LETROZOLE (letrozole 2.5 mg) Dailymed

Generic: letrozole is used for the treatment of Breast Neoplasms Pregnancy

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1 Indications And Usage

Letrozole tablets are an aromatase inhibitor indicated for:

Adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer (1.1)

Extended adjuvant treatment of postmenopausal women with early breast cancer who have received prior standard adjuvant tamoxifen therapy (1.2)

First and second-line treatment of postmenopausal women with hormone receptor positive or unknown advanced breast cancer (1.3)

1.1 Adjuvant Treatment of Early Breast Cancer

Letrozole tablets are indicated for the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer.

1.2 Extended Adjuvant Treatment of Early Breast Cancer

Letrozole tablets are indicated for the extended adjuvant treatment of early breast cancer in postmenopausal women, who have received 5 years of adjuvant tamoxifen therapy. The effectiveness of letrozole tablets in extended adjuvant treatment of early breast cancer is based on an analysis of disease-free survival in patients treated with letrozole tablets for a median of 60 months [see Clinical Studies (14.2, 14.3)].

1.3 First and Second-Line Treatment of Advanced Breast Cancer

Letrozole tablets are indicated for first-line treatment of postmenopausal women with hormone receptor positive or unknown, locally advanced or metastatic breast cancer. Letrozole tablets are also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy [see Clinical Studies (14.4, 14.5)].

2 Dosage And Administration

Letrozole tablets are taken orally without regard to meals (2):

Recommended dose: 2.5 mg once daily (2.1)

Patients with cirrhosis or severe hepatic impairment: 2.5 mg every other day (2.5, 5.3)

2.1 Recommended Dose

The recommended dose of letrozole tablets is one 2.5 mg tablet administered once a day, without regard to meals.

2.2 Use in Adjuvant Treatment of Early Breast Cancer

In the adjuvant setting, the optimal duration of treatment with letrozole is unknown. In both the adjuvant study and the postapproval adjuvant study, median treatment duration was 5 years. Treatment should be discontinued at relapse [see Clinical Studies (14.1)].

2.3 Use in Extended Adjuvant Treatment of Early Breast Cancer

In the extended adjuvant setting, the optimal treatment duration with letrozole tablets is not known. The planned duration of treatment in the study was 5 years. In the final updated analysis, conducted at a median follow-up of 62 months, the median treatment duration for letrozole tablets was 60 months. Seventy-one (71%) percent of patients were treated for at least 3 years and 58% of patients completed at least 4.5 years of extended adjuvant treatment. The treatment should be discontinued at tumor relapse [see Clinical Studies (14.2)].

2.4 Use in First and Second-Line Treatment of Advanced Breast Cancer

In patients with advanced disease, treatment with letrozole tablets should continue until tumor progression is evident. [see Clinical Studies (14.4, 14.5)]

2.5 Use in Hepatic Impairment

No dosage adjustment is recommended for patients with mild to moderate hepatic impairment, although letrozole tablets blood concentrations were modestly increased in subjects with moderate hepatic impairment due to cirrhosis. The dose of letrozole tablets in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50% [see Warnings and Precautions (5.3)]. The recommended dose of letrozole tablets for such patients is 2.5 mg administered every other day. The effect of hepatic impairment on letrozole tablets exposure in noncirrhotic cancer patients with elevated bilirubin levels has not been determined.

2.6 Use in Renal Impairment

No dosage adjustment is required for patients with renal impairment if creatinine clearance is greater than or equal to 10 mL/min. [see Clinical Pharmacology (12.3)].

3 Dosage Forms And Strengths

2.5 mg tablets: Yellow colored, film-coated, round shaped tablets debossed with one side 'N' and other side 'L'.

2.5 mg tablets (3)

4 Contraindications

Pregnancy: Letrozole can cause fetal harm [see Use in Specific Populations (8.1)].

Known hypersensitivity to the active substance, or to any of the excipients [see Adverse Reactions (6)].

Pregnancy (4)

Known hypersensitivity to the active substance, or to any of the excipients (4)

5 Warnings And Precautions

Decreases in bone mineral density may occur. Consider bone mineral density monitoring (5.1)

Increases in total cholesterol may occur. Consider cholesterol monitoring. (5.2)

Fatigue, dizziness and somnolence may occur. Exercise caution when operating machinery (5.4)

Embryo-Fetal toxicity: Can cause fetal harm when administered to pregnant women. Obtain a pregnancy test in females of reproductive potential. Advise females of reproductive potential to use effective contraception (5.6, 8.1, 8.3)

5.1 Bone Effects

Use of letrozole tablets may cause decreases in bone mineral density (BMD). Consideration should be given to monitoring BMD. Results of a safety study to evaluate safety 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) [see Adverse Reactions (6)]. Updated results from the BMD substudy (MA-17B) in the extended adjuvant setting demonstrated that at 2 years patients receiving letrozole had a median decrease from baseline of 3.8% in hip BMD compared to a median decrease of 2.0% in the placebo group. The changes from baseline in lumbar spine BMD in letrozole and placebo treated groups were not significantly different [see Adverse Reactions (6)].

In the adjuvant trial (BIG 1-98) the incidence of bone fractures at any time after randomization was 14.7% for letrozole and 11.4% for tamoxifen at a median follow-up of 96 months. The incidence of osteoporosis was 5.1% for letrozole and 2.7% for tamoxifen [see Adverse Reactions (6)]. In the extended adjuvant trial (MA-17), the incidence of bone fractures at any time after randomization was 13.3% for letrozole and 7.8% for placebo at a median follow-up of 62 months. The incidence of new osteoporosis was 14.5% for letrozole and 7.8% for placebo [see Adverse Reactions (6)].

5.2 Cholesterol

Consideration should be given to monitoring serum cholesterol. In the adjuvant trial (BIG 1-98), hypercholesterolemia was reported in 52.3% of letrozole patients and 28.6% of tamoxifen patients. Grade 3-4 hypercholesterolemia was reported in 0.4% of letrozole patients and 0.1% of tamoxifen patients. Also in the adjuvant setting, an increase of greater than or equal to 1.5 × upper limit of normal (ULN) in total cholesterol (generally nonfasting) was observed in patients on monotherapy who had baseline total serum cholesterol within the normal range (i.e., less than =1.5 × ULN) in 155/1843 (8.4%) patients on letrozole vs 71/1840 (3.9%) patients on tamoxifen. Lipid lowering medications were required for 29% of patients on letrozole and 20% on tamoxifen [see Adverse Reactions (6)].

5.3 Hepatic Impairment

Subjects with cirrhosis and severe hepatic impairment who were dosed with 2.5 mg of letrozole tablets experienced approximately twice the exposure to letrozole tablets as healthy volunteers with normal liver function [see Clinical Pharmacology (12.3)]. Therefore, a dose reduction is recommended for this patient population. The effect of hepatic impairment on letrozole tablets exposure in cancer patients with elevated bilirubin levels has not been determined. [see Dosage and Administration (2.5)].

5.4 Fatigue and Dizziness

Because fatigue, dizziness, and somnolence have been reported with the use of letrozole tablets, caution is advised when driving or using machinery until it is known how the patient reacts to letrozole tablets use.

5.5 Laboratory Test Abnormalities

No dose-related effect of letrozole tablets on any hematologic or clinical chemistry parameter was evident. Moderate decreases in lymphocyte counts, of uncertain clinical significance, were observed in some patients receiving letrozole tablets 2.5 mg. This depression was transient in about half of those affected. Two patients on letrozole tablets developed thrombocytopenia; relationship to the study drug was unclear. Patient withdrawal due to laboratory abnormalities, whether related to study treatment or not was infrequent.

5.6 Embryo-Fetal Toxicity

Based on post-marketing reports, findings from animal studies and the mechanism of action, letrozole tablets can cause fetal harm and is contraindicated for use in pregnant women. In post-marketing reports, use of letrozole during pregnancy resulted in cases of spontaneous abortions and congenital birth defects. Letrozole caused embryo-fetal toxicities in rats and rabbits at maternal exposures that were below the maximum recommended human dose (MHRD) on a mg/m² basis. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during therapy with letrozole tablets and for at least 3 weeks after the last dose [see Postmarketing Experience (6.2), Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

6 Adverse Reactions

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

Bone effects [see Warnings and Precautions (5.1)]

Increases in cholesterol [see Warnings and Precautions (5.2)]

Fatigue and Dizziness [see Warnings and Precautions (5.4)]

The most common adverse reactions (greater than 20%) were hot flashes, arthralgia; flushing, asthenia, edema, headache, dizziness, hypercholesterolemia, sweating increased, bone pain; and musculoskeletal (6).

To report SUSPECTED ADVERSE REACTIONS, contact Breckenridge Pharmaceutical, Inc., at 1-800-367-3395 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 letrozole tablets 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)

Adverse Reactions Grades 1-4 Grades 3-4

Letrozole tabletsN=2448n (%) TamoxifenN=2447n (%) Letrozole tabletsN=2448n (%) TamoxifenN=2447n (%)

TIA = Transient ischemic attackNote: Cardiovascular events (including cerebrovascular and thromboembolic events), skeletal and urogenital/endometrial events and second primary malignancies were collected life -long. All of these events were assumed to be of CTC Grade 3 to 5 and were not individually graded

Patients with any adverse reaction 2309 (94.3) 2212 (90.4) 636 (26.0) 606 (24.8)

HypercholesterolemiaTarget events pre-specified for analysis 1280 (52.3) 700 (28.6) 11 (0.4) 6 (0.2)

Hot flashes 819 (33.5) 929 (38.0) - - - -

Arthralgia/arthritis 621 (25.4) 504 (20.6) 84 (3.4) 50 (2.0)

Bone fracturesAt median follow-up of 96 months (i.e. any time after randomization) for letrozole tablets (range up to 144 months) and 95 months for tamoxifen (range up to 143 months ) 361 (14.7) 280 (11.4) - - - -

Night sweats 356 (14.5) 426 (17.4) - - - -

Weight increase 317 (12.9) 378 (15.4) 27 (1.1) 39 (1.6)

Nausea 284 (11.6) 277 (11.3) 6 (0.2) 9 (0.4)

Bone fracturesEvents pre-printed on CRF At median treatment duration of 60 months (i.e. during treatment + 30 days after discontinuation of treatment) for letrozole tablets and tamoxifen (range up to 68 months) 249 (10.2) 175 (7.2) - - - -

Fatigue (lethargy, malaise, asthenia) 235 (9.6) 250 (10.2) 6 (0.2) 7 (0.3)

Myalgia 221 (9.0) 212 (8.7) 18 (0.7) 14 (0.6)

Vaginal bleeding 129 (5.3) 320 (13.1) 1 (<0.1) 8 (0.3)

Edema 164 (6.7) 160 (6.5) 3 (0.1) 1 (<0.1)

Weight decrease 140 (5.7) 129 (5.3) 8 (0.3) 5 (0.2)

Osteoporosis 126 (5.1) 67 (2.7) 10 (0.4) 5 (0.2)

Back pain 125 (5.1) 136 (5.6) 7 (0.3) 11 (0.4)

Bone pain 123 (5.0) 109 (4.5) 6 (0.2) 4 (0.2)

Depression 119 (4.9) 114 (4.7) 16 (0.7) 14 (0.6)

Vaginal irritation 112 (4.6) 77 (3.1) 2 (<0.1) 2 (<0.1)

Headache 105 (4.3) 94 (3.8) 8 (0.3) 4 (0.2)

Pain in extremity 103 (4.2) 79 (3.2) 6 (0.2) 4 (0.2)

Osteopenia 87 (3.6) 76 (3.1) 0 - 3 (0.1)

Dizziness/light-headedness 84 (3.4) 80 (3.3) 1 (<0.1) 6 (0.2)

Alopecia 83 (3.4) 84 (3.4) - - - -

Vomiting 80 (3.3) 80 (3.3) 3 (0.1) 5 (0.2)

Cataract 49 (2.0) 54 (2.2) 16 (0.7) 17 (0.7)

Constipation 49 (2.0) 71 (2.9) 3 (0.1) 1 (<0.1)

Myocardial infarction 42 (1.7) 28 (1.1) - - - -

Breast pain 37 (1.5) 43 (1.8) 1 (<0.1) - -

Anorexia 20 (0.8) 20 (0.8) 1 (<0.1) 1 (<0.1)

Endometrial proliferation disorders 14 (0.6) 86 (3.5) 0 - 14 (0.6)

Ovarian cyst 11 (0.4) 18 (0.7) 4 (0.2) 4 (0.2)

Endometrial hyperplasia/cancer 11 (0.4) 72 (2.9) - - - -

Endometrial hyperplasia/cancer ^, Excluding women who had undergone hysterectomy before study entry 6/1909 (0.3) 57/1943 (2.9) - - - -

Other endometrial disorders 2 (<0.1) 3 (0.1) 0 - 0 -

Myocardial infarction 24 (1.0) 12 (0.5) - - - -

Myocardial ischemia 6 (0.2) 9 (0.4) - - - -

Cerebrovascular accident/TIA 74 (3.0) 68 (2.8) - - - -

Cerebrovascular accident/TIA 51 (2.1) 47 (1.9) - - - -

Angina requiring surgery 35 (1.4) 33 (1.3) - - - -

Angina requiring surgery 25 (1.0) 25 (1.0) - - - -

Thromboembolic event 79 (3.2) 113 (4.6) - - - -

Thromboembolic event 51 (2.1) 89 (3.6) - - - -

Cardiac failure 39 (1.6) 34 (1.4) - - - -

Cardiac failure 27 (1.1) 15 (0.6) - - - -

Hypertension 160 (6.5) 175 (7.2) - - - -

Hypertension 138 (5.6) 139 (5.7) - - - -

Other cardiovascular 172 (7.0) 174 (7.1) - - - -

Other cardiovascular 120 (4.9) 119 (4.9) - - - -

Second primary malignancy 129 (5.3) 150 (6.1) - - - -

Second primary malignancy 54 (2.2) 79 (3.2) - - - -

When considering all grades during study treatment, a higher incidence of events was seen for letrozole tablets regarding fractures (10.1% vs 7.1%), myocardial infarctions (1.0% vs 0.5%), and arthralgia (25.2% vs 20.4%) (letrozole tablets 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%) (letrozole tablets vs tamoxifen respectively).

At a median follow-up of 96 months, a higher incidence of events was seen for letrozole tablets (14.7%) than for tamoxifen (11.4%) regarding fractures. A higher incidence was seen for tamoxifen compared to letrozole tablets regarding thromboembolic events (4.6% vs 3.2%), and endometrial hyperplasia or cancer (2.9% vs 0.4%) (tamoxifen vs letrozole tablets, 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)

Adverse Reactions LetrozoleN = 2049n (%) AnastrozoleN = 2062n (%)

Grade 3/4n (%) All gradesn (%) Grade 3/4n (%) All gradesn (%)

Patients with at least one AR 628 (30.6) 2049 (100.0) 591 (28.7) 2062 (100.0)

Arthralgia 80 (3.9) 987 (48.2) 69 (3.3) 987 (47.9)

Hot flush 17 (0.8) 666 (32.5) 9 (0.4) 666 (32.3)

Fatigue 8 (0.4) 345 (16.8) 10 (0.5) 343 (16.6)

Osteoporosis 5 (0.2) 223 (10.9) 11 (0.5) 225 (10.9)

Myalgia 16 (0.8) 233 (11.4) 15 (0.7) 212 (10.3)

Back pain 11 (0.5) 212 (10.3) 17 (0.8) 193 (9.4)

Osteopenia 4 (0.2) 203 (9.9) 1 (0.0) 173 (8.4)

Pain in extremity 9 (0.4) 168 (8.2) 3 (0.1) 174 (8.4)

Lymphoedema 5 (0.2) 159 (7.8) 2 (0.1) 179 (8.7)

Insomnia 7 (0.3) 160 (7.8) 3 (0.1) 149 (7.2)

Hypercholesterolemia 2 (0.1) 155 (7.6) 1 (0.0) 151 (7.3)

Hypertension 25 (1.2) 156 (7.6) 20 (1.0) 149 (7.2)

Depression 16 (0.8) 147 (7.2) 13 (0.6) 137 (6.6)

Bone pain 10 (0.5) 138 (6.7) 9 (0.4) 122 (5.9)

Nausea 6 (0.3) 137 (6.7) 5 (0.2) 152 (7.4)

Headache 3 (0.1) 130 (6.3) 5 (0.2) 168 (8.1)

Alopecia 2 (0.1) 127 (6.2) 0 (0.0) 134 (6.5)

Musculoskeletal pain 6 (0.3) 123 (6.0) 9 (0.4) 147 (7.1)

Radiation skin injury 11 (0.5) 120 (5.9) 6 (0.3) 88 (4.3)

Dyspnea 16 (0.8) 118 (5.8) 10 (0.5) 96 (4.7)

Cough 1 (0.0) 106 (5.2) 1 (0.0) 120 (5.8)

Musculoskeletal stiffness 2 (0.1) 102 (5.0) 2 (0.1) 84 (4.1)

Dizziness 2 (0.2) 94 (4.6) 7 (0.3) 109 (5.3)

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 letrozole tablets 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

Number (%) of Patients with Grade 1-4 Adverse Reactions Number (%) of Patients with Grade 3-4 Adverse Reactions

Letrozole tabletsN=2563 PlaceboN=2573 Letrozole tabletsN=2563 PlaceboN=2573

Any Adverse Reaction 2232 (87.1) 2174 (84.5) 419 (16.3) 389 (15.1)

Vascular Disorders 1375 (53.6) 1230 (47.8) 59 (2.3) 74 (2.9)

  Flushing 1273 (49.7) 1114 (43.3) 3 (0.1) 0

General Disorders 1154 (45) 1090 (42.4) 30 (1.2) 28 (1.1)

  Asthenia 862 (33.6) 826 (32.1) 16 (0.6) 7 (0.3)

  Edema NOS 471 (18.4) 416 (16.2) 4 (0.2) 3 (0.1)

Musculoskeletal Disorders 978 (38.2) 836 (32.5) 71 (2.8) 50 (1.9)

  Arthralgia 565 (22) 465 (18.1) 25 (1) 20 (0.8)

  Arthritis NOS 173 (6.7) 124 (4.8) 10 (0.4) 5 (0.2)

  Myalgia 171 (6.7) 122 (4.7) 8 (0.3) 6 (0.2)

  Back Pain 129 (5) 112 (4.4) 8 (0.3) 7 (0.3)

Nervous System Disorders 863 (33.7) 819 (31.8) 65 (2.5) 58 (2.3)

  Headache 516 (20.1) 508 (19.7) 18 (0.7) 17 (0.7)

  Dizziness 363 (14.2) 342 (13.3) 9 (0.4) 6 (0.2)

Skin Disorders 830 (32.4) 787 (30.6) 17 (0.7) 16 (0.6)

  Sweating Increased 619 (24.2) 577 (22.4) 1 (<0.1) 0

Gastrointestinal Disorders 725 (28.3) 731 (28.4) 43 (1.7) 42 (1.6)

  Constipation 290 (11.3) 304 (11.8) 6 (0.2) 2 (<0.1)

  Nausea 221 (8.6) 212 (8.2) 3 (0.1) 10 (0.4)

  Diarrhea NOS 128 (5) 143 (5.6) 12 (0.5) 8 (0.3)

Metabolic Disorders 551 (21.5) 537 (20.9) 24 (0.9) 32 (1.2)

  Hypercholesterolemia 401 (15.6) 398 (15.5) 2 (<0.1) 5 (0.2)

Reproductive Disorders 303 (11.8) 357 (13.9) 9 (0.4) 8 (0.3)

  Vaginal Hemorrhage 123 (4.8) 171 (6.6) 2 (<0.1) 5 (0.2)

  Vulvovaginal Dryness 137 (5.3) 127 (4.9) 0 0

Psychiatric Disorders 320 (12.5) 276 (10.7) 21 (0.8) 16 (0.6)

  Insomnia 149 (5.8) 120 (4.7) 2 (<0.1) 2 (<0.1)

Respiratory Disorders 279 (10.9) 260 (10.1) 30 (1.2) 28 (1.1)

  Dyspnea 140 (5.5) 137 (5.3) 21 (0.8) 18 (0.7)

Investigations 184 (7.2) 147 (5.7) 13 (0.5) 13 (0.5)

Infections and Infestations 166 (6.5) 163 (6.3) 40 (1.6) 33 (1.3)

Renal Disorders 130 (5.1) 100 (3.9) 12 (0.5) 6 (0.2)

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 letrozole tablets was 5.9% (152) and placebo was 5.5% (142). The incidence of self-reported osteoporosis was higher in patients who received letrozole tablets 6.9% (176) than in patients who received placebo 5.5% (141). Bisphosphonates were administered to 21.1% of the patients who received letrozole tablets 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 letrozole tablets 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 Warnings and Precautions (5.1)].

Lipid Substudy: In the extended adjuvant setting, based on a median duration of follow-up of 62 months, there was no significant difference between letrozole tablets 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. [see Warnings and Precautions (5.2)].

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 [see Adverse Reactions (6)]. 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 letrozole tablets (10.4%) compared to placebo (5.8%), as also a higher rate of osteoporosis (letrozole tablets 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 letrozole tablets 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 letrozole tablets 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. [see Warnings and Precautions (5.2)].

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 letrozole tablets arm (median 6 months in the tamoxifen arm). The incidence of adverse reactions was similar for letrozole tablets 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 letrozole tablets and in 15/455 (3%) of patients on tamoxifen.

Adverse reactions that were reported in at least 5% of the patients treated with letrozole tablets 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

Adverse Reaction Letrozole tablets2.5 mg(N=455)% Tamoxifen20 mg(N=455)%

General Disorders

  Fatigue 13 13

  Chest Pain 8 9

  Edema Peripheral 5 6

  Pain NOS 5 7

  Weakness 6 4

Investigations

  Weight Decreased 7 5

Vascular Disorders

  Hot Flushes 19 16

  Hypertension 8 4

Gastrointestinal Disorders

  Nausea 17 17

  Constipation 10 11

  Diarrhea 8 4

  Vomiting 7 8

Infections/Infestations

  Influenza 6 4

  Urinary Tract Infection NOS 6 3

Injury, Poisoning and Procedural Complications

  Post-Mastectomy Lymphedema 7 7

Metabolism and Nutrition Disorders

  Anorexia 4 6

Musculoskeletal and Connective Tissue Disorders

  Bone Pain 22 21

  Back Pain 18 19

  Arthralgia 16 15

  Pain in Limb 10 8

Nervous System Disorders

  Headache NOS 8 7

Psychiatric Disorders

  Insomnia 7 4

Reproductive System and Breast Disorders

  Breast Pain 7 7

Respiratory, Thoracic and Mediastinal Disorders

  Dyspnea 18 17

  Cough 13 13

  Chest Wall Pain 6 6

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 letrozole tablets 0.5 mg, in 4/174 (2.3%) on letrozole tablets 2.5 mg, and in 15/190 (7.9%) on megestrol acetate. There were fewer thromboembolic events at both letrozole tablets doses than on the megestrol acetate arm (0.6% vs 4.7%). There was also less vaginal bleeding (0.3% vs 3.2%) on letrozole tablets 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 letrozole tablets, 7/185 (3.8%) on 2.5 mg letrozole tablets, 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 letrozole tablet 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 letrozole tablets 0.5 mg, letrozole tablets 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

Adverse Reaction Pooled Letrozole tablets2.5 mg(N=359)% Pooled Letrozole tablets0.5 mg(N=380)% megestrol acetate160 mg(N=189)% aminoglutethimide500 mg(N=178)%

Body as a Whole

  Chest Pain 6 3 7 3

  Peripheral EdemaIncludes peripheral edema, leg edema, dependent edema, edema 5 5 8 3

  Asthenia 4 5 4 5

  Weight Increase 2 2 9 3

Cardiovascular

  Hypertension 5 7 5 6

Digestive System

  Nausea 13 15 9 14

  Vomiting 7 7 5 9

  Constipation 6 7 9 7

  Diarrhea 6 5 3 4

  Pain-Abdominal 6 5 9 8

  Anorexia 5 3 5 5

  Dyspepsia 3 4 6 5

Infections/Infestations

  Viral Infection 6 5 6 3

Lab Abnormality

  Hypercholesterolemia 3 3 0 6

Musculoskeletal System

  MusculoskeletalIncludes musculoskeletal pain, skeletal pain, back pain, arm pain, leg pain 21 22 30 14

  Arthralgia 8 8 8 3

Nervous System

  Headache 9 12 9 7

  Somnolence 3 2 2 9

  Dizziness 3 5 7 3

Respiratory System

  Dyspnea 7 9 16 5

  Coughing 6 5 7 5

Skin and Appendages

  Hot Flushes 6 5 4 3

  RashIncludes rash, erythematous rash, maculopapular rash, psoriasiform rash, vesicular rash 5 4 3 12

  Pruritus 1 2 5 3

Other less frequent (less than 5%) adverse reactions considered consequential and reported in at least 3 patients treated with letrozole tablets, 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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of letrozole tablets. 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

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)
Adverse Reactions	Grades 1-4	Grades 3-4
TIA = Transient ischemic attackNote: Cardiovascular events (including cerebrovascular and thromboembolic events), skeletal and urogenital/endometrial events and second primary malignancies were collected life -long. All of these events were assumed to be of CTC Grade 3 to 5 and were not individually graded
Patients with any adverse reaction	2309	(94.3)	2212	(90.4)	636	(26.0)	606	(24.8)
HypercholesterolemiaTarget events pre-specified for analysis	1280	(52.3)	700	(28.6)	11	(0.4)	6	(0.2)
Hot flashes	819	(33.5)	929	(38.0)	-	-	-	-
Arthralgia/arthritis	621	(25.4)	504	(20.6)	84	(3.4)	50	(2.0)
Bone fracturesAt median follow-up of 96 months (i.e. any time after randomization) for letrozole tablets (range up to 144 months) and 95 months for tamoxifen (range up to 143 months )	361	(14.7)	280	(11.4)	-	-	-	-
Night sweats	356	(14.5)	426	(17.4)	-	-	-	-
Weight increase	317	(12.9)	378	(15.4)	27	(1.1)	39	(1.6)
Nausea	284	(11.6)	277	(11.3)	6	(0.2)	9	(0.4)
Bone fracturesEvents pre-printed on CRF At median treatment duration of 60 months (i.e. during treatment + 30 days after discontinuation of treatment) for letrozole tablets and tamoxifen (range up to 68 months)	249	(10.2)	175	(7.2)	-	-	-	-
Fatigue (lethargy, malaise, asthenia)	235	(9.6)	250	(10.2)	6	(0.2)	7	(0.3)
Myalgia	221	(9.0)	212	(8.7)	18	(0.7)	14	(0.6)
Vaginal bleeding	129	(5.3)	320	(13.1)	1	(<0.1)	8	(0.3)
Edema	164	(6.7)	160	(6.5)	3	(0.1)	1	(<0.1)
Weight decrease	140	(5.7)	129	(5.3)	8	(0.3)	5	(0.2)
Osteoporosis	126	(5.1)	67	(2.7)	10	(0.4)	5	(0.2)
Back pain	125	(5.1)	136	(5.6)	7	(0.3)	11	(0.4)
Bone pain	123	(5.0)	109	(4.5)	6	(0.2)	4	(0.2)
Depression	119	(4.9)	114	(4.7)	16	(0.7)	14	(0.6)
Vaginal irritation	112	(4.6)	77	(3.1)	2	(<0.1)	2	(<0.1)
Headache	105	(4.3)	94	(3.8)	8	(0.3)	4	(0.2)
Pain in extremity	103	(4.2)	79	(3.2)	6	(0.2)	4	(0.2)
Osteopenia	87	(3.6)	76	(3.1)	0	-	3	(0.1)
Dizziness/light-headedness	84	(3.4)	80	(3.3)	1	(<0.1)	6	(0.2)
Alopecia	83	(3.4)	84	(3.4)	-	-	-	-
Vomiting	80	(3.3)	80	(3.3)	3	(0.1)	5	(0.2)
Cataract	49	(2.0)	54	(2.2)	16	(0.7)	17	(0.7)
Constipation	49	(2.0)	71	(2.9)	3	(0.1)	1	(<0.1)
Myocardial infarction	42	(1.7)	28	(1.1)	-	-	-	-
Breast pain	37	(1.5)	43	(1.8)	1	(<0.1)	-	-
Anorexia	20	(0.8)	20	(0.8)	1	(<0.1)	1	(<0.1)
Endometrial proliferation disorders	14	(0.6)	86	(3.5)	0	-	14	(0.6)
Ovarian cyst	11	(0.4)	18	(0.7)	4	(0.2)	4	(0.2)
Endometrial hyperplasia/cancer	11	(0.4)	72	(2.9)	-	-	-	-
Endometrial hyperplasia/cancer ^, Excluding women who had undergone hysterectomy before study entry	6/1909	(0.3)	57/1943	(2.9)	-	-	-	-
Other endometrial disorders	2	(<0.1)	3	(0.1)	0	-	0	-
Myocardial infarction	24	(1.0)	12	(0.5)	-	-	-	-
Myocardial ischemia	6	(0.2)	9	(0.4)	-	-	-	-
Cerebrovascular accident/TIA	74	(3.0)	68	(2.8)	-	-	-	-
Cerebrovascular accident/TIA	51	(2.1)	47	(1.9)	-	-	-	-
Angina requiring surgery	35	(1.4)	33	(1.3)	-	-	-	-
Angina requiring surgery	25	(1.0)	25	(1.0)	-	-	-	-
Thromboembolic event	79	(3.2)	113	(4.6)	-	-	-	-
Thromboembolic event	51	(2.1)	89	(3.6)	-	-	-	-
Cardiac failure	39	(1.6)	34	(1.4)	-	-	-	-
Cardiac failure	27	(1.1)	15	(0.6)	-	-	-	-
Hypertension	160	(6.5)	175	(7.2)	-	-	-	-
Hypertension	138	(5.6)	139	(5.7)	-	-	-	-
Other cardiovascular	172	(7.0)	174	(7.1)	-	-	-	-
Other cardiovascular	120	(4.9)	119	(4.9)	-	-	-	-
Second primary malignancy	129	(5.3)	150	(6.1)	-	-	-	-
Second primary malignancy	54	(2.2)	79	(3.2)	-	-	-	-

Table 2: Adverse Reactions (CTC Grades 1-4), Occurring in at least 5% of Patients in Either Treatment Arm, by Preferred Term (Safety set)
Adverse Reactions	LetrozoleN = 2049n (%)	AnastrozoleN = 2062n (%)
Patients with at least one AR	628 (30.6)	2049 (100.0)	591 (28.7)	2062 (100.0)
Arthralgia	80 (3.9)	987 (48.2)	69 (3.3)	987 (47.9)
Hot flush	17 (0.8)	666 (32.5)	9 (0.4)	666 (32.3)
Fatigue	8 (0.4)	345 (16.8)	10 (0.5)	343 (16.6)
Osteoporosis	5 (0.2)	223 (10.9)	11 (0.5)	225 (10.9)
Myalgia	16 (0.8)	233 (11.4)	15 (0.7)	212 (10.3)
Back pain	11 (0.5)	212 (10.3)	17 (0.8)	193 (9.4)
Osteopenia	4 (0.2)	203 (9.9)	1 (0.0)	173 (8.4)
Pain in extremity	9 (0.4)	168 (8.2)	3 (0.1)	174 (8.4)
Lymphoedema	5 (0.2)	159 (7.8)	2 (0.1)	179 (8.7)
Insomnia	7 (0.3)	160 (7.8)	3 (0.1)	149 (7.2)
Hypercholesterolemia	2 (0.1)	155 (7.6)	1 (0.0)	151 (7.3)
Hypertension	25 (1.2)	156 (7.6)	20 (1.0)	149 (7.2)
Depression	16 (0.8)	147 (7.2)	13 (0.6)	137 (6.6)
Bone pain	10 (0.5)	138 (6.7)	9 (0.4)	122 (5.9)
Nausea	6 (0.3)	137 (6.7)	5 (0.2)	152 (7.4)
Headache	3 (0.1)	130 (6.3)	5 (0.2)	168 (8.1)
Alopecia	2 (0.1)	127 (6.2)	0 (0.0)	134 (6.5)
Musculoskeletal pain	6 (0.3)	123 (6.0)	9 (0.4)	147 (7.1)
Radiation skin injury	11 (0.5)	120 (5.9)	6 (0.3)	88 (4.3)
Dyspnea	16 (0.8)	118 (5.8)	10 (0.5)	96 (4.7)
Cough	1 (0.0)	106 (5.2)	1 (0.0)	120 (5.8)
Musculoskeletal stiffness	2 (0.1)	102 (5.0)	2 (0.1)	84 (4.1)
Dizziness	2 (0.2)	94 (4.6)	7 (0.3)	109 (5.3)

Table 3: Adverse Reactions Occurring in at least 5% of Patients in either Treatment Arm
	Number (%) of Patients with Grade 1-4 Adverse Reactions	Number (%) of Patients with Grade 3-4 Adverse Reactions
Any Adverse Reaction	2232 (87.1)	2174 (84.5)	419 (16.3)	389 (15.1)
Vascular Disorders	1375 (53.6)	1230 (47.8)	59 (2.3)	74 (2.9)
Flushing	1273 (49.7)	1114 (43.3)	3 (0.1)	0
General Disorders	1154 (45)	1090 (42.4)	30 (1.2)	28 (1.1)
Asthenia	862 (33.6)	826 (32.1)	16 (0.6)	7 (0.3)
Edema NOS	471 (18.4)	416 (16.2)	4 (0.2)	3 (0.1)
Musculoskeletal Disorders	978 (38.2)	836 (32.5)	71 (2.8)	50 (1.9)
Arthralgia	565 (22)	465 (18.1)	25 (1)	20 (0.8)
Arthritis NOS	173 (6.7)	124 (4.8)	10 (0.4)	5 (0.2)
Myalgia	171 (6.7)	122 (4.7)	8 (0.3)	6 (0.2)
Back Pain	129 (5)	112 (4.4)	8 (0.3)	7 (0.3)
Nervous System Disorders	863 (33.7)	819 (31.8)	65 (2.5)	58 (2.3)
Headache	516 (20.1)	508 (19.7)	18 (0.7)	17 (0.7)
Dizziness	363 (14.2)	342 (13.3)	9 (0.4)	6 (0.2)
Skin Disorders	830 (32.4)	787 (30.6)	17 (0.7)	16 (0.6)
Sweating Increased	619 (24.2)	577 (22.4)	1 (<0.1)	0
Gastrointestinal Disorders	725 (28.3)	731 (28.4)	43 (1.7)	42 (1.6)
Constipation	290 (11.3)	304 (11.8)	6 (0.2)	2 (<0.1)
Nausea	221 (8.6)	212 (8.2)	3 (0.1)	10 (0.4)
Diarrhea NOS	128 (5)	143 (5.6)	12 (0.5)	8 (0.3)
Metabolic Disorders	551 (21.5)	537 (20.9)	24 (0.9)	32 (1.2)
Hypercholesterolemia	401 (15.6)	398 (15.5)	2 (<0.1)	5 (0.2)
Reproductive Disorders	303 (11.8)	357 (13.9)	9 (0.4)	8 (0.3)
Vaginal Hemorrhage	123 (4.8)	171 (6.6)	2 (<0.1)	5 (0.2)
Vulvovaginal Dryness	137 (5.3)	127 (4.9)	0	0
Psychiatric Disorders	320 (12.5)	276 (10.7)	21 (0.8)	16 (0.6)
Insomnia	149 (5.8)	120 (4.7)	2 (<0.1)	2 (<0.1)
Respiratory Disorders	279 (10.9)	260 (10.1)	30 (1.2)	28 (1.1)
Dyspnea	140 (5.5)	137 (5.3)	21 (0.8)	18 (0.7)
Investigations	184 (7.2)	147 (5.7)	13 (0.5)	13 (0.5)
Infections and Infestations	166 (6.5)	163 (6.3)	40 (1.6)	33 (1.3)
Renal Disorders	130 (5.1)	100 (3.9)	12 (0.5)	6 (0.2)

Table 4: Adverse Reactions Occurring in at least 5% of Patients in either Treatment Arm
Adverse Reaction	Letrozole tablets2.5 mg(N=455)%	Tamoxifen20 mg(N=455)%
General Disorders
Fatigue	13	13
Chest Pain	8	9
Edema Peripheral	5	6
Pain NOS	5	7
Weakness	6	4
Investigations
Weight Decreased	7	5
Vascular Disorders
Hot Flushes	19	16
Hypertension	8	4
Gastrointestinal Disorders
Nausea	17	17
Constipation	10	11
Diarrhea	8	4
Vomiting	7	8
Infections/Infestations
Influenza	6	4
Urinary Tract Infection NOS	6	3
Injury, Poisoning and Procedural Complications
Post-Mastectomy Lymphedema	7	7
Metabolism and Nutrition Disorders
Anorexia	4	6
Musculoskeletal and Connective Tissue Disorders
Bone Pain	22	21
Back Pain	18	19
Arthralgia	16	15
Pain in Limb	10	8
Nervous System Disorders
Headache NOS	8	7
Psychiatric Disorders
Insomnia	7	4
Reproductive System and Breast Disorders
Breast Pain	7	7
Respiratory, Thoracic and Mediastinal Disorders
Dyspnea	18	17
Cough	13	13
Chest Wall Pain	6	6

Table 5: Adverse Reactions Occurring at a Frequency of at Least 5% of Patients in Either Treatment Arm
Adverse Reaction	Pooled Letrozole tablets2.5 mg(N=359)%	Pooled Letrozole tablets0.5 mg(N=380)%	megestrol acetate160 mg(N=189)%	aminoglutethimide500 mg(N=178)%
Body as a Whole
Chest Pain	6	3	7	3
Peripheral EdemaIncludes peripheral edema, leg edema, dependent edema, edema	5	5	8	3
Asthenia	4	5	4	5
Weight Increase	2	2	9	3
Cardiovascular
Hypertension	5	7	5	6
Digestive System
Nausea	13	15	9	14
Vomiting	7	7	5	9
Constipation	6	7	9	7
Diarrhea	6	5	3	4
Pain-Abdominal	6	5	9	8
Anorexia	5	3	5	5
Dyspepsia	3	4	6	5
Infections/Infestations
Viral Infection	6	5	6	3
Lab Abnormality
Hypercholesterolemia	3	3	0	6
Musculoskeletal System
MusculoskeletalIncludes musculoskeletal pain, skeletal pain, back pain, arm pain, leg pain	21	22	30	14
Arthralgia	8	8	8	3
Nervous System
Headache	9	12	9	7
Somnolence	3	2	2	9
Dizziness	3	5	7	3
Respiratory System
Dyspnea	7	9	16	5
Coughing	6	5	7	5
Skin and Appendages
Hot Flushes	6	5	4	3
RashIncludes rash, erythematous rash, maculopapular rash, psoriasiform rash, vesicular rash	5	4	3	12
Pruritus	1	2	5	3

7 Drug Interactions

Tamoxifen

Coadministration of letrozole tablets 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 letrozole tablets therapy is not impaired if letrozole tablets are 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 letrozole tablets in combination with other anticancer agents.

8 Use In Specific Populations

Lactation: Advise not to breastfeed. (8.2)

8.1 Pregnancy

Risk Summary

Based on post-marketing reports, findings from animal studies and the mechanism of action, letrozole tablets can cause fetal harm and are contraindicated for use in pregnant women. In post-marketing reports, use of letrozole during pregnancy resulted in cases of spontaneous abortions and congenital birth defects; however, the data are insufficient to inform a drug-associated risk. [see Contraindications (4), Warnings and Precautions (5.6), Postmarketing Experience (6.2), and Clinical Pharmacology (12.1)].

In animal reproduction studies, administration of letrozole to pregnant animals during organogenesis resulted in increased post-implantation pregnancy loss and resorption, fewer live fetuses, and fetal malformation affecting the renal and skeletal systems in rats and rabbits at doses approximately 0.1 times the daily maximum recommended human dose (MRHD) on a mg/m² basis (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies.

Data

Animal Data

In a fertility and early embryonic development toxicity study in female rats, oral administration of letrozole starting 2 weeks before mating until pregnancy day 6 resulted in an increase in pre-implantation loss at doses ≥ 0.003 mg/kg/day (approximately 0.01 times the maximum recommended human dose on a mg/m² basis).

In an embryo-fetal developmental toxicity study in rats, daily administration of oral letrozole during the period of organogenesis at doses ≥ 0.003 mg/kg (approximately 0.01 times the maximum recommended human dose on a mg/m² basis) resulted in embryo-fetal toxicity including intrauterine mortality, increased resorptions and postimplantation loss, decreased numbers of live fetuses and fetal anomalies including absence and shortening of renal papilla, dilation of ureter, edema and incomplete ossification of frontal skull and metatarsals. Letrozole was teratogenic to rats at a dose of 0.03 mg/kg (approximately 0.01 times the maximum recommended human dose on a mg/m² basis) and caused fetal domed head and cervical/centrum vertebral fusion.

In the embryo-fetal development toxicity study in rabbits, daily administration of oral letrozole during the period of organogenesis at doses ≥ 0.002 mg/kg (approximately 0.01 times the maximum recommended human dose on a mg/m² basis) resulted in embryo-fetal toxicity including intrauterine mortality, increased resorption, increased postimplantation loss and decreased numbers of live fetuses. Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore- and hind legs.

8.2 Lactation

Risk Summary

It is not known if letrozole is present in human milk. There are no data on the effects of letrozole on the breastfed infant or milk production. Exposure of lactating rats to letrozole was associated with impaired reproductive performance of the male offspring (see Data). Because of the potential for serious adverse reactions in breastfed infants from letrozole, advise lactating women not to breastfeed while taking letrozole and for at least 3 weeks after the last dose.

Data

Animal Data

In a postnatal developmental toxicity study in lactating rats, letrozole was administered orally at doses of 1, 0.003, 0.03 or 0.3 mg/kg/day on day 0 through day 20 of lactation. The reproductive performance of the male offspring was impaired at letrozole dose as low as 0.003 mg/kg/day (approximately 0.01 times the maximum recommended human dose on a mg/m² basis), as reflected by decreased mating and pregnancy ratios. There were no effects on the reproductive performance of female offspring.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Based on animal studies, letrozole tablets can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Females of reproductive potential should have a pregnancy test prior to starting treatment with letrozole tablets.

Contraception

Females

Based on animal studies, letrozole tablets can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with letrozole tablets and for at least 3 weeks after the last dose.

Infertility

Females

Based on studies in female animals, letrozole tablets may impair fertility in females of reproductive potential [see Nonclinical Toxicology (13.1)].

Males

Based on studies in male animals, letrozole tablets may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness in pediatric patients have not been established.

Letrozole administration to young (postnatal day 7) rats for 12 weeks duration at 0.003, 0.03, 0.3 mg/kg/day by oral gavage resulted in adverse skeletal/growth effects (bone maturation, bone mineral density) and neuroendocrine and reproductive developmental perturbations of the hypothalamic-pituitary axis. Administration of 0.3 mg/kg/day resulted in AUC values that were similar to the AUC in adult patients receiving the recommended dose of 2.5 mg/day. Decreased fertility was accompanied by hypertrophy of the hypophysis and testicular changes that included degeneration of the seminiferous tubular epithelium and atrophy of the female reproductive tract. Young rats in this study were allowed to recover following discontinuation of letrozole treatment for 42 days. Histopathological changes were not reversible at clinically relevant exposures.

8.5 Geriatric Use

The median age of patients in all studies of first-line and second-line treatment of metastatic breast cancer was 64-65 years. About 1/3 of the patients were greater than or equal to 70 years old. In the first-line study, patients greater than or equal to 70 years of age experienced longer time to tumor progression and higher response rates than patients less than 70.

For the extended adjuvant setting (MA-17), more than 5,100 postmenopausal women were enrolled in the clinical study. In total, 41% of patients were aged 65 years or older at enrollment, while 12% were 75 or older. In the extended adjuvant setting, no overall differences in safety or efficacy were observed between these older patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

In the adjuvant setting (BIG 1-98), more than 8,000 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. More adverse reactions were generally reported in elderly patients irrespective of study treatment allocation. However, in comparison to tamoxifen, no overall differences with regard to the safety and efficacy profiles were observed between elderly patients and younger patients.

10 Overdosage

Isolated cases of letrozole tablets overdose have been reported. In these instances, the highest single dose ingested was 62.5 mg or 25 tablets. While no serious adverse reactions were reported in these cases, because of the limited data available, no firm recommendations for treatment can be made. However, emesis could be induced if the patient is alert. In general, supportive care and frequent monitoring of vital signs are also appropriate. 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.

Lethality was observed in mice and rats following single oral doses that were equal to or greater than 2,000 mg/kg (about 4,000 to 8,000 times the daily maximum recommended human dose on a mg/m² basis); death was associated with reduced motor activity, ataxia and dyspnea. Lethality was observed in cats following single IV doses that were equal to or greater than 10 mg/kg (about 50 times the daily maximum recommended human dose on a mg/m² basis); death was preceded by depressed blood pressure and arrhythmias.

11 Description

Letrozole tablets for oral administration contain 2.5 mg of letrozole, a nonsteroidal aromatase inhibitor (inhibitor of estrogen synthesis). It is chemically described as 4,4'-(1H-1,2,4-Triazol-1-ylmethylene)dibenzonitrile, and its structural formula is

Letrozole is a white to yellowish crystalline powder, practically odorless, freely soluble in dichloromethane, slightly soluble in ethanol, and practically insoluble in water. It has a molecular weight of 285.31, empirical formula C₁₇H₁₁N₅, and a melting range of 184°C to 185°C.

Letrozole tablets are available as 2.5 mg tablets for oral administration.

Inactive Ingredients: Colloidal silicon dioxide, ferric oxide (yellow), hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, polyethylene glycol, sodium starch glycolate, talc and titanium dioxide.

12 Clinical Pharmacology

12.1 Mechanism of Action

The growth of some cancers of the breast is stimulated or maintained by estrogens. Treatment of breast cancer thought to be hormonally responsive (i.e., estrogen and/or progesterone receptor positive or receptor unknown) has included a variety of efforts to decrease estrogen levels (ovariectomy, adrenalectomy, hypophysectomy) or inhibit estrogen effects (antiestrogens and progestational agents). These interventions lead to decreased tumor mass or delayed progression of tumor growth in some women.

In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.

Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system; it inhibits the conversion of androgens to estrogens. In adult nontumor- and tumor-bearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum LH, and causing the regression of estrogen-dependent tumors. In contrast to ovariectomy, treatment with letrozole does not lead to an increase in serum FSH. Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis.

Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. Treatment of women with letrozole significantly lowers serum estrone, estradiol and estrone sulfate and has not been shown to significantly affect adrenal corticosteroid synthesis, aldosterone synthesis, or synthesis of thyroid hormones.

12.2 Pharmacodynamics

In postmenopausal patients with advanced breast cancer, daily doses of 0.1 mg to 5 mg letrozole tablets suppress plasma concentrations of estradiol, estrone, and estrone sulfate by 75% to 95% from baseline with maximal suppression achieved within two-three days. Suppression is dose-related, with doses of 0.5 mg and higher giving many values of estrone and estrone sulfate that were below the limit of detection in the assays. Estrogen suppression was maintained throughout treatment in all patients treated at 0.5 mg or higher.

Letrozole is highly specific in inhibiting aromatase activity. There is no impairment of adrenal steroidogenesis. No clinically-relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, ACTH or in plasma renin activity among postmenopausal patients treated with a daily dose of letrozole tablets 0.1 mg to 5 mg. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1, 0.25, 0.5, 1, 2.5, and 5 mg did not indicate any attenuation of aldosterone or cortisol production. Glucocorticoid or mineralocorticoid supplementation is, therefore, not necessary.

No changes were noted in plasma concentrations of androgens (androstenedione and testosterone) among healthy postmenopausal women after 0.1, 0.5, and 2.5 mg single doses of letrozole tablets or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 0.1 mg to 5 mg. This indicates that the blockade of estrogen biosynthesis does not lead to accumulation of androgenic precursors. Plasma levels of LH and FSH were not affected by letrozole in patients, nor was thyroid function as evaluated by TSH levels, T3 uptake, and T4 levels.

12.3 Pharmacokinetics

Absorption and Distribution: Letrozole is rapidly and completely absorbed from the gastrointestinal tract and absorption is not affected by food. It is metabolized slowly to an inactive metabolite whose glucuronide conjugate is excreted renally, representing the major clearance pathway. About 90% of radiolabeled letrozole is recovered in urine. Letrozole's terminal elimination half-life is about 2 days and steady-state plasma concentration after daily 2.5 mg dosing is reached in 2-6 weeks. Plasma concentrations at steady state are 1.5 to 2 times higher than 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. These steady-state levels are maintained over extended periods, however, and continuous accumulation of letrozole does not occur. Letrozole is weakly protein bound and has a large volume of distribution (approximately 1.9 L/kg).

Elimination

Metabolism and Excretion: Metabolism to a pharmacologically-inactive carbinol metabolite (4,4'-methanol-bisbenzonitrile) and renal excretion of the glucuronide conjugate of this metabolite is the major pathway of letrozole clearance. Of the radiolabel recovered in urine, at least 75% was the glucuronide of the carbinol metabolite, about 9% was two unidentified metabolites, and 6% was unchanged letrozole.

In human microsomes with specific CYP isozyme activity, CYP3A4 metabolized letrozole to the carbinol metabolite while CYP2A6 formed both this metabolite and its ketone analog. In human liver microsomes, letrozole inhibited CYP2A6 and CYP2C19, however, the clinical significance of these findings is unknown.

Specific Populations

Pediatric, Geriatric and Race: In the study populations (adults ranging in age from 35 to greater than 80 years), no change in pharmacokinetic parameters was observed with increasing age. Differences in letrozole pharmacokinetics between adult and pediatric populations have not been studied. Differences in letrozole pharmacokinetics due to race have not been studied.

Renal Impairment: In a study of volunteers with varying renal function (24-hour creatinine clearance: 9 to 116 mL/min), no effect of renal function on the pharmacokinetics of single doses of 2.5 mg of letrozole tablets was found. In addition, in a study (AR/BC2) of 347 patients with advanced breast cancer, about half of whom received 2.5 mg letrozole tablets and half 0.5 mg letrozole tablets, renal impairment (calculated creatinine clearance: 20 to 50 mL/min) did not affect steady-state plasma letrozole concentrations.

Hepatic Impairment: In a study of subjects with mild to moderate non-metastatic hepatic dysfunction (e.g., cirrhosis, Child-Pugh classification A and B), the mean area under curve (AUC) values of the volunteers with moderate hepatic impairment were 37% higher than in normal subjects, but still within the range seen in subjects without impaired function.

In a pharmacokinetic study, subjects with liver cirrhosis and severe hepatic impairment (Child-Pugh classification C, which included bilirubins about 2-11 times ULN with minimal to severe ascites) had two-fold increase in exposure (AUC) and 47% reduction in systemic clearance. Breast cancer patients with severe hepatic impairment are thus expected to be exposed to higher levels of letrozole than patients with normal liver function receiving similar doses of this drug. [see Dosage and Administration (2.5)]

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A conventional carcinogenesis study in mice at doses of 0.6 to 60 mg/kg/day (about 1 to 100 times the daily maximum recommended human dose on a mg/m² basis) administered by oral gavage for up to 2 years revealed a dose-related increase in the incidence of benign ovarian stromal tumors. The incidence of combined hepatocellular adenoma and carcinoma showed a significant trend in females when the high dose group was excluded due to low survival. In a separate study, plasma AUC_0-12hr levels in mice at 60 mg/kg/day were 55 times higher than the AUC_0-24hr level in breast cancer patients at the recommended dose. The carcinogenicity study in rats at oral doses of 0.1 to 10 mg/kg/day (about 0.4 to 40 times the daily maximum recommended human dose on a mg/m² basis) for up to 2 years also produced an increase in the incidence of benign ovarian stromal tumors at 10 mg/kg/day. Ovarian hyperplasia was observed in females at doses equal to or greater than 0.1 mg/kg/day. At 10 mg/kg/day, plasma AUC_0-24hr levels in rats were 80 times higher than the level in breast cancer patients at the recommended dose. The benign ovarian stromal tumors observed in mice and rats were considered to be related to the pharmacological inhibition of estrogen synthesis and may be due to increased luteinizing hormone resulting from the decrease in circulating estrogen.

Letrozole tablets were not mutagenic in in vitro tests (Ames and E.coli bacterial tests) but were observed to be a potential clastogen in in vitro assays (CHO K1 and CCL 61 Chinese hamster ovary cells). Letrozole was not clastogenic in vivo (micronucleus test in rats).

In a fertility and early embryonic development toxicity study in female rats, oral administration of letrozole starting 2 weeks before mating until pregnancy day 6 resulted in an increase in pre-implantation loss at doses ≥ 0.03 mg/kg/day (approximately 0.1 times the maximum recommended human dose on a mg/m² basis). In repeat-dose toxicity studies, administration of letrozole caused sexual inactivity in females and atrophy of the reproductive tract in males and females at doses of 0.6, 0.1 and 0.03 mg/kg in mice, rats and dogs, respectively (approximately 1, 0.4 and 0.4 times the daily maximum recommended human dose on a mg/m² basis, respectively).

14 Clinical Studies

14.1 Updated Adjuvant Treatment of Early Breast Cancer

In a multicenter study (BIG 1-98, NCT00004205) enrolling over 8,000 postmenopausal women with resected, receptor-positive early breast cancer, one of the following treatments was randomized in a double-blind manner:

Option 1:

A.tamoxifen for 5 years

B.Letrozole tablets for 5 years

C.tamoxifen for 2 years followed by letrozole tablets for 3 years

D.Letrozole tablets for 2 years followed by tamoxifen for 3 years

Option 2:

A.tamoxifen for 5 years

B.Letrozole tablets for 5 years

The study in the adjuvant setting, BIG 1-98 was designed to answer two primary questions: whether letrozole tablets for 5 years was superior to Tamoxifen for 5 years (Primary Core Analysis) and whether switching endocrine treatments at 2 years was superior to continuing the same agent for a total of 5 years (Sequential Treatments Analysis). Selected baseline characteristics for the study population are shown in Table 6.

The primary endpoint of this trial was disease-free survival (DFS) (i.e., interval between randomization and earliest occurrence of a local, regional, or distant recurrence, or invasive contralateral breast cancer, or death from any cause). The secondary endpoints were overall survival (OS), systemic disease-free survival (SDFS), invasive contralateral breast cancer, time to breast cancer recurrence (TBR) and time to distant metastasis (TDM).

The Primary Core Analysis (PCA) included all patients and all follow-up in the monotherapy arms in both randomization options, but follow-up in the two sequential treatments arms was truncated 30 days after switching treatments. The PCA was conducted at a median treatment duration of 24 months and a median follow-up of 26 months. Letrozole tablets were superior to tamoxifen in all endpoints except overall survival and contralateral breast cancer [e.g., DFS: hazard ratio, HR 0.79; 95% CI (0.68, 0.92); P=0.002; SDFS: HR 0.83; 95% CI (0.70, 0.97); TDM: HR 0.73; 95% CI (0.60, 0.88); OS: HR 0.86; 95% CI (0.70, 1.06)].

In 2005, based on recommendations by the independent Data Monitoring Committee, the tamoxifen arms were unblinded and patients were allowed to complete initial adjuvant therapy with letrozole tablets (if they had received tamoxifen for at least 2 years) or to start extended adjuvant treatment with letrozole tablets (if they had received tamoxifen for at least 4.5 years) if they remained alive and disease-free. In total, 632 patients crossed to letrozole tablets or another aromatase inhibitor. Approximately 70% (448) of these 632 patients crossed to letrozole tablets to complete initial adjuvant therapy and most of these crossed in years 3 to 4. All of these patients were in Option 1. A total of 184 patients started extended adjuvant therapy with letrozole tablets (172 patients) or with another aromatase inhibitor (12 patients). To explore the impact of this selective crossover, results from analyses censoring follow-up at the date of the selective crossover (in the tamoxifen arm) are presented for the MAA.

The PCA allowed the results of letrozole tablets for 5 years compared with tamoxifen for 5 years to be reported in 2005 after a median follow-up of only 26 months. The design of the PCA is not optimal to evaluate the effect of letrozole tablets after a longer time (because follow-up was truncated in two arms at around 25 months). The MAA (ignoring the two sequential treatment arms) provided follow-up equally as long in each treatment and did not over-emphasize early recurrences as the PCA did. The MAA thus provides the clinically appropriate updated efficacy results in answer to the first primary question, despite the confounding of the tamoxifen reference arm by the selective crossover to letrozole tablets. The updated results for the MAA are summarized in Table 7. Median follow-up for this analysis is 73 months.

The Sequential Treatments Analysis (STA) addresses the second primary question of the study. The primary analysis for the STA was from switch (or equivalent time-point in monotherapy arms) + 30 days (STA-S) with a two-sided test applied to each pair-wise comparison at the 2.5% level. Additional analyses were conducted from randomization (STA-R) but these comparisons (added in light of changing medical practice) were under-powered for efficacy.

Table 6: Adjuvant Study - Patient and Disease Characteristics (ITT Population)

Primary Core Analysis(PCA) Monotherapy Arms Analysis(MAA)

Characteristic Letrozole tabletsN=4003n (%) TamoxifenN=4007n (%) Letrozole tabletsN=2463n (%) TamoxifenN=2459n (%)

Age (median, years) 61 61 61 61

Age range (years) 38-89 39-90 38-88 39-90

Hormone receptor status (%)

  ER+ and/or PgR+ 99.7 99.7 99.7 99.7

  Both unknown 0.3 0.3 0.3 0.3

Nodal status (%)

  Node negative 52 52 50 52

  Node positive 41 41 43 41

  Nodal status unknown 7 7 7 7

Prior adjuvant chemotherapy (%) 24 24 24 24

Table 7: Updated Adjuvant Study Results - Monotherapy Arms Analysis (Median Follow-up 73 Months)

Letrozole tabletsN=2463 TamoxifenN=2459 Hazard ratio

Events(%) 5-year rate Events(%) 5-year rate (95% CI) P

ITT analysis ignores selective crossover in tamoxifen arms.

Censored analysis censors follow-up at the date of selective crossover in 632 patients who crossed to letrozole tablets or another aromatase inhibitor after the tamoxifen arms were unblinded in 2005.

Definition of:

Disease-free survivalDisease-free survival: Interval from randomization to earliest event of invasive loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, or death without a prior event. ITT 445 (18.1) 87.4 500 (20.3) 84.7 0.87 (0.76, 0.99) 0.03

Censor 445 87.4 483 84.2 0.84 (0.73, 0.95)

  0 positive nodes ITT 165 92.2 189 90.3 0.88 (0.72, 1.09)

  1-3 positive nodes ITT 151 85.6 163 83.0 0.85 (0.68, 1.06)

  >=4 positive nodes ITT 123 71.2 142 62.6 0.81 (0.64, 1.03)

  Adjuvant chemotherapy ITT 119 86.4 150 80.6 0.77 (0.60, 0.98)

  No chemotherapy ITT 326 87.8 350 86.1 0.91 (0.78, 1.06)

Systemic DFSSystemic disease-free survival: Interval from randomization to invasive regional recurrence, distant metastasis, or death without a prior cancer event. ITT 401 88.5 446 86.6 0.88 (0.77, 1.01)

Time to distant metastasisTime to distant metastasis: Interval from randomization to distant metastasis. ITT 257 92.4 298 90.1 0.85 (0.72, 1.00)

  Adjuvant chemotherapy ITT 84 - 109 - 0.75 (0.56, 1.00)

  No chemotherapy ITT 173 - 189 - 0.90 (0.73, 1.11)

Distant DFSDistant disease-free survival: Interval from randomization to earlier event of relapse in a distant site or death from any cause ITT 385 89.0 432 87.1 0.87 (0.76, 1.00)

Contralateral breast cancer ITT 34 99.2 44 98.6 0.76 (0.49, 1.19)

Overall survival ITT 303 91.8 343 90.9 0.87 (0.75, 1.02)

Censor 303 91.8 338 90.1 0.82 (0.70, 0.96)

  0 positive nodes ITT 107 95.2 121 94.8 0.90 (0.69, 1.16)

  1-3 positive nodes ITT 99 90.8 114 90.6 0.81 (0.62, 1.06)

  >=4 positive nodes ITT 92 80.2 104 73.6 0.86 (0.65, 1.14)

  Adjuvant chemotherapy ITT 76 91.5 96 88.4 0.79 (0.58, 1.06)

  No chemotherapy ITT 227 91.9 247 91.8 0.91 (0.76, 1.08)

Figure 1 shows the Kaplan-Meier curves for Disease-Free Survival Monotherapy Analysis

Figure 1 Disease-Free Survival (Median follow-up 73 months, ITT Approach)

DFS events defined as loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, or death from any cause (i.e., definition excludes second non-breast primary cancers).

The medians of overall survival for both arms were not reached for the MAA. There was no statistically significant difference in overall survival. The hazard ratio for survival in the letrozole tablets arm compared to the tamoxifen arm was 0.87, with 95% CI (0.75, 1.02) (see Table 7).

There were no significant differences in DFS, OS, SDFS, and Distant DFS from switch in the Sequential Treatments Analysis with respect to either monotherapy (e.g., [Tamoxifen 2 years followed by] letrozole tablets 3 years versus tamoxifen beyond 2 years, DFS HR 0.89; 97.5% CI 0.68, 1.15 and [letrozole tablets 2 years followed by] tamoxifen 3 years versus letrozole tablets beyond 2 years, DFS HR 0.93; 97.5% CI 0.71, 1.22).

There were no significant differences in DFS, OS, SDFS, and Distant DFS from randomization in the Sequential Treatments Analyses.

14.2 Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 24 Months

A double-blind, randomized, placebo-controlled trial (MA-17, NCT00003140) of letrozole tablets was performed in over 5,100 postmenopausal women with receptor-positive or unknown primary breast cancer who were disease free after 5 years of adjuvant treatment with tamoxifen.

The planned duration of treatment for patients in the study was 5 years, but the trial was terminated early because of an interim analysis showing a favorable letrozole tablets effect on time without recurrence or contralateral breast cancer. At the time of unblinding, women had been followed for a median of 28 months, 30% of patients had completed 3 or more years of follow-up and less than 1% of patients had completed 5 years of follow-up.

Selected baseline characteristics for the study population are shown in Table 8.

Table 8: Selected Study Population Demographics (Modified ITT Population)

Baseline Status Letrozole tabletsN=2582 PlaceboN=2586

Hormone Receptor Status (%)

  ER+ and/or PgR+ 98 98

  Both Unknown 2 2

Nodal Status (%)

  Node Negative 50 50

  Node Positive 46 46

  Nodal Status Unknown 4 4

Chemotherapy 46 46

Table 9 shows the study results. Disease-free survival was measured as the time from randomization to the earliest event of loco-regional or distant recurrence of the primary disease or development of contralateral breast cancer or death. DFS by hormone receptor status, nodal status and adjuvant chemotherapy were similar to the overall results. Data were premature for an analysis of survival.

Table 9: Extended Adjuvant Study Results

Letrozole tabletsN = 2582 PlaceboN = 2586 Hazard Ratio(95% CI) P-Value

CI = confidence interval for hazard ratio. Hazard ratio of less than 1.0 indicates difference in favor of letrozole tablets (lesser risk of recurrence); hazard ratio greater than 1.0 indicates difference in favor of placebo (higher risk of recurrence with letrozole tablets).

P-value based on stratified log-rank test.

Disease Free Survival (DFS)First event of loco-regional recurrence, distant relapse, contralateral breast cancer or death from any cause. Events 122 (4.7%) 193 (7.5%) 0.62 (0.49, 0.78)Analysis stratified by receptor status, nodal status and prior adjuvant chemotherapy (stratification factors as at randomization). 0.00003

  Local Breast Recurrence 9 22

  Local Chest Wall Recurrence 2 8

  Regional Recurrence 7 4

  Distant Recurrence 55 92 0.61 (0.44 - 0.84) 0.003

  Contralateral Breast Cancer 19 29

  Deaths Without Recurrence or Contralateral Breast Cancer 30 38

14.3 Updated Analyses of Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 60 Months

Table 10: Update of Extended Adjuvant Study Results

Letrozole tabletsN = 2582(%) PlaceboN = 2586(%) Hazard RatioAdjusted by receptor status, nodal status and prior chemotherapy (95% CI) P-ValueStratified log-rank test, stratified by receptor status, nodal status and prior chemotherapy

Disease Free Survival (DFS) eventsDFS events defined as earliest of loco-regional recurrence, distant metastasis, contralateral breast cancer or death from any cause, and ignoring switches to letrozole tablets in 60% of the placebo arm. 344 (13.3) 402 (15.5) 0.89 (0.77, 1.03) 0.12

Breast cancer recurrence (Protocol definition of DFS eventsProtocol definition does not include deaths from any cause) 209 286 0.75 (0.63, 0.89) 0.001

  Local Breast Recurrence 15 44

  Local Chest Wall Recurrence 6 14

  Regional Recurrence 10 8

  Distant Recurrence 140 167

  Distant Recurrence  (first or subsequent events) 142 169 0.88 (0.70, 1.10) 0.246

  Contralateral Breast Cancer 37 53

  Deaths Without Recurrence or Contralateral Breast Cancer 135 116

Updated analyses were conducted at a median follow-up of 62 months. In the letrozole tablets arm, 71% of the patients were treated for at least 3 years and 58% of patients completed at least 4.5 years of extended adjuvant treatment. After the unblinding of the study at a median follow-up of 28 months, approximately 60% of the selected patients in the placebo arm opted to switch to letrozole tablets.

In this updated analysis shown in Table 10, letrozole tablets significantly reduced the risk of breast cancer recurrence or contralateral breast cancer compared with placebo (HR 0.75; 95% CI 0.63, 0.89; P=0.001). However, in the updated DFS analysis (interval between randomization and earliest event of loco-regional recurrence, distant metastasis, contralateral breast cancer, or death from any cause) the treatment difference was heavily diluted by 60% of the patients in the placebo arm switching to letrozole tablets and accounting for 64% of the total placebo patient-years of follow-up. Ignoring these switches, the risk of DFS event was reduced by a non-significant 11% (HR 0.89; 95% CI 0.77, 1.03). There was no significant difference in distant disease-free survival or overall survival.

14.4 First-Line Treatment of Advanced Breast Cancer

A randomized, double-blind, multinational trial (P025) compared letrozole tablets 2.5 mg with tamoxifen 20 mg in 916 postmenopausal patients with locally advanced (Stage IIIB or loco-regional recurrence not amenable to treatment with surgery or radiation) or metastatic breast cancer. Time to progression (TTP) was the primary endpoint of the trial. Selected baseline characteristics for this study are shown in Table 11.

Table 11: Selected Study Population Demographics

Baseline Status Letrozole tabletsN=458 TamoxifenN=458

Stage of Disease

  IIIB 6% 7%

  IV 93% 92%

Receptor Status

  ER and PgR Positive 38% 41%

  ER or PgR Positive 26% 26%

  Both Unknown 34% 33%

  ER^- or PgR^-/Other Unknown <1% 0

Previous Antiestrogen Therapy

  Adjuvant 19% 18%

  None 81% 82%

Dominant Site of Disease

  Soft Tissue 25% 25%

  Bone 32% 29%

  Viscera 43% 46%

Letrozole tablets were superior to tamoxifen in TTP and rate of objective tumor response (see Table 12). Table 12 summarizes the results of the trial, with a total median follow-up of approximately 32 months. (All analyses are unadjusted and use 2-sided P-values.)

Table 12: Results of First-Line Treatment of Advanced Breast Cancer

Letrozole tablets2.5 mgN=453 Tamoxifen20 mgN=454 Hazard or OddsRatio (95% CI) P-Value (2-Sided)

Median Time to Progression 9.4 months 6.0 months 0.72 (0.62, 0.83)Hazard ratio P<0.0001

Objective Response Rate

  (CR + PR) 145 (32%) 95 (21%) 1.77 (1.31, 2.39)Odds ratio P=0.0002

  (CR) 42 (9%) 15 (3%) 2.99 (1.63, 5.47) P=0.0004

Duration of Objective Response

  Median 18 months(N=145) 16 months(N=95)

Overall Survival 35 months(N=458) 32 months(N=458) P=0.5136Overall log-rank test

Figure 2 shows the Kaplan-Meier curves for TTP.

Figure 2 Kaplan-Meier Estimates of Time to Progression (Study P025)

Table 13 shows results in the subgroup of women who had received prior antiestrogen adjuvant therapy, Table 14, results by disease site and Table 15, the results by receptor status.

Table 13: Efficacy in Patients Who Received Prior Antiestrogen Therapy

Variable Letrozole tablets2.5 mgN=84 Tamoxifen20 mgN=83

Median Time to Progression (95% CI) 8.9 months (6.2, 12.5) 5.9 months (3.2, 6.2)

  Hazard Ratio for TTP (95% CI) 0.60 (0.43, 0.84)

Objective Response Rate

  (CR + PR) 22 (26%) 7 (8%)

  Odds Ratio for Response (95% CI) 3.85 (1.50, 9.60)

Hazard ratio less than 1 or odds ratio greater than 1 favors letrozole tablets; hazard ratio greater than 1 or odds ratio less than 1 favors tamoxifen.

Table 14: Efficacy by Disease Site

Letrozole tablets2.5 mg Tamoxifen20 mg

Dominant Disease Site

Soft Tissue: N=113 N=115

  Median TTP 12.1 months 6.4 months

  Objective Response Rate 50% 34%

Bone: N=145 N=131

  Median TTP 9.5 months 6.3 months

  Objective Response Rate 23% 15%

Viscera: N=195 N=208

  Median TTP 8.3 months 4.6 months

  Objective Response Rate 28% 17%

Table 15: Efficacy by Receptor Status

Variable Letrozole tablets2.5 mg Tamoxifen20 mg

Receptor Positive N=294 N=305

  Median Time to Progression (95% CI) 9.4 months (8.9, 11.8) 6.0 months (5.1, 8.5)

  Hazard Ratio for TTP (95% CI) 0.69 (0.58, 0.83)

  Objective Response Rate (CR+PR) 97 (33%) 66 (22%)

  Odds Ratio for Response (95% CI) 1.78 (1.20, 2.60)

Receptor Unknown N=159 N=149

  Median Time to Progression (95% CI) 9.2 months (6.1, 12.3) 6.0 months (4.1, 6.4)

  Hazard Ratio for TTP (95% CI) 0.77 (0.60, 0.99)

  Objective Response Rate (CR+PR) 48 (30%) 29 (20%)

  Odds Ratio for Response (95% CI) 1.79 (1.10, 3.00)

Hazard ratio less than 1 or odds ratio greater than 1 favors letrozole tablets; hazard ratio greater than 1 or odds ratio less than 1 favors tamoxifen.

Figure 3 shows the Kaplan-Meier curves for survival.

Figure 3 Survival by Randomized Treatment Arm

Legend: Randomized letrozole tablets: n=458, events 57%, median overall survival 35 months (95% CI 32 to 38 months)

Randomized tamoxifen: n=458, events 57%, median overall survival 32 months (95% CI 28 to 37 months)

Overall log-rank P=0.5136 (i.e., there was no significant difference between treatment arms in overall survival). The median overall survival was 35 months for the letrozole tablets group and 32 months for the tamoxifen group, with a P-value 0.5136. Study design allowed patients to cross over upon progression to the other therapy. Approximately 50% of patients crossed over to the opposite treatment arm and almost all patients who crossed over had done so by 36 months. The median time to crossover was 17 months (letrozole tablets to tamoxifen) and 13 months (tamoxifen to letrozole tablets). In patients who did not cross over to the opposite treatment arm, median survival was 35 months with letrozole tablets (n=219, 95% CI 29 to 43 months) vs 20 months with tamoxifen (n=229, 95% CI 16 to 26 months).

14.5 Second-Line Treatment of Advanced Breast Cancer

Letrozole tablets were initially studied at doses of 0.1 mg to 5.0 mg daily in six non-comparative trials (AR/BC1, P01, AR/ST1, AR/PS1, AR/ES1 and NJO-03) in 181 postmenopausal estrogen/progesterone receptor positive or unknown advanced breast cancer patients previously treated with at least antiestrogen therapy. Patients had received other hormonal therapies and also may have received cytotoxic therapy. Eight (20%) of forty patients treated with letrozole tablets 2.5 mg daily in trials achieved an objective tumor response (complete or partial response).

Two large randomized, controlled, multinational (predominantly European) trials (AR/BC2, AR/BC3) were conducted in patients with advanced breast cancer who had progressed despite antiestrogen therapy. Patients were randomized to letrozole tablets 0.5 mg daily, letrozole tablets 2.5 mg daily, or a comparator [megestrol acetate 160 mg daily in one study (AR/BC2); and aminoglutethimide 250 mg twice a day with corticosteroid supplementation in the other study (AR/BC3)]. In each study over 60% of the patients had received therapeutic antiestrogens, and about one-fifth of these patients had had an objective response. The megestrol acetate controlled study was double-blind; the other study was open label. Selected baseline characteristics for each study are shown in Table 16.

Table 16: Selected Study Population Demographics

Parameter megestrol acetate study aminoglutethimide study

No. of Participants 552 557

Receptor Status

  ER/PR Positive 57% 56%

  ER/PR Unknown 43% 44%

Previous Therapy

  Adjuvant Only 33% 38%

  Therapeutic +/- Adj. 66% 62%

Sites of Disease

  Soft Tissue 56% 50%

  Bone 50% 55%

  Viscera 40% 44%

Confirmed objective tumor response (complete response plus partial response) was the primary endpoint of the trials. Responses were measured according to the Union Internationale Contre le Cancer (UICC) criteria and verified by independent, blinded review. All responses were confirmed by a second evaluation 4 to 12 weeks after the documentation of the initial response.

Table 17 shows the results for the first trial (AR/BC2), with a minimum follow-up of 15 months, that compared letrozole tablets 0.5 mg, letrozole tablets 2.5 mg, and megestrol acetate 160 mg daily. (All analyses are unadjusted.)

Table 17: Megestrol Acetate Study Results

Letrozole tablets0.5 mgN=188 Letrozole tablets2.5 mgN=174 megestrol acetateN=190

Objective Response (CR + PR) 22 (11.7%) 41 (23.6%) 31 (16.3%)

Median Duration of Response 552 days (Not reached) 561 days

Median Time to Progression 154 days 170 days 168 days

Median Survival 633 days 730 days 659 days

Odds Ratio for Response Letrozole tablets 2.5: Letrozole tablets 0.5=2.33(95% CI: 1.32, 4.17); P=0.004Two-sided P-value Letrozole tablets 2.5: megestrol=1.58(95% CI: 0.94, 2.66); P=0.08

Relative Risk of Progression Letrozole tablets 2.5: Letrozole tablets 0.5=0.81(95% CI: 0.63, 1.03); P=0.09 Letrozole tablets 2.5: megestrol=0.77(95% CI: 0.60, 0.98); P=0.03

The Kaplan-Meier curves for progression for the megestrol acetate study are shown in Figure 4.

Figure 4 Kaplan-Meier Estimates of Time to Progression (Megestrol Acetate Study)

The results for the study comparing letrozole tablets to aminoglutethimide (AR/BC3), with a minimum follow-up of 9 months, are shown in Table 18. (Unadjusted analyses are used.)

Table 18: Aminoglutethimide Study Results

Letrozole tablets0.5 mgN=193 Letrozole tablets2.5 mgN=185 aminoglutethimideN=179

Objective Response (CR + PR) 34 (17.6%) 34 (18.4%) 22 (12.3%)

Median Duration of Response 619 days 706 days 450 days

Median Time to Progression 103 days 123 days 112 days

Median Survival 636 days 792 days 592 days

Odds Ratio for Response Letrozole tablets 2.5: Letrozole tablets 0.5=1.05(95% CI: 0.62, 1.79); P=0.85Two-sided P-value Letrozole tablets 2.5: aminoglutethimide=1.61(95% CI: 0.90, 2.87); P=0.11

Relative Risk of Progression Letrozole tablets 2.5: Letrozole tablets 0.5=0.86(95% CI: 0.68, 1.11); P=0.25 Letrozole tablets 2.5: aminoglutethimide=0.74(95% CI: 0.57, 0.94); P=0.02

The Kaplan-Meier curves for progression for the aminoglutethimide study is shown in Figure 5

Figure 5 Kaplan-Meier Estimates of Time to Progression (Aminoglutethimide Study)

16 How Supplied/storage And Handling

Packaged in HDPE bottles with a child resistant closure (30 tablets & 90 tablets) and continuous thread closure (1000 tablets).

2.5 milligram tablets

  Bottles of 30 tablets NDC 51991-759-33

  Bottle of 90 tablets NDC 51991-759-90

  Bottles of 1000 tablets NDC 51991-759-10

STORAGE AND HANDLING SECTION

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

17 Patient Counseling Information

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during letrozole tablets therapy and for at least 3 weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with letrozole tablets [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1, 8.3)].

Lactation

Advise women not to breastfeed during letrozole tablets treatment and for at least 3 weeks after the last dose [see Use in Specific Populations (8.2)].

Infertility

Advise females and males of reproductive potential of the potential for reduced fertility from letrozole tablets [see Use in Specific Populations (8.3)].

Fatigue and Dizziness

Since fatigue and dizziness have been observed with the use of letrozole tablets and somnolence was uncommonly reported, caution is advised when driving or using machinery.

Bone Effects

Consideration should be given to monitoring bone mineral density.

Distributed by: Breckenridge Pharmaceutical, Inc. Berkeley Heights, NJ 07922

Manufactured by: Natco Pharma Limited. Visakhapatnam - 531019 AP, India.

xxxxxxxx

Principal Display Panel - 2.5 Mg Tablet Bottle Label

NDC 51991-759-90

Letrozole Tablets, USP

2.5 mg

Rx Only 90 Tablets

breckenridge A Towa Company

Table 6: Adjuvant Study - Patient and Disease Characteristics (ITT Population)
	Primary Core Analysis(PCA)	Monotherapy Arms Analysis(MAA)
Age (median, years)	61	61	61	61
Age range (years)	38-89	39-90	38-88	39-90
Hormone receptor status (%)
ER+ and/or PgR+	99.7	99.7	99.7	99.7
Both unknown	0.3	0.3	0.3	0.3
Nodal status (%)
Node negative	52	52	50	52
Node positive	41	41	43	41
Nodal status unknown	7	7	7	7
Prior adjuvant chemotherapy (%)	24	24	24	24

Table 7: Updated Adjuvant Study Results - Monotherapy Arms Analysis (Median Follow-up 73 Months)
		Letrozole tabletsN=2463	TamoxifenN=2459	Hazard ratio
ITT analysis ignores selective crossover in tamoxifen arms.
Censored analysis censors follow-up at the date of selective crossover in 632 patients who crossed to letrozole tablets or another aromatase inhibitor after the tamoxifen arms were unblinded in 2005.
Definition of:
Disease-free survivalDisease-free survival: Interval from randomization to earliest event of invasive loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, or death without a prior event.	ITT	445 (18.1)	87.4	500 (20.3)	84.7	0.87 (0.76, 0.99)	0.03
	Censor	445	87.4	483	84.2	0.84 (0.73, 0.95)
0 positive nodes	ITT	165	92.2	189	90.3	0.88 (0.72, 1.09)
1-3 positive nodes	ITT	151	85.6	163	83.0	0.85 (0.68, 1.06)
>=4 positive nodes	ITT	123	71.2	142	62.6	0.81 (0.64, 1.03)
Adjuvant chemotherapy	ITT	119	86.4	150	80.6	0.77 (0.60, 0.98)
No chemotherapy	ITT	326	87.8	350	86.1	0.91 (0.78, 1.06)
Systemic DFSSystemic disease-free survival: Interval from randomization to invasive regional recurrence, distant metastasis, or death without a prior cancer event.	ITT	401	88.5	446	86.6	0.88 (0.77, 1.01)
Time to distant metastasisTime to distant metastasis: Interval from randomization to distant metastasis.	ITT	257	92.4	298	90.1	0.85 (0.72, 1.00)
Adjuvant chemotherapy	ITT	84	-	109	-	0.75 (0.56, 1.00)
No chemotherapy	ITT	173	-	189	-	0.90 (0.73, 1.11)
Distant DFSDistant disease-free survival: Interval from randomization to earlier event of relapse in a distant site or death from any cause	ITT	385	89.0	432	87.1	0.87 (0.76, 1.00)
Contralateral breast cancer	ITT	34	99.2	44	98.6	0.76 (0.49, 1.19)
Overall survival	ITT	303	91.8	343	90.9	0.87 (0.75, 1.02)
	Censor	303	91.8	338	90.1	0.82 (0.70, 0.96)
0 positive nodes	ITT	107	95.2	121	94.8	0.90 (0.69, 1.16)
1-3 positive nodes	ITT	99	90.8	114	90.6	0.81 (0.62, 1.06)
>=4 positive nodes	ITT	92	80.2	104	73.6	0.86 (0.65, 1.14)
Adjuvant chemotherapy	ITT	76	91.5	96	88.4	0.79 (0.58, 1.06)
No chemotherapy	ITT	227	91.9	247	91.8	0.91 (0.76, 1.08)

Table 8: Selected Study Population Demographics (Modified ITT Population)
Baseline Status	Letrozole tabletsN=2582	PlaceboN=2586
Hormone Receptor Status (%)
ER+ and/or PgR+	98	98
Both Unknown	2	2
Nodal Status (%)
Node Negative	50	50
Node Positive	46	46
Nodal Status Unknown	4	4
Chemotherapy	46	46

Table 9: Extended Adjuvant Study Results
	Letrozole tabletsN = 2582	PlaceboN = 2586	Hazard Ratio(95% CI)	P-Value
CI = confidence interval for hazard ratio. Hazard ratio of less than 1.0 indicates difference in favor of letrozole tablets (lesser risk of recurrence); hazard ratio greater than 1.0 indicates difference in favor of placebo (higher risk of recurrence with letrozole tablets).
P-value based on stratified log-rank test.
Disease Free Survival (DFS)First event of loco-regional recurrence, distant relapse, contralateral breast cancer or death from any cause. Events	122 (4.7%)	193 (7.5%)	0.62 (0.49, 0.78)Analysis stratified by receptor status, nodal status and prior adjuvant chemotherapy (stratification factors as at randomization).	0.00003
Local Breast Recurrence	9	22
Local Chest Wall Recurrence	2	8
Regional Recurrence	7	4
Distant Recurrence	55	92	0.61 (0.44 - 0.84)	0.003
Contralateral Breast Cancer	19	29
Deaths Without Recurrence or Contralateral Breast Cancer	30	38

Table 10: Update of Extended Adjuvant Study Results
	Letrozole tabletsN = 2582(%)	PlaceboN = 2586(%)	Hazard RatioAdjusted by receptor status, nodal status and prior chemotherapy (95% CI)	P-ValueStratified log-rank test, stratified by receptor status, nodal status and prior chemotherapy
Disease Free Survival (DFS) eventsDFS events defined as earliest of loco-regional recurrence, distant metastasis, contralateral breast cancer or death from any cause, and ignoring switches to letrozole tablets in 60% of the placebo arm.	344 (13.3)	402 (15.5)	0.89 (0.77, 1.03)	0.12
Breast cancer recurrence (Protocol definition of DFS eventsProtocol definition does not include deaths from any cause)	209	286	0.75 (0.63, 0.89)	0.001
Local Breast Recurrence	15	44
Local Chest Wall Recurrence	6	14
Regional Recurrence	10	8
Distant Recurrence	140	167
Distant Recurrence (first or subsequent events)	142	169	0.88 (0.70, 1.10)	0.246
Contralateral Breast Cancer	37	53
Deaths Without Recurrence or Contralateral Breast Cancer	135	116

Table 11: Selected Study Population Demographics
Baseline Status	Letrozole tabletsN=458	TamoxifenN=458
Stage of Disease
IIIB	6%	7%
IV	93%	92%
Receptor Status
ER and PgR Positive	38%	41%
ER or PgR Positive	26%	26%
Both Unknown	34%	33%
ER^- or PgR^-/Other Unknown	<1%	0
Previous Antiestrogen Therapy
Adjuvant	19%	18%
None	81%	82%
Dominant Site of Disease
Soft Tissue	25%	25%
Bone	32%	29%
Viscera	43%	46%

Table 12: Results of First-Line Treatment of Advanced Breast Cancer
	Letrozole tablets2.5 mgN=453	Tamoxifen20 mgN=454	Hazard or OddsRatio (95% CI) P-Value (2-Sided)
Median Time to Progression	9.4 months	6.0 months	0.72 (0.62, 0.83)Hazard ratio P<0.0001
Objective Response Rate
(CR + PR)	145 (32%)	95 (21%)	1.77 (1.31, 2.39)Odds ratio P=0.0002
(CR)	42 (9%)	15 (3%)	2.99 (1.63, 5.47) P=0.0004
Duration of Objective Response
Median	18 months(N=145)	16 months(N=95)
Overall Survival	35 months(N=458)	32 months(N=458)	P=0.5136Overall log-rank test

Table 13: Efficacy in Patients Who Received Prior Antiestrogen Therapy
Variable	Letrozole tablets2.5 mgN=84	Tamoxifen20 mgN=83
Median Time to Progression (95% CI)	8.9 months (6.2, 12.5)	5.9 months (3.2, 6.2)
Hazard Ratio for TTP (95% CI)	0.60 (0.43, 0.84)
Objective Response Rate
(CR + PR)	22 (26%)	7 (8%)
Odds Ratio for Response (95% CI)	3.85 (1.50, 9.60)

Table 14: Efficacy by Disease Site
	Letrozole tablets2.5 mg	Tamoxifen20 mg
Dominant Disease Site
Soft Tissue:	N=113	N=115
Median TTP	12.1 months	6.4 months
Objective Response Rate	50%	34%
Bone:	N=145	N=131
Median TTP	9.5 months	6.3 months
Objective Response Rate	23%	15%
Viscera:	N=195	N=208
Median TTP	8.3 months	4.6 months
Objective Response Rate	28%	17%

Table 15: Efficacy by Receptor Status
Variable	Letrozole tablets2.5 mg	Tamoxifen20 mg
Receptor Positive	N=294	N=305
Median Time to Progression (95% CI)	9.4 months (8.9, 11.8)	6.0 months (5.1, 8.5)
Hazard Ratio for TTP (95% CI)	0.69 (0.58, 0.83)
Objective Response Rate (CR+PR)	97 (33%)	66 (22%)
Odds Ratio for Response (95% CI)	1.78 (1.20, 2.60)
Receptor Unknown	N=159	N=149
Median Time to Progression (95% CI)	9.2 months (6.1, 12.3)	6.0 months (4.1, 6.4)
Hazard Ratio for TTP (95% CI)	0.77 (0.60, 0.99)
Objective Response Rate (CR+PR)	48 (30%)	29 (20%)
Odds Ratio for Response (95% CI)	1.79 (1.10, 3.00)

Table 16: Selected Study Population Demographics
Parameter	megestrol acetate study	aminoglutethimide study
No. of Participants	552	557
Receptor Status
ER/PR Positive	57%	56%
ER/PR Unknown	43%	44%
Previous Therapy
Adjuvant Only	33%	38%
Therapeutic +/- Adj.	66%	62%
Sites of Disease
Soft Tissue	56%	50%
Bone	50%	55%
Viscera	40%	44%

Table 17: Megestrol Acetate Study Results
	Letrozole tablets0.5 mgN=188	Letrozole tablets2.5 mgN=174	megestrol acetateN=190
Objective Response (CR + PR)	22 (11.7%)	41 (23.6%)	31 (16.3%)
Median Duration of Response	552 days	(Not reached)	561 days
Median Time to Progression	154 days	170 days	168 days
Median Survival	633 days	730 days	659 days
Odds Ratio for Response	Letrozole tablets 2.5: Letrozole tablets 0.5=2.33(95% CI: 1.32, 4.17); P=0.004Two-sided P-value	Letrozole tablets 2.5: megestrol=1.58(95% CI: 0.94, 2.66); P=0.08
Relative Risk of Progression	Letrozole tablets 2.5: Letrozole tablets 0.5=0.81(95% CI: 0.63, 1.03); P=0.09	Letrozole tablets 2.5: megestrol=0.77(95% CI: 0.60, 0.98); P=0.03

Table 18: Aminoglutethimide Study Results
	Letrozole tablets0.5 mgN=193	Letrozole tablets2.5 mgN=185	aminoglutethimideN=179
Objective Response (CR + PR)	34 (17.6%)	34 (18.4%)	22 (12.3%)
Median Duration of Response	619 days	706 days	450 days
Median Time to Progression	103 days	123 days	112 days
Median Survival	636 days	792 days	592 days
Odds Ratio for Response	Letrozole tablets 2.5: Letrozole tablets 0.5=1.05(95% CI: 0.62, 1.79); P=0.85Two-sided P-value	Letrozole tablets 2.5: aminoglutethimide=1.61(95% CI: 0.90, 2.87); P=0.11
Relative Risk of Progression	Letrozole tablets 2.5: Letrozole tablets 0.5=0.86(95% CI: 0.68, 1.11); P=0.25	Letrozole tablets 2.5: aminoglutethimide=0.74(95% CI: 0.57, 0.94); P=0.02

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Adverse Reactions	Grades 1-4				Grades 3-4
	Letrozole tabletsN=2448n (%)		TamoxifenN=2447n (%)		Letrozole tabletsN=2448n (%)		TamoxifenN=2447n (%)
TIA = Transient ischemic attackNote: Cardiovascular events (including cerebrovascular and thromboembolic events), skeletal and urogenital/endometrial events and second primary malignancies were collected life -long. All of these events were assumed to be of CTC Grade 3 to 5 and were not individually graded
Patients with any adverse reaction	2309	(94.3)	2212	(90.4)	636	(26.0)	606	(24.8)
HypercholesterolemiaTarget events pre-specified for analysis	1280	(52.3)	700	(28.6)	11	(0.4)	6	(0.2)
Hot flashes	819	(33.5)	929	(38.0)	-	-	-	-
Arthralgia/arthritis	621	(25.4)	504	(20.6)	84	(3.4)	50	(2.0)
Bone fracturesAt median follow-up of 96 months (i.e. any time after randomization) for letrozole tablets (range up to 144 months) and 95 months for tamoxifen (range up to 143 months )	361	(14.7)	280	(11.4)	-	-	-	-
Night sweats	356	(14.5)	426	(17.4)	-	-	-	-
Weight increase	317	(12.9)	378	(15.4)	27	(1.1)	39	(1.6)
Nausea	284	(11.6)	277	(11.3)	6	(0.2)	9	(0.4)
Bone fracturesEvents pre-printed on CRF At median treatment duration of 60 months (i.e. during treatment + 30 days after discontinuation of treatment) for letrozole tablets and tamoxifen (range up to 68 months)	249	(10.2)	175	(7.2)	-	-	-	-
Fatigue (lethargy, malaise, asthenia)	235	(9.6)	250	(10.2)	6	(0.2)	7	(0.3)
Myalgia	221	(9.0)	212	(8.7)	18	(0.7)	14	(0.6)
Vaginal bleeding	129	(5.3)	320	(13.1)	1	(<0.1)	8	(0.3)
Edema	164	(6.7)	160	(6.5)	3	(0.1)	1	(<0.1)
Weight decrease	140	(5.7)	129	(5.3)	8	(0.3)	5	(0.2)
Osteoporosis	126	(5.1)	67	(2.7)	10	(0.4)	5	(0.2)
Back pain	125	(5.1)	136	(5.6)	7	(0.3)	11	(0.4)
Bone pain	123	(5.0)	109	(4.5)	6	(0.2)	4	(0.2)
Depression	119	(4.9)	114	(4.7)	16	(0.7)	14	(0.6)
Vaginal irritation	112	(4.6)	77	(3.1)	2	(<0.1)	2	(<0.1)
Headache	105	(4.3)	94	(3.8)	8	(0.3)	4	(0.2)
Pain in extremity	103	(4.2)	79	(3.2)	6	(0.2)	4	(0.2)
Osteopenia	87	(3.6)	76	(3.1)	0	-	3	(0.1)
Dizziness/light-headedness	84	(3.4)	80	(3.3)	1	(<0.1)	6	(0.2)
Alopecia	83	(3.4)	84	(3.4)	-	-	-	-
Vomiting	80	(3.3)	80	(3.3)	3	(0.1)	5	(0.2)
Cataract	49	(2.0)	54	(2.2)	16	(0.7)	17	(0.7)
Constipation	49	(2.0)	71	(2.9)	3	(0.1)	1	(<0.1)
Myocardial infarction	42	(1.7)	28	(1.1)	-	-	-	-
Breast pain	37	(1.5)	43	(1.8)	1	(<0.1)	-	-
Anorexia	20	(0.8)	20	(0.8)	1	(<0.1)	1	(<0.1)
Endometrial proliferation disorders	14	(0.6)	86	(3.5)	0	-	14	(0.6)
Ovarian cyst	11	(0.4)	18	(0.7)	4	(0.2)	4	(0.2)
Endometrial hyperplasia/cancer	11	(0.4)	72	(2.9)	-	-	-	-
Endometrial hyperplasia/cancer ^, Excluding women who had undergone hysterectomy before study entry	6/1909	(0.3)	57/1943	(2.9)	-	-	-	-
Other endometrial disorders	2	(<0.1)	3	(0.1)	0	-	0	-
Myocardial infarction	24	(1.0)	12	(0.5)	-	-	-	-
Myocardial ischemia	6	(0.2)	9	(0.4)	-	-	-	-
Cerebrovascular accident/TIA	74	(3.0)	68	(2.8)	-	-	-	-
Cerebrovascular accident/TIA	51	(2.1)	47	(1.9)	-	-	-	-
Angina requiring surgery	35	(1.4)	33	(1.3)	-	-	-	-
Angina requiring surgery	25	(1.0)	25	(1.0)	-	-	-	-
Thromboembolic event	79	(3.2)	113	(4.6)	-	-	-	-
Thromboembolic event	51	(2.1)	89	(3.6)	-	-	-	-
Cardiac failure	39	(1.6)	34	(1.4)	-	-	-	-
Cardiac failure	27	(1.1)	15	(0.6)	-	-	-	-
Hypertension	160	(6.5)	175	(7.2)	-	-	-	-
Hypertension	138	(5.6)	139	(5.7)	-	-	-	-
Other cardiovascular	172	(7.0)	174	(7.1)	-	-	-	-
Other cardiovascular	120	(4.9)	119	(4.9)	-	-	-	-
Second primary malignancy	129	(5.3)	150	(6.1)	-	-	-	-
Second primary malignancy	54	(2.2)	79	(3.2)	-	-	-	-

Adverse Reactions	LetrozoleN = 2049n (%)		AnastrozoleN = 2062n (%)
	Grade 3/4n (%)	All gradesn (%)	Grade 3/4n (%)	All gradesn (%)
Patients with at least one AR	628 (30.6)	2049 (100.0)	591 (28.7)	2062 (100.0)
Arthralgia	80 (3.9)	987 (48.2)	69 (3.3)	987 (47.9)
Hot flush	17 (0.8)	666 (32.5)	9 (0.4)	666 (32.3)
Fatigue	8 (0.4)	345 (16.8)	10 (0.5)	343 (16.6)
Osteoporosis	5 (0.2)	223 (10.9)	11 (0.5)	225 (10.9)
Myalgia	16 (0.8)	233 (11.4)	15 (0.7)	212 (10.3)
Back pain	11 (0.5)	212 (10.3)	17 (0.8)	193 (9.4)
Osteopenia	4 (0.2)	203 (9.9)	1 (0.0)	173 (8.4)
Pain in extremity	9 (0.4)	168 (8.2)	3 (0.1)	174 (8.4)
Lymphoedema	5 (0.2)	159 (7.8)	2 (0.1)	179 (8.7)
Insomnia	7 (0.3)	160 (7.8)	3 (0.1)	149 (7.2)
Hypercholesterolemia	2 (0.1)	155 (7.6)	1 (0.0)	151 (7.3)
Hypertension	25 (1.2)	156 (7.6)	20 (1.0)	149 (7.2)
Depression	16 (0.8)	147 (7.2)	13 (0.6)	137 (6.6)
Bone pain	10 (0.5)	138 (6.7)	9 (0.4)	122 (5.9)
Nausea	6 (0.3)	137 (6.7)	5 (0.2)	152 (7.4)
Headache	3 (0.1)	130 (6.3)	5 (0.2)	168 (8.1)
Alopecia	2 (0.1)	127 (6.2)	0 (0.0)	134 (6.5)
Musculoskeletal pain	6 (0.3)	123 (6.0)	9 (0.4)	147 (7.1)
Radiation skin injury	11 (0.5)	120 (5.9)	6 (0.3)	88 (4.3)
Dyspnea	16 (0.8)	118 (5.8)	10 (0.5)	96 (4.7)
Cough	1 (0.0)	106 (5.2)	1 (0.0)	120 (5.8)
Musculoskeletal stiffness	2 (0.1)	102 (5.0)	2 (0.1)	84 (4.1)
Dizziness	2 (0.2)	94 (4.6)	7 (0.3)	109 (5.3)

	Number (%) of Patients with Grade 1-4 Adverse Reactions		Number (%) of Patients with Grade 3-4 Adverse Reactions
	Letrozole tabletsN=2563	PlaceboN=2573	Letrozole tabletsN=2563	PlaceboN=2573
Any Adverse Reaction	2232 (87.1)	2174 (84.5)	419 (16.3)	389 (15.1)
Vascular Disorders	1375 (53.6)	1230 (47.8)	59 (2.3)	74 (2.9)
Flushing	1273 (49.7)	1114 (43.3)	3 (0.1)	0
General Disorders	1154 (45)	1090 (42.4)	30 (1.2)	28 (1.1)
Asthenia	862 (33.6)	826 (32.1)	16 (0.6)	7 (0.3)
Edema NOS	471 (18.4)	416 (16.2)	4 (0.2)	3 (0.1)
Musculoskeletal Disorders	978 (38.2)	836 (32.5)	71 (2.8)	50 (1.9)
Arthralgia	565 (22)	465 (18.1)	25 (1)	20 (0.8)
Arthritis NOS	173 (6.7)	124 (4.8)	10 (0.4)	5 (0.2)
Myalgia	171 (6.7)	122 (4.7)	8 (0.3)	6 (0.2)
Back Pain	129 (5)	112 (4.4)	8 (0.3)	7 (0.3)
Nervous System Disorders	863 (33.7)	819 (31.8)	65 (2.5)	58 (2.3)
Headache	516 (20.1)	508 (19.7)	18 (0.7)	17 (0.7)
Dizziness	363 (14.2)	342 (13.3)	9 (0.4)	6 (0.2)
Skin Disorders	830 (32.4)	787 (30.6)	17 (0.7)	16 (0.6)
Sweating Increased	619 (24.2)	577 (22.4)	1 (<0.1)	0
Gastrointestinal Disorders	725 (28.3)	731 (28.4)	43 (1.7)	42 (1.6)
Constipation	290 (11.3)	304 (11.8)	6 (0.2)	2 (<0.1)
Nausea	221 (8.6)	212 (8.2)	3 (0.1)	10 (0.4)
Diarrhea NOS	128 (5)	143 (5.6)	12 (0.5)	8 (0.3)
Metabolic Disorders	551 (21.5)	537 (20.9)	24 (0.9)	32 (1.2)
Hypercholesterolemia	401 (15.6)	398 (15.5)	2 (<0.1)	5 (0.2)
Reproductive Disorders	303 (11.8)	357 (13.9)	9 (0.4)	8 (0.3)
Vaginal Hemorrhage	123 (4.8)	171 (6.6)	2 (<0.1)	5 (0.2)
Vulvovaginal Dryness	137 (5.3)	127 (4.9)	0	0
Psychiatric Disorders	320 (12.5)	276 (10.7)	21 (0.8)	16 (0.6)
Insomnia	149 (5.8)	120 (4.7)	2 (<0.1)	2 (<0.1)
Respiratory Disorders	279 (10.9)	260 (10.1)	30 (1.2)	28 (1.1)
Dyspnea	140 (5.5)	137 (5.3)	21 (0.8)	18 (0.7)
Investigations	184 (7.2)	147 (5.7)	13 (0.5)	13 (0.5)
Infections and Infestations	166 (6.5)	163 (6.3)	40 (1.6)	33 (1.3)
Renal Disorders	130 (5.1)	100 (3.9)	12 (0.5)	6 (0.2)

	Primary Core Analysis(PCA)		Monotherapy Arms Analysis(MAA)
Characteristic	Letrozole tabletsN=4003n (%)	TamoxifenN=4007n (%)	Letrozole tabletsN=2463n (%)	TamoxifenN=2459n (%)
Age (median, years)	61	61	61	61
Age range (years)	38-89	39-90	38-88	39-90
Hormone receptor status (%)
ER+ and/or PgR+	99.7	99.7	99.7	99.7
Both unknown	0.3	0.3	0.3	0.3
Nodal status (%)
Node negative	52	52	50	52
Node positive	41	41	43	41
Nodal status unknown	7	7	7	7
Prior adjuvant chemotherapy (%)	24	24	24	24

		Letrozole tabletsN=2463		TamoxifenN=2459		Hazard ratio
		Events(%)	5-year rate	Events(%)	5-year rate	(95% CI)	P
ITT analysis ignores selective crossover in tamoxifen arms.
Censored analysis censors follow-up at the date of selective crossover in 632 patients who crossed to letrozole tablets or another aromatase inhibitor after the tamoxifen arms were unblinded in 2005.
Definition of:
Disease-free survivalDisease-free survival: Interval from randomization to earliest event of invasive loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, or death without a prior event.	ITT	445 (18.1)	87.4	500 (20.3)	84.7	0.87 (0.76, 0.99)	0.03
	Censor	445	87.4	483	84.2	0.84 (0.73, 0.95)
0 positive nodes	ITT	165	92.2	189	90.3	0.88 (0.72, 1.09)
1-3 positive nodes	ITT	151	85.6	163	83.0	0.85 (0.68, 1.06)
>=4 positive nodes	ITT	123	71.2	142	62.6	0.81 (0.64, 1.03)
Adjuvant chemotherapy	ITT	119	86.4	150	80.6	0.77 (0.60, 0.98)
No chemotherapy	ITT	326	87.8	350	86.1	0.91 (0.78, 1.06)
Systemic DFSSystemic disease-free survival: Interval from randomization to invasive regional recurrence, distant metastasis, or death without a prior cancer event.	ITT	401	88.5	446	86.6	0.88 (0.77, 1.01)
Time to distant metastasisTime to distant metastasis: Interval from randomization to distant metastasis.	ITT	257	92.4	298	90.1	0.85 (0.72, 1.00)
Adjuvant chemotherapy	ITT	84	-	109	-	0.75 (0.56, 1.00)
No chemotherapy	ITT	173	-	189	-	0.90 (0.73, 1.11)
Distant DFSDistant disease-free survival: Interval from randomization to earlier event of relapse in a distant site or death from any cause	ITT	385	89.0	432	87.1	0.87 (0.76, 1.00)
Contralateral breast cancer	ITT	34	99.2	44	98.6	0.76 (0.49, 1.19)
Overall survival	ITT	303	91.8	343	90.9	0.87 (0.75, 1.02)
	Censor	303	91.8	338	90.1	0.82 (0.70, 0.96)
0 positive nodes	ITT	107	95.2	121	94.8	0.90 (0.69, 1.16)
1-3 positive nodes	ITT	99	90.8	114	90.6	0.81 (0.62, 1.06)
>=4 positive nodes	ITT	92	80.2	104	73.6	0.86 (0.65, 1.14)
Adjuvant chemotherapy	ITT	76	91.5	96	88.4	0.79 (0.58, 1.06)
No chemotherapy	ITT	227	91.9	247	91.8	0.91 (0.76, 1.08)

	Bottles of 30 tablets	NDC 51991-759-33
	Bottle of 90 tablets	NDC 51991-759-90
	Bottles of 1000 tablets	NDC 51991-759-10

LETROZOLE (letrozole 2.5 mg) Dailymed

Drug Classes

Version History

Generic: letrozole is used for the treatment of Breast Neoplasms Pregnancy

All Imprints

FDA Adverse Reactions

1 Indications And Usage

1.1 Adjuvant Treatment of Early Breast Cancer

1.2 Extended Adjuvant Treatment of Early Breast Cancer

1.3 First and Second-Line Treatment of Advanced Breast Cancer

2 Dosage And Administration

2.1 Recommended Dose

2.2 Use in Adjuvant Treatment of Early Breast Cancer

2.3 Use in Extended Adjuvant Treatment of Early Breast Cancer

2.4 Use in First and Second-Line Treatment of Advanced Breast Cancer

2.5 Use in Hepatic Impairment

2.6 Use in Renal Impairment

3 Dosage Forms And Strengths

4 Contraindications

5 Warnings And Precautions

5.1 Bone Effects

5.2 Cholesterol

5.3 Hepatic Impairment

5.4 Fatigue and Dizziness

5.5 Laboratory Test Abnormalities

5.6 Embryo-Fetal Toxicity

6 Adverse Reactions

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 Drug Interactions

8 Use In Specific Populations

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

10 Overdosage

11 Description

12 Clinical Pharmacology

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 Clinical Studies

14.1 Updated Adjuvant Treatment of Early Breast Cancer

14.2 Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 24 Months

14.3 Updated Analyses of Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 60 Months

14.4 First-Line Treatment of Advanced Breast Cancer

14.5 Second-Line Treatment of Advanced Breast Cancer

16 How Supplied/storage And Handling

STORAGE AND HANDLING SECTION

17 Patient Counseling Information

Principal Display Panel - 2.5 Mg Tablet Bottle Label