Route of Administration	Dosage Form/Strength	Clinically Relevant Nonmedicinal Ingredients
Oral	Tablets, 2.5 mg	Not applicable For a complete listing see Dosage Forms, Composition and Packaging.

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

Approval is based on superior Disease Free Survival (DFS) compared to tamoxifen from the overall study population, at a median follow-up of 26 months. However, DFS advantage of FEMARA over tamoxifen was not observed in the subset of patients with node negative disease.

FEMARA (letrozole) is also indicated for the extended adjuvant treatment of hormone receptor-positive early breast cancer in postmenopausal women who have received approximately 5 years of prior standard adjuvant tamoxifen therapy. Although the intended duration of extended adjuvant therapy with Femara is 5 years, data on efficacy endpoints is limited to a median follow-up of 28 months. The clinical evidence collected to date demonstrates a statistically significant increase in disease-free survival, but no overall survival advantage has been consistently demonstrated. To date (median follow-up of 30 months), an insignificant increase in deaths (P=0.749) occurred on the letrozole arm in node-negative patients (HR 1.1 (CI 0.62, 1.96): 24/1298 in the letrozole arm versus 22/1301 in the placebo arm).

• Premenopausal endocrine status, pregnancy, lactation.

  
  

• Patients who are hypersensitive to letrozole, other aromatase inhibitors, or to any ingredient in the formulation or component of the container. For a complete listing, see Dosage Forms, Composition and Packaging.

  
  

Clinical evidence (median follow-up duration of 28 months) is insufficient to assess adverse effects associated with long term use of letrozole.

Since fatigue and dizziness have been observed with the use of FEMARA, and somnolence has been reported uncommonly, caution is advised when driving or using machines.

In the adjuvant setting, the use of some aromatase inhibitors, including FEMARA, may increase the risk of cardiovascular events compared to tamoxifen. The overall incidence of cardiovascular events in the BIG 1-98 study for FEMARA and tamoxifen arms was 9.7 vs. 10.5%, respectively. However, a higher incidence of events was seen for FEMARA vs. tamoxifen, including cardiac failure (0.9 vs. 0.4%, respectively), myocardial infarction (0.8 vs. 0.4%, respectively), fatal cardiac events (0.6 vs. 0.3%, respectively) and numerically higher fatal stroke (0.15%, 6 cases vs. 0.03%, 1 case, respectively), and a lower incidence was seen for thromboembolic events (1.4% vs 3.0%, respectively). Patients with non-malignant systemic diseases (cardiovascular, renal, hepatic, lung embolism etc.) which would prevent prolonged follow-up were ineligible from enrolment in the BIG 1-98 trial (see Clinical Trial Adverse Drug Reactions).

FEMARA reduces circulating estrogen levels. The use of estrogen lowering agents, including FEMARA, may cause a reduction in bone mineral density (BMD) with a possible consequent increased risk of osteoporosis and fracture. (See Clinical Trial Adverse Drug Reactions.) Clinical experience is insufficient to assess future risk of fractures. Women should have their osteoporosis risk assessed and managed according to local clinical practice and guidelines.

In the adjuvant setting, the use of aromatase inhibitors, including FEMARA, may increase lipid levels. See Clinical Trial Adverse Drug Reactions. Women should have their cholesterol levels assessed and managed according to current clinical practice and guidelines.

Letrozole was evaluated for maternal toxicity as well as embryotoxic, fetotoxic and teratogenic potential in female rats following oral administration of daily doses of 0.003, 0.01 or 0.03 mg/kg on gestation days 6 through 17. Oral administration of letrozole to pregnant rats resulted in teratogenicity and maternal toxicity at 0.03 mg/kg. Embryotoxicity and fetotoxicity were seen at doses of 0.003 mg/kg and there was an increase in the incidence of fetal malformation among the animals treated. However it is not known whether this was an indirect consequence of the pharmacological activity of FEMARA (inhibition of estrogen biosynthesis) or a direct drug effect.

In a 5-year, phase III trial for extended adjuvant therapy, after a median follow-up of 2.4 years, fracture rates in patients with a history of osteoporosis were 10.6% in the letrozole arm compared to 7.3% in the placebo arm, the difference is not statistically significant ( P=0.161). In patients with a previous history of fractures, fracture rates were 12.2% in the letrozole arm compared to 8.7% in the placebo arm, the difference is not statistically significant (P=0.177). The study is ongoing.

In a single dose trial with 2.5 mg letrozole in volunteers with hepatic impairment, mean AUC values of the volunteers with moderate hepatic impairment was 37% higher than in normal subjects, but still within the range seen in subjects with normal hepatic function. In a study comparing the pharmacokinetics of letrozole after a single oral dose of 2.5 mg in eight subjects with liver cirrhosis and severe non metastatic hepatic impairment (Child-Pugh score C) to those in healthy volunteers (N=8), AUC and t_½ increased by 95 % and 187%, respectively. Breast cancer patients with severe hepatic impairment are thus expected to be exposed to higher levels of letrozole than patients without severe hepatic dysfunction. Long term effects of this increased exposure have not been studied.

These results indicate that no dosage adjustment is necessary for breast cancer patients with mild to moderate hepatic dysfunction. However, since letrozole elimination depends mainly on intrinsic metabolic clearance, caution is recommended. Insufficient data are available to recommend a dose adjustment in breast cancer patients with severe non-metastatic hepatic impairment. Therefore, such patients should be kept under close supervision for adverse events.

Pharmacokinetics of a single 2.5 mg letrozole dose were unchanged in a study in postmenopausal women with varying degrees of renal function (24-hour creatinine clearance=9-116 mL/min.). In a study in 364 patients with advanced breast cancer there was no significant association between letrozole plasma levels and calculated CL_cr (range 22.9-211.9 mL/min). No dosage adjustment is required in patients with CL_cr 10 mL/min. No data are available for patients with CL_cr 9 mL/min. The potential risks and benefits to such patients should be considered carefully before prescribing letrozole.

Letrozole should not be given to pregnant women.

Letrozole should not be administered to nursing mothers.

In the adjuvant setting, more than 8000 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. Although more adverse events were generally reported in elderly patients irrespective of study treatment allocation, the differences between the two treatment groups were similar to those of younger patients.

In a 5 year, phase III trial for extended adjuvant therapy, after a median follow-up of 2.4 years, fracture rates in patients 65 years and older were 7.1% in the letrozole arm compared to 7.5% in the placebo arm, the difference is not statistically significant (P=0.738). The study is ongoing.

FEMARA was generally well tolerated as adjuvant treatment of early breast cancer and as extended adjuvant treatment in women who have received prior standard adjuvant tamoxifen treatment. In the adjuvant setting (26 months median follow-up) approximately 91% vs. 86% of the patients allocated to FEMARA or tamoxifen, respectively, and approximately 40% of the patients treated in the extended adjuvant setting (both FEMARA and placebo groups) experienced adverse reactions. Generally, the observed adverse reactions are mainly mild or moderate in nature, and most are associated with estrogen deprivation. The most frequently reported adverse reactions in the adjuvant setting were hot flushes (letrozole: 33.7%, tamoxifen 38.0%), arthralgia/arthritis (letrozole: 21.2%, tamoxifen 13.5%), and night sweats (letrozole: 14.1%, tamoxifen 16.4%), and for the extended adjuvant setting were arthralgia/arthritis (letrozole: 27.7%, placebo: 22.2%) and osteoporosis (letrozole: 6.9%, placebo: 5.5%). The adverse drug reactions reported from the clinical trials are summarized in Table 1 and Table 2 for adjuvant treatment and extended adjuvant treatment, respectively.

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.

Most adverse events reported (82%) were grade 1 and grade 2 applying the Common Toxicity Criteria Version 2.0. Serious adverse events that were suspected to be related to study treatment were significantly less frequent with FEMARA (177 patients, 4.5%) than with tamoxifen (276 patients, 6.9%). Table 1 describes the most frequently reported adverse events irrespective of relationship to study treatment in the adjuvant BIG 1-98 trial (safety population, during treatment or within 30 days of stopping treatment).

In the adjuvant setting, total cholesterol levels remained stable over 5 years (median 1-3% decrease) in the FEMARA arm whereas there was an expected slight decrease (median 10-15% decrease) over time observed in the tamoxifen arm. Hypercholesterolemia recorded at least once as a check-listed adverse event was more frequent in patients treated with FEMARA (43%) compared with tamoxifen (19%). Hypercholesterolemia recorded from non-fasting laboratory evaluations was defined as an increase in total serum 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 ULN at least one time. The incidence of laboratory evaluated hypercholesterolemia was more frequent in patients treated with letrozole (5.6%) compared to tamoxifen (1.3%) (see Table 1).

Overall, the incidence of cardiovascular events was similar in the FEMARA and tamoxifen arms (9.7 vs. 10.5%, respectively), although more patients receiving FEMARA compared to tamoxifen were reported to have cardiac failure (0.9 vs. 0.4%, respectively), myocardial infarction (0.8 vs. 0.4%, respectively), fatal cardiac events (0.6 vs. 0.3%, respectively), and numerically higher fatal stroke (0.15%, 6 cases vs. 0.03%, 1 case, respectively). As expected, thromboembolic events were more frequent in patients on tamoxifen compared to FEMARA (3.0 vs. 1.4%), respectively.

Patients with other non-malignant systemic diseases (cardiovascular, renal, hepatic, lung embolism etc.) which would prevent prolonged follow-up were ineligible from enrollment in the BIG 1-98 trial. Patients with previous DVT (deep vein thrombosis) were only included if medically suitable.

See Extended Adjuvant Therapy in Early Breast Cancer for data with respect to placebo.

FEMARA treatment was associated with a significantly higher risk of osteoporosis (2.0 vs. 1.1% with tamoxifen). Bone fractures were significantly higher in the FEMARA arm than the tamoxifen arm (5.7 vs. 4.0%, respectively).

Table 1: FEMARA (Adjuvant and Extended Adjuvant Treatment in Early Breast Cancer)

Most Frequently Reported Adverse Events Irrespective of Relationship to Study Drug in the Adjuvant Trial BIG 1-98

^a. Based on number of patients with normal serum cholesterol levels at baseline, and developing at least one value greater than 1.5 times the upper limit of normal in the laboratory measuring total serum cholesterol. Approximately 90% of the measured values were non-fasting measurements.
^b. Denominator is number of patients with baseline measurements of total serum cholesterol—letrozole, n=3105; tamoxifen, n=3129.

Table 2 describes the adverse events occurring at a frequency of at least 2% in any treatment group in a well-controlled clinical study in which over 5100 postmenopausal patients with receptor positive or unknown primary breast cancer patients who had remained disease-free after completion of adjuvant treatment with tamoxifen were randomly assigned either FEMARA or placebo. The median duration of extended adjuvant follow-up was 28 months for patients receiving letrozole and placebo. Most adverse events reported were grade 1 or grade 2 based on the Common Toxicity Criteria Version 2.0.

Table 2: FEMARA (Adjuvant and Extended Adjuvant Treatment in Early Breast Cancer)

Most Frequently Reported Adverse Events During Chronic Treatment (Median Follow-up 28 Months)

^a. Includes terms “hot flashes/hot flushes”.

The incidence of self reported osteoporosis from the MA-17 core study was significantly higher in patients who received FEMARA 6.9% (176) than in patients who received placebo 5.5% (141) (P=0.042). The incidence of clinical fractures was 5.9% (152) in patients who received FEMARA compared to 5.5% (142) in patients who received placebo, the difference is not statistically significant (P=0.548).

Results (median duration of follow-up was 20 months) from the MA-17 bone substudy demonstrated that, at 2 years, compared to baseline, patients receiving letrozole had a mean decrease (versus baseline) of 3% versus 0.4% (P=0.048) in placebo for hip bone mineral density. There was no significant difference in terms of lumbar spine bone mineral density.

The incidence of cardiovascular ischemic events from the MA-17 core study was comparable between patients who received FEMARA 6.8% (175) and placebo 6.5% (167) (P=NS).

Results from the MA-17 lipid study (median follow-up 36 months) did not show significant differences between the FEMARA and placebo groups. Subjects did not have a prior history of hyperlipidemia. The study continues to investigate the long term impact of FEMARA on lipid levels. As per normal clinical practice and guidelines for post-menopausal women, physicians should continue their routine monitoring of lipid levels on a regular basis.

Other adverse reactions, ranked according to frequency: uncommon ≥0.1% to <1%; rare ≥0.01% to <0.1%; very rare <0.01%, including isolated reports, included the following:

Uncommon: urinary tract infection.

Uncommon: leukopenia.

Common: anorexia, appetite increase. Uncommon: hypercholesterolemia, general edema.

Uncommon: depression, anxiety{*Including nervousness, irritability.}.

Common: headache, dizziness. Uncommon: somnolence, insomnia, memory impairment, dysesthesia{†Including paresthesia, hypoesthesia.}, taste disturbance. Rare: cerebrovascular accident.

Uncommon: cataract, eye irritation, blurred vision.

Uncommon: palpitations, tachycardia.

Uncommon: thrombophlebitis{‡Including superficial and deep thrombophlebitis.}, hypertension. Rare: pulmonary embolism, arterial thrombosis, cerebrovascular infarction, ischemic cardiac events.

Uncommon: dyspnea.

Common: nausea, vomiting, dyspepsia, constipation, diarrhea. Uncommon: abdominal pain, stomatitis, dry mouth.

Uncommon: increased hepatic enzymes.

Common: alopecia, increased sweating, rash{¶Including erythematous, maculopapular, psoriaform and vesicular rash.}. Uncommon: pruritus, dry skin, urticaria.

Very common: arthralgia. Common: myalgia, bone pain. Uncommon: arthritis, osteoporosis, bone fractures.

Uncommon: increased urinary frequency.

Uncommon: vaginal bleeding, vaginal discharge, vaginal dryness, breast pain.

Very common: hot flushes. Common: fatigue{§Including asthenia and malaise.}, peripheral oedema. Uncommon: pyrexia, mucosal dryness, thirst.

Common: weight increase. Uncommon: weight loss, increase in aminotransferases.

Clinical trials of interaction with FEMARA (letrozole) and cimetidine or warfarin indicate that coadministration does not result in clinically significant drug interactions.

A review of the clinical trial database indicated no evidence of other clinically relevant interactions with other commonly prescribed drugs.

In vitro, letrozole inhibits the cytochrome P450 isoenzymes 2A6 and moderately 2C19. CYP2A6 does not play a major role in drug metabolism. In in vitro experiments letrozole was not able to substantially inhibit the metabolism of diazepam (a substrate of CYP2C19) at concentrations approximately 100-fold higher than those observed in plasma at steady-state. Thus clinically relevant interactions with CYP2C19 are unlikely to occur. However, caution should be used in the concomitant administration of drugs whose disposition is mainly dependent on these isoenzymes and whose therapeutic index is narrow.

Co-administration of FEMARA and tamoxifen 20 mg daily resulted in a reduction of letrozole plasma levels by 38% on average. The clinical significance of this finding has not been explored in prospective clinical trials.

There is no clinical experience to date on the use of FEMARA in combination with other anticancer agents.

Food slightly decreases the rate of absorption (median t_max 1 hour fasted vs. 2 hours fed and mean C_max 129±20.3 nmol/L fasted vs 98.7±18.6 nmol/L fed), but the extent of absorption (area under the curve (AUC)) remains unchanged. This minor effect on absorption rate is not considered to be of clinical relevance and therefore letrozole may be taken with or without food.

No clinically significant changes in the results of clinical laboratory tests have been observed.