Exemestane is an irreversible, steroidal aromatase inhibitor. Exemestane is used in postmenopausal women as second-line hormonal therapy of advanced breast cancer and as adjuvant therapy in postmenopausal women with estrogen-receptor positive early breast cancer. An advantage of exemestane is the lack of cross-resistance with other non-steroidal aromatase inhibitors, anastrazole and letrozole, and tamoxifen; patients whose breast cancer progresses while receiving these agents may still respond to exemestane. Exemestane produces more complete estrogen blockade than anastrazole or letrozole. In comparison to megestrol in postmenopausal women with advanced breast cancer, exemestane achieved a similar objective response rate as megestrol, but the time to tumor progression and survival was significantly prolonged with exemestane. In a subset of patients with visceral disease (lung and liver involvement), exemestane achieved higher overall response rates and survival than megestrol. In addition, exemestane caused less weight gain than megestrol. In early breast cancer, the results of the Intergroup Exemestane Study (IES), which investigated whether switching to exemestane after 2-3 years of tamoxifen, indicate that exemestane provides a disease-free survival advantage over 5 years of continuous tamoxifen. The trial was discontinued early because of a significant disease-free survival advantage seen with exemestane after a median of 30.6 months (32% relative risk reduction; 4.7% absolute risk reduction). Aromatase inhibitors are considered to be a standard of therapy and drug class of choice for the treatment of early breast cancer in postmenopausal women with hormone-receptor positive disease. The American Society of Clinical Oncology recommends that all postmenopausal women with hormone receptor-positive early breast cancer receive adjuvant aromatase inhibitor therapy. Options include 5 years of an aromatase inhibitor or sequential therapy with 2-3 years or 5 years of tamoxifen followed by 2-3 years or 5 years of an aromatase inhibitor. The optimal duration of therapy and regimen are not known. The FDA approved exemestane for the treatment of advanced breast cancer in postmenopausal women who have progressed on tamoxifen therapy in October 1999. In October 2005, exemestane was approved as adjuvant hormonal therapy in postmenopausal women with estrogen-receptor positive early breast cancer. Specifically, women who have received 2-3 years of tamoxifen therapy can be switched to exemestane for the completion of a total of five years of adjuvant hormonal therapy.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 1
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
Route-Specific Administration
Oral Administration
-Administer orally after meals.
Pain was reported in 13% of postmenopausal women with advanced breast cancer who received exemestane (n = 358) in a randomized, double-blind, comparative study. Tumor-site pain occurred in 8% of patients with advanced breast cancer who received exemestane in the overall clinical trials program (n = 1058).
Elevated creatinine levels were reported in 5.8% of postmenopausal women with early breast cancer who received adjuvant therapy with exemestane (n = 2252) in a randomized, double-blind, comparative study. Additionally, elevated creatinine levels occurred in 5.5% of patients who received adjuvant exemestane therapy (n = 73) compared with 0% of patients who received placebo (n = 73) in a randomized, double-blind, parallel group study.
Musculoskeletal adverse events including arthralgia (2-14.6%), back pain (2-8.6%), and bone fractures (2-5%) have been reported with exemestane therapy. Arthralgia (14.6%), limb pain (9%), back pain (8.6%), osteoarthritis (5.9%), osteoporosis (4.6%), clinical bone fractures (4.2%), carpal tunnel syndrome (2.4%), muscle cramps (1.5%), osteochondrosis (0.3%), and trigger finger (0.3%) were reported in postmenopausal women with early breast cancer who received adjuvant therapy with exemestane (n = 2252) in a randomized, double-blind, comparative study. Additionally, myalgia occurred in 5.5% of patients who received adjuvant exemestane therapy (n = 73) compared with 4.1% of patients who received placebo (n = 73) in a randomized, double-blind, parallel group study. From baseline to 24 months, lumbar spine bone mineral density (BMD) decreased by 3.14% and 3.51% and femoral neck BMD decreased by 4.15% and 4.57% in these 2 studies. Pathological bone fractures were reported in 2-5% of postmenopausal women with advanced breast cancer who received exemestane (n = 358) in a randomized, double-blind, comparative study. Arthralgia, back pain, and skeletal pain occurred in 2-5% of patients with advanced breast cancer who received exemestane in the overall clinical trials program (n = 1058).
Gastrointestinal adverse events including nausea (8.5-18%) and diarrhea (4-9.6%) have been reported with exemestane therapy. Nausea (8.5%), diarrhea (4.2%), and peptic ulcer (0.7%) were reported in postmenopausal women with early breast cancer who received adjuvant therapy with exemestane (n = 2252) in a randomized, double-blind, comparative study. Most patients who developed a peptic ulcer were receiving concomitant therapy with non-steroidal anti-inflammatory agents and/or had a prior history of peptic ulcer disease. Additionally, diarrhea occurred in 9.6% of patients who received adjuvant exemestane therapy (n = 73) compared with 1.4% of patients who received placebo (n = 73) in a randomized, double-blind, parallel group study. Nausea (18%), vomiting (7%), abdominal pain (6%), anorexia (6%), constipation (5%), diarrhea (4%), and increased appetite (3%) were reported in postmenopausal women with advanced breast cancer who received exemestane (n = 358) in a randomized, double-blind, comparative study; drug-related (or of indeterminate cause) nausea occurred in 9% of patients in this study. Dyspepsia occurred in 2-5% of patients with advanced breast cancer who received exemestane in the overall clinical trials program (n = 1058).
Visual impairment/disturbance was reported in 5% of postmenopausal women with early breast cancer who received adjuvant therapy with exemestane (n = 2252) in a randomized, double-blind, comparative study.
Fatigue was reported in 16.1% of postmenopausal women with early breast cancer who received adjuvant therapy with exemestane (n = 2252) in a randomized, double-blind, comparative study. Additionally, fatigue occurred in 22% of postmenopausal women with advanced breast cancer who received exemestane (n = 358) in a randomized, double-blind, comparative study; drug-related (or of indeterminate cause) fatigue occurred in 8% of patients in this study; drug-related (or of indeterminate cause) fatigue occurred in 8% of patients in this study.
Nervous system adverse events including headache (6.9-13.1%), dizziness (8-9.7%), and paresthesias (2-5%) have been reported with exemestane therapy. Headache (13.1%), dizziness (9.7%), paresthesia (2.6%), and neuropathy (0.6%) were reported in postmenopausal women with early breast cancer who received adjuvant therapy with exemestane (n = 2252) in a randomized, double-blind, comparative study. Additionally, headache occurred in 6.9% of patients who received adjuvant exemestane therapy (n = 73) compared with 4.1% of patients who received placebo (n = 73) in a randomized, double-blind, parallel group study. Headache (8%) and dizziness (8%) were reported in postmenopausal women with advanced breast cancer who received exemestane (n = 358) in a randomized, double-blind, comparative study; paresthesias occurred in 2%-5% of patients in this study. Hypoesthesia occurred in 2-5% of patients with advanced breast cancer who received exemestane in the overall clinical trials program (n = 1058).
Psychological adverse events including insomnia (11-12.4%) and depression (6.2-13%) have been reported with exemestane therapy. Insomnia (12.4%) and depression (6.2%) were reported in postmenopausal women with early breast cancer who received adjuvant therapy with exemestane (n = 2252) in a randomized, double-blind, comparative study. Additionally, depression occurred in 9.6% of patients who received adjuvant exemestane therapy (n = 73) compared with 6.9% of patients who received placebo (n = 73) in a randomized, double-blind, parallel group study. Depression (13%), insomnia (11%), and anxiety (10%) were reported in postmenopausal women with advanced breast cancer who received exemestane (n = 358) in a randomized, double-blind, comparative study. Confusion occurred in 2-5% of patients with advanced breast cancer who received exemestane in the overall clinical trials program (n = 1058).
Dermatologic adverse effects including hyperhidrosis (4-11.8%) and alopecia (2-15.1%) have been reported with exemestane therapy. Hyperhidrosis was reported in 11.8% of postmenopausal women with early breast cancer who received adjuvant therapy with exemestane (n = 2252) in a randomized, double-blind, comparative study. Alopecia (15.1% vs 4.1%) and dermatitis (8.2% vs 1.4%) occurred more often in patients who received adjuvant exemestane therapy (n = 73) compared with placebo (n = 73) in a randomized, double-blind, parallel group study. Hyperhidrosis occurred in 6% of postmenopausal women with advanced breast cancer who received exemestane (n = 358) in a randomized, double-blind, comparative study; drug-related (or of indeterminate cause) hyperhidrosis occurred in 4% of patients in this study. In this study, rash (unspecified) occurred in 2-5% of patients. Alopecia occurred in 2-5% of patients with advanced breast cancer who received exemestane in the overall clinical trials program (n = 1058). Acute generalized exanthematous pustulosis was reported in post-marketing experience; 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.
Hot flashes/flushes have been reported in 13-32.9% of exemestane-treated patients. Hot flushes were reported in 21.2% of postmenopausal women with early breast cancer who received adjuvant therapy with exemestane (n = 2252) in a randomized, double-blind, comparative study. Additionally, hot flushes occurred in 32.9% of patients who received adjuvant exemestane therapy (n = 73) compared with 24.7% of patients who received placebo (n = 73) in a randomized, double-blind, parallel group study. Hot flashes occurred in 13% of postmenopausal women with advanced breast cancer who received exemestane (n = 358) in a randomized, double-blind, comparative study.
Hypertension has been reported in 5-15.1% of exemestane-treated patients. Hypertension was reported in 9.8% of postmenopausal women with early breast cancer who received adjuvant therapy with exemestane (n = 2252) in a randomized, double-blind, comparative study. Additionally, hypertension occurred in 15.1% of patients who received adjuvant exemestane therapy (n = 73) compared with 6.9% of patients who received placebo (n = 73) in a randomized, double-blind, parallel group study. Hypertension occurred in 5% of postmenopausal women with advanced breast cancer who received exemestane (n = 358) in a randomized, double-blind, comparative study. Chest pain (unspecified) occurred in 2-5% of patients with advanced breast cancer who received exemestane in the overall clinical trials program (n = 1058).
Weight gain was reported in 8% of postmenopausal women with advanced breast cancer who received exemestane (n = 358) in a randomized, double-blind, comparative study.
Edema including peripheral edema was reported in 7% of postmenopausal women with advanced breast cancer who received exemestane (n = 358) in a randomized, double-blind, comparative study; lymphedema occurred in 2-5% of patients in this study.
Dyspnea (10%) and cough (6%) were reported in postmenopausal women with advanced breast cancer who received exemestane (n = 358) in a randomized, double-blind, comparative study.
Fever was reported in 2-5% of postmenopausal women with advanced breast cancer who received exemestane (n = 358) in a randomized, double-blind, comparative study. Fever occurred in 5% of patients with advanced breast cancer who received exemestane in the overall clinical trials program (n = 1058).
Generalized weakness was reported in 2-5% of postmenopausal women with advanced breast cancer who received exemestane (n = 358) in a randomized, double-blind, comparative study. Asthenia occurred in 6% of patients with advanced breast cancer who received exemestane in the overall clinical trials program (n = 1058).
Infection has been reported with exemestane therapy. Influenza like symptoms were reported in 6% of postmenopausal women with advanced breast cancer who received exemestane (n = 358) in a randomized, double-blind, comparative study; bronchitis, sinusitis, and urinary tract infection were reported in 2-5% of patients in this study. Infection, upper respiratory tract infection, pharyngitis, and rhinitis occurred in 2-5% of patients with advanced breast cancer who received exemestane in the overall clinical trials program (n = 1058).
Pruritus was reported in 2-5% of postmenopausal women with advanced breast cancer who received exemestane (n = 358) in a randomized, double-blind, comparative study. In post-marketing surveillance, hypersensitivity reactions, pruritus, and urticaria were reported in patients who received exemestane therapy.
Hyperbilirubinemia (5.3%) and increased alkaline phosphatase levels (15%) were reported in postmenopausal women with early breast cancer who received adjuvant therapy with exemestane (n = 2252) in a randomized, double-blind, comparative study; grade 3 or 4 bilirubin elevations occurred in 0.9% of exemestane-treated patients. Additionally, hyperbilirubinemia (6.9% vs 0%) and increased alkaline phosphatase levels (13.7% vs 6.9%) occurred more often in patients who received adjuvant exemestane therapy (n = 73) compared with placebo (n = 73) in a randomized, double-blind, parallel group study. Grade 3 or higher elevated hepatic enzymes (e.g., AST, ALT, alkaline phosphatase, and gamma glutamyl transferase (GGT) levels > 5 times the upper limit of the normal) have been reported rarely in patients with advanced breast cancer who received exemestane; however, most cases were attributed to the presence of liver and/or bone metastases. Grade 3 or 4 increased GGT levels (without evidence of liver metastasis) were reported in 2.7% of postmenopausal women with advanced breast cancer who received exemestane (n = 358) in a randomized, double-blind, comparative study. In post-marketing surveillance and in clinical trials, hepatitis including hepatitis with cholestasis was reported in patients who received exemestane therapy.
Thromboembolism was reported in 0.9% of postmenopausal women with early breast cancer who received adjuvant therapy with exemestane (n = 2252) in a randomized, double-blind, comparative study.
Endometrial hyperplasia (0.6%) and uterine polyps (0.4%) were reported in postmenopausal women with early breast cancer who received adjuvant therapy with exemestane (n = 2252) in a randomized, double-blind, comparative study.
Grade 3 or 4 lymphopenia was reported in 20% of patients with advanced breast cancer who received exemestane clinical trials. Most patients (89%) had lymphopenia prior to treatment and lymphopenia resolved or improved in 40% of these patients during exemestane therapy.
In clinical trials, reductions in bone mineral density over time have been seen in patients taking exemestane; exemestane therapy has been associated with an increased risk of fractures over tamoxifen, albeit a nonsignificant increased risk. Pre-existing osteoporosis or osteopenia does not contraindicate the use of exemestane; however, the concomitant use of bisphosphonates should be considered in these populations. Patients with pre-existing osteoporosis, osteopenia, or risk factors for the development of osteoporosis should have bone mineral density formally assessed prior to starting treatment with exemestane. Monitor patients for signs and symptoms of osteoporosis, including decreased bone mineral density (BMD), during treatment with exemestane as appropriate. Currently, the effects of combination exemestane and bisphosphonates on bone mineral density and fractures is unknown; studies are currently ongoing to investigate the effects of their combined use.
Vitamin D deficiency is common in women with early breast cancer; therefore, evaluate 25-hydroxy vitamin D concentrations prior to initiating exemestane therapy. Begin vitamin D supplementation in patients with vitamin D deficiency.
Pregnancy should be avoided by females of reproductive potential during treatment and for at least 1 month after the last dose. Although there are no adequately controlled studies in pregnant animals or humans, exemestane can cause fetal harm and is expected to result in adverse reproductive effects because of its mechanism of action. In animal studies following oral administration of exemestane 1 mg/kg, radioactivity related to 14-C-exemestane and its metabolites crossed the placenta of rats, with concentrations in maternal and fetal blood approximately equivalent. When rats were given 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 approximately 1.5 times the recommended human 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 approximately 7.5 times the recommended human dose on a mg/m2 basis. In rabbits, daily doses of exemestane during organogenesis caused a decrease in placental weight at 70 times the recommended human dose on a mg/m2 basis, and in the presence of maternal toxicity, abortions, increased resorptions, and reduced fetal weight occurred at 210 times the recommended human dose on a mg/m2 basis. Fetal malformations were not seen in rats or rabbits at approximately 320 and 210 times the recommended human dose on a mg/m2 basis, respectively.
Counsel patients about the reproductive risk and contraception requirements during exemestane treatment. Exemestane can cause fetal harm if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during and for at least 1 month after treatment with exemestane. Females of reproductive potential should undergo pregnancy testing within 7 days prior to initiation of exemestane. Women who become pregnant while receiving exemestane should be apprised of the potential hazard to the fetus. In addition, based on animal data, exemestane treatment may result in impaired fertility or infertility in both males and females.
Due to the potential for serious adverse reactions in nursing infants from exemestane, advise women to discontinue breast-feeding during treatment and for 1 month after the final dose. Exemestane is not indicated for premenopausal women and thus should not be given to women who are breast-feeding their infants. It is not known if exemestane is excreted into human breast milk; however, it has been detected in the breast milk of animals.
For the treatment of breast cancer in postmenopausal women:
-for the adjuvant treatment of estrogen receptor-positive early breast cancer in postmenopausal women who have already received 2 to 3 years of tamoxifen therapy, and who are switched to exemestane for completion of a total of 5 consecutive years of adjuvant hormonal therapy:
NOTE: Exemestane is not indicated for the treatment of breast cancer in premenopausal women.
Oral dosage:
Postmenopausal females: 25 mg by mouth once daily after a meal; a dose adjustment is necessary if coadministered with potent CYP3A4 inducers. Treatment with exemestane should be continued in the absence of recurrent or contralateral breast cancer until a total of 5 years of adjuvant hormonal therapy is completed. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In the Intergroup Exemestane Study 031 (IES), a multicenter, randomized, double-blind study (n = 4,742), conversion to exemestane hormonal therapy after 2 to 3 years of tamoxifen therapy significantly improved disease-free survival (primary outcome) when compared with 5 continuous years of tamoxifen therapy. Additionally, distant recurrence-free survival and time to contralateral breast cancer were significantly improved with exemestane therapy. Exemestane did not have a statistically significant effect on overall survival. Exemestane therapy was associated with an increase in the incidence of arthralgia, fractures, and osteoporosis. Tamoxifen-only therapy was associated with a significant increase in thromboembolic events, as well as an increase in gynecological symptoms vaginal bleeding.
-for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy:
NOTE: Exemestane is not indicated for the treatment of breast cancer in premenopausal women.
Oral dosage:
Postmenopausal females: 25 mg by mouth once daily after a meal until tumor progression is evident. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with exemestane (n = 366) resulted in a similar objective response rate compared with megestrol acetate (n = 403) in postmenopausal women with advanced breast cancer and disease progression after tamoxifen in a multicenter, randomized, double-blind clinical trial (15% vs. 12.4%). The median duration of response was 76.1 weeks for patients treated with exemestane compared with 71 weeks for those who received megestrol; the median time to progression was 20.3 weeks vs. 16.6 weeks, respectively. There were too few deaths to draw conclusions regarding overall survival. In two single-arm trials, response rates for exemestane were 23.4% and 28.1%.
-for the treatment of estrogen receptor positive, HER2 negative, locally advanced or metastatic breast cancer in postmenopausal women refractory to letrozole or anastrozole, in combination with everolimus*:
NOTE: Everolimus (Afinitor) is FDA-approved for use in combination with exemestane for the treatment of hormone receptor-positive, HER2-negative advanced breast cancer in postmenopausal women who have failed treatment with letrozole or anastrozole.
Oral dosage:
Postmenopausal females: 25 mg PO once daily plus everolimus (10 mg PO once daily). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a randomized, double-blind, phase 3 clinical trial, treatment with everolimus significantly improved median investigator-assessed progression-free survival (PFS) compared with exemestane monotherapy (7.8 months vs. 3.2 months) in postmenopausal women with ER-positive, HER2-negative metastatic or locally advanced breast cancer, refractory to letrozole or anastrozole (n = 724); PFS was also significantly improved when assessed by central radiology review (11 months vs. 4.1 months). At a median follow-up time of 39.3 months, median overall survival was 31 months in patients treated with combination therapy compared with 26.6 months in those who received exemestane alone. Selected grade 3 and 4 adverse events reported more often in the combination arm included stomatitis (8% vs. less than 1%), anemia (less than 8% vs. less than 2%), hyperglycemia (less than 6% vs. less than 1%), fatigue (less than 5% vs. 1%), and dyspnea (less than 6% vs. less than 2%).
Maximum Dosage Limits:
-Adults
25 mg/day PO; if a potent CYP3A4 inducer is co-prescribed the maximum is 50 mg/day PO. Higher doses are tolerated but do not result in clinically significant increases in estrogen suppression.
-Elderly
25 mg/day PO; if a potent CYP3A4 inducer is co-prescribed the maximum is 50 mg/day PO. Higher doses are tolerated but do not result in clinically significant increases in estrogen suppression.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
The safety of chronic dosing of exemestane in patients with moderate or severe hepatic impairment has not been studied. It does not appear dosage adjustments are necessary based on experience with exemestane at repeated doses of 200 mg/day.
Patients with Renal Impairment Dosing
The safety of chronic dosing of exemestane in patients with renal impairment has not been studied. It does not appear dosage adjustments are necessary based on experience with exemestane at repeated doses of 200 mg/day.
*non-FDA-approved indication
Apalutamide: (Major) If coadministration of exemestane with apalutamide is necessary, increase the dose of exemestane to 50 mg once daily after a meal. Exemestane is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exemestane exposure by 54%.
Carbamazepine: (Major) If coadministration of exemestane with carbamazepine is necessary, increase the dose of exemestane to 50 mg once daily after a meal. Exemestane is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exemestane exposure by 54%.
Conjugated Estrogens: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Conjugated Estrogens; Bazedoxifene: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Conjugated Estrogens; Medroxyprogesterone: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Desogestrel; Ethinyl Estradiol: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Dienogest; Estradiol valerate: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Drospirenone; Estetrol: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Drospirenone; Estradiol: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Drospirenone; Ethinyl Estradiol: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Elagolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Encorafenib: (Major) If coadministration of exemestane with encorafenib is necessary, increase the dose of exemestane to 50 mg once daily after a meal. Exemestane is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased exemestane exposure by 54%.
Enzalutamide: (Major) If coadministration of exemestane with enzalutamide is necessary, increase the dose of exemestane to 50 mg once daily after a meal. Exemestane is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exemestane exposure by 54%.
Eslicarbazepine: (Moderate) Use caution if coadministration of exemestane with eslicarbazepine is necessary, and monitor for a possible decrease in the efficacy of exemestane. Exemestane is a CYP3A4 substrate; eslicarbazepine is a moderate CYP3A4 inducer. In a pharmacokinetic interaction study (n = 10) with a strong CYP3A4 inducer, rifampicin (600 mg daily for 14 days), the mean Cmax and AUC of exemestane (single dose) decreased by 41% and 54%, respectively. The manufacturer of exemestane recommends a dose increase when concomitant use with a strong CYP3A4 inducer is necessary; recommendations are not available for moderate CYP3A4 inducers.
Esterified Estrogens: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Esterified Estrogens; Methyltestosterone: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Estradiol: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Estradiol; Levonorgestrel: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Estradiol; Norethindrone: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Estradiol; Norgestimate: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Estradiol; Progesterone: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Estrogens: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Estropipate: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Ethinyl Estradiol; Norelgestromin: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Ethinyl Estradiol; Norethindrone Acetate: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Ethinyl Estradiol; Norgestrel: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Ethynodiol Diacetate; Ethinyl Estradiol: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Etonogestrel; Ethinyl Estradiol: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Fosphenytoin: (Major) If coadministration of exemestane with fosphenytoin is necessary, increase the dose of exemestane to 50 mg once daily after a meal. Exemestane is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exemestane exposure by 54%.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) If coadministration of exemestane with rifampin is necessary, increase the dose of exemestane to 50 mg once daily after a meal. Exemestane is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased exemestane exposure by 54%.
Isoniazid, INH; Rifampin: (Major) If coadministration of exemestane with rifampin is necessary, increase the dose of exemestane to 50 mg once daily after a meal. Exemestane is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased exemestane exposure by 54%.
Levonorgestrel; Ethinyl Estradiol: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Lumacaftor; Ivacaftor: (Major) If coadministration of exemestane with lumacaftor; ivacaftor is necessary, increase the dose of exemestane to 50 mg once daily after a meal. Exemestane is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exemestane exposure by 54%.
Lumacaftor; Ivacaftor: (Major) If coadministration of exemestane with lumacaftor; ivacaftor is necessary, increase the dose of exemestane to 50 mg once daily after a meal. Exemestane is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exemestane exposure by 54%.
Mitotane: (Major) If coadministration of exemestane with mitotane is necessary, increase the dose of exemestane to 50 mg once daily after a meal. Exemestane is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exemestane exposure by 54%.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Norethindrone; Ethinyl Estradiol: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Norgestimate; Ethinyl Estradiol: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Phenobarbital: (Major) If coadministration of exemestane with phenobarbital is necessary, increase the dose of exemestane to 50 mg once daily after a meal. Exemestane is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exemestane exposure by 54%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) If coadministration of exemestane with phenobarbital is necessary, increase the dose of exemestane to 50 mg once daily after a meal. Exemestane is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exemestane exposure by 54%.
Phenytoin: (Major) If coadministration of exemestane with phenytoin is necessary, increase the dose of exemestane to 50 mg once daily after a meal. Exemestane is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exemestane exposure by 54%.
Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Major) Prasterone, dehydroepiandrosterone, DHEA is converted via hydrosteroid dehydrogenases and aromatase into androstenedione, testosterone, and estradiol by peripheral tissues. Prasterone or DHEA supplements should not be given concurrently with any aromatase inhibitors, as DHEA could interfere with the pharmacologic action of the aromatase inhibitor and compromise aromatase inhibitor effectiveness. Conversely, aromatase inhibitors (e.g., aminoglutethimide, anastrozole, exemestane, letrozole, testolactone, vorozole) could interfere with biotransformation of DHEA.
Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Major) Prasterone, dehydroepiandrosterone, DHEA is converted via hydrosteroid dehydrogenases and aromatase into androstenedione, testosterone, and estradiol by peripheral tissues. Prasterone or DHEA supplements should not be given concurrently with any aromatase inhibitors, as DHEA could interfere with the pharmacologic action of the aromatase inhibitor and compromise aromatase inhibitor effectiveness. Conversely, aromatase inhibitors (e.g., aminoglutethimide, anastrozole, exemestane, letrozole, testolactone, vorozole) could interfere with biotransformation of DHEA.
Primidone: (Major) If coadministration of exemestane with primidone is necessary, increase the dose of exemestane to 50 mg once daily after a meal. Exemestane is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exemestane exposure by 54%.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
Rifampin: (Major) If coadministration of exemestane with rifampin is necessary, increase the dose of exemestane to 50 mg once daily after a meal. Exemestane is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased exemestane exposure by 54%.
Rifapentine: (Major) If coadministration of exemestane with rifapentine is necessary, increase the dose of exemestane to 50 mg once daily after a meal. Exemestane is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exemestane exposure by 54%.
Segesterone Acetate; Ethinyl Estradiol: (Major) Avoid concomitant use of estrogens and exemestane. Estrogen-containing therapies may reduce the effectiveness of aromatase inhibitors, such as exemestane.
St. John's Wort, Hypericum perforatum: (Major) If coadministration of exemestane with St. John's Wort is necessary, increase the dose of exemestane to 50 mg once daily after a meal. Exemestane is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer, although the amount of individual constituents of various St. John's Wort products may alter its inducing effects, making drug interactions unpredictable. Coadministration with another strong CYP3A4 inducer decreased exemestane exposure by 54%.
Exemestane irreversibly inhibits aromatase activity (approximately 98%) and reduces plasma estrone, estradiol and estrone sulphate levels by 85-95%. Exemestane is 150-times more potent than aminoglutethimide in inhibiting aromatase. Maximal aromatase suppresion occurs at exemestane doses of 10-25 mg. In postmenopausal women, the principal source of circulating estrogens is from the conversion of adrenal and ovarian androgens (androstenedione and testosterone) to estrogens (estrone and estradiol) by aromatase in peripheral tissues. Exemestane is structurally related to androstenedione and functions as false substrate for aromatase. Exemestane is processed to an intermediate that binds irreversibly to the active site of aromatase causing its inactivation, also known as "suicide inhibition." Non-steroidal aromatase inhibitors (e.g., anastrazole and letrozole) competitively bind to a different part of the aromatase enzyme. Exemestane has no detectable effect on adrenal biosynthesis of corticosteroids or aldosterone. Exemestane has no effect on other enzymes involved in steroid synthesis up to a concentration of at least 600-times higher than that needed to inhibit aromatase. Exemestane has a slight affinity for the androgen receptor. The binding of the 17-dihydrometabolite is 100-times that of exemestane; however, significant increases testosterone or androstenedione have only been seen at exemestane doses > 200 mg/day. A dose-dependent decrease in sex hormone binding globulin (SHBG) has been observed with doses of exemestane > 2.5 mg/day. Slight, nondose-dependent increases in serum lutenizing hormone (LH) and follicle-stimulating hormone (FSH) levels have been observed as a consequence of feedback at the pituitary level.
Exemestane is given orally. It is extensively distributed into tissues and is 90% bound to plasma proteins, including albumin and alpha1-acid glycoprotein. Maximal suppression of circulating endogenous estrogens occurs 2 to 3 days after beginning treatment with 25 mg/day orally and persists for 4 to 5 days. Exemestane is extensively metabolized via oxidation of the methylene group in position 6 and reduction of the 17-keto group with subsequent formation of many secondary metabolites. CYP3A4 is the principle isoenzyme involved in the oxidation. The metabolites are inactive or inhibit aromatase to a lesser degree than the parent drug. The 17-dihydrometabolite may have androgenic activity. The terminal half-life is about 24 hours.
Affected cytochrome P450 isoenzymes: CYP3A4
Exemestane is metabolized by CYP3A4 and aldoketoreductases. Strong inducers of CYP3A4 may significantly decrease exposure to exemestane. However, coadministration with ketoconazole, a strong CYP3A4 inhibitor, had no significant effect on exemestane exposure suggesting interactions with CYP3A4 inhibitors are unlikely. Exemestane does not inhibit any of the major CYP enzymes.
-Route-Specific Pharmacokinetics
Oral Route
Exemestane is rapidly absorbed after oral administration; the Tmax in breast cancer patients was 1.2 hours. The bioavailability of exemestane is about 42% and is increased by approximately 40% following a high-fat breakfast. Additionally, a high-fat breakfast increased the AUC and Cmax by 59% and 39%, respectively.
-Special Populations
Hepatic Impairment
The AUC of exemestane is approximately 3 times higher in patients with moderate to severe hepatic as compared to healthy volunteers. Patients with hepatic impairment demonstrated a moderate increase in non-life threatening adverse events with repeated doses of 200 mg/day; however, dosage adjustment in these patients is not necessary.
Renal Impairment
The AUC of exemestane is approximately 3 times higher in patients with moderate to severe renal insufficiency as compared to healthy volunteers. Patients with renal impairment demonstrated a moderate increase in non-life threatening adverse events with repeated doses of 200 mg/day; however, dosage adjustment in these patients is not necessary.
Pediatrics
The pharmacokinetics of exemestane have not been studied in pediatric patients.
Gender Differences
Exemestane appears to be more rapidly absorbed in women with breast cancer than in healthy women (Tmax 1.2 hours and 2.9 hours, respectively). The oral clearance of exemestane is 45% lower in postmenopausal women with breast cancer than in healthy postmenopausal women. The mean AUC values following repeated doses in women with breast cancer (75.4 ng x hour/mL) were about twice those in healthy women (41.4 ng x hour/mL).