Bravelle® (urofollitropin injection) is a drug that should only be used by physicians who are thoroughly familiar with infertility problems. It is a potent gonadotropic substance capable of causing Ovarian Hyperstimulation Syndrome [OHSS] with or without pulmonary or vascular complications in women. Bravelle® (urofollitropin injection) therapy requires a certain time commitment by physicians and supportive health professionals, and its use requires the availability of appropriate monitoring facilities (see PRECAUTIONS - Laboratory Tests). Bravelle® (urofollitropin injection) should be used with a great deal of care.

Overstimulation of the Ovary During Bravelle® (urofollitropin injection) Therapy

Ovarian Enlargement: Mild to moderate uncomplicated ovarian enlargement which may be accompanied by abdominal distension and/or abdominal pain occurs in approximately 20% of those treated with follitropin and hCG, and generally regresses without treatment within two or three weeks.

In order to minimize the hazard associated with the occasional abnormal ovarian enlargement, which may occur with FSH - hCG therapy, the lowest dose consistent with expectation of good results should be used. Careful monitoring of ovarian response can further minimize the risk of overstimulation.

If the ovaries are abnormally enlarged on the last day of Bravelle® (urofollitropin injection) therapy, hCG should not be administered in the course of therapy; this will reduce the chances of development of the Ovarian Hyperstimulation Syndrome.

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 vascularper-meability, 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, hemo-concentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic events (see "Pulmonary and Vascular Complications" below). 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 the Ovarian Hyperstimulation Syndrome (OHSS).

In a clinical study of ovulation induction, 6 of 72 (8.33%) Bravelle® (urofollitropin injection) treated women developed OHSS and two were classified as severe. In a clinical study for multiple follicular development during IVF, 3 of 60 Bravelle® (urofollitropin injection) treated women developed OHSS and 1 was classified as severe. 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. Most often, OHSS occurs after treatment has been discontinued and reaches its maximum at about 7 to 10 days after treatment. Usually, in cases where OHSS may be developing prior to hCG administration (see PRECAUTIONS - Laboratory Tests), the hCG should be withheld.

If severe OHSS occurs, treatment must be stopped and the patient should be hospitalized.

A physician experienced in the management of the 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) have been reported. In addition, thromboembolic events both in association with, and separate from, the Ovarian Hyperstimulation Syndrome have been reported following FSH therapy. Intravascular thrombosis and embolism, which may originate in venous or arterial vessels, 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 Pregnancies

Multiple pregnancies have occurred following treatment with Bravelle® (urofollitropin injection) SC and IM.

Pregnancy outcomes in a controlled study of 72 patients undergoing ovulation induction with Bravelle® (urofollitropin injection) are shown in Table 4.

Table 4. FPI FSH 99-03 Outcome of Pregnancies

The pregnancy outcomes in a controlled study of 60 patients undergoing treatment with Bravelle® (urofollitropin injection) in IVF are shown in Table 5.

Table 5. FPI FSH 2001-01 Outcome of Pregnancies

The patient and her partner should be advised of the potential risk of multiple births before starting treatment.

Hypersensitivity/Anaphylactic Reactions

Hypersensitivity/anaphylactic reactions associated with follitropins 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.

General

Careful attention should be given to the diagnosis of infertility in the selection of candidates for Bravelle® therapy (see INDICATIONS AND USAGE - Selection of patients).

Laboratory Tests

The combination of both estradiol levels and ultrasonography are useful for monitoring the growth and development of follicles, timing hCG administration, as well as minimizing the risk of the Ovarian Hyperstimulation Syndrome and multiple gestations.

The clinical confirmation of ovulation, is determined by:

1. A rise in basal body temperature,
2. Increase in serum progesterone, and
3. Menstruation following the shift in basal body temperature.

When used in conjunction with 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:

1. Fluid in the cul-de-sac,
2. Ovarian stigmata, and
3. Collapsed follicle.

Because of the subjectivity of the various tests for the determination of follicular maturation and ovulation, it cannot be overemphasized that the physician should choose tests with which he/she is thoroughly familiar.

Carcinogenesis and Mutagenesis

Long-term toxicity studies in animals and in vitro mutagenicity tests have not been performed to evaluate the carcinogenic potential of urofollitropin for injection, purified.

Pregnancy

Pregnancy Category X: See CONTRAINDICATIONS section.

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 Bravelle® (urofollitropin injection) , 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 Patients

Safety and effectiveness in pediatric patients have not been established.

Geriatric Patients

Safety and effectiveness in geriatric patients have not been established.

Last reviewed on RxList: 11/18/2008
This monograph has been modified to include the generic and brand name in many instances.