INDICATIONS AND USAGE Women Gonal-f® (follitropin alfa for injection) is indicated for the induction of ovulation and pregnancy in the anovulatory infertile patient in whom the cause of infertility is functional and not due to primary ovarian failure. Gonal-f® 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® 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® 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® therapy. Evaluation of the partner's fertility potential should be included in the initial evaluation. Men Gonal-f® (follitropin alfa for injection) is indicated for the induction of spermatogenesis in men with primary and secondary hypogonadotropic hypogonadism in whom the cause of infertility is not due to primary testicular failure. Selection of Patients Before treatment with Gonal-f® is instituted for azoospermia, a thorough medical and endocrinologic evaluation must be performed. Hypogonadotropic hypogonadism should be confirmed, and primary testicular failure should be excluded by the determination of gonadotropin levels. Prior to Gonal-f® therapy for azoospermia in patients with hypogonadotropic hypogonadism, serum testosterone levels should be normalized.
CONTRAINDICATIONS Gonal-f® (follitropin alfa for injection) is contraindicated in women and men 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. And in women who exhibit: Abnormal uterine bleeding of undetermined origin (see "Selection of Patients"). Ovarian cyst or enlargement of undetermined origin (see "Selection of Patients"). Pregnancy.
ADVERSE REACTIONS Women The safety of Gonal-f® was examined in four clinical studies that enrolled 691 patients into two studies for ovulation induction (454 patients) and two studies for ART (237 patients). Adverse events occurring in more than 10% of patients were headache, ovarian cyst, nausea, and upper respiratory tract infection in the U.S. ovulation induction study and headache in the U.S. ART study. Adverse events (without regard to causality assessment) occurring in at least 2% of patients are listed in Table 13 and Table 14. Table 13: US Controlled Trial in Ovulation Induction, Study 5727 Body System Preferred Term Gonal-f® Patients (%) Experiencing Events Treatment cycles = 288up to 3 cycles of therapy n=118 Urofollitropin Patients (%) Experiencing Events Treatment cycles = 277 n= 114 Reproductive, Female Intermenstrual Bleeding 9.3% 4.4% Breast Pain Female 4.2% 6.1% Ovarian HyperstimulationSevere = 0.8% of 118 patients in Study 5727 6.8% 3.5% Dysmenorrhea 2.5% 6.1% Ovarian Disorder 1.7% 2.6% Cervix Lesion 2.5% 0.9% Menstrual Disorder 2.5% 0.9% Gastro-intestinal System Abdominal Pain 9.3% 12.3% Nausea 13.6% 3.5% Flatulence 6.8% 8.8% Diarrhea 7.6% 3.5% Vomiting 2.5% 2.6% Dyspepsia 1.7% 3.5% Central and Peripheral Nervous System Headache 22.0% 20.2% Dizziness 2.5% 0.0% Neoplasm Ovarian Cyst 15.3% 28.9% Body as a Whole- General Pain 5.9% 6.1% Back Pain 5.1% 1.8% Influenza-like Symptoms 4.2% 2.6% Fever 4.2% 1.8% Respiratory System Upper Respiratory Tract Infection 11.9% 7.9% Sinusitis 5.1% 5.3% Pharyngitis 2.5% 3.5% Coughing 1.7% 2.6% Rhinitis 0.8% 2.6% Skin and Appendages Acne 4.2% 2.6% Psychiatric Emotional Lability 5.1% 2.6% Urinary System Urinary Tract Infection 1.7% 4.4% Resistance Mechanism Moniliasis Genital 2.5% 0.9% Application Site Injection Site Pain 2.5% 0.9% Additional adverse events not listed in Table 13 that occurred in 1 to 2% of Gonal-f® treated patients in the US ovulation induction study included the following: leukorrhea, vaginal hemorrhage, migraine, fatigue, asthma, nervousness, somnolence, and hypotension. Table 14: US Controlled Trial in ART, Study 5533 Body System Preferred Term Gonal-f® Patients (%) Experiencing Events n=59 Urofollitropin Patients (%) Experiencing Events n= 61 Reproductive, Female Intermenstrual Bleeding 3.6% 5.2% Leukorrhea 1.7% 3.4% Vaginal Hemorrhage 3.6% 3.4% Gastro-intestinal System Nausea 5.4% 1.7% Flatulence 3.6% 0.0% Central and Peripheral Nervous System Headache 12.5% 3.4% Body as a Whole- General Abdominal Pain 8.9% 3.4% Pelvic Pain Female 7.1% 1.7% Respiratory System Upper Respiratory Tract Infection 3.6% 1.7% Metabolic and Nutritional Weight Increase 3.6% 0.0% Additional adverse events not listed in Table 14 that occurred in 1 to 2% of Gonal-f® treated patients in the U.S. Assisted Reproductive Technology (ART) study included the following: D&C following delivery or abortion, dysmenorrhea, vaginal hemorrhage, diarrhea, tooth disorder, vomiting, dizziness, paraesthesia, abdomen enlarged, chest pain, fatigue, dyspnea, anorexia, anxiety, somnolence, injection site inflammation, injection site reaction, pruritus, pruritus genital, myalgia, thirst, and palpitation. Two additional clinical studies (for ovulation induction and ART, respectively) were conducted in Europe. The safety profiles from these two studies were comparable to that of the data presented above. Gonal-f® Multi-Dose was examined in twenty-five healthy volunteers who received 300 IU each of Gonal-f® from single- dose ampules and multi-dose vials. Overall, both presentations were well tolerated and local tolerability between the two groups was comparable. Injection site inspections revealed very rare local reactions (mild redness in one patient after single-dose injection and mild bruising in two subjects after multi-dose injection). Subjective assessments indicated minimal or mild transient pain in two and five subjects who received Gonal-f® single-dose and Gonal-f® multi-dose, respectively. 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 Two incidents of congenital cardiac malformations have been reported in children born following pregnancies resulting from treatment with Gonal-f® and hCG in Gonal-f® clinical studies 5642 and 5727. In addition, a pregnancy occurring in study 5533 following treatment with Gonal-f® and hCG was complicated by apparent failure of intrauterine growth and terminated for a suspected syndrome of congenital abnormalities. No specific diagnosis was made. The incidence does not exceed that found in the general population. The following adverse reactions have been previously reported during menotropin 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. Men The safety of Gonal-f® was examined in 3 clinical studies that enrolled 72 patients for induction of spermatogenesis and fertility of whom 56 patients received Gonal-f®. One hundred and twenty-three adverse events, including 7 serious events, were reported in 34 of the 56 patients during Gonal-f® treatment. In Study 5844, 21 adverse events, including 4 serious adverse events, were reported by 14 of the 26 patients (53.8%) treated with Gonal-f®. Events occurring in more than one patient were varicocele (4) and injection site reactions (4). The 4 serious adverse events were testicular surgery for cryptorchidism, which existed prestudy, hemoptysis, an infected pilonidal cyst, and lymphadenopathy associated with an Epstein-Barr viral infection. In Study 6410, 3 adverse events were reported in 2 of the 8 patients (24%) treated with Gonal-f®. One serious adverse event was reported, surgery for gynecomastia which existed at baseline. In the interim analysis of Study 6793, 18 of 22 patients (81.8%) reported a total of 99 adverse events during Gonal-f® treatment. The most common events of possible, probable, or definite relationship to study drug therapy occurring in more than 2 patients were: acne (25 events in 13 patients; 59% of patients); breast pain (4 events in 3 patients; 13.6% of patients); and fatigue, gynecomastia, and injection site pain (each of which was reported as 2 events by 2 patients; 9.1% of patients). Two serious adverse events (hospitalization for drug abuse and depression) were reported by a single patient in the interim analysis. A total of 12,026 injections of Gonal-f® were administered by the 56 patients who received Gonal-f® in Studies 5844, 6410, and 6793 combined. The injections were well-tolerated, with no or mild reactions (redness, swelling, bruising and itching) reported by patients for 93.3% of injections. Moderate and severe reactions, consisting primarily of pain, were reported for 4.8% of injections, and no self-assessment was available for 1.9% of injections. Postmarketing Experience In addition to adverse events reported from clinical trials, the following events have been reported during postmarketing use of Gonal-f®. Because these reactions were reported voluntarily from a population of uncertain size, the frequency or a causal relationship to Gonal-f®, can not be reliably determined. Body as a Whole - General: Hypersensitivity reactions including anaphylactoid reactions. Respiratory System: asthma
Drug-Drug Interactions No drug-drug interaction studies have been conducted (see PRECAUTIONS).