CLOMIPHENE Drug Interactions: What You Need to Know

DRUG INTERACTIONS Drug Interactions Drug interactions with clomiphene citrate have not been documented. Carcinogenesis, Mutagenesis, Impairment of Fertility 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.

CONTRAINDICATIONS Hypersensitivity Clomiphene citrate tablets are contraindicated in patients with a known hypersensitivity or allergy to clomiphene citrate or to any of its ingredients.

Pregnancy

Clomiphene citrate tablets use in pregnant women is contraindicated, as clomiphene citrate does not offer benefit in this population. Available human data do not suggest an increased risk for congenital anomalies above the background population risk when used as indicated. However, animal reproductive toxicology studies showed increased embryo-fetal loss and structural malformations in offspring. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risks to the fetus (See PRECAUTIONS: Pregnancy).

Liver

Disease. Clomiphene citrate tablets therapy is contraindicated in patients with liver disease or a history of liver dysfunction (see also INDICATIONS AND USAGE and ADVERSE REACTIONS).

Abnormal Uterine

Bleeding. Clomiphene citrate tablets are contraindicated in patients with abnormal uterine bleeding of undetermined origin (see INDICATIONS AND USAGE).

Ovarian

Cysts. Clomiphene citrate tablets are contraindicated in patients with ovarian cysts or enlargement not due to polycystic ovarian syndrome (see INDICATIONS AND USAGE and WARNINGS). Other. Clomiphene citrate tablets are contraindicated in patients with uncontrolled thyroid or adrenal dysfunction or in the presence of an organic intracranial lesion such as pituitary tumor (see INDICATIONS AND USAGE).

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. These visual symptoms increase in incidence with increasing total dose or therapy duration. These visual disturbances are usually reversible; however, cases of prolonged visual disturbance have been reported with some occurring after clomiphene citrate tablets discontinuation. The visual disturbances may be irreversible, especially with increased dosage or duration of therapy. 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 tablet 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 tablets 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 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. OHSS may progress rapidly (within 24 hours to several days) and become a serious medical disorder. 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 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 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 tablets 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. Some patients with polycystic ovary syndrome who are unusually sensitive to gonadotropin may have an exaggerated response to usual doses of clomiphene citrate tablets. 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 tablets 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 therapy usually regresses spontaneously within a few days or weeks after discontinuing treatment. The potential benefit of subsequent clomiphene citrate tablets 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.