Exemarin

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

Composition:

Active substance: exemestane;

1 tablet contains 25 mg of exemestane;

Excipients: mannite (E 421), copovidone (type A), crospovidone (type A), microcrystalline cellulose, colloidal anhydrous silicon dioxide, sodium starch glycolate (type A), magnesium stearate (E 470);

coating Advantia Prime White 190100BA01: hypromellose (E 464), macrogol 400, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: white or almost white, round, biconvex, film-coated tablets with the imprint "25" on one side and smooth on the other.

Pharmacotherapeutic group.

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

Pharmacological Properties

Pharmacodynamics

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. Blocking estrogen synthesis 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 diagnosed with breast cancer who received 25 mg of the drug daily, total aromatase levels decreased 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. During studies of prolonged daily administration, exemestane did not affect the biosynthesis of hormones such as cortisol or aldosterone in the adrenal glands, as assessed by measurements before and after ACTH (adrenocorticotropic hormone) testing; this demonstrated its selectivity regarding 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; this effect, however, is expected for drugs in this pharmacological class and is likely due to a feedback mechanism at the pituitary level: reduced estrogen concentrations stimulate pituitary gonadotropin secretion (also in postmenopausal women).

Clinical Efficacy and Safety

Adjuvant Therapy for Early-Stage Breast Cancer

In the Intergroup Exemestane Study (IES), postmenopausal women with primary breast cancer and either estrogen receptor-positive or estrogen receptor-unknown status, who had not experienced recurrence after 2–3 years of adjuvant tamoxifen therapy, were randomized to receive either exemestane (25 mg/day) or continued tamoxifen (20 or 30 mg/day) for an additional 2–3 years, completing a total of 5 years of hormonal therapy.

Follow-up Results 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, 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 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 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 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 systemic recurrence or death due to breast cancer.

d Overall survival is defined as death from any cause.

In a supplementary analysis of the subgroup of patients with positive or unknown estrogen receptor status, the unadjusted hazard ratio for overall survival was 0.83 (log-rank test: p=0.04250), representing 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 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 tamoxifen (4.5% vs. 3.3%, respectively; p=0.038).

Findings from the supplementary endometrial assessment study within the Intergroup Exemestane Study indicate that after 2 years of treatment, a median 33% reduction in endometrial thickness was observed 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 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 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. A trend favoring exemestane was 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.

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 this 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.

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 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 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 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 a result of osteoporosis.

Final follow-up with a median of 119 months in the Intergroup Exemestane Study.

After a median treatment duration of approximately 30 months and a median follow-up of approximately 119 months, results showed that sequential treatment with exemestane following 2–3 years of adjuvant tamoxifen therapy was associated with a clinically and statistically significant improvement in DFS compared to continuing tamoxifen. The analysis showed that over the study observation period, exemestane reduced the risk of breast cancer recurrence by 14% compared to tamoxifen (hazard ratio 0.86, p = 0.00393). The advantage of exemestane over tamoxifen in terms of DFS was evident regardless of nodal status or prior chemotherapy.

Exemestane also significantly prolonged breast cancer-free survival (hazard ratio 0.83, p<0.00152) and long-term distant recurrence-free survival (hazard ratio 0.86, p=0.02213). Exemestane also reduced the risk of developing contralateral breast cancer, although this effect was no longer statistically significant (hazard ratio 0.75, p=0.10707).

In the overall study population, overall survival did not differ statistically between the two groups: 467 deaths (19.9%) in the exemestane group and 510 deaths (21.5%) in the tamoxifen group (hazard ratio 0.91, p = 0.15737, unadjusted for multiple testing). In the subgroup of patients with positive or unknown estrogen receptor status, the unadjusted overall hazard ratio for 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; Wald chi-square test: p = 0.0257) was observed with exemestane compared to tamoxifen after adjustment for predefined prognostic factors (i.e., ER status, nodal status, prior chemotherapy, use of HRT, and use of bisphosphonates).

Patients receiving exemestane had a lower incidence of other second (non-breast) primary cancers compared to those receiving tamoxifen only (9.9% vs. 12.4%).

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

Treatment of advanced breast cancer.

In a study evaluating the use of exemestane at a daily dose of 25 mg, a statistically significant improvement in survival duration, time to disease progression, and time to treatment failure was demonstrated 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 of exemestane tablets, the drug 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 approximately 5% in rats and dogs. Following a single 25 mg dose, mean plasma concentrations reach peak levels of 18 ng/mL within 2 hours. 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 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.

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

Special populations

Age.

No significant correlation between systemic exposure to exemestane and age has been observed.

Patients with renal impairment.

In patients with severe renal impairment (creatinine clearance < 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 is 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 therapeutically 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.

Exemarine is contraindicated in patients with known 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 women who are pregnant or breastfeeding.

Interaction with other medicinal products and other forms of interaction.

In vitro studies have shown that this drug is metabolized by cytochrome P450 (CYP) 3A4 and aldo-keto reductases and does not inhibit any of the major CYP isoenzymes. A clinical pharmacokinetic study demonstrated that specific inhibition of CYP3A4 by ketoconazole does not affect the pharmacokinetics of exemestane.

In a drug interaction study, rifampicin, a potent CYP450 inducer administered at a dose of 600 mg daily, reduced the area under the concentration-time curve (AUC) of exemestane by 54% and the maximum concentration (C_max) by 41% when co-administered with a single 25 mg dose of exemestane. Since the clinical significance of this effect has not been fully evaluated, 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 CYP3A4 inducers, may reduce the efficacy of exemestane.

Exemarine should be used with caution when administered with medicinal products metabolized by CYP3A4 and having a narrow therapeutic index. Clinical experience with concomitant use of Exemarine and other anticancer medicinal products is lacking.

Exemestane should not be used with medicinal products containing estrogens, as they may exert a negative pharmacological effect when used concomitantly.

Special precautions for use.

Before 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 additional vitamin D supplementation.

Due to its mechanism of action, Exemarin should not be prescribed to women with a premenopausal endocrine status. Therefore, in appropriate clinical cases, postmenopausal status should be confirmed by evaluating levels of LH, FSH, and estradiol.

Given that Exemarin is a drug that substantially reduces estrogen levels, decreased bone mineral density and increased fracture rates have been observed following treatment with this agent (see section "Pharmacodynamics"). At the beginning of adjuvant therapy with this drug, 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 effect of therapy on drug-induced bone mineral loss during treatment with Exemarin are lacking, patients receiving this drug should be monitored, and treatment or prophylaxis of osteoporosis should be initiated in those at risk.

Exemarin should be used with caution in patients with impaired liver or kidney function.

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, Exemarin is contraindicated during pregnancy.

Breastfeeding. It is unknown whether exemestane is excreted in human milk. Exemarin should not be administered to 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 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.

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

During treatment with the drug, somnolence, drowsiness, asthenia, and dizziness have been reported. If these effects occur, patients should be advised that their physical and/or mental abilities required for driving or operating machinery may be impaired.

Method of Administration and Dosage

Adults and Elderly Patients

Exemarin is recommended to be taken at a dose of 25 mg once daily, preferably after food.

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

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

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

Children

The drug is not recommended for use in children.

Overdose

Clinical studies have been conducted using exemestane at single doses of up to 800 mg in healthy female volunteers and at doses up to 600 mg per day in postmenopausal women with advanced breast cancer; study data indicate good tolerability of these doses. The single dose of Exemarin 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). 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 when administered at the standard dose of 25 mg/day; adverse events were usually mild to moderate in severity. The discontinuation rate due to adverse events was 7.4% in patients with early-stage breast cancer receiving adjuvant therapy with Exemestane following initial adjuvant therapy with tamoxifen. The most commonly reported adverse events were hot flushes (22%), arthralgia (18%), and increased fatigue (16%).

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

Most adverse events can be explained by the normal pharmacological consequences of estrogen blockade (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 enzyme levels, 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: 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. 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 change significantly in these patients, and no corresponding 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.

The table below lists the frequency of pre-specified adverse reactions and disorders in the Intergroup Exemestane Study in patients with early-stage breast cancer, regardless of causal relationship, observed in patients who received investigational drug treatment and during the period up to 30 days after treatment 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 (3.7% vs. 2.1%).

In a separate double-blind, randomized study in postmenopausal women with early-stage breast cancer at low risk, 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 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 medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals are requested to report any suspected adverse reactions.

Shelf life. 2 years.

Storage conditions.

No special storage conditions required.

Keep out of reach of children.

Packaging.

10 film-coated tablets in a blister made of polyvinyl chloride film and aluminum foil. 3 blisters in a cardboard carton.

Prescription status. Prescription only.

Manufacturer.

AeGene Pharma Limited.

Manufacturer's address and location of its business operations.

Westside Business Park, Old Kilmeaden Road, Waterford, Ireland.

In case of any adverse events, adverse reactions, or lack of therapeutic effect, please report to ZENTIVA UKRAINE LLC, 5I Brovarskyi Avenue, Kyiv, 02660, Ukraine; tel./fax +38 044 517-75-00; e-mail [email protected].