clomiphene (Rx)

>10%

Ovarian enlargement (14%)

Vasomotor flushing (10%)

1-10%

Abdominal discomfort (6%)

Blurred vision (1.5%)

Breast discomfort (2%)

Nausea/vomiting (2%)

Postmarketing Reports

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

Genitourinary: Endometriosis, ovarian cyst (ovarian enlargement or cysts could, as such, be complicated by adnexal torsion), ovarian hemorrhage, tubal pregnancy, uterine hemorrhage; reduced endometrial thickness

Hepatic: Transaminases increased, hepatitis, pancreatitis

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 abscess); 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

Metabolism disorders: Hypertriglyceridemia

Other: Leukocytosis, thyroid disorder

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

Contraindications

Pregnancy

Liver disease

Undiagnosed abnormal uterine bleeding

Uncontrolled thyroid or adrenal dysfunction

Endometrial cancer

Ovarian cysts not due to PCOS

Cautions

Careful attention should be given to selection of candidates for therapy; pelvic examination is necessary prior to treatment and before each subsequent course

Uterine fibroids, pituitary or ovarian failure may occur

Risk of ovarian enlargement & ovarian hyperstimulation syndrome (OHSS); transient liver function test abnormalities suggestive of hepatic dysfunction, which may be accompanied by morphologic changes on liver biopsy, reported in association with OHSS, which is a medical event distinct from uncomplicated ovarian enlargement; death due to hypovolemic shock, hemoconcentration, or thromboembolism has occurred; if enlargement of ovary occurs, additional therapy should not be given until ovaries have returned to pretreatment size, and dosage or duration of next course should be reduced; ovarian enlargement and cyst formation associated with therapy usually regresses spontaneously within a few days or weeks after discontinuing treatment; potential benefit of subsequent therapy in these cases should exceed risk

Potential for multiple births, especially at 100 mg dosage

Risk of visual disturbance (like scotoma & photopsia); patients should be warned that visual symptoms may render activities such as driving a car or operating machinery more hazardous than usual, particularly under conditions of variable lighting; while etiology of visual symptoms is not yet understood, patients with any visual symptoms should discontinue treatment and have complete ophthalmological evaluation carried out promptly

Cases of hypertriglyceridemia reported; preexisting or family history of hyperlipidemia and use of higher than recommended dose and/or longer duration of treatment are associated with risk of hypertriglyceridemia; periodic monitoring of plasma triglycerides is recommended in patients with preexisting or family history of hyperlipidemia; pretreatment screening of triglyceride levels is recommended in patients initiating therapy

Cases of pancreatitis reported

Prolonged use of clomiphene citrate tablets USP may increase risk of a borderline or invasive ovarian tumor

Pregnancy

Use in pregnant women is contraindicated, as treatment does not offer benefit in this population; to avoid inadvertent administration during early pregnancy, appropriate tests should be utilized during each treatment cycle to determine whether ovulation and/or pregnancy occurs; patients should be evaluated carefully to exclude ovarian enlargement or ovarian cyst formation between each treatment cycle; the next course of therapy should be delayed until these conditions have been excluded

Available human data from epidemiologic studies do not show apparent cause and effect relationship between clomiphene citrate periconceptual exposure and an increased risk of overall birth defects, or any specific anomaly

Lactation

It is not known whether drug is excreted in human milk; because many drugs are excreted in human milk, caution should be exercised if drug is administered to a nursing woman; in some patients, therapy may reduce lactation

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Binds to estrogen receptors, induces ovulation by increase output of pituitary gonadotropins

Pharmacokinetics

Half-Life elimination: 5-7 days

Onset: Within 5-10 days

Peak plasma time 6.5 hours

Bioavailability: Readily absorbed from GI tract

Metabolism: Enterohepatically circulated

Excretion: feces 37-51%; small amount in urine