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Drug Safety-related Labeling Changes (SrLC)

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AROMASIN (NDA-020753)

(EXEMESTANE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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12/16/2024 (SUPPL-25)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

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.

Musculoskeletal and connective tissue disorder- tendon disorders including tendon rupture, tendonitis, and tenosynovitis

11/17/2021 (SUPPL-22)

Approved Drug Label (PDF)

6 Adverse Reactions

6 ADVERSE REACTIONS

Additions and/or revisions underlined: 

The following clinically significant adverse reactions are described elsewhere in the labeling:

  • Reductions in Bone Mineral Density (BMD) [see Warnings and Precautions (5.1)]

6.1 Clinical Trial Experience

Additions and/or revisions underlined: 

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

In the adjuvant treatment of early breast cancer, the most common adverse reactions occurring in greater than or equal to 10% of patients in any treatment group (AROMASIN vs. tamoxifen) were hot flushes (21% vs. 20%), fatigue (16% vs. 15%), arthralgia (15% vs. 9%), headache (13% vs. 11%), insomnia (12% vs. 9%), and increased sweating (12% vs. 10%). Discontinuation rates due to AEs were similar between AROMASIN and tamoxifen (6% vs. 5%). 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%.

Treatment of Advanced Breast Cancer

A total of 1058 patients were treated with exemestane 25 mg once daily in the clinical trials program. 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, 3% of the patients discontinued treatment with exemestane because of adverse reactions, 2.7% of patients discontinued exemestane within the first 10 weeks of treatment.

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 reactions than those treated with megestrol acetate (2% vs. 5%). Adverse reactions 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%).

In the treatment of advanced breast cancer, the most common adverse reactions 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.

6.2 Post-Marketing Experience

Additions and/or revisions underlined: 

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

07/25/2016 (SUPPL-18)

Approved Drug Label (PDF)

5 Warnings and Precautions

Embryo-Fetal Toxicity (added)

  • 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.

Use in Premenopausal Women (added)

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

8 Use in Specific Populations

Females and Males of Reproductive Potential (PLLR Conversion)

Pregnancy Testing
  • Pregnancy testing is recommended for females of reproductive potential within seven days prior to initiating AROMASIN.
Contraception
Females
  • AROMASIN can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with AROMASIN and for 1 month after the final dose.
Infertility
  • Based on findings in animals, male and female fertility may be impaired by treatment with AROMASIN.
Lactation (PLLR Conversion)

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. 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.
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 14C-exemestane.
Pregnancy (PLLR Conversion)

Risk Summary
  • 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.
  • The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Animal Data
  • In animal reproduction studies in rats and rabbits, exemestane caused embryo-fetal toxicity, and was abortifacient. Radioactivity related to 14C-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).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PCI - Embryo-Fetal Toxicity (addition)

  • Advise pregnant women and females of reproductive potential that exposure during pregnancy or within 1 month prior to conception can result in fetal harm. Advise females to inform their healthcare provider of a known or suspected pregnancy.
  • Advise females of reproductive potential to use effective contraception while taking AROMASIN and for 1 month after the last dose.
PCI - Lactation (addition)

  • Advise women not to breastfeed during treatment with AROMASIN and for 1 month after the last dose.