Data from FDA - Curated by Toby Galbraith - Last updated 02 September 2017

Indication(s)

INDICATIONS AND USAGE Clomiphene citrate tablets USP is indicated for the treatment of ovulatory dysfunction in women desiring pregnancy. Impediments to achieving pregnancy must be excluded or adequately treated before beginning clomiphene citrate tablets USP therapy. Those patients most likely to achieve success with clomiphene therapy include patients with polycystic ovary syndrome (see WARNINGS: Ovarian Hyperstimulation Syndrome), amenorrhea-galactorrhea syndrome, psychogenic amenorrhea, post-oral-contraceptive amenorrhea, and certain cases of secondary amenorrhea of undetermined etiology. Properly timed coitus in relationship to ovulation is important. A basal body temperature graph or other appropriate tests may help the patient and her physician determine if ovulation occurred. Once ovulation has been established, each course of clomiphene citrate tablets USP should be started on or about the 5th day of the cycle. Long-term cyclic therapy is not recommended beyond a total of about six cycles (including three ovulatory cycles). (See DOSAGE AND ADMINISTRATION and PRECAUTIONS.) Clomiphene citrate tablets USP 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 tablets USP 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 tablets USP 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 tablets USP 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 tablets USP 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 tablets USP 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 tablets USP 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 tablets USP 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 tablets USP is not known. Although the medical literature suggests various methods, there is no universally accepted standard regimen for combined therapy (i.e., clomiphene citrate tablets USP in conjunction with other ovulation-inducing drugs). Similarly, there is no standard clomiphene citrate tablets USP regimen for ovulation induction in in vitro fertilization programs to produce ova for fertilization and reintroduction. Therefore, clomiphene citrate tablets USP is not recommended for these uses.

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Advisory information

contraindications
CONTRAINDICATIONS Hypersensitivity Clomiphene citrate tablets USP is contraindicated in patients with a known hypersensitivity or allergy to clomiphene citrate or to any of its ingredients. Pregnancy Clomiphene citrate tablets USP should not be administered during pregnancy. Clomiphene citrate tablets USP may cause fetal harm in animals (see Animal Fetotoxicity). Although no causative evidence of a deleterious effect of clomiphene citrate tablets USP therapy on the human fetus has been established, there have been reports of birth anomalies which, during clinical studies, occurred at an incidence within the range reported for the general population (see Fetal/Neonatal Anomalies and Mortality; ADVERSE REACTIONS). To avoid inadvertent clomiphene citrate tablets USP administration during early pregnancy, appropriate tests should be utilized during each treatment cycle to determine whether ovulation occurs. The patient should be evaluated carefully to exclude pregnancy, ovarian enlargement, or ovarian cyst formation between each treatment cycle. The next course of clomiphene citrate tablets USP therapy should be delayed until these conditions have been excluded. Fetal/Neonatal Anomalies and Mortality. The following fetal abnormalities have been reported subsequent to pregnancies following ovulation induction therapy with clomiphene citrate tablets USP 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 birth anomalies from pregnancies associated with maternal clomiphene citrate tablets USP ingestion during clinical studies was within the range of that reported for the general population. In addition, reports of birth anomalies have been received during postmarketing surveillance of clomiphene citrate tablets USP (see ADVERSE REACTIONS). Animal Fetotoxicity. Oral administration of clomiphene citrate to pregnant rats during organogenesis at doses of 1 to 2 mg/kg/day resulted in hydramnion and weak, edematous fetuses with wavy ribs and other temporary bone changes. Doses of 8 mg/kg/day or more also caused increased resorptions and dead fetuses, dystocia, and delayed parturition, and 40 mg/kg/day resulted in increased maternal mortality. Single doses of 50 mg/kg caused fetal cataracts, while 200 mg/kg caused cleft palate. Following injection of clomiphene citrate 2 mg/kg to mice and rats during pregnancy, the offspring exhibited metaplastic changes of the reproductive tract. Newborn mice and rats injected during the first few days of life also developed metaplastic changes in uterine and vaginal mucosa, as well as premature vaginal opening and anovulatory ovaries. These findings are similar to the abnormal reproductive behavior and sterility described with other estrogens and antiestrogens. In rabbits, some temporary bone alterations were seen in fetuses from dams given oral doses of 20 or 40 mg/kg/day during pregnancy, but not following 8 mg/kg/day. No permanent malformations were observed in those studies. Also, rhesus monkeys given oral doses of 1.5 to 4.5 mg/kg/day for various periods during pregnancy did not have any abnormal offspring. Liver Disease. Clomiphene citrate tablets USP 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 USP is contraindicated in patients with abnormal uterine bleeding of undetermined origin (see INDICATIONS AND USAGE). Ovarian Cysts. Clomiphene citrate tablets USP is contraindicated in patients with ovarian cysts or enlargement not due to polycystic ovarian syndrome (see INDICATIONS AND USAGE and WARNINGS). Other. Clomiphene citrate tablets USP is 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).
Special warnings and precautions
PRECAUTIONS General Careful attention should be given to the selection of candidates for clomiphene citrate tablets USP therapy. Pelvic examination is necessary prior to clomiphene citrate tablets USP treatment and before each subsequent course (see CONTRAINDICATIONS and WARNINGS). Information for Patients The purpose and risks of clomiphene citrate tablets USP therapy should be presented to the patient before starting treatment. It should be emphasized that the goal of clomiphene citrate tablets USP therapy is ovulation for subsequent pregnancy. The physician should counsel the patient with special regard to the following potential risks: Visual Symptoms: Advise that blurring or other visual symptoms occasionally may occur during or shortly after clomiphene citrate tablets USP therapy. Warn that visual symptoms may render such activities as driving a car or operating machinery more hazardous than usual, particularly under conditions of variable lighting (see WARNINGS). The patient should be instructed to inform the physician whenever any unusual visual symptoms occur. If the patient has any visual symptoms, treatment should be discontinued and complete ophthalmologic evaluation performed. Abdominal/Pelvic Pain or Distention: Ovarian enlargement may occur during or shortly after therapy with clomiphene citrate tablets USP. To minimize the risks associated with ovarian enlargement, the patient should be instructed to inform the physician of any abdominal or pelvic pain, weight gain, discomfort, or distention after taking clomiphene citrate tablets USP (see WARNINGS). Multiple Pregnancy: Inform the patient that there is an increased chance of multiple pregnancy, including bilateral tubal pregnancy and coexisting tubal and intrauterine pregnancy, when conception occurs in relation to clomiphene citrate tablets USP therapy. The potential complications and hazards of multiple pregnancy should be explained. Pregnancy Wastage and Birth Anomalies: The physician should explain the assumed risk of any pregnancy, whether ovulation is induced with the aid of clomiphene citrate tablets USP or occurs naturally. The patient should be informed of the greater risks associated with certain characteristics or conditions of any pregnant woman, eg., age of female and male partner, history of spontaneous abortions, Rh genotype, abnormal menstrual history, infertility history, organic heart disease, diabetes, exposure to infectious agents such as rubella, familial history of birth anomaly, that may be pertinent to the patient for whom clomiphene citrate tablets USP is being considered. Based upon the evaluation of the patient, genetic counseling may be indicated. The overall incidence of reported birth anomalies from pregnancies associated with maternal clomiphene citrate tablets USP ingestion during the investigational studies was within the range of that reported in published references for the general population. (See CONTRAINDICATIONS: Pregnancy.) During clinical investigation, the experience from patients with known pregnancy outcome (Table 1) shows a spontaneous abortion rate of 20.4% and stillbirth rate of 1.0%. (See CLINICAL PHARMACOLOGY.) Drug Interactions Drug interactions with clomiphene citrate tablets USP 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 tablets USP 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. Pregnancy Pregnancy Category X. (See CONTRAINDICATIONS.) Nursing Mothers It is not known whether clomiphene citrate tablets USP is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if clomiphene citrate tablets USP is administered to a nursing woman. In some patients, clomiphene citrate tablets USP may reduce lactation. Ovarian Cancer Prolonged use of clomiphene citrate tablets USP may increase the risk of a borderline or invasive ovarian tumor (see ADVERSE REACTIONS).
Adverse reactions
ADVERSE REACTIONS Clinical Trial Adverse Events. Clomiphene citrate tablets USP, at recommended dosages, is generally well tolerated. Adverse reactions usually have been mild and transient and most have disappeared promptly after treatment has been discontinued. Adverse experiences reported in patients treated with clomiphene citrate during clinical studies are shown in Table 2. Table 2. Incidence of Adverse Events in Clinical Studies (Events Greater than 1%) (n = 8029*) Adverse Event % Ovarian Enlargement 13.6 Vasomotor Flushes 10.4 Abdominal-Pelvic Discomfort/Distention/Bloating 5.5 Nausea and Vomiting 2.2 Breast Discomfort 2.1 Visual Symptoms 1.5 Blurred vision, lights, floaters, waves, unspecified visual complaints, photophobia, diplopia, scotomata, phosphenes Headache 1.3 Abnormal Uterine Bleeding 1.3 Intermenstrual spotting, menorrhagia * Includes 498 patients whose reports may have been duplicated in the event totals and could not be distinguished as such. Also, excludes 47 patients who did not report symptom data. The following adverse events have been reported in fewer than 1% of patients in clinical trails: 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 tablets USP 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 tablets USP 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 citrate tablets USP may increase the risk of a borderline or invasive ovarian tumor. Postmarketing Adverse Events The following adverse experiences were reported spontaneously with clomiphene citrate tablets USP. The cause and effect relationship of the listed events to the administration of clomiphene citrate tablets USP is not known. Dermatologic: Acne, allergic reaction, erythema, erythema multiforme, erythema nodosum, hypertrichosis, pruritus Central Nervous System: Migraine headache, paresthesia, seizure, stroke, syncope 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 loss of vision Cardiovascular: Arrhythmia, chest pain, edema, hypertension, palpitation, phlebitis, pulmonary embolism, shortness of breath, tachycardia, thrombophlebitis Musculoskeletal: Arthralgia, back pain, myalgia Hepatic: Transaminases increased, hepatitis 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); and neoplasms of offspring (neuroectodermal tumor, thyroid tumor, hepatoblastoma, lymphocytic leukemia) Genitourinary: Endometriosis, ovarian cyst (ovarian enlargement or cysts could, as such, be complicated by adnexal torsion), ovarian hemorrhage, tubal pregnancy, uterine hemorrhage Body as a Whole: Fever, tinnitus, weakness Other: Leukocytosis, thyroid disorder Fetal/Neonatal Anomalies. The following fetal abnormalities have also been reported during postmarketing surveillance: delayed development; abnormal bone development including skeletal malformations of the skull, face, nasal passages, jaw, hand, limb (ectromelia including amelia, hemimelia, and phocomelia), foot, and joints; tissue malformations including imperforate anus, tracheoesophageal fistula, diaphragmatic hernia, renal agenesis and dysgenesis, and malformations of the eye and lens (cataract), ear, lung, heart (ventricular septal defect and tetralogy of Fallot), and genitalia; as well as dwarfism, deafness, mental retardation, chromosomal disorders, and neural tube defects (including anencephaly).

Usage information

Dosing and administration
DOSAGE AND ADMINISTRATION General Considerations The workup and treatment of candidates for clomiphene citrate tablets USP therapy should be supervised by physicians experienced in management of gynecologic or endocrine disorders. Patients should be chosen for therapy with clomiphene citrate tablets USP only after careful diagnostic evaluation (see INDICATIONS AND USAGE). The plan of therapy should be outlined in advance. Impediments to achieving the goal of therapy must be excluded or adequately treated before beginning clomiphene citrate tablets USP. The therapeutic objective should be balanced with potential risks and discussed with the patient and others involved in the achievement of a pregnancy. Ovulation most often occurs from 5 to 10 days after a course of clomiphene citrate tablets USP. Coitus should be timed to coincide with the expected time of ovulation. Appropriate tests to determine ovulation may be useful during this time. Recommended Dosage Treatment of the selected patient should begin with a low dose, 50 mg daily (1 tablet) for 5 days. The dose should be increased only in those patients who do not ovulate in response to cyclic 50 mg clomiphene citrate tablets USP. A low dosage or duration of treatment course is particularly recommended if unusual sensitivity to pituitary gonadotropin is suspected, such as in patients with polycystic ovary syndrome (see WARNINGS; Ovarian Hyperstimulation Syndrome). The patient should be evaluated carefully to exclude pregnancy, ovarian enlargement, or ovarian cyst formation between each treatment cycle. If progestin-induced bleeding is planned, or if spontaneous uterine bleeding occurs prior to therapy, the regimen of 50 mg daily for 5 days should be started on or about the 5th day of the cycle. Therapy may be started at any time in the patient who has had no recent uterine bleeding. When ovulation occurs at this dosage, there is no advantage to increasing the dose in subsequent cycles of treatment. If ovulation does not appear to occur after the first course of therapy, a second course of 100 mg daily (two 50 mg tablets given as a single daily dose) for 5 days should be given. This course may be started as early as 30 days after the previous one after precautions are taken to exclude the presence of pregnancy. Increasing the dosage or duration of therapy beyond 100 mg/day for 5 days is not recommended. The majority of patients who are going to ovulate will do so after the first course of therapy. If ovulation does not occur after three courses of therapy, further treatment with clomiphene citrate tablets USP is not recommended and the patient should be reevaluated. If three ovulatory responses occur, but pregnancy has not been achieved, further treatment is not recommended. If menses does not occur after an ovulatory response, the patient should be reevaluated. Long-term cyclic therapy is not recommended beyond a total of about 6 cycles (see PRECAUTIONS).
Pregnancy and lactation
Nursing Mothers It is not known whether clomiphene citrate tablets USP is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if clomiphene citrate tablets USP is administered to a nursing woman. In some patients, clomiphene citrate tablets USP may reduce lactation.

Interactions

Drug Interactions Drug interactions with clomiphene citrate tablets USP have not been documented.

More information

Category Value
Authorisation number NDA016131
Agency product number 1B8447E7YI
Orphan designation No
Product NDC 43063-250
Date Last Revised 09-06-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1093060
Marketing authorisation holder PD-Rx Pharmaceuticals, Inc.