Side Effects of Femara (letrozole)

Femara (letrozole) is an anti-estrogen drug that is used to treat postmenopausal women with breast cancer. 

The growth of some breast cancers in postmenopausal women is promoted by estrogens that circulate in the blood, and the adrenal glands are the main source of these circulating estrogens. Femara inhibits the enzyme in the adrenal glands (aromatase) that produces the estrogens, estradiol and estrone. 

Common side effects of Femara include

• nausea,
• vomiting,
• fatigue,
• headache,
• muscle aches,
• diarrhea,
• constipation, and
• chest pain.

Serious side effects of Femara include

• increased cholesterol levels, and
• decreased bone mineral density, which increases the risk of osteoporosis and fractures.

Drug interactions of Femara include tamoxifen, which reduces blood levels of Femara when both drugs are administered together. However, in clinical studies the benefit of Femara was not reduced when administered immediately after tamoxifen. 

Femara is an anti-estrogen drug. Therefore, estrogen containing products counteract the effect of Femara. 

Femara damages a fetus. It should not be taken by pregnant women. It is unknown if Femara is secreted into breast milk. Consult your doctor before breastfeeding.

The most common side effects with letrozole are:

• nausea,
• vomiting,
• fatigue,
• headache,
• muscle aches,
• diarrhea,
• constipation, and
• chest pain.

Cholesterol levels may increase during letrozole therapy. Cholesterol levels should be monitored and some patients may require treatment for high cholesterol levels. Letrozole decreases bone mineral density, increasing the risk of osteoporosis and fractures.

The following adverse reactions are discussed in greater detail in other sections of the labeling.

• Bone effects
• Increases in cholesterol
• Fatigue and Dizziness

Clinical Trials Experience

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

• In study, BIG 1-98, the median treatment duration of adjuvant treatment was 60 months and the median duration of follow-up for safety was 96 months for patients receiving Femara and tamoxifen.
• Certain adverse reactions were prospectively specified for analysis (see Table 1), based on the known pharmacologic properties and side effect profiles of the two drugs.
• Adverse reactions were analyzed irrespective of whether a symptom was present or absent at baseline.
• Most adverse reactions reported (approximately 75% of patients who reported AEs) were
  • Grade 1 or Grade 2 applying the Common Toxicity Criteria (CTC) Version 2.0/Common Terminology Criteria for Adverse Events (CTCAE),
  • Version 3.0. Table 1 describes adverse reactions (Grades 1-4 and Grades 3-4) 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,) in the Adjuvant Study – Monotherapy Arms Analysis (Median Follow-up 96 Months; Median Treatment 60 Months)

• 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 96 months, a higher incidence of events was seen for Femara (14.7%) than for tamoxifen (11.4%) regarding fractures.
• A higher incidence was seen for tamoxifen compared to Femara regarding
  • thromboembolic events (4.6% vs 3.2%), and
  • endometrial hyperplasia or cancer (2.9% vs 0.4%) (tamoxifen vs Femara, respectively).

Bone Study

• Results of a safety trial in 263 postmenopausal women with resected receptor positive early breast cancer in the adjuvant setting comparing the effect on lumbar spine (L2-L4) BMD of adjuvant treatment with letrozole to that with tamoxifen showed at 24 months a median decrease in lumbar spine BMD of 4.1% in the letrozole arm compared to a median increase of 0.3% in the tamoxifen arm (difference = 4.4%) (P < 0.0001).
• No patients with a normal BMD at baseline became osteoporotic over the 2 years and only 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 safety trial in 263 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.

In another postapproval randomized, multicenter, open label, study of letrozole vs anastrozole in the adjuvant treatment of postmenopausal women with hormone receptor and node positive breast cancer (FACE, NCT00248170), the median duration of treatment was 60 months for both treatment arms. Table 2 describes adverse reactions (Grades 1-4 and Grades 3-4) irrespective of relationship to study treatment in the adjuvant study (safety population).

Table 2: Adverse Reactions (CTC Grades 1-4), Occurring in at least 5% of Patients in Either Treatment Arm, by Preferred Term (Safety set)

The following adverse reactions were also identified in less than 5% of the 2049 patients treated with letrozole and not included in the table:

• fall,
• vertigo,
• hyperbilirubinemia,
• jaundice, and
• chest pain.

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

In study MA-17, 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 3 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 CTC 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 3: Adverse Reactions Occurring in at least 5% of Patients in either Treatment Arm

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 Substudy: See prescribing information.

Lipid Substudy: 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.

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

• The extended adjuvant treatment trial (MA-17) 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 substudy

• In the extended adjuvant setting (MA-17), 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.

First-Line Treatment Of Advanced Breast Cancer

In study P025 a total of 455 patients were treated for a median time of exposure of 11 months in the Femara arm (median 6 months in the tamoxifen arm). 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 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 4.

Table 4: Adverse Reactions Occurring in at least 5% of Patients in either Treatment Arm

• Other less frequent (less than or equal to 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 (AR/BC2) 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 (AR/BC3), 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 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 AR/BC2 and AR/BC3 are shown in Table 5.

Table 5: Adverse Reactions Occurring at a Frequency of at Least 5% of Patients in Either Treatment Arm

• Other less frequent (less than 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 postmarketing 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

The following adverse reactions have been identified during postapproval use of Femara. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Eye Disorders: blurred vision
• Hepatobiliary Disorders: increased hepatic enzymes, hepatitis
• Immune System Disorders: anaphylactic reactions, hypersensitivity reactions
• Nervous System Disorders: carpal tunnel syndrome, trigger finger
• Pregnancy: spontaneous abortions, congenital birth defects
• Skin and subcutaneous disorders: angioedema, toxic epidermal necrolysis, erythema multiforme

Tamoxifen

Coadministration of Femara and tamoxifen 20 mg daily resulted in a reduction of letrozole plasma levels of 38% on average (study P015). Clinical experience in the second-line breast cancer trials (AR/BC2 and AR/BC3) 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 (study P004) showed no clinically significant effect on letrozole pharmacokinetics.

Warfarin

• An interaction study (P017) 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.