WARNINGS SECTION
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. 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 therapy is discontinued. However, prolonged visual disturbances have been reported after clomiPHENE citrate therapy has been discontinued and these disturbances may be irreversible. Patients should be warned that these visual symptoms may render such activities 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 daily 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 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 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, OHSS 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 hepatic 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. It may progress rapidly (within 24 hours to several days) to become a serious medical event. 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 OHSS are abdominal pain and distention, 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 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. Some patients with polycystic ovary syndrome who are unusually sensitive to gonadotropin may have an exaggerated response to usual doses of clomiPHENE citrate. 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 clomiPHENE citrate 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 therapy usually regress spontaneously within a few days or weeks after discontinuing treatment. The potential benefit of subsequent clomiPHENE citrate 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 SECTION
GENERAL PRECAUTIONS SECTION
Careful attention should be given to the selection of candidates for clomiPHENE citrate therapy. Pelvic examination is necessary prior to clomiPHENE citrate treatment and before each subsequent course (see CONTRAINDICATIONS and WARNINGS).
INFORMATION FOR PATIENTS SECTION
The purpose and risks of clomiPHENE citrate therapy should be presented to the patient before starting treatment. It should be emphasized that the goal of clomiPHENE citrate 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 therapy. It should be made clear that, in some instances, visual disturbances may be prolonged and, possibly, irreversible. 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 symptoms, 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. To minimize the risks associated with ovarian enlargement, the patient should be instructed to inform the physician of any abdominal or pelvic pain, weight gain, discomfort, or distention after taking clomiPHENE citrate (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 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 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 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 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) show a spontaneous abortion rate of 20.4% and stillbirth rate of 1.0%. (See CLINICAL PHARMACOLOGY)
DRUG INTERACTIONS SECTION
Drug interactions with clomiPHENE citrate have not been documented.
CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION
Long-term toxicity studies in animals have not been performed to evaluate the carcinogenic or mutagenic potential of clomiPHENE citrate.
Oral administration of clomiPHENE citrate to male rats at doses of 0.3 or 1 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 ova and corpora lutea, while 3 mg/kg/day inhibited ovulation.
PREGNANCY SECTION
Pregnancy Category X. (See CONTRAINDICATIONS.)
NURSING MOTHERS SECTION
It is not known whether clomiPHENE citrate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if clomiPHENE citrate is administered to a nursing woman. In some patients, clomiPHENE citrate 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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