Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: 4,4′-(1H-1,2,4-triazol-1-ylmethylene)bis-benzonitrile
Molecular Formula: C17H11N5
CAS Number: 112809-51-5
Uses for Letrozole
Adjuvant treatment in postmenopausal women with early-stage hormone receptor-positive breast cancer.1 39 40 41 Superior to tamoxifen when each drug was given alone;1 40 52 efficacy of sequential therapy (tamoxifen for 2 years followed by letrozole for 3 years, or vice versa) similar to that of letrozole given for 5 years.39 52
Aromatase inhibitors are a treatment of choice for adjuvant hormonal therapy to lower risk of breast cancer recurrence in postmenopausal women with early-stage hormone receptor-positive breast cancer.9 41 An aromatase inhibitor-containing regimen is modestly more effective than tamoxifen alone.9 41
ASCO states that most postmenopausal women with early-stage hormone receptor-positive breast cancer should consider receiving an aromatase inhibitor during the course of adjuvant therapy, either as primary (initial) therapy or following 2–3 years of tamoxifen (sequential therapy), for a total of 5 years of adjuvant endocrine therapy.41 Data also support switching to an aromatase inhibitor following 5 years of adjuvant tamoxifen (extended adjuvant therapy).41 ASCO states that women who receive extended adjuvant therapy should receive tamoxifen for 5 years followed by an aromatase inhibitor for 3–5 years.41
Consider adverse effects, patient preference, and preexisting conditions when selecting an adjuvant regimen.41 Fracture, MI, hypercholesterolemia, and arthralgia reported more frequently in patients receiving adjuvant letrozole, whereas thromboembolic events, vaginal bleeding, and endometrial disorders reported more frequently in those receiving adjuvant tamoxifen.1 39 40
First-line therapy for hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer in postmenopausal women; superior to tamoxifen in producing objective tumor response and delaying tumor progression.1 9 18 20
In combination with lapatinib for treatment of hormone receptor-positive metastatic breast cancer that overexpresses the human epidermal receptor type 2 (HER2) protein in postmenopausal women who are candidates for hormonal therapy.44 49 53 Combined therapy with an aromatase inhibitor and lapatinib has not been compared with trastuzumab-containing chemotherapy for treatment of metastatic breast cancer.49
Has been used to induce ovulation† in anovulatory women desiring pregnancy.d Letrozole is not FDA-labeled for this indication;e manufacturer states that the drug is contraindicated in women who may become or are pregnant.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Letrozole Dosage and Administration
Administer orally once daily without regard to meals.1
Adjuvant Treatment of Early-stage Breast CancerOral
Initial adjuvant therapy: Planned duration of treatment in clinical study was 5 years; 73% of patients completed therapy.1 Optimal duration unknown.1 In patients who discontinue aromatase inhibitor therapy prior to 5 years, ASCO recommends consideration of tamoxifen to complete the 5-year adjuvant regimen.41
Sequential adjuvant therapy: Optimal time to switch from tamoxifen to aromatase inhibitor therapy is unknown.41 ASCO states that disease-free patients may switch to an aromatase inhibitor after 2–3 years of adjuvant tamoxifen therapy to complete a 5-year sequential adjuvant regimen.41
Extended adjuvant therapy: Initiate letrozole after completion of 5 years of adjuvant tamoxifen therapy.1 25 41 Planned duration of letrozole treatment in clinical study was 5 years;1 25 71% of patients completed ≥3 years and 58% completed ≥4.5 years of treatment.1 ASCO recommends administering an aromatase inhibitor for 3–5 years beyond the initial 5 years of tamoxifen therapy, for a total of 8–10 years of adjuvant endocrine therapy.41 Optimal duration unknown.1 25
First-line Treatment of Locally Advanced or Metastatic Breast CancerOral
Second-line Treatment of Advanced Breast CancerOral
Adjuvant Treatment of Early-stage Breast CancerOral
Cirrhosis and severe hepatic impairment (Child-Pugh class C): Decrease dosage to 2.5 mg every other day.1
Mild to moderate hepatic impairment: No dosage adjustment recommended.1
Clcr ≥10 mL/minute: No dosage adjustment necessary.1
No dosage adjustment necessary.1
Cautions for Letrozole
Premenopausal women.1 (See Premenopausal Women under Cautions.)
Pregnancy.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Fetal/Neonatal Morbidity and Mortality
May cause fetal harm.1 Embryotoxic, fetotoxic, and teratogenic in animals.1 Contraindicated in women who are or may become pregnant (i.e., premenopausal women).1 If inadvertently used during pregnancy or patient becomes pregnant, apprise of fetal hazard.1 Women who are perimenopausal or recently have become postmenopausal should use adequate contraception until postmenopausal state is fully established.1
Effects on Bone
Postmenopausal women receiving an aromatase inhibitor as adjuvant therapy are at high risk for osteoporosis.29
Bone mineral density (BMD) at lumbar spine decreased by 4.1% over 2 years in patients receiving adjuvant letrozole and increased by 0.3% in those receiving tamoxifen; results for hip BMD were similar, but difference was less pronounced.1 Incidence of osteoporosis (5 versus 3%) and fractures (14 versus 10%) was higher during or after treatment with letrozole versus tamoxifen.1
Hip BMD decreased by 4 or 2% over 2 years in patients receiving extended adjuvant therapy with letrozole or placebo, respectively.1 Incidence of osteoporosis (14 versus 8%) and fracture (13 versus 8%) was higher during or after treatment with letrozole versus placebo.1
Lifestyle changes (e.g., weight-bearing exercise, abstinence from smoking, moderation in alcohol consumption) and supplemental calcium and vitamin D recommended in all women receiving adjuvant letrozole therapy.25 29 37
Hypercholesterolemia reported in 52% of patients receiving letrozole as initial adjuvant therapy, 16% of patients receiving the drug as extended adjuvant therapy, and 3% of patients receiving the drug as second-line therapy for advanced disease.1
Hypercholesterolemia (52 versus 29%) and use of antilipemic agents (25 versus 16%) reported more frequently in patients receiving letrozole versus tamoxifen as initial adjuvant therapy.1 Among patients with normal baseline serum cholesterol concentrations, elevated total cholesterol concentrations reported in 8 or 3% of those receiving letrozole or tamoxifen, respectively.1
Moderate decreases in lymphocyte counts observed in some patients, but of uncertain clinical importance and transient in about half of those affected.1
Thrombocytopenia reported but causality is unclear.1
Category X.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Not known whether letrozole is distributed into human milk; discontinue nursing or the drug.1
Safety and efficacy not established in children of any age.1
Initial adjuvant therapy: 36% of study patients were ≥65 years of age and 12% were ≥75 years of age.1 Adverse effects generally more common in geriatric patients regardless of their assigned study treatment; however, no overall differences in safety and efficacy of letrozole versus tamoxifen were observed between geriatric patients and younger adults.1
Extended adjuvant therapy: 41% of study patients were ≥65 years of age and 12% were ≥75 years of age.1 No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1
First- and second-line treatment: Median patient age in all studies was 64–65 years; one-third were ≥70 years of age.1 In the first-line clinical study, patients ≥70 years of age experienced longer time to tumor progression and higher response rates than patients <70 years of age.1
Dosage reduction recommended in patients with cirrhosis and severe hepatic impairment.1 Effect of hepatic impairment on drug exposure in noncirrhotic cancer patients with increased bilirubin concentrations not determined.1
Common Adverse Effects
Initial adjuvant therapy: Hypercholesterolemia, hot flushes (flashes), arthralgia/arthritis.1
Extended adjuvant therapy: Flushing, asthenia, arthralgia, headache, increased sweating, edema, hypercholesterolemia.1
Advanced-stage disease: Bone pain, hot flushes, back pain, dyspnea, nausea, arthralgia.1
Interactions for Letrozole
No clinical experience with concomitant use to date1
No clinically important effect on letrozole pharmacokinetics1
Antagonistic pharmacologic effectsb
Concomitant use not recommendedb
Decreased plasma letrozole concentrations1
Therapeutic effect of letrozole not impaired if used immediately after tamoxifen1
No clinically important effects on warfarin pharmacokinetics1
Rapidly and completely absorbed after oral administration.1
Plasma estradiol, estrone, and estrone sulfate reduced by 75–95% within 2–3 days with daily dosages of 0.1–5 mg.1
Estrogen suppression maintained throughout therapy in patients receiving ≥0.5 mg daily.1
Food does not affect absorption.1
Not known if distributed into milk.1
Plasma Protein Binding
Principally metabolized to inactive carbinol metabolite by CYP3A4 and CYP2A6.1
Excreted in urine as glucuronide of carbinol metabolite (≥75%), unidentified metabolites (about 9%), and unchanged drug (6%).1
Renal function did not affect the pharmacokinetics of a single 2.5-mg dose in adults with varying renal function.1 Renal impairment (Clcr 20–50 mL/minute) did not affect steady-state plasma concentrations in patients with advanced breast cancer.1
AUC was increased twofold and clearance was decreased in adults with cirrhosis and severe hepatic impairment (Child-Pugh class C); higher letrozole concentrations are expected in breast cancer patients with severe hepatic impairment compared with patients with normal liver function.1
AUC was increased (37%) in adults with moderate hepatic impairment (e.g., cirrhosis, Child-Pugh class A and B); drug exposure was within range observed in patients without hepatic impairment.1
25°C (may be exposed to 15–30°C).1
Advice to Patients
Risk of dizziness, fatigue, or somnolence; use caution when driving or operating machinery.1
Risk of osteoporosis.1 29 Life-style changes (e.g., weight-bearing exercise, abstinence from smoking, moderation of alcohol consumption) and dietary supplementation with calcium and vitamin D advised.25 29 37 Importance of considering BMD monitoring.1
Risk of fetal harm if used during pregnancy.1 Necessity for perimenopausal or recently postmenopausal women to use adequate contraception until postmenopausal state is fully established.1 Contraindicated in premenopausal women.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Femara 2.5MG Tablets (NOVARTIS): 10/$188.98 or 30/$516.96
Letrozole 2.5MG Tablets (DR.REDDY'S LABORATORIES): 30/$499.96 or 60/$984.93
AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 9, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
1. Novartis. Femara (letrozole) tablets prescribing information. East Hanover, NJ; 2011 Dec.
2. Ingle JN, Johnson PA, Suman VJ et al. A randomized phase II trial of two dosage levels of letrozole as third-line hormonal therapy for women with metastatic breast carcinoma. Cancer. 1997; 80:218-24. [IDIS 391347] [PubMed 9217033]
3. Lonning PE. Aromatase inhibition for breast cancer treatment. Acta Oncol. 1996; 35(Suppl 5):38-43. [PubMed 9142963]
4. Higa GM, AlKhouri N. Anastrazole: a selective aromatase inhibitor for the treatment of breast cancer. Am J Health-Syst Pharm. 1998; 55:445-52. [IDIS 401376] [PubMed 9522927]
5. Winer EP, Morrow M, Osborne CK et al. Malignant tumors of the breast. In: DeVita VT Jr, Hellman S, Rosenberg SA eds. Cancer: principles and practice of oncology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2001:1651-717.
6. Iveson TJ, Smith IE, Ahern J et al. Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in postmenopausal patients with advanced breast cancer. Cancer Res. 1993; 53:266-70. [IDIS 308191] [PubMed 8417819]
7. Dombernowsky P, Smith I, Falkson G et al. Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol. 1998; 16:453-61. [IDIS 401174] [PubMed 9469328]
8. Gershanovich M, Chaudri HA, Campos D et al. Letrozole, a new oral aromatase inhibitor: randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Letrozole International Trial Group (AR/BC3). Ann Oncol. 1998; 9:639-45. [PubMed 9681078]
9. Breast cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2011 Nov 21.
10. Anon. Toremifene and letrozole for advanced breast cancer. Med Lett Drugs Ther. 1998; 40:43-5. [PubMed 9580744]
11. Bisagni G, Scaglione F et al. Letrozole, a new non-steroidal aromatase inhibitor in treating postmenopausal patients with advanced breast cancer. A pilot study. Ann Oncol. 1996; 7:99-102.
12. Bhatnagar AS, Hausler A, Schieweck K et al. Highly selective inhibition of estrogen biosynthesis by CGS 20267, a new non-steroidal aromatase inhibitor. J Steroid Biochem Mol Biol. 1990; 37:1021-7. [PubMed 2149502]
13. Ibrahim NK, Budar AU. Aromatase inhibitors: current status. Am J Clin Oncol. 1995; 18:407-17. [IDIS 354571] [PubMed 7572758]
14. Novartis, East Hanover, NJ: Personal communication.
15. Smith IE. Pivotal trials of letrozole: a new aromatase inhibitor. Oncology. 1998; 12(Suppl 5):41-4. [PubMed 9556791]
16. Food and Drug Administration. Labeling and prescription drug advertising; content and format for labeling for human prescription drugs. 21 CFR Parts 201 and 202. Final Rule. [Docket No. 75N-0066] Fed Regist. 1979; 44:37434-67.
17. Department of Health and Human Services, Food and Drug Administration. Subpart B—Labeling requirements for prescription drugs and/or insulin. (21 CFR Ch. 1 (4-1-87 Ed.)). 1987:18-24.
18. Anon. Drugs of choice for cancer. Treat Guidel Med Lett. 2003; 1:41-52. [PubMed 15529105]
19. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 020726: Medical Reviews. From FDA web site.
20. Mouridsen H, Gershanovich M, Sun Y et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol. 2001; 19:2596-606. [IDIS 464670] [PubMed 11352951]
21. Mouridsen H, Gershanovich M, Sun Y et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol. 2003; 21:2101-9. [IDIS 498882] [PubMed 12775735]
22. Buzdar A, Douma J, Davidson N et al. Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate. J Clin Oncol. 2001; 19:3357-66. [IDIS 466492] [PubMed 11454883]
23. Dowsett M, Pfister C, Johnston SR et al. Impact of tamoxifen on the pharmacokinetics and endocrine effects of the aromatase inhibitor letrozole in postmenopausal women with breast cancer. Clin Cancer Res. 1999; 5:2338-43. [IDIS 432914] [PubMed 10499602]
24. Ingle JN, Suman VJ, Johnson PA et al. Evaluation of tamoxifen plus letrozole with assessment of pharmacokinetic interaction in postmenopausal women with metastatic breast cancer. Clin Cancer Res. 1999; 5:1642-9. [IDIS 431256] [PubMed 10430063]
25. Goss PE, Ingle JN, Martino S et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003; 349: 1793-802. [IDIS 506722] [PubMed 14551341]
26. Winer EP, Hudis C, Burstein HJ et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for women with hormone receptor-positive breast cancer: status report 2002. J Clin Oncol. 2002; 20:3317-27. [IDIS 486566] [PubMed 12149306]
27. Bryant J, Wolmark N. Letrozole after tamoxifen for breast cancer;—what is the price of success? N Engl J Med. 2003; 349:1855-7. Editorial.
28. Burstein HJ. Beyond tamoxifen—extending endocrine treatment for early-stage breast cancer. N Engl J Med. 2003; 349:1857-9. [IDIS 506724] [PubMed 14551340]
29. Hilner BE, Ingle JN, Chelbowski RT et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol. 2003; 21:4042-57. [IDIS 513063] [PubMed 12963702]
30. Mackey JR, Joy AA. Letrozole in second-line therapy of advanced breast cancer: more questions than answers. J Clin Oncol. 2001; 19:4353-4. [IDIS 473674] [PubMed 11731524]
31. Buzdar AU, Chaudri HA, Trunet PF. Letrozole: which dose to be used? J Clin Oncol. 2000; 18:1802-3. Letter.
32. Simpson D, Curran MP, Perry CM. Letrozole: a review of its use in postmenopausal women with breast cancer. Drugs. 2004; 641:1213-30.
33. Geisler J, Haynes B, Anker G et al. Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study. J Clin Oncol. 2002; 20:751-7. [IDIS 478622] [PubMed 11821457]
34. Rose C, Vtoraya O, Pluzanska A et al. An open randomised trial of second-line endocrine therapy in advanced breast cancer: comparison of the aromatase inhibitors letrozole and anastrozole. Eur J Cancer. 2003; 39:2318-27. [PubMed 14556923]
35. Twombly R. Critics question price of success in halted clinical trial of aromatase inhibitor letrozole. J Natl Cancer Inst. 2003; 95:1738-9. [PubMed 14652229]
36. Sperone P, Gorzegno G, Berruti A et al. Reversible pancytopenia caused by oral letrozole assumption in a patient with recurrent breast cancer. J Clin Oncol. 2002; 20:3747-8. [IDIS 485996] [PubMed 12202678]
37. Reviewers’ comments (personal observations).
38. Gilardi J, Fox K (Novartis). Femara gains U.S. FDA approval as only post-tamoxifen treatment for early breast cancer. Basel, Switzerland; 2004 Oct 29. Press release.
39. BIG 1-98 Collaborative Group, Mouridsen H, Giobbie-Hurder A et al. Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. N Engl J Med. 2009; 361:766-76. [PubMed 19692688]
40. Breast International Group (BIG) 1-98 Collaborative Group, Thürlimann B, Keshaviah A et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005; 353:2747-57. [PubMed 16382061]
41. Burstein HJ, Prestrud AA, Seidenfeld J et al. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol. 2010; 28:3784-96. [PubMed 20625130]
42. Wasan KM, Goss PE, Pritchard PH et al. The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA.17L). Ann Oncol. 2005; 16:707-15. [PubMed 15817595]
43. Perez EA, Josse RG, Pritchard KI et al. Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: a companion study to NCIC CTG MA.17. J Clin Oncol. 2006; 24:3629-35. [PubMed 16822845]
44. Johnston S, Pippen J, Pivot X et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009; 27:5538-46. [PubMed 19786658]
48. Rabaglio M, Sun Z, Price KN et al. Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial. Ann Oncol. 2009; 20:1489-98. [PubMed 19474112]
49. GlaxoSmithKline. Tykerb (lapatinib) prescribing information. Research Triangle Park, NC; 2011 Aug.
50. Ingle JN, Tu D, Pater JL et al. Intent-to-treat analysis of the placebo-controlled trial of letrozole for extended adjuvant therapy in early breast cancer: NCIC CTG MA.17. Ann Oncol. 2008; 19:877-82. [PubMed 18332043]
51. Letrozole in treating women with primary breast cancer who have received 5 years of aromatase inhibitor therapy. Clinical Trials (PDQ) (database). Bethesda, MD: National Cancer Institute; 2012 Apr 25.
52. Regan MM, Neven P, Giobbie-Hurder A et al. Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up. Lancet Oncol. 2011; 12:1101-8. [PubMed 22018631]
53. Schwartzberg LS, Schwarzberg LS, Franco SX et al. Lapatinib plus letrozole as first-line therapy for HER-2+ hormone receptor-positive metastatic breast cancer. Oncologist. 2010; 15:122-9. [PubMed 20156908]
b. Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med. 2003; 348:2431-42. [PubMed 12802030]
d. Holzer H, Casper R, Tulaudi T. A new era in ovulation induction. Fertil Seril. 2006; 85:277-84.
e. Hohneker JA and Prestifilippo J. Dear healthcare provider letter- Femara. East Hanover, NJ: Novartis Oncology; 2005 Dec 5.
More about letrozole
- Other brands: Femara