Letrozole

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Letrozole
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]

Disclaimer

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Overview

Letrozole is an aromatase inhibitor that is FDA approved for the {{{indicationType}}} of adjuvant treatment of early breast cancer, extended adjuvant treatment of early breast cancer, first and second-line treatment of advanced breast cancer. Common adverse reactions include hot flashes, arthralgia, flushing, asthenia, edema, arthralgia, headache, dizziness, hypercholesterolemia, sweating increased, and bone pain.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Adjuvant Treatment of Early Breast Cancer

Letrozole tablets, USP are indicated for the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer.

The recommended dose of letrozole tablets is one 2.5 mg tablet administered once a day, without regard to meals.

Extended Adjuvant Treatment of Early Breast Cancer

Letrozole tablets, USP are indicated for the extended adjuvant treatment of early breast cancer in postmenopausal women, who have received 5 years of adjuvant tamoxifen therapy. The effectiveness of letrozole in extended adjuvant treatment of early breast cancer is based on an analysis of disease-free survival in patients treated with letrozole tablets for a median of 60 months [see Clinical Studies (14.2, 14.3)].

First and Second-Line Treatment of Advanced Breast Cancer

Letrozole tablets, USP are indicated for first-line treatment of postmenopausal women with hormone receptor positive or unknown, locally advanced or metastatic breast cancer. Letrozole tablets are also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Condition1
  • Developed by:
  • Class of Recommendation:
  • Strength of Evidence:
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding Off-Label Guideline-Supported Use of Letrozole in adult patients.

Non–Guideline-Supported Use

Condition1
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding Off-Label Non–Guideline-Supported Use of Letrozole in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Condition1
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding FDA-Labeled Use of Letrozole in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

Condition1
  • Developed by:
  • Class of Recommendation:
  • Strength of Evidence:
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding Off-Label Guideline-Supported Use of Letrozole in pediatric patients.

Non–Guideline-Supported Use

Condition1
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding Off-Label Non–Guideline-Supported Use of Letrozole in pediatric patients.

Contraindications

  • Letrozole tablets may cause fetal harm when administered to a pregnant woman and the clinical benefit to premenopausal women with breast cancer has not been demonstrated. Letrozole tablets are contraindicated in women who are or may become pregnant. If letrozole tablets are used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Warnings

Precautions

  • Bone Effects
  • Use of letrozole may cause decreases in bone mineral density (BMD). Consideration should be given to monitoring BMD. Results of a substudy to evaluate safety in the adjuvant setting comparing the effect on lumbar spine (L2 to L4) bone mineral density (BMD) of adjuvant treatment with letrozole to that with tamoxifen showed at 24 months a median decrease in lumbar spine BMD of 4.1% in the letrozole arm compared to a median increase of 0.3% in the tamoxifen arm (difference = 4.4%) (P < 0.0001) [see Adverse reactions (6.1)]. Updated results from the BMD sub-study in the extended adjuvant setting demonstrated that at 2 years patients receiving letrozole had a median decrease from baseline of 3.8% in hip BMD compared to a median decrease of 2% in the placebo group. The changes from baseline in lumbar spine BMD in letrozole and placebo treated groups were not significantly different [see Adverse Reactions (6.2)].
  • In the adjuvant trial the incidence of bone fractures at any time after randomization was 13.8% for letrozole and 10.5% for tamoxifen. The incidence of osteoporosis was 5.1% for letrozole and 2.7% for tamoxifen [see Adverse Reactions (6.1)]. In the extended adjuvant trial the incidence of bone fractures at any time after randomization was 13.3% for letrozole and 7.8% for placebo. The incidence of new osteoporosis was 14.5% for letrozole and 7.8% for placebo [see Adverse Reactions (6.3)].
  • Cholesterol
  • Consideration should be given to monitoring serum cholesterol. In the adjuvant trial hypercholesterolemia was reported in 52.3% of letrozole patients and 28.6% of tamoxifen patients. CTC grade 3 to 4 hypercholesterolemia was reported in 0.4% of letrozole patients and 0.1% of tamoxifen patients. Also in the adjuvant setting, an increase of ≥ 1.5 X ULN in total cholesterol (generally non-fasting) was observed in patients on monotherapy who had baseline total serum cholesterol within the normal range (i.e., < = 1.5 X ULN) in 151/1843 (8.2%) on letrozole vs. 57/1,840 (3.2%). Lipid lowering medications were required for 25% of patients on letrozole and 16% on tamoxifen [see Adverse Reactions (6.1)].
  • Hepatic Impairment
  • Subjects with cirrhosis and severe hepatic impairment who were dosed with 2.5 mg of letrozole experienced approximately twice the exposure to letrozole as healthy volunteers with normal liver function. Therefore, a dose reduction is recommended for this patient population. The effect of hepatic impairment on letrozole exposure in cancer patients with elevated bilirubin levels has not been determined [see Dosage and Administration (2.5)].
  • Fatigue and Dizziness
  • Because fatigue, dizziness and somnolence have been reported with the use of letrozole, caution is advised when driving or using machinery until it is known how the patient reacts to letrozole use.
  • Laboratory Test Abnormalities
  • No dose related effect of letrozole on any hematologic or clinical chemistry parameter was evident. Moderate decreases in lymphocyte counts, of uncertain clinical significance, were observed in some patients receiving letrozole 2.5 mg. This depression was transient in about half of those affected. Two patients on letrozole developed thrombocytopenia; relationship to the study drug was unclear. Patient withdrawal due to laboratory abnormalities, whether related to study treatment or not, was infrequent.

Adverse Reactions

Clinical Trials Experience

Adjuvant Treatment of Early Breast Cancer
  • The median treatment duration of adjuvant treatment was 60 months and the median duration of follow-up for safety was 73 months for patients receiving letrozole and tamoxifen.
  • Certain adverse reactions were prospectively specified for analysis, based on the known pharmacologic properties and side effect profiles of the two drugs.
  • Adverse reactions were analyzed irrespective of whether a symptom was present or absent at baseline. Most adverse reactions reported (approximately 75% of patients reporting one or more AE) were Grade 1 or Grade 2 applying the Common Toxicity Criteria Version 2.0/ Common Terminology Criteria for Adverse Events, version 3.0. Table 1 describes adverse reactions (Grades 1 to 4) irrespective of relationship to study treatment in the adjuvant trial for the monotherapy arms analysis (safety population).

T1

  • When considering all grades during study treatment, a higher incidence of events was seen for letrozole regarding fractures (10.1% vs. 7.1%), myocardial infarctions (1% vs. 0.5%), and arthralgia (25.2% vs. 20.4%) (letrozole vs. tamoxifen respectively). A higher incidence was seen for tamoxifen regarding thromboembolic events (2.1% vs. 3.6%), endometrial hyperplasia/cancer (0.3% vs. 2.9%), and endometrial proliferation disorders (0.3% vs. 1.8%) (letrozole vs. tamoxifen respectively).
  • At a median follow up of 73 months, a higher incidence of events was seen for letrozole (13.8%) than for tamoxifen (10.5%) regarding fractures. A higher incidence was seen for tamoxifen compared to letrozole regarding thromboembolic events (4.5% vs. 2.9%), and endometrial hyperplasia or cancer (2.9% vs. 0.4%) (tamoxifen vs. letrozole, respectively).
  • Bone Study
  • Results of a phase 3 safety trial in 262 post menopausal women with resected receptor positive early breast cancer in the adjuvant setting comparing the effect on lumbar spine (L2 to L4) bone mineral density (BMD) of adjuvant treatment with letrozole to that with tamoxifen showed at 24 months a median decrease in lumbar spine BMD of 4.1% in the letrozole arm compared to a median increase of 0.3% in the tamoxifen arm (difference = 4.4%) (P < 0.0001). No patients with a normal BMD at baseline became osteoporotic over the 2 years and only one patient with osteopenia at baseline (T score of -1.9) developed osteoporosis during the treatment period (assessment by central review). The results for total hip BMD were similar, although the differences between the two treatments were less pronounced. During the 2-year period, fractures were reported by 4 of 103 patients (4%) in the letrozole arm, and 6 of 97 patients (6%) in the tamoxifen arm.
  • Lipid Study
  • In a phase 3 safety trial in 262 post menopausal women with resected receptor positive early breast cancer at 24 months comparing the effects on lipid profiles of adjuvant letrozole to tamoxifen, 12% of patients on letrozole had at least one total cholesterol value of a higher CTCAE grade than at baseline compared with 4% of patients on tamoxifen.
Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 24 Months
  • The median duration of extended adjuvant treatment was 24 months and the median duration of follow-up for safety was 28 months for patients receiving letrozole and placebo.
  • Table 2 describes the adverse reactions occurring at a frequency of at least 5% in any treatment group during treatment. Most adverse reactions reported were Grade 1 and Grade 2 based on the Common Toxicity Criteria Version 2.0. In the extended adjuvant setting, the reported drug-related adverse reactions that were significantly different from placebo were hot flashes, arthralgia/arthritis, and myalgia.

T2

  • Based on a median follow-up of patients for 28 months, the incidence of clinical fractures from the core randomized study in patients who received letrozole was 5.9% (152) and placebo was 5.5% (142). The incidence of self-reported osteoporosis was higher in patients who received letrozole 6.9% (176) than in patients who received placebo 5.5% (141). Bisphosphonates were administered to 21.1% of the patients who received letrozole and 18.7% of the patients who received placebo.
  • The incidence of cardiovascular ischemic events from the core randomized study was comparable between patients who received letrozole 6.8% (175) and placebo 6.5% (167).
  • A patient-reported measure that captures treatment impact on important symptoms associated with estrogen deficiency demonstrated a difference in favor of placebo for vasomotor and sexual symptom domains.
  • Lipid Sub-Study
  • In the extended adjuvant setting, based on a median duration of follow-up of 62 months, there was no significant difference between letrozole and placebo in total cholesterol or in any lipid fraction at any time over 5 years. Use of lipid lowering drugs or dietary management of elevated lipids was allowed [see Warnings and Precautions (5.2)].
Updated Analysis, Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 60 Months
  • The extended adjuvant treatment trial was unblinded early [see Adverse Reactions (6.2)]. At the updated (final analysis), overall the side effects seen were consistent to those seen at a median treatment duration of 24 months.
  • During treatment or within 30 days of stopping treatment (median duration of treatment 60 months) a higher rate of fractures was observed for letrozole (10.4%) compared to placebo (5.8%), as also a higher rate of osteoporosis (letrozole 12.2% vs. placebo 6.4%).
  • Based on 62 months median duration of follow-up in the randomized letrozole arm in the Safety population the incidence of new fractures at any time after randomization was 13.3% for letrozole and 7.8% for placebo. The incidence of new osteoporosis was 14.5% for letrozole and 7.8% for placebo.
  • During treatment or within 30 days of stopping treatment (median duration of treatment 60 months) the incidence of cardiovascular events was 9.8% for letrozole and 7% for placebo.
  • Based on 62 months median duration of follow-up in the randomized letrozole arm in the Safety population the incidence of cardiovascular disease at any time after randomization was 14.4% for letrozole and 9.8% for placebo.
  • Lipid Sub-Study
  • In the extended adjuvant setting, based on a median duration of follow-up of 62 months, there was no significant difference between letrozole and placebo in total cholesterol or in any lipid fraction over 5 years. Use of lipid lowering drugs or dietary management of elevated lipids was allowed [see Warnings and Precautions (5.2)].
First-Line Treatment of Advanced Breast Cancer
  • A total of 455 patients were treated for a median time of exposure of 11 months. The incidence of adverse reactions was similar for letrozole and tamoxifen. The most frequently reported adverse reactions were bone pain, hot flushes, back pain, nausea, arthralgia and dyspnea. Discontinuations for adverse reactions other than progression of tumor occurred in 10/455 (2%) of patients on letrozole and in 15/455 (3%) of patients on tamoxifen.
  • Adverse reactions, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with letrozole 2.5 mg or tamoxifen 20 mg in the first-line treatment study are shown in Table 3.

T3

  • Other less frequent (≤ 2%) adverse reactions considered consequential for both treatment groups, included peripheral thromboembolic events, cardiovascular events, and cerebrovascular events. Peripheral thromboembolic events included venous thrombosis, thrombophlebitis, portal vein thrombosis and pulmonary embolism. Cardiovascular events included angina, myocardial infarction, myocardial ischemia, and coronary heart disease. Cerebrovascular events included transient ischemic attacks, thrombotic or hemorrhagic strokes and development of hemiparesis.
Second-Line Treatment of Advanced Breast Cancer
  • Study discontinuations in the megestrol acetate comparison study for adverse reactions other than progression of tumor were 5/188 (2.7%) on letrozole 0.5 mg, in 4/174 (2.3%) on letrozole 2.5 mg, and in 15/190 (7.9%) on megestrol acetate. There were fewer thromboembolic events at both letrozole doses than on the megestrol acetate arm (0.6% vs. 4.7%). There was also less vaginal bleeding (0.3% vs. 3.2%) on letrozole than on megestrol acetate. In the aminoglutethimide comparison study, discontinuations for reasons other than progression occurred in 6/193 (3.1%) on 0.5 mg letrozole, 7/185 (3.8%) on 2.5 mg letrozole, and 7/178 (3.9%) of patients on aminoglutethimide.
  • Comparisons of the incidence of adverse reactions revealed no significant differences between the high and low dose letrozole groups in either study. Most of the adverse reactions observed in all treatment groups were mild to moderate in severity and it was generally not possible to distinguish adverse reactions due to treatment from the consequences of the patient’s metastatic breast cancer, the effects of estrogen deprivation, or intercurrent illness.
  • Adverse reactions, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with letrozole 0.5 mg, letrozole 2.5 mg, megestrol acetate, or aminoglutethimide in the two controlled trials are shown in Table 4.

T4

  • Other less frequent (< 5%) adverse reactions considered consequential and reported in at least three patients treated with letrozole, included hypercalcemia, fracture, depression, anxiety, pleural effusion, alopecia, increased sweating and vertigo.
First and Second-Line Treatment of Advanced Breast Cancer
  • In the combined analysis of the first- and second-line metastatic trials and post-marketing experiences other adverse reactions that were reported were cataract, eye irritation, palpitations, cardiac failure, tachycardia, dysesthesia (including hypesthesia/paresthesia), arterial thrombosis, memory impairment, irritability, nervousness, urticaria, increased urinary frequency, leukopenia, stomatitis cancer pain, pyrexia, vaginal discharge, appetite increase, dryness of skin and mucosa (including dry mouth), and disturbances of taste and thirst.

Postmarketing Experience

  • Cases of blurred vision, increased hepatic enzymes, angioedema, anaphylactic reactions, toxic epidermal necrolysis, erythema multiforme and hepatitis have been reported. Cases of carpal tunnel syndrome and trigger finger have been identified during post approval use of letrozole.

Drug Interactions

  • Tamoxifen
  • Coadministration of letrozole and tamoxifen 20 mg daily resulted in a reduction of letrozole plasma levels of 38% on average. Clinical experience in the second-line breast cancer trials indicates that the therapeutic effect of letrozole therapy is not impaired if letrozole is administered immediately after tamoxifen.
  • Cimetidine
  • A pharmacokinetic interaction study with cimetidine showed no clinically significant effect on letrozole pharmacokinetics.
  • Warfarin
  • An interaction study with warfarin showed no clinically significant effect of letrozole on warfarin pharmacokinetics.
  • Other Anticancer Agents
  • There is no clinical experience to date on the use of letrozole in combination with other anticancer agents.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

  • Pregnancy Category X
  • Letrozole may cause fetal harm when administered to a pregnant woman and the clinical benefit to premenopausal women with breast cancer has not been demonstrated. Letrozole is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
  • Letrozole caused adverse pregnancy outcomes, including congenital malformations, in rats and rabbits at doses much smaller than the daily maximum recommended human dose (MRHD) on a mg/m2 basis. Effects included increased post-implantation pregnancy loss and resorptions, fewer live fetuses, and fetal malformations affecting the renal and skeletal systems. Animal data and letrozole’s mechanism of action raise concerns that letrozole could be a human teratogen as well.
  • Reproduction studies in rats showed embryo and fetal toxicity at letrozole doses during organogenesis equal to or greater than 1/100 the daily maximum recommended human dose (MHRD) (mg/m2 basis). Adverse effects included: intrauterine mortality; increased resorptions and postimplantation loss; decreased numbers of live fetuses; and fetal anomalies including absence and shortening of renal papilla, dilation of ureter, edema and incomplete ossification of frontal skull and metatarsals. Letrozole doses 1/10 the daily MHRD (mg/m2 basis) caused fetal domed head and cervical/centrum vertebral fusion. In rabbits, letrozole caused embryo and fetal toxicity at doses about 1/100,000 and 1/10,000 the daily MHRD respectively (mg/m2 basis). Fetal anomalies included incomplete ossification of the skull, sternebrae and fore- and hind legs [see Nonclinical Toxicology (13.2)].
  • Physicians should discuss the need for adequate contraception with women who are recently menopausal. Contraception should be used until postmenopausal status is clinically well established.


Pregnancy Category (AUS):

  • Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Letrozole in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Letrozole during labor and delivery.

Nursing Mothers

  • It is not known if letrozole is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from letrozole, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

  • The safety and effectiveness in pediatric patients have not been established.

Geriatic Use

  • The median age of patients in all studies of first-line and second-line treatment of metastatic breast cancer was 64 to 65 years. About 1/3 of the patients were ≥ 70 years old. In the first-line study, patients ≥70 years of age experienced longer time to tumor progression and higher response rates than patients < 70.
  • For the extended adjuvant setting, more than 5,100 postmenopausal women were enrolled in the clinical study. In total, 41% of patients were aged 65 years or older at enrollment, while 12% were 75 or older. In the extended adjuvant setting, no overall differences in safety or efficacy were observed between these older patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
  • In the adjuvant setting, more than 8,000 postmenopausal women were enrolled in the clinical study. In total, 36 % of patients were aged 65 years or older at enrollment, while 12% were 75 or older. More adverse reactions were generally reported in elderly patients irrespective of study treatment allocation. However, in comparison to tamoxifen, no overall differences with regards to the safety and efficacy profiles were observed between elderly patients and younger patients.

Gender

There is no FDA guidance on the use of Letrozole with respect to specific gender populations.

Race

There is no FDA guidance on the use of Letrozole with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Letrozole in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Letrozole in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Letrozole in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Letrozole in patients who are immunocompromised.

Administration and Monitoring

Administration

  • Oral
  • Intravenous

Monitoring

There is limited information regarding Monitoring of Letrozole in the drug label.

  • Description

IV Compatibility

There is limited information regarding IV Compatibility of Letrozole in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

  • Description

Management

  • Description

Chronic Overdose

There is limited information regarding Chronic Overdose of Letrozole in the drug label.

Pharmacology

There is limited information regarding Letrozole Pharmacology in the drug label.

Mechanism of Action

Structure

This image is provided by the National Library of Medicine.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Letrozole in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Letrozole in the drug label.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Letrozole in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Letrozole in the drug label.

How Supplied

Storage

There is limited information regarding Letrozole Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Letrozole in the drug label.

Precautions with Alcohol

  • Alcohol-Letrozole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Look-Alike Drug Names

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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