Femara Side Effects

Generic Name: letrozole

Please note - some side effects for Femara may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Femara - for the Consumer

Femara

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Femara:

Back, leg, or arm pain; breast pain; constipation; cough; diarrhea; dizziness; headache; hot flashes; flushing; increased sweating; indigestion; joint or muscle pain; loss of appetite; mild swelling or fluid retention; nausea; night sweats; sleeplessness; stomach pain; tiredness; vaginal dryness or irritation; vomiting; weakness; weight gain or loss.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); calf pain or tenderness; chest pain; confusion; fever, chills, or sore throat; increased or painful urination; numbness of an arm or leg; one-sided weakness; severe or persistent bone pain; severe stomach pain; shortness of breath; sudden severe headache, vomiting, dizziness, or fainting; swelling of the ankles or feet; unexplained vaginal bleeding or discharge; vision or speech changes.

Femara Side Effects - for the Professional

Femara

Femara® (letrozole tablets) was generally well tolerated across all studies in first-line and second-line metastatic breast cancer, adjuvant treatment, as well as extended adjuvant treatment in women who have received prior adjuvant tamoxifen treatment. Generally, the observed adverse reactions are mild or moderate in nature.

Adjuvant Treatment of Early Breast Cancer in Postmenopausal Women

The median duration of adjuvant treatment was 24 months and the median duration of follow-up for safety was 26 months for patients receiving Femara and tamoxifen.

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

Adverse events were analyzed irrespective of whether a symptom was present or absent at baseline. Most adverse events reported (82%) were Grade 1 and Grade 2 applying the Common Toxicity Criteria Version 2.0. Table 13 describes adverse events (Grades 1-4) irrespective of relationship to study treatment in the adjuvant BIG 1-98 trial (safety population, during treatment or within 30 days of stopping treatment).

Table 13: Patients with Adverse Events (CTC Grades 1-4, Irrespective of Relationship to Study Drug) in the Adjuvant Study BIG 1-98

When considering all grades, a higher incidence of events were seen for Femara regarding fractures (5.7% vs 4%), myocardial infarctions (0.6% vs 0.4%), and arthralgia (21.2% vs 13.5%) (Femara vs tamoxifen, respectively). A higher incidence was seen for tamoxifen regarding thromboembolic events (1.2% vs 2.8%), endometrial cancer (0.2% vs 0.4%), and endometrial proliferative disorders (0.3% vs 1.8%) (Femara vs tamoxifen, respectively).

Extended Adjuvant Treatment of Early Breast Cancer in Postmenopausal Women Who have Received 5 Years of Adjuvant Tamoxifen Therapy 

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 14 describes the adverse events occurring at a frequency of at least 5% in any treatment group during treatment. Most adverse events 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 events that were significantly different from placebo were hot flashes, arthralgia/arthritis, and myalgia.

Table 14: Percentage of Patients with Adverse Events

The duration of follow-up for both the main clinical study and the bone study were insufficient to assess fracture risk associated with long-term use of Femara. 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.

Preliminary results (median duration of follow-up was 20 months) from the bone sub-study (Calcium 500 mg and Vitamin D 400 IU per day mandatory; bisphosphonates not allowed) demonstrated that at 2 years the mean decrease compared to baseline in hip BMD in Femara patients was 3% vs 0.4% for placebo. The mean decrease from baseline BMD results for the lumbar spine at 2 years were Femara 4.6% decrease and placebo 2.2%.

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).

Preliminary results (median duration of follow-up was 30 months) from the lipid sub-study did not show significant differences between the Femara and placebo groups. The HDL:LDL ratio decreased after the first 6 months of therapy but the decrease was similar in both groups and no statistically significant differences were detected.

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.

First-Line Breast Cancer

A total of 455 patients was treated for a median time of exposure of 11 months. The incidence of adverse experiences was similar for Femara and tamoxifen. The most frequently reported adverse experiences were bone pain, hot flushes, back pain, nausea, arthralgia and dyspnea. Discontinuations for adverse experiences other than progression of tumor occurred in 10/455 (2%) of patients on Femara and in 15/455 (3%) of patients on tamoxifen.

Adverse events, 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 15.

Table 15: Percentage (%) of Patients with Adverse Events

Other less frequent (≤2%) adverse experiences 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 Breast Cancer

Femara was generally well tolerated in two controlled clinical trials.

Study discontinuations in the megestrol acetate comparison study for adverse events other than progression of tumor 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 events revealed no significant differences between the high and low dose Femara groups in either study. Most of the adverse events 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 events, 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 16.

Table 16: Percentage (%) of Patients with Adverse Events

Other less frequent (<5%) adverse experiences 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-Line and Second-Line Breast Cancer

In the combined analysis of the first- and second-line metastatic trials and post-marketing experiences other adverse events that were reported were cataract, eye irritation, palpitations, cardiac failure, tachycardia, dysesthesia (including hypoesthesia/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.

Post-Marketing Experiences

Cases of blurred vision, increased hepatic enzymes, angioedema and anaphylactic reactions have been reported. 

Side Effects by Body System

General

General side effects including fatigue (up to 8%), chest pain (up to 6%), peripheral edema (5%), asthenia (up to 5%), and increased weight (2%) have been reported.

Cardiovascular

Cardiovascular side effects including hypertension (up to 7%), palpitations, cardiac failure, arterial thrombosis, angioedema, and tachycardia have been reported.

Gastrointestinal

Gastrointestinal side effects including nausea (up to 15%), vomiting (7%), constipation (up to 7%), diarrhea (up to 6%), abdominal pain (up to 6%), anorexia (up to 5%), dyspepsia (up to 4%), and dryness of mucosa (including dry mouth) have been reported.

Other

In the adjuvant setting, an increase in total cholesterol in patients who had baseline values of total serum cholesterol within the normal range, and then subsequently had an increase in total serum cholesterol of 1.5 time the upper limit of normal (ULN) was 5.4% on letrozole versus 1.2% on tamoxifen. Lipid lowering medications were used by 18% of patients on letrozole and 12% on tamoxifen.

Other side effects including viral infection (up to 6%), dysesthesia, memory impairment, irritability, nervousness, stomatitis cancer pain, pyrexia, increased appetite and disturbances of taste and thirst have been reported.

Musculoskeletal

Musculoskeletal side effects including musculoskeletal effects in general (up to 22%) and arthralgia (up to 8%) have been reported.

In the extended adjuvant setting, preliminary results (median duration of follow-up was 20 months) from the bone sub-study (calcium 500 mg and vitamin D 400 international units per day mandatory; bisphosphonates not allowed) demonstrated that at two years the mean decrease compared to baseline in hip bone mass density in letrozole patients was 3% versus 0.4% for placebo. The mean decrease from baseline bone mass density results for the lumbar spine at two years was letrozole 4.6% decrease and placebo 2.2%. Consideration should be given to monitoring bone mass density.

Nervous system

Nervous system side effects including headache (up to 12%), somnolence (up to 3%), and dizziness (up to 5%) have been reported.

Respiratory

Respiratory side effects including dyspnea (up to 9%) and coughing (up to 6%) have been reported.

Dermatologic

Dermatologic side effects including hot flushes (up to 6%), rash (up to 5%), pruritus (up to 2%), urticaria, and dry skin have been reported.

Hepatic

Hepatic side effects including abnormal liver chemistries (3% in patients where it was not associated with a documented metastases) have been reported.

Hematologic

Hematologic side effects including leukopenia and a case of reversible pancytopenia have been reported.

Ocular

Ocular side effects including cataract, eye irritation, and cases of blurred vision have been reported.

Metabolic

Metabolic side effects including hypercholesterolemia (3%) have been reported.

Genitourinary

Genitourinary side effects including increased urinary frequency and vaginal discharge have been reported.

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