Exemestane

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EXEMESTANE (EXEMESTANE)

Composition:

active ingredient: exemestane;

1 film-coated tablet contains 25 mg of exemestane;

excipients: pregelatinized starch, corn starch, microcrystalline cellulose PH-101, crospovidone, sodium starch glycolate, povidone, polysorbate 80, hydroxypropylcellulose, microcrystalline cellulose PH-102, talc, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry 80W68912 white coating*.

*Composition of Opadry 80W68912 white coating: partially hydrolyzed polyvinyl alcohol, titanium dioxide (E 171), talc, soybean lecithin, xanthan gum.

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: round, biconvex tablets with beveled edges, film-coated, from almost white to white in color, embossed with "25" on one side and smooth on the other side, without any physical damage.

Pharmacotherapeutic group. Hormone antagonists and related agents. Aromatase inhibitors. ATC code L02B G06.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Exemestane is an irreversible steroidal aromatase inhibitor, structurally similar to the natural substrate androstenedione. In postmenopausal women, estrogens are primarily produced by conversion of androgens to estrogens via the enzyme aromatase in peripheral tissues. Blocking estrogen synthesis through inhibition of aromatase is an effective and selective treatment approach for hormone-dependent breast cancer in postmenoupausal women. In postmenopausal women, exemestane significantly reduced serum estrogen concentrations starting at a dose of 5 mg; maximal reduction (> 90%) was achieved at doses of 10–25 mg. In postmenopausal patients with breast cancer receiving 25 mg of the drug daily, total aromatase activity was reduced by 98%.

Exemestane has no progestogenic or estrogenic activity. A minor androgenic activity, likely related to its 17-hydro derivative, was observed mainly when the drug was administered at high doses. In studies of long-term daily administration, exemestane did not affect the biosynthesis of hormones such as cortisol or aldosterone in the adrenal glands, with levels measured before or after ACTH (adrenocorticotropic hormone) testing; this demonstrated selectivity with respect to other enzymes involved in steroid metabolism.

Therefore, there is no need for glucocorticoid or mineralocorticoid replacement therapy. A slight, dose-independent increase in serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) is observed even at low doses. This effect, however, is expected for drugs in this pharmacological class and likely results from a feedback mechanism at the pituitary level due to reduced estrogen concentrations, which stimulate pituitary gonadotropin secretion (also in postmenopausal women).

Clinical efficacy and safety

Adjuvant treatment of early-stage breast cancer

In a multicenter, randomized, double-blind trial (IES – Intergroup Exemestane Study), involving 4724 postmenopausal women with primary breast cancer and positive estrogen receptor status or primary breast cancer with an undefined estrogen receptor status, patients who remained free of recurrence after 2–3 years of adjuvant tamoxifen therapy were randomized to receive either exemestane (25 mg/day) or tamoxifen (20 or 30 mg/day) for an additional 2–3 years to complete a total of 5 years of hormonal therapy.

Follow-up with median 52 months in the Intergroup Exemestane Study

Results with a median treatment duration of approximately 30 months and a median follow-up duration of approximately 52 months demonstrated that continuing treatment with exemestane after 2–3 years of adjuvant tamoxifen was associated with a clinically and statistically significant improvement in disease-free survival (DFS) compared to continuing tamoxifen. The results showed a 24% reduction in the risk of breast cancer recurrence with exemestane compared to tamoxifen (hazard ratio (HR) 0.76; p = 0.00015). The more favorable effect of exemestane over tamoxifen on disease-free survival was evident regardless of lymph node status or prior chemotherapy.

The use of exemestane also significantly reduced the risk of developing contralateral breast cancer (HR 0.57; p = 0.04158).

In the overall study population, a trend toward improved overall survival (OS) was observed with exemestane (222 deaths) compared to tamoxifen (262 deaths), with an HR of 0.85 (log-rank test: p = 0.07362), representing a 15% reduction in the risk of death in favor of exemestane. A statistically significant 23% reduction in the risk of death (HR for overall survival – 0.77; Wald chi-square test: p = 0.0069) was observed with exemestane compared to tamoxifen after adjusting for predefined prognostic factors (i.e., estrogen receptor status, lymph node status, prior chemotherapy, use of hormone replacement therapy, and bisphosphonates).

Key efficacy outcomes in all patients (intention-to-treat population) and in patients with estrogen receptor-positive breast cancer at 52 months

Table 1

* Log-rank test; ER+ patients = patients with positive estrogen receptor test.

a Disease-free survival is defined as the first occurrence of local or systemic recurrence, contralateral breast cancer, or death from any cause.

b Breast cancer-free survival is defined as the first occurrence of local or systemic recurrence, contralateral breast cancer, or death due to breast cancer.

c Distant recurrence-free survival is defined as the first occurrence of distant recurrence or death due to breast cancer.

d Overall survival is defined as time to death from any cause.

In a pre-specified subgroup analysis of patients with positive or unknown estrogen receptor status, the unadjusted hazard ratio for overall survival was 0.83 (log-rank test: p = 0.04250), representing a clinically and statistically significant 17% reduction in the risk of death.

Additional bone health assessments within the intergroup exemestane trial showed a moderate decrease in bone mineral density (BMD) in women who received exemestane after 2–3 years of tamoxifen treatment. In the overall trial, the incidence of fractures occurring after treatment initiation, assessed over a 30-month treatment period, was higher in patients receiving exemestane compared to those on tamoxifen (4.5% vs. 3.3%, respectively; p = 0.038).

Results from the additional endometrial assessment within the intergroup exemestane trial indicate that after 2 years of treatment, endometrial thickness decreased with a median reduction of 33% in patients receiving exemestane, compared to no significant change in those receiving tamoxifen. Endometrial thickening observed at baseline returned to normal (< 5 mm) in 54% of patients treated with exemestane.

Extended follow-up with median 87 months in the intergroup exemestane trial

Results with a median treatment duration of approximately 30 months and median follow-up of approximately 87 months demonstrated that continuing treatment with exemestane after 2–3 years of adjuvant tamoxifen therapy was associated with a clinically and statistically significant improvement in disease-free survival compared to continuing tamoxifen. The results showed a significant 16% reduction in the risk of breast cancer recurrence over the study observation period with exemestane compared to tamoxifen (HR 0.84; p = 0.002).

Overall, the benefit of exemestane over tamoxifen in terms of disease-free survival was evident regardless of lymph node status or prior chemotherapy or hormonal therapy. Statistical significance was not achieved in several small subgroups. Trends favoring exemestane were observed in patients with more than 9 positive nodes or prior CMF chemotherapy (cyclophosphamide, methotrexate, 5-fluorouracil). In patients with unknown nodal status, other prior chemotherapy regimens, or unknown/absent prior hormonal therapy, a statistically non-significant trend favoring tamoxifen was observed.

Furthermore, exemestane also significantly improved breast cancer-free survival (HR 0.82; p = 0.00263) and distant recurrence-free survival (HR 0.85; p = 0.02425).

Exemestane also reduced the risk of contralateral breast cancer, although the effect was no longer statistically significant during this follow-up period in the trial (HR 0.74; p = 0.12983). In the overall study population, a trend toward improved overall survival was observed with exemestane (373 deaths) compared to tamoxifen (420 deaths) (HR 0.89; p = 0.08972), representing an 11% reduction in the risk of death in favor of exemestane. After adjustment for pre-specified prognostic factors (i.e., estrogen receptor status, lymph node status, prior chemotherapy, use of hormone replacement therapy, and bisphosphonates), a statistically significant 18% reduction in the risk of death (HR for overall survival 0.82; chi-square test (Wald test): p = 0.0082) was observed with exemestane compared to tamoxifen in the overall study population.

In a pre-specified subgroup analysis of patients with positive or unknown estrogen receptor status, the unadjusted hazard ratio for overall survival was 0.86 (log-rank test: p = 0.04262), representing a clinically and statistically significant 14% reduction in the risk of death.

Results from the additional bone health assessment indicate that treatment with exemestane for 2–3 years following 2–3 years of tamoxifen led to increased bone loss during this treatment period (mean % change in BMD from baseline at 36 months: -3.37 (spine), -2.96 (total hip) with exemestane vs. -1.29 (spine), -2.02 (total hip) with tamoxifen). However, by the end of the 24-month post-treatment period, the change in BMD from baseline was minimal in both treatment groups, with slightly greater final BMD reduction in the tamoxifen group at all sites (mean % change in BMD at 24 months from baseline: -2.17 (spine), -3.06 (total hip) with exemestane vs. -3.44 (spine), -4.15 (total hip) with tamoxifen).

The total number of fractures recorded during both treatment and extended follow-up periods was significantly higher in the exemestane group compared to the tamoxifen group (169 (7.3%) vs. 122 (5.2%); p = 0.004), but no difference was observed in the number of fractures reported as due to osteoporosis.

Final extended follow-up of 119 months in the Intergroup Exemestane Study (IES)

After a median treatment duration of approximately 30 months and median follow-up of approximately 119 months, results showed that continuing treatment with exemestane after 2–3 years of adjuvant tamoxifen therapy was associated with a clinically and statistically significant improvement in disease-free survival (DFS) compared to continuing tamoxifen. The analysis showed a 14% reduction in the risk of breast cancer recurrence over the study observation period with exemestane compared to tamoxifen (HR 0.86; p = 0.00393). The benefit of exemestane over tamoxifen in terms of DFS was evident regardless of lymph node status or prior chemotherapy.

Exemestane also significantly improved breast cancer-free survival (HR 0.83; p < 0.00152) and distant recurrence-free survival (HR 0.86; p = 0.02213). Exemestane also reduced the risk of contralateral breast cancer, although the effect was no longer statistically significant (HR 0.75; p = 0.10707).

In the overall study population, overall survival (OS) did not differ significantly between the two groups: 467 deaths (19.9%) in the exemestane group and 510 deaths (21.5%) in the tamoxifen group (HR 0.91; p = 0.15737, unadjusted for multiple comparisons). In the subgroup of patients with positive or unknown estrogen receptor status, the unadjusted hazard ratio for overall survival was 0.89 (log-rank test: p = 0.07881) in the exemestane group compared to the tamoxifen group.

In the overall study population, a statistically significant 14% reduction in the risk of death (hazard ratio for OS 0.86; chi-square test (Wald test): p = 0.0257) was observed with exemestane compared to tamoxifen after adjustment for pre-specified prognostic factors (i.e., estrogen receptor status, lymph node status, prior chemotherapy, use of hormone replacement therapy, and bisphosphonates).

Patients receiving exemestane had a lower incidence of new primary cancers (other than breast) compared to those receiving tamoxifen alone (9.9% vs. 12.4%).

In the main trial, where the median follow-up duration for all participants was 119 months (0–163.94) and median duration of exemestane treatment was 30 months (0–40.41), bone fractures were recorded in 169 (7.3%) patients in the exemestane group compared to 122 (5.2%) patients in the tamoxifen group (p = 0.004).

Efficacy results from IES in postmenopausal women with early-stage breast cancer (ITT)

Table 2

Treatment of advanced breast cancer

In a randomized, comparative, controlled clinical trial, administration of exemestane at a daily dose of 25 mg demonstrated a statistically significant increase in survival time, time to disease progression, and time to treatment failure compared to standard hormonal therapy with megestrol acetate in postmenopausal women with advanced breast cancer that had progressed during or after tamoxifen treatment, used either as adjuvant therapy or first-line therapy for advanced disease.

Pharmacokinetics

Absorption

After oral administration, exemestane is rapidly absorbed. The fraction of the dose absorbed from the gastrointestinal tract is high. Absolute bioavailability in humans has not been determined, although extensive first-pass metabolism is expected. A similar effect resulted in an absolute bioavailability of 5% in rats and dogs. Following a single 25 mg dose, the mean plasma concentration reaches peak levels at 2 hours, amounting to 18 ng/mL. Concomitant administration of the drug with food increases its bioavailability by 40%.

Distribution

The volume of distribution of exemestane, uncorrected for oral bioavailability, is approximately 20,000 L. The pharmacokinetics of exemestane are linear, and the terminal elimination half-life is 24 hours. Plasma protein binding is 90% and is independent of concentration. Exemestane and its metabolites do not bind to erythrocytes. Exemestane does not accumulate unpredictably after repeated dosing.

Elimination

Exemestane is metabolized via oxidation of the methylene group (6) by the CYP3A4 isoenzyme and/or via reduction of the 17-keto group by aldoketoreductase, followed by conjugation. The clearance of exemestane is approximately 500 L/h, uncorrected for oral bioavailability.

Regarding aromatase inhibition, these metabolites are either inactive or less active than the parent compound. The amount of unchanged drug excreted in urine amounts to 1% of the dose. An equal amount (40%) of radiolabeled (14C) exemestane was excreted in urine and feces over one week.

Special populations

Age

No significant correlation between systemic exposure to exemestane and patient age was observed.

Patients with impaired renal function

In patients with severe renal impairment (CLcr < 30 mL/min), systemic exposure to exemestane was twice as high compared to healthy volunteers. Given the safety profile of exemestane, dose adjustment is not required.

Patients with impaired hepatic function

In patients with moderate or severe hepatic impairment, exposure to exemestane was 2–3 times higher compared to healthy volunteers. Given the safety profile of exemestane, dose adjustment is not required.

Clinical Characteristics

Indications

Adjuvant therapy in postmenopausal women with early-stage invasive breast cancer and estrogen receptor-positive tumors following 2–3 years of initial adjuvant tamoxifen therapy.

Treatment of advanced breast cancer in women with naturally or artificially induced postmenopausal status in whom disease progression has occurred after antiestrogen therapy. Efficacy has not been demonstrated in patients with estrogen receptor-negative tumors.

Contraindications

Hypersensitivity to the active ingredient or to any of the excipients listed in the section "Composition". The drug is also contraindicated in premenopausal women, as well as in pregnant or breastfeeding women.

Interaction with other medicinal products and other forms of interaction

In vitro studies have shown that this drug is metabolized by cytochrome P450 (CYP3A4) and aldo-keto reductases (see section "Pharmacokinetics"), and does not inhibit any of the major CYP isoenzymes. In a clinical pharmacokinetic study, specific inhibition of CYP3A4 by ketoconazole was shown not to have a significant effect on the pharmacokinetics of exemestane.

In a drug interaction study with rifampicin, a potent inducer of CYP450, administered at a daily dose of 600 mg together with a single 25 mg dose of exemestane, the AUC of exemestane decreased by 54% and Cmax by 41%. Since the clinical significance of this interaction has not been fully established, concomitant use of drugs such as rifampicin, anticonvulsants (e.g., phenytoin and carbamazepine), and herbal preparations containing St. John's wort (Hypericum perforatum), known to induce CYP3A4, may reduce the efficacy of exemestane.

Exemestane should be used with caution in combination with medicinal products metabolized by CYP3A4 and having a narrow therapeutic index. Clinical experience with concomitant use of exemestane and other anticancer medicinal products is lacking.

Exemestane should not be used with medicinal products containing estrogens, as their pharmacological effects may be counteracted when administered concomitantly.

Special precautions for use

Exemestane should not be prescribed to women with a premenopausal endocrine status. Therefore, in appropriate clinical cases, postmenopausal status should be confirmed by assessing levels of LH, FSH, and estradiol.

Exemestane should be administered with caution to patients with impaired liver or kidney function.

Exemestane is a drug that strongly reduces estrogen levels; a decrease in BMD and an increased fracture rate have been observed following treatment with the drug (see section "Pharmacodynamics"). At the beginning of adjuvant therapy with this drug in women who have osteoporosis or are at risk of developing it, baseline BMD assessment should be performed in accordance with current clinical guidelines and practices. BMD in patients with advanced disease should be evaluated on an individual basis.

Although sufficient data on the impact of treatment on preventing BMD loss associated with exemestane are lacking, monitoring of patients receiving exemestane is necessary, and treatment or prophylaxis of osteoporosis should be initiated in patients at risk.

Prior to initiating aromatase inhibitor therapy, standard assessment of 25-hydroxy metabolites of vitamin D should be performed, as severe vitamin D deficiency is common in women with early-stage breast cancer. Women with vitamin D deficiency should receive vitamin D supplementation.

Use during pregnancy or breastfeeding

Pregnancy. There are no clinical data on the use of exemestane in pregnant women. Animal studies have shown reproductive toxicity; therefore, exemestane is contraindicated during pregnancy.

Breastfeeding. It is unknown whether exemestane is excreted in human milk. Exemestane should not be used in women who are breastfeeding.

Perimenopausal women or women of reproductive age

The physician should discuss the need for appropriate contraception with women who may become pregnant, including those who are perimenopausal or who have recently transitioned into the postmenopausal period, until their postmenopausal status is fully confirmed (see sections "Contraindications" and "Special precautions for use").

Ability to influence reaction rate while driving or operating machinery

Exemestane has a moderate effect on the ability to drive or operate machinery.

During treatment with exemestane, somnolence, drowsiness, asthenia, and dizziness have been reported. Patients should be advised that if these symptoms occur, their physical and/or mental reactions required for driving a vehicle or operating machinery may be impaired.

Method of Administration and Dosage

Adults and Elderly Patients

Exemestane is recommended at a dose of 25 mg once daily, preferably after a meal.

In patients with early-stage breast cancer, treatment with exemestane should continue until completion of a 5-year course of sequential adjuvant hormonal therapy (continuation of exemestane treatment following tamoxifen therapy) or until tumor recurrence occurs.

In patients with advanced breast cancer, exemestane treatment should be continued until tumor progression becomes evident.

Dose adjustment is not required in patients with hepatic or renal impairment (see section "Pharmacokinetics").

Children

The drug is not recommended for use in children.

Overdose

Clinical studies have been conducted using single doses of exemestane up to 800 mg in healthy female volunteers and doses up to 600 mg daily in postmenopausal women with advanced breast cancer. These studies indicate good tolerability of these doses. The single dose of exemestane that may cause life-threatening symptoms has not been established. In animal studies, lethality was observed after administration of a single oral dose equivalent to 2000 and 4000 times the recommended human dose in mg/m². There are no specific antidotes for overdose; symptomatic treatment should be administered. General supportive care is indicated, including frequent monitoring of vital signs and careful patient observation.

Adverse Reactions

Exemestane was generally well tolerated in all clinical trials when administered at the standard dose of 25 mg/day. Adverse reactions were usually mild to moderate in severity. The rate of treatment discontinuation due to adverse reactions was 7.4% in patients with early-stage breast cancer who received adjuvant exemestane therapy after initial adjuvant tamoxifen therapy. The most commonly reported adverse reactions were hot flushes (22%), arthralgia (18%), and increased fatigue (16%).

The rate of treatment discontinuation due to adverse reactions was 2.8% in the overall population of patients with advanced breast cancer. The most commonly reported adverse reactions were hot flushes (14%) and nausea (12%).

Most adverse reactions can be explained by the expected pharmacological consequences of estrogen suppression (e.g., hot flushes).

Adverse reactions observed during clinical trials and post-marketing use of the drug are listed below by system organ class and frequency.

Frequency categories are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders: very common – leukopenia**; common – thrombocytopenia**; frequency not known – decreased lymphocyte count**.

Immune system disorders: uncommon – hypersensitivity.

Metabolism and nutrition disorders: common – anorexia.

Psychiatric disorders: very common – depression, insomnia.

Nervous system disorders: very common – headache, dizziness; common – carpal tunnel syndrome, paraesthesia; rare – somnolence.

Vascular disorders: very common – hot flushes.

Gastrointestinal disorders: very common – abdominal pain, nausea; common – vomiting, diarrhea, constipation, dyspepsia.

Hepatobiliary disorders: very common – increased liver enzymes, increased blood bilirubin, increased alkaline phosphatase; rare – hepatitis†, cholestatic hepatitis†.

Skin and subcutaneous tissue disorders: very common – increased sweating; common – alopecia, rash, urticaria, pruritus; rare – acute generalized exanthematous pustulosis†.

Musculoskeletal and connective tissue disorders: very common – joint pain and musculoskeletal pain*; common – fractures, osteoporosis.

General disorders and administration site conditions: very common – pain, increased fatigue; common – peripheral edema, asthenia.

* Includes arthralgia; less frequently, limb pain, osteoarthritis, back pain, arthritis, myalgia, and joint stiffness.

** In patients with advanced breast cancer, thrombocytopenia and leukopenia were reported as rare. Periodic decreases in lymphocyte count were observed in approximately 20% of patients receiving exemestane, particularly in those with pre-existing lymphopenia. However, mean lymphocyte counts over time did not significantly change in these patients, and no increase in the frequency of viral infections was observed. These effects were not seen in patients treated in early-stage breast cancer studies.

† Frequency calculated using the 3/X rule.

Table 3 presents the frequency of predefined adverse reactions and disorders in a comparative study of exemestane in patients with early-stage breast cancer, regardless of causality, recorded in patients receiving investigational drug treatment and during the period up to 30 days after treatment completion.

Table 3

In a comparative study of exemestane, the incidence of myocardial ischemia in the exemestane and tamoxifen treatment groups was 4.5% and 4.2%, respectively. No significant differences were observed for any individual cardiovascular events, including arterial hypertension (9.9% vs. 8.4%), myocardial infarction (0.6% vs. 0.2%), and heart failure (1.1% vs. 0.7%).

In the comparative study of exemestane, treatment with exemestane was associated with a higher incidence of hypercholesterolemia compared to tamoxifen (3.7% vs. 2.1%).

In a separate double-blind, randomized study involving postmenopausal women with early-stage breast cancer at low risk, who received either exemestane (N = 73) or placebo (N = 73) for 24 months, treatment with exemestane was associated with a mean reduction in plasma LDL-cholesterol levels of 7–9% compared to a 1% increase in the placebo group. A reduction in apolipoprotein A1 levels of 5–6% was also observed in the exemestane treatment group compared to a reduction of 0–2% in the placebo group. The effect on all other analyzed lipid parameters (total cholesterol, HDL-cholesterol, triglycerides, apolipoprotein B, and lipoprotein(a)) was similar between the two treatment groups. The clinical significance of these findings is unknown.

In the comparative study of exemestane, gastric ulcer was observed more frequently in the exemestane treatment group compared to the tamoxifen treatment group (0.7% vs. < 0.1%). Most patients who received exemestane and developed gastric ulcer were also concomitantly using or had previously used nonsteroidal anti-inflammatory drugs (NSAIDs).

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach and sight of children.

Packaging

30 tablets in a plastic container, 1 container in a cardboard box.

Prescription status

Prescription only.

Manufacturer

EuJea Pharma Specialities Limited.

Manufacturer's address and location of operations

Unit-1, Survey No. 550, 551 and 552, Koltur Village, Shamirpet Mandal, Medchal – Malkajgiri, District Medchal, Telangana 500101 – India.