CLOMIPHENE CITRATE
Clinical safety rating: safe
Animal studies have demonstrated safety
Selective estrogen receptor modulator; competes with estrogen for binding at estrogen receptors in the hypothalamus, inhibiting negative feedback and increasing gonadotropin-releasing hormone (GnRH) secretion, leading to increased LH and FSH release from the pituitary.
| Metabolism | Hepatic metabolism; excreted in feces; active metabolites (possibly enterohepatic recirculation). |
| Excretion | Primarily fecal (approximately 50%), with about 8% renal excretion of unchanged drug and metabolites. Biliary excretion is significant, with enterohepatic recirculation contributing to prolonged elimination. |
| Half-life | Terminal elimination half-life is approximately 5–7 days (120–168 hours) for the active zu-isomer, with a longer half-life for its metabolites. This prolonged half-life leads to accumulation with repeated dosing and sustained clinical effects. |
| Protein binding | Approximately 80–90% bound to albumin, with significant binding to other plasma proteins including sex hormone-binding globulin (SHBG). |
| Volume of Distribution | Apparent volume of distribution is large, approximately 50–100 L/kg, indicating extensive tissue distribution and accumulation, particularly in the liver and reproductive organs. |
| Bioavailability | Oral: ~100% absorbed, but bioavailability is difficult to quantify due to extensive first-pass metabolism and enterohepatic cycling; essentially complete systemic exposure after oral administration. |
| Onset of Action | Oral: 5–10 days for therapeutic effect on ovulation induction; peak effect on gonadotropin release occurs within 5–10 days of a 5-day course. |
| Duration of Action | Duration of effect on ovulation lasts approximately 5–10 days after a 5-day course, but antiestrogenic effects (e.g., on cervical mucus) may persist for up to 2–3 weeks. The drug can be detected in plasma for up to 6 weeks due to its long half-life. |
| Molecular Weight | 598.08 Da (as clomiphene citrate; clomiphene base is 405.96 Da) |
50 mg orally once daily for 5 days, starting on day 5 of menstrual cycle; may increase to 100 mg orally once daily for 5 days if ovulation not achieved.
| Dosage form | TABLET |
| Renal impairment | No specific dose adjustment guidelines; use with caution in severe renal impairment (CrCl <30 mL/min) due to limited data. |
| Liver impairment | Contraindicated in patients with liver disease or hepatic dysfunction; no Child-Pugh based adjustments available. |
| Pediatric use | Not recommended for use in children; safety and efficacy not established. |
| Geriatric use | Not indicated for use in elderly patients; no specific dosing recommendations. |
| 1st trimester | Clomiphene citrate is contraindicated in pregnancy. It is classified as FDA Pregnancy Category X. There is evidence of fetal harm in animal studies, and it is used for ovulation induction, so pregnancy should be excluded before and during therapy. Use in the first trimester may cause fetal abnormalities, including neural tube defects and congenital heart defects. |
| 2nd trimester | Contraindicated in pregnancy. There is no indication for use during the second trimester. |
| 3rd trimester | Contraindicated in pregnancy. There is no indication for use during the third trimester. |
Clinical note
No significant drug interactions May cause visual disturbances and ovarian hyperstimulation syndrome.
| Placental transfer | Clomiphene citrate and its metabolites have been shown to cross the placenta in animal studies. In humans, placental transfer is expected based on its lipophilic nature and molecular weight, though specific data are limited. Fetal exposure can occur, and it is contraindicated in pregnancy due to teratogenic risk. |
| Breastfeeding |
■ FDA Black Box Warning
Should not be used in patients with liver disease or abnormal uterine bleeding of undetermined origin.
| Common Effects | Ovarian enlargement |
| Serious Effects |
Hypersensitivity to clomiphene or any componentPregnancy (Category X)Liver disease or history of liver dysfunctionAbnormal uterine bleeding of undetermined originOvarian cyst or enlarged ovary not due to polycystic ovary syndromeEndometrial carcinomaThyroid or adrenal dysfunctionIntracranial lesion such as pituitary tumor
| Precautions | Ovarian enlargement/cysts; visual disturbances; multiple pregnancy; ovarian hyperstimulation syndrome; vasomotor symptoms; blurred vision; prolonged use may increase risk of borderline or invasive ovarian tumors. |
| Food/Dietary | No significant food interactions. Avoid excessive alcohol consumption as it may impair fertility. |
Loading safety data…
| It is unknown whether clomiphene citrate is excreted into human milk. Due to the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. The long half-life and potential for hormonal effects suggest caution. |
| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | FDA Pregnancy Category X. Clomiphene citrate is contraindicated in pregnancy. First trimester exposure associated with neural tube defects, cleft palate, and syndactyly. Second and third trimester: no data due to contraindication. Risk of multiple gestation (5-12%) increases risks of preterm labor, low birth weight, and congenital anomalies. |
| Fetal Monitoring | Monitor ovarian response with ultrasound and serum estradiol to detect ovarian hyperstimulation syndrome (OHSS). Perform pregnancy test before each cycle if menses not followed. In pregnancy, monitor for multiple gestation and ectopic pregnancy. Assess for signs of OHSS (rapid weight gain, abdominal pain, oliguria). |
| Fertility Effects | Induces ovulation in anovulatory women by blocking estrogen receptors at hypothalamus, increasing gonadotropin release. May cause luteal phase defects. Overuse may deplete ovarian follicles. No proven negative effect on oocyte quality when used appropriately. |
| Clinical Pearls | Monitor ovarian size and estradiol levels to reduce risk of ovarian hyperstimulation syndrome (OHSS). Use only in patients with ovulatory dysfunction; rule out pregnancy before each cycle. Limit to 6 treatment cycles due to increased risk of ovarian cancer with prolonged use. |
| Patient Advice | Take clomiphene citrate exactly as prescribed, typically for 5 days starting on day 3-5 of menstrual cycle. · Ovulation usually occurs 5-10 days after the last dose; have intercourse every other day during this window. · Common side effects include hot flashes, mood swings, and visual disturbances; report persistent visual changes immediately. · Risk of multiple pregnancy (mainly twins) is increased; discuss with healthcare provider. · Avoid use if pregnant, have liver disease, or have abnormal vaginal bleeding. |