LETROZOLE
Clinical safety rating: avoid
Contraindicated (not allowed)
Letrozole is a nonsteroidal aromatase inhibitor. It inhibits the aromatase enzyme, which converts androgens to estrogens, thereby reducing estrogen levels in postmenopausal women and suppressing estrogen-dependent tumor growth.
| Metabolism | Letrozole is extensively metabolized in the liver, primarily by CYP3A4 and CYP2A6 enzymes, to a pharmacologically inactive carbinol metabolite. |
| Excretion | Primarily hepatic metabolism (CYP3A4, CYP2A6) with 90% excreted in urine as metabolites (glucuronide conjugates) and 10% in feces. <6% excreted unchanged in urine. |
| Half-life | Terminal elimination half-life approximately 45 hours (range 42-52 hours). Steady-state achieved in 2-6 weeks with daily dosing. |
| Protein binding | 60% bound to plasma proteins, mainly albumin (40%) and alpha-1-acid glycoprotein (20%). |
| Volume of Distribution | 1.9 L/kg (range 1.6-2.4 L/kg). Extensive distribution into peripheral tissues including breast tissue, with concentrations higher than serum. |
| Bioavailability | Oral bioavailability is 99.9% (well absorbed, minimal first-pass metabolism). |
| Onset of Action | Oral: Maximal suppression of serum estradiol (80-90%) occurs within 2-3 days of a single 2.5 mg dose; clinical antitumor effect (tumor regression) typically observed after 4-12 weeks of continuous therapy. |
| Duration of Action | Duration of estradiol suppression persists for 48-72 hours after last dose; rebound to baseline estrogen levels may take 7-14 days after treatment discontinuation. Clinical effects (e.g., tumor response) continue as long as estrogen suppression is maintained. |
2.5 mg orally once daily
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for creatinine clearance >=10 mL/min. Not studied in patients with creatinine clearance <10 mL/min. |
| Liver impairment | Child-Pugh A or B: no adjustment. Child-Pugh C: not studied; use with caution. |
| Pediatric use | Safety and efficacy not established in pediatric patients. |
| Geriatric use | No specific dose adjustment; use standard adult dosing in elderly. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Tamoxifen may reduce letrozole levels Estrogen-containing medications should not be used Decreases bone mineral density increasing fracture risk.
| Breastfeeding | It is unknown whether letrozole is excreted in human breast milk. Due to potential for serious adverse effects in nursing infants, breastfeeding is not recommended during letrozole therapy. No M/P ratio has been reported. |
| Teratogenic Risk | Pregnancy Category X. Letrozole is contraindicated in pregnancy due to teratogenic effects observed in animal studies (including embryo-fetal toxicity and malformations at doses lower than human therapeutic doses). In humans, there is a risk of fetal harm if used during pregnancy, particularly during the first trimester when organogenesis occurs. Use in pregnant women is not indicated; effective contraception should be used during treatment. |
■ FDA Black Box Warning
None.
| Common Effects | Hot flashes |
| Serious Effects |
["Pregnancy (teratogenic, embryotoxic)","Hypersensitivity to letrozole or any excipients","Pre-menopausal women (not indicated)","Severe hepatic impairment (Child-Pugh class C)"]
| Precautions | ["Bone effects: Decreased bone mineral density, increased risk of fractures and osteoporosis","Lipid effects: Elevations in total cholesterol and LDL cholesterol","Hepatic effects: Elevated liver enzymes, rare cases of hepatitis and hepatic failure","Fatigue and dizziness: May impair ability to drive or operate machinery","Tumor flare: Transient increase in bone pain or tumor-related symptoms in metastatic disease"] |
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| Fetal Monitoring | For non-pregnant women: Monitor liver function tests (LFTs) periodically, as letrozole may elevate transaminases. In women of reproductive potential, confirm non-pregnant status before starting therapy and advise effective contraception. No specific fetal monitoring is applicable as drug is contraindicated in pregnancy. |
| Fertility Effects | Letrozole is used off-label for ovulation induction due to its anti-estrogenic effects reducing negative feedback on the pituitary, leading to increased FSH and ovulation. However, it may impair implantation if taken during the luteal phase. Within the same menstrual cycle, letrozole can inhibit endometrial thickening. Long-term use in premenopausal women may suppress ovulation; however, after discontinuation, ovulation typically resumes. Letrozole can also decrease libido. |