Exemestane Information
Exemestane () Indications And Usage
Exemestane () Tablets are 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 Exemestane () Tablets for completion of a total of five consecutive years of adjuvant hormonal therapy ().
Exemestane () Tablets are indicated for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy ().
Exemestane () Dosage And Administration
For patients receiving Exemestane () tablets with a potent CYP 3A4 inducer such as rifampicin or phenytoin, the recommended dose of Exemestane () tablets is 50 mg once daily after a meal.
The safety of chronic dosing in patients with moderate or severe hepatic or renal impairment has not been studied. Based on experience with Exemestane () at repeated doses up to 200 mg daily that demonstrated a moderate increase in non life-threatening adverse events, dosage adjustment does not appear to be necessary [seeand]
Exemestane () Dosage Forms And Strengths
Exemestane () Tablets are round, white film coated, biconvex tablets, debossed with product identification "54 571" on one side and plain on the other side. Each tablet contains 25 mg of Exemestane () .
Exemestane () Contraindications
Exemestane () Tablets can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action Exemestane () is expected to result in adverse reproductive effects. In non-clinical studies in rats and rabbits, Exemestane () was embryotoxic, fetotoxic, and abortifacient.
Exemestane () Tablets are contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Exemestane () Tablets should not be administered to premenopausal women [].
Exemestane () Warnings And Precautions
In patients with early breast cancer, the incidence of hematological abnormalities of Common Toxicity Criteria (CTC) grade ≥1 was lower in the Exemestane () treatment group, compared with tamoxifen. Incidence of CTC grade 3 or 4 abnormalities was low (approximately 0.1%) in both treatment groups. Approximately 20% of patients receiving Exemestane () in clinical studies in advanced breast cancer experienced CTC grade 3 or 4 lymphocytopenia. Of these patients, 89% had a pre-existing lower grade lymphopenia. Forty percent of patients either recovered or improved to a lesser severity while on treatment. Patients did not have a significant increase in viral infections, and no opportunistic infections were observed. Elevations of serum levels of AST, ALT, alkaline phosphatase, and gamma glutamyl transferase > 5 times the upper value of the normal range (i.e., ≥ CTC grade 3) have been rarely reported in patients treated for advanced breast cancer but appear mostly attributable to the underlying presence of liver and/or bone metastases. In the comparative study in advanced breast cancer patients, CTC grade 3 or 4 elevation of gamma glutamyl transferase without documented evidence of liver metastasis was reported in 2.7% of patients treated with Exemestane () and in 1.8% of patients treated with megestrol acetate.
In patients with early breast cancer, elevations in bilirubin, alkaline phosphatase, and creatinine were more common in those receiving Exemestane () than either tamoxifen or placebo. Treatment-emergent bilirubin elevations (any CTC grade) occurred in 5.3% of Exemestane () patients and 0.8% of tamoxifen patients on the Intergroup Exemestane () Study (IES), and in 6.9% of Exemestane () treated patients vs. 0% of placebo treated patients in the 027 study. CTC grade 3–4 increases in bilirubin occurred in 0.9% of Exemestane () treated patients compared to 0.1% of tamoxifen treated patients. Alkaline phosphatase elevations of any CTC grade occurred in 15.0% of Exemestane () treated patients on the IES compared to 2.6% of tamoxifen treated patients, and in 13.7% of Exemestane () treated patients compared to 6.9% of placebo treated patients in study 027. Creatinine elevations occurred in 5.8% of Exemestane () treated patients and 4.3% of tamoxifen treated patients on the IES and in 5.5% of Exemestane () treated patients and 0% of placebo treated patients in study 027.
Reductions in bone mineral density (BMD) over time are seen with Exemestane () use. Table 1 describes changes in BMD from baseline to 24 months in patients receiving Exemestane () compared to patients receiving tamoxifen (IES) or placebo (027). Concomitant use of bisphosphonates, vitamin D supplementation, and calcium was not allowed.
Exemestane () Adverse Reactions
Exemestane () was generally well tolerated and adverse events were usually mild to moderate.
In the adjuvant treatment of early breast cancer, adverse events occurring in ≥10% of patients in any treatment group (Exemestane () vs tamoxifen) were hot flushes (21.2% vs 19.9%), fatigue (16.1% vs 14.7%), arthralgia (14.6% vs 8.6%), headache (13.1% vs 10.8%), insomnia (12.4% vs 8.9%), and increased sweating (11.8% vs 10.4%). Discontinuation rates due to AEs were similar between Exemestane () and tamoxifen (6.3% vs 5.1%). Incidence of cardiac ischemic events (myocardial infarction, angina, and myocardial ischemia) were Exemestane () 1.6%, tamoxifen 0.6%. Incidence of cardiac failure: Exemestane () 0.4%, tamoxifen 0.3%.
In the treatment of advanced breast cancer, the most common adverse events were mild to moderate and 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 Exemestane () and megestrol acetate, respectively.
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 practice.
Exemestane () Drug Interactions
In a pharmacokinetic interaction study of 10 healthy postmenopausal volunteers pretreated with potent CYP 3A4 inducer rifampicin 600 mg daily for 14 days followed by a single dose of Exemestane () 25 mg, the mean plasma C and AUC 0–∞ of Exemestane () were decreased by 41% and 54%, respectively.
Significant pharmacokinetic interactions mediated by inhibition of CYP isoenzymes therefore appear unlikely. Comedications 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 potent CYP 3A4 inducer [see ].
Exemestane () Use In Specific Populations
Pregnancy Category X. See “Contraindications” section.
Exemestane () can cause fetal harm when administered to a pregnant woman and the clinical benefit to premenopausal women with breast cancer has not been demonstrated. Exemestane () Tablets are contraindicated in women who are or may become pregnant. There are no adequate and well-controlled studies of Exemestane () in pregnant women.
In non-clinical studies in rats and rabbits, Exemestane () was embryotoxic, fetotoxic, and abortifacient. Radioactivity related to 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/mbasis). Prolonged gestation and abnormal or difficult labor was observed at doses equal to or greater than 20 mg/kg/day. Increased resorption, reduced number of live fetuses, decreased fetal weight, and retarded ossification were also observed at these doses. No malformations were noted when Exemestane () was administered to pregnant rats during the organogenesis period at doses up to 810 mg/kg/day (approximately 320 times the recommended human dose on a mg/mbasis). 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/mbasis). Abortions, an increase in resorptions, and a reduction in fetal body weight were seen at 270 mg/kg/day. There was no increase in the incidence of malformations in rabbits at doses up to 270 mg/kg/day (approximately 210 times the recommended human dose on a mg/mbasis).
If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus and the potential risk for pregnancy loss.
The pharmacokinetics of Exemestane () have been investigated in subjects with moderate or severe hepatic insufficiency (Childs-Pugh B or C). Following a single 25-mg oral dose, the AUC of Exemestane () was approximately 3 times higher than that observed in healthy volunteers.
The safety of chronic dosing in patients with moderate or severe hepatic impairment has not been studied. Based on experience with Exemestane () at repeated doses up to 200 mg daily that demonstrated a moderate increase in non life-threatening adverse events, dosage adjustment does not appear to be necessary.
Exemestane () 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/mmwith 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/mbasis). 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/mbasis) and of 3000 mg/kg (about 4000 times the recommended human dose on a mg/mbasis), 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/mbasis), respectively.
Exemestane () 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 CH O and its structural formula is as follows:
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 Exemestane () 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.
Exemestane () Clinical Pharmacology
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. Estrogen deprivation through aromatase inhibition is an effective and selective treatment for some postmenopausal patients with hormone-dependent breast cancer.
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.
Effect on Estrogens
Effect on Corticosteroids:
Other Endocrine Effects:
Coagulation and Lipid Effects
Following oral administration to healthy postmenopausal women, Exemestane () is rapidly absorbed. After maximum plasma concentration is reached, levels decline polyexponentially with a mean terminal half-life of about 24 hours. Exemestane () is extensively distributed and is cleared from the systemic circulation primarily by metabolism. The pharmacokinetics of Exemestane () are dose proportional after single (10 to 200 mg) or repeated oral doses (0.5 to 50 mg). Following repeated daily doses of Exemestane () 25 mg, plasma concentrations of unchanged drug are similar to levels measured after a single dose.
Pharmacokinetic parameters in postmenopausal women with advanced breast cancer following single or repeated doses have been compared with those in healthy, postmenopausal women. Exemestane () appeared to be more rapidly absorbed in the women with breast cancer than in the healthy women, with a mean -t of 1.2 hours in the women with breast cancer and 2.9 hours in the healthy women. After repeated dosing, the average oral clearance in women with advanced breast cancer was 45% lower than the oral clearance in healthy postmenopausal women, with corresponding higher systemic exposure. Mean AUC values following repeated doses in women with breast cancer (75.4 ng·h/mL) were about twice those in healthy women (41.4 ng·h/mL).
Absorption:
Distribution:
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Metabolism/Elimination:
12.2
Exemestane () is metabolized by cytochrome P 450 3A4 (CYP 3A4) and aldoketoreductases. It does not inhibit any of the major CYP isoenzymes, including CYP 1A2, 2C9, 2D6, 2E1, and 3A4.
Exemestane () Clinical Studies
The Intergroup Exemestane () Study 031 (IES) was a randomized, double-blind, multicenter, multinational study comparing Exemestane () (25 mg/day) vs. tamoxifen (20 or 30 mg/day) in postmenopausal women with early breast cancer. Patients who remained disease-free after receiving adjuvant tamoxifen therapy for 2 to 3 years were randomized to receive an additional 3 or 2 years of Exemestane () or tamoxifen to complete a total of 5 years of hormonal therapy.
The primary objective of the study was to determine whether, in terms of disease-free survival, it was more effective to switch to Exemestane () rather than continuing tamoxifen therapy for the remainder of five years. Disease-free survival was defined as the time from randomization to time of local or distant recurrence of breast cancer, contralateral invasive breast cancer, or death from any cause.
The secondary objectives were to compare the two regimens in terms of overall survival and long-term tolerability. Time to contralateral invasive breast cancer and distant recurrence-free survival were also evaluated.
A total of 4724 patients in the intent-to-treat (ITT) analysis were randomized to Exemestane () tablets 25 mg once daily (N = 2352) or to continue to receive tamoxifen once daily at the same dose received before randomization (N = 2372). Demographics and baseline tumor characteristics are presented in Table 5. Prior breast cancer therapy is summarized in Table 6.
Table 5. Demographic and Baseline Tumor Characteristics from the IES Study of Postmenopausal Women with Early Breast Cancer (ITT Population)
**Only one subject in the Exemestane () group had unknown ER status and positive PgR status.
Table 6. Prior Breast Cancer Therapy of Patients in the IES Study of Postmenopausal Women with Early Breast Cancer (ITT Population)
After a median duration of therapy of 27 months and with a median follow-up of 34.5 months, 520 events were reported, 213 in the Exemestane () group and 307 in the tamoxifen group (Table 7).
Table 7. Primary Endpoint Events (ITT Population)
Disease-free survival in the intent-to-treat population was statistically significantly improved [Hazard Ratio (HR) = 0.69, 95% CI: 0.58, 0.82, P = 0.00003, Table 8, Figure 1] in the Exemestane () arm compared to the tamoxifen arm. In the hormone receptor-positive subpopulation representing about 85% of the trial patients, disease-free survival was also statistically significantly improved (HR = 0.65, 95% CI: 0.53, 0.79, P = 0.00001) in the Exemestane () arm compared to the tamoxifen arm. Consistent results were observed in the subgroups of patients with node negative or positive disease, and patients who had or had not received prior chemotherapy. Overall survival was not significantly different in the two groups, with 116 deaths occurring in the Exemestane () group and 137 in the tamoxifen group.
Table 8. Efficacy Results from the IES Study in Postmenopausal Women with Early Breast Cancer
Figure 1. Disease-Free Survival in the IES Study of Postmenopausal Women with Early Breast Cancer (ITT Population)
Exemestane () 25 mg administered once daily was evaluated in a randomized double-blind, multicenter, multinational comparative study and in two multicenter single-arm studies of postmenopausal women with advanced breast cancer who had disease progression after treatment with tamoxifen for metastatic disease or as adjuvant therapy. Some patients also have received prior cytotoxic therapy, either as adjuvant treatment or for metastatic disease.
The primary purpose of the three studies was evaluation of objective response rate (complete response [CR] and partial response [PR]). Time to tumor progression and overall survival were also assessed in the comparative trial. Response rates were assessed based on World Health Organization (WHO) criteria, and in the comparative study, were submitted to an external review committee that was blinded to patient treatment. In the comparative study, 769 patients were randomized to receive Exemestane () tablets 25 mg once daily (N = 366) or megestrol acetate 40 mg four times daily (N = 403). Demographics and baseline characteristics are presented in Table 9.
Table 9. Demographics and Baseline Characteristics from the Comparative Study of Postmenopausal Women with Advanced Breast Cancer Whose Disease Had Progressed after Tamoxifen Therapy
The efficacy results from the comparative study are shown in Table 10. The objective response rates observed in the two treatment arms showed that Exemestane () was not different from megestrol acetate. Response rates for Exemestane () from the two single-arm trials were 23.4% and 28.1%.
Table 10. Efficacy Results from the Comparative Study of Postmenopausal Women with Advanced Breast Cancer Whose Disease Had Progressed after Tamoxifen Therapy
There were too few deaths occurring across treatment groups to draw conclusions on overall survival differences. The Kaplan-Meier curve for time to tumor progression in the comparative study is shown in Figure 2.
Figure 2. Time to Tumor Progression in the Comparative Study of Postmenopausal Women With Advanced Breast Cancer Whose Disease Had Progressed After Tamoxifen Therapy
Exemestane () How Supplied/storage And Handling
Exemestane () Tablets are supplied as round, white film coated, biconvex tablets, debossed with product identification “54 571” on one side and plain on the other side. Each tablet contains 25 mg of Exemestane () . Exemestane () Tablets are supplied in a child resistant container.
NDC 0054-0080-13 25 mg white tablet, bottle of 30
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature].
Exemestane () Patient Counseling Information
See FDA-Approved Patient Labeling
Patients should be informed that Exemestane () lowers the level of estrogen in the body. This may lead to reduction in bone mineral density (BMD) over time. The lower the BMD, the greater the risk of osteoporosis and fracture.
10003700/02 Revised March 2011
© RLI, 2011
FDA- Approved Patient Labeling
PATIENT INFORMATION
Exemestane () Tablets
Read the patient information leaflet that comes with Exemestane () before you start taking it. Read the leaflet each time you get a refill. There may be new information. This leaflet does not replace talking with your doctor about your condition or treatment. If you have any questions about Exemestane () , ask your nurse, doctor, or pharmacist.
1
Exemestane () tablets are used in women who are past menopause. It is used in:
Certain breast cancers need the female hormone estrogen to grow (estrogen receptor-positive cancer).
While you are taking Exemestane () tablets, your body stops making estrogen. Exemestane () tablets may slow or stop the growth of the cancer.
Exemestane () tablets are hormone therapy. It is not chemotherapy. It is not hormone replacement therapy (HRT).
2
Do not take Exemestane () tablets if:
3
Tell your doctor about all your medical conditions.
Tell your doctor about all the medicines you take.
Be sure to tell your doctor if you take:
Know what medicines you take. Keep a list of them with you. Show it to your doctor or pharmacist each time you get a new prescription.
4
Your doctor may do blood tests to check your liver and kidney function during treatment.
These are not all the side effects with Exemestane () tablets. Ask your cancer nurse or doctor for a more complete list.
5
6
7
Doctors can prescribe medicines for conditions that are not in the patient information leaflet. Use Exemestane () tablets only for what your doctor prescribed. Do not give it to other people, even if they have the same conditions you have. It may harm them.
This leaflet gives the most important information about Exemestane () tablets. For more information about Exemestane () tablets, talk with your doctor, nurse, or pharmacist. You can visit our Web site at www.roxane.com, or call 1-800-962-8364.
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Active ingredient:
Inactive ingredients:
*All trademarks are the property of their respective owners.
10003700/02 Revised March 2011
© RLI, 2011
Exemestane () Package/label Principal Display Panel
Exemestane () Tablets, 25 mg
NDC 0054-0080-13
Rx Only
