Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Subcutaneous:
Gonal-f RFF Rediject: 300 units/0.5 mL (0.5 mL); 450 units/0.75 mL (0.75 mL); 900 units/1.5 mL (1.5 mL) [contains metacresol]
Solution Reconstituted, Injection:
Gonal-f: 450 units (1 ea); 1050 units (1 ea) [contains benzyl alcohol]
Solution Reconstituted, Subcutaneous:
Gonal-f RFF: 75 units (1 ea)
Pharmacology
Mechanism of Action
Follitropin alfa 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
SubQ: Absorption rate is slower than the elimination rate
Distribution
Mean Vd: 0.7 L with in vitro fertilization/embryo transfer patients
Excretion
Clearance: IV: 0.6 L/hour in healthy female volunteers
Onset of Action
Peak effect:
Spermatogenesis, median: 6.8-12.4 months (range: 2.7-18.1 months)
Follicle development: Within cycle
Time to Peak
In healthy volunteers:
Females: SubQ: 8-16 hours
Males: SubQ: 11-20 hours
Half-Life Elimination
SubQ: 24-53 hours in healthy female volunteers; 32-41 hours in healthy male volunteers
Use: Labeled Indications
Multifollicular development during Assisted Reproductive Technology (ART): To stimulate the development of multiple follicles with ART
Ovulation induction: Induction of ovulation and pregnancy in oligo-anovulatory infertile patients in whom the cause of infertility is functional and not caused by primary ovarian failure
Spermatogenesis induction (Gonal-f only): 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 (ovarian or testicular); sex hormone dependent tumors of the reproductive tract and accessory organs; intracranial lesions (eg, pituitary or hypothalamus tumor); uncontrolled thyroid, pituitary or adrenal dysfunction; abnormal uterine bleeding of undetermined origin; ovarian cysts or enlargement of undetermined origin not due to polycystic ovary syndrome; pregnancy
Canadian labeling: Additional contraindications (not in US labeling): Presence of any cause for infertility other than anovulation (unless candidate for ART); lactation
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.
Ovulation induction: Females: SubQ: Initial: 75 units daily; incremental dose adjustments of up to 37.5 units may be considered after 14 days; further dose increases of the same magnitude can be made, if necessary, every 7 days (maximum dose: 300 units daily). Treatment should be continued until follicular growth and/or serum estradiol levels indicate an adequate ovarian response. If response to follitropin is appropriate, hCG is given 1 day following the last dose to induce final oocyte maturation and ovulation. Withhold hCG if serum estradiol is >2000 pg/mL; discontinue if the ovaries are abnormally enlarged, or if abdominal pain occurs. In general, therapy should not exceed 35 days.
Multifollicular development during ART: Females: SubQ: Initiate therapy with follitropin alfa in the early follicular phase (cycle day 2 or day 3) at a dose of 150 units daily, until sufficient follicular development is attained. In most cases, therapy should not exceed 10 days. In patients ≥35 years whose endogenous gonadotropin levels are suppressed, initiate follitropin alfa at a dose of 225 units daily. Continue treatment until adequate follicular development is indicated as determined by ultrasound in combination with measurement of serum estradiol levels. Consider adjustments to dose after 5 days based on the patient's response; adjust subsequent dosage every 3-5 days by ≤75-150 units additionally at each adjustment. Doses >450 units daily are not recommended. Once adequate follicular development is evident, administer hCG to induce final follicular maturation in preparation for oocyte retrieval. Withhold hCG if the ovaries are abnormally enlarged.
Spermatogenesis induction: Males: Gonal-f: SubQ: Therapy should begin with hCG pretreatment until serum testosterone is in normal range, then initiate Gonal-f at 150 units 3 times weekly with hCG 3 times weekly; continue with lowest dose needed to induce spermatogenesis (maximum dose: 300 units 3 times weekly); may be given for up to 18 months
Dosing: Geriatric
Refer to adult dosing. Clinical studies did not include patients >65 years.
Reconstitution
Gonal-f: Dissolve the contents of vial by slowly injecting provided diluent; do not shake. If bubbles appear, allow to settle prior to use. Final concentration: 600 units/mL.
Gonal-f RFF: Powder: Dissolve contents of one or more vials using diluent provided in prefilled syringe. Total concentration should not exceed 450 units/mL. Slowly inject diluent into vial, and gently rotate vial until powder is dissolved; do not shake vial. If bubbles appear, allow to settle prior to use. Use immediately after reconstitution.
Gonal-f RFF Rediject: Allow to warm to room temperature prior to use. Do not attempt to mix any other medications inside of the device.
Administration
SubQ: Administer SubQ. Contents of multidose vials (Gonal-f or Gonal-f RFF) should be administered using the calibrated syringes provided by the manufacturer. Do not shake solution; allow any bubbles to settle prior to administration. Allow Gonal-f RFF Rediject to warm to room temperature for at least 30 minutes prior to administration to avoid discomfort from cold injection. Do not mix other medications inside of the Gonal-f RFF Rediject device.
Storage
Gonal-f: Store powder refrigerated or at room temperature of 2°C to 25°C (36°F to 77°F). Protect from light; do not freeze. Following reconstitution, multidose vials may be stored under refrigeration or at room temperature for up to 28 days.
Gonal-f RFF:
Powder: Store at room temperature or under refrigeration of 2°C to 25°C (36°F to 77°F). Protect from light. Discard unused drug.
Rediject: Prior to dispensing, store under refrigeration at 2°C to 8°C (36°F to 46°F). Upon dispensing, patient may store under refrigeration until product expiration date or at room temperature of 20°C to 25°C (68°F to 77°F) for up to 3 months. Do not freeze. Protect from light. After first use, store pen in the refrigerator (2°C to 8°C [36°C to 46°F]) or at room temperature (20°C to 25°C [68°F to 77°F]); discard unused portion after 28 days.
Drug Interactions
There are no known significant interactions.
Adverse Reactions
Percentage may vary by indication, product formulation
>10%:
Cardiovascular: Varicocele (15%)
Central nervous system: Headache (13% to 27%)
Dermatologic: Acne vulgaris (males 59%)
Endocrine & metabolic: Ovarian cyst (4% to 15%)
Gastrointestinal: Abdominal pain (9% to 23%), nausea (4% to 14%), enlargement of abdomen (1% to 14%)
Genitourinary: Mastalgia (males 14%)
Local: Injection site reaction (males 15%; females 1% to 4%)
Respiratory: Upper respiratory tract infection (4% to 12%)
1% to 10%:
Cardiovascular: Chest pain (1% to 2%), hypotension (1% to 2%), palpitations (1% to 2%)
Central nervous system: Fatigue (males 9%; females 1% to 2%), pain (2% to 6%), emotional lability (5%), migraine (1% to 4%), dizziness (1% to 3%), malaise (2%), anxiety (1% to 2%), drowsiness (1% to 2%), nervousness (1% to 2%), paresthesia (1% to 2%)
Dermatologic: Acne vulgaris (females 4%), pruritus (1% to 2%)
Endocrine & metabolic: Gynecomastia (9%), intermenstrual bleeding (4% to 9%), ovarian hyperstimulation syndrome (5% to 7%; severe: <1%), weight gain (4%), menstrual disease (3%), hot flash (2%), ovarian disease (2%), increased thirst (1% to 2%)
Gastrointestinal: Diarrhea (1% to 8%), flatulence (4% to 7%), toothache (1% to 4%), vomiting (1% to 3%), aphthous stomatitis (2%), constipation (2%), dyspepsia (2%), anorexia (1% to 2%)
Genitourinary: Pelvic pain (7%), mastalgia (females 4% to 6%), vaginal hemorrhage (1% to 6%), cervical lesion (3%), genital candidiasis (3%), dysmenorrhea (1% to 3%), cystitis (2%), gynecological pain (2%), urinary frequency (2%), urinary tract infection (2%), uterine hemorrhage (2%), leukorrhea (1% to 2%)
Infection: Viral infection (2%)
Local: Bruising at injection site (10%), pain at injection site (3% to 9%), inflammation at injection site (1% to 4%), swelling at injection site (3%)
Neuromuscular & skeletal: Back pain (4% to 5%), myalgia (1% to 2%)
Respiratory: Rhinitis (≤7%), pharyngitis (3% to 7%), sinusitis (5% to 6%), flu-like symptoms (4%), cough (2% to 3%), asthma (1% to 2%), dyspnea (1% to 2%)
Miscellaneous: Fever (2% to 4%)
Postmarketing and/or case reports: Anaphylactoid reaction, anaphylaxis, depression, Epstein-Barr infection, hemoperitoneum, hemoptysis, hypersensitivity reaction, ovarian torsion, ovarian neoplasm, ovary enlargement, pulmonary complications (including atelectasis, acute respiratory distress syndrome, exacerbation of asthma), thromboembolism, vascular disease
Warnings/Precautions
Concerns related to adverse effects:
- Abortion: Risk of spontaneous abortion is increased with the use of gonadotropins; causal effect has not been established.
- Ectopic pregnancy: Risk for ectopic pregnancy may be increased in women with tubal abnormalities; intrauterine pregnancy should be confirmed early with hCG testing and transvaginal ultrasound.
- Hypersensitivity: Serious hypersensitivity reactions including anaphylaxis have been reported; discontinue use for serious reactions and treat appropriately.
- Ovarian enlargement: May be accompanied by abdominal distention or abdominal pain, occurs in ~20% of those treated with urofollitropin and hCG, and generally regresses without treatment within 2 to 3 weeks. 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 is a rare exaggerated response to ovulation induction therapy (Corbett 2014; Fiedler 2012). This syndrome may begin within 24 hours of treatment but may become most severe 7 to 10 days after therapy (Corbett 2014). Symptoms of mild/moderate OHSS may include abdominal distention/discomfort, diarrhea, nausea, and/or vomiting. Severe OHSS symptoms may include severe abdominal pain, anuria/oliguria, ascites, severe dyspnea, hypotension, or nausea/vomiting (intractable). Decreased creatinine clearance, 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; SOGC-CFAS 2011). Therapy with gonadotropins should be stopped.
- Ovarian neoplasms: Benign and malignant neoplasms have been reported (infrequently) in women receiving multiple-drug therapy for controlled ovarian stimulation; causal effect has not been established.
- Ovarian torsion: Has been reported following gonadotropin treatment; may be related to OHSS, prior ovarian torsion, prior or current ovarian cyst, polycystic ovaries, pregnancy, or prior abdominal surgery. Early diagnosis and prompt detorsion may limit the extent of ovarian damage.
- 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 (OHSS), 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).
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
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 or by sonographic evidence. The indices of progesterone production most generally used are: urinary or serum luteinizing hormone (LH) rise, rise in basal body temperature, increase in serum progesterone, and menstruation following the shift in basal body temperature. The indices of sonographic evidence of ovulation include: Collapsed follicle, fluid in the cul-de-sac, features consistent with corpus luteum formation, or secretory endometrium.
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) (SOGC-CFAS 2011).
Spermatogenesis: Monitor serum testosterone levels, sperm count
Pregnancy
Pregnancy Considerations
Ectopic pregnancy, congenital abnormalities, spontaneous abortion, 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 Alfa 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 injection site irritation, nausea, acne, headache, abdominal pain, passing gas, diarrhea, loss of strength and energy, back pain, common cold symptoms, stuffy nose, or sore throat. 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 amount of urine 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; chest pain; shortness of breath; fast heartbeat; or coughing up blood), mood changes, abdominal edema, breast pain, enlarged breasts (males), abnormal heartbeat, skin discoloration, pale skin, abnormal vaginal bleeding, or vaginal pain, itching, and discharge (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.
