Exevink

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT EXEVINC (EXEVINC)

Composition:

Active substance: exemestane;

One film-coated tablet contains 25 mg of exemestane;

Excipients: mannitol (E 421), hypromellose, crospovidone, polysorbate 80, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, colloidal anhydrous silicon dioxide, sodium carboxymethylcellulose (E 466), maltodextrin, glucose monohydrate, titanium dioxide (E 171), stearic acid (E 570), yellow iron oxide (E 172), purified water.

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: yellow, biconvex, round, film-coated tablets with "E9MT" engraved on one side and "25" on the other.

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. Blocking estrogen production via inhibition of aromatase 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 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, has been observed mainly when exemestane was administered at high doses. In long-term daily administration studies, exemestane did not affect the biosynthesis of hormones such as cortisol or aldosterone, whose levels were measured before and after ACTH stimulation testing. This demonstrates selectivity over other enzymes involved in hormonal metabolism. Therefore, there is no need for replacement therapy with glucocorticoids or mineralocorticoids.

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 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 4724 postmenopausal women with primary breast cancer and estrogen receptor-positive or estrogen receptor-unknown status, patients who had not experienced recurrence after 2–3 years of adjuvant tamoxifen therapy were randomized to receive either exemestane (25 mg daily) or tamoxifen (20 mg or 30 mg daily) for an additional 2–3 years to complete a total of 5 years of hormonal therapy.

Extended 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 therapy 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.

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 the risk of death in favor of exemestane. A statistically significant 23% reduction in the 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 (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 test results.

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 disease-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 indeterminate 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 conducted within the Intergroup Exemestane Study showed that women receiving exemestane after 2–3 years of tamoxifen therapy experienced moderate decreases in bone mineral density (BMD). Over the 30-month treatment period, the incidence of fractures occurring after treatment initiation was higher in patients receiving exemestane compared to those on tamoxifen (4.5% vs. 3.3%, respectively; p = 0.038).

Results from an additional endometrial assessment 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 those receiving tamoxifen. Endometrial thickening observed at the start of exemestane treatment returned to normal (< 5 mm) in 54% of patients treated with 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 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 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. However, a trend favoring exemestane was observed in patients with more than 9 positive nodes or prior CMF (cyclophosphamide + methotrexate + 5-fluorouracil) chemotherapy. 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 disease-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 pre-specified subgroup analysis of patients with positive or indeterminate 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 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 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 across 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 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 used either as adjuvant therapy or as first-line therapy for advanced disease.

Pharmacokinetics

Absorption. Exemestane is rapidly absorbed after oral administration. The fraction absorbed from the gastrointestinal tract is high. Absolute bioavailability has not been established, although absorption is likely limited by first-pass metabolism. After a single 25 mg dose, the mean plasma concentration peaks at 18 ng/mL 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, and the terminal half-life of exemestane is 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 clinically significant correlation was observed between systemic exposure to exemestane and patient age.

Patients with renal impairment

In patients with severe renal impairment (CLcr < 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, 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 postmenopausal women (naturally or therapeutically induced) in whom disease progression has occurred after antiestrogen therapy. Efficacy has not been demonstrated in patients with estrogen receptor-negative tumors.

Contraindications

The medicinal product Exemvin is contraindicated in patients with hypersensitivity to exemestane or to any of the excipients. The product 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 indicate that Exemvin is metabolized by cytochrome P450 3A4 (CYP3A4) and aldo-keto reductases 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 a drug 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 area under the plasma concentration-time curve (AUC) of exemestane decreased by 54%, and the maximum concentration (C_max) decreased by 41%. Since the clinical significance of this interaction has not been established, 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 Exemvin.

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

Exemvin should not be used in combination with medicinal products containing estrogens, as they may exert antagonistic pharmacological effects when administered concurrently.

Special precautions for use.

The medicinal product Exevinc 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 commonly associated with early stages of breast cancer. Women with vitamin D deficiency should receive supplemental vitamin D.

Exevinc should be prescribed with caution to patients with impaired liver or kidney function.

Exevinc is a medicinal product that strongly reduces estrogen levels; decreased bone mineral density (BMD) and increased fracture rates have been observed following exemestane use (see section "Pharmacodynamics"). At the beginning of adjuvant therapy with this medicinal product in women suffering from osteoporosis or at risk of developing it, BMD should be assessed at baseline according to current clinical guidelines and practices. BMD in patients with advanced disease should be evaluated on an individual basis. Although sufficient data on the effect of therapy on preventing BMD loss caused by exemestane are lacking, monitoring of patients receiving Exevinc is necessary, and treatment or prophylaxis of osteoporosis should be initiated in high-risk patients.

The medicinal product Exevinc may have a mild laxative effect.

Important information about excipients.

If intolerance to certain sugars has been diagnosed, consult a physician before taking this medicinal product.

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, the medicinal product is contraindicated during pregnancy.

Based on animal study results and the mechanism of action, exemestane may exert embryotoxic effects when used during pregnancy. In animal studies, administration of exemestane to pregnant rats and rabbits resulted in increased abortion rates and embryo-fetal toxicity. Pregnant women who are prescribed exemestane should be informed about the potential risk to the fetus. Women of reproductive potential should be advised to use effective contraception during treatment with Exevinc and for 1 month after discontinuation of the medicinal product.

Breastfeeding period.

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

Women of perimenopausal age or with reproductive potential.

The physician should discuss the need for appropriate contraception with women who may become pregnant, as well as with women 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 affect reaction speed when driving or operating machinery.

During treatment with the medicinal product Exevinc, somnolence, drowsiness, asthenia, and dizziness have been reported. Patients should be informed that if these symptoms occur, their physical and/or mental reactions required for driving or operating machinery may be impaired.

Dosage and Administration.

Adults, including elderly patients.

The medicinal product Exeminek is recommended to be taken at a dose of 25 mg once daily, every day, preferably after food. In patients with early-stage breast cancer, treatment with Exeminek should be continued until completion of five-year sequential adjuvant hormonal therapy (continuation of Exeminek therapy after tamoxifen) or until tumor recurrence occurs.

In patients with advanced breast cancer, treatment with Exeminek 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. The 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 in mg/m².

There are no specific antidotes available in case of overdose; symptomatic treatment should be administered.

General supportive care is indicated, including frequent monitoring of vital signs and careful observation of patients.

Adverse reactions

The medicinal product Exemvin was generally well tolerated in all studies when administered at a 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-stage breast cancer who received adjuvant therapy with exemestane following initial adjuvant therapy with tamoxifen. 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 blockade (e.g., hot flushes).

Adverse reactions reported during clinical trials and post-marketing experience with the medicinal product 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), and 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 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 – fracture, 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, cases of 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 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 rule of 3/X.

The table below presents the frequency of predefined adverse reactions and disorders in the Intergroup Exemestane Study in patients with early-stage breast cancer, regardless of causality, recorded in patients who received treatment with the investigational medicinal product and during the period up to 30 days after treatment completion.

In the Intergroup Exemestane Study, 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 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 study in postmenopausal women with early-stage, low-risk breast cancer who received either exemestane (N = 73) or placebo (N = 73) for 24 months, exemestane treatment 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 0–2% reduction in the placebo group. The effect on all other analyzed lipid parameters (levels of 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 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 received exemestane and developed gastric ulcer were also concomitantly or previously using nonsteroidal anti-inflammatory drugs and/or had a history of their 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, pharmacists, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions.

Store in the original packaging, in a place inaccessible to children. No special storage conditions required.

Packaging.

10 tablets per blister; 3 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Cinfa España, S.L.

Manufacturer's address and location of its operations.

C/Castello, no1, Sant Boi de Llobregat, Barcelona, 08830, Spain.