Exemestane Tablets

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, anastrozole 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 anastrozole 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).^[1] 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.^[2] 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.

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.^[4]^[3]

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.^[3]

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.^[3]

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.^[3]

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.^[3]

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).^[3]

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.^[3]

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).^[3]

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).^[3]

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.^[3]

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.^[3]

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).^[3]

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).^[3]

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.^[3]

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.^[3]

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).^[3]

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.^[3]
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.^[3]
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.^[3]

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).^[3]

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).^[3]

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).^[3]
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.^[3]

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.^[3]

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.^[3]

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.^[3]

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.^[3]

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.^[3]

Due to the potential for serious adverse reactions in nursing infants from exemestane, advise women to discontinue breastfeeding 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 breastmilk; however, it has been detected in the breastmilk of animals.^[3]