Tamoxifen Citrate

Approved Indications:

• Breast Cancer (Estrogen Receptor-Positive):
• Adjuvant treatment of early-stage ER-positive breast cancer in both premenopausal and postmenopausal women.
• Metastatic breast cancer in both men and women.
• Ductal carcinoma in situ (DCIS) after breast surgery and radiation therapy to reduce the risk of invasive breast cancer.
• Breast cancer risk reduction in high-risk women (e.g., strong family history, BRCA mutations).

Off-label / Clinically Accepted Uses:

• Gynecomastia in males, particularly associated with prostate cancer treatment.
• Ovulation induction in women with anovulatory infertility (alternative to clomiphene).
• McCune-Albright syndrome and precocious puberty in pediatric patients (limited use).
• Desmoid tumors and hormone-sensitive soft tissue tumors in select patients.

Adults:

• Adjuvant treatment of breast cancer:
  20 mg orally once daily for 5 to 10 years.
• Metastatic breast cancer:
  20 to 40 mg orally per day in divided doses (morning and evening if >20 mg/day).
• Ductal carcinoma in situ (DCIS):
  20 mg orally once daily for 5 years.
• Breast cancer risk reduction:
  20 mg orally once daily for 5 years.

Pediatric Use (limited, specialist supervision):

• Precocious puberty (girls):
  20 mg/day orally; adjusted based on response.

Male Gynecomastia (off-label):

• 10 to 20 mg orally twice daily for up to 3 months.

Ovulation Induction (off-label):

• 10 to 40 mg/day orally from Day 2–5 of cycle for 5 days.

Special Populations:

• Renal Impairment:
  No dose adjustment typically required; monitor closely.
• Hepatic Impairment:
  Use with caution in severe hepatic dysfunction due to extensive hepatic metabolism.
• Elderly:
  No specific dose adjustment required; monitor for thromboembolic events.

Administration Tips:

• Administer with or without food.
• Swallow whole; do not crush or chew tablets.
• Consistency in timing (e.g., same time daily) improves adherence.

Tamoxifen Citrate is a selective estrogen receptor modulator (SERM) that competitively binds to estrogen receptors on tumors and other tissue targets. In breast tissue, it acts as an estrogen antagonist, blocking estrogen-dependent proliferation of cancer cells. In contrast, it can act as an estrogen agonist in the bone, endometrium, and lipid metabolism, which accounts for its complex therapeutic and side effect profile. By preventing estrogen binding, tamoxifen slows or halts the growth of estrogen receptor-positive cancer cells.

• Absorption:
  Well absorbed orally; peak plasma concentrations reached in 4–7 hours.
• Bioavailability:
  High; not significantly affected by food.
• Distribution:
  Highly protein-bound (>99%), mainly to albumin. Widely distributed.
• Metabolism:
  Extensively hepatic via CYP3A4, CYP2D6, and CYP2C9 enzymes.
  Major active metabolite: Endoxifen (4-hydroxy-N-desmethyl tamoxifen), significantly more potent.
• Half-life:
  Tamoxifen: ~5–7 days
  Endoxifen: ~9–14 days
• Elimination:
  Mainly via feces through biliary excretion; minor renal clearance.

• Pregnancy:
  Category D – Positive evidence of human fetal risk. Contraindicated in pregnancy due to teratogenic effects (risk of birth defects, fetal death).
• Lactation:
  Not recommended. Tamoxifen and its metabolites are excreted into breast milk. Potential risk to the infant includes hormonal effects and toxicity. Breastfeeding should be discontinued during therapy.

• Primary Class:
  Selective Estrogen Receptor Modulator (SERM)
• Subclass:
  Nonsteroidal anti-estrogen; First-generation SERM

• Known hypersensitivity to tamoxifen or any component of the formulation.
• History of deep vein thrombosis (DVT) or pulmonary embolism (PE).
• Concurrent use with warfarin for DCIS or breast cancer prevention.
• Pregnancy or women planning to become pregnant.
• Patients with hereditary thromboembolic disorders (e.g., Factor V Leiden mutation).

• Thromboembolic Events:
  Increased risk of DVT, PE, and stroke. Monitor high-risk patients closely.
• Endometrial Cancer Risk:
  Acts as an estrogen agonist in the uterus. Increased risk of endometrial hyperplasia, polyps, and cancer.
• Ocular Effects:
  Risk of cataracts and retinopathy with prolonged use.
• Hepatic Dysfunction:
  Rare reports of fatty liver, cholestasis, and hepatitis; monitor liver enzymes periodically.
• Hypercalcemia:
  May occur in metastatic breast cancer patients; discontinue if symptomatic.
• Menstrual Irregularities:
  May affect fertility; contraception required during treatment and for 2 months after discontinuation.

Common Side Effects:

• General: Fatigue, headache, hot flashes, weight gain
• Gastrointestinal: Nausea, vomiting, constipation
• Reproductive/Endocrine: Irregular menses, vaginal dryness/discharge
• Musculoskeletal: Leg cramps, myalgia
• Dermatologic: Rash, alopecia

Serious or Rare Side Effects:

• Thromboembolism (DVT, PE, stroke)
• Endometrial carcinoma
• Ocular toxicity (cataracts, retinopathy)
• Hepatotoxicity
• Uterine sarcoma (very rare)
• Depression, mood swings

Timing/Severity:

• Estrogenic side effects (hot flashes, menstrual changes) typically appear early.
• Thrombotic and hepatic events may occur months to years later and require regular monitoring.

• Major CYP interactions:
• CYP2D6 inhibitors (e.g., fluoxetine, paroxetine): ↓ Conversion to endoxifen → ↓ Efficacy
• CYP3A4 inducers (e.g., rifampicin): ↓ Tamoxifen levels → ↓ Effectiveness
• Warfarin:
  Increased bleeding risk; contraindicated when used for cancer risk reduction.
• SSRIs (fluoxetine, paroxetine):
  Strong CYP2D6 inhibitors; may reduce tamoxifen efficacy.
• Other estrogen-containing therapies:
  Antagonize tamoxifen action; avoid combination.
• Alcohol:
  May exacerbate liver side effects; use cautiously.

• ASCO (American Society of Clinical Oncology) guidelines support 10 years of tamoxifen use for eligible women with ER-positive breast cancer.
• Recent data highlight the importance of CYP2D6 genotyping in personalizing therapy, especially regarding endoxifen exposure.
• FDA warning label updated to reinforce risks of uterine malignancy and thromboembolism.
• Ongoing research into combining tamoxifen with ovarian suppression in premenopausal women for enhanced benefit.

• Temperature:
  Store below 30°C (86°F) in a dry place.
• Humidity/Light:
  Protect from moisture and direct light.
• Handling Precautions:
  Keep out of reach of children.
  Do not use if tablets are discolored or show signs of deterioration.
• Reconstitution/Refrigeration:
  Not applicable; available in tablet form only.