Exemestane Patient Information Sheet

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For the use only of a Registered Medical Practitioner or a Hospital or a laboratory

Exemestane Tablets 25 mg

XCEL 25

COMPOSITION

xcel 25

Exemestane Tablets 25 mg

Each film coated tablet contains: Exemestane

Excipients q.s

Colour: Titanium Dioxide I.P.

DESCRIPTION

xcel Tablets for oral administration contain 25 mg of exemestane. an irreversible, steroidal aromatase inactivator. Exemestane is chemically described as 6-methylenandrosta-1. 4-diene 3, 17-Dione Its molecular formula is C ,H.,0, and its structural formula is as follows

The active ingredient is a white to slightly yellow crystalline powder with a molecular weight of 796.41 Exemestane is freely soluble in N, N-dimethylformamide, soluble in methanol, and practically insoluble in water

CLINICAL PHARMACOLOGY

Mechanism of Action: Breast cancer cell growth may be estrogen-dependent Aromatase is the principal enzyme that converts androgens to estrogens both in pre and postmenopausal women. While the main source of estrogen (primarily estradiol) is the ovary in premenopausal women, the principal source of circulating estrogens in postmenopausal woman is from conversion of adrenal and ovarian androgens (androstenedione and testosterone) to estrogens (estrone andestradiol) by the aromatase enzyme in peripheral tissues. Estrogen deprivation through aromatase inhibition is an effective and selective treatment for some postmenopausal patients with hormone-dependent breast cancer.

Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural substrate androstenedione. It acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme causing its inactivation, an effect also known as "suicide inhibition." Exemestane significantly lowers circulating estrogen concentrations in postmenopausal women, but has no detectable effect on adrenal biosynthesis of corticosteroids or aldosterone.

Pharmacokinetics: Following oral administration to healthy postmenopausal women, exemestane is rapidly absorbed After maximum plasma concentration is reached, levels decline polyexponentially with a mean terminal half-life of about 24 hours. Exemestane is extensively distributed and is cleared from the systemic circulation primarily by metabolism.

Absorption: Following oral administration of radio labeled exemestane. at least 42% of radioactivity was absorbed from the gastrointestinal tract. Exemestane plasma levels increased by approximately 40% after a high-fat breakfast.

Distribution: Exemestane is distributed extensively into tissues. Exemestane is 90% bound to plasma proteins and the fraction bound is independent of the total concentration. Albumin and 0 -acid glycoprotein both contribute to the binding The distribution of exemestane and its metabolites into blood cells is negligible.

Metabolism and Excretion: Following administration of radiolabeled exemestane to healthy postmenopausal women, the cumulative amounts of radioactivity excreted in urine and feces were similar (42 ± 3% in urine and 42 ± 6% in feces over a 1 -week collection period). The amount of drug excreted unchanged in urine was less than 1% of the dose. Exemestane is extensively metabolized, with levels of the unchanged drug in plasma accounting for less than 10% of the total radioactivity. The initial steps in the metabolism of exemestane are oxidation of the methylene group in position 6 and reduction of the 17-keto group with subsequent formation of many secondary metabolites. Each metabolite accounts only for a limited amount of drug-related material The metabolites are inactive or inhibit aromatase with decreased potency compared with the parent drug. One metabolite may have androgenic activity (see Pharmacodynamics, Other Endocrine Effects). Studies using human liver preparations indicate that cytochrome P 450 3A4 (CYP 3A4) is the principal isoenzyme involved in the oxidation of exemestane.

INDICATIONS AND USAGE

x cel. Tablets are indicated for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy.

CONTRAINDICATIONS

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

DOSAGE AND ADMINISTRATION

The recommended dose of xcel Tablets is 25 mg in early and advanced breast cancer once dairy after a meal.

In postmenopausal women with early breast cancer who have been treated with 2-3 years of tamoxifen, treatment with xcel should continue in the absence of recurrence or contralateral breast cancer until completion of five years of adjuvant endocrine therapy.

For patients with advanced breast cancer, treatment with xcel should continue until tumor progression is evident.

For patients receiving xcel with a potent CYP 3A4 inducer such as rifampicin or phenytoin, the recommended dose of xcel 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 no: appear to be necessary.

ADVERSE REACTIONS

Adjuvant Treatment of Early Breast Cancer: Exemestane tolerability in postmenopausal women with early breast cancer was evaluated in two well-controlled trials: the IES study 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)

Certain adverse events, 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, the median duration of adjuvant treatment was 27.4 months and 27.3 month', for patients receiving exemestane or tamoxilen, respectively, within the IES study and 23.9 months for patients receiving exemestane or placebo within the 027 study. Median duration of observation after randomization for exemestane was 34.5 months and for tamoxifen v.as 34.6 months. Median duration of observation was 30 months for both groups in the 027 study

Exemestane 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 exemestane and tamoxifen, respectively, and in 12.3% and 4 1% of patients receiving exemestane or placebo 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, 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 1.

Table 1. 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

Graded according to Common Toxicity Criteria; 2 75 patients received tamoxifen 30 mg daily; 3 Event actively sought.

In the IES study, as compared to tamoxifen, exemestane was associated with a higher incidence of events in the musculoskeletal disorders and in the 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 tne exemestane group compared to tamoxifen (0.7% versus <0.1%). The majority of patients on exemestane 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%).

Treatment of Advanced Breast Cancer: A total of 1058 patients were treated with exemestane 25 mg once daily in the clinical trials program. Exemestane was generally well tolerated, and adverse events were usually mild to moderate. 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 exemestane and 400 patients treated with megestrol acetate. Fewer patients receiving exemestane 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 Hashes (13% vs. 5%), nausea (9% vs. 5%), fatigue (8% vs. 10%), increased sweating (4% vs. 8%). and increased appetite (3% vs 6%) The proportion of patients experiencing an excessive weight gain (>10% of their baseline weight) was significantly higher with megestrol acetate than with exemestane (17% vs. 8%).

WARNINGS

Pregnancy Category -D'

X cel. Tablets may cause fetal harm when administered to a pregnant woman.

There are no studies in pregnant women using Exemestae. X cel. Is indicated for postmenopausal women. If there is exposure to X cel..during pregnancy, the patient should be apprised of the potential hazard to the fetus and potential risk for loss of the pregnancy.

Nursing Mothers: Xcel. is only indicated in postmenopausal women However, radioactivity related to exemestane appeared in rat milk within 15 minutes of oral administration of radiolabeled exemestane. Concentrations of exemestane and its metabolites were approximately equivalent in the milk and plasma of rats for 24 hours after a single oral dose of 1 mg/kg UC-exemestane. It is not known whether exemestane is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if a nursing woman is inadvertently exposed to

Pediatric Use: The safety and effectiveness of X'cel. in pediatric patients have not been evaluated.

Geriatric Use: the use of X'cel. in geriatric patients does not require special precautions.

PRECAUTIONS

General: X cel tablets should not be administered to premenopausal women. X'cel. should not be co-administered with estrogen-containing agents as these could interfere with its pharmacologic action.

Hepatic Insufficiency: The pharmacokinetics of exemestane have been investigated in subjects with moderate or severe hepatic insufficiency (Childs-Pugh B or C). Following a single 25-mg oral dose, the AUC of exemestane was approximately 3 times higher than that observed in healthy volunteers The safety of chronic dosing in patients with moderate or severe hepatic impairment has not been studied Based on experience with exemestane at repeated doses up to 200 mg dairy that demonstrated a moderate increase in non-life threatening adverse events, dosage adjustment does not appear to be necessary.

Renal Insufficiency: The AUC of exemestane after a single 25 mg dose was approximately 3 times higher in subjects with moderate or severe renal insufficiency (creatinine clearance <35 mL/min/1.73 m') compared with the AUC in healthy volunteers. The safety of chronic dosing in patients with moderaie or severe 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.

Drug-Drug Interactions: Exemestane is metabolized by cytochrome P-450 3A4 (CYP 3A4) and aldoketoreductases. It does not inhibit any of the major CYP isoenzymes, including CYP 1A2. 2C9, 2D6, 2E1, and 3A4. In a clinical pharmacokinetic study, ketoconazole showed no significant influence on the pharmacokinetics of exemestane. Although no other formal drug-drug interaction studies have been conducted, significant effects on exemestane clearance by CYP isoenzymes inhibitors appear unlikely.

Carcinogenesis, Mutagenesis, Impairment of Fertility: A 2 year carcinogenicity study in mice at doses of 50. 150 and 450 mg/kg/day exemestane resulted in an increased incidence of hepatocellular adenomas and/or carcinomas in both genders at the high dose level. Plasma AUCs(024hr) at the high dose were 2575 ± 386 and 5667 ± 1833 nq.hr/mL in males and females (approx. 34 and 75 fold the AUC in postmenopausal patients at the recommended clinical dose). An increased incidence of renal tubular adenomas was observed in male mice at the high dose of 450 mg/kg/day Since the doses tested in mice did not achieve an MTD, neoplastic findings in organs other than liver and kidneys remain unknown

A separate carcinogenicity study was conducted in rats at the doses of 30,100 and 315 mg/kg/day exemestane for 92 weeks in males and 2 years in females. No evidence of carcinogenic activity up to the highest dose tested of 315 mg/kg/day was observed in females. The male rat study was inconclusive since it was terminated prematurely at Week 92. At the highest dose, plasma AUC(024hr) levels in male (1418 +- 287 ng hr/ml) and female (2318 +- 1067 ng.hr/rnl.) rats were 19 and 31 fold higher than those measured in postmenopausal cancer patients, receiving the recommended clinical dose.

OVERDOSAGE

Clinical trials have been conducted with exemestane given as a single dose to healthy female volunteers at doses as high as 800 mg and daily for 12 weeks to postmenopausal women with advanced breast cancer at doses as high as 600 mg. These dosages were well tolerated. There is no specific antidote to overdosage and treatment must be symptomatic. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.

A male child (age unknown) accidentally ingested a 25-mq tablet of exemestane. The initial physical examination was normal, but blood tests performed 1 hour after ingestion indicated leucocytosis (WBC 75000/mm' with 90% neutrophils) Blood tests were repeated 4 days after the incident and were normal. No treatment was given.

Convulsions were observed after single doses of exemestane of 400 mg/kg and 3000 mg/kg in mice and dogs (approximately 80 and 4000 times the recommended human dose on a mg/m3 basis), respectively.

STORAGE

Store at 25°C (77°F); excursions permitted to 15-30"C (59° 86°F) SHELF LIFE 24 Months

HOW SUPPLIED

Exemestane Tablets 25 mg

Each blister contains 10 tablets.

Each pack contains 3 blisters (30 Tablets) in a carton

Trade mark owned by Celon Laboratories Ltd.

Manufactured by.

CELOnTlabs

Celon Laboratories Limited,

# 2, ALEAP Industrial Estate, Gaiularamaram,

R.R. Dist. • 500 072. Andhra Pradesh, India.

Website www.celonlabs.com; Email: vivilon@celonlabs com