Exemestane genepharm

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Exemestane Genepharm (Exemestane Genepharm)

Composition:

active substance: exemestane;

1 tablet contains 25 mg of exemestane;

excipients: polysorbate 80, mannitol, hypromellose 5cP, crospovidone (type A), microcrystalline cellulose, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate;

tablet film coating Opadry OY-S-9622: titanium dioxide (E 171), propylene glycol, hypromellose 5cP.

Pharmaceutical form. Film-coated tablets, 25 mg of exemestane.

Main physicochemical properties: white, round, biconvex, film-coated tablets with the mark "E" on one side.

Pharmacotherapeutic group. Hormone antagonists and related agents. Aromatase inhibitors. ATC code L02BG06.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Exemestane is an irreversible steroidal aromatase inhibitor, structurally similar to the natural substance androstenedione. In postmenopausal women, estrogens are primarily produced through the conversion of androgens into estrogens by the enzyme aromatase in peripheral tissues. Inhibition of estrogen synthesis via aromatase inhibition is an effective and selective treatment approach for hormone-dependent breast cancer in postmenopausal women. In postmenopausal women, exemestane significantly reduces serum estrogen concentrations, starting at a dose of 5 mg; maximum reduction (>90%) is achieved with doses of 10–25 mg. In postmenopausal patients with breast cancer receiving 25 mg of exemestane 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, has been observed mainly at high doses of exemestane. In long-term daily administration studies, exemestane did not affect the biosynthesis of hormones such as cortisol or aldosterone in the adrenal glands, as measured before or after ACTH (adrenocorticotropic hormone) testing; this demonstrated selectivity with respect to other enzymes involved in steroid metabolism.

Therefore, replacement therapy with glucocorticoids or mineralocorticoids is not required.

A slight, dose-independent increase in serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) is observed even at low doses. However, this effect is expected for drugs in this pharmacological class and is likely due to a feedback mechanism at the pituitary level resulting from reduced estrogen concentrations, which stimulate pituitary gonadotropin secretion (also in postmenopausal women).

Clinical Efficacy and Safety

Adjuvant Therapy of Early-Stage Breast Cancer

In a multicenter, randomized, double-blind trial (IES – Intergroup Exemestane Study), involving 4,724 postmenopausal women with primary breast cancer and either estrogen receptor-positive or estrogen receptor-unknown status, patients who remained free of recurrence after 2–3 years of adjuvant tamoxifen therapy were randomized to receive either exemestane (25 mg daily) or tamoxifen (20 or 30 mg daily) for an additional 2–3 years, completing a total of 5 years of adjuvant 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 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 that during the observation period, exemestane reduced the risk of breast cancer recurrence by 24% compared to tamoxifen (hazard ratio 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 contralateral breast cancer (hazard ratio 0.57; p=0.04158).

In the overall study population, a trend toward improved overall survival was observed with exemestane (222 deaths) compared to tamoxifen (262 deaths), with a hazard ratio 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 (overall survival hazard ratio 0.77; Wald chi-square test: p=0.0069) was observed with exemestane compared to tamoxifen when adjusting for prespecified 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

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

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.

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

Results from the additional bone health study within the Intergroup Exemestane Study showed that women who received exemestane after 2–3 years of tamoxifen treatment experienced moderate bone mineral density (BMD) loss. In the overall study, the incidence of fractures occurring after treatment initiation, assessed over a 30-month treatment period, was higher in patients receiving exemestane compared to those receiving tamoxifen (4.5% vs. 3.3%, respectively; p=0.038).

Findings from the additional endometrial health study within the Intergroup Exemestane Study 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 patients receiving tamoxifen. Endometrial thickening observed at the start of exemestane treatment returned to normal (<5 mm) in 54% of patients receiving exemestane.

Extended follow-up with a median of 87 months in the Intergroup Exemestane Study

Results with a median treatment duration of approximately 30 months and a median extended 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 that during the observation period, exemestane significantly reduced the risk of breast cancer recurrence by 16% compared to tamoxifen (hazard ratio 0.84; p=0.002).

Overall, the greater benefit of exemestane compared to 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. These subgroups showed a trend favoring exemestane 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.

Additionally, exemestane also significantly prolonged breast cancer-free survival (hazard ratio 0.82; p=0.00263) and distant recurrence-free survival (hazard ratio 0.85; p=0.02425).

Exemestane also reduced the risk of contralateral breast cancer, although the effect was no longer statistically significant during this observation period in the study (hazard ratio 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), with a hazard ratio of 0.89 (log-rank test: p=0.08972), representing an 11% reduction in the risk of death in favor of exemestane. After adjusting for predefined 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 (hazard ratio for overall survival 0.82; Wald chi-square test: p=0.0082) was observed with exemestane compared to tamoxifen in the overall study population.

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

Results from the additional bone health study indicate that treatment with exemestane for 2–3 years following 3–2 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 the final reduction in BMD slightly greater 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 all 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 recorded as osteoporosis-related.

Treatment of advanced breast cancer

In a randomized, comparative, controlled clinical trial, exemestane administered 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, either as adjuvant therapy or as first-line therapy for advanced disease.

Pharmacokinetics

Absorption

After oral administration, exemestane is rapidly absorbed. The fraction absorbed from the gastrointestinal tract is high. Absolute bioavailability has not been established, although extensive first-pass metabolism is expected. After a single 25 mg dose taken with food, the mean plasma concentration reaches a peak at 2 hours and is 17 ng/mL. Exemestane pharmacokinetics are linear and time-independent, with no accumulation observed during long-term administration. The terminal elimination half-life is approximately 24 hours. Food enhances absorption: plasma levels are 40% higher compared to patients who took the drug in the fasted state.

Distribution

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

Metabolism and excretion

Exemestane is metabolized via oxidation of the methylene group (6) involving the CYP3A4 isoenzyme and/or via reduction of the 17-keto group involving aldo-keto reductase, followed by conjugation. The clearance of exemestane is 500 L/hour. With regard to aromatase inhibition, these metabolites are either inactive or less active than the parent compound. After oral administration of a single radiolabeled (14C) dose of exemestane, elimination of the drug and its metabolites was largely complete within one week, with equal portions of the dose excreted in urine and feces (40% each). 0.1–1% of the radioactive dose was excreted in urine as unchanged radiolabeled exemestane.

Special populations

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

Renal impairment. In patients with impaired renal function (CLcr < 30 mL/min), systemic exposure to exemestane was twice as high compared to healthy volunteers.

Considering the safety data of exemestane, dose adjustment is not necessary.

Hepatic impairment. In patients with moderate or severe hepatic impairment, systemic exposure to exemestane was 2–3 times higher compared to healthy volunteers. Considering the safety data of exemestane, dose adjustment is not necessary.

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 therapy with tamoxifen.

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 substance or to any of the excipients of the medicinal product.

The medicinal product is also contraindicated in premenopausal women, as well as in women during pregnancy or breastfeeding.

Interaction with other medicinal products and other forms of interaction.

In vitro studies have shown that exemestane 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 did not significantly affect 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 area under the plasma concentration-time curve (AUC) of exemestane decreased by 54%, and the maximum concentration (Cmax) decreased by 41%. Since the clinical significance of this interaction has not been studied, concomitant use of rifampicin, anticonvulsants (e.g., phenytoin and carbamazepine), and herbal preparations containing St. John's wort (Hypericum perforatum), which are known to induce CYP3A4, may reduce the efficacy of Exemestane GenePharm.

Exemestane GenePharm should be used with caution when coadministered 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 GenePharm should not be used with medicinal products containing estrogens, as their pharmacological effect may be negated when administered concomitantly.

Special precautions for use.

Exemestane Jenepharm should not be administered to women with a premenopausal endocrine status. Therefore, in appropriate clinical cases, a postmenopausal status should be confirmed by assessing levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol.

The medicinal product should be administered with caution to patients with impaired liver or kidney function.

Exemestane Jenepharm is a potent estrogen-lowering agent; a decrease in bone mineral density (BMD) and an increased frequency of fractures have been observed following exemestane treatment (see section "Pharmacodynamics"). At the beginning of adjuvant therapy with Exemestane Jenepharm in women with osteoporosis or at risk of developing osteoporosis, baseline BMD should be assessed according to current clinical guidelines and practices. BMD in patients with advanced disease should be evaluated on an individual basis.

Although there are insufficient data on the impact of treatment on bone loss induced by exemestane, monitoring of patients receiving Exemestane Jenepharm is recommended, and treatment or prophylaxis of osteoporosis should be initiated in patients at risk.

Prior to initiating aromatase inhibitors, routine 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 supplementation.

The medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, i.e., essentially "sodium-free".

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 Jenepharm is contraindicated in pregnant women.

Based on animal studies and the mechanism of action, exemestane may cause embryotoxic effects when administered during pregnancy. In animal studies, administration of exemestane to pregnant rats and rabbits resulted in increased rates of abortion and embryofetal toxicity. Pregnant women who are prescribed exemestane should be informed of the potential risk to the fetus. Women of reproductive potential should be advised to use effective contraception during treatment with Exemestane Jenepharm and for at least 1 month after the last dose.

Breastfeeding period. It is unknown whether exemestane is excreted in human breast milk. Exemestane Jenepharm should not be administered to women who are breastfeeding.

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

Effects on ability to drive and use machines.

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 psychological reaction time required for driving or operating machinery may be impaired.

Dosage and Administration.

Adult patients, including elderly patients

The recommended dose of Exemestane GenePharm is 1 tablet of 25 mg daily, taken after a meal.

In patients with early-stage breast cancer, treatment with Exemestane GenePharm should continue until completion of a 5-year combined sequential adjuvant hormonal therapy (tamoxifen followed by Exemestane GenePharm) or until tumor recurrence occurs.

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

No dose adjustment is required for patients with hepatic or renal impairment.

Pediatric patients

Exemestane GenePharm is not recommended for use in children.

Overdose

Clinical study data on exemestane administration at single doses up to 800 mg in healthy female volunteers and up to 600 mg in postmenopausal women with advanced breast cancer indicate good tolerability of these doses. A single dose of exemestane that may cause life-threatening symptoms has not been established. In animal studies, mortality was observed after administration of single doses equivalent to 2000 and 4000 times the recommended human dose on a mg/m² basis. There is no specific antidote for overdose; symptomatic treatment should be administered. General supportive measures are indicated, including continuous monitoring of vital signs and careful observation of the patient's clinical status.

Adverse reactions

Exemestane was generally well tolerated in all clinical studies when administered at the standard dose of 25 mg once daily; 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 breast cancer receiving adjuvant exemestane after initial adjuvant tamoxifen therapy. The most frequently 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 frequently reported adverse reactions were hot flushes (14%) and nausea (12%).

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

Adverse reactions observed during clinical studies and post-marketing experience with exemestane 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, diarrhoea, constipation, dyspepsia.

Hepatobiliary disorders:
very common – increased liver enzymes, increased blood bilirubin, increased blood 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 – fracture, osteoporosis.

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

* Includes arthralgia and 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. Transient 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 change significantly, and no increase in the frequency of viral infections was observed. These effects were not observed in patients treated in early breast cancer studies.

† Frequency calculated using the 3/X rule.

The table below presents the frequency of pre-specified adverse reactions and disorders in the Intergroup Exemestane Study in patients with early breast cancer, regardless of causality, recorded in patients receiving exemestane therapy and during the period up to 30 days after its completion.

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

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

In the Intergroup Exemestane Study, 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 developed gastric ulcer while receiving exemestane were also concurrently or previously using nonsteroidal anti-inflammatory drugs (NSAIDs) and/or had a history of NSAID use.

Reporting of suspected adverse reactions. Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions in accordance with applicable legislation.

Shelf life. 3 years.

Storage conditions.

The medicinal product does not require special storage temperature conditions.

Keep out of the reach and sight of children.

Packaging.

10 film-coated tablets in a blister, 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Genepharm S.A.

Manufacturer's address and location of operation.

18th km Marathonos Ave, Pallini Attiki, 15351, Greece.