Prescription Drug Information: Letrozole

LETROZOLE — letrozole tablet, film coated
Aurobindo Pharma Limited

1 INDICATIONS AND USAGE

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

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 post approval 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 are 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: dark yellow, film-coated, round, slightly biconvex, with beveled edges debossed with ‘L2.5’ on one side and plain on other side.

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)].

5 WARNINGS AND PRECAUTIONS

5.1 Bone Effects

Use of letrozole 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 A dverse 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)].

[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 to 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 x 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 x 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 experienced approximately twice the exposure to letrozole 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 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, caution is advised when driving or using machinery until it is known how the patient reacts to letrozole use.

5.5 Laboratory Test Abnormalities

No dose-related effect of letrozole 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 2.5 mg. This depression was transient in about half of those affected. Two patients on letrozole 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 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 and for at least 3 weeks after the last dose [see Adverse Reactions (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.

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 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 to 4 and Grades 3 to 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 to 4,) in the Adjuvant Study – Monotherapy Arms Analysis (Median Follow-up 96 Months; Median Treatment 60 Months)

Grades 1 to 4 Grades 3 to 4
Adverse Reactions Letrozole N=2448 n (%) Tamoxifen N=2447 n (%) Letrozole N=2448 n (%) Tamoxifen N=2447 n (%)
Patients with any adverse reaction 2309 (94.3) 2212 (90.4) 636 (26.0) 606 (24.8)
Hypercholesterolemia* 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 fractures1 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 fractures**2 249 (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 infarction1 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**1 11 (0.4) 72 (2.9)
Endometrial 6/1909 (0.3) 57/194 (2.9)
hyperplasia/cancer**,3 3
Other endometrial disorders* 2 (<0.1) 3 (0.1) 0 0
Myocardial infarction**2 24 (1.0) 12 (0.5)
Myocardial ischemia 6 (0.2) 9 (0.4)
Cerebrovascular accident/TIA**1 74 (3.0) 68 (2.8)
Cerebrovascular accident/TIA**2 51 (2.1) 47 (1.9)
Angina requiring surgery**1 35 (1.4) 33 (1.3)
Angina requiring surgery**2 25 (1.0) 25 (1.0)
Thromboembolic event**1 79 (3.2) 113 (4.6)
Thromboembolic event**2 51 (2.1) 89 (3.6)
Cardiac failure1 39 (1.6) 34 (1.4)
Cardiac failure2 27 (1.1) 15 (0.6)
Hypertension1 160 (6.5) 175 (7.2)
Hypertension2 138 (5.6) 139 (5.7)
Other cardiovascular**1 172 (7.0) 174 (7.1)
Other cardiovascular**2 120 (4.9) 119 (4.9)
Second primary malignancy1 129 (5.3) 150 (6.1)
Second primary malignancy2 54 (2.2) 79 (3.2)

* Target events pre-specified for analysis

** Events pre-printed on CRF

1 At median follow-up of 96 months (i.e. any time after randomization) for letrozole (range up to 144 months) and 95 months for tamoxifen (range up to 143 months )

2 At median treatment duration of 60 months (i.e. during treatment + 30 days after discontinuation of treatment) for letrozole and tamoxifen (range up to 68 months)

3 Excluding women who had undergone hysterectomy before study entry

TIA = Transient ischemic attack

Note: 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

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

At a median follow-up of 96 months, a higher incidence of events was seen for letrozole (14.7%) than for tamoxifen (11.4%) regarding fractures. A higher incidence was seen for tamoxifen compared to letrozole regarding thromboembolic events (4.6% vs 3.2%), and endometrial hyperplasia or cancer (2.9% vs 0.4%) (tamoxifen vs letrozole, 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 to 4 and Grades 3 to 4) irrespective of relationship to study treatment in the adjuvant study (safety population).

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

Adverse Reactions Letrozole N = 2049 n (%) Anastrozole N = 2062 n (%)
Grade 3/4 n (%) All grades n (%) Grade 3/4 n (%) All grades n (%)
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)
Hypercholesterolaemia 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)
Dyspnoea 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 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 to 4 Adverse Reactions Number (%) of Patients with Grade 3 to 4 Adverse Reactions
Letrozole N=2563 Placebo N=2573 Letrozole N=2563 Placebo N=2573
Any Adverse Reactions 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 was 5.9% (152) and placebo was 5.5% (142). The incidence of self-reported osteoporosis was higher in patients who received letrozole 6.9% (176) than in patients who received placebo 5.5% (141). Bisphosphonates were administered to 21.1% of the patients who received letrozole 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 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 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 (10.4%) compared to placebo (5.8%), as also a higher rate of osteoporosis (letrozole 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 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 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 arm (median 6 months in the tamoxifen arm). The incidence of adverse reactions was similar for letrozole 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 and in 15/455 (3%) of patients on tamoxifen.

Adverse reactions that were reported in at least 5% of the patients treated with letrozole 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 Reactions Letrozole 2.5 mg (N=455) % Tamoxifen 20 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 0.5 mg, in 4/174 (2.3%) on letrozole 2.5 mg, and in 15/190 (7.9%) on megestrol acetate. There were fewer thromboembolic events at both letrozole 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 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, 7/185 (3.8%) on 2.5 mg letrozole, 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 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 0.5 mg, letrozole 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 Reactions Pooled Letrozole 2.5 mg (N=359) % Pooled Letrozole 0.5 mg (N=380) % megestrol acetate 160 mg (N=189) % aminoglutethimide 500 mg (N=178) %
Body as a Whole
Chest Pain 6 3 7 3
Peripheral Edema1 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
Musculoskeletal2 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
Rash3 5 4 3 12
Pruritus 1 2 5 3

1 Includes peripheral edema, leg edema, dependent edema, edema

2 Includes musculoskeletal pain, skeletal pain, back pain, arm pain, leg pain

3 Includes rash, erythematous rash, maculopapular rash, psoriasiform rash, vesicular rash

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

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