Fostimon
UkraineINSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT FOSTIMON (FOSTIMON®)
Composition:
1 vial contains:
Active substance: urofollitropin 75 IU or 150 IU;
Excipient: lactose monohydrate.
1 ampoule containing 1 ml of solvent contains:
Active substance: sodium chloride 9 mg;
Excipient: water for injections.
Pharmaceutical form.
Lyophilized powder for solution for injection.
Main physicochemical properties:
Lyophilized porous white mass in vials;
Solvent – clear, colorless solution free from visible mechanical inclusions.
Pharmacotherapeutic group.
Gonadotropins and other ovulation stimulants. Gonadotropic hormones.
ATC code: G03G A04.
Pharmacological properties.
Pharmacodynamics.
Urofollitropin is a gonadotropic hormone, an analogue of follicle-stimulating hormone (FSH). Urofollitropin is a highly purified preparation of urinary follicle-stimulating hormone (FSH) extracted from the urine of postmenopausal women. FSH stimulates the growth and development of follicles and the production of gonadal steroids in women who do not suffer from primary ovarian dysfunction. It stimulates the growth and maturation of ovarian follicles, increases estrogen levels, and promotes endometrial proliferation. It does not exert luteinizing activity.
According to clinical trial data, the pharmacodynamic effects of urofollitropin do not differ from those of recombinant FSH when administered by the same route. After subcutaneous administration, urofollitropin induces the same follicular response, produces similar peak estradiol concentrations, and results in a comparable number of maturing and mature oocytes as recombinant FSH, with no differences in total dose or duration of treatment.
Urofollitropin is typically used following administration of human chorionic gonadotropin (hCG) to induce the final stage of follicular maturation and ovulation.
Pharmacokinetics.
Bioavailability is approximately 70%. After intramuscular administration, the drug binds to ovarian follicle receptors, and a small amount appears unchanged in the urine of proximal renal tubules. After a single subcutaneous injection, absorption of urofollitropin is more prolonged compared to intramuscular administration.
In studies conducted in women undergoing in vitro fertilization (IVF), subcutaneous administration of 225 IU daily for 7 days (with individual dose adjustments) resulted in maximum plasma concentrations of 23.4 pg/mL (± 8.8 pg/mL). The elimination half-life is 30–40 hours. After a single intramuscular dose of urofollitropin, approximately 8% of the administered dose is excreted unchanged in urine.
After intramuscular or subcutaneous administration, the bioavailability of FSH is approximately 70–75%. Elimination occurs in two phases: the first phase has a half-life of 4 hours, and the second phase approximately 70 hours. Thus, 72 hours after administration, FSH plasma levels are significantly lower than before administration. Renal excretion of FSH is minimal.
Clinical characteristics.
Indications.
Anovulatory cycles (including polycystic ovary syndrome) in women unresponsive to clomiphene citrate treatment;
Assisted reproductive technologies (ART).
Contraindications.
Hypersensitivity to follicle-stimulating hormone or any other component of the drug;
Elevated follicle-stimulating hormone levels due to primary ovarian failure;
Ovarian enlargement or presence of ovarian cysts (except in polycystic ovary syndrome);
Gynecological bleeding of unknown etiology;
Ovarian, uterine, or breast cancer;
Pituitary or hypothalamic tumors;
Thyroid or adrenal gland pathology in a decompensated state;
Infertility unrelated to ovarian dysfunction, metrorrhagia;
Premature menopause;
Infertility due to failure of normal follicular development (e.g., tubal or cervical pathology), except when participating in assisted reproductive technology programs;
Hypergonadotropic ovarian insufficiency;
Hyperprolactinemia;
Administration of hCG in suspected ovarian hyperstimulation syndrome, i.e., in simple follicular stimulation: plasma estradiol level ≥ 4 pmol/mL (≥ 1100 pg/mL) and/or presence of 3 or more follicles with diameter ≥ 16 mm;
In multiple follicular stimulation (assisted reproductive technology programs): plasma estradiol level ≥ 11 pmol/mL (≥ 3000 pg/mL) with 20 follicles of diameter ≥ 12 mm.
Pregnancy and breastfeeding.
Fostimon is not indicated in cases where an effective response cannot be expected:
- Primary ovarian failure;
- Developmental abnormalities or pathologies of genital organs incompatible with pregnancy;
- Uterine fibroids incompatible with pregnancy.
Interaction with other medicinal products and other forms of interaction.
Concomitant use of Fostimon and clomiphene citrate may potentiate follicular response.
Concomitant use with gonadotropin-releasing hormone (GnRH) agonists may induce pituitary desensitization (requiring increased Fostimon dosage to achieve adequate ovarian response).
No interactions with other medicinal products have been reported to date; however, Fostimon must not be mixed in the same syringe with other drugs.
Special precautions for use.
The drug must be administered under medical supervision in an appropriate medical facility. Self-administration may be allowed only in urgent cases and only to well-informed and properly trained patients.
No cases of hypersensitivity have been reported in clinical trials with Fostimon. However, anaphylactic reactions may occur in patients with known hypersensitivity to other gonadotropins. The first injection of Fostimon in such patients should be administered under physician supervision in a medical facility equipped with a cardiopulmonary resuscitation unit.
Before initiating treatment, fertility of the partner should be evaluated. It should be confirmed that Fostimon is appropriate for the type of infertility in the couple, and all contraindications to pregnancy should be considered.
Before initiating Fostimon therapy, treatment of hypothyroidism, hyperprolactinemia, or pituitary/hypothalamic tumors should be completed.
Infectious diseases.
When using medicinal products derived from human urine, transmission of infectious agents, including known and unknown viruses and pathogens, cannot be completely excluded. However, this risk is minimized by the extraction/purification process, which includes steps of viral inactivation/removal. These steps have been validated using model viruses, including human immunodeficiency virus (HIV), herpesvirus, and papillomavirus. To date, there have been no reports of viral transmission with gonadotropins derived from human urine.
Gynecological examination in cases of ovarian enlargement should be performed very carefully to avoid rupture of ovarian cysts.
After stimulation of follicular maturation and ovulation, the likelihood of multiple pregnancy increases in natural conception. In assisted conception, the likelihood of multiple pregnancy depends on the number of oocytes transferred.
Ovarian response should be monitored by ultrasound before and during cycle stimulation, especially in patients with polycystic ovary syndrome.
Ectopic pregnancy may occur in patients with tubal pathology.
The rate of early and spontaneous miscarriages in pregnancies achieved after Fostimon treatment is higher than in healthy women but comparable to that in women with fertility disorders.
Ovarian hyperstimulation syndrome (OHSS).
Ovarian hyperstimulation may occur in patients undergoing follicular growth stimulation. Fostimon and human chorionic gonadotropin must be administered in appropriate doses to avoid ovarian hyperstimulation and multiple pregnancy.
Ultrasound assessment of follicular development and measurement of estradiol levels should be performed before treatment initiation and at regular intervals during treatment.
In addition to the development of numerous follicles, estradiol levels may rise rapidly (e.g., more than doubling daily for 2–3 consecutive days), potentially reaching excessively high values.
Diagnosis of ovarian hyperstimulation is confirmed by ultrasound. If this is an undesirable ovarian hyperstimulation (i.e., uncontrolled hyperstimulation during fertility treatment programs), the drug should be discontinued.
In such cases, pregnancy should be avoided, and administration of human chorionic gonadotropin (hCG) should be withheld, as it may induce ovarian hyperstimulation syndrome (OHSS) in addition to multiple ovulation.
Clinical signs and symptoms of mild to moderate OHSS include abdominal and pelvic pain, nausea, diarrhea, bloating, mild ovarian enlargement, and ovarian cysts.
Rarely, severe, life-threatening OHSS may develop, characterized by large ovarian cysts (prone to rupture leading to peritonitis), ascites with or without hydrothorax, hemodynamic disturbances, and weight gain.
In rare cases, OHSS with acute ovarian hypertrophy has been observed, leading to fluid shift into the abdominal and pleural cavities, and venous or arterial thromboembolism. Rarely, thromboembolism may also occur independently of OHSS.
Symptoms of OHSS typically appear 1–2 weeks after hCG administration. Therefore, patients should be monitored for at least 2 weeks after the last injection. If symptoms appear 3 weeks or more after treatment cessation, inevitable miscarriage or ectopic pregnancy should also be considered.
In cases of moderate hyperstimulation, patient observation is usually sufficient. In cases of ascites or severe complications, hospitalization is required with monitoring of hemodynamics and electrolyte status.
The risk of OHSS in women undergoing superovulation may be reduced by aspirating all follicular contents before ovulation occurs.
OHSS may lead to the formation of large ovarian cysts.
Excessive ovarian response to treatment rarely causes hyperstimulation before administration of hCG to trigger ovulation. Therefore, it is advisable to withhold hCG administration and recommend abstinence from sexual intercourse or use of barrier contraception for at least 4 days.
The rate of spontaneous pregnancy loss in patients treated with Fostimon is higher than in healthy women but comparable to that in infertile women.
Excessive estrogenic response caused by the drug usually does not cause symptoms of hyperstimulation.
Reproductive organ neoplasms.
In women repeatedly treated for infertility, both benign and malignant neoplasms of the ovaries and other reproductive organs have been reported. The relationship between gonadotropin treatment and the predisposition to neoplasms in infertile women has not yet been established.
Congenital malformations.
There are no data indicating an increased risk of congenital malformations compared to spontaneous pregnancy. The prevalence of congenital malformations after assisted reproductive technology (ART) programs may be slightly higher than after natural conception. This is believed to be due to parental factors (e.g., maternal age, sperm characteristics) and multiple pregnancies.
Thromboembolic disorders.
Venous or arterial thromboembolic events may occur during or after gonadotropin treatment 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.
In patients with increased risk of thromboembolic complications during Fostimon treatment, prothrombin time and activated partial thromboplastin time (aPTT) should be monitored regularly.
The drug contains lactose and should not be used in patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.
Daily endocrinological and clinical monitoring is required throughout the treatment course and for 2 weeks thereafter.
Use during pregnancy or breastfeeding.
Animal studies and human experience with Fostimon indicate a risk to the fetus; therefore, the drug is contraindicated during pregnancy.
It is unknown whether FSH is excreted in breast milk and how it may affect breastfed infants. The drug is contraindicated during breastfeeding.
Ability to influence reaction rate when 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.
The optimal dose and duration of treatment are determined based on ultrasound examination of the ovaries, assessment of estrogen levels in blood and urine, and clinical observation.
Anovulatory cycle (including polycystic ovary syndrome):
Fostimon is administered to women at a dose of 75–150 IU daily during the first 7 days of the cycle (can be once daily). Treatment may start at 37.5 IU, increasing if necessary to 75 IU. The daily dose should not exceed 225 IU. The interval between treatment courses is 7 or 14 days.
If there is no adequate response after 4 weeks of treatment, the next cycle should restart with a higher dose than the previous cycle, but not exceeding the maximum daily dose of 450 IU.
Treatment response is assessed by follicle size (measured by ultrasound) and/or estrogen concentration. After achieving adequate response, hCG 5000–10000 IU is administered 24–48 hours after the last dose of Fostimon.
On the day of hCG injection, patients are advised to have intercourse and repeat it the following day.
Women undergoing controlled ovarian stimulation for assisted reproductive techniques (e.g., IVF, GIFT, ZIFT) to achieve fertilization (stimulation of multiple follicular growth):
Fostimon is administered at a dose of 150–225 IU daily, starting on cycle days 2–3. Treatment continues until adequate follicular development is achieved. Follicular development is assessed by plasma estrogen concentration and/or ultrasound monitoring. The dose is individualized, not exceeding 450 IU daily.
Adequate follicular development is typically achieved by day 10 of treatment (range: 5–20 days). hCG 5000–10000 IU is administered 24–48 hours after the last dose of Fostimon to trigger follicular rupture.
The injection solution is prepared immediately before use. It is administered intramuscularly or subcutaneously.
Children.
The drug is not used in children (under 18 years of age).
Overdose.
Gonadotropins have very low acute toxicity. However, overdose for more than 2 days may cause ovarian hyperstimulation syndrome (OHSS) — see section "Special precautions for use." Thromboembolic complications are possible.
Severe OHSS occurs in 0.2–0.4% of all Fostimon-stimulated cycles.
Treatment: intravenous administration of small amounts of albumin, hypertonic sodium chloride solution, diuretics; continuous monitoring of blood electrolytes and hematocrit levels. Treatment should be conducted in intensive care units of gynecological departments.
Adverse reactions.
Infections and infestations: urinary tract infections, nasopharyngitis.
The active ingredient of this product is derived from human urine; therefore, transmission of pathogens of known or unknown origin cannot be excluded.
Gastrointestinal disorders: nausea, vomiting, abdominal pain, constipation, diarrhea, flatulence.
Central nervous system disorders: headache, dizziness, lethargy (rare).
Psychiatric disorders: mood lability.
Vascular disorders: hot flushes.
Reproductive system and breast disorders:
Common: moderate ovarian enlargement, ovarian cyst formation, breast induration, breast hypertrophy and pain, hot flushes.
Possible: ovarian hyperstimulation syndrome (mainly in patients with polycystic ovary syndrome), manifested by:
- Moderate form: lower abdominal pain, nausea, diarrhea, slight ovarian enlargement, ovarian cyst development;
- Rare severe cases: development of large cysts, ascites, hydrothorax, and severe thromboembolic complications; weight gain; increased risk of ectopic and multiple pregnancy; miscarriage, vaginal bleeding, vaginal discharge, ovarian torsion.
The frequency of multiple pregnancy (mostly twins) with gonadotropin therapy is approximately 20%. In assisted reproductive technology programs, the risk of multiple pregnancy depends on the number of embryos transferred.
Spontaneous abortions: the rate of miscarriages in pregnancies achieved after Fostimon treatment is higher than in the general population but comparable to that in women with fertility disorders.
Ectopic pregnancy may occur, particularly in women with a history of tubal disease.
Endocrine disorders: hyperthyroidism (rare).
Respiratory disorders: dyspnea, epistaxis (rare).
Musculoskeletal and connective tissue disorders: arthralgia, muscle spasms.
Skin and subcutaneous tissue disorders: dry skin, hair loss.
Immune system disorders: fever, chills, urticaria, possible allergic local and systemic skin reactions, and delayed-type hypersensitivity reactions with gonadotropin preparations.
General disorders and administration site reactions:
Very rare: injection site reactions, including pain, redness, swelling, rash, itching, irritation, hematoma.
Other:
Rare: arterial thromboembolism, peripheral or cerebral venous occlusion (e.g., pulmonary embolism, stroke, peripheral arterial embolism), myalgia, arthralgia, general weakness, fatigue, cystitis, risk of infectious transmission.
Laboratory findings: prolonged bleeding time.
Shelf life.
2 years.
Storage conditions.
Store out of reach of children. Store protected from light at temperatures not exceeding 25 °C.
Incompatibilities.
Since compatibility studies have not been performed, the drug must not be mixed with other medicinal products.
Packaging.
1 vial of powder and 1 ampoule of 1 ml solvent (sodium chloride 9 mg, water for injections) in a pack; 10 packs in a cardboard box with labeling in Ukrainian.
Prescription status.
Prescription only.
Manufacturer.
IBSA Institut Biochimique SA, Switzerland.
Manufacturer's address and place of business.
Via Pian Sciresci 49, 6912 Pazzallo, Switzerland