LEZODEX (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 letrozole over tamoxifen was not observed in the subset of patients with node-negative disease (see CLINICAL TRIALS section).

LEZODEX (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 letrozole is 5 years, randomized, double-blinded data on efficacy endpoints is limited to a median follow-up of 28 months. After this time, the study was unblinded and patients who had received placebo had the option to switch in a non-randomized fashion to treatment with letrozole. At a median follow-up of 30 months, a non- significant increase in deaths (P=0.749) occurred in 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). The clinical evidence collected to date demonstrates a statistically significant increase in disease-free survival, but no overall survival advantage has been consistently demonstrated.

LEZODEX (letrozole) is indicated as first-line therapy in postmenopausal women with advanced breast cancer.

LEZODEX (letrozole) is also indicated for the hormonal treatment of advanced/metastatic breast cancer in women with natural or artificially-induced postmenopausal status, who have disease progression following antiestrogen therapy.

Dosing Considerations

 Insufficient data available to recommend dose adjustment in patients with severe hepatic impairment (see Patients with hepatic and/or renal impairment).

Recommended Dose and Dosage Adjustment

Adult and Elderly Patients: The recommended dose is one 2.5 mg tablet once daily. No dose adjustment is required for elderly patients.

In the adjuvant setting, the intended duration of treatment is 5 years, although data are limited to a median follow-up of 26 months.

In the extended adjuvant setting, treatment with LEZODEX (letrozole) is intended for 5 years, although scientific evidence collected to date covers a median follow-up of 49 months.

In the first- and second-line advanced breast cancer settings, LEZODEX (letrozole) treatment should continue until further tumour progression is evident.

Patients with hepatic and/or renal impairment: No dosage adjustment is required for patients with renal impairment (creatinine clearance ≥10 mL/min) or moderate hepatic impairment. Insufficient data are available to recommend a dose adjustment in breast cancer patients with severe non-metastatic hepatic impairment. Therefore, patients with severe hepatic impairment (Child-Pugh score C) should be kept under close supervision for adverse events (see WARNINGS AND PRECAUTIONS section).

Missed Dose

The missed dose should be taken as soon as the patient remembers. However, if it is almost time for the next dose, the missed dose should be skipped, and the patient should go back to her regular dosage schedule. Do not double doses.

General

Clinical trial evidence (median follow-up duration of 26 months in the adjuvant setting, 49 months in the extended adjuvant setting) is insufficient to assess adverse effects associated with long term use of letrozole for five years.

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

Cardiovascular Disease

In the adjuvant setting, the use of some aromatase inhibitors, including letrozole, may increase the risk of cardiovascular events compared to tamoxifen. The overall incidence of cardiovascular events in the BIG 1-98 study for letrozole and tamoxifen arms was 9.7 vs. 10.5%, respectively. However, a higher incidence of events was seen for letrozole 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 section).

In the extended adjuvant setting, in a 5-year, phase III trial, after a median follow-up of 28 months, the incidence of cardiovascular events any time after randomization was comparable between treatment arms; 6.8% in the letrozole arm compared to 6.5% in the placebo arm. The most frequent cardiovascular events were: new or worsening angina (1.4% in the letrozole arm vs. 1.0% in the placebo arm), myocardial infarction (0.6% in the letrozole arm vs. 0.7% in the placebo arm), and stroke/transient ischemic attack (0.9% in the letrozole arm vs. 0.9% in the placebo arm). These results were obtained prior to unblinding the study.

After the study unblinding, patients randomized to the placebo arm were offered to switch to letrozole or discontinue treatment.

The updated results obtained from this Phase III study after study unblinding showed that after a median follow-up of approximately 49 months, the frequency of cardiovascular events any time after randomization was higher in the letrozole arm than in placebo arm until the switch (11.1% vs. 8.6 %, respectively). The most frequent cardiovascular events included arrhythmia (4.0% in the letrozole arm vs. 3.3% in the placebo arm until switch), new or worsening angina (1.7% on letrozole vs. 1.2% on placebo until switch), and stroke/transient ischemic attack (1.7% on letrozole vs. 1.3% on placebo until the switch).

At a median follow-up of approximately 49 months, the number of deaths attributed to a cardiovascular cause during treatment or within 30 days of stopping treatment was slightly higher in the placebo arm [16/2577 (0.6%)] than in the letrozole arm [10/2566 (0.4%)], but the difference was not statistically significant. Of the 16 deaths attributed to a cardiovascular cause in the placebo arm, 12 occurred in the group of 1129 patients who did not switch to letrozole after study unblinding, and 4 occurred in the group of 1448 patients who did switch to letrozole. There was a statistically significant higher incidence of fatal stroke in the letrozole arm [5/2566 (0.2%)] than in the placebo arm (0/2577) (P<0.0001)). (See also Clinical Trial Adverse Drug Reactions section).

Musculoskeletal

Bone Mineral Density: Letrozole reduces circulating estrogen levels. The use of estrogen lowering agents, including letrozole, may cause a reduction in bone mineral density (BMD) with a possible consequent increased risk of osteoporosis and fracture. Osteoporosis and/or bone fractures have been reported with the use of letrozole (see also Special Populations Geriatrics and Clinical Trial Adverse Drug Reactions sections). Therefore, monitoring of overall bone health is recommended during treatment with letrozole. Women should have their osteoporosis risk assessed and managed according to local clinical practice and guidelines.

In the 5-year, phase III trial for extended adjuvant therapy, after a median follow-up of 28 months, the incidence of self-reported osteoporosis any time after randomization was higher in patients who received letrozole (6.9%) than in patients who received placebo (5.5%) (P=0.042). The incidence of clinical fractures any time after randomization was slightly higher in patients who received letrozole than who received placebo (5.9% vs. 5.5% respectively; P= 0.548, not statistically significant). Fracture rates any time after randomization 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). These results were obtained prior to the study unblinding.

After the study unblinding, patients randomized to the placebo arm were offered to switch to letrozole or discontinue treatment.

The updated results obtained from this phase III trial after unblinding showed that at a median follow-up of approximately 49 months, the incidence of osteoporosis, any time after randomization, was higher in the letrozole arm (12.3%) than in the placebo until switch arm (7.4%) and the letrozole after switch arm (3.6%).

Fracture rates any time after randomization in patients with a history of osteoporosis were 17.7% (55/311) in letrozole arm compared to 10.9% (33/304) in placebo until switch arm and 5.6% (9/162) in the letrozole after switch arm. In patients with a previous history of fractures, fracture rates any time after randomization were 18.1% (52/287) in the letrozole arm compared to 12.2% (37/304) in the placebo arm until switch, and 10.2% (17/167) in the letrozole after switch arm.

The interpretation of the updated results is confounded by the fact that after study unblinding, 56% of patients randomized placebo opted to switch to letrozole, resulting in different median exposure to treatment (47 months for letrozole, 28 months for placebo until switch and 20 months for letrozole after switch). (See also Clinical Trial Adverse Drug Reactions section). The study is ongoing.

Sexual Function/Reproduction

Reproductive Toxicology: 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 letrozole (inhibition of estrogen biosynthesis) or a direct drug effect.

Special Populations

Hepatic Impairment: 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  t½ 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.

Renal Impairment: 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 CLcr (range 22.9 - 211.9 mL/min). No dosage adjustment is required in patients with CLcr ≥10 mL/min. No data are available for patients with CLcr ≤9 mL/min. The potential risks and benefits to such patients should be considered carefully before prescribing letrozole.

Pregnant Women: Letrozole should not be given to pregnant women (see CONTRAINDICATIONS).

Women of Child-Bearing Potential: There have been post-market reports of spontaneous abortions and congenital anomalies in infants of mothers who have taken letrozole. Letrozole should not be given to women with premenopausal endocrine status  (see CONTRAINDICATIONS). Women who are not premenopausal but have the potential to become pregnant, including women who are perimenopausal or who recently became postmenopausal, should use appropriate contraception while being treated with letrozole (see also Sexual Function/Reproduction, Reproductive Toxicology).

Nursing Women:  Letrozole should not be administered to nursing mothers (see CONTRAINDICATIONS).

Geriatrics: There have been no age-related effects observed on the pharmacokinetics of letrozole.

In the adjuvant setting, more than 8000 postmenopausal women were enrolled in the clinical study (see CLINICAL TRIALS section). In total, 36% of patients were aged 65 years or older at enrolment, 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 28 months, fracture rates recorded any time after randomization in patients 65 years and older were 7.1% (77/1090) in the letrozole arm compared to 7.5 % (77/1033) in the placebo arm; the difference is not statistically significant (P= 0.738). These results were obtained prior to study unblinding.

After the study unblinding, patients randomized to the placebo arm were offered to switch to letrozole or discontinue treatment.

The updated results obtained from this phase III trial after unblinding at a median follow-up of approximately 49 months, showed that the fracture rates any time after randomization in patients 65 years and older were 12.2% (133/1090) in letrozole arm compared to 10.2% (105/1032) in placebo until switch arm and 6.9% (34/495) in letrozole after switch arm.

The interpretation of the updated results is confounded by the fact that after study unblinding, 56% of patients randomized placebo opted to switch to letrozole, resulting in different median exposure to treatment (47 months for letrozole, 28 months for placebo until switch and 20 months for letrozole after switch). (See also Clinical Trial Adverse Drug Reactions section). The study is ongoing.

Monitoring and Laboratory Tests

Plasma Lipids: In the adjuvant setting, the use of aromatase inhibitors, including letrozole, may increase lipid levels (see Clinical Trial Adverse Drug Reactions section). Women should have their cholesterol levels assessed and managed according to current clinical practice and guidelines.

Drug-Drug Interactions

Clinical trials of interaction with 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.

Use with Other Anticancer Agents: Co-administration of letrozole 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 letrozole in combination with other anticancer agents.

Drug-Food Interactions

Food slightly decreases the rate of absorption (median tmax 1 hour fasted vs. 2 hours fed and mean Cmax 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.

Drug-Laboratory Interactions

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

Pregnant Women: Letrozole should not be given to pregnant women (see CONTRAINDICATIONS).

Women of Child-Bearing Potential: There have been post-market reports of spontaneous abortions and congenital anomalies in infants of mothers who have taken letrozole. Letrozole should not be given to women with premenopausal endocrine status  (see CONTRAINDICATIONS). Women who are not premenopausal but have the potential to become pregnant, including women who are perimenopausal or who recently became postmenopausal, should use appropriate contraception while being treated with letrozole (see also Sexual Function/Reproduction, Reproductive Toxicology).

Nursing Women:  Letrozole should not be administered to nursing mothers (see CONTRAINDICATIONS).

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

Adverse Drug Reactions Overview

Adverse Events in Adjuvant Study BIG 1-98

The Data and Safety Monitoring Committee, after review of the primary analysis results of the BIG 1-98 study, observed a difference in incidence in grade 5 myocardial infarctions (9 vs. 2 in the letrozole and tamoxifen arms, respectively) and recommended that these cardiac events and certain other safety data be reviewed. As a result, a blinded medical review of more than 2000 patients with pre-specified adverse events (cardiovascular events, fractures, arthritis/arthralgia, myalgia, any adverse event leading to discontinuation) or death without a prior cancer event was conducted following the primary analysis of the adjuvant trial BIG 1-98. This medical review resulted in a change in the cause of death for 25 patients, 19 of which were reclassified from a cardiac cause to either “sudden death, cause unknown” (9 cases in letrozole arm, 7 cases in tamoxifen arm) or to “other” (3 cases in letrozole arm). Some adverse events (such as arthritis/arthralgia and edema) reported in the primary analysis did not meet the definition of a treatment-emergent adverse event as they were present at baseline and did not worsen in severity during treatment. The BIG 1-98 study is currently ongoing, and the medical review is being conducted on an ongoing basis; the updated efficacy and safety results from the study will be made available at the 5-year median treatment duration. It is important to note that these updated safety data will not be comparable with those of the primary analysis. Extrapolation of the absolute risk of these pre-specified events as a function of time cannot be reasonably established.

Letrozole was generally well tolerated as adjuvant treatment of early breast cancer. In the adjuvant setting (26 months median follow-up) approximately 91% vs. 86% of the patients allocated to letrozole or tamoxifen, respectively, experienced adverse events. Generally, the observed adverse events were mainly mild or moderate in nature, and most were associated with estrogen deprivation. The most frequently reported adverse events 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%).

Adverse Events in Extended Adjuvant Study MA-17

Adverse events discussed below were analyzed irrespective of relationship to study treatment.

Letrozole was generally well tolerated as extended adjuvant treatment in women who  have received prior standard adjuvant tamoxifen treatment. In the phase III trial for extended adjuvant therapy, after a median follow-up of 28 months 87.2% vs. 84.5% of the patients on letrozole or placebo experienced adverse events. The most frequent events were: hot flushes (letrozole 49.7% vs. placebo 43.3%), fatigue (lethargy, asthenia, malaise) (letrozole 33.8% vs. placebo 32.2%), arthralgia/arthritis (letrozole 27.7% vs. placebo 22.2%); and sweating (diaphoresis) (24.3% vs. placebo 22.5%).

After the study unblinding, patients randomized to placebo arm were offered to switch to letrozole. The placebo results beyond 28 months median follow-up are confounded by the fact that 56% of patients randomised placebo opted to switch to letrozole and that dates of onset for general adverse events (based on self-report) were not recorded. In most cases, therefore, it cannot be determined if the adverse events in the placebo group occurred before switch to letrozole or after switch to letrozole. General adverse event data after unblinding of the study should therefore be interpreted with caution.

In the extended adjuvant study after study unblinding at a median follow-up of approximately 49 months the overall incidence of adverse events reported during study treatment or within 30 days irrespective of causality was 94.2% in letrozole, 91.1% in placebo not switched and 94.1% in placebo patients switched to letrozole. The most frequent adverse events were: hot flushes (60.3% in letrozole vs. 52.6% in placebo not switched), fatigue (lethargy, malaise, asthenia) (45.0% in letrozole vs. 44.8% in placebo not switched), arthralgia/arthritis (37.9% in letrozole vs. 26.8% in placebo not switched), sweating (diaphoresis) (34.0% in letrozole vs. 29.8% in placebo not switched).

Most frequently reported adverse events from the clinical trials in adjuvant and extended adjuvant are summarized in Tables 1, 2 and 3.

Adverse Events in First-Line and Second-Line Treatment of Advanced Breast Cancer

Letrozole was generally well tolerated across all studies as first-line and second-line treatment for advanced breast cancer. Approximately one third of patients treated with letrozole can be expected to experience adverse reactions. The most frequently reported adverse reactions in the clinical trials were hot flushes, nausea and fatigue. Many adverse reactions can be attributed to the normal physiological consequences of estrogen deprivation (e.g., hot flushes, alopecia and vaginal bleeding). The adverse drug reactions reported from clinical trials are summarized for first- line and second-line treatment with letrozole.

Clinical Trial Adverse Drug Reactions

Adverse Events in 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 letrozole 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 letrozole (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 letrozole 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 letrozole (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 letrozole and tamoxifen arms (9.7 vs. 10.5%, respectively), although more patients receiving letrozole 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 letrozole (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 enrolment in the BIG 1-98 trial. Patients with previous DVT (deep vein thrombosis) were only included if medically suitable.

See Adverse Events in Extended Adjuvant Therapy below for data with respect to placebo.

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

Table 1 - Most frequently reported adverse events irrespective of relationship to study drug in the Adjuvant Trial BIG 1-98

 (1) 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.

(2) Denominator is number of patients with baseline measurements of total serum cholesterol – letrozole, n=3105; tamoxifen, n=3129.

Adverse Events in Extended Adjuvant Therapy in Early Breast Cancer, Median Treatment Duration of 24 Months

Table 2 below 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 letrozole or placebo. 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. Most adverse events reported were grade 1 or grade 2 based on the Common Toxicity Criteria Version 2.0.

Table 2 - Most frequently reported adverse events irrespective of relationship to study drug (median treatment duration 24 months) in the Extended Adjuvant Trial MA-17

 (1) Includes terms “hot flashes/hot flushes”.

(NOS) : Not Otherwise Specified

The incidence of self-reported osteoporosis from the MA-17 core study was significantly higher in patients who received letrozole 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 letrozole 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 sub-study 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 letrozole 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 letrozole and placebo groups. Subjects did not have a prior history of hyperlipidemia. The study continues to investigate the long term impact of letrozole 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.

Adverse Events in Extended Adjuvant Therapy in Early Breast Cancer, Median Treatment Duration of 47 Months and a Median Follow-up of 49 Months

Adverse events discussed below were analyzed irrespective of relationship to study treatment.

Table 3 below compares the self-reported adverse events irrespective of drug relationship experienced in the randomized letrozole arm at a median treatment duration of 24 months and 47 months. The table describes the adverse events occurring in the safety population at a cut-off frequency of at least 2%. Most of these adverse events were grade 1 or grade 2 based on Common Toxicity Criteria Version 2.0. The placebo comparison after unblinding is not reliable due to the fact that 56% of patients randomized placebo opted to switch to letrozole and dates of onset for general adverse events (based on self-report) were not recorded. In most cases, therefore, it cannot be determined if the adverse events in the placebo group occurred before switch to letrozole or after switch to letrozole. The safety population after study unblinding consists of 2566 patients in the letrozole arm, 1129 patients in the placebo not switched arm and 1448 patients in the letrozole after switch from placebo arm. The median 24 months of treatment duration versus the median 47 months of treatment duration comparison is presented to indicate the evolution of adverse events in the letrozole arm over time.

Table 3 - Most frequently reported adverse events irrespective of relationship to study drug in the Extended Adjuvant Trial MA-17

 (1) Includes terms “hot flashes/hot flushes”.

(NOS) : Not Otherwise Specified

The most frequent adverse events irrespective of drug relationship (cut-off frequency of at least 2%) reported in the 604/2566 (23.5%) patients randomized to the letrozole arm who had actually completed 5 years of treatment were: flushing (384, 64%), asthenia (288, 47.4%), increased sweating (241, 40%), headache (221, 37%), arthralgia (220, 36%), hypercholesterolemia (187, 31%), edema NOS (160, 26.5%) and dizziness (145, 24%).

In contrast to general self-reported adverse events presented in the table above, dates of onset were recorded for serious adverse events (SAE) and for targeted adverse events of fracture, osteoporosis and cardiovascular events. The comparison between the letrozole randomized arm to placebo until switch is therefore more meaningful for these events.

Osteoporosis and fracture

After the study unblinding, patients randomized to the placebo arm were offered to switch to letrozole or discontinue treatment.

The updated results from the MA-17 core safety population obtained after unblinding, showed that at a median follow-up of 49 months, the incidence of osteoporosis any time after randomization was higher in patients originally randomized in the letrozole arm than for patients in the placebo until switch arm [12.3% in letrozole arm vs. 7.4% in placebo until switch arm (P<0.001)].

The incidence of bone fractures, any time after randomization, was significantly higher in patients who received letrozole than for placebo until switch (10.9% vs. 7.2%, respectively). In the placebo patients who switched to letrozole, newly diagnosed osteoporosis, any time after switching, was reported in 3.6% while fractures were reported in 5.1% any time after switching.

In the randomized letrozole arm, 1.9% of patients experienced more than one fracture, compared with 1.1% in the placebo until switch group and 1.0% in the letrozole after switch from placebo group. Of the 74/1448 patients  who  experienced a  fracture  after  switching  to letrozole from placebo, 12 patients had previously experienced a fracture on placebo (and 3 of these patients had experienced more than one fracture on placebo).

The interpretation of the updated results in the core study is confounded by the fact that after study unblinding, 56% of patients randomized placebo opted to switch to letrozole, resulting in different median exposure to treatment (47 months for letrozole, 28 months for placebo until switch and 20 months for letrozole after switch from placebo).

Updated results (median follow-up was 40 months) from the bone mineral density (BMD) sub- study conducted in a subset of 219 patients (117 on letrozole and 102 on placebo, including 77 placebo/letrozole switchers), demonstrated that, at 2 years, compared to baseline, patients receiving letrozole had a median decrease of 3.8% in hip BMD compared to 2.0% in the placebo until switch group (P=0.018). There were no statistically significant differences  in  median  % changes from baseline in hip BMD at any other measured time-points other than at 2 years. There were no statistically significant changes in lumbar spine BMD at any time between letrozole and placebo until switch groups. In the 77 placebo patients who switched to letrozole, BMD in the hip and lumbar spine showed a median decrease from baseline of approximately 1-2% at each of the first, second and third annual visits after switching to letrozole. The treatment duration in each group was median 38 months for letrozole, 22 months for placebo until switch and 22 months for letrozole after switch from placebo respectively. (See also WARNINGS AND PRECAUTIONS, Musculoskeletal and Special Populations - Geriatrics sections).

Cardiovascular events

As reported in Table 4 below, at a median follow-up of 49 months, the incidence of cardiovascular events any time after randomization was 11.1% for letrozole versus 8.6% for placebo until switch. This is higher than the incidence reported at 28 months follow-up (6.8% in the letrozole arm compared with 6.5% in the placebo arm, see also WARNINGS AND PRECAUTIONS, Cardiovascular section).

Table 4 - Cardiovascular disease any time after randomization in the MA-17 study (safety population), median follow-up of 49 months

(1) After randomization but until switch to letrozole, if switch occurred; if switch did not occur, then until date of last contact.

(2) After switch until date of last contact.

The most frequent cause of non-cancer death during study treatment or within 30 days of stopping treatment (regardless of treatment arm) was cardiovascular. (See Warnings and Precautions, Cardiovascular section).

The incidence of serious adverse events (all grades 1-5) regardless of study drug relationship was 0.5% in the letrozole group, 1.3% in the placebo not switched arm and 0.3% in letrozole after switch arm. Breast cancer related death reported during treatment or within 30 days of stopping treatment occurred in 0.5% of patients in the letrozole arm, 0.8% in the placebo not switched arm and 0.3% in the letrozole after switch arm. Non-breast cancer related death reported during treatment or within 30 days of stopping treatment occurred in 1.7% of patients in the letrozole arm, 2.6% in the placebo not switched arm and 0.5% in the letrozole after switch arm.

Lipids

Updated results (median follow-up was approximately 50 months) from the lipid sub-study showed no significant differences between the letrozole and placebo groups at any time.

The MA-17 study is ongoing. The final study results are pending.

Adverse Events in First-Line Therapy

Overall, 455 post-menopausal patients with locally advanced or metastatic breast cancer were treated with letrozole in a well-controlled clinical trial and the median time of exposure was 11 months. The incidence of adverse experiences was similar for letrozole 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 tumour occurred in 10/455  (2%)  of  patients  on letrozole and  in 15/455 (3%) of patients  on tamoxifen.

Table 5 below shows the frequency of adverse events considered possibly related to trial drug that have been reported with an incidence of more than 2.0% (whether for letrozole or for tamoxifen) in a well-controlled clinical study with letrozole (2.5 mg daily) and tamoxifen (20 mg daily).

Table 5

Adverse Events in Second-Line Therapy

Table 6 below shows in decreasing order of frequency the AEs - considered possibly related to trial drug according to the investigator - that have been reported with an incidence of more than 1.0% for letrozole in a controlled clinical trial with letrozole (2.5 mg daily) and megestrol acetate (160 mg daily) for up to 33 months.

Table 6

(1) Including: erythematous rash, maculopapular rash.

(2) Including: arm pain, back pain, leg pain, skeletal pain.

There were no differences in the incidence and severity of adverse reactions in patients ≤ 55 years, 55-69 years and ≥70 years.

Post-Market Adverse Drug Reactions

Spontaneously reported adverse drug reactions are presented below. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or clearly establish a causal relationship to letrozole exposure.

Blood and lymphatic system disorders:

Leukopenia

Cardiac disorders:

Palpitations, tachycardia, atrial fibrillation, atrial flutter, cardiac failure

Eye disorders:

Cataract, eye irritation, blurred vision

Gastrointestinal disorders:

Dyspepsia, abdominal pain, stomatitis, dry mouth

General disorders and administration site conditions:

Pyrexia, mucosal dryness, thirst

Hepato-biliary disorders: 

Increased hepatic enzymes, hepatitis

Immune system disorders: 

Anaphylactic reaction

Infections and infestations:

Urinary tract infection

Investigations:

Weight increase, weight loss, increase in aminotransferases

Musculoskeletal and connective tissue disorders:

Myalgia, osteoporosis, bone fractures

Neoplasms benign, malignant and unspecified (incl. cysts and polyps):

Tumour pain

Nervous system disorders:

Memory impairment, dysesthesia (1) , taste disturbance, cerebrovascular accident

Psychiatric disorders:

Anxiety (2)

Renal and urinary disorders:

Increased urinary frequency

Reproductive system and breast disorders:

Vaginal discharge

Respiratory, thoracic and mediastinal disorders:

Cough

Skin and subcutaneous tissue disorders:

Rash (3), pruritis, dry skin, urticaria, angioedema, erythema multiforme, toxic epidermal necrolysis

Vascular disorders:

Thrombophlebitis (4) , hypertension, pulmonary embolism, arterial thrombosis, cerebrovascular infarction, ischemic cardiac events

(1) Including paresthesia, hypoesthesia

(2) Including nervousness, irritability

(3) Including erythematous, maculopapular, psoriaform and vesicular rash

(4) Including superficial and deep thrombophlebitis

Isolated cases of letrozole overdose have been reported. In these instances, the highest single dose ingested was 62.5 mg or 25 tablets. While no serious adverse events were reported in these cases, because of the limited data available, no firm recommendations for treatment can be made. 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.

In general, treatment of overdose with letrozole should be supportive and symptomatic. Vital signs should be monitored in all patients. Complete blood count (CBC) and liver function tests should be monitored in symptomatic patients. Fluid and electrolyte status should be monitored in patients with significant vomiting and/or diarrhea. Administration of activated charcoal may be appropriate in some cases.

Letrozole exerts its antitumour effect by depriving estrogen-dependent breast cancer cells of one of their growth stimuli. In postmenopausal women, estrogens are derived mainly from the action of the aromatase enzyme, which converts adrenal androgens - primarily androstenedione and testosterone - to estrone (E1) and estradiol (E2). The suppression of estrogen biosynthesis in peripheral tissues and the malignant tissue can be achieved by specifically inhibiting the aromatase enzyme.

In healthy postmenopausal women, single oral doses of 0.1, 0.5 and 2.5 mg letrozole suppressed serum estrone by 75-78% and estradiol by 78% from baseline. Maximum suppression is achieved in 48-78 hours.

In postmenopausal women with advanced breast cancer, daily letrozole doses of 0.1 to 5 mg suppress estradiol, estrone and estrone sulphate plasma levels by 75 - 95% from baseline in all patients treated. With 0.5 mg doses and higher, many plasma levels of estrone and estrone sulphate are below the limit of detection of the assays, indicating that higher estrogen suppression is achieved with these doses. Estrogen suppression was maintained throughout treatment in all patients.

Letrozole is highly specific in inhibiting aromatase activity. Impairment of adrenal steroidogenesis has not been observed. No clinically relevant changes in the plasma levels of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, ACTH (adrenocorticotropic  hormone) or in plasma renin activity were found in postmenopausal patients treated with 0.1 to 5 mg letrozole daily. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1 to 5 mg letrozole did not indicate any attenuation of aldosterone or cortisol production. Thus, glucocorticoid or mineralocorticoid supplementation is not required.

Letrozole had no effect on plasma androgen concentrations (androstenedione and testosterone) among healthy postmenopausal women after single doses of 0.1, 0.5 and 2.5 mg, or on plasma androstenedione concentrations among postmenopausal patients treated with daily doses of 0.1 to 5 mg. These results indicate that accumulation of androgenic precursors does not occur. Plasma levels of LH and FSH are not affected by letrozole in patients, nor is thyroid function as evaluated by TSH, T4 and T3 uptake.

Absorption: Letrozole is rapidly and completely absorbed from the gastrointestinal tract (absolute bioavailability = 99.9%). Food slightly decreases the rate of absorption (median tmax 1 hour fasted vs. 2 hours fed and mean Cmax 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.

Distribution: Letrozole is rapidly and extensively distributed into tissues (VdSS = 1.87 ± 1.47  L/kg). Plasma protein binding is approximately 60%, mainly to albumin. The letrozole concentration in erythrocytes is about 80% of that in plasma. After administration of 2.5 mg 14C- labelled letrozole, approximately 82% of the radioactivity in plasma was unchanged compound. Systemic exposure to metabolites is therefore low.

Metabolism: Metabolic clearance to a pharmacologically inactive carbinol metabolite, CGP 44645, is the major elimination pathway of letrozole (Clm = 2.1 L/h), but it is relatively slow when compared to hepatic blood flow (about 90 L/h). The cytochrome P450 isoenzymes 3A4 and 2A6 were found to be capable of converting letrozole to this metabolite. Formation of minor unidentified metabolites and direct renal and fecal excretion play only a minor role in the overall elimination of letrozole.

Within 2 weeks after administration of 2.5 mg 14C-labelled letrozole to healthy postmenopausal volunteers, 88.2 ± 7.6% of the radioactivity was recovered in urine and 3.8 ± 0.9% in feces. At least 75% of the radioactivity recovered in urine up to 216 hours (84.7 ± 7.8% of the dose) was attributed to the glucuronide of the carbinol metabolite, about 9% to two unidentified metabolites, and 6% to unchanged letrozole.

Excretion: The apparent terminal elimination half-life in plasma is about 2 days. After daily administration of 2.5 mg steady-state levels are reached within 2 to 6 weeks. Plasma concentrations at steady-state are approximately 7 times higher than concentrations measured after a single dose of 2.5 mg, while they are 1.5 to 2 times higher than steady-state values 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. Since steady state levels are maintained over time, it can be concluded that no continuous accumulation of letrozole occurs.

 In a variety of preclinical safety studies conducted in standard animal species, there was no evidence of systemic or target organ toxicity.

Letrozole showed a low degree of acute toxicity in rodents exposed up to 2000 mg/kg.  In dogs, letrozole caused signs of moderate toxicity at 100 mg/kg (see Table 13).

In repeated dose toxicity studies of up to 12 months duration in rats treated with 0.3, 3 and 30 mg/kg and dogs treated with 0.03, 0.3 and 3 mg/kg, the main findings can be attributed to the pharmacological action of the compound. Effects on the liver (increased weight, hepatocellular hypertrophy, fatty changes) were observed, mainly at the high dose level. The no-adverse effect level was 0.3 mg/kg in both species (see Table 14). Increased incidences of hepatic vacuolation (both sexes, high dose) and necrosis (intermediate and high dose females) were also noted in rats treated for 104 weeks in a carcinogenicity study. They may have been associated with the endocrine effects and hepatic enzyme-inducing properties of letrozole. However, a direct drug effect cannot be ruled out.

Table 13 - Acute Toxicity

Table 14 - Long-Term Toxicity

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 ≥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 letrozole (inhibition of estrogen biosynthesis) or a direct drug effect.

Two 104-week carcinogenicity studies have been conducted. In one study, rats were treated with letrozole, administered orally, in doses of 0.1, 1.0 and 10 mg/kg/day; in the second study, mice were treated with letrozole orally at doses of 0.6, 6 and 60 mg/kg/day. No treatment related tumours were noted in male animals. In female animals, treatment-related changes in genital tract tumours (a reduced incidence of benign and malignant mammary tumours at all doses in rats and an increased incidence of benign ovarian stromal tumours in mice) were secondary to the pharmacological effect of the compound. In the mouse carcinogenicity study, dermal and systemic inflammation were also noted, particularly in the high dose group, leading to increased mortality at this dose level. It is not known whether these findings were an indirect consequence of the pharmacological activity of letrozole (i.e. linked to long-term estrogen deprivation) or a direct drug effect.

Table 15 - Mutagenicity Studies

 * With or without metabolic activation by a fraction of rat liver microsomes (S-9 mix)

In addition to the active ingredient, letrozole, each tablet also contains the non-medicinal ingredients cellulose compounds (hydroxypropyl cellulose, microcrystalline cellulose and hydroxypropyl methylcellulose), iron oxide yellow, lactose, magnesium stearate, polyethylene glycol, sodium starch glycolate and titanium dioxide..

None Applicable

Protect from heat and moisture, store at room temperature 15 to 30 ºC (59-86ºF). Keep out of reach and sight of children and pets.

Primary packaging: blister of 30 tablets.

Secondary packaging: carton

None applicable.