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Gonal-F

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Gonal-F

Warnings
Precautions

WARNINGS

Gonal-F® (follitropin alfa for injection) should only be used by physicians who are thoroughly familiar with infertility problems and their management.

Gonal-F® (follitropin alfa) is a potent gonadotropic substance capable of causing Ovarian Hyperstimulation Syndrome (OHSS) 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® (follitropin alfa) 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® (follitropin alfa) 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 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, 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 Ovarian Hyperstimulation Syndrome (OHSS).

OHSS occurred in 9 of 228 (3.9%) Gonal-F® (follitropin alfa) treated women during ovulation induction clinical trials and of this number, 1 of 228 (0.4%) was classified as severe. In ART clinical studies OHSS occurred in 0 of 116 (0.0%) Gonal-F® (follitropin alfa) treated women. 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® (follitropin alfa) treatment. In ovulation induction clinical trials, 12.3% of live births were multiple births in women receiving Gonal-F® (follitropin alfa) and 14.5% of live births were multiple births in women receiving urofollitropin. In IVF/ET clinical trials, 44.0% of live births were multiple births in women receiving Gonal-F® (follitropin alfa) and 41.0% of live births were multiple births in women receiving urofollitropin and is dependent on the number of embryos transferred. The patient should be advised of the potential risk of multiple births before starting treatment.

PRECAUTIONS

General

Careful attention should be given to the diagnosis of infertility in candidates for Gonal-F® (follitropin alfa for injection) therapy (see INDICATIONS AND USAGE: Selection of Patients).

Infrormation for Patients

See PATIENT INFORMATION section.

Laboratory Tests

In most instances, treatment with Gonal-F® (follitropin alfa) results only in follicular recruitment and development. In the absence of an endogenous LH surge, hCG is given when monitoring of the patient 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 the development of follicles, for timing of the ovulatory trigger, as well as for detecting ovarian enlargement and minimizing the risk of the Ovarian Hyperstimulation Syndrome and multiple gestation. It is recommended that the number of growing follicles be confirmed using ultrasonography because plasma estrogens do not give an indication of the size or number of follicles.

The clinical confirmation of ovulation with the exception of pregnancy is obtained by direct and indirect indices of progesterone production. The indices most generally used are as follows:

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

When used in conjunction with the 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;
    3. Collapsed follicle; and
    4. Secretory endometrium.

Accurate interpretation of the indices of follicle development and maturation require a physician who is experienced in the interpretation of these tests.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Gonal-F® (follitropin alfa) . However, r-hFSH showed no mutagenic activity in a series of tests performed to evaluate its potential genetic toxicity including bacterial and mammalian cell mutation tests, a chromosomal aberration test and a micronucleus test. Impaired fertility has been reported in rats, exposed to pharmacological doses of r-hFSH (³ 40 IU/kg/day) for extended periods, through reduced fecundity.

Pregnancy

Pregnancy Category X: See CONTRAINDICATIONS.

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 Gonal -F®, 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 Use

Safety and effectiveness in pediatric patients have not been established.

Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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