Exemestane: Package Insert and Label Information

EXEMESTANE- exemestane tablet, film coated
Mylan Pharmaceuticals Inc.

1 INDICATIONS AND USAGE

1.1 Adjuvant Treatment of Postmenopausal Women

Exemestane tablets are indicated for adjuvant treatment of postmenopausal women with estrogen-receptor positive early breast cancer who have received two to three years of tamoxifen and are switched to exemestane tablets for completion of a total of five consecutive years of adjuvant hormonal therapy [see Clinical Studies (14.1)].

1.2 Advanced Breast Cancer in Postmenopausal Women

Exemestane tablets are indicated for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy [see Clinical Studies (14.2)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

The recommended dose of exemestane tablets in early and advanced breast cancer is one 25 mg tablet once daily after a meal.

adjuvant treatment of postmenopausal women with estrogen-receptor positive early breast cancer who have received two to three years of tamoxifen and are switched to exemestane tablets for completion of a total of five consecutive years of adjuvant hormonal therapy.
the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy.

2.2 Dose Modifications

Concomitant use of strong CYP 3A4 inducers decreases exemestane exposure. For patients receiving exemestane tablets with a strong CYP 3A4 inducer such as rifampicin or phenytoin, the recommended dose of exemestane tablets is 50 mg once daily after a meal [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

Exemestane Tablets are available containing 25 mg of exemestane, USP.

The 25 mg tablets are white, film-coated, round, unscored tablets debossed with X on one side of the tablet and M on the other side.

4 CONTRAINDICATIONS

Exemestane tablets are contraindicated in patients with a known hypersensitivity to the drug or to any of the excipients.

5 WARNINGS AND PRECAUTIONS

5.1 Reductions in Bone Mineral Density (BMD)

Reductions in bone mineral density (BMD) over time are seen with exemestane use. Table 1 describes changes in BMD from baseline to 24 months in patients receiving exemestane compared to patients receiving tamoxifen (IES) or placebo (027). Concomitant use of bisphosphonates, vitamin D supplementation, and calcium was not allowed.

Table 1. Percent Change in BMD from Baseline to 24 months, Exemestane vs. Control *
*
For patients who had 24 month data

IES

027

BMD

Exemestane N = 29

Tamoxifen * N = 38

Exemestane N = 59

Placebo * N = 65

Lumbar spine (%)

-3.14

-0.18

-3.51

-2.35

Femoral neck (%)

-4.15

-0.33

-4.57

-2.59

During adjuvant treatment with exemestane, women with osteoporosis or at risk of osteoporosis should have their bone mineral density formally assessed by bone densitometry at the commencement of treatment. Monitor patients for bone mineral density loss and treat as appropriate.

5.2 Vitamin D Assessment

Routine assessment of 25-hydroxy vitamin D levels prior to the start of aromatase inhibitor treatment should be performed, due to the high prevalence of vitamin D deficiency in women with early breast cancer (EBC). Women with vitamin D deficiency should receive supplementation with vitamin D.

5.3 Administration with Estrogen-Containing Agents

Exemestane tablets should not be coadministered with estrogen-containing agents as these could interfere with its pharmacologic action.

5.4 Laboratory Abnormalities

In patients with early breast cancer, the incidence of hematological abnormalities of Common Toxicity Criteria (CTC) grade ≥ 1 was lower in the exemestane treatment group, compared with tamoxifen. Incidence of CTC grade 3 or 4 abnormalities was low (approximately 0.1%) in both treatment groups. Approximately 20% of patients receiving exemestane in clinical studies in advanced breast cancer experienced CTC grade 3 or 4 lymphocytopenia. Of these patients, 89% had a pre-existing lower grade lymphopenia. Forty percent of patients either recovered or improved to a lesser severity while on treatment. Patients did not have a significant increase in viral infections, and no opportunistic infections were observed. Elevations of serum levels of AST, ALT, alkaline phosphatase, and gamma glutamyl transferase > 5 times the upper value of the normal range (i.e., ≥ CTC grade 3) have been rarely reported in patients treated for advanced breast cancer but appear mostly attributable to the underlying presence of liver and/or bone metastases. In the comparative study in advanced breast cancer patients, CTC grade 3 or 4 elevation of gamma glutamyl transferase without documented evidence of liver metastasis was reported in 2.7% of patients treated with exemestane tablets and in 1.8% of patients treated with megestrol acetate.

In patients with early breast cancer, elevations in bilirubin, alkaline phosphatase, and creatinine were more common in those receiving exemestane than either tamoxifen or placebo. Treatment-emergent bilirubin elevations (any CTC grade) occurred in 5.3% of exemestane patients and 0.8% of tamoxifen patients on the Intergroup Exemestane Study (IES), and in 6.9% of exemestane treated patients vs. 0% of placebo treated patients in the 027 study. CTC grade 3–4 increases in bilirubin occurred in 0.9% of exemestane treated patients compared to 0.1% of tamoxifen treated patients. Alkaline phosphatase elevations of any CTC grade occurred in 15.0% of exemestane treated patients on the IES compared to 2.6% of tamoxifen treated patients, and in 13.7% of exemestane treated patients compared to 6.9% of placebo treated patients in study 027. Creatinine elevations occurred in 5.8% of exemestane treated patients and 4.3% of tamoxifen treated patients on the IES and in 5.5% of exemestane treated patients and 0% of placebo treated patients in study 027.

5.5 Use in Premenopausal Women

Exemestane tablets are not indicated for the treatment of breast cancer in premenopausal women.

5.6 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, exemestane tablets can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of exemestane to pregnant rats and rabbits caused increased incidence of abortions and embryo-fetal toxicity. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with exemestane tablets and for 1 month after the last dose [see Use in Specific Populations (8.1), (8.3) and Clinical Pharmacology (12.1)].

6 ADVERSE REACTIONS

In the adjuvant treatment of early breast cancer, the most common adverse reactions occurring in ≥ 10% of patients in any treatment group (exemestane tablets vs. tamoxifen) were mild to moderate hot flushes (21.2% vs. 19.9%), fatigue (16.1% vs. 14.7%), arthralgia (14.6% vs. 8.6%), headache (13.1% vs. 10.8%), insomnia (12.4% vs. 8.9%), and increased sweating (11.8% vs. 10.4%). Discontinuation rates due to AEs were similar between exemestane tablets and tamoxifen (6.3% vs. 5.1%). Incidences of cardiac ischemic events (myocardial infarction, angina, and myocardial ischemia) were exemestane tablets 1.6%, tamoxifen 0.6%. Incidence of cardiac failure: exemestane tablets 0.4%, tamoxifen 0.3%.

In the treatment of advanced breast cancer, the most common adverse reactions were mild to moderate and included hot flushes (13% vs. 5%), nausea (9% vs. 5%), fatigue (8% vs. 10%), increased sweating (4% vs. 8%), and increased appetite (3% vs. 6%) for exemestane tablets and megestrol acetate, respectively.

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction 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 clinical practice.

Adjuvant Therapy

The data described below reflect exposure to exemestane tablets in 2325 postmenopausal women with early breast cancer. Exemestane tablets tolerability in postmenopausal women with early breast cancer was evaluated in two well-controlled trials: the IES study [See Clinical Studies (14.1)] and the 027 study (a randomized, placebo-controlled, double-blind, parallel group study specifically designed to assess the effects of exemestane on bone metabolism, hormones, lipids, and coagulation factors over 2 years of treatment).

The median duration of adjuvant treatment was 27.4 months and 27.3 months for patients receiving exemestane tablets or tamoxifen, respectively, within the IES study and 23.9 months for patients receiving exemestane tablets or placebo within the 027 study. Median duration of observation after randomization for exemestane tablets was 34.5 months and for tamoxifen was 34.6 months. Median duration of observation was 30 months for both groups in the 027 study.

Certain adverse reactions, which were expected based on the known pharmacological properties and side effect profiles of test drugs, were actively sought through a positive checklist. Signs and symptoms were graded for severity using CTC in both studies. Within the IES study, the presence of some illnesses/conditions was monitored through a positive checklist without assessment of severity. These included myocardial infarction, other cardiovascular disorders, gynecological disorders, osteoporosis, osteoporotic fractures, other primary cancer, and hospitalizations.

Within the IES study, discontinuations due to adverse reactions occurred in 6.3% and 5.1% of patients receiving exemestane tablets and tamoxifen, respectively, and in 12.3% and 4.1% of patients receiving exemestane or placebo respectively within study 027.

Deaths due to any cause were reported for 1.3% of the exemestane treated patients and 1.4% of the tamoxifen treated patients within the IES study. There were 6 deaths due to stroke on the exemestane arm compared to 2 on tamoxifen. There were 5 deaths due to cardiac failure on the exemestane arm compared to 2 on tamoxifen.

The incidence of cardiac ischemic events (myocardial infarction, angina, and myocardial ischemia) was 1.6% in exemestane treated patients and 0.6% in tamoxifen treated patients in the IES study. Cardiac failure was observed in 0.4% of exemestane treated patients and 0.3% of tamoxifen treated patients.

Treatment-emergent adverse reactions and illnesses including all causalities and occurring with an incidence of ≥ 5% in either treatment group of the IES study during or within one month of the end of treatment are shown in Table 2.

Table 2. Incidence (%) of Adverse Reactions of all Grades * and Illnesses Occurring in (≥ 5%) of Patients in Any Treatment Group in Study IES in Postmenopausal Women with Early Breast Cancer
*
Graded according to Common Toxicity Criteria;
75 patients received tamoxifen 30 mg daily;
Event actively sought.

% of patients

Body system and Adverse Reaction by MedDRA dictionary

Exemestane Tablets

25 mg daily

(N = 2252)

Tamoxifen

20 mg daily

(N = 2280)

Eye

Visual disturbances

5.0

3.8

Gastrointestinal

Nausea

8.5

8.7

General Disorders

Fatigue

16.1

14.7

Musculoskeletal

Arthralgia

14.6

8.6

Pain in limb

9.0

6.4

Back pain

8.6

7.2

Osteoarthritis

5.9

4.5

Nervous System

Headache

13.1

10.8

Dizziness

9.7

8.4

Psychiatric

Insomnia

12.4

8.9

Depression

6.2

5.6

Skin & Subcutaneous Tissue

Increased sweating

11.8

10.4

Vascular

Hot flushes

21.2

19.9

Hypertension

9.8

8.4

In the IES study, as compared to tamoxifen, exemestane tablets were associated with a higher incidence of events in musculoskeletal disorders and in nervous system disorders, including the following events occurring with frequency lower than 5% (osteoporosis [4.6% vs. 2.8%], osteochondrosis and trigger finger [0.3% vs. 0 for both events], paresthesia [2.6% vs. 0.9%], carpal tunnel syndrome [2.4% vs. 0.2%], and neuropathy [0.6% vs. 0.1%]). Diarrhea was also more frequent in the exemestane group (4.2% vs. 2.2%). Clinical fractures were reported in 94 patients receiving exemestane (4.2%) and 71 patients receiving tamoxifen (3.1%). After a median duration of therapy of about 30 months and a median follow-up of about 52 months, gastric ulcer was observed at a slightly higher frequency in the exemestane tablets group compared to tamoxifen (0.7% vs. < 0.1%). The majority of patients on exemestane tablets with gastric ulcer received concomitant treatment with non-steroidal anti-inflammatory agents and/or had a prior history.

Tamoxifen was associated with a higher incidence of muscle cramps [3.1% vs. 1.5%], thromboembolism [2.0% vs. 0.9%], endometrial hyperplasia [1.7% vs. 0.6%], and uterine polyps [2.4% vs. 0.4%].

Common adverse reactions occurring in study 027 are described in Table 3.

Table 3. Incidence of Selected Treatment-Emergent Adverse Reactions of all CTC Grades * Occurring in ≥ 5% of Patients in Either Arm in Study 027
*
Most events were CTC grade 1-2

Adverse Reaction

Exemestane

N = 73

(% incidence)

Placebo

N = 73

(% incidence)

Hot flushes

32.9

24.7

Arthralgia

28.8

28.8

Increased sweating

17.8

20.6

Alopecia

15.1

4.1

Hypertension

15.1

6.9

Insomnia

13.7

15.1

Nausea

12.3

16.4

Fatigue

11.0

19.2

Abdominal pain

11.0

13.7

Depression

9.6

6.9

Diarrhea

9.6

1.4

Dizziness

9.6

9.6

Dermatitis

8.2

1.4

Headache

6.9

4.1

Myalgia

5.5

4.1

Edema

5.5

6.9

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