The frequency and severity of adverse reactions to clomiphene citrate appear to be dose related and occur most frequently in patients receiving high doses (100 mg or more daily) and/or prolonged therapy.
The most common adverse effects of clomiphene citrate are ovarian enlargement or cyst formation and vasomotor symptoms such as hot flashes. When clomiphene is administered in recommended dosages, abnormal ovarian enlargement is infrequent; however, the usual cyclic variation in ovarian size may be exaggerated and mid-cycle ovarian pain (mittelschmerz) may be accentuated. Ovarian enlargement and cyst formation (usually luteal) may occur more frequently and the luteal phase of the menstrual cycle may be prolonged in patients receiving higher dosages or prolonged administration of the drug. Some patients with polycystic ovary syndrome are unusually sensitive to gonadotropin and may have an exaggerated response to usual doses of clomiphene citrate. Massive ovarian enlargement has been reported rarely. If abnormal enlargement of the ovary occurs during clomiphene therapy, the drug should be discontinued. (See Cautions: Precautions and Contraindications.) Maximal enlargement of the ovary does not occur until several days following discontinuance of clomiphene therapy; however, ovarian enlargement and cyst formation usually regress spontaneously a few days or weeks following discontinuance of the drug. Unless a strong indication for laparotomy exists, most patients with ovarian enlargement or cyst formation should be managed conservatively.
Vasomotor symptoms reported with clomiphene resemble menopausal hot flashes. These effects are usually mild and disappear after clomiphene therapy is discontinued.
Abdominal symptoms or pelvic discomfort including distention, bloating, or pain may occur with clomiphene therapy and may resemble mittelschmerz, premenstrual phenomena, or ovarian enlargement.
Adverse visual symptoms including transient blurring of vision, diplopia, scotomata, phosphenes, or photophobia have occurred in patients receiving clomiphene. These adverse ocular effects appear to be dose related and usually disappear within a few days or weeks following discontinuance of the drug. Visual symptoms seem to result from intensification and prolongation of after-images and often first appear or are accentuated when the patient is exposed to a more brightly-lit environment. Rarely, decreased visual acuity may occur. One patient reportedly developed posterior cortical senile cataracts following clomiphene therapy, but the causal relationship between cataracts and the drug has not been determined. Ophthalmologically definable scotomata and electroretinographic changes in retinal function have also been reported.
Other adverse effects of clomiphene citrate include nausea or vomiting, increased urinary frequency or volume, heavier menses, increased appetite and weight gain, and various dermatologic conditions including urticaria, rash, or allergic dermatitis. Breast discomfort, increased nervous tension, headache, restlessness, insomnia, dizziness, lightheadedness, depression, fatigue, and reversible hair loss may also occur.
Clomiphene citrate has not been reported to produce any clinically important abnormalities in hematologic or renal systems, in protein-bound iodine, or in serum cholesterol when given for short periods; however, following prolonged, continuous administration, elevated concentrations of desmosterol have been reported, indicating a possible interference with cholesterol synthesis.
Increased retention of sulfobromophthalein has occurred during therapy with clomiphene while results of other liver function tests usually have been normal. One case of jaundice due to bile stasis has been reported.