Exemestane (Page 3 of 7)

6.2 Post-Marketing Experience

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

Drugs That Induce CYP 3A4
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 [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on findings in animal studies and its mechanism of action, exemestane can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. 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 [see Data]. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the US general population, the estimate background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data: In animal reproduction studies in rats and rabbits, exemestane caused embryo-fetal toxicity, and was abortifacient. Radioactivity related to14 C-exemestane crossed the placenta of rats following oral administration of 1 mg/kg exemestane. The concentration of exemestane and its metabolites was approximately equivalent in maternal and fetal blood. When rats were administered exemestane from 14 days prior to mating until either days 15 or 20 of gestation, and resuming for the 21 days of lactation, an increase in placental weight was seen at 4 mg/kg/day (approximately 1.5 times the recommended human daily dose on a mg/m2 basis). Increased resorptions, reduced number of live fetuses, decreased fetal weight, retarded ossification, prolonged gestation and abnormal or difficult labor was observed at doses equal to or greater than 20 mg/kg/day (approximately 7.5 times the recommended human daily dose on a mg/m2 basis). Daily doses of exemestane, given to rabbits during organogenesis, caused a decrease in placental weight at 90 mg/kg/day (approximately 70 times the recommended human daily dose on a mg/m2 basis) and in the presence of maternal toxicity, abortions, an increase in resorptions, and a reduction in fetal body weight were seen at 270 mg/kg/day. No malformations were noted when exemestane was administered to pregnant rats or rabbits during the organogenesis period at doses up to 810 and 270 mg/kg/day, respectively (approximately 320 and 210 times the recommended human dose on a mg/m2 basis, respectively).

8.2 Lactation

Risk Summary

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 [see Data]. Because of the potential for serious adverse reactions in breast-fed infants from exemestane, advise a woman not to breastfeed during treatment with exemestane and for 1 month after the final dose.

Data

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 14 C-exemestane.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential within seven days prior to initiating exemestane.

Contraception

Females: Exemestane can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with exemestane and for 1 month after the final dose.

Infertility

Based on findings in animals, male and female fertility may be impaired by treatment with exemestane [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.6 Hepatic Impairment

The AUC of exemestane was increased in subjects with moderate or severe hepatic impairment (Childs-Pugh B or C) [see Clinical Pharmacology (12.3)]. 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.

8.7 Renal Impairment

The AUC of exemestane was increased in subjects with moderate or severe renal impairment (creatinine clearance <35 mL/min/1.73 m2) [see Clinical Pharmacology (12.3)]. 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.

10 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 25,000/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 3,200 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 5,000 mg/kg (about 2,000 times the recommended human dose on a mg/m2 basis) and of 3,000 mg/kg (about 4,000 times the recommended human dose on a mg/m2 basis), respectively.

Convulsions were observed after single doses of exemestane of 400 mg/kg and 3,000 mg/kg in mice and dogs (approximately 80 and 4,000 times the recommended human dose on a mg/m2 basis), respectively.

11 DESCRIPTION

Exemestane 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 C20 H24 O2 and its structural formula is as follows:

exemestane chemical structure.jpg

The active ingredient is a white to slightly yellow crystalline powder with a molecular weight of 296.40. Exemestane is freely soluble in N, N-dimethylformamide, soluble in methanol, and practically insoluble in water.

Each tablet contains the following inactive ingredients: magnesium stearate, mannitol, microcrystalline cellulose, Opadry II (white), polysorbate 80, povidone and sodium starch glycolate. Opadry II (white) contains: hypromellose, polyethylene glycol, polydextrose, titanium dioxide and triacetin.

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