Drugs Details

Drugs Info of Femara
Drugs Details
  • Drugs Type  : FDA
  • Date : 28th Jan 2015 04:45 am
  • Brand Name : Femara
  • Generic Name : letrozole (Pronunciation: LET roe zol)
Descriptions

Femara tablets for oral administration contains 2.5 mg of letrozole, a nonsteroidal aromatase inhibitor (inhibitor of estrogen synthesis). It is chemically described as 4,4'-(1H-1,2,4-Triazol-1ylmethylene)dibenzonitrile, and its structural formula is

 

Femara (letrozole) Structural Formula Illustration

Letrozole is a white to yellowish crystalline powder, practically odorless, freely soluble in dichloromethane, slightly soluble in ethanol, and practically insoluble in water. It has a molecular weight of 285.31, empirical formula C17H11N5, and a melting range of 184°C to 185°C.

Femara is available as 2.5 mg tablets for oral administration.

Inactive Ingredients: Colloidal silicon dioxide, ferric oxide, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, maize starch, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, talc, and titanium dioxide.

What are the possible side effects of letrozole (Femara)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Less serious side effects may include:

  • dizziness, drowsiness, weakness, tired feeling;
  • hot flashes, warmth in your face or chest;
  • flushing (warmth, redness, or tingly feeling);
  • headache;
  • nausea, constipation;
  • bone pain, muscle or joint pain;
  • numbness, tingling, weakness, or stiffness in your hand or fingers;
  • pain in your hand that spreads to your arm, wrist,...

Read All Potential Side Effects and See Pictures of Femara »

What are the precautions when taking letrozole (Femara)?

Before taking letrozole, tell your doctor or pharmacist if you are allergic to it; or to anastrozole; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: high blood fats (cholesterol), bone problems (such as osteopenia, osteoporosis), stroke or blood clots, heart disease (such as chest pain, heart attack, heart failure), high blood pressure, kidney problems, liver problems.

This drug may make you dizzy and tired, and may rarely cause blurred vision. Do not drive, use machinery, or do any activity that requires alertness or clear vision until you are...

Read All Potential Precautions of Femara »

This monograph has been modified to include the generic and brand name in many instances.

Indications

Adjuvant Treatment Of Early Breast Cancer

Femara (letrozole) is indicated for the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer.

Extended Adjuvant Treatment Of Early Breast Cancer

Femara is 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 Femara in extended adjuvant treatment of early breast cancer is based on an analysis of disease-free survival in patients treated with Femara for a median of 60 months [see Clinical Studies].

First and Second-Line Treatment Of Advanced Breast Cancer

Femara is indicated for first-line treatment of postmenopausal women with hormone receptor positive or unknown, locally advanced or metastatic breast cancer. Femara is also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy [see Clinical Studies].

Dosage Administration

Recommended Dose

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

Use In Adjuvant Treatment Of Early Breast Cancer

In the adjuvant setting, the optimal duration of treatment with letrozole is unknown. The planned duration of treatment in the study was 5 years with 73% of the patients having completed adjuvant therapy. Treatment should be discontinued at relapse [see Clinical Studies].

Use In Extended Adjuvant Treatment Of Early Breast Cancer

In the extended adjuvant setting, the optimal treatment duration with Femara is not known. The planned duration of treatment in the study was 5 years. In the final updated analysis, conducted at a median follow-up of 62 months, the median treatment duration was 60 months. Seventy-one percent of patients were treated for at least 3 years and 58% of patients completed least 4.5 years of extended adjuvant treatment. The treatment should be discontinued at tumor relapse [see Clinical Studies].

Use In First And Second-Line Treatment Of Advanced Breast Cancer

In patients with advanced disease, treatment with Femara should continue until tumor progression is evident. [see Clinical Studies]

Use In Hepatic Impairment

No dosage adjustment is recommended for patients with mild to moderate hepatic impairment, although Femara blood concentrations were modestly increased in subjects with moderate hepatic impairment due to cirrhosis. The dose of Femara in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50% [see WARNINGS AND PRECAUTIONS]. The recommended dose of Femara for such patients is 2.5 mg administered every other day. The effect of hepatic impairment on Femara exposure in noncirrhotic cancer patients with elevated bilirubin levels has not been determined.

Use In Renal Impairment

No dosage adjustment is required for patients with renal impairment if creatinine clearance is ≥ 10 mL/min. [see CLINICAL PHARMACOLOGY].

How Supplied

Dosage Forms And Strengths

2.5 mg tablets: dark yellow, film-coated, round, slightly biconvex, with beveled edges (imprinted with the letters FV on one side and CG on the other side).

Storage And Handling

Packaged in HDPE bottles with a safety screw cap.

2.5 milligram tablets Bottles of 30 tablets..............................................NDC 0078-0249-15

Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature].

Novartis Pharmaceuticals Corporation East Hanover, New Jersey, 07936. Revised: Jan 2014

This monograph has been modified to include the generic and brand name in many instances.

Side Effects

The most serious adverse reactions from the use of Femara are:

  • Bone effects [see WARNINGS AND PRECAUTIONS]
  • Increases in cholesterol [see WARNINGS AND PRECAUTIONS]

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

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 Femara and tamoxifen.

Certain adverse reactions wer e prospectively specified for analysis, based on the known pharmacologic properties and side effect profiles of the two drugs.

Adverse reactions wer e analyzed irrespective of whether a symptom was present or absent at baseline. Most adverse reactions reported (approximately 75% of patients reporting 1 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 1-4) irrespective of relationship to study treatment in the adjuvant trial for the monotherapy arms analysis (safety population).

Table 1: Patients with Adverse Reactions (CTC Grades 1-4, Irrespective of Relationship to Study Drug) in the Adjuvant Study – Monotherapy Arms Analysis (Median Follow-up 73 Months; Median Treatment 60 Months)

Adverse Reaction Grades 1-4 Grades 3-4
Femara
N=2448
n (%)
tamoxifen
N=2447
n (%)
Femara
N=2448
n (%)
tamoxifen
N=2447
n (%)
Pts with any adverse event 2310 (94.4) 2214 (90.5) 635 (25.9) 604 (24.7)
Hypercholesterolemia 1280 (52.3) 700 (28.6) 11 ( 0.4) 6 ( 0.2)
Hot Flashes/Flushes 821 (33.5) 929 (38.0) 0 - 0 -
Arthralgia/Arthritis 618 (25.2) 501 (20.4) 85 ( 3.5) 50 ( 2.0)
Night Sweats 357 (14.6) 426 (17.4) 0 - 0 -
Bone Fractures2 338 (13.8) 257 (10.5) - - - -
Weight Increase 317 (12.9) 378 (15.4) 27 ( 1.1) 39 ( 1.6)
Nausea 283 (11.6) 277 (11.3) 6 ( 0.2) 9 ( 0.4)
Bone Fractures1 247 (10.1) 174 ( 7.1) - - - -
Fatigue (Lethargy, Malaise, Asthenia) 235 ( 9.6) 250 (10.2) 6 ( 0.2) 7 ( 0.3)
Myalgia 217 ( 8.9) 212 ( 8.7) 18 ( 0.7) 14 ( 0.6)
Edema 164 ( 6.7) 160 ( 6.5) 3 ( 0.1) 1 ( < 0.1)
Weight Decrease 140 ( 5.7) 129 ( 5.3) 8 ( 0.3) 5 ( 0.2)
Vaginal Bleeding 128 ( 5.2) 320 (13.1) 1 ( < 0.1) 8 ( 0.3)
Back Pain 125 ( 5.1) 136 ( 5.6) 7 ( 0.3) 11 ( 0.4)
Osteoporosis NOS 124 ( 5.1) 66 ( 2.7) 10 ( 0.4) 5 ( 0.2)
Bone pain 123 ( 5.0) 109 ( 4.5) 6 ( 0.2) 4 ( 0.2)
Depression 119 ( 4.9) 114 ( 4.7) 16 ( 0.7) 14 ( 0.6)
Vaginal Irritation 111 ( 4.5) 77 ( 3.1) 2 ( < 0.1) 2 ( < 0.1)
Headache 105 ( 4.3) 94 ( 3.8) 9 ( 0.4) 5 ( 0.2)
Pain in extremity 103 ( 4.2) 79 ( 3.2) 6 ( 0.2) 4 ( 0.2)
Osteopenia 87 ( 3.6) 74 ( 3.0) 0 - 2 ( < 0.1)
Dizziness/Light-Headedness 84 ( 3.4) 84 ( 3.4) 1 ( < 0.1) 6 (0.2)
Alopecia 83 ( 3.4) 84 ( 3.4) 0 - 0 -
Vomiting 80 ( 3.3) 80 ( 3.3) 3 ( 0.1) 5 (0.2)
Cataract 49 ( 2.0) 54 ( 2.2) 16 ( 0.7) 17 ( 0.7)
Constipation 49 ( 2.0) 71 ( 2.9) 3 ( 0.1) 1 ( < 0.1)
Breast pain 37 ( 1.5) 43 ( 1.8) 1 ( < 0.1) 0 -
Anorexia 20 ( 0.8) 20 ( 0.8) 1 ( < 0.1) 1 ( < 0.1)
Endometrial Hyperplasia/ Cancer2, 3 11/1909 ( 0.6) 70/1943 ( 3.6) - -
Endometrial Proliferation Disorders 10 (0.3) 71 (1.8) 0 - 14 (0.6)
Endometrial Hyperplasia/ Cancer1, 3 6/1909 ( 0.3) 57/1943 (2.9) - -
Other Endometrial Disorders 2 ( < 0.1) 3 ( 0.1) 0 0
Myocardial Infarction1 24 ( 1.0) 12 ( 0.5) - -
Myocardial Infarction2 37 ( 1.5) 25 (1.0) - -
Myocardial Ischemia 6 ( 0.2) 9 ( 0.4) - -
Cerebrovascular Accident1 52 ( 2.1) 46 ( 1.9) - -
Cerebrovascular Accident2 70 ( 2.9) 63 ( 2.6) - -
Angina1 26 ( 1.1) 24 ( 1.0) - -
Angina2 32 ( 1.3) 31 ( 1.3) - -
Thromboembolic Event1 51 ( 2.1) 89 ( 3.6) - -
Thromboembolic Event2 71 ( 2.9) 111 ( 4.5) - -
Other Cardiovascular1 260 (10.6) 256 (10.5) - -
Other Cardiovascular2 312 (12.7) 337 (13.8) - -
Second Malignancies1 53 ( 2.2) 78 ( 3.2) - -
Second Malignancies2 102 ( 4.2) 119 ( 4.9) - -
1During study treatment, based on Safety Monotherapy population
2Any time after randomization, including post treatment follow-up
3Excluding women who had undergone hysterectomy before study entry
Note: Cardiovascular (including cerebrovascular and thromboembolic), skeletal and urogenital/endometrial events and second malignancies were collected life-long. All of these events were assumed to be of CTC Grade 3 to 5 and were not individually graded.

When considering all grades during study treatment, a higher incidence of events was seen for Femara regarding fractures (10.1% vs 7.1%), myocardial infarctions (1.0% vs 0.5%), and arthralgia (25.2% vs 20.4%) (Femara 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%) (Femara vs tamoxifen respectively).

At a median follow up of 73 months, a higher incidence of events was seen for Femara (13.8%) than for tamoxifen (10.5%) regarding fractures. A higher incidence was seen for tamoxifen compared to Femara regarding thromboembolic events (4.5% vs 2.9%), and endometrial hyperplasia or cancer (2.9% vs 0.4%) (tamoxifen vs Femara, respectively).

Bone Study: Results of a phase 3 safety trial in 262 postmenopausal women with resected receptor positive early breast cancer in the adjuvant setting comparing the effect on lumbar spine (L2-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 nor mal BMD at baseline became osteoporotic over the 2 years and only 1 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 postmenopausal 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 Femara 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.

Table 2: Percentage of Patients with Adverse Reactions

  Number (%) of Patients with Grade 1-4 Adverse Reaction Number (%) of Patients with Grade 3-4 Adverse Reaction
Femara
N=2563
Placebo
N=2573
Femara
N=2563
Placebo
N=2573
Any Adverse Reaction 2232 (87.1) 2174 (84.5) 419 (16.3) 389 (15.1)
Vascular Disorders 1375 (53.6) 1230 (47.8) 59 (2.3) 74 (2.9)
  Flushing 1273 (49.7) 1114 (43.3) 3 (0.1) 0
General Disorders 1154 (45) 1090 (42.4) 30 (1.2) 28 (1.1)
  Asthenia 862 (33.6) 826 (32.1) 16 (0.6) 7 (0.3)
  Edema NOS 471 (18.4) 416 (16.2) 4 (0.2) 3 (0.1)
Musculoskeletal Disorders 978 (38.2) 836 (32.5) 71 (2.8) 50 (1.9)
  Arthralgia 565 (22) 465 (18.1) 25 (1) 20 (0.8)
  Arthritis NOS 173 (6.7) 124 (4.8) 10 (0.4) 5 (0.2)
  Myalgia 171 (6.7) 122 (4.7) 8 (0.3) 6 (0.2)
  Back Pain 129 (5) 112 (4.4) 8 (0.3) 7 (0.3)
Nervous System Disorders 863 (33.7) 819 (31.8) 65 (2.5) 58 (2.3)
  Headache 516 (20.1) 508 (19.7) 18 (0.7) 17 (0.7)
  Dizziness 363 (14.2) 342 (13.3) 9 (0.4) 6 (0.2)
Skin Disorders 830 (32.4) 787 (30.6) 17 (0.7) 16 (0.6)
  Sweating Increased 619 (24.2) 577 (22.4) 1 (<0.1) 0
Gastrointestinal Disorders 725 (28.3) 731 (28.4) 43 (1.7) 42 (1.6)
  Constipation 290 (11.3) 304 (11.8) 6 (0.2) 2 ( < 0.1)
  Nausea 221 (8.6) 212 (8.2) 3 (0.1) 10 (0.4)
  Diarrhea NOS 128 (5) 143 (5.6) 12 (0.5) 8 (0.3)
Metabolic Disorders 551 (21.5) 537 (20.9) 24 (0.9) 32 (1.2)
  Hypercholesterolemia 401 (15.6) 398 (15.5) 2 ( < 0.1) 5 (0.2)
Reproductive Disorders 303 (11.8) 357 (13.9) 9 (0.4) 8 (0.3)
  Vaginal Hemorrhage 123 (4.8) 171 (6.6) 2 ( < 0.1) 5 (0.2)
  Vulvovaginal Dryness 137 (5.3) 127 (4.9) 0 0
Psychiatric Disorders 320 (12.5) 276 (10.7) 21 (0.8) 16 (0.6)
  Insomnia 149 (5.8) 120 (4.7) 2 ( < 0.1) 2 ( < 0.1)
Respiratory Disorders 279 (10.9) 260 (10.1) 30 (1.2) 28 (1.1)
  Dyspnea 140 (5.5) 137 (5.3) 21 (0.8) 18 (0.7)
Investigations 184 (7.2) 147 (5.7) 13 (0.5) 13 (0.5)
Infections and Infestations 166 (6.5) 163 (6.3) 40 (1.6) 33 (1.3)
Renal Disorders 130 (5.1) 100 (3.9) 12 (0.5) 6 (0.2)

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 Femara was 5.9% (152) and placebo was 5.5% (142). The incidence of self-reported osteoporosis was higher in patients who received Femara 6.9% (176) than in patients who received placebo 5.5% (141). Bisphosphonates were administered to 21.1% of the patients who received Femara 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 Femara 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.

Bone Sub-study: [see WARNINGS AND PRECAUTIONS].

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 Femara 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].

Updated Analysis, Extended Adjuvant Treatment Of Early Breast Cancer, Median Treatment Duration Of 60 Months

The extended adjuvant treatment trial was unblinded early. 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 Femara (10.4%) compared to placebo (5.8%), as also a higher rate of osteoporosis (Femara 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 Femara and 7.0% 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 Femara 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]

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 Femara 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 Femara 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 Femara 2.5 mg or tamoxifen 20 mg in the first-line treatment study are shown in Table 3.

Table 3: Percentage (% ) of Patients with Adverse Reactions

AdverseReaction Femara 2.5 mg
(N=455)
%
tamoxifen 20 mg
(N=455)
%
General Disorders
  Fatigue 13 13
  Chest Pain 8 9
  Edema Peripheral 5 6
  Pain NOS 5 7
  Weakness 6 4
Investigations
  Weight Decreased 7 5
Vascular Disorders
  Hot Flushes 19 16
  Hypertension 8 4
Gastrointestinal Disorders
  Nausea 17 17
  Constipation 10 11
  Diarrhea 8 4
  Vomiting 7 8
Infections/Infestations
  Influenza 6 4
  Urinary Tract Infection NOS 6 3
Injury, Poisoning and Procedural Complications
  Post-Mastectomy Lymphedema 7 7
Metabolism and Nutrition Disorders
  Anorexia 4 6
Musculoskeletal and Connective Tissue Disorders
  Bone Pain 22 21
  Back Pain 18 19
  Arthralgia 16 15
  Pain in Limb 10 8
Nervous System Disorders
  Headache NOS 8 7
  Psychiatric Disorders    
  Insomnia 7 4
Reproductive System and Breast Disorders
  Breast Pain 7 7
Respiratory, Thoracic and Mediastinal Disorders
  Dyspnea 18 17
  Cough 13 13
  Chest Wall Pain 6 6

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 Femara 0.5 mg, in 4/174 (2.3%) on Femara 2.5 mg, and in 15/190 (7.9%) on megestrol acetate. There were fewer thromboembolic events at both Femara doses than on the megestrol acetate arm (0.6% vs 4.7%). There was also less vaginal bleeding (0.3% vs 3.2%) on Femara 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 Femara, 7/185 (3.8%) on 2.5 mg Femara, 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 Femara 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 Femara 0.5 mg, Femara 2.5 mg, megestrol acetate, or aminoglutethimide in the two controlled trials are shown in Table 4.

Table 4: Percentage (% ) of Patients with Adverse Reactions

View Enlarged Table

Other less frequent ( < 5%) adverse reactions considered consequential and reported in at least 3 patients treated with Femara, 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 Femara.

Read the Femara (letrozole) Side Effects Center for a complete guide to possible side effects

Learn More »

Interactions

Tamoxifen

Coadministration of Femara 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 Femara therapy is not impaired if Femara 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 Femara in combination with other anticancer agents.

Read the Femara Drug Interactions Center for a complete guide to possible interactions

Learn More »

This monograph has been modified to include the generic and brand name in many instances.

Warnings

Included as part of the PRECAUTIONS section.

Precautions

Bone Effects

Use of Femara 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-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]. Updated results from the BMD substudy 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 2.0% 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].

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]. 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].

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 3-4 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 57/1840 (3.2%). Lipid lowering medications were required for 25% of patients on letrozole and 16% on tamoxifen [see ADVERSE REACTIONS].

Hepatic Impairment

Subjects with cirrhosis and severe hepatic impairment who were dosed with 2.5 mg of Femara experienced approximately twice the exposure to Femara as healthy volunteers with normal liver function. Therefore, a dose reduction is recommended for this patient population. The effect of hepatic impairment on Femara exposure in cancer patients with elevated bilirubin levels has not been determined. [see DOSAGE AND ADMINISTRATION]

Fatigue And Dizziness

Because fatigue, dizziness, and somnolence have been reported with the use of Femara, caution is advised when driving or using machinery until it is known how the patient reacts to Femara use.

Laboratory Test Abnormalities

No dose-related effect of Femara on any hematologic or clinical chemistry parameter was evident. Moderate decreases in lymphocyte counts, of uncertain clinical significance, were observed in some patients receiving Femara 2.5 mg. This depression was transient in about half of those affected. Two patients on Femara developed thrombocytopenia; relationship to the study drug was unclear. Patient withdrawal due to laboratory abnormalities, whether related to study treatment or not, was infrequent.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

A conventional carcinogenesis study in mice at doses of 0.6 to 60 mg/kg/day (about 1 to 100 times the daily maximum recommended human dose on a mg/m² basis) administered by oral gavage for up to 2 years revealed a dose-related increase in the incidence of benign ovarian stromal tumors. The incidence of combined hepatocellular adenoma and carcinoma showed a significant trend in females when the high dose group was excluded due to low survival. In a separate study, plasma AUC0-12hr levels in mice at 60 mg/kg/day were 55 times higher than the AUC0-24hr level in breast cancer patients at the recommended dose. The carcinogenicity study in rats at oral doses of 0.1 to 10 mg/kg/day (about 0.4 to 40 times the daily maximum recommended human dose on a mg/m² basis) for up to 2 years also produced an increase in the incidence of benign ovarian stromal tumors at 10 mg/kg/day. Ovarian hyperplasia was observed in females at doses equal to or greater than 0.1 mg/kg/day. At 10 mg/kg/day, plasma AUC0-24hr levels in rats were 80 times higher than the level in breast cancer patients at the recommended dose. The benign ovarian stromal tumors observed in mice and rats were considered to be related to the pharmacological inhibition of estrogen synthesis and may be due to increased luteinizing hormone resulting from the decrease in circulating estrogen.

Femara (letrozole) was not mutagenic in in vitro tests (Ames and E.coli bacterial tests) but was observed to be a potential clastogen in in vitro assays (CHO K1 and CCL 61 Chinese hamster ovary cells). Letrozole was not clastogenic in vivo (micronucleus test in rats).

Studies to investigate the effect of letrozole on fertility have not been conducted; however, repeated dosing caused sexual inactivity in females and atrophy of the reproductive tract in males and females at doses of 0.6, 0.1 and 0.03 mg/kg in mice, rats and dogs, respectively (about one, 0.4 and 0.4 the daily maximum recommended human dose on a mg/m² basis, respectively). Oral administration of letrozole to female rats starting 2 weeks before mating until pregnancy day 6 resulted in decreases in the incidence of successful mating and pregnancy at equal to or greater than 0.03 mg/kg/day (approximately 0.1 times the recommended human dose on a mg/m² basis). An increase in pre-implantation loss was observed at doses equal to or greater than 0.003 mg/kg/day (approximately 0.01 times the recommended human dose on a mg/m² basis).

Letrozole administered to young (postnatal day 7) rats for 12 weeks duration at 0.003, 0.03, 0.3 mg/kg/day by oral gavage, resulted in adverse skeletal/growth effects (bone maturation, bone mineral density) and neuroendocrine and reproductive developmental perturbations of the hypothalamic-pituitary axis at exposures less than exposure anticipated at the clinical dose of 2.5 mg/day. Decreased fertility was accompanied by hypertrophy of the hypophysis and testicular changes that included degeneration of the seminiferous tubular epithelium and atrophy of the female reproductive tract. Young rats in this study were allowed to recover following discontinuation of letrozole treatment for 42 days. Histopathological changes were not reversible at clinically relevant exposures.

Animal Toxicology And/Or Pharmacology

Reproductive Toxicology

Reproduction studies in rats at letrozole doses equal to or greater than 0.003 mg/kg (about 1/100 the daily maximum recommended human dose on a mg/m² basis) administered during the period of organogenesis, have shown that letrozole is embryotoxic and fetotoxic, as indicated by intrauterine mortality, increased resorption, increased 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 was teratogenic in rats. A 0.03 mg/kg dose (about 1/10 the daily maximum recommended human dose on a mg/m² basis) caused fetal domed head and cervical/centrum vertebral fusion.

Letrozole is embryotoxic at doses equal to or greater than 0.002 mg/kg and fetotoxic when administered to rabbits at 0.02 mg/kg (about 1/100,000 and 1/10,000 the daily maximum recommended human dose on a mg/m² basis, respectively). Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore-and hind legs.

Use In Specific Populations

Pregnancy

Pregnancy Category X [see CONTRAINDICATIONS]. Femara may cause fetal harm when administered to a pregnant woman and the clinical benefit to premenopausal women with breast cancer has not been demonstrated. Femara 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.

Femara 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].

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.

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.

Geriatric Use

The median age of patients in all studies of first-line and second-line treatment of metastatic breast cancer was 64-65 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.

This monograph has been modified to include the generic and brand name in many instances.

OverDose

Isolated cases of Femara overdose have been reported. In these instances, the highest single dose ingested was 62.5 mg or 25 tablets. While no serious adverse reactions were reported in these cases, because of the limited data available, no firm recommendations for treatment can be made. However, emesis could be induced if the patient is alert. In general, supportive care and frequent monitoring of vital signs are also appropriate. In single-dose studies, the highest dose used was 30 mg, which was well tolerated; in multiple-dose trials, the largest dose of 10 mg was well tolerated.

Lethality was observed in mice and rats following single oral doses that were equal to or greater than 2,000 mg/kg (about 4,000 to 8,000 times the daily maximum recommended human dose on a mg/m² basis); death was associated with reduced motor activity, ataxia and dyspnea. Lethality was observed in cats following single IV doses that were equal to or greater than 10 mg/kg (about 50 times the daily maximum recommended human dose on a mg/m² basis); death was preceded by depressed blood pressure and arrhythmias.

ContrainDications

Femara may cause fetal harm when administered to a pregnant woman and the clinical benefit to premenopausal women with breast cancer has not been demonstrated. Femara is contraindicated in women who are or may become pregnant. If Femara 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. [see Use in Specific Populations]

This monograph has been modified to include the generic and brand name in many instances.

Clinical Pharamacology

Mechanism Of Action

The growth of some cancers of the breast is stimulated or maintained by estrogens. Treatment of breast cancer thought to be hormonally responsive (i.e., estrogen and/or progesterone receptor positive or receptor unknown) has included a variety of efforts to decrease estrogen levels (ovariectomy, adrenalectomy, hypophysectomy) or inhibit estrogen effects (antiestrogens and progestational agents). These interventions lead to decreased tumor mass or delayed progression of tumor growth in some women.

In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.

Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system; it inhibits the conversion of androgens to estrogens. In adult nontumor-and tumor-bearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum LH, and causing the regression of estrogen-dependent tumors. In contrast to ovariectomy, treatment with letrozole does not lead to an increase in serum FSH. Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis.

Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. Treatment of women with letrozole significantly lowers serum estrone, estradiol and estrone sulfate and has not been shown to significantly affect adrenal corticosteroid synthesis, aldosterone synthesis, or synthesis of thyroid hormones.

Pharmacodynamics

In postmenopausal patients with advanced breast cancer, daily doses of 0.1 mg to 5 mg Femara (letrozole) suppress plasma concentrations of estradiol, estrone, and estrone sulfate by 75% to 95% from baseline with maximal suppression achieved within two-three days. Suppression is dose-related, with doses of 0.5 mg and higher giving many values of estrone and estrone sulfate that were below the limit of detection in the assays. Estrogen suppression was maintained throughout treatment in all patients treated at 0.5 mg or higher.

Letrozole is highly specific in inhibiting aromatase activity. There is no impairment of adrenal steroidogenesis. No clinically-relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, ACTH or in plasma renin activity among postmenopausal patients treated with a daily dose of Femara 0.1 mg to 5 mg. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1, 0.25, 0.5, 1, 2.5, and 5 mg did not indicate any attenuation of aldosterone or cortisol production. Glucocorticoid or mineralocorticoid supplementation is, therefore, not necessary.

No changes were noted in plasma concentrations of androgens (androstenedione and testosterone) among healthy postmenopausal women after 0.1, 0.5, and 2.5 mg single doses of Femara or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 0.1 mg to 5 mg. This indicates that the blockade of estrogen biosynthesis does not lead to accumulation of androgenic precursors. Plasma levels of LH and FSH were not affected by letrozole in patients, nor was thyroid function as evaluated by TSH levels, T3 uptake, and T4 levels.

Pharmacokinetics

Absorption and Distribution

Letrozole is rapidly and completely absorbed from the gastrointestinal tract and absorption is not affected by food. It is metabolized slowly to an inactive metabolite whose glucuronide conjugate is excreted renally, representing the major clearance pathway. About 90% of radiolabeled letrozole is recovered in urine. Letrozole's terminal elimination half-life is about 2 days and steady-state plasma concentration after daily 2.5 mg dosing is reached in 2-6 weeks. Plasma concentrations at steady state are 1.5 to 2 times higher than predicted from the concentrations measured after a single dose, indicating a slight non-linearity in the pharmacokinetics of letrozole upon daily administration of 2.5 mg. These steady-state levels are maintained over extended periods, however, and continuous accumulation of letrozole does not occur. Letrozole is weakly protein bound and has a large volume of distribution (approximately 1.9 L/kg).

Metabolism and Excretion

Metabolism to a pharmacologically-inactive carbinol metabolite (4,4'methanol-bisbenzonitrile) and renal excretion of the glucuronide conjugate of this metabolite is the major pathway of letrozole clearance. Of the radiolabel recovered in urine, at least 75% was the glucuronide of the carbinol metabolite, about 9% was two unidentified metabolites, and 6% was unchanged letrozole.

In human microsomes with specific CYP isozyme activity, CYP3A4 metabolized letrozole to the carbinol metabolite while CYP2A6 formed both this metabolite and its ketone analog. In human liver microsomes, letrozole strongly inhibited CYP2A6 and moderately inhibited CYP2C19.

Pediatric, Geriatric and Race

In the study populations (adults ranging in age from 35 to > 80 years), no change in pharmacokinetic parameters was observed with increasing age. Differences in letrozole pharmacokinetics between adult and pediatric populations have not been studied. Differences in letrozole pharmacokinetics due to race have not been studied.

Renal Impairment

In a study of volunteers with varying renal function (24-hour creatinine clearance: 9 to 116 mL/min), no effect of renal function on the pharmacokinetics of single doses of 2.5 mg of Femara was found. In addition, in a study of 347 patients with advanced breast cancer, about half of whom received 2.5 mg Femara and half 0.5 mg Femara, renal impairment (calculated creatinine clearance: 20 to 50 mL/min) did not affect steady-state plasma letrozole concentrations.

Hepatic Impairment

In a study of subjects with mild to moderate non-metastatic hepatic dysfunction (e.g., cirrhosis, Child-Pugh classification A and B), the mean AUC values of the volunteers with moderate hepatic impairment were 37% higher than in normal subjects, but still within the range seen in subjects without impaired function.

In a pharmacokinetic study, subjects with liver cirrhosis and severe hepatic impairment (Child-Pugh classification C, which included bilirubins about 2-11 times ULN with minimal to severe ascites) had twofold increase in exposure (AUC) and 47% reduction in systemic clearance. Breast cancer patients with severe hepatic impairment are thus expected to be exposed to higher levels of letrozole than patients with normal liver function receiving similar doses of this drug. [see DOSAGE AND ADMINISTRATION]

Clinical Studies

Updated Adjuvant Treatment Of Early Breast Cancer

In a multicenter study enrolling over 8,000 postmenopausal women with resected, receptor-positive early breast cancer, one of the following treatments was randomized in a double-blind manner:

Option 1:
  1. tamoxifen for 5 years
  2. Femara for 5 years
  3. tamoxifen for 2 years followed by Femara for 3 years
  4. Femara for 2 years followed by tamoxifen for 3 years
Option 2:
  1. tamoxifen for 5 years
  2. Femara for 5 years

The study in the adjuvant setting, BIG 1-98 was designed to answer two primary questions: whether Femara for 5 years was superior to tamoxifen for 5 years (Primary Cor e Analysis) and whether switching endocrine treatments at 2 years was superior to continuing the same agent for a total of 5 years (Sequential Treatments Analysis). Selected baseline characteristics for the study population are shown in Table 5.

The primary endpoint of this trial was disease-free survival (DFS) (i.e., interval between randomization and earliest occurrence of a local, regional, or distant recurrence, or invasive contralateral breast cancer, or death from any cause). The secondary endpoints were overall survival (OS), systemic disease-free survival (SDFS), invasive contralateral breast cancer, time to breast cancer recurrence (TBR) and time to distant metastasis (TDM).

The Primary Core Analysis (PCA) included all patients and all follow-up in the monotherapy arms in both randomization options, but follow-up in the two sequential treatments arms was truncated 30 days after switching treatments. The PCA was conducted at a median treatment duration of 24 months and a median follow-up of 26 months. Femara was superior to tamoxifen in all endpoints except overall survival and contralateral breast cancer [e.g., DFS: hazard ratio, HR 0.79; 95% CI (0.68, 0.92); P=0.002; SDFS: HR 0.83; 95% CI (0.70, 0.97); TDM: HR 0.73; 95% CI (0.60, 0.88); OS: HR 0.86; 95% CI (0.70, 1.06).

In 2005, based on recommendations by the independent Data Monitoring Committee, the tamoxifen arms were unblinded and patients were allowed to complete initial adjuvant therapy with Femara (if they had received tamoxifen for at least 2 years) or to start extended adjuvant treatment with Femara (if they had received tamoxifen for at least 4.5 years) if they remained alive and disease-free. In total, 632 patients crossed to Femara or another aromatase inhibitor. Approximately 70% (448) of these 632 patients crossed to Femara to complete initial adjuvant therapy and most of these crossed in years 3 to 4. All of these patients were in Option 1. A total of 184 patients started extended adjuvant therapy with Femara (172 patients) or with another aromatase inhibitor (12 patients). To explore the impact of this selective crossover, results from analyses censoring follow-up at the date of the selective crossover (in the tamoxifen arm) are presented for the Monotherapy Arms Analysis (MAA).

The PCA allowed the results of Femara for 5 years compared with tamoxifen for 5 years to be reported in 2005 after a median follow-up of only 26 months. The design of the PCA is not optimal to evaluate the effect of Femara after a longer time (because follow-up was truncated in two arms at around 25 months). The Monotherapy Arms Analysis (ignoring the two sequential treatment arms) provided follow-up equally as long in each treatment and did not over-emphasize early recurrences as the PCA did. The MAA thus provides the clinically appropriate updated efficacy results in answer to the first primary question, despite the confounding of the tamoxifen reference arm by the selective crossover to Femara. The updated results for the MAA are summarized in Table 6. Median follow-up for this analysis is 73 months.

The Sequential Treatments Analysis (STA) addresses the second primary question of the study. The primary analysis for the Sequential Treatments Analysis (STA) was from switch (or equivalent time-point in monotherapy arms) + 30 days (STA-S) with a two-sided test applied to each pair-wise comparison at the 2.5% level. Additional analyses wer e conducted from randomization (STA-R) but these comparisons (added in light of changing medical practice) were under-powered for efficacy.

Table 5: Adjuvant Study -Patient and Disease Characteristics (ITT Population)

Characteristic Primary Core Analysis (PCA) Monotherapy Arms Analysis (MAA)
Femara
N=4003
n (%)
tamoxifen
N=4007
n (%)
Femara
N=2463
n (%)
tamoxifen
N=2459
n (%)
Age (median, years) 61 61 61 61
Age range (years) 38-89 39-90 38-88 39-90
Hormone receptor status (%)
  ER+ and/or PgR+ 99.7 99.7 99.7 99.7
  Both unknown 0.3 0.3 0.3 0.3
Nodal status (%)
  Node negative 52 52 50 52
  Node positive 41 41 43 41
  Nodal status unknown 7 7 7 7
Prior adjuvant chemotherapy (%) 24 24 24 24

Table 6: Updated Adjuvant Study Results -Monotherapy Arms Analysis (Median Follow-up 73 Months)

View Enlarged Table

Figure 1 shows the Kaplan-Meier curves for Disease-Free Survival Monotherapy Analysis

Figure 1 : Disease-Free Survival (Median follow-up 73 months, ITT Approach)

View Enlarged Table

DFS events defined as loco-regional recurrence, distant meta sta sis, inva sive contra latera l brea st cancer, or death from a ny cau se (i.e., definition excludes second non-brea st primary cancers).

The medians of overall survival for both arms were not reached for the Monotherapy Arms Analysis (MAA). There was no statistically significant difference in overall survival. The hazard ratio for survival in the Femara arm compared to the tamoxifen arm was 0.87, with 95% CI (0.75, 1.02) (see Table 6).

There were no significant differences in DFS, OS, SDFS, and Distant DFS from switch in the Sequential Treatments Analysis with respect to either monotherapy (e.g., [Tamoxifen 2 years followed by] Femara 3 years versus tamoxifen beyond 2 years, DFS HR 0.89; 97.5% CI 0.68, 1.15 and [Femara 2 years followed by] tamoxifen 3 years versus Femara beyond 2 years, DFS HR 0.93; 97.5% CI 0.71, 1.22).

There were no significant differences in DFS, OS, SDFS, and Distant DFS from randomization in the Sequential Treatments Analyses.

Extended Adjuvant Treatment Of Early Breast Cancer, Median Treatment Duration Of 24 Months

A double-blind, randomized, placebo-controlled trial of Femarawas performed in over 5,100 postmenopausal women with receptor-positive or unknown primary breast cancer who were disease free after 5 years of adjuvant treatment with tamoxifen.

The planned duration of treatment for patients in the study was 5 years, but the trial was terminated early because of an interim analysis showing a favorable Femara effect on time without recurrence or contralateral breast cancer. At the time of unblinding, women had been followed for a median of 28 months, 30% of patients had completed 3 or more years of follow-up and less than 1% of patients had completed 5 years of follow-up.

Selected baseline characteristics for the study population are shown in Table 7.

Table 7: Selected Study Population Demographics (Modified ITT Population)

Baseline Status Femara
N=2582
Placebo
N=2586
Hormone Receptor Status (%)
  ER+ and/or PgR+ 98 98
  Both Unknown 2 2
Nodal Status (%)
  Node Negative 50 50
  Node Positive 46 46
  Nodal Status Unknown 4 4
Chemotherapy 46 46

Table 8 shows the study results. Disease-free survival was measured as the time from randomization to the earliest event of loco-regional or distant recurrence of the primary disease or development of contralateral breast cancer or death. DFS by hormone receptor status, nodal status and adjuvant chemotherapy were similar to the overall results. Data were premature for an analysis of survival.

Table 8: Extended Adjuvant Study Results

  Femara
N = 2582
Placebo
N = 2586
Hazard Ratio (95% CI) P-Value
Disease Free Survival (DFS)1 Events 122 (4.7%) 193 (7.5%) 0.62 (0.49, 0.78)2 0.00003
  Local Breast Recurrence 9 22    
  Local Chest Wall Recurrence 2 8    
  Regional Recurrence 7 4    
  Distant Recurrence 55 92 0.61 (0.44 -0.84) 0.003
  Contralateral Breast Cancer 19 29    
  Deaths Without Recurrence or Contralateral Breast Cancer 30 38    
CI = confidence interval for hazard ratio. Hazard ratio of less than 1.0 indicates difference in favor of Femara (lesser risk of recurrence); hazard ratio greater than 1.0 indicates difference in favor of placebo (higher risk of recurrence with Femara).
1First event of loco-regional recurrence, distant relapse, contralateral breast cancer or death from any cause
2Analysis stratified by receptor status, nodal status and prior adjuvant chemotherapy (stratification factors as at randomization). P-value based on stratified logrank test.

Updated Analyses Of Extended Adjuvant Treatment Of Early Breast Cancer, Median Treatment Duration Of 60 Months

Table 9: Update of Extended Adjuvant Study Results

  Femara
N = 2582
(%)
Placebo
N = 2586
(%)
Hazard Ratio1 (95% CI) P-Value2
Disease Free Survival (DFS) events3 344 (13.3) 402 (15.5) 0.89 (0.77, 1.03) 0.12
Breast cancer recurrence (Protocol definition of DFS events4) 209 286 0.75 (0.63, 0.89) 0.001
  Local Breast Recurrence 15 44    
  Local Chest Wall Recurrence 6 14    
  Regional Recurrence 10 8    
  Distant Recurrence 140 167    
  Distant Recurrence (first or subsequent events) 142 169 0.88 (0.70,1.10) 0.246
  Contralateral Breast Cancer 37 53    
  Deaths Without Recurrence or Contralateral Breast Cancer 135 116    
1Adjusted by receptor status, nodal status and prior chemotherapy
2Stratified logrank test, stratified by receptor status, nodal status and prior chemotherapy
3DFS events defined as earliest of loco-regional recurrence, distant metastasis, contralateral breast cancer or death from any cause, and ignoring switches to Femara in 60% of the placebo arm.
4Protocol definition does not include deaths from any cause

Updated analyses were conducted at a median follow-up of 62 months. In the Femara arm, 71% of the patients were treated for a least 3 years and 58% of patients completed at least 4.5 years of extended adjuvant treatment. After the unblinding of the study at a median follow-up of 28 months, approximately 60% of the selected patients in the placebo arm opted to switch to Femara.

In this updated analysis shown in Table 9, Femara significantly reduced the risk of breast cancer recurrence or contralateral breast cancer compared with placebo (HR 0.75; 95% CI 0.63, 0.89; P=0.001). However, in the updated DFS analysis (interval between randomization and earliest event of loco-regional recurrence, distant metastasis, contralateral breast cancer, or death from any cause) the treatment difference was heavily diluted by 60% of the patients in the placebo arm switching to Femara and accounting for 64% of the total placebo patient-years of follow-up. Ignoring these switches, the risk of DFS event was reduced by a non-significant 11% (HR 0.89; 95% CI 0.77, 1.03). There was no significant difference in distant disease-free survival or overall survival.

First-Line Treatment Of Advanced Breast Cancer

A randomized, double-blind, multinational trial compared Femara 2.5 mg with tamoxifen 20 mg in 916 postmenopausal patients with locally advanced (Stage IIIB or loco-regional recurrence not amenable to treatment with surgery or radiation) or metastatic breast cancer. Time to progression (TTP) was the primary endpoint of the trial. Selected baseline characteristics for this study are shown in Table 10.

Table 10: Selected Study Population Demographics

Baseline Status Femara
N=458
tamoxifen
N=458
Stage of Disease
  IIIB 6% 7%
  IV 93% 92%
Receptor Status
  ER and PgR Positive 38% 41%
  ER or PgR Positive 26% 26%
  Both Unknown 34% 33%
  ER- or PgR-/Other Unknown < 1% 0
Previous Antiestrogen Therapy
  Adjuvant 19% 18%
  None 81% 82%
Dominant Site of Disease
  Soft Tissue 25% 25%
  Bone 32% 29%
  Viscera 43% 46%

Femara was superior to tamoxifen in TTP and rate of objective tumor response (see Table 11).

Table 11 summarizes the results of the trial, with a total median follow-up of approximately 32 months. (All analyses are unadjusted and use 2-sided P-values.)

Table 11: Results of First-Line Treatment of Advanced Breast Cancer

  Femara 2.5 mg N=453 tamoxifen 20 mg
N=454
Hazard or Odds Ratio (95% CI) P-Value (2-Sided)
Median Time to Progression 9.4 months 6.0 months 0.72 (0.62, 0.83)1
P < 0.0001
Objective Response Rate (CR + PR) 145 (32%) 95 (21%) 1.77 (1.31, 2.39)2
P=0.0002
  (CR) 42 (9%) 15 (3%) 2.99 (1.63, 5.47)2
P=0.0004
Duration of Objective Response
  Median 18 months (N=145) 16 months (N=95)  
Overall Survival 35 months (N=458) 32 months (N=458) P=0.51363
1Hazard ratio
2Odds ratio
3Overall logrank test

Figure 2 shows the Kaplan-Meier curves for TTP.

Figure 2 : Kaplan-Meier Estimates of Time to Progression (Tamoxifen Study)

View Enlarged Table

Table 12 shows results in the subgroup of women who had received prior antiestrogen adjuvant therapy, Table 13, results by disease site and Table 14, the results by receptor status.

Table 12: Efficacy in Patients Who Received Prior Antiestrogen Therapy

Variable Femara 2.5 mg
N=84
tamoxifen 20 mg
N=83
Median Time to Progression (95% CI) 8.9 months (6.2, 12.5) 5.9 months (3.2, 6.2)
  Hazard Ratio for TTP (95% CI) 0.60 (0.43, 0.84)
Objective Response Rate
  (CR + PR) 22 (26%) 7 (8%)
  Odds Ratio for Response (95% CI) 3.85 (1.50, 9.60)

Hazard ratio less than 1 or odds ratio greater than 1 favors Femara; hazard ratio greater than 1 or odds ratio less than 1 favors tamoxifen.

Table 13: Efficacy by Disease Site

  Femara 2.5 mg tamoxifen 20 mg
Dominant Disease Site
Soft Tissue: N=113 N=115
Median TTP 12.1 months 6.4 months
Objective Response Rate 50% 34%
Bone: N=145 N=131
Median TTP 9.5 months 6.3 months
Objective Response Rate 23% 15%
Viscera: N=195 N=208
Median TTP 8.3 months 4.6 months
Objective Response Rate 28% 17%

Table 14: Efficacy by Receptor Status

Variable Femara 2.5 mg tamoxifen 20 mg
Receptor Positive N=294 N=305
  Median Time to Progression (95% CI) 9.4 months (8.9, 11.8) 6.0 months (5.1, 8.5)
  Hazard Ratio for TTP (95% CI) 0.69 (0.58, 0.83)  
  Objective Response Rate (CR+PR) 97 (33%) 66 (22%)
  Odds Ratio for Response 95% CI) 1.78 (1.20, 2.60)  
Receptor Unknown N=159 N=149
  Median Time to Progression (95% CI) 9.2 months (6.1, 12.3) 6.0 months (4.1, 6.4)
  Hazard Ratio for TTP (95% CI) 0.77 (0.60, 0.99)  
  Objective Response Rate (CR+PR)  48 (30%) 29 (20%)
  Odds Ratio for Response (95% CI) 1.79 (1.10, 3.00)  

Hazard ratio less than 1 or odds ratio greater than 1 favors Femara; hazard ratio greater than 1 or odds ratio less than 1 favors tamoxifen.

Figure 3 shows the Kaplan-Meier curves for survival.

Figure 3 : Survival by Randomized Treatment Arm

View Enlarged Table

Legend: Randomized Femara: n=458, events 57%, median overall survival 35 months (95% CI 32 to 38 months) Randomized tamoxifen: n=458, events 57%, median overall survival 32 months (95% CI 28 to 37 months) Overall logrank P=0.5136 (i.e., there was no significant difference between treatment arms in overall survival).

The median overall survival was 35 months for the Femara group and 32 months for the tamoxifen group, with a P-value 0.5136. Study design allowed patients to cross over upon progression to the other therapy. Approximately 50% of patients crossed over to the opposite treatment arm and almost all patients who crossed over had done so by 36 months. The median time to crossover was 17 months (Femara to tamoxifen) and 13 months (tamoxifen to Femara). In patients who did not cross over to the opposite treatment arm, median survival was 35 months with Femara (n=219, 95% Cl 29 to 43 months) vs 20 months with tamoxifen (n=229, 95% Cl 16 to 26 months).

Second-Line Treatment Of Advanced Breast Cancer

Femara was initially studied at doses of 0.1 mg to 5.0 mg daily in six non-comparative Phase I/II trials in 181 postmenopausal estrogen/progesterone receptor positive or unknown advanced breast cancer patients previously treated with at least antiestrogen therapy. Patients had received other hormonal therapies and also may have received cytotoxic therapy. Eight (20%) of forty patients treated with Femara 2.5 mg daily in Phase I/II trials achieved an objective tumor response (complete or partial response).

Two large randomized, controlled, multinational (predominantly European) trials were conducted in patients with advanced breast cancer who had progressed despite antiestrogen therapy. Patients were randomized to Femara 0.5 mg daily, Femara 2.5 mg daily, or a comparator (megestrol acetate 160 mg daily in one study; and aminoglutethimide 250 mg b.i.d. with corticosteroid supplementation in the other study). In each study over 60% of the patients had received therapeutic antiestrogens, and about one-fifth of these patients had an objective response. The megestrol acetate controlled study was double-blind; the other study was open label. Selected baseline characteristics for each study are shown in Table 15.

Table 15: Selected Study Population Demographics

Parameter megestrol acetate study aminoglutethimide study
No. of Participants 552 557
Receptor Status
  ER/PR Positive 57% 56%
  ER/PR Unknown 43% 44%
Previous Therapy
  Adjuvant Only 33% 38%
  Therapeutic +/- Adj. 66% 62%
Sites of Disease
  Soft Tissue 56% 50%
  Bone 50% 55%
  Viscera 40% 44%

Confirmed objective tumor response (complete response plus partial response) was the primary endpoint of the trials. Responses were measured according to the Union Internationale Contre le Cancer (UICC) criteria and verified by independent, blinded review. All responses were confirmed by a second evaluation 4 to 12 weeks after the documentation of the initial response.

Table 16 shows the results for the first trial, with a minimum follow-up of 15 months, that compared Femara 0.5 mg, Femara 2.5 mg, and megestrol acetate 160 mg daily. (All analyses are unadjusted.)

Table 16: Megestrol Acetate Study Results

  Femara 0.5 mg
N=188
Femara 2.5 mg
N=174
megestrol acetate
N=190
Objective Response (CR + PR) 22 (11.7%) 41 (23.6%) 31 (16.3%)
Median Duration of Response 552 days (Not reached) 561 days
Median Time to Progression 154 days 170 days 168 days
Median Survival 633 days 730 days 659 days
Odds Ratio for Response Femara 2.5: Femara 0.5=2.33 (95% CI: 1.32, 4.17); P=0.004* Femara 2.5: megestrol=1.58 (95% CI: 0.94, 2.66); P=0.08*
Relative Risk of Progression Femara 2.5: Femara 0.5=0.81 (95% CI: 0.63, 1.03); P=0.09* Femara 2.5: megestrol=0.77 (95% CI: 0.60, 0.98); P=0.03*
* two-sided P-value

The Kaplan-Meier curves for progression for the megestrol acetate study are shown in Figure 4.

Figure 4 : Kaplan-Meier Estimates of Time to Progression (Megestrol Acetate Study)

Kaplan-Meier Estimates of Time to Progression (Megestrol Acetate Study) - Illustration

The results for the study comparing Femara to aminoglutethimide, with a minimum follow-up of 9 months, are shown in Table 17. (Unadjusted analyses are used.)

Table 17: Aminoglutethimide Study Results

  Femara 0.5 mg
N=193
Femara 2.5 mg
N=185
aminoglutethimide
N=179
Objective Response (CR + PR) 34 (17.6%) 34 (18.4%) 22 (12.3%)
Median Duration of Response 619 days 706 days 450 days
Median Time to Progression 103 days 123 days 112 days
Median Survival 636 days 792 days 592 days
Odds Ratio for Response Femara 2.5: Femara 0.5=1.05 (95% CI: 0.62, 1.79); P=0.85* Femara 2.5: aminoglutethimide= 1.61 (95% CI: 0.90, 2.87); P=0.11*
Relative Risk of Progression Femara 2.5: Femara 0.5=0.86 (95% CI: 0.68, 1.11); P=0.25* Femara 2.5: aminoglutethimide=0.74 (95% CI: 0.57, 0.94); P=0.02*
*2-sided P-value

The Kaplan-Meier curves for progression for the aminoglutethimide study is shown in Figure 5.

Figure 5 : Kaplan-Meier Estimates of Time to Progression (Aminoglutethimide Study)

Kaplan-Meier Estimates of Time to Progression (Aminoglutethimide Study) - Illustration

This monograph has been modified to include the generic and brand name in many instances.

Patient Information

Pregnancy

Femara is contraindicated in women of premenopausal endocrine status. The physician needs to discuss the necessity of adequate contraception with women who have the potential to become pregnant including women who are perimenopausal or who recently became postmenopausal, until their postmenopausal status is fully established.

Fatigue and Dizziness

Since fatigue and dizziness have been observed with the use of Femara and somnolence was uncommonly reported, caution is advised when driving or using machinery.

Bone Effects

Consideration should be given to monitoring bone mineral density.

This monograph has been modified to include the generic and brand name in many instances.

Consumer Overview Uses

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

 

LETROZOLE - ORAL

 

(LET-tro-zole)

 

COMMON BRAND NAME(S): Femara

 

USES: This medication is used to treat certain types of breast cancer (such as hormone-receptor-positive breast cancer) in women after menopause. Letrozole is also used to help prevent the cancer from returning. Some breast cancers are made to grow faster by a natural hormone called estrogen. Letrozole decreases the amount of estrogen the body makes and helps to slow or reverse the growth of these breast cancers.

 

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This medication may also be used to treat infertility in women.

 

HOW TO USE: Read the Patient Information Leaflet provided by your pharmacist before you start using letrozole and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

Take this medication by mouth, usually once daily with or without food or as directed by your doctor.

Dosage is based on your medical condition and response to treatment.

Use this medication regularly to get the most benefit from it. To help you remember, take it at the same time each day.

Since this drug can be absorbed through the skin and lungs, women who are pregnant should not handle this medication or breathe the dust from the tablets. (See also Precautions section.)

Inform your doctor immediately if your condition worsens (such as you get new breast lumps).

Consumer Overview Side Effect

SIDE EFFECTS: Hot flashes, hair loss, joint/bone/muscle pain, tiredness, unusual sweating, nausea, diarrhea, dizziness, and trouble sleeping may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor right away if you have any serious side effects, including: bone fractures, mental/mood changes (such as depression, anxiety), swelling of arms/legs, blurred vision, persistent nausea/vomiting, unusual tiredness, dark urine, yellowing eyes/skin..

This medication (and cancer) may rarely cause serious problems from blood clots (such as heart attack or stroke). Get medical help right away if you experience: sudden shortness of breath, chest/jaw/left arm pain, confusion, coughing up blood, sudden dizziness/fainting, pain/swelling/warmth in the groin/calf, tingling/weakness/numbness in the arms/legs, slurred speech, weakness on one side of the body, vision changes, sudden/severe headache.

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat/neck), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

 

Read the Femara (letrozole) Side Effects Center for a complete guide to possible side effects

Learn More »

PRECAUTIONS: Before taking letrozole, tell your doctor or pharmacist if you are allergic to it; or to anastrozole; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: high blood fats (cholesterol), bone problems (such as osteopenia, osteoporosis), stroke or blood clots, heart disease (such as chest pain, heart attack, heart failure), high blood pressure, kidney problems, liver problems.

This drug may make you dizzy and tired, and may rarely cause blurred vision. Do not drive, use machinery, or do any activity that requires alertness or clear vision until you are sure you can perform such activities safely. Limit alcoholic beverages.

Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

This medication must not be used during pregnancy. It may harm an unborn baby. Letrozole is used mainly in women after menopause. If you have recently gone through menopause, discuss the need for use of reliable forms of birth control with your doctor. Do not use birth control products containing estrogen. Consult your doctor for more details. If you become pregnant or think you may be pregnant, tell your doctor immediately. (See also How to Use section.)

It is not known whether this drug passes into breast milk and may harm a nursing infant. Breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

Consumer Overview Missed Dose

DRUG INTERACTIONS: Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.

Some products that may interact with this drug include: estrogens (such as ethinyl estradiol, conjugated estrogens), estrogen blockers (such as anastrozole, tamoxifen).

 

OVERDOSE: If overdose is suspected, contact a poison control center or emergency room immediately. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center.

 

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (such as bone density tests, cholesterol levels, liver function tests) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

This medication can increase the risk of bone loss (osteoporosis). Talk with your doctor about your risk, and about available treatments for osteoporosis. Lifestyle changes that reduce the risk of bone loss include doing weight-bearing exercise, getting enough calcium and vitamin D, stopping smoking, and limiting alcohol.

 

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

 

STORAGE: Store at room temperature away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

 

Information last revised January 2014. Copyright(c) 2014 First Databank, Inc.

Patient Detailed Side Effect

Brand Names: Femara

Generic Name: letrozole (Pronunciation: LET roe zol)

  • What is letrozole (Femara)?
  • What are the possible side effects of letrozole (Femara)?
  • What is the most important information I should know about letrozole (Femara)?
  • What should I discuss with my healthcare provider before using letrozole (Femara)?
  • How should I take letrozole (Femara)?
  • What happens if I miss a dose (Femara)?
  • What happens if I overdose (Femara)?
  • What should I avoid while taking letrozole (Femara)?
  • What other drugs will affect letrozole (Femara)?
  • Where can I get more information?

What is letrozole (Femara)?

Letrozole lowers estrogen levels in postmenopausal women, which may slow the growth of certain types of breast tumors that need estrogen to grow in the body.

Letrozole is used to treat breast cancer in postmenopausal women. It is often given to women who have been taking tamoxifen (Nolvadex, Soltamox) for 5 years.

Letrozole may also be used for purposes not listed in this medication guide.

Letrozole 2.5 mg-TEV

round, yellow, imprinted with TEVA, B1

What are the possible side effects of letrozole (Femara)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Less serious side effects may include:

  • dizziness, drowsiness, weakness, tired feeling;
  • hot flashes, warmth in your face or chest;
  • flushing (warmth, redness, or tingly feeling);
  • headache;
  • nausea, constipation;
  • bone pain, muscle or joint pain;
  • numbness, tingling, weakness, or stiffness in your hand or fingers;
  • pain in your hand that spreads to your arm, wrist, forearm, or shoulder;
  • night sweats; or
  • weight gain.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Femara (letrozole) Side Effects Center for a complete guide to possible side effects

Learn More »

What is the most important information I should know about letrozole (Femara)?

Letrozole can harm an unborn baby or cause birth defects. Do not use if you are pregnant.

You should not use this medication if you are allergic to letrozole, or if you have not gone completely through menopause.

Before taking letrozole, tell your doctor if you have osteoporosis, high cholesterol, or liver disease (especially cirrhosis).

This medication may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

To be sure letrozole is helping your condition, your blood may need to be tested often. Your bone mineral density may also need to be checked. Visit your doctor regularly.

Tell your doctor about all other medicines you use, especially tamoxifen (Soltamox).

Side Effects Centers
  • Femara

Patient Detailed How Take

What should I discuss with my healthcare provider before using letrozole (Femara)?

You should not use this medication if you are allergic to letrozole, or if you have not gone completely through menopause.

To make sure you can safely take letrozole, tell your doctor if you have any of these other conditions:

  • osteoporosis;
  • high cholesterol; or
  • liver disease (especially cirrhosis).

FDA pregnancy category X. This medication can harm an unborn baby or cause birth defects. Do not use letrozole if you are pregnant, or if you have not gone completely through menopause. Tell your doctor right away if you become pregnant during treatment.

It is not known whether letrozole passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using letrozole.

How should I take letrozole (Femara)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Letrozole is usually taken once per day, or once every other day. Follow your doctor's instructions.

You may take letrozole with or without food.

To be sure this medication is helping your condition, your blood may need to be tested often. Your bone mineral density may also need to be checked. Visit your doctor regularly.

Store at room temperature away from moisture and heat.

Side Effects Centers
  • Femara

Patient Detailed Avoid Taking

What happens if I miss a dose (Femara)?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose (Femara)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking letrozole (Femara)?

This medication may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

What other drugs will affect letrozole (Femara)?

Tell your doctor about all other medicines you use, especially tamoxifen (Soltamox).

There may be other drugs that can interact with letrozole. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Where can I get more information?

Your pharmacist can provide more information about letrozole.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2013 Cerner Multum, Inc. Version: 4.01. Revision date: 6/12/2012.

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