Data from FDA - Curated by EPG Health - Last updated 15 June 2018

Indication(s)

INDICATIONS AND USAGE Gonal-f® RFF (follitropin alfa for injection) is indicated for the induction of ovulation and pregnancy in the oligo-anovulatory infertile patient in whom the cause of infertility is functional and not due to primary ovarian failure. Gonal-f® RFF is also indicated for the development of multiple follicles in the ovulatory patient participating in an Assisted Reproductive Technology (ART) program. Selection of Patients Before treatment with Gonal-f® RFF is instituted, a thorough gynecologic and endocrinologic evaluation must be performed. This should include an assessment of pelvic anatomy. Patients with tubal obstruction should receive Gonal-f® RFF only if enrolled in an in vitro fertilization program. Primary ovarian failure should be excluded by the determination of gonadotropin levels. Appropriate evaluation should be performed to exclude pregnancy. Patients in later reproductive life have a greater predisposition to endometrial carcinoma as well as a higher incidence of anovulatory disorders. A thorough diagnostic evaluation should always be performed in patients who demonstrate abnormal uterine bleeding or other signs of endometrial abnormalities before starting Gonal-f® RFF therapy. Evaluation of the partner's fertility potential should be included in the initial evaluation.

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Advisory information

contraindications
CONTRAINDICATIONS Gonal-f® RFF (follitropin alfa for injection) is contraindicated in women who exhibit: Prior hypersensitivity to recombinant FSH preparations or one of their excipients. High levels of FSH indicating primary gonadal failure. Uncontrolled thyroid or adrenal dysfunction. Sex hormone dependent tumors of the reproductive tract and accessory organs. An organic intracranial lesion such as a pituitary tumor. Abnormal uterine bleeding of undetermined origin (see "Selection of Patients"). Ovarian cyst or enlargement of undetermined origin (see "Selection of Patients"). Pregnancy.
Special warnings and precautions
PRECAUTIONS General Careful attention should be given to the diagnosis of infertility in candidates for Gonal-f® RFF (follitropin alfa for injection) therapy (see "Indications and Usage/ Selection of Patients"). Information for Patients Prior to therapy with Gonal-f® RFF, patients should be informed of the duration of treatment and monitoring of their condition that will be required. The risks of ovarian hyperstimulation syndrome and multiple births in women (see WARNINGS ) and other possible adverse reactions (see " Adverse Reactions ") should also be discussed. See DOSAGE AND ADMINISTRATION for "PATIENT INSTRUCTIONS FOR USE OF GONAL-F® RFF". Laboratory Tests In most instances, treatment of women with Gonal-f® RFF results only in follicular recruitment and development. In the absence of an endogenous LH surge, hCG is given when monitoring of the patient indicates that sufficient follicular development has occurred. This may be estimated by ultrasound alone or in combination with measurement of serum estradiol levels. The combination of both ultrasound and serum estradiol measurement are useful for monitoring the development of follicles, for timing of the ovulatory trigger, as well as for detecting ovarian enlargement and minimizing the risk of the Ovarian Hyperstimulation Syndrome and multiple gestation. It is recommended that the number of growing follicles be confirmed using ultrasonography because plasma estrogens do not give an indication of the size or number of follicles. The clinical confirmation of ovulation, with the exception of pregnancy, is obtained by direct and indirect indices of progesterone production. The indices most generally used are as follows: A rise in basal body temperature; Increase in serum progesterone; and Menstruation following a shift in basal body temperature. When used in conjunction with the indices of progesterone production, sonographic visualization of the ovaries will assist in determining if ovulation has occurred. Sonographic evidence of ovulation may include the following: Fluid in the cul-de-sac; Ovarian stigmata; Collapsed follicle; and Secretory endometrium. Accurate interpretation of the indices of follicle development and maturation require a physician who is experienced in the interpretation of these tests. Drug Interactions No drug/drug interaction studies have been performed. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Gonal-f® RFF. However, follitropin alfa showed no mutagenic activity in a series of tests performed to evaluate its potential genetic toxicity including, bacterial and mammalian cell mutation tests, a chromosomal aberration test and a micronucleus test. Impaired fertility has been reported in rats, exposed to pharmacological doses of follitropin alfa (≥40 IU/kg/day) for extended periods, through reduced fecundity. Pregnancy See CONTRAINDICATIONS . Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in the nursing infant from Gonal-f® RFF, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established.
Adverse reactions
ADVERSE REACTIONS The safety of Gonal-f® RFF was examined in two clinical studies [one ovulation induction study (n=83) and one study in ART (n=237)]. Adverse events (without regard to causality assessment) occurring in at least 2.0% of patients in Study 22240 (ovulation induction) are listed in Table 4. Table 4: Safety Profile in Ovulation Induction Study 22240 Body System Preferred Term Gonal-f® RFF Patients (%) Experiencing Events Treatment cycles=176up to 3 cycles of therapy n=83total patients treated with Gonal-f® RFF Central and Peripheral Nervous System Headache 22 (26.5%) Dizziness 2 (2.4%) Migraine 3 (3.6%) Gastro-intestinal System Abdominal Pain 10 (12.0%) Nausea 3 (3.6%) Flatulence 3 (3.6%) Diarrhea 3 (3.6%) Toothache 3 (3.6%) Dyspepsia 2 (2.4%) Constipation 2 (2.4%) Stomatitis Ulcerative 2 (2.4%) Neoplasm Ovarian Cyst 3 (3.6%) Reproductive, Female Ovarian Hyperstimulation 6 (7.2%) Breast Pain Female 5 (6.0%) Vaginal Haemorrhage 5 (6.0%) Gynecological-related pain 2 (2.4%) Uterine haemorrhage 2 (2.4%) Respiratory System Sinusitis 5 (6.0%) Pharyngitis 6 (7.2%) Rhinitis 6 (7.2%) Coughing 2 (2.4%) Application Site Injection Site Pain 4 (4.8%) Injection Site Inflammation 2 (2.4%) Body as a Whole- General Back Pain 3 (3.6%) Pain 2 (2.4%) Fever 2 (2.4%) Hot Flushes 2 (2.4%) Malaise 2 (2.4%) Skin and Appendages Acne 3 (3.6%) Urinary System Micturition Frequency 2 (2.4%) Cystitis 2 (2.4%) Resistance Mechanism Infection viral 2 (2.4%) Headache occurred in greater than 20% of patients receiving Gonal-f® RFF in this study. Adverse events (without regard to causality assessment) occurring in at least 2.0% of patients in Study 21884 (ART) are listed in Table 5. Table 5: Safety Profile in Assisted Reproductive Technologies Study 21884 Body System Preferred Term Gonal-f® RFF Patients (%) Experiencing Events n=237total patients treated with Gonal-f® RFF Gastro-intestinal System Abdominal Pain 55 (23.2%) Nausea 19 (8.0%) Body as a Whole- General Abdomen Enlarged 33 (13.9%) Pain 7 (3.0%) Central and Peripheral Nervous System Headache 44 (18.6%) Dizziness 5 (2.1)% Application Site Disorders Injection site bruising 23 (9.7%) Injection site pain 13 (5.5%) Injection site inflammation 10 (4.2%) Injection site reaction 10 (4.2)% Application site edema 6 (2.5)% Reproductive, Female Ovarian Hyperstimulation 11 (4.6%) Intermenstrual Bleeding 9 (3.8%) Headache and abdomen enlargement occurred in more than 10% of patients and abdominal pain occurred in more than 20% of patients. The following medical events have been reported subsequent to pregnancies resulting from Gonadotropins in controlled clinical studies: Spontaneous Abortion Ectopic Pregnancy Premature Labor Postpartum Fever Congenital Abnormalities There are no indications that use of gonadotropins during ART is associated with an increased risk of congenital malformations. The following adverse reactions have been previously reported during Gonal-f® RFF therapy: Pulmonary and vascular complications (see WARNINGS ), Adnexal torsion (as a complication of ovarian enlargement), Mild to moderate ovarian enlargement, Hemoperitoneum There have been infrequent reports of ovarian neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for ovulation induction; however, a causal relationship has not been established. Postmarketing Experience In addition to adverse events reported from clinical trials, the following events have been reported during postmarketing use of Gonal-f® RFF. Because these reactions were reported voluntarily from a population of uncertain size, the frequency or a causal relationship to Gonal-f® RFF can not be reliably determined. Body as a Whole - General: hypersensitivity reactions including anaphylactoid reactions Respiratory System: asthma (see WARNINGS, Pulmonary and Vascular Complications ) Vascular disorders: thromboembolism (see WARNINGS, Pulmonary and Vascular Complications )

Usage information

Dosing and administration
DOSAGE AND ADMINISTRATION Each Gonal-f® RFF single-dose vial delivers 75 IU follitropin alfa. Dosage Infertile Patients with oligo-anovulation The dose of Gonal-f® RFF (follitropin alfa for injection) to stimulate development of the follicle must be individualized for each patient. The lowest dose consistent with the expectation of good results should be used. Over the course of treatment, doses of Gonal-f® RFF may range up to 300 IU per day depending on the individual patient response. Gonal-f® RFF should be administered until adequate follicular development is indicated by serum estradiol and vaginal ultrasonography. A response is generally evident after 5 to 7 days. Subsequent monitoring intervals should be based on individual patient response. It is recommended that the initial dose of the first cycle be 75 IU of Gonal-f® RFF per day, ADMINISTERED SUBCUTANEOUSLY. An incremental adjustment in dose of up to 37.5 IU may be considered after 14 days. Further dose increases of the same magnitude could be made, if necessary, every seven days. Treatment duration should not exceed 35 days unless an E2 rise indicates imminent follicular development. To complete follicular development and effect ovulation in the absence of an endogenous LH surge, chorionic gonadotropin, hCG, should be given after the last dose of Gonal-f® RFF. Chorionic gonadotropin should be withheld if the serum estradiol is greater than 2,000 pg/mL. If the ovaries are abnormally enlarged or abdominal pain occurs, Gonal-f® RFF treatment should be discontinued, hCG should not be administered, and the patient should be advised not to have intercourse; this may reduce the chance of development of the Ovarian Hyperstimulation Syndrome and, should spontaneous ovulation occur, reduce the chance of multiple gestation. A follow-up visit should be conducted in the luteal phase. The initial dose administered in the subsequent cycles should be individualized for each patient based on her response in the preceding cycle. Doses larger than 300 IU of FSH per day are not routinely recommended. As in the initial cycle, hCG must be given after the last dose of Gonal-f® RFF to complete follicular development and induce ovulation. The precautions described above should be followed to minimize the chance of development of the Ovarian Hyperstimulation Syndrome. The couple should be encouraged to have intercourse daily, beginning on the day prior to the administration of hCG until ovulation becomes apparent from the indices employed for the determination of progestational activity. Care should be taken to ensure insemination. In light of the indices and parameters mentioned, it should become obvious that, unless a physician is willing to devote considerable time to these patients and be familiar with and conduct the necessary laboratory studies, he/she should not use Gonal-f® RFF. Assisted Reproductive Technologies As in the treatment of patients with oligo-anovulatory infertility, the dose of Gonal-f® RFF to stimulate development of the follicle must be individualized for each patient. For Assisted Reproductive Technologies, therapy with Gonal-f® RFF should be initiated in the early follicular phase (cycle day 2 or 3) at a dose of 150 IU per day, until sufficient follicular development is attained. In most cases, therapy should not exceed ten days. In patients undergoing ART under 35 years old, whose endogenous gonadotropin levels are suppressed, Gonal-f® RFF should be initiated at a dose of 150 IU per day. In patients 35 years old and older whose endogenous gonadotropin levels are suppressed, Gonal-f® RFF should be initiated at a dose of 225 IU per day. Treatment should be continued until adequate follicular development is indicated as determined by ultrasound in combination with measurement of serum estradiol levels. Adjustments to dose may be considered after five days based on the patient's response; subsequently dosage should be adjusted no more frequently than every 3-5 days and by no more than 75-150 IU additionally at each adjustment. Doses greater than 450 IU per day are not recommended. Once adequate follicular development is evident, hCG should be administered to induce final follicular maturation in preparation for oocyte retrieval. The administration of hCG must be withheld in cases where the ovaries are abnormally enlarged on the last day of therapy. This should reduce the chance of developing OHSS. Administration Dissolve the contents of one or more single-dose vials of Gonal-f® RFF in 1.0 mL of Sterile Water for Injection, USP (concentration should not exceed 450 IU/mL) and ADMINISTER SUBCUTANEOUSLY immediately. Any unused reconstituted material should be discarded.
Pregnancy and lactation
Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in the nursing infant from Gonal-f® RFF, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Interactions

Drug Interactions No drug/drug interaction studies have been performed.

More information

Category Value
Authorisation number NDA021765
Orphan designation No
Product NDC 44087-9005
Date Last Revised 23-05-2018
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder EMD Serono, Inc.