EZOLOC is indicated for the adjuvant treatment of postmenopausal women with oestrogenreceptor positive invasive early breast cancer, following 2 – 3 years of initial adjuvanttamoxifen therapy. EZOLOC is indicated for the treatment of advanced breast cancer in women with natural orinduced postmenopausal status whose disease has progressed following anti- oestrogen therapy.Efficacy has not been demonstrated in patients with oestrogen receptor negative status.

Adult and elderly patients

The recommended dose of < EZOLOC > is one film-coated tablet (25mg) to be taken orallyonce a day, after a meal. In patients with early breast cancer, treatment with < EZOLOC > should continue untilcompletion of five years of combined sequential adjuvant hormonal therapy (tamoxifenfollowed by < EZOLOC >), or earlier if tumour relapse occurs. In patients with advanced breast cancer, treatment with < EZOLOC > should continue untiltumour progression is evident. No dose adjustments are required for patients with hepatic or renal insufficiency (see section5.2). 

Children and adolescents

Not recommended for use in children and adolescents 

EZOLOC should not be administered to women with pre-menopausal endocrine status. Therefore, whenever clinically appropriate, the post-menopausal status should be ascertainedby assessment of LH, FSH and oestradiol levels.

EZOLOC should be used with caution in patients with hepatic or renal impairment. EZOLOC is a potent oestrogen lowering agent, and a reduction in bone mineral density andan increased fracture rate has been observed following administration (see section 5.1). Duringadjuvant treatment with < EZOLOC >, women with osteoporosis or at risk of osteoporosisshould have their bone mineral density formally assessed by bone densitometryat the commencement of treatment. Although adequate data to show the effects of therapy inthe treatment of the bone mineral density loss caused by <

EZOLOC > are not available,treatment for osteoporosis should be initiated in at risk patients. Patients treated with EZOLOC should be carefully monitored. 

In vitro evidence showed that the drug is metabolized through cytochrome P450 (CYP) 3A4and aldoketoreductases (see 5.2) and does not inhibit any of the major CYP isoenzymes. In aclinical pharmacokinetic study, the specific inhibition of CYP 3A4 by ketoconazole showed nosignificant effects on the pharmacokinetics of exemestane. In an interaction study with rifampicin, a potent CYP450 inducer, at a dose of 600mg daily anda single dose of exemestane 25mg, the AUC of exemestane was reduced by 54% and Cmax by41%. Since the clinical relevance of this interaction has not been evaluated, the coadministrationof drugs, such as rifampicin, anticonvulsants (e.g. phenytoin andcarbamazepine) and herbal preparations containing hypericumperforatum (St John's Wort)known to induce CYP3A4 may reduce the efficacy of EZOLOC. EZOLOC should be used cautiously with drugs that are metabolized via CYP3A4 and havea narrow therapeutic window. There is no clinical experience of the concomitant use of EZOLOC with other anticancer drugs. EZOLOCshould not be co administered with oestrogen-containing medicines as these would negate its pharmacological action.

Pregnancy

No clinical data on exposed pregnancies are available with Exemestane. Studies on animalshave shown reproductive toxicity (See section 5.3). The potential risk for humans is unknown. EZOLOC is therefore contraindicated in pregnant women.

Lactation

It is not known whether exemestane is excreted into human milk. EZOLOC should not beadministered to lactating woman.

Women of perimenopausal status or child-bearing potential

The physician needs to discuss the necessity of adequate contraception with women whohave the potential to become pregnant including women who are perimenopausal or whohave recently become postmenopausal, until their postmenopausal status is fully established(see sections 4.3 and 4.4).

Drowsiness, somnolence, asthenia and dizziness have been reported with the use of thedrug. Patients should be advised that, if these events occur, their physical and/or mentalabilities required for operating machinery or driving a car may be impaired. 

Exemestane was generally well tolerated across all clinical studies conducted with Exemestane at a standard dose of 25 mg/day, and undesirable effects were usually mild tomoderate. The withdrawal rate due to adverse events was 7.4% in patients with early breast cancerreceiving adjuvant treatment with Exemestane following initial adjuvant tamoxifen therapy.The most commonly reported adverse reactions were hot flushes (22%), arthralgia (18%)and fatigue (16%). The withdrawal rate due to adverse events was 2.8% in the overall patient population withadvanced breast cancer. The most commonly reported adverse reactions were hot flushes(14%) and nausea (12%). Most adverse reactions can be attributed to the normal pharmacological consequences of oestrogen deprivation (e.g. hot flushes). The reported adverse reactions are listed below by system organ class and by frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon(≥1/1000 to < 1/100), rare (≥1/10,000 to <1/1000) 

(*) Includes: arthralgia, and less frequently pain in limb, osteoarthritis, back pain, arthritis,myalgia and joint stiffness

Blood and lymphatic system disorders

In patients with advanced breast cancer thrombocytopenia and leucopenia have been rarelyreported. An occasional decrease in lymphocytes has been observed in approximately 20%of patients receiving Exemestane, particularly in patients with preexisting lymphopenia;however, mean lymphocyte values in these patients did not change significantly over timeand no corresponding increase in viral infections was observed. These effects have not beenobserved in patients treated in early breast cancer studies.

Hepatobiliary disorders

Elevation of liver function test parameters including enzymes, bilirubin and alkalinephosphatase have been observed.

The table below presents the frequency of pre-specified adverse events and illnesses in theearly breast cancer study (IES), irrespective of causality, reported in patients receiving trialtherapy and up to 30 days after cessation of trial therapy

In the IES study, the frequency of ischemic cardiac events in the exemestane and tamoxifentreatment arms was 4.5% versus 4.2%, respectively. No significant difference was noted forany individual cardiovascular event including hypertension (9.9% versus 8.4%), myocardialinfarction (0.6% versus 0.2%) and cardiac failure (1.1% versus 0.7%). In the IES study, exemestane was associated with a greater incidence of hypercholesterolemiacompared with tamoxifen (3.7% vs. 2.1%). In a separate double blinded, randomized study of postmenopausal women with early breastcancer at low risk treated with exemestane (N=73) or placebo (N=73) for 24 months,exemestane was associated with an average 7-9% mean reduction in plasma HDL-cholesterol,versus a 1% increase on placebo. There was also a 5-6% reduction in apolipoprotein A1 in theexemestane group versus 0-2% for placebo. The effect on the other lipid parameters analyzed(total cholesterol, LDL cholesterol, triglycerides, apolipoprotein-B and lipoprotein-a) was verysimilar in the two treatment groups. The clinical significance of these results is unclear. In the IES study, gastric ulcer was observed at a higher frequency in the exemestane armcompared to tamoxifen (0.7% versus <0.1%). The majority of patients on exemestane withgastric ulcer received concomitant treatment with non-steroidal anti-inflammatory agentsand/or had a prior history. Adverse reactions from post-marketing experience Hepatobiliary disorders: Hepatitis, cholestatic hepatitis

 Because reactions are reported voluntarily from a population of uncertain size, it is not alwayspossible to reliably estimate their frequency or establish a causal relationship to drug exposure. 

Clinical trials have been conducted with Exemestane given up to 800 mg in a single dose tohealthy female volunteers and up to 600 mg daily to postmenopausal women with advanced breast cancer; these dosages were well tolerated. The single dose of Exemestane that couldresult in life-threatening symptoms is not known. In rats and dogs, lethality was observed aftersingle oral doses equivalent respectively to 2000 and 4000 times the recommended humandose on a mg/m2 basis. There is no specific antidote to overdosing and treatment must besymptomatic. General supportive care, including frequent monitoring of vital signs and closeobservation of the patient, is indicated. 

Pharmacotherapeutic group: hormone antagonists and related agents, enzyme inhibitors.

ATC: L02BG06

Exemestane is an irreversible, steroidal aromatase inhibitor, structurally related to the naturalsubstrate androstenedione. In post-menopausal women, oestrogens are produced primarily from the conversion of androgens into oestrogens through the aromatase enzyme in peripheraltissues. Oestrogen deprivation through aromatase inhibition is an effective and selectivetreatment for hormone dependent breast cancer in postmenopausal women. Inpostmenopausal women, Exemestanep.o. significantly lowered serum oestrogenconcentrations starting from a 5 mg dose, reaching maximal suppression (>90%) with a doseof 10-25 mg. In postmenopausal breast cancer patients treated with the 25 mg daily dose,whole body aromatization was reduced by 98%. 

Exemestane does not possess any progestogenic or oestrogenic activity. A slight androgenicactivity, probably due to the 17-hydro derivative, has been observed mainly at high doses. Inmultiple daily doses trials, Exemestane had no detectable effects on adrenal biosynthesis ofcortisol or aldosterone, measured before or after ACTH challenge, thus demonstrating itsselectivity with regard to the other enzymes involved in the steroidogenic pathway. Glucocorticoid or mineralocorticoid replacements are therefore not needed. A nondosedependentslight increase in serum LH and FSH levels has been observed even at low doses:this effect is, however, expected for the pharmacological class and is probably the result offeedback at the pituitary level due to the reduction in oestrogen levels that stimulate thepituitary secretion of gonadotropins also in postmenopausal women. Adjuvant Treatment of Early Breast Cancer In a multicenter, randomized, double-blind study, conducted in 4724 postmenopausal patientswith oestrogen-receptor-positive or unknown primary breast cancer, patients who hadremained disease-free after receiving adjuvant tamoxifen therapy for 2 to 3 years wererandomized to receive 3 to 2 years of Exemestane (25 mg/day) or tamoxifen (20 or 30 mg/day)to complete a total of 5 years of hormonal therapy. After a median duration of therapy of about 30 months and a median follow-up of about 52months, results showed that sequential treatment with Exemestane after 2 to 3 years of adjuvanttamoxifen therapy was associated with a clinically and statistically significant improvement indisease-free survival (DFS) compared with continuation of tamoxifen therapy. Analysisshowed that in the observed study period Exemestane reduced the risk of breast cancerrecurrence by 24% compared with tamoxifen (hazard ratio 0.76; p=0.00015). The beneficial effect of exemestane over tamoxifen with respect to DFS was apparentregardless of nodal status or prior chemotherapy. Exemestane also significantly reduced the risk of contralateral breast cancer (hazard ratio 0.57, p=0.04158). In the whole study population, a trend for improved overall survival was observed for exemestane (222 deaths) compared to tamoxifen (262 deaths) with a hazard ratio 0.85 (logranktest: 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 dying (hazard ratio foroverall survival 0.77; Wald chi square test: p = 0.0069) was observed for exemestanecompared to tamoxifen when adjusting for the prespecified prognostic factors (i.e., ER status,nodal status, prior chemotherapy, use of HRT and use of bisphosphonates). Main efficacy results in all patients (intention to treat population) and oestrogen receptorpositive patients are summarized in the table below:

​​​​​

* Log-rank test; ER+ patients = oestrogen receptor positive patients; a Disease-free survival is defined as the first occurrence of local or distant recurrence,contralateral breast cancer, or death from any cause; b Breast cancer free survival is defined as the first occurrence of local or distant recurrence,contralateral breast cancer or breast cancer death; c Distant recurrence free survival is defined as the first occurrence of distant recurrence orbreast cancer death; d Overall survival is defined as occurrence of death from any cause.

In the additional analysis for the subset of patients with oestrogenreceptor positive orunknown status, the unadjusted overall survival hazard ratio was 0.83 (log-rank test: p = 0.04250), representing a clinically and statistically significant 17% reduction in the risk ofdying. Results from a bone sub study demonstrated that women treated with Exemestane following 2to 3 years of tamoxifen treatment experienced moderate reduction in bone mineral density. Inthe overall study, the treatment emergent fracture incidence evaluated during the 30 monthstreatment period was higher in patients treated with EZOLOC compared withtamoxifen (4.5% and 3.3% correspondingly, p=0.038). Results from an endometrial sub study indicate that after 2 years of treatment there was amedian 33% reduction of endometrial thickness in the Exemestane-treated patients comparedwith no notable variation in the tamoxifen-treated patients. Endometrial thickening, reported atthe start of study treatment, was reversed to normal (< 5 mm) for 54% of patients treated with EZOLOC. Treatment of Advanced Breast Cancer In a randomized peer reviewed controlled clinical trial, Exemestane at the daily dose of 25 mghas demonstrated statistically significant prolongation of survival, Time to Progression (TTP), Time to Treatment Failure (TTF) as compared to a standard hormonal treatment with megestrolacetate in postmenopausal patients with advanced breast cancer that had progressed following,or during, treatment with tamoxifen either as adjuvant therapy or as first-line treatment foradvanced disease.

Absorption :

After oral administration of Exemestane tablets, exemestane is absorbed rapidly. The fractionof the dose absorbed from the gastrointestinal tract is high. The absolute bioavailability inhumans is unknown, although it is anticipated to be limited by an extensive first pass effect. Asimilar effect resulted in an absolute bioavailability in rats and dogs of 5%. After a single doseof 25 mg, maximum plasma levels of 18 ng/ml are reached after 2 hours. Concomitant intakewith food increases the bioavailability by 40%. 

Distribution:

The volume of distribution of exemestane, not corrected for the oral bioavailability, is ca 20000 l. The kinetics is linear and the terminal elimination half-life is 24 h. binding to plasma proteinsis 90% and is concentration independent. Exemestane and its metabolites do not bind to red blood cells. Exemestane does not accumulate in an unexpected way after repeated dosing.

Metabolism and excretion:

Exemestane is metabolised by oxidation of the methylene moiety on the 6 position by CYP 3A4isoenzyme and/or reduction of the 17-keto group by aldoketoreductase followed by conjugation.The clearance of exemestane is ca 500 l/h, not corrected for the oral bioavailability.The metabolites are inactive or the inhibition of aromatase is less than the parent compound. The amount excreted unchanged in urine is 1% of the dose. In urine and faeces equal amounts(40%) of 14C-labeled exemestane were eliminated within a week.

Special populations

Age:

No significant correlation between the systemic exposure of Exemestane and the age ofsubjects has been observed.

Renal insufficiency:

In patients with severe renal impairment (CLcr< 30 ml/min) the systemic exposure to exemestane was 2 times higher compared with healthy volunteers. Given the safety profile of exemestane, no dose adjustment is considered to be necessary.

Hepatic insufficiency:

In patients with moderate or severe hepatic impairment the exposure of exemestane is 2-3 foldhigher compared with healthy volunteers. Given the safety profile of exemestane, no doseadjustment is considered to be necessary.

Toxicological studies: Findings in the repeat dose toxicology studies in rat and dog weregenerally attributable to the pharmacological activity of exemestane, such as effects onreproductive and accessory organs. Other toxicological effects (on liver, kidney or centralnervous system) were observed only at exposures considered sufficiently in excess of themaximum human exposure indicating little relevance to clinical use.

Mutagenicity: Exemestane was not genotoxic in bacteria (Ames test), in V79 Chinese hamstercells, in rat hepatocytes or in the mouse micronucleus assay. Although exemestane wasclastogenic in lymphocytes in vitro, it was not clastogenic in two in vivo studies

Reproductive toxicology: Exemestane was embryotoxic in rats and rabbits at systemicexposure levels similar to those obtained in humans at 25 mg/day. There was no evidence of teratogenicity. 

Carcinogenicity: In a two-year carcinogenicity study in female rats, no treatmentrelatedtumors were observed. In male rats the study was terminated on week 92, because of earlydeath by chronic nephropathy. In a two-year carcinogenicity study in mice, an increase in theincidence of hepatic neoplasms in both genders was observed at the intermediate and high doses (150 and 450 mg/kg/day). This finding is considered to be related to the induction ofhepatic microsomal enzymes, an effect observed in mice but not in clinical studies. An increasein the incidence of renal tubular adenomas was also noted in male mice at the high dose (450mg/kg/day). This change is considered to be species- and gender-specific and occurred at adose which represents 63-fold greater exposure than occurs at the human therapeutic dose. None of these observed effects is considered to be clinically relevant to the treatment ofpatients with exemestane.

Tablet core: Mannitol (E421) Copovidone Crospovidone Silicified Microcrystalline Cellulose Sodium Starch Glycolate (Type A) Magnesium Stearate (E470b)

Film coating: Hypromellose (E464) Macrogol 400 Titanium Dioxide(E171) 

Not applicable. 

Store below 30° C. This medicinal product does not require any special storage conditions. 

PVC-PVdC/Aluminum blisters of:

UK/H/1900/001/DC 10, 14, 20, 30, 50x1, 60, 90, 100 (Blisters of 10 or 14) film-coated tablets. Not all pack sizes may be marketed.

UK/H/1901/001/DC 10, 30, 90 (Blisters of 10) film-coated tablets. Not all pack sizes may be marketed.

UK/H/1902/001/DC 30, 90 and 100 tablets (Blisters of 10) film-coated tablets. Not all pack sizes may be marketed.

UK/H/1903/001/DC 10, 14, 20, 30, 60, 90, 100 and 120 (Blisters of 10 or 14) film-coated tablets. Not all pack sizes may be marketed.

UK/H/1904/001/DC 10, 14, 20, 30, 60, 90 and 100 (Blisters of 10 or 14) film-coated tablets. Not all pack sizes may be marketed.

UK/H/1905/001/DC 30 tablets (Blisters of 10) film-coated tablets.

UK/H/1906/001/DC 10, 14, 20, 30, 60, 90, 100 (Blisters of 10or 14) film-coated tablets. Not all pack sizes may be marketed.

UK/H/1907/001/DC 30, 100 (Blisters of 10) film-coated tablets. Not all pack sizes may be marketed.

UK/H/1908/001/DC 14, 30 and 90 (Blisters of 10 or 14) film-coated tablets. Not all pack sizes may be marketed.

Any unused product or waste should be disposed of in accordance with local requirements.