses of Merional generally do not cause hyperstimulation syndrome. It may be induced by gonadotropins. If ovarian hyperstimulation is detected clinically and/or by ultrasound, treatment with Merional should be discontinued. Symptoms of hyperstimulation typically appear on days 4–8 of gonadotropin administration. Therefore, patient monitoring should continue for 2 weeks after the last injection. If symptoms suggestive of hyperstimulation persist for 3 weeks or longer after discontinuation of Merional therapy, this may indicate ectopic pregnancy or spontaneous abortion. In cases of moderate hyperstimulation, careful observation is sufficient. If symptoms worsen, hospitalization and electrolyte and hemodynamic testing are recommended.

In some patients, particularly those with Stein–Leventhal syndrome (PCOS), ovarian cyst formation may occur. This presents as abdominal pain of varying intensity and requires discontinuation of treatment followed by further evaluation.

Although the risk of ovarian hyperstimulation and cyst formation during treatment with Merional is low (>1%), and higher in high-risk groups (>4%), strict adherence to the recommended dosing regimen of Merional is advised to minimize these adverse effects. Treatment should be discontinued immediately at the first signs of developing ovarian hyperstimulation syndrome (abdominal pain and palpable or ultrasound-detected masses in the lower abdomen). Administration of an ovulatory dose of hCG is contraindicated if OHSS has developed. If pregnancy occurs, symptoms of excessive hyperstimulation may intensify and persist for a prolonged period, posing a life-threatening risk to the patient.

Multiple pregnancy.

Multiple pregnancy, especially with a high number of fetuses, increases the risk of complications for both mother and fetuses during the perinatal period.

In patients undergoing assisted reproductive technology (ART) programs, the risk of multiple pregnancy is primarily related to the number of embryos transferred, embryo quality, and maternal age.

Multiple pregnancy occurs in approximately 20% of cases during treatment with Merional, usually resulting in twins. When the drug is used in reproductive programs, the risk of multiple pregnancy increases proportionally with the number of transferred embryos and oocytes.

Patients should be informed prior to treatment about the possibility of multiple pregnancy.

Spontaneous abortion.

The incidence of spontaneous abortions and pregnancy loss is higher in women undergoing follicular maturation stimulation or ART programs compared to natural conception.

Ectopic pregnancy.

Women with a history of uterine disease have an increased risk of ectopic pregnancy, regardless of whether conception occurs spontaneously or as a result of infertility treatment. The incidence of ectopic pregnancy after in vitro fertilization (IVF) is 2–5%, compared to 1–1.5% in the general population.

Ectopic pregnancy may occur due to tubal abnormalities. Thus, treatment does not increase the risk.

Reproductive organ neoplasms.

In women who have repeatedly received medical treatment for infertility, cases of both benign and malignant neoplasms of the ovaries and other reproductive organs have been reported. Currently, it is not established whether gonadotropin therapy or the underlying predisposition in infertile women is responsible for the development of such neoplasms.

Congenital malformations.

The incidence of congenital fetal malformations in women following assisted reproductive technology (ART) programs may be slightly higher than in naturally conceived pregnancies. This is believed to be due to parental factors (e.g., maternal age, sperm characteristics) and multiple pregnancy.

Thromboembolic events.

Thromboembolic events may develop during or after gonadotropin stimulation in women with high-risk factors such as obesity or personal or hereditary predisposition. It should be noted that pregnancy itself also increases the risk of thromboembolic complications.

Infectious diseases.

When using medicinal products derived from human urine, the possibility of transmitting infectious agents—including known and unknown viruses and pathogens—cannot be completely excluded. However, this risk is reduced by the extraction/purification process, which includes steps for viral inactivation/removal. These steps have been validated using viral models, including human immunodeficiency virus (HIV), herpesvirus, and papillomavirus. To date, there have been no reports of viral transmission associated with administration of human urinary-derived gonadotropins.

Prior to prescribing the drug, appropriate treatment of thyroid or adrenal cortex dysfunction, hyperprolactinemia of various etiologies, or hypothalamic-pituitary tumors should be performed.

The drug contains lactose and therefore should not be administered to patients with rare hereditary conditions of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Studies in humans and animals have shown a risk to the fetus. Therefore, the risks associated with administering this drug to pregnant women outweigh any potential benefit. The drug is contraindicated during pregnancy. It is unknown whether human menopausal gonadotropin is excreted in breast milk or how it may affect breastfed infants. This drug is contraindicated during breastfeeding.

Ability to affect driving or operating machinery.

There are no reports on studies evaluating the effect of the drug on reaction speed when driving or operating machinery.

Method of Administration and Dosage.

Merional is administered intramuscularly or subcutaneously after reconstitution with the provided solvent. The injection solution should be prepared immediately before administration and used promptly after reconstitution.

Ovulation induction. The goal of treatment is to induce the maturation of follicles within several days using individually adjusted doses of Merional, followed by ovulation induction with an injection of human chorionic gonadotropin.

Follicular maturation is monitored by hormonal assessments and clinical observations. Hormonal monitoring includes evaluation of plasma estrogen levels. Clinical observations include basal body temperature monitoring, ultrasound assessment of follicular size, and analysis of cervical mucus.

Merional administration should be discontinued when the patient's estrogen levels and follicular size in the preovulatory phase reach the following: plasma estrogens – 1.1–2.9 pmol/mL; diameter of dominant follicles – 18–22 mm; cervical score according to Insler – > 8–12.

Anovulatory cycle. There are significant interindividual variations in ovarian response to exogenous gonadotropins; therefore, the treatment regimen must be individualized. Dose selection requires monitoring of estrogen levels (in blood or urine), ultrasound examination, and/or dynamic clinical assessment of estrogenic activity. Overdosage may result in multiple uni- or bilateral follicular development. A sequential treatment regimen is generally recommended. In this case, therapy begins with daily administration of Merional during the first seven days of the menstrual cycle.

The first injection of one vial of Merional (75 IU) is administered intramuscularly or subcutaneously on days 4–5 after the onset of menstruation or its induction. Daily administration of one vial of Merional (75 IU) should continue for the next 7–12 days, up to complete follicular maturation. The response should be evaluated daily by ultrasound and monitoring of plasma estrogen levels. If the desired effect is not achieved, the daily dose may be increased to 150 IU (2 vials of Merional 75 IU or 1 vial of 150 IU). Daily doses exceeding 150 IU should only be administered under conditions of particularly careful patient monitoring. The maximum daily dose of Merional should not exceed 450 IU (6 vials of 75 IU or 3 vials of 150 IU). If a rapid increase in plasma estrogen levels occurs (>100% within 2–3 days), the dose of Merional should be reduced. A single injection of chorionic gonadotropin (hCG) 5000–10,000 IU is administered 24–48 hours after the last Merional injection, along with final clinical and biochemical assessment of follicular maturation adequacy. Ovulation occurs 32–48 hours after hCG administration. On the day of hCG injection, patients are advised to have intercourse and repeat it the following day.

If ovulation does not occur, administration of chorionic gonadotropin (hCG) may be repeated.

Merional may be administered every other day, but daily administration is generally preferred.

The treatment course may be repeated up to two times, provided that the patient's condition is carefully monitored.

Women undergoing controlled ovarian stimulation in assisted reproductive technologies. In assisted reproductive programs, daily intramuscular or subcutaneous administration of 150–300 IU of Merional is typically used, starting on day 3 of the menstrual cycle, until adequate follicular development is achieved. If Merional is used in combination with FSH, its dose should be reduced. Follicular development is monitored by measuring estrogen levels, ultrasound examination, and/or clinical assessment of estrogenic activity. Ovulation is triggered by injection of 5000–10,000 IU of chorionic gonadotropin (hCG).

Children.

Merional is contraindicated in children (under 18 years of age).

Overdose.

The effects of overdose with Merional are not known. However, the development of ovarian hyperstimulation syndrome cannot be excluded. Treatment is symptomatic.

Adverse Reactions

Central nervous system: very common – headache, dizziness.

Vascular system: very rare – thromboembolism; common – hot flushes.

Gastrointestinal tract: occasionally possible abdominal pain and lower abdominal pain, bloating, nausea, vomiting, diarrhea.

Musculoskeletal system: back pain.

Skin: very rare – erythema, skin rash, facial swelling.

Reproductive system: treatment with hMG preparations may lead to ovarian hyperstimulation, which clinically manifests after administration of human chorionic gonadotropin (hCG) for ovulation induction. This may result in the formation of large ovarian cysts. Additionally, in cases of severe ovarian hyperstimulation, ascites, hydrothorax, oliguria, hypotension, and thromboembolic events may occur; rarely – ovarian torsion, commonly – uterine cramps; increased risk of ectopic and multiple pregnancies.

Immune system: rarely, hypersensitivity reactions may develop, including fever.

In isolated cases, prolonged use of the drug may lead to the formation of antibodies, resulting in treatment inefficacy.

General disorders and administration site reactions: commonly – weakness, fatigue, risk of infectious transmission, reactions at the site of drug administration including pain, redness, bruising, swelling and/or itching, and injection site pain.

If urinary estrogen levels exceed 540 nmol (150 mg)/24 hours or plasma 17β-estradiol levels exceed 3000 pmol/L (800 pg/mL), or if other parameters increase significantly, ovarian hyperstimulation may occur, and treatment with Merional must be discontinued immediately. Ovarian hyperstimulation can be life-threatening and is characterized by large ovarian cysts; rupture of these cysts may lead to acute abdominal pain, ascites, and thromboembolic complications.

Shelf life. 2 years.

Storage conditions.

Keep out of reach of children.

Store protected from light at a temperature not exceeding 25°C.

Incompatibilities.

Merional should be reconstituted with 0.9% sodium chloride injection solution. Data on incompatibilities are lacking.

Packaging.

75 IU or 150 IU of lyophilized powder in glass vials together with solvent No. 1 in cardboard boxes; 10 cardboard boxes per cardboard pack.

Prescription status. Prescription only.

Manufacturer.

IBSA Institut Biochimique S.A., Switzerland.

Manufacturer's address and place of business.

Via al Ponte 13, 6903 Lugano, Switzerland.