Aromasin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AROMASIN (AROMASINÒ)

Composition:

Active substance: exemestane;

1 tablet contains 25 mg of exemestane;

Excipients: mannitol (E 421), hypromellose, polysorbate 80, crospovidone, colloidal anhydrous silicon dioxide, microcrystalline cellulose, sodium starch glycolate (type A), magnesium stearate; sugar coating (hypromellose, simethicone emulsion, macrogol 6000, sucrose, light magnesium carbonate, titanium dioxide (E 171), methylparahydroxybenzoate (E 218), polyvinyl alcohol, cetostearyl alcohol, talc, carnauba wax); printing ink: shellac, iron oxide (E 172), titanium oxide (E 171), ethanol, isobutyl alcohol.

Pharmaceutical form. Sugar-coated tablets.

Main physicochemical characteristics: round, biconvex, sugar-coated tablets of almost white to slightly greyish color, approximately 6 mm in diameter, with the number 7663 printed in black ink 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 to estrogens under the influence of the enzyme aromatase in peripheral tissues. Inhibition of estrogen synthesis via aromatase blockade 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; maximal reduction (> 90%) is achieved with doses of 10–25 mg. In postmenopausal patients with breast cancer receiving 25 mg of the drug daily, total aromatase activity decreased by 98%.

Exemestane has no progestogenic or estrogenic activity. A minor androgenic activity, likely related to the 17-hydro derivative, was observed mainly at high doses. During 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) stimulation testing; this demonstrated selectivity over 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 likely results from feedback mechanisms at the pituitary level due to 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 estrogen receptor-positive tumors or tumors with unknown estrogen receptor status, patients who remained recurrence-free after 2–3 years of adjuvant tamoxifen therapy were randomized to receive either Arromasin (25 mg/day) or tamoxifen (20 or 30 mg/day) for an additional 2–3 years to complete a total of 5 years of hormonal therapy.

Follow-up with median duration of 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 Arromasin 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, Arromasin 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 in terms of disease-free survival was evident regardless of lymph node status or prior chemotherapy.

Treatment with Arromasin 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; chi-square test (Wald 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

Table 1.

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

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

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

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

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

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

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

Further follow-up with a median of 87 months in the intergroup exemestane trial.

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 (DFS) compared to continuing tamoxifen. The results showed that during the observation period, Arimidex 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. 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).

Arimidex also reduced the risk of contralateral breast cancer, although the effect was no longer statistically significant during this observation period in the trial (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 prespecified 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; chi-square test (Wald test): p = 0.0082) was observed with exemestane compared to tamoxifen in the overall study population.

In a post hoc 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 ancillary 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 slightly greater final BMD reduction in the tamoxifen group at all sites (mean % change in BMD at 24 months from baseline: -2.17 (spine), -3.06 (total hip) with exemestane vs. -3.44 (spine), -4.15 (total hip) with tamoxifen).

The total number of 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 due to osteoporosis.

Final follow-up of 119 months in the intergroup exemestane trial (IES)

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

Exemestane also significantly prolonged breast cancer-free survival (hazard ratio – 0.83, p < 0.00152) and distant recurrence-free survival (hazard ratio – 0.86, p = 0.02213). Exemestane also reduced the risk of contralateral breast cancer; however, the 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 comparisons). For the subgroup of patients with positive or unknown estrogen receptor status, the unadjusted hazard ratio for overall survival was 0.89 (log-rank test: p = 0.07881) in the exemestane group compared to the tamoxifen group.

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

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

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

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

Table 2.

Treatment of advanced breast cancer.

In a randomized, comparative, controlled clinical trial, administration of the drug Arromasin at a daily dose of 25 mg demonstrated a statistically significant improvement 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, used either as adjuvant therapy or as first-line therapy for advanced disease.

Pharmacokinetics.

Absorption.

After oral administration of Arromasin tablets, exemestane is rapidly absorbed. The fraction of the dose absorbed from the gastrointestinal tract is high. Absolute bioavailability in humans has not been determined, although extensive first-pass metabolism is expected. A similar effect resulted in an absolute bioavailability of approximately 5% in rats and dogs. After a single 25 mg dose, the mean plasma concentration reaches 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. Exemestane pharmacokinetics 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.

Elimination.

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

Regarding aromatase inhibition, these metabolites are either inactive or less active than the parent compound. The amount of unchanged drug excreted in urine 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 Arromasin 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. Given 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. Given the safety profile of exemestane, dose adjustment is not required.

Clinical characteristics.

Indications.

Adjuvant therapy in postmenopausal women with early-stage invasive estrogen receptor-positive breast cancer after 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 following antiestrogen therapy. Efficacy has not been demonstrated in patients with estrogen receptor-negative tumors.

Contraindications.

Hypersensitivity to the active ingredient or to any of the excipients listed in the section "Composition". The drug is also contraindicated in premenopausal women, as well as in 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 (CYP3A4) and aldo-keto reductases (see section "Pharmacokinetics") and does not inhibit any of the major CYP isoenzymes. A clinical pharmacokinetic study demonstrated that specific inhibition of CYP3A4 by ketoconazole does 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 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 established, concomitant use of drugs such as rifampicin, anticonvulsants (e.g. phenytoin and carbamazepine), and herbal preparations containing St. John’s wort (Hypericum perforatum), known to induce CYP3A4, may reduce the efficacy of Arromasin.

Arromasin should be used with caution when co-administered with medicinal products metabolized by CYP3A4 and having a narrow therapeutic index. There is no clinical experience with concomitant use of Arromasin and other anticancer medicinal products.

Arromasin should not be used with medicinal products containing estrogens, as their pharmacological effects are counteracted when used concomitantly.

Special precautions for use

Exemestane 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.

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

Exemestane tablets contain sucrose and therefore should not be administered to patients with rare hereditary forms of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

Exemestane tablets contain methyl parahydroxybenzoate (methylparaben, E 218), which may cause allergic reactions (possibly delayed).

Exemestane is a drug that markedly reduces estrogen levels. A decrease in bone mineral density and an increased fracture rate have been observed during treatment with this drug (see section "Pharmacodynamics"). At the beginning of adjuvant therapy with exemestane in women who have osteoporosis or are at risk of developing it, baseline bone mineral density should be assessed 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 treatment on bone mineral density loss induced by exemestane are lacking, patients receiving exemestane should be monitored, and treatment or prophylaxis for osteoporosis should be initiated in patients at risk.

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

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

One tablet contains 30.2 mg of sucrose and 0.003 mg of methylparahydroxybenzoate (E 218).

Use during pregnancy or breastfeeding

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

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

Effects on ability to drive and use machines

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

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

Method of Administration and Dosage.

Adults and elderly patients.

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

In patients with early-stage breast cancer, treatment with Aromasin should be continued until completion of a five-year course of combined sequential adjuvant hormonal therapy (continuation of Aromasin treatment after tamoxifen) or until tumor recurrence occurs.

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

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

Children.

The drug is not recommended for use in children.

Overdose.

Clinical studies have been conducted using single doses of Aromasin up to 800 mg in healthy female volunteers and doses up to 600 mg daily in postmenopausal women with advanced breast cancer; data from these studies indicate good tolerability of these doses. The single dose of Aromasin that may cause life-threatening symptoms has not been established. In animal studies, lethality was observed after 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 patient observation.

Adverse reactions

Arimidex was generally well tolerated in all clinical studies when administered at the standard dose of 25 mg/day; adverse events were usually mild to moderate in severity. The rate of treatment discontinuation due to adverse events was 7.4% in patients with early-stage breast cancer who received adjuvant therapy with Arimidex following initial adjuvant therapy with tamoxifen. 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 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 expected pharmacological consequences of estrogen blockade (e.g., hot flushes).

Adverse reactions observed during clinical studies 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, diarrhoea, 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 oedema, 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 Arimidex, particularly in those with pre-existing lymphopenia. However, mean lymphocyte counts over time did not significantly change in these patients, and no increase in the frequency of viral infections was observed. These effects were not seen in patients treated in early breast cancer studies.

† Frequency calculated according to the rule of 3/X.

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

Table 3.

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

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

In a separate double-blind, randomized study involving postmenopausal women with early-stage, low-risk breast cancer who received either exemestane (N = 73) or placebo (N = 73) for 24 months, treatment with exemestane was associated with a mean decrease in plasma LDL-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 (total cholesterol, HDL-cholesterol, triglycerides, apolipoprotein-B, and lipoprotein-a levels) 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 received exemestane and developed gastric ulcer were also concomitantly or previously treated with nonsteroidal anti-inflammatory drugs and/or aspirin.

Reporting of suspected adverse reactions.

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

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C.

Keep out of reach and sight of children.

Packaging.

15 tablets in a blister, 2 blisters in a cardboard box, or 20 tablets in a blister, 5 blisters in a cardboard box.

Prescription category.

Prescription only.

Manufacturer.

Pfizer Italia S.r.l./Pfizer Italia S.r.l.

Manufacturer's address and location of operations.

Localita Marino del Tronto – 63100 Ascoli Piceno (AP), Italy.