Foligraph

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FOLIGRAF® (FOLIGRAF®)

Composition:

Active substance: follitropin alpha;

1 vial contains 75 IU of follitropin alpha (recombinant human follicle-stimulating hormone (r-hFSH)), equivalent to 5.5 μg;

Excipients: disodium hydrogen phosphate anhydrous, mannite (E 421), sucrose, methionine, polysorbate 20, sodium hydroxide, phosphoric acid, water for injections;

Solvent: sterile water for injections.

Pharmaceutical form. Lyophilisate for solution for injection in a set with solvent.

Main physicochemical characteristics: lyophilized solid as a white or almost white cake; solvent – clear, colorless, odorless liquid.

Pharmacotherapeutic group.
Sex hormones and modulators of the genital system. Gonadotrophins. ATC code G03G A05.

Pharmacological properties.

Pharmacodynamics.

Foligraph® is a preparation of follicle-stimulating hormone (FSH) obtained by recombinant DNA technology using Chinese hamster ovary cells. In women, the most important effect of parenteral administration of FSH is the development of mature Graafian follicles.

The drug exerts gonadotropic (stimulates endometrial proliferation, ovulation in women with suppressed endogenous gonadotropin secretion) and estrogenic (stimulates growth and maturation of ovarian follicles, promotes development of multiple follicles during controlled ovarian hyperstimulation within assisted reproductive technology programs) effects.

Clinical efficacy and safety in women

In clinical studies, patients with severe deficiency of FSH and luteinizing hormone (LH) were defined by a serum level of endogenous LH < 1.2 IU/L, as measured in a central laboratory assay. However, it should be noted that LH levels may vary between different laboratories.

In clinical studies comparing recombinant human FSH (r-hFSH) (follitropin alfa) with urinary FSH in assisted reproductive technology (ART) procedures (see Table 1) and ovulation induction, follitropin alfa was shown to be more effective than urinary FSH, as demonstrated by a lower total dose and shorter treatment duration required to induce follicular maturation. The use of lower doses of follitropin alfa over a shorter treatment period in ART resulted in a higher number of oocytes retrieved compared to urinary FSH.

Table 1

Results of study GF 8407 (a randomized, parallel-group study comparing the efficacy and safety of follitropin alfa and urinary FSH in assisted reproductive technology)

Parameter	Follitropin alfa (n = 130)	Urinary FSH (n = 116)
Number of oocytes retrieved	11.0 ± 5.9	8.8 ± 4.8
Required duration of stimulation (days) when using FSH	11.7 ± 1.9	14.5 ± 3.3
Total required dose of FSH (number of 75 IU FSH vials)	27.6 ± 10.2	40.7 ± 13.6
Dose escalation required (%)	56.2	85.3

For all the listed criteria, the difference between the two groups was statistically significant (p < 0.05).

Clinical efficacy and safety in men

In men with FSH deficiency, concomitant administration of follitropin alfa and LH for at least 4 months promotes induction of spermatogenesis.

Pharmacokinetics

After intravenous administration, follitropin alfa distributes into the extracellular fluid with an initial elimination half-life of approximately 2 hours and is eliminated from the body with a terminal half-life of about 1 day. The volume of distribution at steady state and total clearance are 10 L and 0.6 L/hour, respectively. One-eighth of the administered dose of follitropin alfa is excreted in urine.

After subcutaneous administration, the absolute bioavailability of follitropin alfa is approximately 70%. Repeated administration leads to a threefold increase in drug accumulation, reaching steady-state levels within 3–4 days. It has been demonstrated that in women with suppressed endogenous gonadotropin secretion, follitropin alfa effectively stimulates follicular development and steroidogenesis despite low LH levels below the limit of detection.

Clinical characteristics.

Indications.

Adult women

• Anovulation (including polycystic ovary syndrome) in women who have been found to be resistant to clomiphene citrate treatment.
• Stimulation of multiple follicular development in patients undergoing controlled ovarian hyperstimulation as part of assisted reproductive technologies (ART), such as in vitro fertilization (IVF), gamete intrafallopian transfer (GIFT), and zygote intrafallopian transfer (ZIFT).
• Folitropin alfa in combination with luteinizing hormone (LH)-containing preparations is recommended for follicular development in women with severe LH and FSH deficiency. In clinical studies, such patients were defined by endogenous serum LH levels < 1.2 IU/L.

Adult men

• Folitropin alfa is indicated for stimulation of spermatogenesis in men with congenital or acquired hypogonadotropic hypogonadism, in combination with human chorionic gonadotropin (hCG) therapy.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients;
• tumors of the hypothalamus or pituitary gland;
• ovarian enlargement or ovarian cysts unrelated to polycystic ovary syndrome;
• gynecological bleeding of unknown etiology;
• carcinomas of the ovaries, uterus, or breasts.

The drug must not be used when an effective response to treatment cannot be achieved, for example, in the presence of:

• primary ovarian insufficiency;
• genital tract abnormalities incompatible with pregnancy;
• uterine fibroids incompatible with pregnancy;
• primary testicular insufficiency.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of folitropin alfa with other agents used for ovulation induction (such as hCG, clomiphene citrate) may enhance follicular response, whereas concomitant use with gonadotropin-releasing hormone (GnRH) agonists or antagonists inducing pituitary desensitization may necessitate higher doses of Foligraf**®** to achieve an adequate ovarian response. No other clinically significant drug interactions have been reported during therapy with folitropin alfa.

Special precautions for use.

Traceability

To improve the traceability of biological medicinal products and reporting of suspected adverse reactions, healthcare professionals should clearly record the brand name and batch number of the administered product in the patient’s medical record.

Since follitropin alfa has significant gonadotropic activity capable of causing adverse reactions ranging from mild to severe, it should only be prescribed by physicians who are well experienced in the management of infertility and its treatment.

Therapy with gonadotropins requires a significant time commitment from physicians and other healthcare professionals, as well as appropriate equipment for monitoring treatment. Safe and effective use of follitropin alfa in women requires regular monitoring of ovarian response by ultrasound, performed either alone or preferably in combination with regular measurement of serum estradiol levels. Individual variability in response to FSH administration may occur; thus, some patients may exhibit a poor response to FSH, while others may show an excessive response. For treatment of both women and men, the lowest effective dose of the drug should be used according to the treatment goal.

Porphyria

Patients with porphyria or a family history of porphyria should be under close medical supervision during treatment with follitropin alfa. If early signs of porphyria develop or the condition worsens, treatment discontinuation may be necessary.

Treatment of women

Prior to initiating treatment, the cause of infertility should be thoroughly investigated and contraindications to pregnancy identified. In particular, patients should be evaluated for hypothyroidism, adrenal insufficiency, hyperprolactinemia, and appropriate treatment initiated if necessary.

During follicular stimulation in the treatment of anovulatory infertility or assisted reproductive technologies (ART), ovarian enlargement or ovarian hyperstimulation may occur. Adherence to the recommended dosage and administration regimen of follitropin alfa, along with careful monitoring of therapy, can reduce the frequency of such events. Accurate interpretation of follicular development and maturation requires an experienced specialist.

Clinical studies have shown increased ovarian sensitivity to follitropin alfa when administered concomitantly with lutropin alfa. If an increase in FSH dose is considered necessary, dose adjustments should preferably be made at 7–14 day intervals, with stepwise increments of 37.5–75 IU.

Direct comparison of follitropin alfa/LH versus human menopausal gonadotropin (hMG) has not been conducted. However, available data suggest that the ovulation rate achieved with follitropin alfa/LH is similar to that achieved with hMG.

Ovarian hyperstimulation syndrome (OHSS)

A predictable consequence of controlled ovarian stimulation is some degree of ovarian enlargement. This phenomenon, most commonly observed in women with polycystic ovary syndrome (PCOS), is usually self-limiting.

In contrast to uncomplicated ovarian enlargement, OHSS is a syndrome that may progress in severity. It is characterized by marked ovarian enlargement, high serum sex steroid levels, and increased vascular permeability, which may lead to fluid accumulation in the abdominal, pleural, and occasionally pericardial cavities.

In severe cases of OHSS, symptoms may include abdominal pain and distension, significant ovarian enlargement, weight gain, dyspnea, oliguria, and gastrointestinal symptoms such as nausea, vomiting, and diarrhea. Clinical examination may reveal hypovolemia, hemoconcentration, electrolyte imbalance, ascites, hemoperitoneum, pleural effusions, hydrothorax, or acute respiratory distress syndrome. In rare cases, severe OHSS may be complicated by ovarian torsion and thromboembolic events such as pulmonary embolism, ischemic stroke, or myocardial infarction.

Independent risk factors for OHSS include polycystic ovary syndrome, high or rapidly rising serum estradiol levels (e.g., >900 pg/mL or >3300 pmol/L in anovulation; >3000 pg/mL or >11000 pmol/L in ART), and a large number of developing follicles (e.g., >3 follicles ≥14 mm in diameter in anovulation; ≥20 follicles ≥12 mm in diameter in ART).

Adherence to the recommended dosage and administration regimen of follitropin alfa may minimize the risk of ovarian hyperstimulation (see sections "Dosage and administration" and "Adverse reactions"). Monitoring of stimulation cycles using ultrasound and estradiol level measurements is recommended for early identification of risk factors.

It is known that hCG plays a key role in initiating OHSS, which may become more severe and prolonged if pregnancy occurs. Therefore, in the presence of signs of ovarian hyperstimulation, such as serum estradiol levels >5500 pg/mL (>20200 pmol/L) and/or total number of follicles ≥40, hCG administration should be withheld and patients advised to abstain from sexual intercourse or use barrier contraception for at least 4 days. OHSS may progress rapidly (within 24 hours) and become a serious medical complication within a few days. It most commonly occurs after discontinuation of hormonal therapy and peaks approximately 7–10 days after treatment ends. Therefore, patients should remain under medical supervision for at least 2 weeks after hCG administration.

The incidence of hyperstimulation during ART may be reduced by aspirating all follicles prior to ovulation.

Mild or moderate forms of OHSS usually resolve spontaneously. In cases of severe OHSS, gonadotropin treatment should be discontinued if still ongoing, and the patient should be hospitalized and receive appropriate supportive therapy.

Multiples pregnancy

The rate of multiple pregnancies following ovulation induction is higher than after natural conception. Most multiple pregnancies are twins. Multiple pregnancies, especially higher-order multiples, carry an increased risk of adverse outcomes for mother, fetus, and newborn.

To reduce the risk of multiple pregnancy, careful monitoring of ovarian response is recommended.

In ART procedures, the risk of multiple pregnancy is primarily related to the number of embryos transferred, embryo quality, and patient age.

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

Pregnancy loss

In women undergoing follicular stimulation for ovulation induction or ART, the rate of pregnancy loss due to miscarriage or spontaneous abortion is higher than after natural conception.

Ectopic pregnancy

Women with a history of tubal disease are at risk of ectopic pregnancy regardless of whether conception occurs spontaneously or following infertility treatment. The incidence of ectopic pregnancy has been reported to be higher in women after ART compared to the general population.

Reproductive system neoplasms

There have been reports of both benign and malignant neoplasms of the ovaries and other reproductive organs in women who have undergone various infertility treatments. It has not yet been established whether gonadotropin therapy increases the risk of such tumors in infertile women.

Congenital malformations

The incidence of congenital malformations after ART may be slightly higher than after spontaneous conception. This is believed to be due to parental health characteristics (e.g., maternal age, paternal sperm characteristics) and multiple pregnancies.

Thromboembolic complications

In women with recent or existing thromboembolic disorders or those with established risk factors for thromboembolic events (e.g., personal or family history), gonadotropin therapy may further increase the risk of exacerbation or occurrence of such events. In such patients, the benefit of gonadotropin use should be weighed against the existing risk of complications. However, it should be noted that pregnancy itself and OHSS both increase the risk of thromboembolic complications.

Treatment of men

Elevated endogenous FSH levels indicate primary testicular failure. Such patients are unresponsive to treatment with follitropin alfa/hCG and should not receive this therapy if an effective response is not expected.

Semen analysis is recommended 4–6 months after initiation of treatment to assess response.

Sodium content

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

Use during pregnancy or breastfeeding.

Pregnancy

There are no indications for the use of follitropin alfa during pregnancy. Data from a limited number of cases (fewer than 300) suggest no increased risk of congenital malformations or fetal/neonatal toxicity with follitropin alfa exposure during pregnancy.

Teratogenic effects were not observed in animal studies. However, clinical data are insufficient to exclude a teratogenic effect of follitropin alfa when used during pregnancy.

Breastfeeding

Follitropin alfa is not indicated for use during breastfeeding.

Fertility

Follitropin alfa is indicated for the treatment of infertility (see section "Indications").

Ability to affect reaction speed when driving or operating machinery.

Foligraf**®** is expected to have no effect or a negligible effect on the ability of patients to drive or operate machinery.

Method of administration and dosage.

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

Daily doses, administration schedule, and monitoring procedures with follitropin alfa should not differ from those used with urinary FSH preparations. Clinical studies have shown that a lower total dose of follitropin alfa administered over a shorter treatment period is required compared to urinary FSH, allowing not only optimization of treatment but also reduction in the risk of unwanted ovarian hyperstimulation.

The recommended starting doses outlined below should be followed.

Women with anovulation, including polycystic ovary syndrome

Follitropin alfa is administered as a course of daily injections. In women with regular menstrual cycles, treatment should begin within the first 7 days of the menstrual cycle.

The usual starting regimen is 75–150 IU FSH daily. If necessary, the dose may be increased by 37.5 IU (preferably) or 75 IU at 7-day or (preferably) 14-day intervals to achieve an adequate but not excessive response. Treatment should be individualized based on patient response assessed by ultrasound measurement of follicle size and/or serum estrogen levels. The maximum daily dose generally does not exceed 225 IU FSH. If a patient does not respond adequately after 4 weeks, the treatment cycle should be discontinued, further evaluation performed, and treatment restarted in the next cycle with a higher starting dose than in the previous cycle.

When optimal response is achieved, a single dose of 250 mcg recombinant hCG (r-hCG) or 5000–10000 IU hCG should be administered 24–48 hours after the last follitropin alfa injection. Patients are advised to have intercourse on the day of hCG administration and the following day. Alternatively, intrauterine insemination may be performed.

If an excessive response occurs, treatment must be discontinued and hCG administration withheld (see section "Special precautions for use"). In the next treatment cycle, therapy should begin with a lower FSH dose than in the previous cycle.

Stimulation of multiple follicular development in women undergoing superovulation for ART or in vitro fertilization

The usual regimen for superovulation involves daily administration of 150–225 IU follitropin alfa, starting on day 2 or 3 of the cycle. Treatment continues until adequate follicular development is achieved (assessed by serum estrogen levels and/or ultrasound). The dose is adjusted according to patient response but generally should not exceed 450 IU daily. Adequate follicular development is usually achieved by day 10 of treatment (range: 5–20 days).

To induce final follicular maturation, a single injection of 250 mcg r-hCG or 5000–10000 IU hCG is administered 24–48 hours after the last follitropin alfa injection.

To suppress the premature surge of endogenous LH and control tonic LH levels, pituitary down-regulation with GnRH agonists or antagonists is usually employed. In a standard protocol, follitropin alfa administration begins approximately 2 weeks after starting the agonist, and both are continued until adequate follicular development is achieved. For example, after 2 weeks of agonist treatment, 150–225 IU follitropin alfa is administered daily for the first 7 days, with subsequent dose adjustments based on ovarian response.

Overall IVF experience indicates that treatment success rates remain stable during the first four attempts and then gradually decline.

Women with anovulation due to severe deficiency of LH and FSH secretion

In women with severe deficiency of LH and FSH secretion (hypogonadotropic hypogonadism; endogenous LH level <1.2 IU/L), the goal of combined therapy with follitropin alfa and lutropin alfa is the development of a single mature Graafian follicle, from which an oocyte will be released after hCG administration. Follitropin alfa is administered as a course of daily injections simultaneously with lutropin alfa. Since such patients are amenorrheic and have low endogenous estrogen secretion, treatment may be initiated at any time.

The recommended regimen starts with 75 IU lutropin alfa administered daily together with 75–150 IU FSH. Treatment should be individualized based on patient response assessed by estrogen secretion levels and ultrasound measurement of follicle size.

If an increase in FSH dose is necessary, it should preferably be adjusted at 7–14 day intervals by 37.5–75 IU increments. Stimulation duration may be extended up to 5 weeks within one cycle.

When optimal response is achieved, a single dose of 250 mcg r-hCG or 5000–10000 IU hCG is administered 24–48 hours after the last injection of follitropin alfa and lutropin alfa. Patients are advised to have intercourse on the day of hCG administration and the following day. Alternatively, intrauterine insemination may be performed.

During treatment, luteal phase support should be considered, as the absence of substances with luteotropic activity (LH/hCG) after ovulation may lead to premature luteal phase deficiency.

If an excessive response occurs, treatment must be discontinued and hCG administration withheld. In the next treatment cycle, therapy should begin with a lower FSH dose than in the previous cycle.

Men with hypogonadotropic hypogonadism

Follitropin alfa is administered at a dose of 150 IU three times weekly, in combination with hCG, for at least 4 months. If no response is observed after this period, combined treatment may be continued. Clinical experience indicates that treatment may be extended for at least 18 months if necessary to achieve spermatogenesis.

Special patient groups.

Elderly patients

There are no appropriate indications for the use of follitropin alfa in elderly patients. Safety and efficacy in this population have not been established.

Patients with renal or hepatic impairment

Safety, efficacy, and pharmacokinetic parameters of follitropin alfa in patients with renal or hepatic impairment have not been established.

Foligraf**®** is intended for subcutaneous administration. Self-administration may be performed only by properly trained patients who have access to expert consultation if needed. The first injection of Foligraf**®** must be administered under direct medical supervision. Subsequent injections should be given at the same time each day, with the injection site rotated. The solution must not be administered if it is cloudy or contains particulate matter.

Immediately before use, the powder should be reconstituted with the water for injection provided in the package.

Children.

There are no appropriate indications for the use of follitropin alfa in pediatric patients.

Overdose.

Symptoms of follitropin alfa overdose are unknown, but the development of ovarian hyperstimulation syndrome (OHSS) cannot be excluded (see section "Special precautions for use").

Adverse Reactions

Summary of safety profile

The most commonly reported adverse reactions are headache, ovarian cysts, and injection site reactions (e.g., pain, erythema, hematoma, swelling, and/or irritation at the injection site).

Cases of mild or moderate ovarian hyperstimulation syndrome (OHSS) have been frequently reported and should be considered an inherent risk of the stimulation procedure. Severe forms of OHSS are uncommon (see section "Special precautions for use").

Very rare cases of thromboembolism may occur (see section "Special precautions for use").

The following frequency categories are used to classify adverse reactions:

• Very common: ≥ 1/10 (occurs in more than 1 in 10 individuals)
• Common: ≥ 1/100 to < 1/10 (occurs in up to 1 in 10 individuals)
• Uncommon: ≥ 1/1000 to < 1/100 (occurs in up to 1 in 100 individuals)
• Rare: ≥ 1/10,000 to < 1/1000 (occurs in up to 1 in 1,000 individuals)
• Very rare: < 1/10,000 (occurs in less than 1 in 10,000 individuals)

Adverse Reactions in Women

Immune system disorders

• Rare: Hypersensitivity reactions ranging from mild to severe, including anaphylactic reactions and shock.

Nervous system disorders

• Very common: Headache.

Vascular disorders

• Rare: Thromboembolism (both associated with OHSS and occurring independently).

Respiratory, thoracic and mediastinal disorders

• Rare: Exacerbation or worsening of asthma.

Gastrointestinal disorders

• Common: Abdominal pain, sensation of abdominal distension and discomfort, nausea, vomiting, diarrhea.

Reproductive system and breast disorders

• Very common: Ovarian cysts.
• Common: Mild to moderate OHSS (including associated symptoms).
• Uncommon: Severe OHSS (including associated symptoms) (see section "Special precautions for use").
• Rare: Complications of severe OHSS.

General disorders and administration site conditions

• Very common: Injection site reactions (e.g., pain, erythema, hematoma, swelling, and/or irritation at the injection site).

Treatment in Men

Immune system disorders

• Rare: Hypersensitivity reactions ranging from mild to severe, including anaphylactic reactions and shock.

Respiratory, thoracic and mediastinal disorders

• Rare: Exacerbation or worsening of asthma.

Skin and subcutaneous tissue disorders

• Common: Acne.

Reproductive system and breast disorders

• Common: Gynecomastia, varicocele.

General disorders and administration site conditions

• Very common: Injection site reactions (e.g., pain, erythema, hematoma, swelling, and/or irritation at the injection site).

Laboratory and instrumental findings

• Common: Increase in body weight.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, patients, or their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life

• Shelf life of the medicinal product: 2 years
• Shelf life of the solvent: 5 years

Storage conditions

Store at 2–8°C, protected from light and kept out of reach of children. Do not freeze.

The reconstituted solution should be used immediately after preparation.

Any unused solution should be discarded.

The solvent should be stored at a temperature not exceeding 25°C.

Packaging

1 vial of lyophilisate for injection solution with 1 ampoule of solvent (0.5 mL of sterile water for injection) in a blister pack. One blister pack per cardboard box.

Prescription status
Prescription only.

Manufacturer

Bharat Serums and Vaccines Limited.

Manufacturer's address and place of business

Plot No: K-27, parts K-27 and K-27/1, Anand Nagar, Jambewali Village, Edishnal MIDS, Ambernath (I) - 421506, Taluka: AMBERNATH CITY, District: THANE - Zone 6, India.