Femara

Generic Name: Letrozole
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

Introduction

Antineoplastic agent; selective aromatase inhibitor.^{1 2 3 6 11 13 15}

Uses for Femara

Breast Cancer

Adjuvant treatment in postmenopausal women with ER-positive early breast cancer.^{a c} Efficacy based on analysis of disease-free survival in women treated with letrozole for a median of 24 months.^a Follow-up analysis needed to determine long-term safety and efficacy.^a

Extended adjuvant treatment in postmenopausal women with early-stage breast cancer who have received 5 years of adjuvant tamoxifen therapy.^{a 9 25 38} Efficacy based on analysis of disease-free survival in women treated with letrozole for a median of 24 months.^a Further data needed to determine long-term outcome.^a

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}

Second-line therapy for advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy (e.g., tamoxifen).^{1 9 10}

Female Infertility

Has been used to induce ovulation† in anovulatory women desiring pregnancy.^d Letrozole is not approved by FDA for this indication;^e manufacturer states that the drug should not be given to women who may become or are pregnant.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Femara Dosage and Administration

General

• 
  

  Administration of corticosteroid replacement therapy not necessary.¹ (See Actions.)

  
  

Administration

Oral Administration

Administer orally once daily without regard to meals.¹

Dosage

Adults

Breast Cancer

Adjuvant Treatment of Early-stage Breast Cancer

Oral

2.5 mg once daily.^a Optimal duration unknown.^a Planned duration of treatment in clinical study was 5 years; median duration of treatment at time of analysis was 24 months; median duration of follow-up was 26 months.^a Discontinue if relapse occurs.^a

Extended Adjuvant Treatment of Early-stage Breast Cancer

Oral

2.5 mg once daily.^a Optimal duration unknown.^a Planned duration of treatment in clinical study was 5 years; median duration of treatment at time of analysis was 24 months; median duration of follow-up was 28 months.^a Discontinue if relapse occurs.^a

First-line Treatment of Locally Advanced or Metastatic Breast Cancer

Oral

2.5 mg once daily.¹ Continue therapy until tumor progresses.¹

Second-line Treatment of Advanced Breast Cancer

Oral

2.5 mg once daily.¹ Continue therapy until tumor progresses.¹

Special Populations

Hepatic Impairment

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

Renal Impairment

Cl_cr ≥10 mL/minute: No dosage adjustment necessary.¹

Geriatric Patients

No dosage adjustment necessary.¹

Cautions for Femara

Contraindications

• 
  

  Known hypersensitivity to letrozole or any ingredient in the formulation.¹

  
  

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.¹ Embryotoxic, fetotoxic, and teratogenic in animals.¹ If inadvertently used during pregnancy or patient becomes pregnant, apprise of fetal hazard and potential risk of pregnancy loss.¹

General Precautions

CNS Effects

Fatigue and dizziness reported; somnolence reported uncommonly.¹ Caution advised when driving or using machinery.¹

Hepatic Effects

Abnormal liver function test results not associated with documented liver metastases reported in women receiving second-line therapy.¹

Lipid Effects

Increases in total serum cholesterol reported in women receiving adjuvant treatment.^a

Effects on Bone

Risk of osteoporosis.^{a 29} Use of letrozole in women receiving calcium and vitamin D who were not receiving bisphosphonates has been associated with loss of bone mineral density (BMD) in the hip and/or lumbar spine.^a Consider monitoring BMD.^{29 37 a}

Specific Populations

Pregnancy

Category D.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether letrozole is distributed into human milk; caution advised.¹

Pediatric Use

Safety and efficacy not established in children of any age.¹

Geriatric Use

No substantial differences in safety or efficacy relative to younger patients when used for adjuvant therapy.^a Possibility exists of greater sensitivity in some older individuals.^a

In all studies of first- and second-line treatment, median patient age 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

Premenopausal Women

Not approved by FDA for use in premenopausal women.^{a e}

Hepatic Impairment

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

Bone pain, hot flushes, back pain, nausea, arthralgia, dyspnea.¹

Interactions for Femara

Metabolized by CYP3A4 and CYP2A6.¹ Inhibits CYP2A6 and, to a lesser extent, CYP2C19 in vitro.¹

Specific Drugs

Drug	Interaction	Comments
Antineoplastic agents	No clinical experience with concomitant use to date1
Cimetidine	No clinically important effect on letrozole pharmacokinetics1
Diazepam	No substantial effect on letrozole or diazepam metabolism in vitro1
Estrogens	Antagonistic pharmacologic effectsb	Concomitant use not recommendedb
Tamoxifen	Decreased plasma letrozole concentrations1	Therapeutic effect of letrozole not impaired if used immediately after tamoxifen1
Warfarin	No clinically important effects on warfarin pharmacokinetics1

Femara Pharmacokinetics

Absorption

Bioavailability

Rapidly and completely absorbed after oral administration.¹

Onset

Plasma estradiol, estrone, and estrone sulfate reduced by 75–95% within 2–3 days with daily dosages of 0.1–5 mg.¹

Duration

Estrogen suppression maintained throughout therapy in patients receiving ≥0.5 mg daily.¹

Food

Food does not affect absorption.¹

Distribution

Extent

Not known if distributed into milk.¹

Plasma Protein Binding

Weakly bound.¹

Elimination

Metabolism

Principally metabolized to inactive carbinol metabolite by CYP3A4 and CYP2A6.¹

Elimination Route

Excreted in urine as glucuronide of carbinol metabolite (≥75%), unidentified metabolites (about 9%), and unchanged drug (6%).¹

Half-life

2 days.¹

Special Populations

Renal function did not affect the pharmacokinetics of a single 2.5-mg dose in adults with varying renal function.¹ Renal impairment (Cl_cr 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

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).¹

ActionsActions

• 
  

  Selectively inhibits conversion of androgens to estrogens.^{1 2 6}

  
  


• 
  

  Decreased serum and tumor concentrations of estrogen inhibit breast tumor growth and delay disease progression.^{1 4}

  
  


• 
  

  Does not affect synthesis of adrenal corticosteroid, aldosterone, or thyroid hormone.^{1 6}

  
  

Advice to Patients

• 
  

  Risk of dizziness, fatigue, or somnolence; use caution when driving or operating machinery.¹

  
  


• 
  

  Importance of informing clinicians of any existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.¹

  
  


• 
  

  Risk of osteoporosis.^{a 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 women informing their clinician if they are or plan to become pregnant or plan to breast-feed; warn of potential hazard to the fetus in cases of inadvertent exposure of pregnant women to letrozole.¹

  
  


• 
  

  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Letrozole

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	2.5 mg	Femara	Novartis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. 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

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions June 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Novartis. Femara (letrozole) tablets prescribing information. East Hanover, NJ; 2003 Feb.

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; 2004 May 19.

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.

a. Novartis Pharmaceuticals Corporation. Femara (letrozole) tablets prescribing information. East Hanover, NJ; 2005 Dec.

b. Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med. 2003; 348:2431-42. [PubMed 12802030]

c. Thurlimann B, Keshaviah A, Coates AS 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]

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 Femara resources

• Femara Side Effects (in more detail)
• Femara Use in Pregnancy & Breastfeeding
• Drug Images
• Femara Drug Interactions
• Femara Support Group
• 15 Reviews for Femara - Add your own review/rating

• Femara Prescribing Information (FDA)


• Femara Consumer Overview


• Femara Advanced Consumer (Micromedex) - Includes Dosage Information


• Femara MedFacts Consumer Leaflet (Wolters Kluwer)


• Letrozole Prescribing Information (FDA)


• Letrozole Professional Patient Advice (Wolters Kluwer)

Compare Femara with other medications

• Breast Cancer
• Breast Cancer, Adjuvant
• Breast Cancer, Metastatic
• Female Infertility