Clomifene

BRAND NAMES

• Clomid – most widely known brand name globally

• Serophene – commonly used in North America

• Omifin – available in Europe and parts of Asia

• Clostilbegyt – widely used in Eastern Europe

• Fertomid – common in India and other Asian markets

• Milophene – used in select international markets

MECHANISM OF ACTION

Clomifene is a selective estrogen receptor modulator (SERM) that acts mainly by blocking estrogen receptors in the hypothalamus. This reduces the normal negative feedback of estrogen, making the brain perceive low estrogen levels. As a result, the hypothalamus increases secretion of gonadotropin-releasing hormone (GnRH), which stimulates the pituitary gland to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH).

PHARMACOKINETICS

Absorption

Clomifene is well absorbed orally from the gastrointestinal tract after administration. It undergoes extensive first-pass metabolism in the liver, resulting in active metabolites with a long half-life. Peak plasma levels are usually reached within a few hours, but the drug and its metabolites persist in the body for several days due to enterohepatic recirculation.

Distribution

Clomifene has a high volume of distribution (Vd), typically indicating extensive distribution into tissues. It is highly lipophilic, widely distributed in body fat, and strongly bound to plasma proteins, which contributes to its prolonged presence in the body.

Metabolism

Clomifene is extensively metabolized in the liver, mainly by hepatic enzymes, into active and inactive metabolites. It undergoes enterohepatic recirculation, which prolongs its duration of action. The metabolites, especially zuclomifene and enclomifene, contribute to its pharmacological effects and long half-life.

Elimination

Clomifene is eliminated mainly through feces via biliary excretion, with a small amount excreted in urine. Because of enterohepatic recycling and tissue accumulation, it has a long elimination half-life, and the drug and its metabolites may persist in the body for several days to weeks after stopping treatment.

PHARMACODYNAMICS

Clomifene is a selective estrogen receptor modulator that acts mainly as an estrogen antagonist in the hypothalamus. It blocks negative feedback of estrogen, increasing GnRH release, which raises FSH and LH levels. This stimulates ovarian follicle growth and induces ovulation.

ADMINISTRATION

Clomifene is administered orally in tablet form. It is usually given in low doses for 5 days early in the menstrual cycle (commonly starting on day 2–5) to induce ovulation. Dosage is adjusted based on patient response and clinical monitoring.

DOSAGE AND STRENGTH

Clomifene is commonly available as oral tablets in strengths of 25 mg and 50 mg. The usual starting dose for ovulation induction is 50 mg once daily for 5 days, typically beginning on day 2–5 of the menstrual cycle. If ovulation does not occur, the dose may be increased in subsequent cycles up to a maximum of 150 mg per day for 5 days, under medical supervision.

DRUG INTERACTIONS

Clomifene may interact with estrogen-containing drugs, which can reduce its effect by restoring normal negative feedback. Drugs affecting liver enzymes may alter its metabolism, while combination with other fertility agents can increase the risk of ovarian hyperstimulation and multiple pregnancies.

FOOD INTERACTIONS

Clomifene has no significant food interactions, and it can be taken with or without food. However, maintaining a consistent dosing schedule is recommended to ensure stable absorption and effectiveness.

CONTRAINDICATIONS

Clomifene is contraindicated in pregnancy, liver disease, and in patients with uncontrolled thyroid or adrenal disorders. It should not be used in those with abnormal uterine bleeding of unknown cause, ovarian cysts not related to polycystic ovary syndrome, or hormone-dependent tumors. It is also avoided in individuals with hypersensitivity to the drug.

SIDE EFFECTS

• Hot flushes

• Abdominal discomfort

• Nausea

• Breast tenderness

• Headache

• Mood changes

• Visual disturbances

• Ovarian enlargement

• Ovarian hyperstimulation syndrome

• Multiple pregnancies

OVRE DOSE

• Ovarian hyperstimulation (enlarged ovaries, abdominal pain, ascites) 

• Severe pelvic pain 

• Nausea and vomiting 

• Visual disturbances (blurred vision, flashes) 

• Hot flushes 

• Abdominal distension 

TOXICITY

Clomifene toxicity is usually due to excessive ovarian stimulation, leading to ovarian hyperstimulation syndrome with abdominal pain, ovarian enlargement, nausea, and vomiting. It may also cause visual disturbances and abdominal distension. Severe cases can rarely lead to thromboembolic complications, and management is mainly supportive with drug discontinuation.