Humog - 75 i.u.

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT HuMoG-75 V.O.

Composition:

Active substance: 1 vial contains highly purified menotropin, equivalent to follicle-stimulating hormone (FSH) activity of 75 IU and luteinizing hormone (LH) activity of 75 IU in a 1:1 ratio;

Excipients: mannite (E 421), sucrose, disodium phosphate anhydrous, sodium ascorbate, phosphoric acid (diluted), sodium hydroxide (diluted);

Solvent: 0.9% sodium chloride for injections.

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical properties: white powder or lump.

Pharmacotherapeutic group.

Gonadotrophins and other ovulation stimulants. Human menopausal gonadotrophin (hMG).

ATC code G03G A02.

Pharmacological Properties

Pharmacodynamics

The active ingredient of the drug is highly purified human menopausal gonadotropin. The preparation contains follicle-stimulating and luteinizing hormones produced by the human pituitary gland, in doses of 75 or 150 IU in a 1:1 ratio. The active substance is obtained from the urine of postmenopausal women.

Menopausal gonadotropin exerts a follicle-stimulating effect. It increases sex hormone concentrations in blood plasma. In women, it increases estrogen levels in the blood, stimulates ovarian growth, follicular maturation, and ovulation, and induces endometrial proliferation.

In men, it stimulates spermatogenesis (by promoting the synthesis of androgen-binding proteins in the seminiferous tubules and Sertoli cells). It enhances steroid hormone production by the gonads. The efficacy is primarily due to FSH activity.

Pharmacokinetics

Single doses of 300 IU menotropins (Ferring European formula) were administered subcutaneously and intramuscularly in a two-period crossover study to 16 healthy women with suppressed endogenous follicle-stimulating hormone and luteinizing hormone. Based on the ratio of FSH maximum concentration (Cmax) and area under the concentration-time curve (AUC), subcutaneous and intramuscular administration of menotropins are not bioequivalent. Subcutaneous administration of menotropins, compared to intramuscular, results in a 35% and 20% increase in FSH Cmax and AUC, respectively. The mean accumulation factors following subcutaneous and intramuscular administration of six doses ranging from 150 IU to 450 IU per day are 1.6 and 1.4, respectively. When six doses of 150 IU per day are administered subcutaneously and intramuscularly, observed serum FSH concentrations range from 1.7 to 15.9 mIU/mL and from 0.5 to 10.1 mIU/mL, respectively. Serum LH concentrations following multiple subcutaneous doses are low and variable. No apparent trend toward increasing serum LH concentrations is observed following subcutaneous or intramuscular administration of doses ranging from 150 to 450 IU per day. After the sixth dose of 150 IU per day administered subcutaneously or intramuscularly, the range of baseline-corrected serum LH concentrations is 0–3.2 mIU/mL for both routes of administration.

Absorption. The geometric mean FSH Cmax and AUC following a single subcutaneous dose of menotropins are 5.62 mIU/mL and 385.2 mIU·h/mL, respectively; the corresponding geometric mean FSH tmax is 12 hours. The geometric mean FSH Cmax and AUC following a single intramuscular dose of menotropins are 4.15 mIU/mL and 320.1 mIU·h/mL, respectively; the corresponding geometric mean FSH tmax is 18 hours.

Distribution. Tissue and organ distribution of FSH and LH in humans has not been studied.

Metabolism and Excretion. The metabolism of FSH and LH in humans has not been studied. The mean elimination half-life of FSH following subcutaneous and intramuscular administration of a single dose of menotropins is 53.7 and 59.2 hours, respectively.

Clinical Characteristics.

Indications.

In women:

anovulation (including polycystic ovary syndrome);

controlled ovarian hyperstimulation, including induction of multiple follicular development in the context of assisted reproductive technologies (e.g., in vitro fertilization / embryo transfer (IVF/ET) and intracytoplasmic sperm injection (ICSI)).

In men:

impaired spermatogenesis due to hypogonadotropic hypogonadism.

Contraindications.

Women:

• pituitary or hypothalamic tumors;
• pregnancy and lactation;
• ovarian cysts or ovarian enlargement unrelated to polycystic ovary syndrome;
• absence of the uterus, premature menopause, tubal occlusion;
• tumors of the uterus, ovaries, or mammary glands;
• vaginal bleeding of unknown etiology;
• hypersensitivity to any component of the drug.

Men:

• prostate carcinoma;
• testicular tumors;
• hypersensitivity to any component of the drug.

ХuМоГ should not be administered in cases where a favorable treatment outcome is unlikely:

• in primary ovarian or primary testicular insufficiency;
• in congenital genital abnormalities incompatible with pregnancy;
• in uterine fibroids incompatible with pregnancy.

In cases of thyroid or adrenal dysfunction, hyperprolactinemia, possibly associated with pituitary or hypothalamic tumors, appropriate treatment should be performed prior to initiating therapy with LH.

Interaction with other medicinal products and other forms of interaction.

No studies on interactions between HuMG and other medicinal products have been conducted.

Even in the absence of clinical experience, concomitant use of HuMG and clomiphene citrate is expected to enhance follicular response. When gonadotropin-releasing hormone (GnRH) agonists are used for pituitary desensitization, higher doses of HuMG may be required to achieve adequate follicular response.

Special precautions for use.

Since HuMOnG has potent gonadotropic activity which may cause side effects ranging from mild to moderate severity, the drug should be administered under the supervision of physicians specialized in infertility treatment and experienced in such therapy.

Treatment with gonadotropins requires significant time commitment from physicians and other medical personnel, as well as appropriate, regular monitoring of ovarian response, including ultrasound examinations, possibly combined with serum estradiol level measurements. Patient response to menotropin administration varies considerably, with some patients showing poor response to treatment. The lowest effective dose corresponding to the treatment goal should be used.

The first injection of HuMOnG should be administered under direct physician supervision.

Prior to initiating treatment, infertility should be confirmed in the couple, and any contraindications to pregnancy should be ruled out. In particular, patients should be evaluated for hypothyroidism, adrenal insufficiency, hyperprolactinemia, and pituitary or hypothalamic tumors, and appropriate treatment initiated if necessary.

In patients undergoing follicular stimulation for anovulatory infertility or assisted reproductive technologies (ART), ovarian enlargement or hyperstimulation may occur. These risks can be minimized by strict adherence to recommended dosing and administration regimens, as well as careful therapy monitoring.

Assessment of follicular development and maturation should be performed by a physician experienced in interpreting the relevant tests.

Ovarian Hyperstimulation Syndrome (OHSS).

OHSS is a distinct clinical condition, different from uncomplicated ovarian enlargement. OHSS is a syndrome with variable severity. Signs of OHSS include ovarian enlargement, elevated serum sex hormone levels, and increased vascular permeability, which may lead to fluid accumulation in the peritoneal, pleural, and, in rare cases, pericardial cavities.

Severe OHSS may present with abdominal pain, abdominal distension, marked ovarian enlargement, weight gain, dyspnea, oliguria, and gastrointestinal symptoms such as nausea, vomiting, and diarrhea. Clinical examination may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusion, hydrothorax, acute respiratory distress, and thromboembolism.

Excessive ovarian response to gonadotropin therapy rarely progresses to OHSS unless human chorionic gonadotropin (hCG) is administered to trigger ovulation. Therefore, if ovarian hyperstimuplation is detected, hCG should not be administered. Patients should be advised to abstain from sexual intercourse or use barrier contraception for at least 4 days. OHSS can progress rapidly (within 24 hours to several days) and become severe; thus, patients should remain under medical supervision for at least 2 weeks after hCG administration.

The risk of ovarian hyperstimulation and multiple pregnancy can be minimized by adhering to the recommended dosing and administration regimen of Menopur and careful monitoring of treatment. In ART procedures, the risk of hyperstimulation can be reduced by aspirating all follicles prior to ovulation.

OHSS may become more severe and prolonged if pregnancy occurs. OHSS most commonly develops after completion of hormonal therapy, peaking approximately 7–10 days after treatment ends. Typically, OHSS resolves spontaneously with the onset of menstruation.

In cases of severe OHSS, gonadotropin therapy should be discontinued. If symptoms persist, hospitalization and specific treatment for OHSS are required.

This syndrome is more commonly observed in women with polycystic ovary syndrome.

Multiple pregnancy.

Multiple pregnancy increases the risk of complications for both mother and child.

The rate of multiple pregnancies is higher in patients undergoing gonadotropin-induced ovulation compared to natural conception. Most multiple pregnancies involve twins. Careful monitoring of ovarian response is recommended to reduce the risk of multiple pregnancy.

In patients undergoing ART procedures, the risk of multiple pregnancy primarily depends on the number of embryos transferred, embryo quality, and patient age.

Patients should be informed about the potential risk of multiple pregnancy before initiating treatment.

Preterm delivery/spontaneous abortion.

Preterm delivery and spontaneous abortion occur more frequently in patients undergoing ART procedures or follicular stimulation for ovulation induction compared to the general population.

Ectopic pregnancy.

Women with a history of tubal disease are at increased risk of ectopic pregnancy, regardless of whether conception occurs spontaneously or following infertility treatment. Following IVF, the reported rate of ectopic pregnancy is 2–5%, compared to 1–1.5% in the general population.

Reproductive system neoplasms.

Cases of benign and malignant neoplasms of the ovaries and other reproductive organs have been reported in women treated with multiple fertility drugs. To date, it has not been established whether gonadotropin therapy increases the baseline risk of such tumors in infertile women.

Congenital malformations.

The incidence of congenital malformations following ART may be slightly higher than after spontaneous conception. This may be attributable to differences in parental characteristics (e.g., maternal age, sperm parameters) and multiple pregnancy.

Thromboembolic disorders.

Venous or arterial thromboembolic events may occur during or after gonadotropin therapy in women with increased risk due to hereditary predisposition, significant obesity (body mass index > 30 kg/m²), or thrombophilia. It should be noted that pregnancy itself also increases the risk of thromboembolic complications.

Menotropin use may result in a positive doping test.

The use of menotropin as a doping agent may impair health.

Men.

Elevated endogenous FSH levels indicate primary testicular disorders. Such patients do not respond to treatment with HuMOnG/hCG.

Semen analysis should be performed 4–6 months after initiation of therapy to assess patient response.

Use during pregnancy or breastfeeding.

The drug is contraindicated.

Ability to affect reaction speed when driving or operating machinery.

No effect.

Method of administration and dosage.

HuMOnG is intended for intramuscular or subcutaneous administration.

Treatment duration varies depending on the indication.

The dosing regimens described below apply to both subcutaneous and intramuscular administration.

Women.

Ovarian response to gonadotropins varies among women and over time. Therefore, a universal dosing regimen cannot be established. Dosage should be individualized according to ovarian response. HuMOnG may be used as monotherapy or in combination with GnRH agonists or antagonists. Recommended doses and treatment duration depend on the treatment protocol used.

Anovulation.

HuMOnG therapy should be initiated within the first 7 days of the menstrual cycle. A daily dose of 75 to 150 IU should be administered for at least 7 days. Subsequent treatment should be individualized based on clinical monitoring (including ultrasound, preferably combined with estradiol measurement). Dose increases should not occur earlier than after 7 days of treatment, and each increase should not exceed 75 IU. The maximum daily dose should not exceed 225 IU. If there is inadequate response after 4 weeks of treatment, the cycle should be discontinued and a new cycle initiated with a higher starting dose.

Upon achieving optimal response, a single injection of 5000 to 10,000 IU of hCG should be administered the day after the last HuMOnG injection. The patient should engage in sexual intercourse on the day of hCG administration and the following day. Alternatively, intrauterine insemination may be performed. The patient should remain under close medical supervision for at least 2 weeks after hCG administration. If excessive response to treatment occurs, therapy should be discontinued and hCG should not be administered. The patient should use non-hormonal contraception or abstain from sexual intercourse until the next menstrual period.

Controlled ovarian hyperstimulation for multiple follicular development in assisted reproductive technologies.

Based on clinical trial data using hMG in combination with a GnRH agonist for down-regulation, HuMOnG therapy should be initiated approximately 2 weeks after starting the GnRH agonist. For at least the first 5 days of treatment, a daily dose of 150 to 225 IU of HuMOnG is recommended. Subsequent treatment should be individualized based on clinical monitoring (including ultrasound, preferably combined with estradiol measurement), with dose increases not exceeding 150 IU. The maximum daily dose should not exceed 450 IU. Overall, treatment duration should not exceed 20 days.

For protocols without down-regulation, HuMOnG therapy should be initiated on day 2 or 3 of the menstrual cycle. The same dosing and administration regimen as for protocols with GnRH agonists is recommended.

Upon achieving optimal response, a single injection of 10,000 IU of hCG should be administered to complete follicular maturation and prepare for oocyte retrieval. The patient should remain under close medical supervision for at least 2 weeks after hCG administration. If excessive response occurs, treatment should be discontinued and hCG should not be administered. The patient should use non-hormonal contraception or abstain from sexual intercourse until the next menstrual period.

Men.

After testosterone levels have been normalized by administration of an appropriate hCG dose (e.g., 1500 to 5000 IU three times weekly) for 4–6 months, HuMOnG should be administered three times weekly at a dose of 75 to 150 IU, in combination with hCG at the recommended dose of 1500 IU three times weekly. Combined therapy should continue for at least 3–4 months until spermatogenesis improves. If no response is observed during this period, continued combination therapy should be pursued until spermatogenesis is achieved. Current clinical data indicate that an 18-month treatment course may be required to achieve spermatogenesis.

Children.

The drug is not indicated for use in pediatric practice.

Overdose.

Treatment with hMG may lead to ovarian hyperstimulation, which becomes clinically significant primarily when hCG is administered to trigger ovulation.

In mild hyperstimulation (Grade I), characterized by slight ovarian enlargement (ovary size 5–7 cm), excessive steroid hormone secretion, and abdominal discomfort, specific treatment is not required. However, the patient should be informed and closely monitored. In moderate hyperstimulation (Grade II), with ovarian cysts (ovary size 8–10 cm), abdominal symptoms, nausea, and vomiting, clinical monitoring and symptomatic treatment are indicated, or, if necessary, intravenous administration of high-molecular-weight plasma expanders. In severe hyperstimulation (Grade III), characterized by large ovarian cysts (ovary size >10 cm), ascites, hydrothorax, abdominal distension, dyspnea, salt retention, hemoconcentration, increased blood viscosity, and platelet aggregation with risk of thromboembolism, hospitalization is mandatory, as life-threatening conditions may develop requiring intensive medical intervention.

Adverse reactions

Adverse reactions were classified according to the following frequency: very common (≥ 1/10); common (from ≥ 1/100 to < 1/10); uncommon (from ≥ 1/1000 to < 1/100); rare (from ≥ 1/10000 to < 1/1000); very rare (< 1/10000).

Gastrointestinal disorders: common – nausea, abdominal distension, abdominal pain, vomiting.

Immune system disorders: very rare – hypersensitivity.

Nervous system disorders: common – headache.

Reproductive system disorders: common – mild, moderate and severe ovarian hyperstimulation syndrome, pelvic pain.

Skin disorders: common – rash.

General disorders: very common – injection site reactions and injection site pain; common – influenza-like symptoms, skin rash; uncommon – fever.

Reactions at the injection site were observed in 55–60% of patients. In approximately 12% of cases, these reactions were considered severe. In most cases, such reactions occurred after subcutaneous administration. After intramuscular administration, injection site reactions were observed in nearly 13% of patients.

Rare cases of anaphylactic reactions have been observed during treatment with hMG.

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

In cases of ovarian hyperstimulation, the use of gonadotropins has led to rare cases of thromboembolic complications and ovarian torsion. Furthermore, in pronounced ovarian hyperstimulation, ascites, hydrothorax, oliguria, and arterial hypotension may occur. This may lead to the formation of large-sized ovarian cysts.

Pregnancies achieved through infertility treatment with gonadotropins such as hMG are more likely to end in spontaneous abortion compared to normal pregnancies.

Men: With gonadotropin use, cases of gynecomastia, acne, and increased body weight have been reported.

Shelf life. 3 years.

Storage conditions.

Store in a light-protected and child-resistant place at a temperature between 2 °C and 8 °C.

Do not freeze.

The reconstituted solution should be used immediately after preparation.

Any unused solution should be discarded.

Packaging.

1 vial of lyophilisate in combination with 1 ampoule of solvent (1 ml of 0.9% sodium chloride solution) in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Bharat Serums and Vaccines Limited.

Manufacturer's address and location of business operations.

PLOT NO: K-27, PARTS K-27 AND K-27/1, ANAND NAGAR, VILLAGE JAMBIWLI, EDISHINAL MIDS, AMBERNATH (I) – 421506
Taluka: AMBERNATH CITY, District: THANE - ZONE 6, India.

Marketing Authorization Holder.

Bharat Serums and Vaccines Limited.

Address of the Marketing Authorization Holder.

17th Floor, Hoechst House, Nariman Point, Mumbai – 400021, India.