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warnings
WARNINGS Gonal-f ® RFF Pen (follitropin alfa injection) should only be used by physicians who are thoroughly familiar with infertility problems and their management. Gonal-f ® RFF Pen is a potent gonadotropic substance capable of causing Ovarian Hyperstimulation Syndrome (OHSS) in women with or without pulmonary or vascular complications. Gonadotropin therapy requires a certain time commitment by physicians and supportive health professionals, and requires the availability of appropriate monitoring facilities (see " Precautions/Laboratory Tests "). Safe and effective use of Gonal-f ® RFF Pen in women requires monitoring of ovarian response with serum estradiol and vaginal ultrasound on a regular basis. The lowest effective dose should be used. Overstimulation of the Ovary During FSH Therapy Ovarian Enlargement Mild to moderate uncomplicated ovarian enlargement which may be accompanied by abdominal distention and/or abdominal pain occurs in approximately 20% of those treated with urofollitropin and hCG, and generally regresses without treatment within two or three weeks. Careful monitoring of ovarian response can further minimize the risk of overstimulation. If the ovaries are abnormally enlarged on the last day of Gonal-f ® RFF Pen therapy, hCG should not be administered in this course of therapy. This will reduce the chances of development of Ovarian Hyperstimulation Syndrome. Ovarian Hyperstimulation Syndrome (OHSS) OHSS is a medical event distinct from uncomplicated ovarian enlargement. Severe OHSS may progress rapidly (within 24 hours to several days) to become a serious medical event. It is characterized by an apparent dramatic increase in vascular permeability which can result in a rapid accumulation of fluid in the peritoneal cavity, thorax, and potentially, the pericardium. The early warning signs of development of OHSS are severe pelvic pain, nausea, vomiting, and weight gain. The following symptomatology has been seen with cases of OHSS: abdominal pain, abdominal distension, gastrointestinal symptoms including nausea, vomiting and diarrhea, severe ovarian enlargement, weight gain, dyspnea, and oliguria. Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic events (see " Pulmonary and Vascular Complications "). Transient liver function test abnormalities suggestive of hepatic dysfunction, which may be accompanied by morphologic changes on liver biopsy, have been reported in association with Ovarian Hyperstimulation Syndrome (OHSS). OHSS occurred in 6 of 83 (7.2%) Gonal-f ® RFF treated women in Study 22240 (ovulation induction); none were classified as severe. In Study 21884 (ART), OHSS occurred in 11 of 237 (4.6%) Gonal-f ® RFF treated women and 1 (0.42%) was classified as severe. OHSS may be more severe and more protracted if pregnancy occurs. OHSS develops rapidly; therefore, patients should be followed for at least two weeks after hCG administration. Most often, OHSS occurs after treatment has been discontinued and reaches its maximum at about seven to ten days following treatment. Usually, OHSS resolves spontaneously with the onset of menses. If there is evidence that OHSS may be developing prior to hCG administration (see " Precautions / Laboratory Tests "), the hCG must be withheld. If severe OHSS occurs, treatment must be stopped and the patient should be hospitalized. A physician experienced in the management of this syndrome, or who is experienced in the management of fluid and electrolyte imbalances should be consulted. Pulmonary and Vascular Complications Serious pulmonary conditions (e.g., atelectasis, acute respiratory distress syndrome and exacerbation of asthma) have been reported. In addition, thromboembolic events both in association with, and separate from Ovarian Hyperstimulation Syndrome have been reported. Intravascular thrombosis and embolism can result in reduced blood flow to critical organs or the extremities. Sequelae of such events have included venous thrombophlebitis, pulmonary embolism, pulmonary infarction, cerebral vascular occlusion (stroke), and arterial occlusion resulting in loss of limb. In rare cases, pulmonary complications and/or thromboembolic events have resulted in death. Multiple Births Reports of multiple births have been associated with Gonal-f ® RFF treatment. In Study 22240 for women receiving Gonal-f ® RFF over three treatment cycles, 20% of live births were multiple births. In Study 21884, 35.1% of live births were multiple births in women receiving Gonal-f ® RFF. The rate of multiple births is dependent on the number of embryos transferred. The patient should be advised of the potential risk of multiple births before starting treatment.
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 Patients (%) Experiencing Events Treatment cycles = 176 up to 3 cycles of therapy Preferred Term n=83 total 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 Patients (%) Experiencing Events Preferred Term n=237 total 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 therapy 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 Pen. Because these reactions were reported voluntarily from a population of uncertain size, the frequency or a causal relationship to Gonal-f ® RFF Pen, can not be reliably determined. Body as a Whole - General: Hypersensitivity reactions including anaphylactoid reactions. Respiratory System: asthma