WARNINGS
Visual symptoms
Patients should be advised that blurring or other visual
symptoms such as spots or flashes (scintillating scotomata)
may occasionally occur during therapy with clomiphene
citrate tablets USP. These visual symptoms increase in
incidence with increasing total dose or therapy duration
and generally disappear within a few days or weeks after
clomiphene citrate tablets USP is discontinued. Patients
should be warned that these visual symptoms may render
such activites as driving a car or operating machinery
more hazardous than usual, particularly under conditions
of variable lighting.
These visual symptoms appear to be due to intensification
and prolongation of afterimages. Symptoms often first
appear or are accentuated with exposure to a brightly
lit environment. While measured visual acuity usually
has not been affected, a study patient taking 200 mg clomiphene
citrate tablets USP dally developed visual blurring on
the 7th day of treatment, which progressed to severe diminution
of visual acuity by the 10th day. No other abnormality
was found, and the visual acuity returned to normal on
the 3rd day after treatment was stopped.
Ophthalmologically definable scotomata and retinal cell
function (electroretinographic) changes have also been
reported. A patient treated during clinical studies developed
phosphenes and scotomata during prolonged clomiphene citrate
tablets USP administration. which disappeared by the 32nd
day after stopping therapy.
Postmarketing surveillance of adverse events has also
revealed other visual signs and symptoms during clomiphene
citrate tablets USP therapy (see ADVERSE REACTIONS).
While the etiology of these visual symptoms is not yet
understood, patients with any visual symptoms should discontinue
treatment and have a complete ophthalmological evaluation
carried out promptly.
Ovarian Hyperstimulation Syndrome
The ovarian hyperstimulation syndrome (OHSS) has been
reported to occur in patients receiving clomiphene citrate
therapy for ovulation induction. In some cases, O.S. occurred
following cyclic use of clomiphene citrate therapy or
when clomiphene citrate was used in combination with gonadotropins.
Transient liver function test abnormalities suggestive
of hepatrc dysfunction, which may be accompanied by morphologic
changes on liver biopsy, have been reported in association
with ovarian hyperstimulation syndrome (OHSS).
OHSS is a medical event distinct from uncomplicated ovarian
enlargement. The clinical signs of this syndrome in severe
cases can include gross ovarian enlargement, gastrointestinal
symptoms, ascites, dyspnea, oliguria, and pleural effusion.
In addition, the following symptoms have been reported
in association with this syndrome: pericardial effusion,
anasarca, hydrothorax, acute abdomen, hypotension, renal
failure, pulmonary edema, intraperitoneal and ovarian
hemorrhage, deep venous thrombosis, torsion of the ovary.
and acute respiratory distress. The early warning signs
of O.S. are abdominal pain and distentron, nausea, vomiting,
diarrhea, and weight gain. Elevated urinary steroid levels,
varying degrees of electrolyte imbalance, hypovolemia,
hemoconcentration, and hypoproteinemia may occur. Death
due to hypovolemic shock, hemoconcentration, or thromboembolism
has occurred. Due to fragility of enlarged ovaries in
severe cases, abdominal and pelvic examination should
be performed very cautiously. If conception results, rapid
progression to the severe form of the syndrome may occur.
To minimize the hazard associated with occasional abnormal
ovarian enlargement associated with clomiphene citrate
tablets USP therapy, the lowest dose consistent with expected
clinical results should be used. Maximal enlargement of
the ovary, whether physiologic or abnormal, may not occur
until several days after discontinuation of the recommended
dose of clomiphene citrate tablets USP. Some patients
with polycystic ovary syndrome who are unusually sensitive
to gonadotropin may have an exaggerated response to usual
doses of clomiphene citrate tablets USP. Therefore, patients
with polycystic ovary syndrome should be started on the
lowest recommended dose and shortest treatment duration
for the first course of therapy (see DOSAGE AND ADMINISTRATION).
If enlargement of the ovary occurs, additional clomtphene
citrate tablets USP therapy should not be given until
the ovaries have returned to pretreatment size, and the
dosage or duration of the next course should be reduced.
Ovarian enlargement and cyst formation associated with
clomiphene citrate tablets USP therapy usually regress
spontaneously within a few days or weeks after discontinuing
treatment. The potential benefit of subsequent ctomiphene
citrate tablets USP therapy in these cases should exceed
the risk. Unless surgical indication for laparotomy exists,
such cystic enlargement should always be managed conservatively.
A causal relationship between ovarian hyperstimulation
and ovarian cancer has not been determined. However, because
a correlation between ovarian cancer and nulliparity,
infertility, and age has been suggested, if ovarian cysts
do not regress spontaneously, a thorough evaluation should
be performed to rule out the presence of ovarian neoplasia.
PRECAUTIONS
General
Careful attention should be given to the selection of
candidates for clomiphene citrate tablets USP therapy.
Pelvic examination is necessary prior to clomiphene citrate
tablets USP treatment and before each subsequent course
(see CONTRAINDICATIONS and
WARNINGS
).
Information for Patients
The purpose and risks of clomiphene citrate tablets USP
therapy should be presented to the patient before starting
treatment. It should be emphasized that the goal of clomiphene
citrate tablets USP therapy is ovulation for subsequent
pregnancy. The physician should counsel the patient with
special regard to the following potential risks:
Visual Symptoms: Advise that
blurring or other visual symptoms occasionally may occur
during or shortly after clomiphene citrate tablets USP
therapy. Warn that visual symptoms may render such activities
as driving a car or operating machinery more hazardous
than usual, particularly under conditions of variable
lighting (see
WARNINGS
).
The patient should be instructed to inform the physician
whenever any unusual visual symptoms occur. If the patient
has any visual symptom, treatment should be discontinued
and complete ophthalmologic evaluation performed.
Abdominal/ Pelvic Pain or Distention:
Ovarian enlargement may occur during or shortly after
therapy with clomiphene citrate tablets USP. To minimize
the risks associated with ovarian enlargement, the patient
should be instructed to inform the physician of any abdominal
or elvic pain, weight gain, discomfort, or distention
after taking clomiphene citrate tablets USP (see
WARNINGS
).
Multiple Pregnancy: Inform
the patient that there is an increased chance of multiple
pregnancy, including bilateral tubal pregnancy and coexisting
tubal and intrauterine pregnancy, when conception occurs
in relation to clomiphene citrate tablets USP therapy.
The potential complications and hazards of multiple pregnancy
should be explained.
Pregnancy Wastage and Birth Anomalies:
The physician should explain the assumed risk of any pregnancy,
whether ovulation is induced with the aid of clomiphene
citrate tablets USP or occurs naturally. The patient should
be informed of the greater risks associated with certain
characteristics or conditions of any pregnant woman, eg,
age of female and male partner, history of spontaneous
abortions, Rh genotype, abnormal menstrual history, infertility
history, organic heart disease, diabetes, exposure to
infectious agents such as rubella, familial history of
birth anomaly, that may be pertinent to the patient for
whom clomiphene citrate tablets USP is being considered.
Based upon the evaluation of the patient, genetic counseling
may be indicated.
The overall incidence of reported birth anomalies from
pregnancies associated with maternal clomiphene citrate
tablets USP ingestion during the investigational studies
was within the range of that reported in published references
for the general population. (See CONTRAINDICATIONS, Pregnancy)
During clinical investigation, the experience from patients
with known pregnancy outcome (Table 1) shows a spontaneous
abortion rate of 20.4% and stillbirth rate of 1.0%. (See
CLINICAL PHARMACOLOGY).
Drug Interactions
Drug interactions with clomiphene citrate tablets USP
have not been documented.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term toxicity study in animals have not been performed
to evaluate the carcinogenic or mutagenic potential of
clomiphene citrate.
Oral administration of clomiphene citrate tablets USP
to male rats at doses of 0.3 or 1.0 mg/kg/day caused decreased
fertility, while higher doses caused temporary infertility.
Oral doses of 0.1 mg/ kg/ day in female rats temporarily
interrupted the normal cyclic vaginal smear pattern and
prevented conception. Doses of 0.3 mg/kg/day slightly
reduced the number of ovulated and corpora lutea, while
3 mg/kg/day inhibited ovulation.
Pregnancy
Pregnancy Category X (See CONTRAINDICATIONS).
Nursing Mothers
It is not known whether clomiphene citrate tablets USP
is excreted in human milk. Because many drugs are excreted
in human milk, caution should be exercised if clomiphene
citrate tablets USP is administered to a nursing woman.
In some patients, clomiphene citrate tablets USP may reduce
lactation.
Ovarian Cancer
Prolonged use of clomiphene citrate tablets USP may increase
the risk of a borderline or invasive ovarian tumor (see
ADVERSE REACTIONS).
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