Meriofert 150 mo

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MERIOFERT 75 IU MERIOFERT 150 IU

Composition:

Active substance: human menopausal gonadotropin;

1 vial of powder contains 75 IU or 150 IU of menotropin (LH, human menopausal gonadotropin), corresponding 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: sodium chloride and water for injections.

Pharmaceutical form. Powder and solvent for solution for injection.

Main physicochemical properties:

powder – white lyophilized mass or powder;

solvent – clear, colorless, odorless solution.

Pharmacotherapeutic group.

Gonadotropins and other ovulation stimulants. Human menopausal gonadotropin.

ATC code G03G A02.

Pharmacological properties.

Pharmacodynamics.

The active substance of the medicinal product Meriofert is highly purified human menopausal gonadotropin.

The FSH component is obtained from the urine of postmenopausal women; the LH component is obtained both from the urine of postmenopausal women and from the urine of pregnant women. The preparation is standardized so that the FSH/LH activity ratio is approximately 1.

In the ovaries, FSH as a component of HMG induces an increase in the number of growing follicles and stimulates their development. FSH increases estradiol production in granulosa cells by aromatization of androgens originating from theca cells under the influence of luteinizing hormone.

Pharmacokinetics.

The biological efficacy of menotropin is primarily determined by its FSH content. The pharmacokinetics of menotropin after intramuscular or subcutaneous administration show high variability. According to studies conducted with menotropin, after a single 300 IU injection, peak serum FSH levels are reached approximately 19 hours after intramuscular administration and 22 hours after subcutaneous administration. Peak FSH concentrations were 6.5 ± 2.1 IU/L with an AUC0-t of 438.0 ± 124.0 IU × h/L following intramuscular administration. After subcutaneous administration, Cmax reached 7.5 ± 2.8 IU/L with an AUC0-t of 485.0 ± 93.5 IU × h/L.

AUC and Cmax values for luteinizing hormone were significantly lower in the subcutaneous group compared to the intramuscular group. This result may be attributed to the very low LH levels detected (close to or below the limit of detection) in both groups and to high intra- and inter-individual variability.

Serum LH levels decrease with a half-life elimination period. The elimination half-life is approximately 45 hours after intramuscular administration and 40 hours after subcutaneous administration.

Menotropin is primarily excreted via the kidneys.

Pharmacokinetic studies in patients with hepatic or renal impairment have not been conducted.

Clinical characteristics.

Indications.

For ovulation induction: for induction of ovulation in women with amenorrhea or anovulation who are unresponsive to clomiphene citrate treatment.

For controlled ovarian stimulation in assisted reproductive technology (ART): induction of multiple follicular development in women undergoing assisted reproductive techniques such as in vitro fertilization (IVF).

Contraindications.

Hypersensitivity to menotropin or to any excipient.

Ovarian enlargement or ovarian cysts unrelated to polycystic ovary syndrome.

Gynecological bleeding of unknown origin.

Ovarian, uterine, or breast carcinoma.

Tumors of the hypothalamus or pituitary gland.

Conditions in which an effective response cannot be achieved, for example:

primary ovarian insufficiency;

congenital or acquired genital tract abnormalities incompatible with pregnancy;

uterine fibroids incompatible with pregnancy.

Interaction with other medicinal products and other forms of interaction.

No studies of interactions between Meriofert and other medicinal products in humans have been conducted. Although clinical experience is lacking, concomitant use of Meriofert 75 IU or 150 IU and clomiphene citrate is expected to enhance follicular response.

Higher doses of Meriofert 75 IU or 150 IU may be required when used concomitantly with GnRH agonists for pituitary desensitization.

Special precautions for use

Anaphylactic reactions may occur, particularly in patients with known hypersensitivity to gonadotropins. The first injection of Meriofert must always be administered under direct medical supervision and with resuscitation equipment for cardio-pulmonary emergencies immediately available.

Only trained and well-informed patients who have been instructed on how to perform subcutaneous injections, where injections may be administered, and how to prepare the injection solution should self-administer Meriofert injections.

Prior to initiating treatment, the infertility of the couple should be evaluated and any contraindications to pregnancy should be ruled out. In particular, patients should be assessed for hypothyroidism, adrenal insufficiency, cortical insufficiency, hyperprolactinemia, and pituitary or hypothalamic tumors, for which appropriate specific treatment should be initiated.

Ovarian hyperstimulation syndrome (OHSS)

Ultrasound assessment of follicular development, measurement of estradiol levels, and regular monitoring during treatment should be performed before starting therapy.

In addition to the development of a large number of follicles, estradiol levels may rise rapidly—for example, more than doubling daily for two or three consecutive days—and may reach excessively high values. Diagnosis of ovarian hyperstimulation can be confirmed by ultrasound. If such undesirable ovarian hyperstimulation occurs (i.e., not part of a controlled ovarian hyperstimulation in assisted reproductive technology programs), Meriofert should be discontinued. In such cases, pregnancy should be avoided, and hCG should not be administered, as this may lead not only to multiple ovulation but also to ovarian hyperstimulation syndrome (OHSS). Clinical symptoms and signs of mild OHSS include abdominal pain, nausea, diarrhea, mild to moderate ovarian enlargement, and ovarian cysts. In rare cases, severe OHSS, which may be life-threatening, may occur. This is characterized by large ovarian cysts (prone to rupture), ascites, often pleural effusion, and increased body weight. In rare cases, venous or arterial thromboembolism may occur in association with OHSS.

Multiple pregnancy

In patients undergoing assisted reproductive technology (ART) procedures, the risk of multiple pregnancy is primarily related to the number of embryos transferred. In patients receiving treatment for ovulation induction, the frequency of multiple pregnancies and multiple births is increased compared to natural conception. The majority of multiple pregnancies are twins. To minimize the risk of multiple pregnancy, careful monitoring of ovarian response is recommended.

Pregnancy loss

The rate of spontaneous abortion in patients treated with FSH is higher than in the general population but comparable to that in women with other fertility disorders.

Ectopic pregnancy

Since tubal abnormalities are frequently observed in infertile women undergoing assisted reproduction, particularly in vitro fertilization (IVF), the frequency of ectopic pregnancy may be increased. Therefore, early ultrasound confirmation that the pregnancy is intrauterine is essential.

Reproductive organ neoplasms

Benign and malignant neoplasms of the ovaries and other reproductive organs have been reported in women who have undergone multiple cycles of infertility treatment. It has not yet been established whether gonadotropin therapy increases the baseline risk of tumors in infertile women.

Congenital malformations

The frequency of congenital malformations after ART may be slightly higher than after natural conception. This is believed to be related to differences in parental characteristics (e.g., maternal age, sperm characteristics) and multiple pregnancies.

Thromboembolic disorders

Women with well-recognized 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 after gonadotropin treatment. In these women, the benefits of gonadotropin therapy should be carefully weighed against the risks.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

Meriofert should not be used during pregnancy.

No teratogenic risk has been observed after controlled ovarian stimulation in clinical use with urinary gonadotropins. Currently, no other relevant epidemiological data are available.

Animal studies have not indicated a teratogenic effect.

Meriofert should not be used during breastfeeding.

During lactation, prolactin secretion may cause a negative response to ovarian stimulation.

Ability to affect reaction speed when driving or operating machinery

There are no reports regarding the effect of this medicinal product on the ability to drive or operate machinery.

Administration and Dosage.

Treatment with Meriofert should be initiated under the supervision of a physician experienced in the management of infertility.

There is considerable inter- and intra-individual variation in ovarian response to exogenous gonadotropins, making it impossible to establish a single dosage regimen. Therefore, dosing should be individually adjusted according to ovarian response, requiring ultrasound monitoring and possibly including estradiol level assessment.

Women with anovulation

The goal of Meriofert treatment is the maturation of a single dominant Graafian follicle, from which the oocyte will be released following administration of human chorionic gonadotropin (hCG).

Meriofert injections may be administered daily. In patients with regular menstruation, treatment should begin within the first 7 days of the menstrual cycle.

The standard regimen starts with a daily dose of 75–150 IU FSH, which may be increased by 37.5 IU (up to 75 IU), preferably at intervals of 7 or 14 days, as needed, until an adequate but not excessive response is achieved.

The maximum daily dose of Meriofert should generally not exceed 225 IU.

Treatment response should be monitored by measuring follicular size via ultrasonography and/or serum estrogen levels.

The daily dose is maintained until preovulatory conditions are reached. This is usually achieved within 7–14 days of treatment.

Meriofert administration is then discontinued, and ovulation may be triggered by administration of human chorionic gonadotropin (hCG).

If the number of responding follicles is too high or if estradiol levels rise too rapidly (i.e., more than doubling daily for two or three consecutive days), the daily dose should be reduced. Since follicles larger than 14 mm can lead to pregnancy, multiple preovulatory follicles exceeding 14 mm in diameter carry a risk of multiple pregnancy. In such cases, hCG administration should be withheld and pregnancy avoided to prevent multiple gestation. The patient should use a barrier contraceptive method or abstain from sexual intercourse until the onset of the next menstrual period. The next treatment cycle should begin with a lower dose than the previous cycle.

If no adequate response is observed after 4 weeks of treatment, the drug should be discontinued in that cycle, and the next cycle should begin with a higher initial dose.

Once an optimal response is achieved, a single injection of 5000 IU to 10,000 IU of hCG should be administered 24–48 hours after the last Meriofert injection.

Patients are advised to have intercourse on the day of hCG injection and the following day.

Alternatively, intrauterine insemination may be performed.

Women undergoing ovarian stimulation for multiple follicular development as part of assisted reproductive technology

Pituitary suppression to prevent endogenous LH surge and control baseline LH levels is typically achieved by administering a gonadotropin-releasing hormone agonist (GnRH agonist) or gonadotropin-releasing hormone antagonist (GnRH antagonist).

According to the standard protocol, Meriofert administration begins approximately two weeks after starting GnRH agonist therapy, with both treatments continuing until adequate follicular development is achieved. For example, after two weeks of pituitary suppression with a GnRH agonist, 150–225 IU of Meriofert is administered daily for the first five to seven days. The dose is then adjusted according to the patient’s ovarian response.

An alternative protocol for controlled ovarian hyperstimulation involves daily administration of 150–225 IU of Meriofert starting on day 2 or 3 of the cycle. Treatment continues until sufficient follicular development is achieved (assessed by monitoring serum estrogen levels and/or ultrasound), with dose adjustments based on patient response (usually not exceeding 450 IU daily). Adequate follicular development is typically achieved on average around day 10 of treatment (range: 5–20 days).

When optimal response is achieved, a single dose of 5000 IU to 10,000 IU of hCG administered 24–48 hours after the last Meriofert injection induces final follicular maturation.

Oocyte retrieval is performed 34–35 hours later.

Route of Administration

Meriofert is intended for subcutaneous and intramuscular administration.

The powder must be reconstituted with the provided solvent immediately before use.

To minimize injection site pain and leakage, Meriofert should be injected slowly subcutaneously. Injection sites should be rotated to prevent lipodystrophy. Any unused solution should be discarded.

Patients may self-administer subcutaneous injections provided they strictly follow the physician’s instructions and recommendations.

Children

Not recommended for use in children (under 18 years of age).

Overdose

There are no data on acute toxicity of menotropin in humans; however, acute toxicity of gonadotropin preparations in animal studies has been found to be very low. Excessive doses of menotropin may lead to ovarian hyperstimulation.

Adverse reactions

The most important adverse reaction observed with the medicinal product in clinical trials of Meriofert is (dose-dependent) ovarian hyperstimulation (OHSS), usually mild, with slight enlargement of the ovaries, abdominal discomfort or pain. Only one case of OHSS was severe.

The most commonly reported adverse reactions during administration of Meriofert were headache, abdominal bloating, as well as nausea, fatigue, dizziness, and injection site pain.

The table below lists the main adverse reactions (> 1%) reported in women receiving Meriofert in clinical trials, classified by organ system and frequency of occurrence. Within each frequency group, adverse reactions are listed in order of decreasing severity.

Within each organ system class, adverse reactions are categorized by frequency, starting with the most frequent, according to the following criteria: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from available data).

*The most appropriate MedDRA term has been used to describe a specific reaction; synonyms or related conditions are not listed but should also be considered.

Published studies have reported the following adverse reactions in patients receiving hCG treatment.

Severe ovarian hyperstimulation (OHSS) with marked enlargement of the ovaries and cyst formation, acute abdominal pain, ascites, pleural effusion, hypovolemia, shock, and thromboembolic disorders.

Ovarian torsion, usually in association with severe cases of OHSS.

Rupture of ovarian cysts with intraperitoneal hemorrhage, including cases with fatal outcome, has been reported.

Allergic reactions, including generalized symptoms, have been reported after treatment with gonadotropin-containing preparations.

Injection site reactions such as pain, redness, bruising, swelling and/or irritation are expected following administration of gonadotropins.

The frequency of such reactions is expected to be higher with intramuscular than with subcutaneous administration.

Shelf life. 2 years.

After reconstitution, use immediately.

Storage conditions.

Store at temperatures not exceeding 25 °C. Keep in the original packaging to protect from light.

Keep out of reach of children.

Incompatibilities.

Due to lack of compatibility studies, Meriofert must not be mixed with other medicinal products.

Packaging.

1 glass vial containing menotropin and 1 ampoule (1 ml) of solvent per cardboard box; 10 boxes per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

IBSA Institut Biochimique SA, Switzerland.

Manufacturer's address.

Via Piano Scaini 49, 6912 Pazzallo, Switzerland