A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Femara Side Effects, and Drug Interactions - Letrozole
Femara Side Effects, and Drug Interactions - Letrozole
SIDE EFFECTS
Femara® (letrozole tablets) was generally well tolerated across all studies in first-line and second-line metastatic breast cancer as well as extended adjuvant treatment in women who have received prior standard adjuvant tamoxifen treatment. Generally, the observed adverse reactions are mild or moderate in nature.
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 letrozole and placebo.
Table 11 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 11 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 letrozole. 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% versus 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 favour 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 12.
Table 12: Percentage (%) of Patients with Adverse Events Adverse Femara® tamoxifen
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 occurred in 5/188 (2.7%) of patients on Femara 0.5 mg, in 4/174 (2.3%) of the patients on Femara 2.5 mg, and in 15/190 (7.9%) of patients on megestrol acetate. There were fewer thromboembolic events at both Femara doses than on the megestrol acetate arm (2 of 362 patients or 0.6% vs. 9 of 190 patients or 4.7%). There was also less vaginal bleeding (1 of 362 patients or 0.3% vs. 6 of 190 patients or 3.2%) on letrozole than on megestrol acetate. In the aminoglutethimide comparison study, discontinuations for reasons other than progression occurred in 6/193 (3.1%) of patients on 0.5 mg Femara, 7/185 (3.8%) of patients 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 13.
Table 13: Percentage (%) of Patients with Adverse Events
2 Includes musculoskeletal pain, skeletal pain, back pain, arm pain, leg pain
3 Includes rash, erythematous rash, maculopapular rash, psoriasiform rash, vesicular rash
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.
Post-Marketing Experiences
Cases of blurred vision and increased hepatic enzyme have been uncommonly (<1%) reported since market introduction.
DRUG INTERACTIONS
Clinical interaction studies with cimetidine
and warfarin indicated that the coadministration
of Femara with these drugs does not result in clinically- significant
drug interactions. (See
CLINICAL PHARMACOLOGY)
Coadministration of Femara and tamoxifen 20 mg daily resulted in a reduction of letrozole plasma levels by 38% on average. There is no clinical experience to date on the use of Femara in combination with other anticancer agents.
Drug/Laboratory Test-Interactions
None observed.
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