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FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1 Adjuvant Treatment of Postmenopausal Women

1.2 Advanced Breast Cancer in Postmenopausal Women

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

2.2 Dose Modifications

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Hypersensitivity

4.2 Pregnancy

5 WARNINGS AND PRECAUTIONS

5.1 Administration with Estrogen-Containing Agents

5.2 Laboratory Tests

5.3 Reductions in Bone Mineral Density (BMD)

5.4 Vitamin D Assessment

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience

6.2 Post-Marketing Experience

7 DRUG INTERACTIONS

7.1 Drugs That Induce CYP 3A4

7.2 Drugs That Inhibit CYP 3A4

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Insufficiency

8.7 Renal Insufficiency

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 Adjuvant Treatment in Early Breast Cancer

14.2 Treatment of Advanced Breast Cancer

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Premenopausal Women

17.2 Other Estrogen-Containing Agents

17.3 Bone Effects

* Sections or subsections omitted from the full prescribing information are not listed.

 

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Adjuvant Treatment of Postmenopausal Women

AROMASIN is 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 AROMASIN 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

AROMASIN is 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 AROMASIN 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 AROMASIN 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

For patients receiving AROMASIN with a potent CYP 3A4 inducer such as rifampicin or phenytoin, the recommended dose of AROMASIN is 50 mg once daily after a meal.

The safety of chronic dosing in patients with moderate or severe hepatic or renal impairment has not been studied. Based on experience with exemestane at repeated doses up to 200 mg daily that demonstrated a moderate increase in non life-threatening adverse events, dosage adjustment does not appear to be necessary [see Use In Specific Populations (8.6 and 8.7)].

3 DOSAGE FORMS AND STRENGTHS

AROMASIN Tablets are round, biconvex, and off-white to slightly gray. Each tablet contains 25 mg of exemestane. The tablets are printed on one side with the number "7663" in black.

4 CONTRAINDICATIONS

4.1 Hypersensitivity

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

4.2 Pregnancy

AROMASIN may cause fetal harm when administered to a pregnant woman. Based on its mechanism of action AROMASIN is expected to result in adverse reproductive effects. In non-clinical studies in rats and rabbits, exemestane was embryotoxic, fetotoxic, and abortifacient.

AROMASIN is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

AROMASIN Tablets should not be administered to premenopausal women [see Use in Specific Populations (8.1)].

5 WARNINGS AND PRECAUTIONS

5.1 Administration with Estrogen-Containing Agents

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

5.2 Laboratory Tests

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 AROMASIN 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.

5.3 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. Control1

 

            IES

            027

BMD

Exemestane
  N=29

Tamoxifen1 
  N=38

Exemestane
  N=59

Placebo1 
  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. Patients treated with exemestane should be carefully monitored and treatment for osteoporosis should be initiated as appropriate.

5.4 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.

6 ADVERSE REACTIONS

AROMASIN was generally well tolerated and adverse events were usually mild to moderate.

In the adjuvant treatment of early breast cancer, adverse events occurring in ≥10% of patients in any treatment group (AROMASIN vs. tamoxifen) were 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 AROMASIN and tamoxifen (6.3% vs. 5.1%). Incidences of cardiac ischemic events (myocardial infarction, angina, and myocardial ischemia) were AROMASIN 1.6%, tamoxifen 0.6%. Incidence of cardiac failure: AROMASIN 0.4%, tamoxifen 0.3%.

In the treatment of advanced breast cancer, the most common adverse events 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 AROMASIN 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 AROMASIN in 2325 postmenopausal women with early breast cancer. AROMASIN tolerability in postmenopausal women with early breast cancer was evaluated in two well-controlled trials: the IES study (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 AROMASIN or tamoxifen, respectively, within the IES study and 23.9 months for patients receiving AROMASIN or placebo within the 027 study. Median duration of observation after randomization for AROMASIN 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 events, 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.

AROMASIN was generally well tolerated and adverse events were usually mild to moderate. Within the IES study, discontinuations due to adverse events occurred in 6.3% and 5.1% of patients receiving AROMASIN 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 events 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 Events of all Grades* and Illnesses Occurring in (≥5%) of Patients in Any Treatment Group in Study IES in Postmenopausal Women with Early Breast Cancer

 

% of patients

Body system and Adverse Event by MedDRA dictionary

AROMASIN
25 mg daily
(N=2252)

Tamoxifen
20 mg daily† 
(N=2280)

* Graded according to Common Toxicity Criteria;

† 75 patients received tamoxifen 30 mg daily;

‡ Event actively sought.

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, AROMASIN was 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 AROMASIN group compared to tamoxifen (0.7% vs. <0.1%). The majority of patients on AROMASIN 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 events occurring in study 027 are described in Table 3.

Table 3. Incidence of Selected Treatment-Emergent Adverse Events of all CTC Grades* Occurring in ≥ 5% of Patients in Either Arm in Study 027

Adverse Event

Exemestane
N=73
(% incidence)

Placebo
N=73
(% incidence)

* Most events were CTC grade 1–2

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

Anxiety

4.1

5.5

Treatment of Advanced Breast Cancer

A total of 1058 patients were treated with exemestane 25 mg once daily in the clinical trials program. Only one death was considered possibly related to treatment with exemestane; an 80-year-old woman with known coronary artery disease had a myocardial infarction with multiple organ failure after 9 weeks on study treatment. In the clinical trials program, only 3% of the patients discontinued treatment with exemestane because of adverse events, mainly within the first 10 weeks of treatment; late discontinuations because of adverse events were uncommon (0.3%).

In the comparative study, adverse reactions were assessed for 358 patients treated with AROMASIN and 400 patients treated with megestrol acetate. Fewer patients receiving AROMASIN discontinued treatment because of adverse events than those treated with megestrol acetate (2% vs. 5%). Adverse events that were considered drug related or of indeterminate cause included hot flashes (13% vs. 5%), nausea (9% vs. 5%), fatigue (8% vs. 10%), increased sweating (4% vs. 8%), and increased appetite (3% vs. 6%) for AROMASIN and megestrol acetate, respectively. The proportion of patients experiencing an excessive weight gain (>10% of their baseline weight) was significantly higher with megestrol acetate than with AROMASIN (17% vs. 8%). Table 4 shows the adverse events of all CTC grades, regardless of causality, reported in 5% or greater of patients in the study treated either with AROMASIN or megestrol acetate.

Table 4. Incidence (%) of Adverse Events of all Grades* and Causes Occurring in ≥5% of Advanced Breast Cancer Patients In Each Treatment Arm in the Comparative Study

Body system and Adverse Event by WHO ART dictionary

AROMASIN
25 mg
once daily
(N=358)

Megestrol Acetate
40 mg QID (N=400)

* Graded according to Common Toxicity Criteria

Autonomic Nervous

   

  Increased sweating

6

9

Body as a Whole

   

  Fatigue

22

29

  Hot flashes

13

6

  Pain

13

13

  Influenza-like symptoms

6

5

  Edema (includes edema, peripheral edema, leg edema)

7

6

Cardiovascular

   

  Hypertension

5

6

Nervous

   

  Depression

13

9

  Insomnia

11

9

  Anxiety

10

11

  Dizziness

8

6

  Headache

8

7

Gastrointestinal

   

  Nausea

18

12

  Vomiting

7

4

  Abdominal pain

6

11

  Anorexia

6

5

  Constipation

5

8

  Diarrhea

4

5

  Increased appetite

3

6

Respiratory

   

  Dyspnea

10

15

  Coughing

6

7

Less frequent adverse events of any cause (from 2% to 5%) reported in the comparative study for patients receiving AROMASIN 25 mg once daily were fever, generalized weakness, paresthesia, pathological fracture, bronchitis, sinusitis, rash, itching, urinary tract infection, and lymphedema.

Additional adverse events of any cause observed in the overall clinical trials program (N = 1058) in 5% or greater of patients treated with exemestane 25 mg once daily but not in the comparative study included pain at tumor sites (8%), asthenia (6%), and fever (5%). Adverse events of any cause reported in 2% to 5% of all patients treated with exemestane 25 mg in the overall clinical trials program but not in the comparative study included chest pain, hypoesthesia, confusion, dyspepsia, arthralgia, back pain, skeletal pain, infection, upper respiratory tract infection, pharyngitis, rhinitis, and alopecia.

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post approval use of AROMASIN. Because 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.

Immune system disorders- hypersensitivity

Hepatobiliary disorders- hepatitis including cholestatic hepatitis

Nervous system disorders- paresthesia

Skin and subcutaneous tissue disorders- acute generalized exanthematous pustulosis, urticaria, pruritus

7 DRUG INTERACTIONS

7.1 Drugs That Induce CYP 3A4

In a pharmacokinetic interaction study of 10 healthy postmenopausal volunteers pretreated with potent CYP 3A4 inducer rifampicin 600 mg daily for 14 days followed by a single dose of exemestane 25 mg, the mean plasma Cmax and AUC0–∞ of exemestane were decreased by 41% and 54%, respectively.

Significant pharmacokinetic interactions mediated by inhibition of CYP isoenzymes therefore appear unlikely. Co-medications that induce CYP 3A4 (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, or St. John's wort) may significantly decrease exposure to exemestane. Dose modification is recommended for patients who are also receiving a potent CYP 3A4 inducer [see Dosage and Administration (2.2)].

7.2 Drugs That Inhibit CYP 3A4

In a clinical pharmacokinetic study, coadministration of ketoconazole, a potent inhibitor of CYP 3A4, has no significant effect on exemestane pharmacokinetics. Although no other formal drug-drug interaction studies have been conducted, significant effects on exemestane clearance by CYP isoenzyme inhibitors appear unlikely.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category X. See "Contraindications" section.

AROMASIN can cause fetal harm when administered to a pregnant woman and the clinical benefit to premenopausal women with breast cancer has not been demonstrated. AROMASIN is contraindicated in women who are or may become pregnant. There are no adequate and well-controlled studies of AROMASIN in pregnant women.

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Aromasin 25 Mg 30 Tablets

  • Brand: Pfizer
  • Product Code: 8699532128515
  • Availability: In Stock
  • $39.00

Tags: Aromasin 25 Mg 30 Tablets, Pfizer, All Products, Anticancer, Women Health