Arostanil

Arostanil

exemestane

Manufacturer:

Intas

Distributor:

Sandoz
Full Prescribing Info
Contents
Exemestane.
Description
Each film-coated tablet contains 25 mg of Exemestane.
Action
Pharmacotherapeutic Group: Steroidal aromatase inhibitor; antineoplastic agent. ATC Code: L02BG06.
Pharmacology: Pharmacodynamics: Exemestane is an irreversible, steroidal aromatase inhibitor, structurally related to the natural substrate androstenedione. In postmenopausal women, oestrogens are produced primarily from the conversion of androgens into oestrogens through the aromatase enzyme in peripheral tissues. Oestrogen deprivation through aromatase inhibition is an effective and selective treatment for hormone-dependent breast cancer in postmenopausal women. In postmenopausal women, exemestane p.o. significantly lowered serum oestrogen concentrations starting from a 5 mg dose, reaching maximal suppression (>90%) with a dose of 10-25 mg. In postmenopausal breast cancer patients treated with the 25 mg daily dose, whole body aromatisation was reduced by 98%.
Exemestane does not possess any progestogenic or oestrogenic activity. A slight androgenic activity, probably due to the 17-hydro derivative, has been observed mainly at high doses. In multiple daily dose trials, exemestane had no detectable effects on adrenal biosynthesis of cortisol or aldosterone, measured before or after ACTH challenge, thus demonstrating its selectivity with regard to the other enzymes involved in the steroidogenic pathway.
Glucocorticoid or mineralocorticoid replacements are therefore not needed. A non dose-dependent slight 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 of feedback at the pituitary level due to the reduction in oestrogen levels that stimulate the pituitary secretion of gonadotropins also in postmenopausal women.
Adjuvant treatment of early breast cancer: In a multicentre, randomised, double-blind study, conducted in 4,724 postmenopausal patients with oestrogen-receptor-positive or unknown primary breast cancer, patients who had remained disease-free after receiving adjuvant tamoxifen therapy for 2 to 3 years were randomised 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 52 months, results showed that sequential treatment with exemestane after 2 to 3 years of adjuvant tamoxifen therapy was associated with a clinically and statistically significant improvement in disease-free survival (DFS) compared with continuation of tamoxifen therapy. Analysis showed that, in the observed study period, exemestane reduced the risk of breast cancer recurrence by 24% compared with tamoxifen (hazard ratio 0.76; p=0.00015). The beneficial effect of exemestane over tamoxifen with respect to DFS was apparent regardless 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 (log-rank test: p=0.07362), representing a 15% reduction in the risk of death in favour of exemestane. A statistically significant 23% reduction in the mortality risk (hazard ratio for overall survival 0.77; Wald chi square test: p=0.0069) was observed for exemestane compared to tamoxifen when adjusting for the pre-specified prognostic factors (i.e. ER status, nodal status, prior chemotherapy, use of HRT and use of bisphosphonates).
Main efficacy outcomes in all patients (intention-to-treat population) and oestrogen-receptor positive patients are summarised in the table as follows: (See Table 1.)

Click on icon to see table/diagram/image

Results from a bone substudy demonstrated that women treated with exemestane following 2 to 3 years of tamoxifen treatment experienced a moderate reduction in bone mineral density. In the overall study, the treatment-emergent fracture incidence evaluated during the 30-month treatment period was higher in patients treated with exemestane compared with tamoxifen (4.5% and 3.3% respectively, p=0.038).
Results from an endometrial substudy indicate that, after 2 years of treatment, there was a median 33% reduction in endometrial thickness among the exemestane-treated patients compared with no notable variation in the tamoxifen-treated patients. Endometrial thickening, reported at the start of study treatment, was reversed to normal (<5 mm) for 54% of patients treated with exemestane.
Treatment of advanced breast cancer: In a randomised, peer-reviewed, controlled clinical trial, exemestane at the daily dose of 25 mg has demonstrated statistically significant prolongation of survival, Time to Progression (TTP) and Time to Treatment Failure (TTF), as compared to a standard hormonal treatment with megestrol acetate 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 for advanced disease.
Pharmacokinetics: Absorption: After oral administration of exemestane tablets, exemestane is rapidly absorbed. The fraction of the dose absorbed from the gastrointestinal tract is high. Absolute bioavailability in humans is unknown, although it is anticipated to be limited by an extensive first-pass effect. A similar effect resulted in an absolute bioavailability in rats and dogs of 5%. After a single dose of 25 mg, maximum plasma levels of 18 ng/mL are reached after 2 hours. Concomitant intake with food increases the bioavailability by 40%.
Distribution: The volume of distribution of exemestane, not corrected for oral bioavailability, is about 20,000 L. The kinetics is linear and the terminal elimination half-life is 24 h. Binding to plasma proteins is 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 CYP3A4 isoenzyme and/or reduction of the 17-keto group by aldoketoreductase followed by conjugation. The clearance of exemestane is about 500 L/h, not corrected for oral bioavailability.
The metabolites are inactive or 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-labelled exemestane were eliminated within one week.
Special populations: Age: No significant correlation between the systemic exposure of exemestane and the age of subjects 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 necessary.
Hepatic insufficiency: In patients with moderate or severe hepatic impairment, the exposure of exemestane is 2-3 fold higher compared with healthy volunteers. Given the safety profile of exemestane, no dose adjustment is considered necessary.
Toxicology: Preclinical safety data: Toxicological studies: Findings in the repeat-dose toxicology studies in rat and dog were generally attributable to the pharmacological activity of exemestane, such as effects on reproductive and accessory organs. Other toxicological effects (on liver, kidney or central nervous system) were observed only at exposures considered sufficiently in excess of the maximum human exposure, indicating little relevance to clinical use.
Mutagenicity: Exemestane was not genotoxic in bacteria (Ames test), V79 Chinese hamster cells, rat hepatocytes or in the mouse micronucleus assay. Although exemestane was clastogenic in lymphocytes in vitro, it was not clastogenic in two in vivo studies.
Reproductive toxicology: Exemestane was embryotoxic in rats and rabbits at systemic exposure 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 treatment-related tumours were observed. In male rats, the study was terminated in week 92 due to early death by chronic nephropathy. In a two-year carcinogenicity study in mice, an increase in the incidence 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 of hepatic microsomal enzymes, an effect observed in mice but not in clinical studies. An increase in the incidence of renal tubular adenomas was also noted in male mice at the high dose (450 mg/kg/day). This change is considered to be species- and gender-specific, occurring at a dose which represents 63-fold greater exposure than with the human therapeutic dose. None of these observed effects is considered to be clinically relevant to the treatment of patients with exemestane.
Indications/Uses
Exemestane is indicated for the adjuvant treatment of postmenopausal women with oestrogen-receptor positive invasive early breast cancer, following 2-3 years of initial adjuvant tamoxifen therapy.
Exemestane is indicated for the treatment of advanced breast cancer in women with natural or induced postmenopausal status whose disease has progressed following anti-oestrogen therapy. Efficacy has not been demonstrated in patients with oestrogen-receptor negative status.
Dosage/Direction for Use
Adult and elderly patients: The recommended dose of exemestane is one 25 mg tablet to be taken once a day after a meal.
In patients with early breast cancer, treatment with exemestane should continue until completion of five years of combined sequential adjuvant hormonal therapy (tamoxifen followed by exemestane), or earlier if tumour relapse occurs.
In patients with advanced breast cancer, treatment with exemestane should continue until tumour progression is evident.
No dose adjustments are required for patients with hepatic or renal insufficiency (see Pharmacology: Pharmacokinetics under Actions).
Children: Not recommended for use in children.
Overdosage
Clinical trials have been conducted with exemestane up to 800 mg as a single dose in healthy female volunteers and up to 600 mg daily in postmenopausal women with advanced breast cancer; these dosages were well tolerated. The single dose of exemestane that could result in life-threatening symptoms is not known. In rats and dogs, lethality was observed after single oral doses equivalent respectively to 2,000 and 4,000 times the recommended human dose on a mg/m2 basis. There is no specific antidote to overdose and treatment must be symptomatic. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.
Contraindications
Exemestane tablets are contraindicated in patients with known hypersensitivity to the active substance or to any of the excipients, in pre-menopausal women and in pregnant or lactating women (see Use in Pregnancy & Lactation).
Special Precautions
Exemestane should not be administered to women with premenopausal endocrine status. Therefore, whenever clinically appropriate, the postmenopausal status should be ascertained by assessment of LH, FSH and oestradiol levels.
Exemestane should be used with caution in patients with hepatic or renal impairment.
Exemestane tablets contain a prohibited substance which can produce positive results in doping control tests.
Exemestane is a potent oestrogen lowering agent; a reduction in bone mineral density and an increased fracture rate have been observed following administration (see Pharmacology: Pharmacodynamics under Actions). During adjuvant treatment with exemestane, women with osteoporosis or at risk of osteoporosis should have their bone mineral density formally assessed by bone densitometry using DEXA (Dual-Energy X-Ray Absorptiometry) at the commencement of treatment. Although there are no adequate data available to show the effects of therapy in the treatment of the bone mineral density loss caused by exemestane, treatment for osteoporosis should be initiated in at-risk patients. Patients treated with exemestane should be carefully monitored.
Effects on ability to drive and use machines: Drowsiness, somnolence, asthenia and dizziness have been reported with the use of exemestane. Patients should be advised that, if these events occur, their physical and/or mental abilities required for operating machinery or driving a car may be impaired. If a hypoglycaemic episode is severe or prolonged, and even if it is temporarily controlled by intake of sugar, immediate medical treatment or even hospitalization is required.
Use In Pregnancy & Lactation
Pregnancy: No clinical data on exposed pregnancies are available with exemestane. Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). Exemestane is therefore contraindicated in pregnant women.
Lactation: It is unknown whether exemestane is excreted in human milk. Exemestane should not be administered to lactating women.
Women of perimenopausal status or child-bearing potential: The physician needs to discuss the necessity of adequate contraception with women of childbearing potential, including women who are perimenopausal or have recently become postmenopausal, until their postmenopausal status is fully established (see Contraindications and Precautions).
Adverse Reactions
Exemestane was generally well tolerated across all clinical studies conducted with exemestane at a standard dose of 25 mg/day undesirable effects were usually mild to moderate.
The withdrawal rate due to adverse events was 7.4% in patients with early breast cancer receiving 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 with advanced 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 sequoias 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 (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from available data). (See Table 2.)

Click on icon to see table/diagram/image

Blood and lymphatic system disorders: In patients with advanced breast cancer, thrombocytopenia and leucopenia have been rarely reported. An occasional decrease in lymphocytes has been observed in approximately 20% of patients receiving exemestane, particularly in patients with pre-existing lymphopenia; however, mean lymphocyte values in these patients did not change significantly over time and no corresponding increase in viral infections was observed. These effects have not been observed in patients treated in early breast cancer studies.
Hepatobiliary disorders: Elevation of liver function test parameters, including enzymes, bilirubin and alkaline phosphatase, has been observed.
The table below presents the frequency of pre-specified adverse events and illnesses in the early breast cancer study (IES), irrespective of causality, reported in patients receiving trial therapy and up to 30 days after cessation of trial therapy. (See Table 3.)

Click on icon to see table/diagram/image

In the IES study, the frequency of ischaemic cardiac events in the exemestane and tamoxifen treatment arms was 4.5% versus 4.2%, respectively. No significant difference was noted for any individual cardiovascular event, including hypertension (9.9% versus 8.4%), myocardial infarction (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 hypercholesterolaemia compared with tamoxifen (3.7% vs. 2.1%).
In a separate double-blind, randomised study of postmenopausal women with early breast cancer 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 the exemestane group versus 0-2% for placebo. The effect on the other lipid parameters analysed (total cholesterol, LDL cholesterol, triglycerides, apolipoprotein-B and lipoproteins) was very similar 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 arm compared to tamoxifen (0.7% versus <0.1%). The majority of patients on exemestane with gastric ulcer received concomitant treatment with non-steroidal anti-inflammatory agents and/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 always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Drug Interactions
In vitro evidence showed that exemestane is metabolised through cytochrome P450 (CYP) 3A4 and aldoketoreductases (see Pharmacology: Pharmacokinetics under Actions) and does not inhibit any of the major CYP isoenzymes. In a clinical pharmacokinetic study, the specific inhibition of CYP3A4 by ketoconazole showed no significant effects on the pharmacokinetics of exemestane.
In an interaction study with rifampicin, a potent CYP450 inducer, at a dose of 600 mg daily and a single dose of 25 mg exemestane, the AUC of exemestane was reduced by 54% and Cmax by 41%. Since the clinical relevance of this interaction has not been evaluated, co-administration of medicines such as rifampicin, anticonvulsants (e.g. phenytoin and carbamazepine) and herbal preparations containing Hypericum perforatum (St John's wort) known to induce CYP3A4 may reduce the efficacy of exemestane. Exemestane should be used cautiously with agents metabolised via CYP3A4 and with a narrow therapeutic window. There is no clinical experience with the concomitant use of exemestane with other anticancer agents.
Exemestane should not be co-administered with oestrogen-containing medicines, as these would negate its pharmacological action.
Caution For Usage
Incompatibilities: Not applicable.
Storage
Store at temperatures not exceeding 25°C.
ATC Classification
L02BG06 - exemestane ; Belongs to the class of enzyme inhibitors. Used in treatment of neoplastic diseases.
Presentation/Packing
FC tab 25 mg (white to off-white, round, biconvex debossed with 'E25' on one side and plain on the other) x 28's, 30's.
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