Bravelle (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Ferring Arzneimittel, GmbH (Germany)

Manufactured By

Ferring, GmbH (Germany)

Labeled By

FERRING INTERNATIONAL CENTER, S.A. (Switzerland)

ATC Code

G03GA04 (Urofollitropin)

Active Substance

Urofollitropin (Rec.INN registered by WHO)

Dosage Form

Bravelle

Lyophilisate for the preparation of a solution for intramuscular and subcutaneous administration 75 IU: fl. 5 or 10 pcs. in a set with a solvent

Dosage Form, Packaging, and Composition

Lyophilisate for the preparation of a solution for intramuscular and subcutaneous administration in the form of a lyophilized mass from almost white to light yellow in color; solvent is a transparent, colorless solution.

Excipients: lactose monohydrate – 21 mg, sodium hydrogen phosphate heptahydrate – 0.268 mg, polysorbate 20 – 0.005 mg, phosphoric acid – 0.0001-0.0006 ml.

Solvent: sodium chloride – 9 mg, hydrochloric acid 10% – 0.007-0.02 mg, water for injection – 995.4 mg.

75 IU – glass vials (5) in a set with solvent (1 ml amp. 5 pcs.) – blister packs (1) – cardboard boxes.
75 IU – glass vials (5) in a set with solvent (1 ml amp. 5 pcs.) – blister packs (2) – cardboard boxes.

Clinical-Pharmacological Group

Recombinant human follicle-stimulating hormone

Pharmacotherapeutic Group

Follicle-stimulating agent

Pharmacological Action

Gonadotropic hormone, an analogue of FSH. Stimulates the growth and maturation of ovarian follicles, increases estrogen levels, and stimulates endometrial proliferation. Does not have a luteinizing effect.

Pharmacokinetics

After a single subcutaneous administration at a dose of 300 IU, the time to reach T_max is 21.33±9.18 hours, C_max is 5.74±0.95 IU/l. AUC is 541.22±113.83 IU/l x h. T_1/2 is approximately 50 hours. Bioavailability after intramuscular administration is approximately 70%.

Indications

For stimulation of ovarian follicle growth in women with infertility due to hypothalamic-pituitary disorders (with the aim of stimulating the growth of one dominant follicle); during assisted reproductive technology procedures to achieve conception (stimulation of multiple follicle growth).

ICD codes

Dosage Regimen

Determine the dosage individually for each patient based on ovarian response.

Initiate treatment under the supervision of a physician experienced in infertility management.

Administer the reconstituted solution by intramuscular or subcutaneous injection.

Adjust the dose and duration of therapy based on ultrasound monitoring of follicular development and measurement of estrogen levels.

For ovulation induction in anovulatory women, start with 75 IU to 150 IU daily.

Continue this initial dose for at least the first seven days of treatment.

Make subsequent dose adjustments, not exceeding 37.5 IU to 75 IU per adjustment, at weekly intervals.

Do not exceed a total daily dose of 450 IU.

Continue treatment until an adequate follicular response is observed, typically for 7 to 14 days.

Discontinue treatment if the ovarian response is inadequate after 4 weeks.

Administer human chorionic gonadotropin (hCG) as a single dose of 5,000 IU to 10,000 IU following adequate follicular development.

Withhold hCG administration to avoid the risk of Ovarian Hyperstimulation Syndrome (OHSS) if the ovaries are abnormally enlarged on the last day of urofollitropin therapy.

Advise the patient to have coitus daily, beginning on the day prior to hCG administration and continuing until ovulation occurs.

For controlled ovarian stimulation in assisted reproductive technology (ART) cycles, start with 150 IU to 225 IU daily.

Initiate treatment on day 2 or 3 of the cycle.

Make subsequent dose adjustments based on the patient’s ovarian response.

Administer hCG to induce final follicular maturation prior to egg retrieval.

Adverse Reactions

Endocrine system disorders: infrequently – hyperthyroidism.

Psychiatric disorders: infrequently – mood lability, depression.

Nervous system disorders: frequently – headache; infrequently – lethargy, dizziness.

Respiratory system disorders: infrequently – dyspnea, epistaxis.

Gastrointestinal system disorders: frequently – constipation, abdominal distension; infrequently – nausea, abdominal pain, dyspepsia.

Skin and subcutaneous tissue disorders: infrequently – erythema, pruritus.

Urinary system disorders: infrequently – cystitis.

Reproductive system and breast disorders: frequently – ovarian hyperstimulation syndrome; infrequently – breast enlargement, breast tenderness, hot flushes.

General disorders and administration site conditions: frequently – pain, feeling of tiredness; infrequently – prolonged bleeding; rarely – injection site hyperemia and hematoma.

Contraindications

Hypersensitivity to urofollitropin; tumors of the pituitary gland or hypothalamus; decompensated diseases – hypothyroidism, adrenal cortex insufficiency, hyperprolactinemia; persistent ovarian enlargement, ovarian cysts (not associated with PCOS); developmental anomalies of the genital organs incompatible with pregnancy; uterine fibroids incompatible with pregnancy; vaginal bleeding of unknown etiology; estrogen-dependent tumors (ovarian cancer, uterine cancer, or breast cancer); primary ovarian insufficiency; pregnancy, breastfeeding period; children and adolescents under 18 years of age.

Use with caution

In the presence of risk factors for thromboembolic complications, such as individual or family predisposition, severe obesity (body mass index >30 kg/m²), or thrombophilia, as in this case there is an increased risk of venous or arterial thrombosis and thromboembolism during or after the use of gonadotropins. In this case, it is necessary to assess the ratio of the expected benefit from treatment with gonadotropins and the potential risk from their use.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Special Precautions

Treatment with urofollitropin should be carried out only under the supervision of a physician with appropriate specialization and experience in the treatment of infertility.

Before starting treatment, it is recommended to analyze the sperm of the sexual partner; if necessary, treat hypothyroidism, adrenal cortex insufficiency, hyperprolactinemia, tumors of the pituitary gland or hypothalamus. Gynecological examination with enlarged ovaries should be performed very carefully to avoid rupture of ovarian cysts; for the same purpose, it is recommended to avoid sexual intercourse.

After stimulation of follicle maturation and ovulation, the possibility of multiple pregnancy increases with natural conception. In the case of artificial conception, the likelihood of multiple pregnancy depends on the number of oocytes introduced.

The possibility of ectopic pregnancy should be considered, especially in cases with a history of fallopian tube diseases. The frequency of early and spontaneous miscarriages in pregnancy occurring after treatment with urofollitropin is higher than in healthy patients but comparable to that in infertility of other etiologies.

Ovarian hyperstimulation syndrome most often occurs on days 7-10 after ovulation stimulated by the administration of human chorionic gonadotropin (it can also occur during assisted reproductive technology procedures).

The possibility of developing ovarian hyperstimulation syndrome in women during superovulation (created during assisted reproductive technology procedures) may be reduced if the contents of all follicles are aspirated before ovulation occurs.

There are reports of ovarian neoplasms and other neoplasms of the reproductive system, both benign and malignant, in women who have undergone infertility treatment using several ART methods. To date, it has not been established whether treatment with gonadotropins increases the baseline risk of these tumors in women with infertility.

The prevalence of congenital malformations of the fetus with the use of ART is somewhat higher than with natural conception. It is believed that this may be associated with the individual characteristics of the parents (maternal age, sperm characteristics) and multiple pregnancies.

Drug Interactions

With the simultaneous use of urofollitropin and clomiphene citrate, a potentiation of the follicular response is possible.

Concomitant use with GnRH agonists may induce pituitary desensitization (an increase in the dose of urofollitropin is required to obtain an adequate ovarian response).

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.