Clomiphene therapy is generally well tolerated, and side effects do not commonly interfere with the continuation of treatment. Many patients experience vasomotor "hot flashes" (10.4%), which result from the anti-estrogen effects; these subside at the completion of each 5 day dosage cycle. Mild pelvic discomfort without enlargement of the ovaries occurs in roughly 5.5%. Breast tenderness/mastalgia was reported in 2.1% of patients. Less frequent side effects include dizziness (< 1%), fatigue (< 1%), and headache (1.3%). Abnormal uterine bleeding, reported as menorrhagia or breakthrough bleeding, occurred in 1.3% of patients.[51449] Menstrual irregularity and an increase in pain associated with ovulation (mittelschmerz) may occur (< 1.5%).

The normal thinning of the cervical mucus in preparation for ovulation and conception may be impaired by clomiphene therapy. Cervical mucus thickening may result in up to 25% of patients taking clomiphene and may potentially decrease the ability of sperm to reach the oocyte. Vaginal dryness may also occur. Although controversial, estrogens have been administered in some patients on cycle day 10 to the time of the LH surge (ovulation) in order to combat mucus drying and thickening. There is little documentation of the efficacy of estrogen in improving pregnancy rates.

Roughly 14% (1 out of every 7 women) on clomiphene therapy experience uncomplicated ovarian enlargement. Pelvic examinations should be performed in patients who complain of abdominal discomfort (pelvic pain) during therapy. If enlargement or ovarian cyst(s) are present, the current clomiphene cycle should be discontinued and further therapy withheld until resolution of the signs and symptoms and until the ovary is no longer enlarged. Use the lowest dose consistent with expected clinical results to minimize the hazard associated with occasional abnormal ovarian enlargement associated with clomiphene. Maximal enlargement of the ovary may not occur until several days after discontinuation of the recommended clomiphene dose. If substantial ovarian enlargement occurs after ovulation, sexual intercourse should be prohibited because of the risk of hemoperitoneum secondary to ruptured ovarian cysts. Adjunctive agents (i.e., human chorionic gonadotropin, HCG) should be withheld if ovarian enlargement is present in order to prevent progression to ovarian hyperstimulation (OHSS). Most ovarian cysts or enlargements will regress within a few days to weeks after discontinuation of clomiphene. Laparoscopy is rarely needed. Once recovery occurs, the dosage or duration of the next cycle of clomiphene should be reduced. Ovarian enlargement or ovarian cyst formation may be more likely to occur in patients with polycystic ovary syndrome (PCOS) or in those patients on higher cyclic clomiphene dosages, receiving treatment beyond 5 days in each cycle, or receiving more than 6 total cycles of therapy.[51449]

Abdominal pain, nausea/vomiting (2.2%), acute abdomen (< 1%), constipation (< 1%), diarrhea (< 1%), and weight gain (< 1%) have been noted with clomiphene. Of note, some of the early warning signs of the ovarian hyperstimulation syndrome are abdominal pain and distention, nausea, vomiting, diarrhea, and weight gain. Instruct the patient to report any abdominal or pelvic pain, weight gain, discomfort, or distention.[51449]

Clomiphene therapy can result in ovarian hyperstimulation syndrome (OHSS). The incidence of OHSS with clomiphene is less than that which occurs with the administration of menotropins or follicle-stimulating hormone. OHSS is a medical event distinct from uncomplicated ovarian enlargement and requires inpatient care for supportive management of the patient. The syndrome may be severe. The pathogenesis of this syndrome is still unknown, but probably results from the production and secretion of several substances (i.e., prostaglandin, cytokines, vascular endothelial growth factor, and activation of the ovarian-renin-angiotensin system) in response to the stimulation of ovulation. Patients have exhibited increased plasma angiotensin-converting enzyme (ACE) activity in association with this syndrome. Some early warning signs include severe abdominal pain and distention, pelvic pain, nausea/vomiting, diarrhea, and weight gain. Severe cases produce clinical signs such as gross ovarian enlargement, gastrointestinal symptoms, ascites, dyspnea, oliguria, and pleural effusion. Other reported symptoms of OHSS include pericardial effusion, anasarca, hydrothorax, acute abdomen, elevated hepatic enzymes, hypotension, renal failure (unspecified), pulmonary edema, intraperitoneal and ovarian hemorrhage, deep venous thrombosis, stroke, and acute respiratory distress. Ovarian enlargement or cysts could, as such, be complicated by adnexal ovarian torsion. Elevated urinary steroid levels, electrolyte imbalance, hypovolemia, hemoconcentration, and hypoalbuminemia may also occur. Hemoconcentration, hypovolemic shock, or thrombotic events may be fatal. Abdominal and pelvic examination should be done carefully in severe cases of OHSS due to the fragility of the enlarged ovaries. Conception may result in progression to the severe form of OHSS. Clomiphene therapy should not be reinstated until ovary size has returned to normal.[51449]

Clomiphene can cause treatment-associated visual impairment in roughly 1.5% of patients. Although these events are infrequent, the incidence may increase with increasing dosage. Vision changes require that the patient notify the prescriber. Adverse effects include blurred vision, diplopia, scintillating scotomata (spots and flashes), and photophobia. Postmarketing, abnormal accommodation, cataracts, ocular pain, macular edema, optic neuritis, photopsia, posterior vitreous detachment, retinal hemorrhage, retinal vascular spasm, and temporary loss of vision have been reported. There are rare reports of temporary but severe diminished visual acuity (blindness). Visual symptoms are accentuated upon exposure to bright light. These effects can impair a patient's ability to operate heavy machinery or drive an automobile. If visual disturbances occur, clomiphene therapy should be discontinued, and complete ophthalmologic testing should be performed. In most cases, clomiphene induced visual changes are reversible within several days of drug discontinuation.[51449]

Dermatological adverse reactions to clomiphene therapy include dermatitis or rash (unspecified) (< 1%) and alopecia (< 1%). Postmarketing, erythema multiforme, urticaria, pruritus, acne vulgaris, erythema, erythema nodosum, hypertrichosis, and allergic dermatitis have been reported.[51449]

Central nervous system (CNS) adverse effects do not happen frequently (< 1% of patients using clomiphene). CNS adverse effects include anxiety, depression, insomnia, lightheadedness, and restlessness. Postmarketing, migraine, psychosis, emotional lability, and irritability have been reported.[51449]

Rare side effects occurring in < 1% of patients using clomiphene include appetite stimulation, increased urinary frequency, and weight loss.[51449]

Postmarketing, pulmonary embolism, thrombo-phlebitis, retinal thrombosis, arrhythmia, chest pain (unspecified), edema, hypertension, palpitations, dyspnea, and sinus tachycardia have been reported with clomiphene.[51449] Rare thromboembolic events, such as pulmonary embolism, arterial occlusion, and phlebitis have been reported in the literature in association with clomiphene therapy in women who have not had concurrent ovarian hyperstimulation. The association of clomiphene with the development of thromboembolic disease is not clear. Certain patients with other risk factors for thromboembolism may be at higher risk.

Prolonged use of clomiphene may increase the risk of a borderline or invasive ovarian tumor, although a causal relationship between ovarian hyperstimulation and ovarian cancer has not been determined. If ovarian cysts do not regress spontaneously, perform a thorough evaluation to rule out ovarian neoplasia. Postmarketing, various cancers have been noted including but not limited to breast, ovarian, liver, endometrial, nervous system, trophoblastic, and neoplasms of offspring.[51449] Some observational studies and a number of case reports gave rise to the speculation that infertility treatments might enhance the risk of new primary malignancy in women (i.e, breast cancer or ovarian cancer). However, infertility alone is an independent risk factor for the development of either breast or ovarian cancer. Case reports and observational studies suggesting an association of cancer to fertility treatments rarely control for other independent confounding factors such as delay in parity or family history. In one long-term cohort study of 1,197 infertile women, the incidence of ovarian or breast cancer was not significantly elevated in the groups receiving fertility treatments versus those not treated. The breast cancer rate, in particular, was not significantly different in either group versus the general female population.[25857] While more studies are needed, the current data do not support an association between the use of fertility drugs and increased cancer risk.

Clomiphene does not appear to increase the risk of congenital abnormalities or spontaneous abortion with normal use. The overall incidence of reported birth anomalies from pregnancies associated with maternal clomiphene ingestion during the investigational studies was within the range of that reported in published references for the general population.[51449] However, data suggest that teratogenesis might occur during organogenesis if clomiphene is inadvertently continued in early pregnancy. Numerous congenital malformations have been reported postmarketing. Further, animal studies reveal a possible connection of clomiphene use with congenital ocular and bowel syndromes or other structural malformations. It is important that clomiphene therapy be continued in subsequent fertility treatment cycles only after pregnancy has been ruled out and normal withdrawal bleeding (menses) has occurred.

Postmarketing, elevated hepatic enzymes and hepatitis have been noted with clomiphene. Of note, transient liver function test abnormalities suggestive of hepatic dysfunction that may be accompanied by morphologic changes on liver biopsy have been reported in association with the ovarian hyperstimulation syndrome.[51449]

Clomiphene will only be effective at inducing ovulation in women with an intact hypothalamic-pituitary tract and ovarian response. Patients with untreated adrenal insufficiency; pituitary insufficiency or primary pituitary failure, pituitary adenoma or other pituitary tumor; primary ovarian failure; or untreated thyroid disease will not respond to clomiphene treatment.

Reduced responses to clomiphene therapy may occur in some females with diabetes mellitus, hirsutism (or hyperandrogenism), hyperinsulinemia, obesity, or lowered levels of endogenous estrogen. In some cases, the use of other medications with clomiphene may increase the chances of successful conception.

In men, clomiphene has only been effective for treating idiopathic oligospermia. Men with other infertility problems, including primary testicular failure or disruption of hypothalamic-pituitary function, are not expected to respond to clomiphene treatment.

Clomiphene is contraindicated for use in patients with abnormal or dysfunctional uterine bleeding of undetermined origin. Neoplasm (e.g., ovarian cancer or endometrial cancer) should be ruled out before clomiphene use. Because clomiphene may stimulate endometrial growth, it should be used cautiously in patients with uterine leiomyomata (fibroids) or endometriosis. It has been suggested that the use of fertility drugs, including clomiphene, might increase the risk of developing certain cancers. Some observational studies and a number of case reports gave rise to the speculation that the increased number of ovulatory follicles and/or high gonadotropin and estrogen levels induced by infertility treatment might enhance the development of breast cancer or ovarian cancer. However, infertility alone is an independent risk factor for the development of either breast or ovarian cancer. Also, case reports rarely control for other independent confounding factors such as delay in parity or family history. In one long-term cohort study of 1,197 infertile women, the incidence of ovarian or breast cancer was not significantly elevated in the groups receiving fertility treatments versus those not treated. The breast cancer rate, in particular, was not significantly different in either group versus the general female population. While more studies are needed, current data do not support an association between the use of fertility drugs and increased cancer risks.[25857]

Prior to initiation of clomiphene treatment in women, a full gynecologic exam should be performed. Clomiphene should not be administered to patients with ovarian enlargement or a preexisting ovarian cyst that is not due to polycystic ovarian syndrome (PCOS). Clomiphene therapy should not be initiated until the diagnostic cause of the cyst or enlargement has been determined and ovary size has returned to normal. To minimize the risk of either uncomplicated ovarian enlargement or OHSS in any female, the lowest dose of clomiphene that produces ovulation should be used. Once an ovulatory dose has been determined, there is no advantage to increasing the dose. Some patients with polycystic ovary syndrome (PCOS) are unusually sensitive to gonadotropins and may have an exaggerated response to clomiphene treatment; lower dosages may be needed. All female patients should be instructed to report symptoms of ovarian enlargement, including abdominal pain or pelvic pain; nausea; vomiting; ascites (fluid and distension in the abdomen); or weight gain immediately. The current cycle of clomiphene should be halted if ovarian enlargement or OHSS occurs or if cysts develop; maximal ovarian enlargement may not be evident until several days after drug discontinuation. Clomiphene therapy should not be reinstated until ovary size has returned to normal. A complete pelvic exam should be repeated in all female patients prior to each treatment cycle.

Clomiphene is contraindicated for use after conception has occurred. There are no adequate human studies of the effects of clomiphene on the fetus. The use of clomiphene for ovulation stimulation does not appear to increase the risk of congenital abnormalities or spontaneous abortion (miscarriage) compared to rates in the general population. However, if clomiphene is inadvertently continued during early pregnancy, it is possible that fetal harm may occur. Animal reproduction studies have shown adverse fetal effects in early gestation, including the development of ocular defects and congenital structural bladder and bowel changes. To avoid inadvertent clomiphene citrate administration during early pregnancy, appropriate tests should be utilized during each treatment cycle to determine whether ovulation and/or pregnancy occurs (e.g., pregnancy testing). In addition to potential effects on the fetus, clomiphene use does slightly increase the risk of multiple gestation and the risks inherent with such pregnancies.[49417]

Per the manufacturer, it is not known whether clomiphene is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if clomiphene is administered to an individual who is breast-feeding. In some patients, clomiphene citrate may reduce lactation.[49417] [49400] In a study using liquid chromatography-tandem mass spectrometry (LC-MS/MS) clomiphene was detected in breast milk in small amounts (mean concentration: 300 ng/mL) in one lactating individual; the authors estimated the infant exposure via the breast milk would be approximately 45 mcg/kg/day. No adverse effects were observed on the breastfed infant per the mother; however, the infant was not breastfed frequently at the time of sampling. The authors recommended caution for an infant that is exclusively breastfed.[69021]

Clomiphene is contraindicated in those patients with a history of hepatic disease or dysfunction. Reduced clearance of clomiphene may result in higher plasma concentrations and may potentially increase the risk of certain side effects. In addition, hepatotoxicity has occurred in some patients in conjunction with ovarian hyperstimulation syndrome (OHSS). Determinations of liver function should be performed in all patients prior to clomiphene therapy.

Clomiphene should be used cautiously in patients with major depression or psychosis. There is a possibility that the condition may be exacerbated. Depression may be common in the infertile population due to the experience of loss present in cycles in which no pregnancy occurs.

Clomiphene should be used extremely cautiously in patients with active thrombophlebitis or other active thromboembolic disease. Like other selective estrogen receptor modifiers (SERMs), clomiphene exhibits some estrogenic activity. Rarely, thromoembolic events have been reported in patients receiving clomiphene.

Clomiphene may make patients dizzy, or they may have blurred vision. Caution patients against driving or operating machinery, or performing tasks that need mental alertness, until they are aware of how clomiphene affects them. The patient should promptly report any visual disturbance to their health care prescriber, and an ophthalmologic examination should be performed.

Tobacco smoking is a lifestyle choice that may decrease fertility or the effectiveness of fertility treatments in some women and/or men. Patients should be encouraged to avoid tobacco consumption and pursue smoking cessation while pursuing fertility therapies such as the use of clomiphene.[64706]