Exemestane-vista ac

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EXEMESTANE-VISTA AC (EXEMESTANE-VISTA AC)

Composition:

Active substance: exemestane;

One film-coated tablet contains 25 mg of exemestane;

Excipients: colloidal anhydrous silicon dioxide, crospovidone, hypromellose 5cP, magnesium stearate, mannitol, microcrystalline cellulose (PH 102), polysorbate 80, sodium starch glycolate (Type A);

Coating composition: hypromellose 5cP, macrogol (PEG 400), titanium dioxide (E 171), talc, macrogol (PEG 600).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex tablets, film-coated.

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 to 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 diagnosed with breast cancer who received 25 mg of exemestane daily, total aromatase activity decreased by 98%.

Exemestane has no progestogenic or estrogenic activity. A slight androgenic activity, likely related to its 17-hydro derivative, was observed mainly when exemestane was administered at high doses. During studies of prolonged daily administration, exemestane did not affect the biosynthesis of cortisol or aldosterone; levels of these hormones remained unchanged before and after ACTH testing. This demonstrates selectivity with respect to other enzymes involved in hormonal metabolism. Therefore, replacement therapy with glucocorticoids or mineralocorticoids is not required.

A slight increase in serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) is observed even at low doses. This effect is expected for drugs in this pharmacological class and is likely due to a feedback mechanism at the pituitary level: reduced estrogen concentration stimulates the pituitary secretion of gonadotropins (also in postmenopausal women). Clinical Efficacy and Safety.

Adjuvant Therapy of Early-Stage Breast Cancer.

In a multicenter, randomized, double-blind study (IES – Intergroup Exemestane Study), involving 4724 postmenopausal women with primary breast cancer and estrogen receptor-positive tumors or tumors with an unknown estrogen receptor status, patients who remained recurrence-free 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 adjuvant hormonal therapy.

Follow-up with a median of 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 of the Exemestane Study, 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.

Exemestane use also significantly reduced the risk of developing 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 risk of death in favor of exemestane. A statistically significant 23% reduction in risk of death (hazard ratio for overall survival – 0.77; Wald chi-square test: p = 0.0069) was observed with exemestane compared to tamoxifen when 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 (Intent-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 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. Results from a supplementary bone study within the Intergroup Exemestane Study showed that women who received exemestane after 2–3 years of tamoxifen treatment experienced moderate bone mineral density loss. In the overall study, the incidence of fractures occurring after the start of treatment, 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).

Results from a supplementary endometrial study within the Intergroup Exemestane Study indicate that after 2 years of treatment, endometrial thickness decreased by a median 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 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 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. 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.

Furthermore, 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 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 (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. In a supplementary analysis of the subgroup 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 supplementary bone study 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 bone mineral density (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 BMD reduction 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 the treatment and 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 duration, 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 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. Following a single 25 mg dose, peak plasma concentrations averaging 18 ng/mL are reached within 2 hours. Concomitant administration of exemestane with food increases its bioavailability by 40%.

Distribution. The volume of distribution of exemestane, uncorrected for oral bioavailability, is approximately 20,000 L. Exemestane pharmacokinetics are linear, with a terminal 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) 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. With respect to aromatase inhibition, these metabolites are either inactive or less active than the parent compound. Only 1% of the dose is excreted unchanged in urine. An equal amount of radiolabeled (14C) exemestane (40%) 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 renal impairment.

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

Patients with 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 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.

Exemestane-Vista AS is contraindicated in patients with hypersensitivity to exemestane or to any other component of the medicinal product. Exemestane-Vista AS is also contraindicated in premenopausal women, as well as in women who are pregnant or breastfeeding.

Interaction with other medicinal products and other forms of interaction.

In vitro studies have shown that this medicinal product is metabolized by cytochrome P450 3A4 (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 affect the pharmacokinetics of exemestane. In an interaction study with rifampicin, a potent CYP450 inducer, administered at a daily dose of 600 mg and 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 studied, concomitant use of drugs such as 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 effectiveness of Exemestane-Vista AS.

Exemestane-Vista AS should be used with caution when coadministered with medicinal products metabolized by CYP3A4 and having a narrow therapeutic index. There is no experience with the concomitant clinical use of Exemestane-Vista AS with other anticancer medicinal products.

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

Special precautions for use.

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

Prior to initiating treatment with aromatase inhibitors, assessment of 25-hydroxy vitamin D levels in the body should be performed, as severe deficiency is frequently observed and associated with early stages of breast cancer. Women with vitamin D deficiency should receive supplemental vitamin D.

Exemestane-Vista AS should be prescribed with caution to patients with impaired liver or kidney function.

Exemestane-Vista AS is a medicinal product that substantially reduces estrogen levels; a decrease in bone mineral density and an increased frequency of fractures have been observed following exemestane use (see section "Pharmacodynamics"). At the beginning of adjuvant therapy with this medicinal product, bone mineral density should be assessed at baseline in women with osteoporosis or at risk of developing it, in accordance with current clinical guidelines and practices. Bone mineral density in patients with advanced disease should be evaluated on an individual basis.

Although sufficient data on the impact of therapy on exemestane-induced bone mineral density loss are lacking, patients receiving Exemestane-Vista AS should be monitored, and treatment or prophylaxis for osteoporosis should be initiated in patients at risk.

The medicinal product Exemestane-Vista AS may have a mild laxative effect.

Important information on excipients.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e. essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy. Clinical data on the use of exemestane in pregnant women are lacking. Animal studies have shown reproductive toxicity; therefore, exemestane is contraindicated during pregnancy.

Breastfeeding. It is unknown whether exemestane is excreted in human breast milk. The medicinal product should not be administered to women during breastfeeding.

Perimenopausal women or women of reproductive potential. The physician should discuss the need for appropriate contraception with women who may become pregnant, including perimenopausal women or those 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 speed when driving or operating machinery.

During treatment with this medicinal product, somnolence, drowsiness, asthenia, and dizziness have been reported. Patients should be advised that if these symptoms occur, their physical and/or mental reaction times required for driving a car or operating machinery may be impaired.

Dosage and Administration.

Adults, including elderly patients.

Exemestane-Vista AS is recommended to be taken at a dose of 25 mg once daily, consistently, preferably after a meal. In patients with early-stage breast cancer, treatment with Exemestane-Vista AS should continue until completion of a 5-year course of sequential adjuvant hormonal therapy (continuation of Exemestane-Vista AS after tamoxifen) or until tumor recurrence occurs.

In patients with advanced breast cancer, treatment with Exemestane-Vista AS should be continued until tumor progression becomes evident.

Dose adjustment is not required in patients with hepatic or renal impairment.

Children.

The medicinal product is not recommended for use in children.

Overdose.

Clinical studies have been conducted using exemestane at single doses up to 800 mg in healthy female volunteers and at doses up to 600 mg daily in postmenopausal women with advanced breast cancer; study data indicate good tolerability of these doses.

Symptoms. A single dose of exemestane that may cause life-threatening symptoms has not been established. In animal studies, mortality was observed after administration of a single oral dose equivalent to 2000 and 4000 times the recommended human dose on a mg/m² basis.

Treatment. 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 observation of the patient.

Adverse Reactions

Exemestane was generally well tolerated in all studies at a dose of 25 mg/day, and adverse events were usually mild to moderate in severity. The rate of treatment discontinuation due to adverse events was 7.4% in breast cancer patients with early-stage disease who received adjuvant exemestane therapy after initial adjuvant tamoxifen treatment. The most commonly reported adverse events were hot flushes (22%), arthralgia (18%), and increased fatigue (16%). The rate of treatment discontinuation due to adverse events was 2.8% in the overall group of patients with advanced breast cancer. The most commonly reported adverse events in this group were hot flushes (14%) and nausea (12%).

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

Adverse reactions observed during clinical trials and post-marketing experience with the medicinal product are listed below by system organ class and frequency of occurrence. 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), and 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 levels, increased blood alkaline phosphatase levels;
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 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 in these patients did not change significantly over time, and no corresponding increase in the incidence of viral infections was observed. These effects were not seen in patients treated in early breast cancer studies.

† Frequency calculated using the 3/X rule.

The table below presents the frequency rates of predefined adverse reactions and disorders in the Intergroup Exemestane Study in patients with early breast cancer, regardless of causal relationship, recorded in patients receiving investigational drug treatment and during the period up to 30 days after treatment completion.

In a comparative study of exemestane, the incidence of myocardial ischemia events 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, placebo-controlled trial in 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 HDL-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, 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 comparative study of exemestane, gastric ulcer was observed more frequently in the exemestane treatment group compared to the tamoxifen group (0.7% vs. < 0.1%). Most patients who developed gastric ulcer while receiving exemestane were also concurrently using and/or had previously used nonsteroidal anti-inflammatory drugs (NSAIDs).

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after a medicine has been authorized is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy of the medicine to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua/

Shelf life. 3 years.

Storage conditions.

No special storage conditions required. Keep out of reach and sight of children.

Packaging.

10 tablets in a blister; 3 blisters per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Remedica Limited

Manufacturer's address and place of business

Acharnon Street, Limassol Industrial Estate, Limassol, 3056, Cyprus