warnings and cautions
5 WARNINGS AND PRECAUTIONS BRAVELLE ® should only be used by physicians who are experienced in infertility treatment. BRAVELLE ® contains gonadotropic substances capable of causing in women, Ovarian Hyperstimulation Syndrome [OHSS] with or without pulmonary or vascular complications [see Warnings and Precautions (5.3 , 5.4) ] and multiple births [see Warnings and Precautions (5.6) ] . Gonadotropin therapy requires the availability of appropriate monitoring facilities [see Warnings and Precautions (5.11) ] . Use the lowest effective dose. Abnormal Ovarian Enlargement ( 5.2 ) Ovarian Hyperstimulation Syndrome ( 5.3 ) Pulmonary and Vascular Complications ( 5.4 ) Ovarian Torsion ( 5.5 ) Multi-fetal Gestation and Birth ( 5.6 ) Congenital Malformations ( 5.7 ) Ectopic Pregnancy ( 5.8 ) Spontaneous Abortion ( 5.9 ) Ovarian Neoplasms ( 5.10 ) 5.1 Hypersensitivity and Anaphylactic Reactions Hypersensitivity/anaphylactic reactions associated with urofollitropins for injection, purified administration have been reported in some patients. These reactions presented as generalized urticaria, facial edema, angioneurotic edema, and/or dyspnea suggestive of laryngeal edema. The relationship of these symptoms to uncharacterized urinary proteins is uncertain. 5.2 Abnormal Ovarian Enlargement In order to minimize the hazard associated with abnormal ovarian enlargement that may occur with BRAVELLE ® therapy, the lowest effective dose should be used [see Dosage and Administration (2.2 , 2.3) ]. Use of ultrasound monitoring of ovarian response and/or measurement of serum estradiol levels is important to minimize the risk of ovarian stimulation [see Warnings and Precautions (5.11) ] . If the ovaries are abnormally enlarged on the last day of BRAVELLE ® therapy, hCG should not be administered in order to reduce the chances of development of the Ovarian Hyperstimulation Syndrome [see Warnings and Precautions (5.3) ] . Prohibit intercourse in women with significant ovarian enlargement because of the danger of hemoperitoneum resulting from rupture of ovarian cysts [see Warnings and Precautions (5.3) ] . 5.3 Ovarian Hyperstimulation Syndrome (OHSS) OHSS: OHSS is a medical event distinct from uncomplicated ovarian enlargement. OHSS may progress rapidly 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. Abdominal pain, abdominal distension, gastrointestinal symptoms including nausea, vomiting and diarrhea, severe ovarian enlargement, weight gain, dyspnea, and oliguria have been reported with OHSS. Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic events [see Warnings and Precautions (5.4) ]. 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 OHSS. OHSS occurs after treatment has been discontinued and reaches its maximum at about 7 to 10 days after treatment. Usually, OHSS resolves spontaneously with the onset of menses. If there is evidence that OHSS may be developing prior to hCG administration [see Warnings and Precautions (5.2) ] , the hCG must be withheld. Cases of OHSS are more common, more severe and more protracted if pregnancy occurs. OHSS develops rapidly; therefore patients should be followed for at least two weeks after hCG administration. If severe OHSS occurs, gonadotropins, including hCG, must be stopped and consideration should be given as to whether the woman needs be hospitalized. Treatment is primarily symptomatic and overall should consist of bed rest, fluid and electrolyte management, and analgesics (if needed). Because the use of diuretics can accentuate the diminished intravascular volume, diuretics should be avoided except in the late phase of resolution as described below. The management of OHSS may be divided into three phases as follows: Acute Phase: Management should be directed at preventing hemoconcentration due to loss of intravascular volume to the third space and minimizing the risk of thromboembolic phenomena and kidney damage. Fluid intake and output, weight, hematocrit, serum and urinary electrolytes, urine specific gravity, BUN and creatinine, total proteins with albumin: globulin ratio, coagulation studies, electrocardiogram to monitor for hyperkalemia, and abdominal girth should be thoroughly assessed daily or more often based on the clinical need. Treatment, consisting of limited intravenous fluids, electrolytes, human serum albumin, is intended to normalize electrolytes while maintaining an acceptable but somewhat reduced intravascular volume. Full correction of the intravascular volume deficit may lead to an unacceptable increase in the amount of third space fluid accumulation. Chronic Phase: After the acute phase is successfully managed as above, excessive fluid accumulation in the third space should be limited by instituting severe potassium, sodium, and fluid restriction. Resolution Phase: As third space fluid returns to the intravascular compartment, a fall in hematocrit and increasing urinary output are observed in the absence of any increase in intake. Peripheral and/or pulmonary edema may result if the kidneys are unable to excrete third space fluid as rapidly as it is mobilized. Diuretics may be indicated during the resolution phase, if necessary, to combat pulmonary edema. Do not remove ascitic, pleural, and pericardial fluid unless there is the necessity to relieve symptoms such as pulmonary distress or cardiac tamponade. OHSS increases the risk of injury to the ovary. Pelvic examination or intercourse may cause rupture of an ovarian cyst, which may result in hemoperitoneum, and should be avoided. If bleeding occurs and requires surgical intervention, the clinical objective should be to control the bleeding and retain as much ovarian tissue as possible. A physician experienced in the management of this syndrome, or who is experienced in the management of fluid and electrolyte imbalances, should be consulted. In a clinical study of induction of ovulation indication, 6 of 72 (8.33%) BRAVELLE ® treated women developed OHSS and 2 were classified as severe. In a clinical study for the development of multiple follicles as part of an IVF cycle, 3 of 60 women treated with BRAVELLE ® developed OHSS and 1 was classified as severe. 5.4 Pulmonary and Vascular Complications Serious pulmonary conditions (e.g., atelectasis, acute respiratory distress syndrome) have been reported in women treated with gonadotropins. In addition, thromboembolic events both in association with, and separate from, the Ovarian Hyperstimulation Syndrome have been reported in women treated with gonadotropins. Intravascular thrombosis and embolism, which may originate in venous or arterial vessels, can result in reduced blood flow to critical organs or the extremities. Women with generally recognized risk factors for thrombosis, such as personal or family history, severe obesity, or thrombophilia, may have an increased risk of venous or arterial thromboembolic events during or following treatment with gonadotropins. Sequelae of such reactions have included venous thrombophlebitis, pulmonary embolism, pulmonary infarction, cerebral vascular occlusion (stroke), and arterial occlusion resulting in loss of limb and rarely in myocardial infarctions. In rare cases, pulmonary complications and/or thromboembolic events have resulted in death. In women with recognized risk factors, the benefits of ovulation induction and assisted reproductive technology need to be weighed against the risks. Pregnancy also carries an increased risk of thrombosis. 5.5 Ovarian Torsion Ovarian torsion has been reported after treatment with gonadotropins. This may be related to OHSS, pregnancy, previous abdominal surgery, past history of ovarian torsion, previous or current ovarian cyst and polycystic ovaries. Damage to the ovary due to reduced blood supply can be limited by early diagnosis and immediate detorsion. 5.6 Multi-fetal Gestation and Birth Multi-fetal gestation and births have been reported with all gonadotropin therapy including therapy with BRAVELLE ® . In a controlled study of 72 patients undergoing induction of ovulation, 66.7% of pregnancies of women treated with subcutaneous BRAVELLE ® were multiples, while 28.6% of pregnancies in women treated with intramuscular BRAVELLE ® were multiples. In a controlled study of 60 patients undergoing IVF, 34.8% of pregnancies of women treated with subcutaneous BRAVELLE ® were multiples. Before beginning treatment with BRAVELLE ® , advise the woman and her partner of the potential risk of multi-fetal gestation and birth. 5.7 Congenital Malformations The incidence of congenital malformations after some ART [specifically in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI)] may be slightly higher than after spontaneous conception. This slightly higher incidence is thought to be related to differences in parental characteristics (e.g., maternal age, maternal and paternal genetic background, sperm characteristics) and to the higher incidence of multi-fetal gestations after IVF or ICSI. There are no indications that the use of gonadotropins during IVF or ICSI is associated with an increased risk of congenital malformations. 5.8 Ectopic Pregnancy Since infertile women undergoing ART often have tubal abnormalities, the incidence of ectopic pregnancy may be increased. Early confirmation of intrauterine pregnancy should be determined by β-hCG testing and transvaginal ultrasound. 5.9 Spontaneous Abortion The risk of spontaneous abortion (miscarriage) is increased with gonadotropin products. However, causality has not been established. The increased risk may be a factor of the underlying infertility . 5.10 Ovarian Neoplasms There have been infrequent reports of ovarian neoplasms, both benign and malignant, in women who have had multiple drug therapy for controlled ovarian stimulation; however, a causal relationship has not been established. 5.11 Laboratory Tests In most instances, treatment of women with BRAVELLE ® will result only in follicular growth and maturation. In the absence of an endogenous LH surge, hCG is given when monitoring of the woman 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 follicular growth and maturation, timing of the ovulatory trigger, detecting ovarian enlargement and minimizing the risk of the Ovarian Hyperstimulation Syndrome and multiple gestation. The clinical confirmation of ovulation is obtained by direct or indirect indices of progesterone production as well as sonographic evidence of ovulation. Direct or indirect indices of progesterone production: Urinary or serum luteinizing hormone (LH) rise A rise in basal body temperature Increase in serum progesterone Menstruation following the shift in basal body temperature Sonographic evidence of ovulation: Collapsed follicle Fluid in the cul-de-sac Features consistent with corpus luteum formation Secretory endometrium