Cleopa

Posology

Adult and elderly patients

The recommended dose of Cleopa is one 25 mg tablet to be taken once daily, preferably after a meal.

In patients with early breast cancer, treatment with Cleopa should continue until completion of five years of combined sequential adjuvant hormonal therapy (tamoxifen followed by Cleopa), or earlier if tumour relapse occurs.

In patients with advanced breast cancer, treatment with Cleopa should continue until tumour progression is evident.

No dose adjustments are required for patients with hepatic or renal insufficiency.

Paediatric population

Not recommended for use in children.

Posology

Adult and elderly patients

The recommended dose of Cleopa is one 25 mg tablet to be taken once daily, preferably after a meal.

In patients with early breast cancer, treatment with Cleopa should continue until completion of five years of combined sequential adjuvant hormonal therapy (tamoxifen followed by Cleopa), or earlier if tumour relapse occurs.

In patients with advanced breast cancer, treatment with Cleopa should continue until tumour progression is evident.

No dose adjustments are required for patients with hepatic or renal insufficiency.

Paediatric population

Not recommended for use in children.

Method of administration

Cleopa 25 mg coated tablets are for oral use.

-menopausal women and in pregnant or lactating women.

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

Cleopa should be used with caution in patients with hepatic or renal impairment.

Cleopa tablets contain sucrose and should not be administered to patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency.

Cleopa tablets contain methyl-p-hydroxybenzoate which may cause allergic reactions (possibly delayed).

Cleopa is a potent oestrogen lowering agent, and a reduction in bone mineral density (BMD) and an increased fracture rate have been observed following administration. At the commencement of adjuvant treatment with Cleopa, women with osteoporosis or at risk of osteoporosis should have treatment baseline bone mineral health assessment based on current clinical guidelines and practice. Patients with advanced disease should have their bone mineral density assessed on a case-by-case basis. Although adequate data to show the effects of therapy in the treatment of the bone mineral density loss caused by Cleopa are not available, patients treated with Cleopa should be carefully monitored and treatment for, or prophylaxis of, osteoporosis should be initiated in at risk patients.

Routine assessment of 25 hydroxy vitamin D levels prior to the start of aromatase inhibitor treatment should be considered, due to the high prevalence of severe deficiency in women with early breast cancer. Women with Vitamin D deficiency should receive supplementation with Vitamin D.

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

Cleopa should be used with caution in patients with hepatic or renal impairment.

Cleopa tablets contain sucrose and should not be administered to patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency.

Cleopa is a potent oestrogen lowering agent, and a reduction in bone mineral density (BMD)and an increased fracture rate has been observed following administration. At the commencement of adjuvant treatment with Cleopa, women with osteoporosis or at risk of osteoporosis should have treatment baseline bone mineral health assessment, based on current clinical guidelines and practice. Patients with advanced disease should have their bone mineral density assessed on a case-by-case basis. Although adequate data to show the effects of therapy in the treatment of the bone mineral density loss caused by Cleopa are not available, patients treated with Cleopa should be carefully monitored and treatment for, or prophylaxis of, osteoporosis should be initiated in at risk patients.

Routine assessment of 25 hydroxy vitamin D levels prior to the start of aromatase inhibitor treatment should be considered, due to the high prevalence of severe deficiency in women with early breast cancer. Women with Vitamin D deficiency should receive supplementation with Vitamin D.

Athletes must be aware that this medicine may cause a positive reaction to 'anti-doping' tests.

Cleopa was generally well tolerated across all clinical studies conducted with Cleopa at a standard dose of 25 mg/day, and 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 Cleopa 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 consequences of oestrogen deprivation (e.g., hot flushes).

The reported adverse reactions from clinical studies and post-marketing experience 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); Not known (cannot be estimated from the available data).

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

⁽**⁾ 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 Cleopa, 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.

^{(†)} Frequency calculated by rule of 3/X.

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

In the IES study, the frequency of ischemic 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 hypercholesterolemia compared with tamoxifen (3.7% versus. 2.1%).

In a separate double blinded, randomized 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 lipoprotein-a) 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard

Cleopa was generally well tolerated across all clinical studies conducted with Cleopa at a standard dose of 25 mg/day, and 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 Cleopa 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 consequences of oestrogen deprivation (e.g. hot flushes).

The reported adverse reactions from clinical studies and post-marketing experience 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); Not known (cannot be estimated from the available data).

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

^(**) 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 Cleopa, 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.

^{(†)} Frequency calculated by rule of 3/X

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.

In the IES study, the frequency of ischaemic cardiac events in the Cleopa 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, Cleopa was associated with a greater incidence of hypercholesterolemia compared with tamoxifen (3.7% vs. 2.1%).

In a separate double blinded, randomized study of postmenopausal women with early breast cancer at low risk treated with Cleopa (N=73) or placebo (N=73) for 24 months , Cleopa 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 Cleopa group versus 0-2% for placebo. The effect on the other lipid parameters analysed (total cholesterol, LDL cholesterol, triglycerides, apolipoprotein-B and lipoprotein-a) 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 Cleopa arm compared to tamoxifen (0.7% versus <0.1%). The majority of patients on Cleopa with gastric ulcer received concomitant treatment with non-steroidal anti-inflammatory agents and/or had a prior history.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

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

Clinical trials have been conducted with Cleopa given up to 800 mg in a single dose to healthy female volunteers and up to 600 mg daily to postmenopausal women with advanced breast cancer; these dosages were well tolerated. The single dose of Cleopa that could result in life-threatening symptoms is not known. In rats and dogs, lethality was observed after single oral doses equivalent respectively to 2000 and 4000 times the recommended human dose on a mg/m² basis.

There is no specific antidote to overdosage and treatment must be symptomatic. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.

Pharmacotherapeutic group: steroidal aromatase inhibitor; anti-neoplastic agent

ATC: L02BG06

Mechanism of action

Exemestane is an irreversible, steroidal aromatase inhibitor, structurally related to the natural substrate androstenedione. In post-menopausal 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, Cleopa 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 aromatization 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 doses trials, Cleopa 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.

Clinical efficacy and safety

Adjuvant treatment of early breast cancer

In a multicentre, randomised, double-blind study (IES), conducted in 4724 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 Cleopa (25 mg/day) or tamoxifen (20 or 30 mg/day) to complete a total of 5 years of hormonal therapy.

IES 52-month median follow-up

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 Cleopa 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 Cleopa 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.

Cleopa 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 risk of dying (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).

52 month main efficacy results in all patients (intention to treat population) and oestrogen receptor positive patients

* 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 or breast cancer death;

^d Overall survival is defined as occurrence of death from any cause.

In the additional analysis for the subset of patients with oestrogen receptor positive or unknown 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 of dying.

Results from the IES bone substudy demonstrated that women treated with Cleopa following 2 to 3 years of tamoxifen treatment experienced moderate reduction in bone mineral density. In the overall study, the treatment emergent fracture incidence evaluated during the 30 months treatment period was higher in patients treated with Cleopa compared with tamoxifen (4.5% and 3.3% correspondingly, p = 0.038).

Results from the IES endometrial substudy indicate that after 2 years of treatment there was a median 33% reduction of endometrial thickness in the Cleopa-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 Cleopa.

IES 87-month median follow-up

After a median duration of therapy of about 30 months and a median follow-up of about 87 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 DFS compared with continuation of tamoxifen therapy. Results showed that in the observed study period Cleopa significantly reduced the risk of breast cancer recurrence by 16% compared with tamoxifen (hazard ratio 0.84; p = 0.002).

Overall, the beneficial effect of exemestane over tamoxifen with respect to DFS was apparent regardless of nodal status or prior chemotherapy or hormonal therapy. Statistical significance was not maintained in a few sub-groups with small sample sizes. These showed a trend favouring exemestane in patients with more than 9 nodes positive, or previous chemotherapy CMF. In patients with nodal status unknown, previous chemotherapy other, as well as unknown/missing status of previous hormonal therapy a non statistically significant trend favouring tamoxifen was observed.

In addition, 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).

Cleopa also reduced the risk of contralateral breast cancer, although the effect was no longer statistically significant in this observed study period (hazard ratio 0.74, p = 0.12983). In the whole study population, a trend for improved overall survival was observed for exemestane (373 deaths) compared to tamoxifen (420 deaths) with a hazard ratio 0.89 (log rank test: p = 0.08972), representing an 11% reduction in the risk of death in favour of exemestane. When adjusting for the pre-specified prognostic factors (i.e., ER status, nodal status, prior chemotherapy, use of HRT and use of bisphosphonates), a statistically significant 18% reduction in the risk of dying (hazard ratio for overall survival 0.82; Wald chi square test: p = 0.0082) was observed for exemestane compared to tamoxifen in the whole study population.

In the additional analysis for the subset of patients with oestrogen receptor positive or unknown status, the unadjusted overall survival hazard ratio was 0.86 (log-rank test: p = 0.04262), representing a clinically and statistically significant 14% reduction in the risk of dying.

Results from a bone sub-study indicate that treatment with exemestane for 2 to 3 years following 3 to 2 years of tamoxifen treatment increased bone loss while on treatment (mean % change from baseline for BMD at 36 months: -3.37 [spine], -2.96 [total hip] for exemestane and -1.29 [spine], -2.02 [total hip], for tamoxifen). However, by the end of the 24 month post treatment period there were minimal differences in the change in BMD from baseline for both treatment groups, the tamoxifen arm having slightly greater final reductions in BMD at all sites (mean % change from baseline for BMD at 24 months post treatment -2.17 [spine], -3.06 [total hip] for exemestane and -3.44 [spine], -4.15 [total hip] for tamoxifen).

The all fractures reported on-treatment and during follow-up was significantly higher in the exemestane group than on tamoxifen (169 [7.3%] versus 122 [5.2%]; p = 0.004), but no difference was noted in the number of fractures reported as osteoporotic.

IES 119-month final follow-up

After a median duration of therapy of about 30 months and a median follow-up of about 119 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 DFS compared with continuation of tamoxifen therapy. Analysis showed that over the observed study period exemestane reduced the risk of breast cancer recurrence by 14% compared with tamoxifen (hazard ratio 0.86, p = 0.00393). The beneficial effect of exemestane over tamoxifen with respect to DFS was apparent regardless of nodal 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 risk of contralateral breast cancer; however, the effect was no longer statistically significant (hazard ratio 0.75, p = 0.10707).

In the whole study population, overall survival was not statistically different between the two groups with 467 deaths (19.9%) occurring in the exemestane group and 510 deaths (21.5%) in the tamoxifen group (hazard ratio 0.91, p = 0.15737, not adjusted for multiple testing). For the subset of patients with oestrogen receptor positive or unknown status, the unadjusted overall survival hazard ratio was 0.89 (log-rank test: p = 0.07881) in the exemestane group relative to the tamoxifen group.

In the whole study population, a statistically significant 14% reduction in the risk of dying (hazard ratio for OS 0.86; Wald chi square test: p = 0.0257) was observed for exemestane compared with tamoxifen when adjusting for the pre-specified prognostic factors (i.e., ER status, nodal status, prior chemotherapy, use of HRT and use of bisphosphonates).

A lower incidence of other second (non-breast) primary cancers was observed in exemestane-treated patients compared with tamoxifen only-treated patients (9.9% versus. 12.4%).

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

Treatment of advanced breast cancer

In a randomised peer reviewed controlled clinical trial, Cleopa at the daily dose of 25 mg has demonstrated statistically significant prolongation of survival, Time to Progression (TTP), 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.

Pharmacotherapeutic group: Hormone antagonist and related agents, enzyme inhibitors

ATC code: L02BG06

Cleopa 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, oral Cleopa 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%.

Cleopa 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 doses trials, Cleopa 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 2 to 3 years of Cleopa (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 exemestan 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 Cleopa reduced the risk of breast cancer recurrence by 24% compared with tamoxifen (hazard ratio 0.76; p=0.00015). The beneficial effect of Cleopa over tamoxifen with respect to DFS was apparent regardless of nodal status or prior chemotherapy.

Cleopa 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 Cleopa (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 Cleopa. A statistically significant 23% reduction in the risk of dying (hazard ratio for overall survival 0.77; Wald chi square test: p = 0.0069) was observed for Cleopa 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 results in all patients (intention to treat population) and oestrogen receptor positive patients are summarised 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 or breast cancer death;

^d Overall survival is defined as occurrence of death from any cause.

In the additional analysis for the subset of patients with oestrogen receptor positive or unknown 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 of dying.

Results from a bone substudy demonstrated that women treated with Cleopa following 2 to 3 years of tamoxifen treatment experienced moderate reduction in bone mineral density. In the overall study, the treatment emergent fracture incidence evaluated during the 30 months treatment period was higher in patients treated with Cleopa compared with tamoxifen (4.5% and 3.3% correspondingly, p=0.038).

Results from an endometrial substudy indicate that after 2 years of treatment there was a median 33% reduction of endometrial thickness in the Cleopa-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 Cleopa.

Treatment of Advanced Breast Cancer

In a randomised peer reviewed controlled clinical trial, Cleopa at the daily dose of 25 mg has demonstrated statistically significant prolongation of survival, Time to Progression (TTP), 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.

Absorption

After oral administration of Cleopa tablets, exemestane is absorbed rapidly. The fraction of the dose absorbed from the gastrointestinal tract is high. The 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 the oral bioavailability, is ca 20000 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.

Elimination

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 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 Cleopa and the age of subjects has been observed.

Renal impairment

In patients with severe renal impairment (CL_cr <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 impairment

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 to be necessary.

Absorption

After oral administration of Cleopa tablets, Cleopa is absorbed rapidly. The fraction of the dose absorbed from the gastrointestinal tract is high. The 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 Cleopa, not corrected for the oral bioavailability, is approx. 20,000 l. The kinetic is linear and the terminal elimination half-life is 24 h. Binding to plasma proteins is 90% and is concentration independent. Cleopa and its metabolites do not bind to red blood cells.

Cleopa does not accumulate in an unexpected way after repeated dosing.

Metabolism and excretion

Cleopa 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 Cleopa is approx. 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 Cleopa were eliminated within a week.

Special populations

Age : No significant correlation between the systemic exposure of Cleopa and the age of subjects has been observed.

Renal insufficiency

In patients with severe renal impairment (Clcr < 30 ml/min) the systemic exposure to Cleopa was 2 times higher compared with healthy volunteers.

Given the safety profile of Cleopa, no dose adjustment is considered to be necessary.

Hepatic insufficiency

In patients with moderate or severe hepatic impairment the exposure of Cleopa is 2-3 fold higher compared with healthy volunteers. Given the safety profile of Cleopa, no dose adjustment is considered to be necessary.

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), in V79 Chinese hamster cells, in 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 on week 92, because of 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 and occurred at a dose 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 of patients with exemestane.

Toxicological studies

Findings in the repeat dose toxicology studies in rat and dog were generally attributable to the pharmacological activity of Cleopa, 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

Cleopa was not genotoxic in bacteria (Ames test), in V79 Chinese hamster cells, in rat hepatocytes or in the mouse micronucleus assay. Although Cleopa was clastogenic in lymphocytes in vitro, it was not clastogenic in two in vivo studies.

Reproductive toxicology

Cleopa 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 on week 92, because of 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 and occurred at a dose 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 of patients with Cleopa

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