Brand names: Clomid, Serophene
Drug class: Estrogen Agonists-Antagonists
- Antiestrogens
ATC class: G03XC
VA class: HS400
CAS number: 50-41-9

Introduction

Estrogen agonist-antagonist; a nonsteroidal ovulatory stimulant.

Uses for clomiPHENE

Female Infertility

Used to induce ovulation in appropriately selected anovulatory women desiring pregnancy in whom ovulatory dysfunction has been demonstrated. (See General under Dosage and Administration and also see Contraindications under Cautions.)

Optimum results obtained in patients with adequately functioning anterior pituitary gland, adrenals, ovaries, and thyroid, including women with polycystic ovary syndrome, amenorrhea-galactorrhea syndrome, psychogenic amenorrhea, post-oral-contraceptive amenorrhea, and certain cases of secondary amenorrhea of unknown etiology. Better results usually obtained in patients with adequate serum estrogen concentrations; however, reduced serum estrogen concentrations do not always preclude successful therapy.

Use recommended only in women who are not pregnant, without ovarian cysts or ovarian enlargement (unless enlargement is due to polycystic ovarian syndrome), with normal liver function, and with no abnormal vaginal bleeding. (See General under Dosage and Administration and also see Contraindications under Cautions.)

Ineffective in patients with primary pituitary or ovarian failure; not a substitute for appropriate therapy of other conditions that may cause ovulatory dysfunction (e.g., thyroid or adrenal disease).

Manufacturer states that clomiphene is not recommended to induce ovulation associated with in vitro fertilization programs.

clomiPHENE Dosage and Administration

General

• Should be prescribed by clinicians experienced in management of gynecologic and endocrine disorders.

• Carefully evaluate patient prior to each course of therapy to exclude pregnancy, ovarian enlargement, or ovarian cyst formation. (See the following sections under Cautions: Ovarian Enlargement and Cyst Formation, and Ovarian Hyperstimulation Syndrome, and Adequate Patient Evaluation and Monitoring, and Contraindications.)

• Prior to initiating therapy, carefully evaluate patient for adequate endogenous estrogen levels, for primary pituitary or ovarian failure, and for the presence of endometriosis, endometrial carcinoma, or uterine fibroids. Exclude or treat all impediments to achieving ovulation and conception (e.g., thyroid disorders, adrenal disorders, hyperprolactinemia, male partner infertility). (See Adequate Patient Evaluation and Monitoring and also see Uterine Fibroids, under Cautions.)

• Therapy may be started at any time in patients with no recent uterine bleeding. If progestin-induced bleeding is planned, or if spontaneous uterine bleeding occurs prior to therapy, initiate regimen on the fifth day of the menstrual cycle. Once ovulation has been established, initiate each subsequent course of therapy on the fifth day of the menstrual cycle. Reevaluate patient if ovulatory menses does not occur.

• Majority of responding patients will ovulate after the first course of therapy, generally within 5–10 days.

• Prolonged amenorrhea may be less responsive and may require ≥2 cycles of therapy.

• Likelihood of conception decreases with each succeeding course of therapy.

Administration

Oral Administration

Administer orally once daily.

Dosage

Available as clomiphene citrate; dosage expressed in terms of the salt.

Adults

Female Infertility

Oral

Initially, 50 mg once daily for 5 days.

If ovulation occurs after initial course of therapy, continue with initial dosage of 50 mg once daily for 5 days starting on the fifth day of the menstrual cycle in subsequent treatment cycles. If 3 ovulatory responses occur, but pregnancy is not achieved, further treatment not recommended.

If ovulation does not occur after initial course of therapy, increase to 100 mg daily for 5 days, starting ≥30 days after previous course of therapy. If ovulation does not occur after 3 courses of therapy, further treatment not recommended; reevaluate patient.

≥6 cycles of therapy (including 3 ovulatory cycles) not recommended.

Prescribing Limits

Adults

Female Infertility

Oral

Maximum 100 mg daily for 5 days.

Maximum 6 cycles of therapy (including 3 ovulatory cycles); safety of long-term cyclic use not conclusively demonstrated.

Special Populations

No special population dosage recommendations at this time.

Cautions for clomiPHENE

Contraindications

• Pregnancy. (See Fetal/Neonatal Morbidity and Morality under Cautions.)

• Liver disease or history of liver dysfunction.

• Abnormal uterine bleeding of undetermined origin.

• Ovarian cysts or enlargement (unless due to polycystic ovarian syndrome). (See Ovarian Hyperstimulation Syndrome under Cautions.)

• Uncontrolled thyroid or adrenal dysfunction.

• Presence of an organic intracranial lesion (e.g., pituitary tumor).

• Known hypersensitivity to clomiphene or any ingredient in the formulation.

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and fetotoxicity demonstrated in animals.

Contraindicated in pregnant women. Carefully observe patients to determine if ovulation occurs; record basal body temperature throughout all treatment cycles, and discontinue therapy if pregnancy is suspected. Exclude pregnancy, ovarian cyst, or ovarian enlargement between treatment cycles.

Ocular Effects

Dose-related adverse ocular effects (i.e., blurring of vision, scotomata, electroretinographic changes in retinal function, phosphenes, diplopia, photophobia, decreased visual acuity) reported; adverse ocular effects generally disappear a few days to weeks following discontinuance of therapy.

Visual symptoms may result from intensification and prolongation of after-images and may be precipitated by a brightly lit environment.

Discontinue therapy if visual symptoms occur; prompt ophthalmologic evaluation recommended.

Ovarian Enlargement and Cyst Formation

Risk of uncomplicated ovarian enlargement and cyst formation; may be accompanied by abdominal or pelvic pain, or distension. Generally regresses within days or weeks after discontinuing therapy.

Monitor for signs and symptoms of excessive ovarian stimulation (e.g., pelvic pain). If ovarian enlargement or cyst development occurs, withhold therapy until ovaries return to pretreatment size; maximum enlargement of ovaries may not occur until several days after therapy is discontinued. If benefits of continuing therapy outweigh risks, reduce dosage or duration of the next course of therapy.

Ovarian Hyperstimulation Syndrome (OHSS)

Risk of potentially severe OHSS; may progress rapidly and is initially manifested by abdominal pain and distension, nausea, vomiting, diarrhea, and weight gain. Other symptoms include gross ovarian enlargement, ascites, dyspnea, oliguria, and pleural effusion. Pericardial effusion, anasarca, hydrothorax, acute abdomen, hypotension, renal failure, pulmonary edema, intraperitoneal and ovarian hemorrhage, deep-venous thrombosis, torsion of the ovary, acute respiratory distress, elevated urinary steroid levels, electrolyte imbalances, and hypoproteinemia may occur. Fatalities due to hypovolemia, hemoconcentration, and thromboembolism reported.

Transient liver function test abnormalities, which may be accompanied by morphologic changes (as detected by liver biopsy) have been reported.

If ovaries are abnormally enlarged, discontinue therapy until ovaries return to pretreatment size; reduce dosage or duration of the next course of therapy. Perform abdominal and pelvic examinations with caution due to fragility of enlarged ovaries.

Hepatic Effects

Increased retention of sulfobromophthalein has occurred. One case of jaundice (due to bile stasis) has been reported.

Polycystic Ovary Syndrome

Potential for exaggerated response (e.g, ovarian hyperstimulation) to usual dosages of clomiphene in patients with polycystic ovary syndrome who are overly sensitive to gonadotropin. (See Ovarian Hyperstimulation Syndrome under Cautions.) Initially, administer lowest recommended dose and shortest treatment duration. (See Dosage under Dosage and Administration.)

Ovarian Cancer

Risk of borderline or invasive ovarian tumors; may be associated with prolonged therapy. Careful evaluation to rule out ovarian cancer recommended if ovarian cysts do not regress spontaneously.

General Precautions

Adequate Patient Evaluation and Monitoring

Prior to initiating therapy and each subsequent course of therapy, perform a thorough pelvic examination and rule out pregnancy, ovarian enlargement, or ovarian cyst. (See Contraindications under Cautions.)

Prior to initiating therapy, evaluate for adequate endogenous estrogen levels (e.g., from vaginal smears, endometrial biopsy, urinary estrogen assay, and bleeding response to progesterone).

Prior to initiating therapy, evaluate liver function.

If abnormal vaginal bleeding is present, evaluate carefully to rule out neoplastic lesions.

Perform endometrial biopsy prior to initiating therapy in women with increased risk of endometriosis or endometrial carcinoma (e.g., older women).

Uterine Fibroids

Possible enlargement of existing uterine fibroids; use with caution in women with uterine fibroids.

Plural Gestation

Risk of multiple ovulations with resulting plural gestations, including bilateral tubal pregnancy and coexisting tubal and intrauterine pregnancy; may be associated with higher dosages. (See Prescribing Limits under Dosage and Administration.)

Specific Populations

Pregnancy

Category X. (See Fetal/Neonatal Morbidity and Mortality and also see Contraindications, under Cautions.)

Lactation

Not known whether clomiphene is distributed into milk. Caution if used in nursing women. Clomiphene may reduce lactation in some women.

Men

Testicular tumors and gynecomastia reported; however, causal relationship between testicular tumors and clomiphene not determined.

Common Adverse Effects

Ovarian enlargement; abdominal or pelvic discomfort including distention, bloating, or pain; hot flushes (flashes).

Drug Interactions

No known drug interactions.

clomiPHENE Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration.

Elimination

Metabolism

Exact metabolic fate not clearly established; drug appears to be metabolized in the liver.

Elimination Route

Excreted in the feces (42%) and urine (8%).

Half-life

5 days; however, radioactivity detected in feces up to 6 weeks following oral administration of radiolabeled drug.

Stability

Storage

Oral

Tablets

Tight, light resistant containers at 15–30°C; protect from heat and excess humidity.

Actions

• Exhibits estrogenic and anti-estrogenic properties; precise mechanism of action in ovulation induction of anovulatory women unknown.

• Interacts with estrogen-receptor containing tissues (e.g., hypothalamus, pituitary, ovary, endometrium, vagina, cervix). May compete with estrogen for estrogen-receptor-binding sites and may delay replenishment of estrogen receptors.

• Appears to stimulate release of the pituitary gonadotropins, FSH and LH, which results in development and maturation of the ovarian follicle, ovulation, and subsequent development and function of the corpus luteum. May also directly affect the biosynthesis of ovarian hormones.

• No known progestational, androgenic, or antiandrogenic effects; does not appear to affect pituitary-adrenal or pituitary-thyroid function.

Advice to Patients

• Importance of discussing purpose and risks of therapy and required monitoring procedures.

• Risk of multiple pregnancy; importance of informing patients about potential complications and risks associated with multiple pregnancies.

• Importance of properly timed sexual intercourse (i.e., coinciding with expected time of ovulation). Importance of using a basal body temperature graph or an appropriate ovulation predicting test to determine if ovulation has occurred.

• Risk of visual disturbances (e.g., blurring, diplopia, photophobia); importance of informing clinicians if any adverse visual symptoms occur. Use caution when driving or operating machinery, particularly under conditions of variable lighting.

• Importance of informing clinicians if pelvic or abdominal pain, weight gain, discomfort, or distention occurs.

• Importance of advising women of risk of fetal harm if administered during pregnancy; importance of excluding pregnancy before each course of treatment.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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Frequently asked questions

• What are the uses and side effects of enclomiphene capsules?

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