Data from FDA - Curated by Marshall Pearce - Last updated 06 November 2017

Indication(s)

INDICATIONS AND USAGE Clomiphene citrate 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 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 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 is indicated only in patients with demonstrated ovulatory dysfunction who meet the conditions described below (see CONTRAINDICATIONS): 1.Patients who are not pregnant. 2.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. 3.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. 4.Patients with normal liver function. In addition, patients selected for clomiphene citrate therapy should be evaluated in regard to the following: 1.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. 2.Primary Pituitary or Ovarian Failure. Clomiphene citrate therapy cannot be expected to substitute for specific treatment of other causes of ovulatory failure. 3.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. 4.Other Impediments to Pregnancy. Impediments to pregnancy can include thyroid disorders, adrenal disorders, hyperprolactinemia, and male factor infertility. 5.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.

Learning Zones

An epgonline.org Learning Zone (LZ) is an area of the site dedicated to providing detailed self-directed medical education about a disease, condition or procedure.

ALP Lab Assessment

ALP Lab Assessment

Discover and overview of hypophosphatasia and details required to facilitate the timely and accurate detection of low alkaline phosphatase.

Acute and Advanced Heart Failure

Acute and Advanced Heart Failure

What are the most effective treatments for acute heart failure? Can you define advanced heart failure? Discover here...

+ 3 more

Airway Disease

Airway Disease

The Airway Disease Learning Zone is an area where you can access the information about VisionAir and see video presentations from the forum. The Inhalation Technology page features a video presentation from the live broadcast presented by key faculty.

Load more

Related Content

Advisory information

contraindications
CONTRAINDICATIONS Hypersensitivity Clomiphene citrate is contraindicated in patients with a known hypersensitivity or allergy to clomiphene citrate or to any of its ingredients. Pregnancy Pregnancy Category X. Clomiphene citrate use in pregnant women is contraindicated, as clomiphene citrate does not offer benefit in this population. Available human data do not suggest an increased risk for congenital anomalies above the background population risk when used as indicated. However, animal reproductive toxicology studies showed increased embryo-fetal loss and structural malformations in offspring. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risks to the fetus. (See PRECAUTIONS: Pregnancy). Liver Disease. Clomiphene citrate 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 is contraindicated in patients with abnormal uterine bleeding of undetermined origin (see INDICATIONS AND USAGE). Ovarian Cysts. Clomiphene citrate is contraindicated in patients with ovarian cysts or enlargement not due to polycystic ovarian syndrome (see INDICATIONS AND USAGE and WARNINGS). Other. Clomiphene citrate 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 therapy. Pelvic examination is necessary prior to clomiphene citrate treatment and before each subsequent course (see CONTRAINDICATIONS and WARNINGS). Information for Patients The purpose and risks of clomiphene citrate therapy should be presented to the patient before starting treatment. It should be emphasized that the goal of clomiphene citrate 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 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. 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 (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 therapy. The potential complications and hazards of multiple pregnancy should be explained. Spontaneous Abortion and Congenital Anomalies: Inform the patient that the available data suggest no increase in the rates of spontaneous abortion (miscarriage) or congenital anomalies with maternal clomiphene citrate use compared to rates in the general population. 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 STUDIES). Among the birth anomalies spontaneously reported as individual cases since commercial availability of clomiphene citrate, the proportion of neural tube defects has been high among pregnancies associated with ovulation induced by clomiphene citrate, but this has not been supported by data from population-based studies. Drug Interactions Drug interactions with clomiphene citrate have not been documented. Carcinogenesisand Mutagenesis andImpairment 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 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 Fetal Risk Summary Pregnancy Category X. (See CONTRAINDICATIONS.) Clomiphene citrate use in pregnant women is contraindicated, as clomiphene citrate treatment does not offer benefit in this population. Available human data do not suggest an increased risk for congenital anomalies above the background population risk. However, animal reproductive toxicology studies showed increased embryo-fetal loss and structural malformations in offspring. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risks to the fetus. Clinical Considerations 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. Patients should be evaluated carefully to exclude ovarian enlargement or ovarian cyst formation between each treatment cycle. The next course of clomiphene citrate therapy should be delayed until these conditions have been excluded. Human Data The available human data from epidemiologic studies do not show any apparent cause and effect relationship between clomiphene citrate periconceptual exposure and an increased risk of overall birth defects, or any specific anomaly. However, due to the small number of cases of congenital anomalies occurring in clomiphene citrate treated women, these epidemiologic studies were only able to rule out large differences in risk. The studies did not consider factors associated with female subfertility and were unable to adjust for other important confounders. In addition, available data do not support an increase rate of spontaneous abortion among subfertile women treated with clomiphene for ovulation induction. Animal Data 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. Nursing Mothers It is not known whether clomiphene citrate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if clomiphene citrate is administered to a nursing woman. In some patients, clomiphene citrate 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, 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*) *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. 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 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.

Usage information

Dosing and administration
DOSAGE AND ADMINISTRATION GeneralConsiderations The workup and treatment of candidates for clomiphene citrate therapy should be supervised by physicians experienced in management of gynecologic or endocrine disorders. Patients should be chosen for therapy with clomiphene citrate 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. 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. Coitus should be timed to coincide with the expected time of ovulation. Appropriate tests to determine ovulation may be useful during this time. RecommendedDosage 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. 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 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 six cycles (see PRECAUTIONS).

More information

Category Value
Authorisation number ANDA075528
Agency product number 1B8447E7YI
Orphan designation No
Product NDC 50090-0678
Date Last Revised 19-10-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1093060
Marketing authorisation holder A-S Medication Solutions