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® 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® 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®
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® 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® 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® treatment. In ovulation induction clinical
trials, 12.3% of live births were multiple births in women
receiving Gonal-F® 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® 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® 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®.
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.
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