### Ovarian Enlargement

Mild to moderate uncomplicated ovarian enlargement which may be accompanied by abdominal distention and/or abdominal pain may occur in patients treated with FSH 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 FSH therapy, choriogonadotropin alfa should not be administered in this course of therapy. This will reduce the risk 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 4 of 236 (1.7 %) patients treated with Ovidrel® 250 µg during clinical trials for ART and 3 of 99 (3.0%) patients treated in the OI trial. OHSS occurred in 8 of 89 (9.0%) patients who received Ovidrel® 500 µg. Two patients treated with Ovidrel® 500 µg developed severe OHSS.

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 with gonadotropins 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.

#### Multiple Births

As with other hCG products, reports of multiple births have been associated with Ovidrel® treatment. In ART, the risk of multiple births correlates to the number of embryos transferred. Multiple births occurred in 17 of 55 live deliveries (30.9 %) experienced by women receiving Ovidrel® 250 µg in the ART studies. In the ovulation induction clinical trial, 2 of 15 live deliveries (13.3%) were associated with multiple births in women receiving Ovidrel®. The patient should be advised of the potential risk of multiple births before starting treatment.

#### Pulmonary and Vascular Complications

As with other hCG products, a potential for the occurrence of arterial thromboembolism exists.