Medically reviewed on Nov 15, 2018
(LET roe zole)
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Femara: 2.5 mg
Generic: 2.5 mg
Brand Names: U.S.
- Antineoplastic Agent, Aromatase Inhibitor
Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system which binds to the heme group of aromatase, a cytochrome P450 enzyme which catalyzes conversion of androgens to estrogens (specifically, androstenedione to estrone and testosterone to estradiol). This leads to inhibition of the enzyme and a significant reduction in plasma estrogen (estrone, estradiol and estrone sulfate) levels. Letrozole does not appear to affect synthesis of adrenal or thyroid hormones, aldosterone, or androgens.
Rapid and well absorbed; not affected by food
Vd: ~1.9 L/kg
Hepatic via CYP3A4 and 2A6 to an inactive carbinol metabolite
Urine (~90%; 6% as unchanged drug, 75% as glucuronide carbinol metabolite, 9% as unidentified metabolites)
Time to Peak
Steady state, plasma: 2 to 6 weeks; steady state serum concentrations are 1.5 to 2 times higher than single-dose values. In girls 3 to 9 years, steady state concentrations were 25% to 67% that of the mean adult values (Feuillan 2007)
Terminal: ~2 days
Special Populations: Hepatic Function Impairment
AUC was 37% higher in patients with mild to moderate hepatic impairment (Child-Pugh class A and B). AUC was increased 2-fold and systemic clearance was reduced 47% in patients with severe hepatic impairment (Child-Pugh class C).
Use: Labeled Indications
Breast cancer in postmenopausal women: Adjuvant treatment of hormone receptor-positive early breast cancer, extended adjuvant treatment of early breast cancer after 5 years of tamoxifen; treatment of advanced breast cancer with disease progression following antiestrogen therapy; first-line treatment of hormone receptor-positive or hormone receptor-unknown, locally-advanced, or metastatic breast cancer
Off Label Uses
Infertility/ovulation stimulation in anovulatory females with polycystic ovarian syndrome
Two meta-analyses of randomized placebo-controlled studies suggest letrozole is superior to clomiphene for ovulation induction in subfertile females with polycystic ovarian syndrome (PCOS). A greater increase in ovulation rates, clinical pregnancy rates, and live birth rates was observed with letrozole compared to clomiphene; complications were not found to differ between treatments [Franik 2018], [Hu 2018].
Based on the American College of Obstetricians and Gynecologists guidelines (ACOG) and an international guideline published by the Australian National Health and Medical Research Council (NHMRC) in partnership with the American Society of Reproductive Medicine (ASRM) and the European Society of Human Reproductions and Embryology (ESHRE), letrozole is the preferred first-line pharmacologic treatment for ovulation induction in females with PCOS and anovulatory infertility when no other causes of infertility are present [ACOG 194 2018], [ACOG 738 2018], [Teede 2018].
Ovarian (epithelial) cancer, recurrent
Data from a small phase II study support the use of letrozole in the treatment of platinum- and taxane-resistant recurrent epithelial ovarian cancer [Ramierz 2008]. Additional trials may be necessary to further define the role of letrozole in this condition.
Hypersensitivity to letrozole or any component of the formulation; pregnancy
Canadian labeling: Additional contraindications (not in the US labeling): Hypersensitivity to other aromatase inhibitors; use in patients <18 years of age; premenopausal endocrine status; breastfeeding
Breast cancer, advanced (first- or second-line treatment): Females: Postmenopausal: Oral: 2.5 mg once daily; continue until tumor progression
Breast cancer, early (adjuvant treatment): Females: Postmenopausal: Oral: 2.5 mg once daily for a planned duration of 5 years; discontinue at relapse.
Duration of therapy: American Society of Clinical Oncology (ASCO) guidelines for Adjuvant Endocrine Therapy of Hormone Receptor-Positive Breast Cancer (Focused Update) recommend a maximum duration of 5 years of aromatase inhibitor therapy for postmenopausal women; aromatase inhibitors may be combined with tamoxifen for a total duration of up to 10 years of endocrine therapy. Refer to the guidelines for specific recommendations based on menopausal status and tolerability (Burstein 2014). Treatment with an additional 5 years of therapy (for a total of 10 years of aromatase inhibitor therapy) has demonstrated a significantly improved rate of disease-free survival and a decreased risk of disease recurrence and contralateral breast cancer (when compared to placebo), although overall survival was not significantly different between groups and bone-related adverse events occurred more frequently with letrozole versus placebo (Goss 2016).
Breast cancer, early (extended adjuvant treatment): Females: Postmenopausal: Oral: 2.5 mg once daily for a planned duration of 5 years (after 5 years of tamoxifen); discontinue at relapse. In clinical trials, letrozole was initiated within 3 months of discontinuing tamoxifen (Goss 2003; Jin 2012).
Duration of therapy: ASCO guidelines for Adjuvant Endocrine Therapy of Hormone Receptor-Positive Breast Cancer (Focused Update) recommend a maximum duration of 5 years of aromatase inhibitor therapy for postmenopausal women; aromatase inhibitors may be combined with tamoxifen for a total duration of up to 10 years of endocrine therapy. Refer to the guidelines for specific recommendations based on menopausal status and tolerability (Burstein 2014). Treatment with an additional 5 years of therapy (for a total of 10 years of aromatase inhibitor therapy) has demonstrated a significantly improved rate of disease-free survival and a decreased risk of disease recurrence and contralateral breast cancer (when compared to placebo), although overall survival was not significantly different between groups and bone-related adverse events occurred more frequently with letrozole versus placebo (Goss 2016). The decision to extend aromatase inhibitor therapy for an additional 5 years should include initial adjuvant therapy (tamoxifen versus an aromatase inhibitor) and an assessment of the risk of recurrence.
Breast cancer off-label combinations:
Breast cancer, advanced, estrogen receptor-positive, HER2-negative: Females: Postmenopausal: Oral: 2.5 mg once daily (in combination with palbociclib) until disease progression or unacceptable toxicity (Finn 2015) or 2.5 mg once daily (in combination with ribociclib) until disease progression or unacceptable toxicity (Hortobagyi 2016) or 2.5 mg once daily (in combination with abemaciclib) until disease progression or unacceptable toxicity (Goetz 2017)
Breast cancer, metastatic, hormone receptor-positive, HER2-positive: Females: Postmenopausal: Oral: 2.5 mg once daily (in combination with lapatinib) until disease progression or unacceptable toxicity (Johnston 2009)
Infertility/ovulation stimulation in anovulatory females with polycystic ovarian syndrome (PCOS) (off-label use): Oral: Initial dose: 2.5 mg once daily for 5 days, starting on day 3, 4, or 5 following menses or progestin induced bleed; may increase to 5 mg/day for 5 days in subsequent cycles if ovulation does not occur. Maximum dose: 7.5 mg/day (ACOG 194 2018; ACOG 738 2018; Legro 2014). Dosing for up to 5 cycles was used in 1 study (Legro 2014).
Ovarian (epithelial) cancer, recurrent (off-label use): Oral: 2.5 mg once daily; continue until disease progression or unacceptable toxicity (Ramirez 2008)
Refer to adult dosing.
Dosing: Renal Impairment
CrCl ≥10 mL/minute: No dosage adjustment necessary.
CrCl <10 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling.
Dosing: Hepatic Impairment
Mild to moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.
Severe impairment (Child-Pugh class C) and cirrhosis: 2.5 mg every other day
Noncirrhotic patients with elevated bilirubin: There are no dosage adjustments provided in the manufacturer's labeling (effect has not been determined).
Oral: Administer without regard to meals.
Calcium and vitamin D supplementation are recommended.
Store at room temperature of 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Methadone: Aromatase Inhibitors may increase the serum concentration of Methadone. Monitor therapy
Tamoxifen: May decrease the serum concentration of Letrozole. Monitor therapy
Cardiovascular: Flushing (50%), edema (7% to 18%)
Central nervous system: Headache (4% to 20%), dizziness (3% to 14%), fatigue (10% to 13%)
Dermatologic: Diaphoresis (24%), night sweats (15%)
Endocrine & metabolic: Hypercholesterolemia (3% to 52%), hot flash (6% to 34%), weight gain (2% to 13%)
Gastrointestinal: Nausea (9% to 17%), constipation (2% to 11%)
Neuromuscular & skeletal: Weakness (4% to 34%), arthralgia (8% to 25%), arthritis (7% to 25%), ostealgia (5% to 22%), musculoskeletal pain (21%), back pain (5% to 18%), bone fracture (10% to 15%), osteoporosis (5% to 15%)
Respiratory: Dyspnea (6% to 18%), cough (6% to 13%)
1% to 10%:
Cardiovascular: Chest pain (6% to 8%), hypertension (5% to 8%), chest wall pain (6%), peripheral edema (5%), cerebrovascular accident (2% to 3%), thromboembolism (≤3%; including portal vein thrombosis, pulmonary embolism, thrombophlebitis, venous thrombosis), transient ischemic attacks (≤3%), angina pectoris (≤2%), hemorrhagic stroke (≤2%), ischemic heart disease (≤2%), thrombotic stroke (≤2%), cardiac failure (1% to 2%), myocardial infarction (1% to 2%)
Central nervous system: Insomnia (6% to 7%), pain (5%), anxiety (<5%), depression (<5%), vertigo (<5%), drowsiness (3%), hemiparesis (≤2%)
Dermatologic: Skin rash (5%), alopecia (<5%), pruritus (1%)
Endocrine & metabolic: Weight loss (6% to 7%), hypercalcemia (<5%)
Gastrointestinal: Diarrhea (5% to 8%), vomiting (3% to 7%), abdominal pain (6%), anorexia (1% to 5%), dyspepsia (3%)
Genitourinary: Mastalgia (2% to 7%), urinary tract infection (6%), vaginal dryness (5%), vaginal hemorrhage (5%), vaginal irritation (5%)
Hematologic & oncologic: Lymphedema (7%; post-mastectomy), second primary malignant neoplasm (2% to 5%)
Infection: Infection (7%), influenza (6%), viral infection (6%)
Neuromuscular & skeletal: Limb pain (4% to 10%), myalgia (7% to 9%), osteopenia (4%)
Ophthalmic: Cataract (2%)
Renal: Renal disease (5%)
Respiratory: Pleural effusion (<5%)
<1%, postmarketing, and/or case reports: Anaphylaxis, angioedema, arterial thrombosis, blurred vision, carpal tunnel syndrome, dysesthesia, dysgeusia, endometrial carcinoma, endometrium disease, endometrial hyperplasia, erythema multiforme, eye irritation, fever, hepatitis, hypersensitivity reaction, increased appetite, increased liver enzymes, increased thirst, irritability, leukopenia, memory impairment, nervousness, ovarian cyst, palpitations, paresthesia, spontaneous abortion, stomatitis, tachycardia, tenosynovitis (trigger finger), thrombocytopenia, toxic epidermal necrolysis, urinary frequency, urticaria, vaginal discharge, xeroderma, xerostomia
Concerns related to adverse effects:
• CNS depression: May cause dizziness, fatigue, and somnolence; patients should be cautioned before performing tasks which require mental alertness (eg, operating machinery or driving).
• Decreased bone mineral density: May cause decreases in bone mineral density (BMD). In one study, a decrease in hip BMD by 3.8% from baseline in letrozole-treated patients vs 2% in placebo at 2 years was demonstrated, however, while lumbar spine BMD was decreased, the difference was not statistically significant. Results of a safety study did demonstrate a decrease in lumbar spine BMD with letrozole (compared to tamoxifen). Osteoporosis and bone fractures have occurred at higher rates when compared to tamoxifen or to placebo. Monitor BMD.
• Increased cholesterol: May increase total serum cholesterol. In patients treated with adjuvant therapy and cholesterol levels within normal limits, an increase of ≥1.5 x ULN in total cholesterol (non-fasting) has been demonstrated in 8.2% of letrozole-treated patients (25% requiring lipid-lowering medications) vs 3.2% of tamoxifen-treated patients (16% requiring medications). Monitor cholesterol panel; may require antihyperlipidemics.
• Hepatic impairment: Use with caution in patients with hepatic impairment; dose adjustment recommended in patients with cirrhosis or severe hepatic dysfunction.
Concurrent drug therapy issues:
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Cholesterol, hepatic function tests; bone density; pregnancy test (prior to treatment in females of reproductive potential). Monitor adherence.
For infertility/ovarian stimulation (off-label use), a pregnancy test is recommended prior to initiation. Midluteal progestin concentrations (in a clinical study, nonresponse to treatment was defined as a progesterone concentration <3 ng/mL during the midluteal phase; poor ovulatory response was defined as progesterone concentrations indicating ovulation but just above the cutoff point) (Legro 2014).
Use is contraindicated in women with an established pregnancy.
Breast cancer: Letrozole is approved for the treatment of breast cancer in postmenopausal women. Based on the mechanism of action and data from animal reproduction studies, letrozole may cause fetal harm if used during pregnancy. A pregnancy test is recommended prior to letrozole therapy in women of reproductive potential and effective contraception should be used during letrozole therapy and for at least 3 weeks following the last letrozole dose.
Infertility associated with polycystic ovarian syndrome (PCOS): Letrozole is used off-label for ovulation induction in females with PCOS and anovulatory infertility when no other causes of infertility are present (ACOG 194 2018; ACOG 738 2018; Teede 2018). Baseline testing is done prior to letrozole therapy to rule out unexpected ovulation, which prevents exposure in early pregnancy (Legro 2016). Because information related to newborn outcomes following maternal use is limited, guidelines recommend counseling females of the off-label status prior to use (ACOG 194 2018; ACOG 738 2018).
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience loss of strength and energy, hot flashes, nausea, vomiting, cough, back pain, muscle pain, joint pain, constipation, diarrhea, night sweats, sweating a lot, insomnia, weight loss, abdominal pain, hair loss, or weight gain. Have patient report immediately to prescriber signs of a urinary tract infection (hematuria, burning or painful urination, polyuria, fever, lower abdominal pain, or pelvic pain), swollen glands, edema, angina, severe dizziness, passing out, shortness of breath, severe headache, vision changes, vaginal bleeding, depression, urinary retention, or change in amount of urine passed (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
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- Drug class: aromatase inhibitors
Other brands: Femara