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Follitropin Beta

Pronunciation

(foe li TRO pin BAY ta)

Index Terms

  • Follicle Stimulating Hormone, Recombinant
  • FSH
  • rFSH-beta
  • rhFSH-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); 150 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]

Brand Names: U.S.

  • Follistim AQ

Pharmacologic Category

  • Gonadotropin
  • Ovulation Stimulator

Pharmacology

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.

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 Assisted Reproductive Technology (ART) (eg, in vitro fertilization [IVF], intracytoplasmic sperm injection [ICSI])

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 follitropins 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

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.

Ovulation induction: Females:

Follistim® AQ: IM, SubQ: Stepwise approach: Initiate therapy with 75 units/day for at least the first 7 days. Increase by 25 or 50 units at weekly intervals until follicular growth or serum estradiol levels indicate an adequate 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, hCG is given 1 day following the last dose. Withhold hCG if the ovaries are abnormally enlarged, or if abdominal pain occurs.

Follistim® AQ Cartridge: SubQ: Stepwise approach: Initiate therapy with 50 units/day for at least the first 7 days. Increase by 25 or 50 units at weekly intervals until follicular growth or serum estradiol levels indicate an adequate 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. Withhold hCG if the ovaries are abnormally enlarged, or if abdominal pain occurs. See "Note" for dosage adjustment for this product.

ART: Females:

Follistim® AQ: IM, SubQ: Stepwise approach: A starting dose of 150-225 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 34-36 hours later. Withhold hCG in cases where the ovaries are abnormally enlarged on the last day of follitropin beta therapy.

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 34-36 hours later. Withhold hCG in cases where the ovaries are abnormally enlarged on the last day of follitropin beta therapy. See "Note" for dosage adjustment for this product.

Spermatogenesis induction: Males: Follistim® AQ, Follistim® AQ Cartridge: 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 this product.

Note: Dose adjustment for Follistim® AQ Cartridge: When administered using the Follistim Pen®, the Follistim® AQ Cartridge delivers 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 Follistim® AQ Cartridge. The following dose conversion may be used:

Follistim® AQ Dosing Conversion1

Dose Administered Using Powder for Solution/Conventional Syringe

Follistim® AQ Dose Administered Using Follistim Pen®

1Values listed are rounded to the nearest 25 unit increment.

75 units

50 units

150 units

125 units

225 units

175 units

300 units

250 units

375 units

300 units

450 units

375 units

Table has been converted to the following text.

Follistim® AQ Dosing Conversion

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

Dose using powder for solution/conventional syringe: 75 units

Follistim® AQ dose using Follistim Pen®: 50 units

Dose using powder for solution/conventional syringe: 150 units

Follistim® AQ dose using Follistim Pen®: 125 units

Dose using powder for solution/conventional syringe: 225 units

Follistim® AQ dose using Follistim Pen®: 175 units

Dose using powder for solution/conventional syringe: 300 units

Follistim® AQ dose using Follistim Pen®: 250 units

Dose using powder for solution/conventional syringe: 375 units

Follistim® AQ dose using Follistim Pen®: 300 units

Dose using powder for solution/conventional syringe: 450 units

Follistim® AQ dose using Follistim Pen®: 375 units

Dosing: Renal Impairment

No dosage adjustment provided in manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment

No dosage adjustment provided in manufacturer's labeling (has not been studied).

Administration

Follistim® AQ: Administered by IM or SubQ injection

Follistim® AQ Cartridge: Follistim® AQ cartridge may be administered only by SubQ injection using the Follistim 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 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%)

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

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

<1% (Limited to important or life-threatening): 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: If ovaries are abnormally enlarged on the last day of treatment, withhold hCG to reduce the risk of ovarian hyperstimulation syndrome (OHSS).

• Ovarian hyperstimulation syndrome (OHSS): OHSS, an exaggerated response to ovulation induction therapy, is characterized by an increase in vascular permeability which causes a fluid shift from intravascular space to third space compartments (eg, peritoneal cavity, thoracic cavity) (ASRM, 2008; SOGC-CFAS, 2011). This syndrome may begin within 24 hours of treatment, but may become most severe 7 to 10 days after therapy (SOGC-CFAS, 2011). OHSS is typically self-limiting with spontaneous resolution, although it may be more severe and protracted if pregnancy occurs (ASRM, 2008). Symptoms of mild/moderate OHSS may include abdominal distention/discomfort, diarrhea, nausea, and/or vomiting. Severe OHSS symptoms may include abdominal pain that is severe, acute respiratory distress syndrome, anuria/oliguria, ascites, dyspnea, hypotension, nausea/vomiting (intractable), pericardial effusions, tachycardia, or thromboembolism. Decreased creatinine clearance, hemoconcentration, hypoproteinemia, elevated liver enzymes, elevated WBC, and electrolyte imbalances may also be present (ASRM, 2008; Fiedler, 2012; SOGC-CFAS, 2011). If severe OHSS occurs, stop treatment and consider hospitalizing the patient (ASRM, 2008; SOGC-CFAS, 2011). Treatment is primarily symptomatic and includes fluid and electrolyte management, analgesics, and prevention of thromboembolic complications (ASRM, 2008; SOGC-CFAS, 2011). The ascitic, pleural, and pericardial fluids may be removed if needed to relieve symptoms (eg, pulmonary distress or cardiac tamponade) (ASRM, 2008; SOGC-CFAS, 2011). Women with OHSS should avoid pelvic examination and/or intercourse (ASRM, 2008; SOGC-CFAS, 2011 ).

• 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 (atelectasis, acute respiratory distress syndrome, and exacerbation of asthma) have been reported.

• Thromboembolic events: In association with and separate from ovarian hyperstimulation syndrome, thromboembolic events have been reported.

Dosage form specific issues:

• Multiple dose injection pens: According to the Centers for Disease Control and Prevention (CDC), 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).

• Neomycin: May contain trace amounts of neomycin.

• Streptomycin: May contain trace amounts of streptomycin.

Other warnings/precautions:

• Appropriate use: To minimize risks, use only at the lowest effective dose. Monitor ovarian response with serum estradiol and vaginal ultrasound on a regular basis.

• 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 sufficient follicular maturation. This may be directly estimated by sonographic visualization of the ovaries and endometrial lining or measuring serum estradiol levels. The combination of both ultrasonography and measurement of estradiol levels is useful for monitoring for the growth and development of follicles and timing hCG administration.

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).

The clinical confirmation of ovulation is obtained by direct and indirect indices of progesterone production. The indices most generally used are: rise in basal body temperature, increase in serum progesterone, and menstruation following the shift in basal body temperature.

Monitor for signs and symptoms of OHSS for at least 2 weeks following hCG administration.

OHSS: Monitoring of hospitalized patients should include abdominal circumference, albumin, cardiorespiratory status, electrolytes, fluid balance, hematocrit, hemoglobin, serum creatinine, urine output, urine specific gravity, vital signs, weight (all daily or as necessary), and liver enzymes (weekly) (ASRM, 2008; SOGC-CFAS, 2011).

Males: Monitor for sufficient spermatogenesis. This can be directly estimated by semen analysis, or indirectly estimated by serum testosterone level.

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 ART than with spontaneous conception; higher incidence may be related to parenteral characteristics (maternal age, sperm characteristics). Follitropin Beta is used for the induction of ovulation; use is contraindicated in women who are already pregnant.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, acne, headache, or loss of strength and energy. Have patient report immediately to prescriber signs of ovarian hyperstimulation syndrome (severe abdominal pain or bloating; severe nausea, vomiting, or diarrhea; excessive weight gain; shortness of breath; or change in how much urine is passed), signs of blood clots (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; angina; shortness of breath; fast heartbeat; or coughing up blood), breast pain or soreness, enlarged breasts, vaginal bleeding, severe injection site irritation, pale skin, or skin discoloration (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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