Follitropin Beta

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Injection:

Follistim AQ: 75 units/0.5 mL (0.5 mL [DSC])

Solution, Subcutaneous:

Follistim AQ: 300 units/0.36 mL (0.42 mL); 600 units/0.72 mL (0.78 mL); 900 units/1.08 mL (1.17 mL) [contains benzyl alcohol]

Pharmacology

Mechanism of Action

Follitropin beta is a human FSH preparation of recombinant DNA origin. Follitropins stimulate ovarian follicular growth in women who do not have primary ovarian failure and stimulate spermatogenesis in men with hypogonadotrophic hypogonadism. FSH is required for normal follicular growth, maturation, gonadal steroid production, and spermatogenesis.

Pharmacokinetics/Pharmacodynamics

Absorption

Females: IM: 76%; SubQ: 78%

Distribution

Females: 8 L

Onset of Action

Peak effect: Females: Follicle development: Within cycle

Time to Peak

Females: SubQ: 13 hours

Half-Life Elimination

Females: IM: 44 hours (single dose), 27-30 hours (multiple doses); SubQ: 33 hours (single dose)

Use: Labeled Indications

Females: Induction of ovulation and pregnancy in anovulatory infertile patients in whom the cause of infertility is functional and not caused by primary ovarian failure; induction of pregnancy in normal ovulatory women undergoing controlled ovarian stimulation as part of in vitro fertilization, or intracytoplasmic sperm injection.

Males: Induction of spermatogenesis in men with primary and secondary hypogonadotropic hypogonadism in whom the cause of infertility is not due to primary testicular failure.

Contraindications

Hypersensitivity to recombinant human follicle-stimulating hormone (FSH) products, streptomycin, neomycin, or any component of the formulation; high levels of FSH indicating primary gonadal failure; uncontrolled nongonadal endocrinopathies (eg, adrenal, pituitary, or thyroid disorders); tumor of the ovary, breast, uterus, testis, hypothalamus, or pituitary gland.

Females: Additional contraindications: Abnormal vaginal bleeding of undetermined origin; ovarian cysts or enlargement not due to polycystic ovary syndrome; pregnancy.

Canadian labeling: Additional contraindications (not in the US labeling): Lactation; conditions incompatible with pregnancy (eg, malformation of reproductive organs, uterine fibroid tumors); use in children.

Dosage and Administration

Dosing: Adult

Note: Dose should be individualized. Use the lowest dose consistent with the expectation of good results. Over the course of treatment, doses may vary depending on individual patient response. Doses may need adjustment when changing between products and/or methods of administration.

Ovulation induction: Females:

Follistim AQ (vials): IM, SubQ: Stepwise approach: Initiate therapy with 75 units/day for at least the first 7 days. Increase dose by 25 or 50 units at weekly intervals until follicular growth indicates an adequate ovarian response. The maximum (individualized) daily dose that has been safely used for ovulation induction in patients during clinical trials is 300 units. If response to follitropin is appropriate, human chorionic gonadotrophin (hCG) is given 1 day following the last dose to induce final oocyte maturation and ovulation. Follow current clinical practice to reduce the risk of ovarian hyperstimulation syndrome (OHSS).

Follistim AQ Cartridge: SubQ: Stepwise approach: Initiate therapy with 50 units/day for at least the first 7 days. Increase dose by 25 or 50 units at weekly intervals until follicular growth indicates an adequate ovarian response. The maximum (individualized) daily dose that has been safely used for ovulation induction in patients during clinical trials is 250 units. If response to follitropin is appropriate, hCG is given 1 day following the last dose to induce final oocyte maturation and ovulation. Follow current clinical practice to reduce the risk of OHSS. See "Note" for dosage adjustment for the pen with cartridge.

Puregon (vials) [Canadian product] (IM, SubQ), Puregon Cartridge [Canadian product] (SubQ): Stepwise approach: Initiate therapy with 50 units/day for at least the first 7 days. Increase dose gradually until follicular growth and/or plasma estradiol levels indicate an adequate response (daily increase of estradiol levels of 40% to 100% is considered optimal). If response to follitropin is appropriate, hCG is given 1 day following the last dose to induce final oocyte maturation and ovulation. Decrease hCG dose if the number of responding follicles is too high or estradiol levels increase too rapidly (eg, greater than daily doubling for estradiol for 2 or 3 consecutive days); withhold hCG if the ovaries are abnormally enlarged or if abdominal pain occurs. See "Note" for dosage adjustment for the pen with cartridge.

Controlled ovarian stimulation: Females:

Follistim AQ (vials): IM, SubQ: Stepwise approach: A starting dose of 150 to 225 units is recommended for at least the first 4 days of treatment. The dose may be adjusted for the individual patient based upon their ovarian response. The maximum daily dose used in clinical studies is 600 units. When a sufficient number of follicles of adequate size are present, the final maturation of the follicles is induced by administering hCG. Oocyte retrieval is performed 34 to 36 hours later. Follow current clinical practice to reduce the risk of OHSS.

Follistim AQ Cartridge: SubQ: Stepwise approach: A starting dose of 200 units is recommended for at least the first 7 days of treatment. The dose may be adjusted for the individual patient based upon their ovarian response. The maximum daily dose used in clinical studies is 500 units. When a sufficient number of follicles of adequate size are present, the final maturation of the follicles is induced by administering hCG. Oocyte retrieval is performed 34 to 36 hours later. Follow current clinical practice to reduce the risk of OHSS. See "Note" for dosage adjustment for the pen with cartridge.

Puregon vials [Canadian product] (IM, SubQ), Puregon Cartridge [Canadian product] (SubQ): A starting dose of 150 to 225 units is recommended for at least the first 4 days of treatment. The dose may be adjusted for the individual patient based upon their ovarian response. The maximum daily dose safely used in clinical studies is 450 units (limited experience with higher doses). When a sufficient number of follicles of adequate size are present, the final maturation of the follicles is induced by administering hCG 30 to 40 hours after the last follitropin beta dose. Withhold hCG in cases where the ovaries are abnormally enlarged on the last day of follitropin beta therapy. See "Note" for dosage adjustment for the pen with cartridge.

Spermatogenesis induction: Males:

Follistim AQ (vials), Follistim AQ Cartridge, Puregon (vials) [Canadian product], Puregon Cartridge [Canadian product]: Note: Pretreatment with hCG monotherapy is required prior to concomitant therapy with follitropin beta and hCG. Follitropin beta therapy may be initiated after normal serum testosterone levels have been reached. SubQ: 450 units/week (administered as 225 units twice weekly or 150 units 3 times/weekly). A lower dose of Follistim AQ Cartridge may be considered. See "Note" for dosage adjustment for the pen with cartridge.

Note: Dose adjustment for follitropin beta pen with cartridge: When administered using the pen, the follitropin cartridge delivers on average 18% more follitropin beta when compared to dissolved lyophilized follitropin beta administered by a conventional syringe. If the above starting doses were previously used when administering a recombinant lyophilized gonadotropin product via a conventional syringe, lower starting and maintenance doses should be considered when switching to follitropin pen with cartridge. The following dose conversion may be used:

Table has been converted to the following text.

Follitropin Beta Dosing Conversion

(values listed are rounded to the nearest 25 unit increment)

Dose using powder for solution/conventional syringe: 75 units

Dose using pen: 50 units

Dose using powder for solution/conventional syringe: 150 units

Dose using pen: 125 units

Dose using powder for solution/conventional syringe: 225 units

Dose using pen: 175 units

Dose using powder for solution/conventional syringe: 300 units

Dose using pen: 250 units

Dose using powder for solution/conventional syringe: 375 units

Dose using pen: 300 units

Dose using powder for solution/conventional syringe: 450 units

Dose using pen: 375 units

Administration

SubQ injection may be given in the abdomen just below the navel or upper thigh. IM injection may be given in the upper outer quadrant of the buttock. Avoid areas that are tender, red, bruised, or hard.

Follistim AQ, Puregon [Canadian product]: Vials: Administer by IM or SubQ injection.

Follistim AQ Cartridge, Puregon Cartridge [Canadian product]: Cartridge: Administer by SubQ injection only, using the Follistim Pen or the Puregon Pen, which can be set to deliver the appropriate dose.

Storage

Prior to dispensing, store refrigerated at 2°C to 8°C (36°F to 46°F). After dispensed, may be stored under refrigeration at 2°C to 8°C (36°F to 46°F) or ≤25˚C (77˚F) for up to 3 months. Once cartridge is pierced, must be stored at 2°C to 25°C (36°F to 77°F) and used within 28 days. Do not freeze. Protect from light.

Drug Interactions

There are no known significant interactions.

Adverse Reactions

Frequency may vary based on indication.

1% to 10%:

Central nervous system: Headache (7%), fatigue (2%)

Dermatologic: Acne vulgaris (7%), skin rash (3%)

Endocrine & metabolic: Ovarian hyperstimulation (6% to 8%), gynecomastia (3%), ovarian cyst (3%)

Gastrointestinal: Nausea (4%), abdominal distress (3%), abdominal pain (3%), lower abdominal pain (3%)

Genitourinary: Pelvic symptoms (discomfort: 8%), pelvic pain (6%)

Local: Injection site reaction (7%), pain at injection site (7%)

Miscellaneous: Cyst (dermoid: 3%)

Postmarketing: Abdominal distention, breast tenderness, constipation, diarrhea, ovarian neoplasm, ovarian torsion, ovary enlargement, spontaneous abortion, thromboembolism, uterine hemorrhage, vaginal hemorrhage

Warnings/Precautions

Concerns related to adverse effects:

• Ovarian enlargement: The lowest effective dose should be used to decrease the risk of abnormal ovarian enlargement. If ovaries are abnormally enlarged on the last day of follitropin beta treatment, follow current clinical practice to reduce the risk of ovarian hyperstimulation syndrome (OHSS).
• Ovarian hyperstimulation syndrome: OHSS is a rare, exaggerated response to ovulation induction therapy (Corbett 2014; Fiedler 2012). This syndrome may begin within 24 hours of hCG treatment but may become most severe 7 to 10 days after therapy (Corbett 2014). Mild/moderate OHSS signs/symptoms may include abdominal distention/discomfort, diarrhea, nausea, vomiting, and mild/moderate enlargement of ovaries/ovarian cysts. Severe OHSS signs/symptoms may include severe abdominal pain, anuria/oliguria, ascites, severe dyspnea, hypotension, hydrothorax, nausea/vomiting (intractable), pleural effusion, rapid weight gain, venous thrombosis, and large ovarian cysts. Decreased CrCl, hemoconcentration, hypoproteinemia, elevated liver enzymes, elevated WBC, and electrolyte imbalances may also be present (ASRM 2016; Corbett 2014; Fiedler 2012). Treatment is primarily symptomatic and includes fluid and electrolyte management, analgesics, and prevention of thromboembolic complications (ASRM 2016; Shmorgun 2017).
• Ovarian torsion: May occur in relation to OHSS, pregnancy, previous or current ovarian cyst and polycystic ovaries, previous abdominal surgery, and previous history of ovarian torsion.
• Pulmonary effects: Serious pulmonary conditions, including acute respiratory distress syndrome, have been reported.
• Thromboembolic events: In association with and separate from OHSS, thromboembolic events have been reported. Risk may be increased in patients with a personal or family history of thromboembolic events, severe obesity, or thrombophilia.

Dosage form specific issues:

• Multiple dose injection pens: According to the Centers for Disease Control and Prevention, pen-shaped injection devices should never be used for more than one person (even when the needle is changed) because of the risk of infection. The injection device should be clearly labeled with individual patient information to ensure that the correct pen is used (CDC 2012).

Other warnings/precautions:

• Appropriate use: To minimize risks, use only at the lowest effective dose. Monitor ovarian response with transvaginal ultrasound; concurrent measurement of estradiol levels may also be useful.
• Experienced physician: These medications should only be used by physicians who are thoroughly familiar with infertility problems and their management.
• Multiple births: May result from the use of these medications; advise patient of the potential risk of multiple births before starting the treatment.

Monitoring Parameters

Females: Monitor follicular growth by transvaginal ultrasound to determine adequate ovarian response and timing of human chorionic gonadotrophin (hCG) administration. Concurrent measurement of estradiol levels may also be useful.

The clinical evaluation of estrogenic activity (changes in vaginal cytology and changes in appearance and volume of cervical mucus) provides an indirect estimate of the estrogenic effect upon the target organs and, therefore, it should only be used adjunctively with more direct estimates of follicular development (ultrasonography and serum estradiol determinations).

Monitor for signs and symptoms of ovarian hyperstimulation syndrome (OHSS) for at least 2 weeks following hCG administration. Initial symptoms of moderate to severe OHSS may include a sensation of bloating, abdominal pain, rapid weight gain, and decreased urine output (Shmorgun 2017).

OHSS: Monitoring of hospitalized patients should include albumin, degree of ascites, cardiorespiratory status, electrolytes, fluid balance, hematocrit, hemoglobin, serum creatinine, urine output, urine specific gravity, signs of thromboembolism, vital signs, weight (all daily or as necessary), and liver enzymes (weekly) (Shmorgun 2017).

Males: Monitor for sufficient spermatogenesis. This can be directly estimated by semen analysis, or indirectly estimated by serum testosterone level. Semen analysis is recommended 4 to 6 months after starting treatment (Puregon Canadian product labeling 2019). Therapy should continue for 3 to 4 months before improvement in spermatogenesis can be expected.

Pregnancy

Pregnancy Risk Factor

X

Pregnancy Considerations

Ectopic pregnancies, congenital abnormalities, and multiple births have been reported. The incidence of congenital abnormality may be slightly higher after in vitro fertilization or intracytoplasmic sperm injection than with spontaneous conception; higher incidence may be related to parenteral characteristics (maternal age, sperm characteristics).

Evaluate pregnancy status as well as the fertility of the male partner prior to ovulation induction. Follitropin beta is used for the induction of ovulation; use is contraindicated in women who are already pregnant. Evaluate fertility status of the female partner prior to induction of spermatogenesis.

Patient Education

What is this drug used for?

• It is used to help women get pregnant.
• It is used to help make sperm.

Frequently reported side effects of this drug

• Nausea
• Injection site irritation
• Acne
• Headache
• Loss of strength and energy
• Pelvic pain (females)
• Abdominal pain (females)

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Ovarian hyperstimulation syndrome like severe abdominal pain or bloating; severe nausea, vomiting, or diarrhea; excessive weight gain; shortness of breath; or change in amount of urine passed
• Blood clots like numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood
• Enlarged breasts (males)
• Abnormal vaginal bleeding
• Pale skin
• Skin discoloration
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.