AROMASIN® (exemestane) tablets

AROMASIN® (exemestane) tablets

AROMASIN® (exemestane)

AROMASIN® 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 C20H24O2.

The active ingredient is a white to slightly yellow crystalline powder with a molecular weight of 296.41. Exemestane is freely soluble in N, N-dimethylformamide, soluble in methanol, and practically insoluble in water.

Each AROMASIN Tablet contains the following inactive ingredients: mannitol, crospovidone, polysorbate 80, hypromellose, colloidal silicon dioxide, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, simethicone, polyethylene glycol 6000, sucrose, magnesium carbonate, titanium dioxide, methylparaben, and polyvinyl alcohol.

INDICATIONS AND USAGE

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.

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.

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 women is from conversion of adrenal and ovarian androgens (androstenedione and testosterone) to estrogens (estrone and estradiol) by the aromatase enzyme in peripheral tissues.

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. Exemestane has no effect on other enzymes involved in the steroidogenic pathway up to a concentration at least 600 times higher than that inhibiting the aromatase enzyme.

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.

Dose Modifications

Concomitant use of strong CYP 3A4 inducers decreases exemestane exposure, for patients receiving AROMASIN with a strong CYP 3A4 inducer such as rifampicin or phenytoin, the recommended dose of AROMASIN is 50 mg once daily after a meal.

CONTRAINDICATIONS

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

WARNINGS AND PRECAUTIONS

Reductions in Bone Mineral Density (BMD)

Reductions in bone mineral density (BMD) over time are seen with exemestane use. Concomitant use of bisphosphonates, vitamin D supplementation, and calcium was not allowed.

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.

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.

Administration with Estrogen-Containing Agents

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

Use in Premenopausal Women

AROMASIN is not indicated for the treatment of breast cancer in premenopausal women.

Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, AROMASIN 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 AROMASIN and for 1 month after the last dose.

ADVERSE REACTIONS

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

  • Immune system disorders-hypersensitivity
  • Hepatobiliary disorders-hepatitis including cholestatic hepatitis
  • Nervous system disorders-paresthesia
  • Musculoskeletal and connective tissue disorder-tenosynovitis stenosans
  • Skin and subcutaneous tissue disorders-acute generalized exanthematous pustulosis, urticaria, pruritus

DRUG INTERACTIONS

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 strong CYP 3A4 inducer.

USE IN SPECIFIC POPULATIONS

Pregnancy

Based on findings in animal studies and its mechanism of action, AROMASIN can cause fetal harm when administered to a pregnant woman. Limited human data from case reports are insufficient to inform a drug-associated risk. In animal reproduction studies, administration of exemestane to pregnant rats and rabbits caused increased incidence of abortions, embryo-fetal toxicity, and prolonged gestation with abnormal or difficult labor. Advise pregnant women of the potential risk to a fetus.

Lactation

There is no information on the presence of exemestane in human milk, or on its effects on the breastfed infant or milk production. Exemestane is present in rat milk at concentrations similar to maternal plasma. Because of the potential for serious adverse reactions in breast-fed infants from AROMASIN, advise a woman not to breastfeed during treatment with AROMASIN and for 1 month after the final dose.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Hepatic Impairment

The AUC of exemestane was increased in subjects with moderate or severe hepatic impairment (Childs-Pugh B or C). However, based on experience with exemestane at repeated doses up to 200 mg daily that demonstrated a moderate increase in non-life-threatening adverse reactions, dosage adjustment does not appear to be necessary.

Renal Impairment

The AUC of exemestane was increased in subjects with moderate or severe renal impairment (creatinine clearance <35 mL/min/1.73 m2). However, based on experience with exemestane at repeated doses up to 200 mg daily that demonstrated a moderate increase in non-life-threatening adverse reactions, dosage adjustment does not appear to be necessary.

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-mg tablet of exemestane. The initial physical examination was normal, but blood tests performed 1 hour after ingestion indicated leucocytosis (WBC 25000/mm3 with 90% neutrophils). Blood tests were repeated 4 days after the incident and were normal. No treatment was given.

In mice, mortality was observed after a single oral dose of exemestane of 3200 mg/kg, the lowest dose tested (about 640 times the recommended human dose on a mg/m2 basis). In rats and dogs, mortality was observed after single oral doses of exemestane of 5000 mg/kg (about 2000 times the recommended human dose on a mg/m2 basis) and of 3000 mg/kg (about 4000 times the recommended human dose on a mg/m2 basis), respectively.

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/m2 basis), respectively.

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