Menopur Multidose, lyophilizate 600 me fsg+600 me lg

Pharmacodynamics

The active ingredient in Menopur® Multidose is high purity human menopausal gonadotropin (hMG) derived from the urine of postmenopausal women. It contains follicle stimulating hormone (FSH) and luteinizing hormone (LH).

The target organs for the hormonal effect of hMG in women are the ovaries. hMH stimulates gametogenesis and the synthesis of sex hormones.

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 physiological processes leading to the development of a complete preovulatory follicle. Stimulation of follicular growth under the action of FSH, in the complete absence of LH, ends in the pathological development of the follicle associated with a low concentration of estradiol and the inability to luteinize the neovulatory follicle in response to the normal ovulatory stimulus.

In consideration of the LH effect of increasing sex hormone synthesis, Menopur® Multidose in IVF/ICSI cycles is associated with higher plasma estradiol concentrations than recombinant FSH products. This aspect should be considered when monitoring the response to the use of the drug by the dynamics of changes in estradiol concentrations. No differences in estradiol concentrations were found in the protocols when using low doses of the drug 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 predominantly affects the division of the convoluted tubule cells 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 pharmacokinetic profile of FSH in Menopur® Multidose has been established.

Absorption and distribution

The maximum plasma concentration (Cmaõ) of FSH is reached within 7 hours after subcutaneous (p/k) administration. The volume of distribution determined in healthy female volunteers with reduced receptors after repeated doses of 150 IU for 7 days is 8.9 ± 3.5 IU/L.

Elimation

The elimination half-life on repeated administration is 30 ± 11 h. Excreted primarily by the kidneys.

The curves of LH concentration versus time show an increase in LH concentration after administration of Menopur® Multidose, but these data are insufficient for pharmacokinetic analysis.

There have been no studies of the pharmacokinetic properties of Menopur® Multidose in patients with hepatic or renal impairment.

Indications

In women:

In men:

Active ingredient

Composition

1 vial of lyophilizate contains:

the active ingredient: menotropins (human menopausal gonadotropin high purity, hMG) – 600 ME FSH + 600 ME LH or 1200 ME FSH + 1200 ME LH; auxiliary substances: lactose monohydrate 21.0 mg, polysorbate-20 0.005 mg, sodium hydrophosphate heptahydrate 0.268 mg, phosphoric acid solution 1 M q.s., sodium hydrophosphate solution 0.5 M q.s.

1 syringe with solvent contains:

metacresol 3.63 mg, water for injection to 1.1 ml.

How to take, the dosage

Menopur® Multidose is given by injection by injection after dissolving the lyophilizate in the included solvent.

The treatment with Menopur® Multidose should only be given under the supervision of a physician who has appropriate expertise and experience in treating infertility.

The ovaries have been found to respond differently to gonadotropin administration. For this reason, it is not possible to develop a universal dosing regimen. The dose has to be adjusted individually depending on the ovarian response. Menopur® Multidose is used as monotherapy or in combination with gonadotropin-releasing hormone (GnRH) agonists or antagonists. The recommended doses and duration of therapy depend on the treatment regimen used.

In women:

Anovulation (including PCOS)

.The goal of treatment with Menopur® Multidose is to develop a single mature follicle that will produce an oocyte after administration of chorionic gonadotropin (hCG) products.

Treatment usually begins in the first 7 days of the menstrual cycle. The recommended starting dose of Menopur® Multidose is 75-150 IU per day for at least seven days. Further scheme of treatment is chosen after monitoring of ovarian response to therapy on the basis of ultrasound investigation (USG) together with determination of estradiol concentration in plasma. In the absence of ovarian response, the dose is increased by 37.5 IU (one injection) no more than once a week, each subsequent increase should not exceed 75 IU. The maximum daily dose should not exceed 225 IU. If the therapeutic response is not achieved within 4 weeks, the treatment should be stopped and a new cycle should be started with higher starting doses.

If an adequate ovarian response is achieved on the day after the last injection of Menopur® Multidose, 5000-10000 IU of hCG should be injected once for ovulation induction. Patients are advised to have sexual intercourse on the day of hCG injection and the day after the injection. Intrauterine insemination is an alternative method. The patient should be kept under constant observation for at least two weeks after hCG injection. If the ovaries overreact to Menopur® Multidose, discontinue treatment and stop hCG. Patients are advised to use barrier methods of contraception or abstain from sexual intercourse until their periods.

Controlled ovarian hyperstimulation for the induction of multiple follicle growth in HRT

The use of hCG agonists is recommended in the protocol.The GnRH agonist feedback loop protocol suggests that Menopur® Multidose should be given approximately two weeks after starting treatment with a GnRH agonist. If the treatment regimen does not involve prior use of GnRH agonists, Menopur® Multidose should be started on day 2 or 3 of the menstrual cycle in combination with GnRH antagonists. Menopur® Multidose is recommended as a starting daily dose of 150-225 IU for at least first 5 days. Further treatment regimen is selected after monitoring ovarian response to therapy on the basis of ultrasound findings combined with determination of plasma estradiol concentration. The recommended booster dose should not exceed 150 IU. The maximum daily dose of Menopur® Multidose should not exceed 450 IU. The total therapy duration should not exceed 20 days.

When the ovaries react optimally after the last Menopur® Multidose injection one dose of hCG is administered to induce final follicle maturation and oocyte release. The patient must be continuously monitored for at least 2 weeks after the hCG injection. If the ovaries overreact to Menopur® Multidose, discontinue treatment and stop hCG. The patient is advised to use barrier methods of contraception or abstain from sexual intercourse until her period.

In men:

.Menopur® Multidose is recommended for male hypogonadotropic hypogonadism to stimulate spermatogenesis in a dose of 75 IU to 150 IU three times weekly in combination with hCG injections at a dose of 1500 IU three times weekly if the prior therapy with hCG (injection of 1500-5000 IU hCG three times weekly) during 4-6 months resulted in normalization of plasma testosterone concentration. Treatment according to this scheme should be continued for at least 4 months until spermatogenesis improves. If there is no positive effect during this time the combined therapy can be continued until a positive result of therapy. According to studies, at least 18 months of treatment may be needed to improve spermatogenesis.

Application in special clinical cases

Hepatic or renal dysfunction

Clinical studies have not been performed in patients with impaired hepatic or renal function.

Children under 18 years of age

There are no indications for the use of Menopur® Multidose in children and adolescents under 18 years of age.

Interaction

There have been no drug interaction studies of Menopur® Multidose.

The concomitant use of Menopur® Multidose with clomiphene may increase follicle growth stimulation, although there are no clinical data on the combined use of these drugs. Co-administration with GnRH agonists may require increasing the dose of Menopur® Multidose to achieve optimal ovarian response.

The product should not be mixed with other medicines in the same syringe!

Directions for use

Instruction for preparing the solution

The solution is prepared immediately prior to administration by dissolving the lyophilizate in the solvent provided. The ready solution can be repeatedly administered for at least 28 days.

Menopur® Multidose is not to be mixed with other medicines in the same syringe.

Please remove the plastic cap from the lyophilizate bottle. Attach the syringe preparation needle to the solvent syringe and remove the protective cap.

1. Slowly inject the solvent into the vial.

The vial needs to be held vertically.

2. Using a circular motion, gently stir the contents of the bottle until a clear solution is obtained. It usually dissolves in 1-2 minutes. Do not shake! Do not use the solution if there are undissolved particles or discoloration!

3. Draw the desired amount of solution into the syringe for injection.

4. Wipe the injection site with an alcohol wipe, remove any air bubbles from the syringe, and inject the solution.

Special Instructions

Menopur® Multidose has pronounced gonadotropic activity, therefore adverse reactions of varying severity may occur. Treatment should be performed under the supervision of a doctor experienced in the diagnosis and treatment of infertility!

The use of gonadotropins requires the presence of qualified medical personnel as well as appropriate equipment. The ovaries (ultrasound and plasma estradiol concentrations) should be monitored before prescribing Menopur® Multidose and during treatment. The lowest effective dose consistent with the treatment goals should be used.

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

Women

Before starting Menopur®. Multidose, 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 it is necessary to examine women for hypothyroidism, adrenal insufficiency, hyperprolactinemia, tumors of hypothalamic-pituitary area and, if necessary, to provide appropriate treatment.

Without any indication for use in women, controlled follicle growth stimulation may lead to ovarian enlargement with the development of hyperstimulation.

If the dosing regimen and route of administration of the drug are followed in conjunction with monitoring of ongoing therapy, it is possible to minimize the risk of the above reactions.

The evaluation of follicular development should be performed by a physician with appropriate experience.

SGYA

SGYA is a syndrome distinct from uncomplicated ovarian enlargement whose manifestations vary in severity. It includes significant ovarian enlargement, high plasma estrogen concentrations, and increased vascular permeability, which can lead to fluid accumulation in the abdominal, pleural and, less frequently, pericardial cavities.

In severe cases of SUI, 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.

The overreaction of the ovaries to gonadotropin administration rarely results in SVF unless hCG is administered to stimulate ovulation. Therefore, in cases of ovarian hyperstimulation, hCG should not be administered, and the patient should be warned to abstain from sexual intercourse or use barrier methods of contraception for at least 4 days. HCG can progress rapidly (within 24 hours to several days), becoming a serious iatrogenic complication, so patients should be closely monitored for at least 2 weeks after hCG administration.

Menopur® Multidose, the regimen of administration, and close monitoring of therapy can minimize cases of ovarian hyperstimulation and multiple pregnancies by following the recommended doses. With ART, aspiration of the contents of all follicles before ovulation can reduce the risk of SGF.

SGF can be more severe and prolonged in the development of pregnancy. Most often, SGN develops after discontinuation of gonadotropin treatment and peaks in severity 7-10 days after treatment ends. Typically, SGN passes spontaneously after the onset of menstruation.

In the case of severe SGN, treatment is discontinued, the patient is hospitalized and specific therapy is started.

The development of SGN is more common in patients with PCOS.

Multiple pregnancies

Multiple pregnancies have an increased risk of adverse maternal and perinatal outcomes.

Menotropin use has a higher rate of multiple pregnancies than natural conception. The highest rate of twin pregnancies has been noted. To reduce the risk of multiple pregnancies careful monitoring of the ovarian response to stimulation is recommended.

In the case of HRT the probability of multiple pregnancies depends on the number of embryos injected, their quality and the age of the patient.

The patient should be advised of the potential risk of multiple pregnancies before starting fertility treatment.

Complications of pregnancy

The incidence of spontaneous abortions and premature births in pregnancies after treatment with Menopur® Multidose is higher than in healthy women.

Ectopic pregnancy

Patients with a history of fallopian tube disease, whether conceiving naturally or under fertility treatment, are at high risk for ectopic pregnancy. The prevalence of ectopic pregnancy after IVF is 2 to 5%, compared with 1 to 1.5% in the general population.

Reproductive system neoplasms

There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have received multiple fertility drugs. It is not currently known whether gonadotropin treatment increases the baseline risk of these tumors in women with infertility.

Congenital malformations

The prevalence of congenital fetal malformations with ART is somewhat higher than with natural conception. It is thought that this may be due to the individual characteristics of the parents (age of the mother, characteristics of the sperm) and multiple pregnancies.

Thromboembolic complications

Women with known risk factors for thromboembolic complications, such as individual or familial predisposition, obesity (BMI > 30 kg/m2) or thrombophilia may have an increased risk of venous or arterial thromboembolic complications during or after gonadotropin treatment. In such cases, the benefits of their use should be weighed against the possible risks. Note that pregnancy itself also increases the risk of thromboembolic complications.

Men

The use of Menopur® Multidose in men with high FSH concentrations is ineffective. Semen analysis is performed 4-6 months after the start of treatment to evaluate the effectiveness of treatment.

Influence on the ability to drive and operate vehicles

There have been no studies of the effect of menotropins on the ability to drive and operate vehicles. Menopur® Multidose is unlikely to have an adverse effect on driving and other machinery.

Synopsis

Lyophilisate:white or almost white amorphous mass.

Solvent:colorless clear solution.

Contraindications

In women:

In men:

If there is a history of thyroid or adrenal disease, hyperprolactinemia, or hypothalamic-pituitary tumors, appropriate treatment should be given before starting hMG therapy.

With caution

In women, presence of risk factors for thromboembolic complications (individual or family predisposition, obesity with body mass index (BMI) > 30 kg/m2), thrombophilia); history of fallopian tube disease.

Side effects

Frequency of adverse reactions: frequently (≥1/100 to <1/10), infrequently (≥1/1000 to <1/100), rarely (≥1/10000 to <1/1000), frequency unknown (no data on the incidence of adverse reactions are currently available, reported during post-registration use of the drug).

The most serious and frequent adverse reactions reported with Menopur® Multidose in clinical studies with an incidence of up to 5% were ovarian hyperstimulation syndrome (OHSS), abdominal pain, headache, bloating, and injection site pain. The main adverse reactions identified in clinical trials and during post-registration use are shown in the table below.

– Immune system disorders: Hypersensitivity reactions* (Frequency unknown)

– Nervous system disorders: Headache (Frequently (≥1/100, <1/10)), Dizziness (Infrequently (≥1/1000, <1/100))

– Visual disturbances: Transient blindness, diplopia, mydriasis, scotoma, photopsia, transient clouding of the vitreous, decreased visual clarity (Frequency unknown)

– Vascular disorders: Hot flashes (Infrequent (≥1/1000, <1/100)), Venous and arterial thromboembolism (usually in SUI) (Frequency unknown)

– Gastrointestinal disorders: Abdominal pain, abdominal bloating, nausea, abdominal enlargement (Frequent), Vomiting, abdominal discomfort, diarrhea (Infrequent)

– Skin and subcutaneous tissue disorders: Acne, skin rash (Rare), Skin itching, urticaria (Frequency unknown)

– Musculoskeletal and connective tissue disorders: Joint pain, back and neck pain, limb pain (Frequency unknown)

– Genital and breast disorders: OBG**, pelvic pain*** (Frequent) Ovarian cysts, Breast disorders**** (Infrequent), Ovarian torsion** (Frequency unknown)

– General and injection site disorders: Pain at the injection site (Frequent), Increased fatigue (Infrequent), Increased body temperature, malaise (Frequency unknown)

– Laboratory and instrumental findings: Increased body weight (Frequency unknown)

*Rare cases of local or general allergic reactions, including cases of anaphylactic reactions, have been noted.

**In clinical studies, gastrointestinal abnormalities such as bloating and abdominal discomfort, nausea, vomiting, and diarrhea associated with the development of SUI have been noted. In cases of severe CGY, ascites and pelvic fluid accumulation, exudative pleurisy, shortness of breath, oliguria, thromboembolic complications and ovarian torsion are possible as rare complications.

*** Pain in the uterine appendages.

**** Breast pain and discomfort, breast engorgement and swelling, nipple pain.

In men, gynecomastia, acne, and weight gain have been reported with menotropins.

If any of the adverse reactions listed in the instructions worsen, or if you notice any other adverse reactions not listed in the instructions, tell your doctor.

Overdose

Pregnancy use