Constitutional delay of growth and puberty (CDGP): Limited data available: Male Adolescents ≥14 years: Oral: 2.5 mg once daily with or without testosterone therapy (Ref). A phase 3 randomized comparative controlled trial in adolescent males (n= 30; mean age: ~15 years; testosterone group n=15; letrozole n=15) reported subjects treated with letrozole showed higher levels of the puberty markers LH, FSH, testosterone, and inhibin B and significantly greater testicular growth compared to the testosterone treatment group (Ref). When used in combination with testosterone, bone maturation was delayed, predicted adult height values were significantly increased, and markers of puberty progressed during the 12 months of therapy (Ref).
McCune-Albright syndrome; precocious puberty: Very limited data available: Female Children >2 to 8 years at time of treatment initiation: Oral: Initial: 0.5 mg/m2/day in divided doses every 12 hours for days 1 to 7, then 1 mg/m2/day in divided doses every 12 hours on days 8 to 14, then 1.5 mg/m2/day in divided doses every 12 hours beginning on day 15; if needed, may further increase to 2 mg/m2/day in divided doses if markers of precocious puberty including serum estradiol levels continue to progress. Dosing based on a pilot study of nine girls (3 to 8 years at time of therapy initiation) which showed long-term therapy (up to 36 months) decreased rates of growth and bone maturation; although ovarian volume decreased during the first 6 months of treatment, the mean ovarian volume increased over 1 to 2 years of therapy with cyst redevelopment in some patients. During the pilot study, dosing was divided twice daily to alleviate GI discomfort; however, pharmacokinetic analysis showed once daily dosing would be appropriate for young children if tolerated (Ref). In a case series (n=3, age range at treatment: 3 to 7 years), a fixed dose of 2.5 mg once daily was used for 5 to 19 months duration (Ref).
Short stature; idiopathic: Limited data available: Male Children ≥9 years and Adolescents <17 years: Oral: 2.5 mg once daily. Dosing based on experience in a double-blind, placebo-controlled trial of 30 males (treatment group: n=16; age range: 9 to 14 years) and a retrospective observation (n=24; age range: 9 to 16 years); the duration of letrozole therapy was up to 2 years (range: 4 to 24 months); bone maturation delay with increases in predicted adult height values were observed with treatment (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no pediatric-specific recommendations; based on experience in adult patients, data suggests no dosage adjustment is required.
There are no pediatric-specific recommendations; based on experience in adult patients, dosing adjustment suggested.
(For additional information see "Letrozole: Drug information")
Breast cancer, adjuvant therapy:
Early breast cancer, adjuvant treatment: Postmenopausal patients: Oral: 2.5 mg once daily for a planned duration of 5 years; discontinue at relapse.
Early breast cancer, extended adjuvant treatment: Postmenopausal patients: 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 (Ref).
Early breast cancer, high-risk, adjuvant treatment in premenopausal patients (off-label use): Oral: 2.5 mg once daily (in combination with ovarian function suppression) for a duration of 5 years (Ref).
Duration of adjuvant endocrine therapy: American Society of Clinical Oncology (ASCO) guidelines for adjuvant endocrine therapy for women with hormone receptor–positive (HR+) breast cancer (focused update) recommend a duration of 5 to 10 years of adjuvant endocrine therapy; some patients may be appropriate candidates for extended aromatase inhibitor (AI) therapy for up to a total of 10 years based on disease recurrence risk and nodal disease status. Refer to the guidelines for specific recommendations based on menopausal status and tolerability (Ref). Treatment with an additional 5 years of AI therapy (for a total of 10 years of endocrine therapy) 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 (Ref).
Breast cancer, advanced, first- or second-line treatment: Postmenopausal patients: Oral: 2.5 mg once daily; continue until tumor progression.
Breast cancer off-label combinations:
Breast cancer, advanced, estrogen receptor-positive, HER2-negative, first-line treatment: Postmenopausal patients: Oral: 2.5 mg once daily (in combination with palbociclib) until disease progression or unacceptable toxicity (Ref) or 2.5 mg once daily (in combination with ribociclib) until disease progression or unacceptable toxicity (Ref) or 2.5 mg once daily (in combination with abemaciclib) until disease progression or unacceptable toxicity (Ref).
Breast cancer, metastatic, hormone receptor–positive, HER2-positive: Postmenopausal patients: Oral: 2.5 mg once daily (in combination with lapatinib) until disease progression or unacceptable toxicity (Ref).
Breast cancer, metastatic, hormone receptor–positive, HER2-positive, salvage therapy: Postmenopausal patients: Oral: 2.5 mg once daily (in combination with trastuzumab and lapatinib) until disease progression or unacceptable toxicity (Ref). Note: Patients in the study had received prior endocrine therapy and had disease progression during or after a prior regimen containing trastuzumab plus chemotherapy in the neo(adjuvant) setting and/or first-line metastatic setting.
Breast cancer in male patients, hormone receptor positive (off-label use): Note: Should be used in combination with a gonadotropin-releasing hormone agonist/antagonist (Ref).
Adjuva nt therapy (alternative agent): May be used as adjuvant therapy in male patients with hormone receptor–positive (HR+) breast cancer with a contraindication to tamoxifen. ASCO guidelines for management of male breast cancer recommend an initial duration of 5 years of adjuvant endocrine therapy; if there still is a high risk of recurrence, 5 additional years of endocrine therapy may be offered if the initial 5 years of adjuvant therapy have been completed and tolerated (Ref).
Advanced or metastatic disease: Oral: 2.5 mg once daily until disease progression or unacceptable toxicity (Ref). Endocrine therapy for males with advanced or metastatic, HR+, HER2-negative breast cancer may be sequenced as in females (Ref).
Infertility/Ovulation stimulation in anovulatory patients with polycystic ovary syndrome (off-label use): Initial dose: Oral: 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 (Ref). Dosing for up to 5 cycles was used in 1 study (Ref).
Ovarian cancer, epithelial, recurrent (off-label use): Oral: 2.5 mg once daily; continue until disease progression or unacceptable toxicity (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Kenar D. Jhaveri, MD; Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function: No dosage adjustment necessary for any degree of kidney dysfunction (Ref).
Hemodialysis, intermittent (thrice weekly): Unlikely to be dialyzed (lipophilic and relatively large Vd): No supplemental dose or dosage adjustment necessary (Ref).
Peritoneal dialysis: Unlikely to be dialyzed (lipophilic and relatively large Vd): No dosage adjustment necessary (Ref).
CRRT: No dosage adjustment necessary (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (Ref).
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).
Letrozole is associated with a decreased bone mineral density (BMD); decreases (from baseline) in total hip and lumbar spine BMD have been reported. Letrozole has been linked to bone resorption in postmenopausal females, an increased risk of osteoporosis and bone fracture should be considered with administering treatment (Ref).
Mechanism: Time-related; letrozole decreases plasma estrogen levels. Low levels of estrogen have been linked to bone resorption leading to decreased BMD, especially at the lumbar spine and hip. This results in increased risk of osteoporosis and fracture (Ref).
Onset: Delayed; bone loss occurred during the first 2 years of treatment (Ref).
Risk factors:
• Longer durations of aromatase inhibitors (>3 years of therapy) (Ref)
• Preexisting known risk factors for BMD loss, osteoporosis, and fracture; includes preexisting osteopenia, age >65 years, years since menopause, body mass index <20 kg/m2, personal/family history, chronic glucocorticoid use >6 months, prior fragility fracture history, low bone mineral density, rheumatoid arthritis, and smoking (Ref)
Ischemic heart disease has been reported, with an increased incidence of ischemic cardiovascular events in patients with preexisting ischemic heart disease. Angina pectoris and acute myocardial infarction (MI) have occurred.
Mechanism: Non–dose-related; idiosyncratic. Aromatase inhibitors (AI), such as letrozole, reduce the protective effects of estrogen, consequently leading to increases in vasoconstriction and atherosclerosis. Additionally, there is dysregulation of lipid metabolism and potential risk of hyperlipidemia. Together, these factors may increase the risk of cardiovascular disease (CVD) in patients receiving AI for breast cancer treatment (Ref).
Onset: Varied; cardiac ischemia may occur at any time during treatment (Ref).
Risk factors:
• Preexisting CVD (including ischemic heart disease) or risk factors associated with CVD. In a large SEER-Medicare cohort evaluating MI risk with adjuvant hormone therapy, several preexisting conditions were associated with MI including diabetes with complications, heart failure, prior MI, coronary artery disease, and peripheral vascular disease. In patients with prior history of MI, hazard ratio was nearly 3-fold higher (Ref).
• Longer durations of AI therapy (>3 years of therapy) are associated with 18% to 26% increased risk of CVD (Ref).
Musculoskeletal effects (including new onset or exacerbation of existing arthralgia, joint stiffness, and/or ostealgia) may occur with letrozole (Ref). Aromatase inhibitor-induced arthralgia presents with symmetrical joint pains most commonly affecting hands, wrists, and knees (Ref). Tenosynovitis (trigger finger) and carpal tunnel syndrome may also be common complaints (Ref). These adverse reactions may significantly affect quality of life and the risk of treatment nonadherence or discontinuation should be considered (Ref).
Mechanism: Non–dose-related; idiosyncratic. Exact mechanism is unknown; however, multiple mechanisms have been proposed involving estrogen depletion either as a direct or indirect cause. Proposed estrogen depletion mechanisms include direct local effects on joint tissues, increased inflammatory parameters, such as IL-6 indirectly affecting central and peripheral nociception (Ref), decreased estradiol leading to a decrease in endogenous opioid levels (Ref), collagen degradation, and impaired regulation of cartilage structure (Ref).
Onset: Varied; the median time to onset of symptoms is 1.6 months with a range of 0.4 to 10 months. Symptoms have been shown to peak ~6 months after initiation of treatment (Ref).
Risk factors:
• Prior menopausal hormone therapy and previous chemotherapy (Ref)
• Certain CYP19A1 single nucleotide polymorphisms (SNPs) have been associated with increased arthralgia symptoms and/or association with discontinuation of therapy due to intolerable arthralgia (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Cardiovascular: Edema (7% to 18%), flushing (50%)
Dermatologic: Diaphoresis (24%), night sweats (15%)
Endocrine & metabolic: Hot flash (19% to 34%), hypercholesterolemia (52%), weight gain (13%)
Gastrointestinal: Nausea (9% to 17%)
Nervous system: Dizziness (3% to 14%), fatigue (10% to 13%)
Neuromuscular & skeletal: Arthralgia (≤25%) (table 1) , arthritis (≤25%) (table 2) , asthenia (6% to 34%) (table 3) , back pain (5% to 18%), bone fracture (10% to 15%), ostealgia (5% to 22%) (table 4) , osteoporosis (5% to 15%) (table 5)
Drug (Letrozole) |
Comparator |
Placebo |
Indication |
Number of Patients (Letrozole) |
Number of Patients (Comparator) |
Number of Patients (Placebo) |
Comments |
---|---|---|---|---|---|---|---|
≤25% |
≤21% |
N/A |
Adjuvant treatment of early breast cancer |
2,448 |
2,447 |
N/A |
Comparator: Tamoxifen; described as "arthralgia/arthritis" |
22% |
N/A |
18% |
Adjuvant treatment of early breast cancer |
2,563 |
N/A |
2,573 |
N/A |
16% |
15% |
N/A |
First-line treatment of advanced breast cancer |
455 |
455 |
N/A |
Comparator: Tamoxifen |
Drug (Letrozole) |
Comparator |
Placebo |
Indication |
Number of Patients (Letrozole) |
Number of Patients (Comparator) |
Number of Patients (Placebo) |
Comments |
---|---|---|---|---|---|---|---|
≤25% |
≤21% |
N/A |
Adjuvant treatment of early breast cancer |
2,448 |
2,447 |
N/A |
Comparator: Tamoxifen; described as "arthralgia/arthritis" |
7% |
N/A |
5% |
Adjuvant treatment of early breast cancer |
2,563 |
N/A |
2,573 |
N/A |
Drug (Letrozole) |
Comparator |
Placebo |
Indication |
Number of Patients (Letrozole) |
Number of Patients (Comparator) |
Number of Patients (Placebo) |
Comments |
---|---|---|---|---|---|---|---|
34% |
N/A |
32% |
Adjuvant treatment of early breast cancer |
2,563 |
N/A |
2,573 |
N/A |
6% |
4% |
N/A |
First-line treatment of advanced breast cancer |
455 |
455 |
N/A |
Comparator: Tamoxifen |
Drug (Letrozole) |
Comparator |
Indication |
Number of Patients (Letrozole) |
Number of Patients (Comparator) |
Comments |
---|---|---|---|---|---|
5% |
5% |
Adjuvant treatment of early breast cancer |
2,448 |
2,447 |
Comparator: Tamoxifen |
22% |
21% |
First-line treatment of advanced breast cancer |
455 |
455 |
Comparator: Tamoxifen |
Drug (Letrozole) |
Comparator |
Placebo |
Indication |
Number of Patients (Letrozole) |
Number of Patients (Comparator) |
Number of Patients (Placebo) |
Comments |
---|---|---|---|---|---|---|---|
15% |
N/A |
8% |
Adjuvant treatment of early breast cancer |
N/A |
N/A |
N/A |
N/A |
12% |
N/A |
6% |
Adjuvant treatment of early breast cancer |
N/A |
N/A |
N/A |
N/A |
5% |
3% |
N/A |
Adjuvant treatment of early breast cancer |
2,448 |
2,447 |
N/A |
Comparator: Tamoxifen |
Respiratory: Cough (13%), dyspnea (6% to 18%)
1% to 10%:
Cardiovascular: Acute myocardial infarction (1% to 2%) (table 6) , angina pectoris (1%) (table 7) , cardiac failure (1% to 2%), cerebrovascular accident (≤3%), chest pain (6% to 8%), chest wall pain (6%), hemorrhagic stroke (≤2%), hypertension (6% to 8%), peripheral edema (5%), thromboembolism (≤3%; including portal vein thrombosis, pulmonary embolism, thrombophlebitis, venous thrombosis), thrombotic stroke (≤2%), transient ischemic attacks (≤3%)
Drug (Letrozole) |
Comparator |
Indication |
Number of Patients (Letrozole) |
Number of Patients (Comparator) |
Comments |
---|---|---|---|---|---|
2% |
1% |
Adjuvant treatment of early breast cancer |
2,448 |
2,447 |
At median follow-up of 96 months; comparator: Tamoxifen |
1% |
0.5% |
Adjuvant treatment of early breast cancer |
2,448 |
2,447 |
At median treatment duration of 60 months; comparator: Tamoxifen |
Drug (Letrozole) |
Comparator |
Indication |
Number of Patients (Letrozole) |
Number of Patients (Comparator) |
Comments |
---|---|---|---|---|---|
1% |
1% |
Adjuvant treatment of early breast cancer |
2,448 |
2,447 |
Angina pectoris requiring surgery; at median follow-up of 96 months; comparator: Tamoxifen |
1% |
1% |
Adjuvant treatment of early breast cancer |
2,448 |
2,447 |
Angina pectoris requiring surgery; at median treatment duration of 60 months; comparator: Tamoxifen |
Dermatologic: Alopecia (3%)
Endocrine & metabolic: Weight loss (6% to 7%)
Gastrointestinal: Anorexia (≤4%), constipation (2% to 10%), diarrhea (8%), vomiting (3% to 7%)
Genitourinary: Mastalgia (2% to 7%), urinary tract infection (6%), vaginal hemorrhage (5%), vaginal irritation (5%)
Hematologic & oncologic: Lymphedema (7%; post-mastectomy), second primary malignant neoplasm (2% to 5%)
Infection: Infection (7%), influenza (6%)
Nervous system: Depression (5%), headache (4% to 8%), hemiparesis (≤2%), insomnia (6% to 7%), lethargy (<10%), malaise (<10%), pain (5%)
Neuromuscular & skeletal: Limb pain (4% to 10%), myalgia (7% to 9%) (table 8) , osteopenia (4%) (table 9)
Drug (Letrozole) |
Comparator |
Placebo |
Indication |
Number of Patients (Letrozole) |
Number of Patients (Comparator) |
Number of Patients (Placebo) |
Comments |
---|---|---|---|---|---|---|---|
9% |
9% |
N/A |
Adjuvant treatment of early breast cancer |
2,448 |
2,447 |
N/A |
Comparator: Tamoxifen |
7% |
N/A |
5% |
Adjuvant treatment of early breast cancer |
2,563 |
N/A |
2,573 |
N/A |
Drug (Letrozole) |
Comparator |
Indication |
Number of Patients (Letrozole) |
Number of Patients (Comparator) |
Comments |
---|---|---|---|---|---|
4% |
3% |
Adjuvant treatment of early breast cancer |
2,448 |
2,447 |
Comparator: Tamoxifen |
Ophthalmic: Cataract (2%)
Renal: Renal disease (5%)
<1%:
Cardiovascular: Ischemic heart disease (table 10)
Drug (Letrozole) |
Comparator |
Indication |
Number of Patients (Letrozole) |
Number of Patients (Comparator) |
Comments |
---|---|---|---|---|---|
0.2% |
0.4% |
Adjuvant treatment of early breast cancer |
2,448 |
2,447 |
Comparator: Tamoxifen |
Endocrine & metabolic: Ovarian cyst
Genitourinary: Endometrial hyperplasia
Hematologic & oncologic: Endometrial carcinoma, thrombocytopenia
Postmarketing:
Cardiovascular: Arterial thrombosis, hypersensitivity angiitis (Kim 2020), palpitations, prolonged QT interval on ECG (Grouthier 2018), tachycardia, ventricular arrhythmia (Grouthier 2018)
Dermatologic: Erythema multiforme, erythema nodosum (Kim 2020), skin rash (Finn 2016), toxic epidermal necrolysis (Chia 2006), urticaria, xeroderma (Finn 2016)
Endocrine & metabolic: Increased thirst
Gastrointestinal: Abdominal pain (Finn 2016), dysgeusia (Finn 2016), dyspepsia (Finn 2016), increased appetite, stomatitis (Finn 2016), xerostomia
Genitourinary: Urinary frequency, vaginal discharge
Hematologic & oncologic: Anemia (Finn 2016), leukopenia (Finn 2016), neutropenia (Finn 2016)
Hepatic: Hepatitis
Hypersensitivity: Anaphylaxis, angioedema
Nervous system: Anxiety (Finn 2016), carpal tunnel syndrome (Niravath 2013), dysesthesia, irritability (Goodwin 2006), memory impairment, nervousness, paresthesia
Neuromuscular & skeletal: Decreased bone mineral density (Perez 2006), subacute cutaneous lupus erythematosus (Kim 2020), tenosynovitis (trigger finger) (Niravath 2013)
Ophthalmic: Blurred vision, dry eye syndrome (Turaka 2013), eye irritation
Miscellaneous: Fever (Finn 2016)
Known 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 patients; breastfeeding.
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).
• 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 (nonfasting) has been demonstrated in 8.2% of letrozole-treated patients (25% requiring lipid-lowering medications) versus 3.2% of tamoxifen-treated patients (16% requiring medications).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Femara: 2.5 mg
Generic: 2.5 mg
Yes
Tablets (Femara Oral)
2.5 mg (per each): $31.79
Tablets (Letrozole Oral)
2.5 mg (per each): $10.41 - $18.13
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Femara: 2.5 mg [contains corn starch]
Generic: 2.5 mg
Oral: May administer without regard to meals.
Oral: Administer without regard to meals.
Hazardous agent (NIOSH 2016 [group 1]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Store at room temperature of 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Adjuvant treatment of hormone receptor positive early breast cancer; extended adjuvant treatment of early breast cancer after 5 years of tamoxifen; first-line treatment of hormone receptor positive or hormone receptor unknown, locally advanced or metastatic breast cancer; treatment of advanced breast cancer with disease progression following antiestrogen therapy (All indications: FDA approved in postmenopausal patients); has also been used in treatment of precocious puberty associated with McCune-Albright Syndrome (MAS) in females; and constitutional delay of growth and puberty (not due to growth hormone deficiency) and idiopathic short stature in males.
Femara may be confused with Famvir, femhrt, Provera
Letrozole may be confused with anastrozole
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs (chemotherapeutic agent, parenteral and oral; contraindicated in pregnancy) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).
Letaris, a formerly marketed Dutch brand name product for letrozole, may be confused with Letairis, a US brand name for ambrisentan.
Substrate of CYP2A6 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program
Levomethadone: Aromatase Inhibitors may increase the serum concentration of Levomethadone. Risk C: Monitor therapy
Methadone: Aromatase Inhibitors may increase the serum concentration of Methadone. Risk C: Monitor therapy
Nintedanib: Letrozole may increase the serum concentration of Nintedanib. Risk C: Monitor therapy
Tamoxifen: May decrease the serum concentration of Letrozole. Risk X: Avoid combination
Calcium and vitamin D supplementation are recommended.
A pregnancy test is recommended prior to starting letrozole therapy in all patients who could become pregnant.
When used for management of breast cancer, effective contraception should be used during letrozole therapy and for at least 3 weeks following the last letrozole dose.
Letrozole is used off-label for ovulation induction in patients with polycystic ovarian syndrome (PCOS) and anovulatory infertility when no other causes of infertility are present (ACOG 194 2018; Teede 2018). Baseline pregnancy testing is done prior to letrozole therapy to rule out unexpected ovulation, which prevents exposure in early pregnancy (Legro 2016). Because data related to newborn outcomes following maternal use are limited, guidelines recommend counseling patients of the off-label status prior to use (ACOG 194 2018).
Use is contraindicated in patients with an established pregnancy.
Based on the mechanism of action and data from animal reproduction studies, letrozole may cause fetal harm if used during pregnancy.
Monitor periodically during therapy: Complete blood counts, thyroid function tests; serum electrolytes, cholesterol, transaminases, and creatinine; blood pressure; bone density.
Delayed puberty and short stature: In the pediatric clinical trials (study durations: 1 to 2 years) the following were monitored (at baseline, and then typically 2 to 3 months, 5 to 6 months, 12 months, and 18 months): Growth indices (eg, height, adult height predictions, bone age, lumbar and femoral bone mineral density), sexual maturity rating and serum concentration of key hormones, and other biochemical markers (eg, 17-B estradiol, LH, FSH, testosterone), lipid profile (Hero 2005; Shulman 2008; Varimo 2019; Wickman 2001).
McCune-Albright syndrome: In the pediatric clinical trial (study duration: 12 to 36 months), the following were monitored (baseline, every 6 months): Rates of growth and bone age advance, levels of indices of bone metabolism (eg, osteocalcin, alkaline phosphatase); and urinary markers of steroid metabolism (eg, hydroxyproline, pyridinoline, etc.), mean ovarian volume, episodes of vaginal bleeding and serum concentrations of estradiol (Feuillan 2007).
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.
Absorption: Rapid and well absorbed; not affected by food
Distribution: Vd: ~1.9 L/kg
Protein binding, plasma: Weak
Metabolism: Hepatic via CYP3A4 and 2A6 to an inactive carbinol metabolite
Half-life elimination: Terminal: ~2 days
Time to 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)
Excretion: Urine (~90%; 6% as unchanged drug, 75% as glucuronide carbinol metabolite, 9% as unidentified metabolites)
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).
Do you want to add Medilib to your home screen?