ge and administration and precautions.) clomiphene citrate is indicated only in patients with demonstrated ovulatory dysfunction who meet the conditions described below (see contraindications): patients who are not pregnant. patients without ovarian cysts. clomiphene citrate should not be used in patients with ovarian enlargement except those with polycystic ovary syndrome. pelvic examination is necessary prior to the first and each subsequent course of clomiphene citrate treatment. patients without abnormal vaginal bleeding. if abnormal vaginal bleeding is present, the patient should be carefully evaluated to ensure that neoplastic lesions are not present. patients with normal liver function. in addition, patients selected for clomiphene citrate therapy should be evaluated in regard to the following: estrogen levels. patients should have adequate levels of endogenous estrogen (as estimated from vaginal smears, endometrial biopsy, assay of urinary estrogen, or from bleeding in response to progesterone). reduced estrogen levels, while less favorable, do not preclude successful therapy. primary pituitary or ovarian failure. clomiphene citrate therapy cannot be expected to substitute for specific treatment of other causes of ovulatory failure. endometriosis and endometrial carcinoma. the incidence of endometriosis and endometrial carcinoma increases with age as does the incidence of ovulatory disorders. endometrial biopsy should always be performed prior to clomiphene citrate therapy in this population. other impediments to pregnancy. impediments to pregnancy can include thyroid disorders, adrenal disorders, hyperprolactinemia, and male factor infertility. uterine fibroids. caution should be exercised when using clomiphene citrate in patients with uterine fibroids due to the potential for further enlargement of the fibroids. there are no adequate or well-controlled studies that demonstrate the effectiveness of clomiphene citrate in the treatment of male infertility. in addition, testicular tumors and gynecomastia have been reported in males using clomiphene. the cause and effect relationship between reports of testicular tumors and the administration of clomiphene citrate is not known. although the medical literature suggests various methods, there is no universally accepted standard regimen for combined therapy (i.e., clomiphene citrate in conjunction with other ovulation-inducing drugs). similarly, there is no standard clomiphene citrate regimen for ovulation induction in vitro fertilization programs to produce ova for fertilization and reintroduction. therefore, clomiphene citrate is not recommended for these uses.

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. ovarianhyperstimulationsyndrome 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 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.

rhagia the following adverse events have been reported in fewer than 1% of patients in clinical trials: acute abdomen, appetite increase, constipation, dermatitis or rash, depression, diarrhea, dizziness, fatigue, hair loss/dry hair, increased urinary frequency/volume, insomnia, light-headedness, nervous tension, vaginal dryness, vertigo, weight gain/loss. patients on prolonged clomiphene citrate therapy may show elevated serum levels of desmosterol. this is most likely due to a direct interference with cholesterol synthesis. however, the serum sterols in patients receiving the recommended dose of clomiphene citrate are not significantly altered. ovarian cancer has been infrequently reported in patients who have received fertility drugs. infertility is a primary risk factor for ovarian cancer; however, epidemiology data suggest that prolonged use of clomiphene may increase the risk of a borderline or invasive ovarian tumor. post marketing adverse events postmarketing adverse events the following adverse reactions have been identified during the post approval use of clomiphene citrate. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. body as a whole: fever, tinnitus, weakness cardiovascular: arrhythmia, chest pain, edema, hypertension, palpitation, phlebitis, pulmonary embolism, shortness of breath, tachycardia, thrombophlebitis central nervous system: migraine headache, paresthesia, seizure, stroke, syncope dermatologic: acne, allergic reaction, erythema, erythema multiforme, erythema nodosum, hypertrichosis, pruritus, urticaria fetal/neonatal anomalies: abnormal bone development: skeletal malformations of the skull, face, nasal passages, jaw, hand, limb (ectromelia including amelia, hemimelia, and phocomelia),foot (clubfoot), spine and joints cardiac abnormalities: septal heart defects, muscular ventricular septal defect, patent ductus arteriosus, tetralogy of fallot, and coarctation of the aorta chromosomal disorders:downs syndrome ear abnormalities and deafness gastrointestinal tract abnormalities: cleft lip and palate, imperforate anus, tracheoesophageal fistula, diaphragmatic hernia, omphalocele genitalia abnormalities: hypospadias, cloacal exstrophy lung tissue malformations malformations of the eye and lens (cataract) neoplasms: neuroectodermal tumor, thyroid tumor, hepatoblastoma, lymphocytic, leukemia nervous system abnormalities: neural tube defects (anencephaly, meningomyelocele),microcephaly, and hydrocephalus renal abnormalities: renal agenesis and renal dysgenesis others: dwarfism, mental retardation genitourinary: endometriosis, ovarian cyst (ovarian enlargement or cysts could, as such, be complicated by adnexal torsion), ovarian hemorrhage, tubal pregnancy, uterine hemorrhage. hepatic: transaminases increased, hepatitis. musculoskeletal: arthralgia, back pain, myalgia. neoplasms: liver (hepatic hemangiosarcoma, liver cell adenoma, hepatocellular carcinoma); breast (fibrocystic disease, breast carcinoma); endometrium (endometrial carcinoma); nervous system (astrocytoma, pituitary tumor, prolactinoma, neurofibromatosis, glioblastoma multiforme, brain abcess); ovary (luteoma of pregnancy, dermoid cyst of the ovary, ovarian carcinoma); trophoblastic (hydatiform mole, choriocarcinoma); miscellaneous (melanoma, myeloma, perianal cysts, renal cell carcinoma, hodgkin’s lymphoma, tongue carcinoma, bladder carcinoma); psychiatric: anxiety, irritability, mood changes, psychosis. visual disorders: abnormal accommodation, cataract, eye pain, macular edema, optic neuritis, photopsia, posterior vitreous detachment, retinal hemorrhage, retinal thrombosis, retinal vascular spasm, temporary or prolonged loss of vision, possibly irreversible. other: leukocytosis, thyroid disorder. drugabuse and dependence tolerance, abuse, or dependence with clomiphene citrate has not been reported.

gesterone and estradiol rise and fall as they would in a normal ovulatory cycle. available data suggest that both the estrogenic and antiestrogenic properties of clomiphene may participate in the initiation of ovulation. the two clomiphene isomers have been found to have mixed estrogenic and antiestrogenic effects, which may vary from one species to another. some data suggest that zuclomiphene has greater estrogenic activity than enclomiphene. clomiphene citrate has no apparent progestational, androgenic, or antiandrogenic effects and does not appear to interfere with pituitary-adrenal or pituitary-thyroid function. although there is no evidence of a “carryover effect” of clomiphene citrate, spontaneous ovulatory menses have been noted in some patients after clomiphene citrate therapy. pharmacokinetics based on early studies with 14c-labeled clomiphene citrate, the drug was shown to be readily absorbed orally in humans and excreted principally in the feces. cumulative urinary and fecal excretion of the 14c averaged about 50% of the oral dose and 37% of an intravenous dose after 5 days. mean urinary excretion was approximately 8% with fecal excretion of about 42%. some 14c label was still present in the feces 6 weeks after administration. subsequent single-dose studies in normal volunteers showed that zuclomiphene (cis) has a longer half-life than enclomiphene (trans). detectable levels of zuclomiphene persisted for longer than a month in these subjects. this may be suggestive of stereo-specific enterohepatic recycling or sequestering of the zuclomiphene. thus, it is possible that some active drug may remain in the body during early pregnancy in women who conceive in the menstrual cycle during clomiphene citrate therapy.

h each appeared grossly normal. table 1. outcome of reported pregnancies in clinical trials (n = 2369) * includes 28 ectopic pregnancies, 4 hydatiform moles, and 1 fetus papyraceous. † indicates percentage of surviving infants from these pregnancies. outcome total number of pregnancies survival rate pregnancy wastage spontaneous abortions 483* stillbirths 24 live births single births 1697 98.16%† multiple births 165 83.26%† the overall survival of infants from multiple pregnancies including spontaneous abortions, stillbirths, and neonatal deaths is 73%. fetal/neonatal anomalies and mortality the following fetal abnormalities have been reported subsequent to pregnancies following ovulation induction therapy with clomiphene citrate during clinical trials. each of the following fetal abnormalities were reported at a rate of <1% (experiences are listed in order of decreasing frequency): congenital heart lesions, down syndrome, club foot, congenital gut lesions, hypospadias, microcephaly, harelip, and cleft palate, congenital hip, hemangioma, undescended testicles, polydactyly, conjoined twins and teratomatous malformation, patent ductus arteriosus, amaurosis, arteriovenous fistula, inguinal hernia, umbilical hernia, syndactyly, pectus excavatum, myopathy, dermoid cyst of scalp, omphalocele, spina bifida occulta, ichthyosis, and persistent lingual frenulum. neonatal death and fetal death/stillbirth in infants with birth defects have also been reported at a rate of <1%. the overall incidence of reported congenital anomalies from pregnancies associated with maternal clomiphene citrate ingestion during clinical studies was within the range of that reported for the general population. in addition, reports of congenital anomalies have been received during postmarketing surveillance of clomiphene citrate (see adverse reactions).