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|Follitropin Alfa

Follitropin Alfa

Trade Names:
Gonal-f
- Powder for injection, lyophilized 82 units follicle-stimulating hormone (FSH) activity (to deliver 75 units)
- Powder for injection, lyophilized 600 units FSH activity (to deliver 450 units)
- Powder for injection, lyophilized 1,200 units FSH activity (to deliver 1,050 units)

Trade Names:
Gonal-f RFF Pen
- Injection 415 units FSH activity (to deliver at least 300 units per 0.05 mL)
- Injection 568 units FSH activity (to deliver at least 450 units per 0.75 mL)
- Injection 1,026 units FSH activity (to deliver at least 900 units per 1.5 mL)

Mechanism of Action

Pharmacology

Stimulates ovarian follicular growth in women who do not have primary ovarian failure.

Pharmacokinetics

Absorption

T _max is about 25 hr for an IM dose and about 16 hr for a subcutaneous dose. AUC is about 206 units•hr/L for an IM dose and about 176 units•hr/L for a subcutaneous dose. C _max is about 3 units/L and about 9 units/L at steady state. Bioavailability is about 76% for IM dosing and about 66% for subcutaneous dosing.

Distribution

Mean Vd is 10 L.

Elimination

Total Cl is 0.6 L/hr for an IV dose. The t _½ is about 50 hr for an IM dose and about 24 hr for a subcutaneous dose.

Indications and Usage

Induction of ovulation and pregnancy in anovulatory infertile patients in whom the cause of infertility is functional and not caused by primary ovarian failure; to stimulate development of multiple follicles in ovulatory patients undergoing assisted reproductive therapy (ART [eg, in vitro fertilization]); induction of spermatogenesis in men with primary and secondary hypogonadotropic hypogonadism in whom the cause of infertility is not primary testicular failure (except prefilled pen).

Contraindications

Women and men who exhibit the following: 1) prior hypersensitivity to recombinant FSH preparations or 1 of their excipients; 2) high levels of FSH indicating primary ovarian failure; 3) uncontrolled thyroid or adrenal dysfunction; 4) an organic intracranial lesion such as a pituitary tumor; 5) sex hormone-dependent tumors of the reproductive tract and accessory organs; and in women who exhibit: 6) abnormal uterine bleeding of undetermined origin; 7) ovarian cyst or enlargement of undetermined origin; and 8) pregnancy.

Dosage and Administration

Subcutaneous Initial dose of first cycle is 75 units/day; an incremental dosage adjustment of up to 37.5 units may be considered after 14 days. Further dose increases of 37.5 units may be made q 7 days if necessary. Treatment duration should not exceed 35 days unless serum estradiol increase indicates imminent follicular development. To complete follicular development and effect ovulation in the absence of an endogenous LH surge, administer 5,000 units human chorionic gonadotropin (hCG) 1 day after last dose of follitropin alfa. Withhold hCG if serum estradiol is over 2,000 pg/mL. In subsequent cycles, individualize initial dose for each patient. Max daily dose is 300 units.

Subcutaneous 150 units/day started in early follicular phase (cycle day 2 or 3) until sufficient follicular development is attained (in most cases therapy should not exceed 10 days).

In patients undergoing ART whose endogenous gonadotropin levels are suppressed, initiate follitropin alfa at a dose of 150 units/day (under 35 yr of age) or 225 units/day (35 yr of age and older). Continue treatment until adequate follicular development is indicated as determined by ultrasound in combination with serum estradiol level measurements. Consider adjusting the dose after 5 days based on patients response; adjust subsequent dosages q 3 to 5 days and by no more than 75 to 150 units additionally at each adjustment (max, 450 units/day). Administer hCG (5,000 to 10,000 units) once adequate follicular development is evident.

Pretreat with hCG alone (1,000 to 2,250 units 2 to 3 times/wk). Continue hCG for a period sufficient to achieve serum testosterone levels within normal range, which may take 3 to 6 mo. It may be necessary to increase the hCG dose to achieve normal testosterone levels. After normal testosterone levels are reached, follitropin alfa may be administered. Subcutaneous 150 units follitropin alfa 3 times/wk and hCG 1,000 units 3 times/wk. If azoospermia persists, the follitropin alfa dose may be increased to a max of 300 units 3 times/wk. It may be necessary to administer therapy for up to 18 mo to achieve adequate spermatogenesis.

General Advice

• For subcutaneous administration only. Not for intradermal, IM, or IV administration.
• Follow manufacturer"s instructions for reconstituting the powder for injection in single- or multi-dose vials using supplied diluent.
• If using prefilled pen, prepare the pen following manufacturer"s instructions. Select prescribed dose by turning dosage dial to the proper dose mark on the dial in front of the arrow mark. Load the pen by pulling on injection button and check red dosage confirmation scale on injection button before administering dose.
• If using prefilled pen or multidose vial that has been stored in refrigerator, allow solution to adjust to room temperature before administering dose.
• Do not administer if solution is discolored or cloudy, or if particulate matter is noted.

Storage/Stability

Store unopened single-dose ampules in refrigerator (36° to 46°F) or at controlled room temperature (68° to 77°F). Protect from light. Use immediately after reconstitution. Discard any unused solution.

Store unopened multidose vials in refrigerator or at controlled room temperature. Store reconstituted solution in refrigerator or at controlled room temperature. Protect from light and freezing. Discard any unused solution after 28 days.

Store prefilled injection pen in refrigerator until dispensed. Upon dispensing, store pen in refrigerator until expiration date, or at controlled room temperature for up to 1 mo or until the expiration date, whichever occurs first. After the first injection, store pen in refrigerator or at controlled room temperature for up to 28 days. Protect from light. Do not freeze. Discard any unused solution after 28 days.

Drug Interactions

None well documented.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Palpitation (2%).

CNS

Headache (22%); emotional lability (5%); migraine (4%); dizziness (3%); anorexia, anxiety, somnolence, fatigue (2%).

Dermatologic

Acne (4%); injection site pain (3%); pruritus (2%).

EENT

Rhinitis (7%); pharyngitis (3%).

GI

Nausea (14%); abdominal pain (9%); diarrhea (8%); flatulence (7%); vomiting (3%); dyspepsia, paresthesia, constipation, ulcerative stomatitis (2%).

Genitourinary

Ovarian cyst (15%); intermenstrual bleeding (9%); ovarian hyperstimulation (7%); female breast pain, vaginal hemorrhage (4%); dysmenorrhea, cervix lesion, genital moniliasis, menstrual disorder (3%); genital pruritus, leukorrhea, UTI, ovarian disorder, micturition frequency (2%).

Metabolic

Weight increase (4%).

Respiratory

Upper respiratory tract infection (12%); sinusitis (5%); coughing, dyspnea (2%).

Miscellaneous

Pain (6%); back pain (5%); influenza-like symptoms, fever (4%); enlarged abdomen, chest pain, tooth disorder, thirst, myalgia, hot flashes, malaise (2%); hemoptysis; pilonidal cyst; lymphadenopathy; spontaneous abortion; ectopic pregnancy; premature labor; postpartum fever.

Precautions

Pregnancy

Category X .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Health care provider use

Follitropin alfa should be used only by health care providers thoroughly familiar with infertility problems and their management.

Multiple births

In ovulation induction trials, 12.3% of live births were multiple births; in in vitro fertilization clinical trials, 44% of live births were multiple births.

Ovarian enlargement

Mild to moderate uncomplicated ovarian enlargement may occur in about 20% of women treated and generally regresses without treatment within 2 to 3 wk.

Ovarian hyperstimulation syndrome (OHSS)

Warning signs include difficulty breathing, severe pelvic pain, nausea, vomiting, rapid weight gain, stomach pain or bloating, diarrhea, and infrequent urination. May progress within 24 hr to several days to become a serious medical event. Treatment must be stopped and patient hospitalized.

To reduce risk of overstimulation of the ovary in women, ensure ovarian response to therapy is closely monitored (eg, serum estradiol levels and ultrasonography). Do not administer hCG to patient if serum estradiol level is more than 2,000 pg/mL. If the ovaries are abnormally enlarged or abdominal pain occurs, discontinue follitropin alfa therapy, do not administer hCG, and caution patient to avoid intercourse.

Pulmonary and vascular complications

Intravascular thrombosis and embolism can reduce blood flow to critical organs (eg, pulmonary infarct, cerebral vascular occlusion) or the extremities (may cause loss of limbs).

Overdosage

Symptoms

OHSS, multiple gestations.

Patient Information

• Explain names, actions, and potential side effects of the treatment regimen, including risk of multiple births. Review the treatment regimen, including duration of treatment and monitoring that will be required.
• If patient will be administering at home, teach patient how to store, prepare, and administer the dose, and dispose of used equipment and supplies. Advise patient to review the Patient Education Leaflet that comes with the multidose vials or, if using the prefilled syringe, the Patient Information Leaflet that comes with the prefilled pen, before starting therapy.
• Advise patient that if medication has been stored in refrigerator to allow solution to warm to room temperature before administering dose.
• Caution patient not to change the dose or stop taking unless advised by health care provider.
• Caution patient that if a dose is missed not to double the dose to catch up. Advise patient to contact health care provider for further instructions.
• Remind women that drug is administered to promote follicular growth and egg production, and that hCG will need to be administered to induce ovulation.
• Remind men that drug is administered to promote sperm development and that hCG will need to also be administered to normalize testosterone levels.
• Encourage women receiving drug for infertility to have intercourse daily, beginning on the day prior to administration of hCG until ovulation has become apparent.
• Warn women that close monitoring for overstimulation of the ovary is required and to report any of the following immediately to health care provider: difficulty breathing, severe pelvic pain, nausea, vomiting, rapid weight gain, stomach pain or bloating, diarrhea, or infrequent urination.
• Advise patient to inform health care provider of any side effects, symptoms, or physical changes, or bothersome injection site reactions.
• Instruct patient not to take any prescription or OTC medications, herbal preparations, or dietary supplements unless advised by health care provider.
• Advise patient that follow-up visits and laboratory tests will be required to monitor therapy and to keep appointments.