AROMASIN Dosage Forms, Composition And Packaging

SUMMARY PRODUCT INFORMATION

AROMASIN (exemestane) is indicated for the sequential adjuvant treatment of postmenopausal women with estrogen receptor-positive early breast cancer who have received 2-3 years of initial adjuvant tamoxifen therapy.

Approval is based on improved disease-free survival for sequential AROMASIN in comparison to continuous tamoxifen.  However, overall survival was not significantly different between the two treatments (see PART II, CLINICAL TRIALS). 

AROMASIN (exemestane) is also indicated for hormonal treatment of advanced breast cancer in women with natural or artificially induced postmenopausal status whose disease has progressed following antiestrogen therapy. 

AROMASIN (exemestane) Tablets are contraindicated in patients with a known hypersensitivity to the drug or to any of the excipients.

General:

AROMASIN should not be administered to women with premenopausal endocrine status as safety and efficacy have not been established in these patients. AROMASIN should not be coadministered with estrogen-containing agents as these could interfere with its pharmacologic action.

Drug Interactions
In patients receiving tamoxifen and warfarin concurrently, re-titration of the warfarin dose may be required following the switch from tamoxifen to exemestane. Possible interaction between tamoxifen and warfarin that required dose adjustments have been described. As a result, patients on warfarin treatment were excluded from the IES trial because the risk of experiencing a coagulation problem in switching from previous tamoxifen to exemestane could not be excluded. Although a potential interaction between warfarin and exemestane has not been studied clinically, in vitro studies have demonstrated that exemestane does not inhibit the activity of CYP2C9 (enzyme responsible for the metabolism of s-warfarin) and exemestane is not anticipated to alter the pharmacokinetics of warfarin. Therefore, the dosage of warfarin should be controlled by periodic determinations of prothrombin times (PT) ratio/International Normalized Ratio (INR) or other suitable coagulation tests at the time of switch from tamoxifen to exemestane as per recommendations in the warfarin Product Monograph

Effects on Coagulation
To date, there is no indication that exemestane affects antithrombin III. Some steroidal compounds are known to affect antithrombin III, increasing the risk of thromboembolic events. Preclinical data evaluating exemestane’s potential to affect antithrombin III is not available; however, studies in humans are ongoing. In a study in postmenopausal women with early breast cancer at low risk treated with exemestane (n=73) or placebo (n=73) (Study 027), there was no change in the coagulation parameters activated partial thromboplastin time [APTT], prothrombin time [PT] and fibrinogen.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

In a carcinogenicity study conducted in rats, exemestane was administered by gavage at doses of 30, 100 and 315 mg/kg/day for 92 weeks in males and 104 weeks in females. No evidence of carcinogenic activity was observed in female rats. The male rat study was inconclusive since it was terminated prematurely at Week 92.

In a 2-year carcinogenicity study in mice, exemestane, dosed at 50, 150 and 450 mg/kg/day, induced an increased incidence of hepatocellular adenomas and carcinomas at the high dose in both sexes. An increased incidence of renal tubular adenomas was also observed in male mice at the high dose. Plasma levels in male and female mice at the high dose were approximately 34 and 75-fold higher than the AUC in postmenopausal patients at the therapeutic dose. Since the doses tested in mice did not achieve an MTD, neoplastic findings in organs other than liver and kidneys remain unknown. (see Toxicology: Carcinogenicity).

Cardiovascular disease

The use of aromatase inhibitors, including AROMASIN, may increase the risk of ischemic cardiovascular diseases. During the Intergroup Exemestane Study (IES), more patients receiving exemestane were reported to have ischemic cardiac events (myocardial infarction, angina, and myocardial ischemia) compared to patients receiving tamoxifen (treatment-emergent cases: 2.0% versus 1.3%; all-cases [either on treatment or during follow up]: 5.8% versus 3.8%). In addition, a larger number of events were reported for exemestane in comparison to tamoxifen for some individual treatment-emergent cardiovascular events including hypertension (9.9% versus 8.4%), myocardial infarction (0.6% versus 0.2%) and cardiac failure (1.1% versus 0.7%). Women with significant cardiac disorders were excluded from the clinical studies of exemestane in early breast cancer.

Endocrine and Metabolism

The use of aromatase inhibitors, including AROMASIN, may increase the occurrence of hypercholesterolemia. During the IES study, more patients receiving exemestane were reported to have treatment-emergent hypercholesterolemia compared to patients receiving tamoxifen (3.7% vs. 2.1%, respectively).

In a study in postmenopausal women with early breast cancer at low risk treated with exemestane (n=73) or placebo (n=73) (Study 027) plasma HDL cholesterol was decreased 6-9% in exemestane-treated patients; total cholesterol, LDL-cholesterol, triglycerides, apolipoprotein-A1, apolipoprotein-B, and lipoprotein-a were unchanged. An 18% increase in homocysteine levels was observed in exemestane-treated patients compared with a 12% increase seen with placebo. Exemestane induced a significant increase in both bone formation and bone resorption markers [bone-specific alkaline phosphatase (BAP), serum procollagen type I N propeptide (PINP) and serum osteocalcin; serum and urinary C-terminal cross-linked telopeptide of type 1 collagen (CTX-I), and urinary N-terminal cross-linked telopeptide of type I collagen (NTX-I)].

Gastrointestinal

The use of AROMASIN may increase the risk of gastric ulcer. In the early breast cancer IES trial, gastric ulcer was observed at a slightly 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.

Hematologic

In patients with early breast cancer (IES Study) the incidence of hematological abnormalities of Common Toxicity Criteria (CTC) grade ≥1 was lower in the exemestane treatment group, compared with tamoxifen. Incidence of CTC grade 3 or 4 abnormalities was low (approximately 0.1%) in both treatment groups. Approximately 20% of patients receiving AROMASIN in clinical studies in advanced breast cancer, particularly those with pre-existing lymphocytopenia, experienced a moderate transient decrease in lymphocytes. However, mean lymphocyte values in these patients did not change significantly over time. Patients did not have a significant increase in viral infections, and no opportunistic infections were observed.

Hepatic/Biliary/Pancreatic

In patients with early breast cancer, elevations in bilirubin and alkaline phosphatase were more common in those receiving exemestane than either tamoxifen or placebo. Treatment emergent bilirubin elevations occurred in 5.9% of exemestane-treated patients compared to 0.9% of tamoxifen-treated patients on the IES, and in 6.9% of exemestane-treated patients versus 0% of placebo-treated patients on the 027 study; CTC grade 3-4 increases in bilirubin occurred in 0.9% of exemestane-treated patients compared to 0.1% of tamoxifen-treated patients on the IES. Alkaline phosphatase elevations occurred in 15.9% of exemestane-treated patients compared to 3.1% of tamoxifen-treated patients on the IES, and in 13.7% of exemestane-treated patients compared to 6.9% of placebo-treated patients on Study 027.

In patients treated for advanced breast cancer, elevation of the serum levels of AST, ALT, alkaline phosphatase and gamma glutamyl transferase >5 times the upper value of the normal range have been reported rarely. These changes were mostly attributable to the underlying presence of liver and/or bone metastases. However, in the Phase III study in advanced breast cancer patients, elevation of the gamma glutamyl transferase without documented evidence of liver metastasis was reported in 2.7% of patients treated with AROMASIN and in 1.8% of patients treated with megestrol acetate. Additionally, in post-market surveillance elevations of the serum levels of AST, ALT, alkaline phosphatase and gamma glutamyl transferase >5 times the upper value of the normal range were not necessarily due to liver or bone metastases and normalization of liver enzyme values post discontinuation of drug has been observed.

Rare cases of hepatitis including cholestatic hepatitis have been observed in other clinical trials with additional reports identified through post-marketing surveillance.

Musculoskeletal

The use of estrogen lowering agents, including AROMASIN, may cause a reduction in bone mineral density (BMD) with a possible consequent increased risk of fracture. Women should have their osteoporosis risk assessed and managed according to local clinical practice and guidelines. Women with clinical evidence of severe osteoporosis or a history of osteoporotic fracture were excluded from the clinical studies of exemestane in early breast cancer.

Reductions in BMD over time were seen with exemestane use in these clinical trials; Table 1 describes changes in BMD from baseline to 24 months in patients receiving exemestane compared to patients receiving tamoxifen (IES) or placebo (027).

The use of aromatase inhibitors, including AROMASIN, may cause arthralgias and/or myalgias, which may impact on treatment compliance and quality of life.  In the IES study, 17.6% of patients in exemestane arm reported arthralgia as an adverse event versus 10.8% of patients in tamoxifen arm.  Arthralgia-related disorders such as arthralgia, back pain, and pain in limb led to study drug discontinuation more often in AROMASIN-treated patients than tamoxifen-treated patients (1.3% versus 0.3% of total patients treated, respectively).

Renal

In patients with early breast cancer, elevations in creatinine were more common in those receiving exemestane than either tamoxifen or placebo. Creatinine elevations occurred in 6.4% of exemestane-treated patients versus 5.0% of tamoxifen-treated patients on the IES and in 5.5% of exemestane-treated patients versus 0% of placebo-treated patients on Study 027.

Skin

Severe cutaneous reactions erythema multiforme and acute generalized exanthematus pustulosis (AGEP) have been reported in association with AROMASIN. The latency of AGEP was 2 weeks after starting exemestane treatment, which is consistent with the temporal pattern of drug-related AGEP. Patients that experience severe cutaneous reactions should permanently discontinue AROMASIN.

Special population

Pregnant Women:

AROMASIN (exemestane) should not be used in women who are or may become pregnant because it may cause harm to the fetus. Exemestane caused placental enlargement, dystocia, and prolonged gestation when given to pregnant rats at doses greater than 4 mg/kg/day (24 mg/m²/day), approximately 1.5 times the recommended human daily dose (16.0 mg/m²/day) on a mg/m² basis. There are no adequate and well-controlled studies in pregnant women using exemestane. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus or the potential risk for loss of the pregnancy.

Increased resorption, reduced number of live fetuses, decreased fetal weight, and retarded ossification were also observed at these doses. The administration of exemestane to pregnant rats at doses of 50 mg/kg/day during the organogenesis period caused an increase in fetal resorption, but there was no evidence of teratogenicity up to the dose of 810 mg/kg/day (4860 mg/m²/day).

Daily doses of exemestane 270 mg/kg/day (4320 mg/m²/day), which is greater than 200 times the recommended human daily dose, given to rabbits during organogenesis caused abortions, an increase in resorptions, and a reduction in fetal body weight; there was no increase in the incidence of malformations (see TOXICOLOGY: Reproduction and Teratology).

Hepatic Impairment:

Following a single 25-mg oral dose, the AUC of exemestane in patients with hepatic dysfunction (moderate hepatic impairment, Child Pugh B; severe hepatic impairment, Child Pugh C) was approximately 3 times higher than that observed in healthy volunteers. However, no dosage adjustment is required for patients with liver impairment since exemestane was well tolerated in patients with breast cancer at doses 8 to 24 times higher than the recommended 25 mg daily dose (see ACTION AND CLINICAL PHARMACOLOGY).

Renal Impairment:

The AUC of exemestane after a single 25-mg dose was approximately 3 times higher in subjects with severe renal insufficiency (creatinine clearance <30 mL/min/1.73 m²) compared with the AUC in healthy volunteers. However, no dosage adjustment is required for patients with renal impairment since exemestane was well tolerated in patients with breast cancer at doses 8 to 24 times higher than the recommended dose (see ACTION AND CLINICAL PHARMACOLOGY).

Nursing Women:

Although it is not known whether exemestane is excreted in human milk, the drug was shown to be excreted in the milk of lactating rats. Because there is a potential for serious adverse reactions in nursing infants, nursing should be discontinued when receiving therapy with AROMASIN.

Pediatrics:

The safety and effectiveness of AROMASIN in pediatric patients have not been established.

Geriatrics:

Healthy postmenopausal women aged 43 to 68 years were studied in the pharmacokinetic trials. Age-related alterations in exemestane pharmacokinetics were not seen over this age range (see ACTION AND CLINICAL PHARMACOLOGY).

Monitoring and Laboratory Tests:

Women should have their cholesterol levels and osteoporosis risks assessed and managed according to current clinical practice and guidelines.

Adjuvant Treatment of Early Breast Cancer

Adverse Drug Reaction Overview:

AROMASIN (exemestane) Tablets tolerability in postmenopausal women with early breast cancer was evaluated in two well-controlled trials: the Intergroup Exemestane Study 031 (IES) (see CLINICAL STUDIES) and the 027 study (a randomized, placebo-controlled, double-blind, parallel group, phase II study specifically designed to assess the effects of exemestane on bone metabolism, hormones, lipids and coagulation factors over 2 years of treatment).

Certain adverse events, expected based on the known pharmacological properties and side effect profiles of test drugs, were actively sought through a positive checklist. Signs and symptoms were graded for severity using CTC in both studies. Within the IES study, the presence of some illnesses/conditions was monitored through a positive checklist without assessment of severity. These included myocardial infarction, other cardiovascular disorders, gynecological disorders, osteoporosis, osteoporotic fractures, other primary cancer, and hospitalizations.

The median duration of adjuvant treatment was 30.0 months and 29.9 months for patients receiving AROMASIN or tamoxifen, respectively, within the IES study, and 23.9 months for patients receiving AROMASIN or placebo within the 027 study. Median duration of observation after randomization at the time of primary analysis, for AROMASIN was 40.4 months and for tamoxifen 39.1 months; and at the time of the updated analysis for AROMASIN was 53.6 months and for tamoxifen 51.6 months. Median duration of observation was 30 months for both groups in the 027 study.

AROMASIN was generally well tolerated, and adverse events were usually mild to moderate. Within the IES study discontinuations due to adverse events occurred in 7.4% and 6.2% of patients receiving AROMASIN and tamoxifen, respectively, and in 12.3% and 4.1% of patients receiving exemestane or placebo within Study 027. Within the IES study, the most commonly reported adverse reactions were hot flushes (AROMASIN 22%; tamoxifen 20%), arthralgias (AROMASIN 18%; tamoxifen 11%), and fatigue (AROMASIN 16%; tamoxifen 15%). On-treatment deaths due to any cause were reported for 1.5% of the exemestane-treated patients, and 1.5% of the tamoxifen-treated patients within the IES study. There were 6 on-treatment deaths due to stroke and 3 due to cardiac failure in the AROMASIN-treated patients compared with 2 deaths due to stroke and 1 due to cardiac failure in the tamoxifen-treated patients. There were no deaths in Study 027.

Clinical Trial Adverse Drug Reactions:

Treatment-emergent adverse events and illnesses including all causalities and occurring with an incidence of >5% in either treatment group of the IES study during or within one month of the end of treatment are shown in Table 2.

In the IES study, more patients receiving exemestane were reported to have ischemic cardiac events (myocardial infarction, angina, and myocardial ischemia) compared to patients receiving tamoxifen (treatment-emergent cases: 2.0% versus 1.3%; all-cases [either on treatment or during follow up]: 5.8% versus 3.8%). No significant difference was noted for any individual treatment-emergent cardiovascular event including hypertension (9.9% versus 8.4%), myocardial infarction (0.6% versus 0.2%) and cardiac failure (1.1% versus 0.7%). The proportion of patients reporting hypercholesterolemia was 3.7% in the AROMASIN-treated group versus 2.1% in the tamoxifen-treated group.

In the IES study, as compared to tamoxifen, AROMASIN was associated with a higher incidence of events in the musculoskeletal disorders and in the nervous system disorders, including the following events occurring with frequency lower than 5%: paraesthesia (2.8% vs. 1.0%), carpal tunnel syndrome (2.8% vs. 0.2%) and neuropathy (0.5% vs. <0.1%).

AROMASIN was associated with a significantly higher incidence of gastric ulcer events in comparison to tamoxifen (0.7% vs. <0.1%). In addition, diarrhea was also more frequent in the AROMASIN group (4.2% vs. 2.2%). The majority of patients on AROMASIN with gastric ulcer received concomitant treatment with non-steroidal anti-inflammatory agents and/or had a prior history.

Clinical fractures were reported in 101 patients receiving exemestane (4.5%) and 75 patients receiving tamoxifen (3.3%).

Tamoxifen was associated with a greater incidence of muscle cramps (3.2% vs. 1.4%), uterine polyps (1.8% vs. 0.4%), venous thromboembolic disease (1.8% vs. 0.7%), endometrial hyperplasia (0.9% vs. <0.1%) and uterine polypectomy (0.8% vs. 0.2%).

A lower incidence of other second (non-breast) primary cancers was observed in the AROMASIN-treated patients versus tamoxifen-treated patients (3.6% vs. 5.3%) in the IES study.

Based on reports of adverse events in 73 postmenopausal women in each treatment group in the 027 study, Table 3 shows treatment-emergent adverse events including all causalities and occurring with an incidence of > 5% in either treatment group.

Events were mostly grade 1 or 2 in severity for both AROMASIN and placebo treated patients.

Treatment of Advanced Breast Cancer after Failure on Tamoxifen:

Adverse Drug Reaction Overview:

A total of 1058 patients who had failed prior tamoxifen therapy were treated with AROMASIN (exemestane) Tablets 25 mg once daily in the clinical trials program. AROMASIN was generally well tolerated and adverse events were usually mild to moderate. Only one death was potentially related to treatment with AROMASIN; an 80-year-old woman with known coronary artery disease had a myocardial infarction with multiple organ failure after 9 weeks on study treatment. In the clinical trials program, only 2.8% of the patients discontinued treatment with AROMASIN because of adverse events, mainly within the first 10 weeks of treatment; late discontinuations due to adverse events were uncommon (0.3%).

Clinical Trial Adverse Drug Reactions:

In the Phase III study, 358 patients were treated with AROMASIN and 400 patients were treated with megestrol acetate. Fewer patients receiving exemestane discontinued treatment because of adverse events than those treated with megestrol acetate (1.7% versus 5%). Adverse events in the Phase III study that were considered drug related or of indeterminate cause included hot flashes (12.6%), nausea (9.2%), fatigue (7.5%), increased sweating (4.5%), and increased appetite (2.8%). The proportion of patients experiencing an excessive weight gain (>10% of their baseline weight) was significantly higher with megestrol acetate than with exemestane (17.1% versus 7.6%, p=0.001). The following table (Table 4) shows the adverse events of all National Cancer Institute (NCI) Common Toxicity grades regardless of causality reported in 5% or greater of patients in the Phase III study treated either with AROMASIN or megestrol acetate.

In the overall clinical trials program for advanced cancer (N = 1058), additional adverse events reported in 5% or greater of patients treated with AROMASIN 25 mg once daily included pain at tumor site (8%), peripheral edema (7.6%), asthenia (5.8%) and fever (5%). Less frequent but common adverse events (1% to 5%) reported in these patients were liver enzyme abnormalities (AST, ALT, alkaline phosphatase), elevated bilirubin, arthralgia, peripheral edema, back pain, dyspepsia, paresthesia, bronchitis, rash, chest pain, edema, hypertension, upper respiratory tract infection, pruritus, urinary tract infection, pathological fracture, alopecia, leg edema, sinusitis, skeletal pain, infection, pharyngitis, rhinitis, hypoesthesia, confusion, and lymphedema.

Post-Market Adverse Drug Reactions

Post-market adverse events/illnesses include case observed in other clinical trials (not described above) as well as reports from post-marketing surveillance. Because these events are not uniformly reported, it is not always possible to reliably estimate their frequency or clearly establish a causal relationship to AROMASIN exposure. The following events are listed according to MedDRA system organ class.

Vascular disorders: Cerebrovascular accident, pulmonary embolus and deep vein thrombosis were among the most frequently reported adverse events/illnesses in the post-market setting.

Cardiac disorders: Cardiac failure and myocardial infarction have been reported in association with AROMASIN.

Nervous System disorders: Carpal tunnel and paraesthesia has been reported frequently in the post-market setting.

Hepatobilliary disorders: Rare cases of hepatitis including cholestatic hepatitis have been observed in other clinical trials with additional reports identified through post-marketing surveillance.

Investigations: ALT, AST, blood bilirubin and blood alkaline phosphatase increases that have been reported as common events above have also been reported as very common events in other clinical trials. Additionally, in post-market surveillance elevation of the serum levels of AST, ALT, alkaline phosphatase and gamma glutamyl transferase >5 times the upper value of the normal range have been observed. Increase in liver enzymes was not necessarily due to liver or bone metastases and normalization of liver enzyme values post discontinuation of drug has been observed.

Skin and subcutaneous tissue disorders: Severe cutaneous reactions erythema multiforme and acute generalized exanthematus pustulosis have been reported in association with AROMASIN. Urticaria and pruritus have also been reported in association with AROMASIN.

Immune System disorders: Hypersensitivity, including anaphylactic reactions, has occurred between 8 hours to 26 days of starting exemestane therapy.

Drug-Drug Interactions:

In vitro evidence showed that AROMASIN (exemestane) is metabolized by cytochrome P450 (CYP) 3A4 and aldoketoreductases, and does not inhibit any of the major CYP isoenzymes, including CYP 1A2, 2C9, 2D6, 2E1, and 3A.  In a clinical pharmacokinetic study, the specific inhibition of CYP3A4 by ketoconazole administration showed no significant influence on the pharmacokinetics of exemestane.  Although pharmacokinetic effects were observed in a pharmacokinetic interaction study with rifampin, a potent CYP3A4 inducer, the suppression of plasma estrogen concentrations (estrone sulfate) produced by exemestane was not affected and a dosage adjustment is not required.

In patients receiving tamoxifen and warfarin concurrently, re-titration of the warfarin dose may be required following the switch from tamoxifen to exemestane.  Possible interaction between tamoxifen and warfarin that required dose adjustments have been described.  As a result, patients on warfarin treatment were excluded from the IES trial because the risk of experiencing a coagulation problem in switching from previous tamoxifen to exemestane could not be excluded.  Although a potential interaction between warfarin and exemestane has not been studied clinically, in vitro studies have demonstrated that exemestane does not inhibit the activity of CYP2C9 (enzyme responsible for the metabolism of s-warfarin) and exemestane is not anticipated to alter the pharmacokinetics of warfarin.  Therefore, the dosage of warfarin should be controlled by periodic determinations of prothrombin times (PT) ratio/International Normalized Ratio (INR) or other suitable coagulation tests at the time of switch from tamoxifen to exemestane as per recommendations in the warfarin Product Monograph.

Drug-Laboratory Interactions:

No clinically relevant changes in the results of clinical laboratory tests have been observed.

Recommended Dose and Dosage Adjustment:

The recommended dose of AROMASIN (exemestane) Tablets in early and advanced breast cancer is 25 mg once daily after a meal.

In postmenopausal women with early breast cancer, treatment with AROMASIN should continue until completion of five years of adjuvant endocrine therapy, or until local or distant recurrence or new contralateral breast cancer.

In patients with advanced breast cancer, treatment with AROMASIN should continue until tumor progression is evident. 

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

Clinical trials have been conducted with AROMASIN (exemestane) Tablets given up to 800 mg as a single dose to healthy female volunteers and up to 600 mg daily for 12 weeks to postmenopausal women with advanced breast cancer. These dosages were well tolerated. 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.

A male child (age unknown) accidentally ingested a 25-mg tablet of exemestane. The initial physical examination was normal, but blood tests performed 1 hour after ingestion indicated leucocytosis (WBC:25000/mm³ with 90% neutrophils). Blood tests were repeated 4 days after the incident and were normal. No treatment was given.

In rats and dogs, mortality was observed after single oral doses of 5000 mg/kg (about 2000 times the recommended human dose on a mg/m² basis) and of 3000 mg/kg (about 4000 times the recommended human dose on a mg/m² basis), respectively.

Mechanism of Action:

Breast cancer cell growth is often estrogen-dependent and anti-tumour activity is expected following effective and continuous estrogen suppression in patients with hormone-sensitive breast cancer. Aromatase is the key enzyme that converts androgens to estrogens both in pre- and postmenopausal women. While the main source of estrogen (primarily estradiol) is the ovary in premenopausal women, the principal source of circulating estrogens in postmenopausal women is from conversion of adrenal and ovarian androgens (mainly androstenedione) to estrogens (primarily estrone) by the aromatase enzyme in peripheral tissues. This occurs mainly in the adipose tissue, but also in the liver, muscle, hair follicles, and breast tissue. Estrogen deprivation through aromatase inhibition is an effective and selective treatment for postmenopausal patients with hormone-dependent breast cancer.

AROMASIN (exemestane) is a potent aromatase inactivator, causing estrogen suppression and inhibition of peripheral aromatisation. It is a steroidal irreversible Type I aromatase inhibitor, structurally related to the natural substrate androstenedione. Exemestane is a specific competitive inactivator of human placental aromatase, which has been shown to be more potent than the irreversible aromatase inhibitor formestane or the reversible inhibitor aminoglutethimide in vitro.

In vivo studies of aromatase inactivation indicate that exemestane, by the oral route, is several times more potent than formestane. It acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme causing its inactivation, an effect also known as “suicide inhibition”. De novo aromatase enzyme synthesis is required for recovery of enzyme activity.  Exemestane significantly lowers circulating estrogen concentrations in postmenopausal women, but has no detectable effect on adrenal biosynthesis of corticosteroids or aldosterone. Exemestane has no effect on other enzymes involved in the steroidogenic pathway up to a concentration at least 600 times higher than that inhibiting the aromatase enzyme.

Pharmacokinetics:

Absorption:

Following oral administration of radiolabeled exemestane, at least 42% of radioactivity was absorbed from the gastrointestinal tract. Maximum exemestane plasma concentration (C_max) was observed within 2 hours of receiving exemestane. Exemestane plasma levels increased by approximately 40% after a high-fat breakfast; however, no further effect on estrogen suppression was observed since maximum activity was already achieved under fasting conditions. Exemestane appears to be more rapidly absorbed in women with breast cancer than in healthy women.  After repeated doses, mean T_max was 1.2 hours in the women with breast cancer and 2.9 hours in the healthy women. Mean AUC values following repeated doses were approximately 2-fold higher in women with breast cancer (75.4 ng.h/mL) compared with healthy women (41.4 ng.h/mL).  However, there was considerable overlap between the range of pharmacokinetic parameters observed in these two populations. 

Distribution:

Exemestane is distributed extensively into tissues. Exemestane is 90% bound to plasma proteins and the fraction bound is independent of the total concentration. Albumin and α₁-acid glycoprotein contribute equally to the binding. The distribution of exemestane and its metabolites into blood cells is negligible.

Metabolism and Excretion:

After reaching maximum plasma concentration, exemestane levels declined polyexponentially with a mean terminal half-life of about 24 hours.  Following administration of a single oral dose of radiolabeled exemestane, the elimination of drug-related products was essentially complete within 1 week. Approximately equal proportions of the dose were eliminated in urine and feces. The amount of drug excreted unchanged in urine was less than 1% of the dose, indicating that renal excretion is a limited elimination pathway. Exemestane was extensively metabolized, with levels of the unchanged drug in plasma accounting for less than 10% of the total radioactivity. The initial steps in the metabolism of exemestane are oxidation of the methylene group in position 6 and reduction of the 17-keto group with subsequent formation of many secondary metabolites.  Each metabolite accounts only for a limited amount of drug-related material. The metabolites are inactive or demonstrate minimal ability to inhibit aromatase compared with the parent drug. Studies using human liver preparations indicate that cytochrome P-450 3A4 (CYP 3A4) is the principal isoenzyme involved in the oxidation of exemestane. Additional studies in humans demonstrated that exemestane does not affect the activity of CYP3A4 to any great extent. No significant inhibition of any of the CYP isoenzymes (including CYP3A4) involved in xenobiotic metabolism was observed in human liver preparations. This would suggest that possible drug-drug interactions involving inhibition of CYP by co-administration with exemestane are unlikely.

Special Populations and Conditions:

Geriatrics:

Although women ranging in age up to 99 years were enrolled in the clinical studies (see WARNINGS AND PRECAUTIONS), healthy postmenopausal women aged 43 to 68 years were enrolled in the pharmacokinetic trials. Age-related alterations in exemestane pharmacokinetics were not seen over this age range.

Gender:

The pharmacokinetics of exemestane following administration of a single, 25 mg tablet to fasted healthy males (mean age 32 years; range 19 to 51 years) or to fasted healthy postmenopausal women (mean age 55 years; range 45 to 68 years) have been compared. Mean C_max and AUC values in healthy males (12.3 ± 5.8 ng/mL and 28.4 ± 17.3 ng.h/mL, respectively) were similar to those determined in healthy postmenopausal women (11.1 ± 4.4 ng/mL and 29.7 ± 7.8 ng.h/mL, respectively). Thus, the pharmacokinetics of exemestane does not appear to be influenced by gender.

Race:

The influence of race on exemestane pharmacokinetics has not been formally evaluated.

Hepatic Insufficiency:

The pharmacokinetics of exemestane have been investigated in subjects with moderate and severe hepatic insufficiency. Following a single 25-mg oral dose, the AUC of exemestane was approximately 3 times higher than that observed in healthy volunteers. However no dosage adjustment is required for patients with liver impairment since exemestane was well tolerated in patients with breast cancer at doses 8 to 24 times higher than the recommended 25-mg daily dose (see WARNINGS AND PRECAUTIONS).

Renal Insufficiency:

The AUC of exemestane after a single 25-mg dose was approximately 3 times higher in subjects with severe renal insufficiency (creatinine clearance <30 mL/min/1.73 m²) compared with the AUC in healthy volunteers.  However, no dosage adjustment is required for patients with renal impairment since exemestane was well tolerated in patients with breast cancer at doses 8 to 24 times higher than the recommended dose (see WARNINGS AND PRECAUTIONS).

Pediatrics:

The pharmacokinetics of exemestane have not been studied in pediatric patients.

Store between 15° to 30° C.

Not applicable.

AROMASIN (exemestane) Tablets are round, biconvex, and off-white to slightly gray. Each tablet contains 25 mg of exemestane. The tablets are printed on one side with the number “7663” in black. AROMASIN is supplied as follows:

HDPE bottles of 30 tablets with a child-resistant screw cap: 25 mg.
Aluminium-PVDC/PVC-PVDC opaque white blisters of 30 tablets: 25 mg.
Aluminium-PVDC/PVC-PVDC opaque white blisters of 15 tablets: 25 mg.

Composition:

AROMASIN Tablets for oral administration contain 25 mg of exemestane. Each AROMASIN Tablet contains the following inactive ingredients: mannitol, crospovidone, polysorbate 80, hydroxypropyl methylcellulose, silicon dioxide, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, simethicone, polyethyleneglycol 6000, sucrose, magnesium carbonate, titanium dioxide, methyl-p-hydroxybenzoate, polyvinyl alcohol, cetyl esters wax, talc, carnauba wax, shellac and iron oxides.

Control #: 204398
March 6, 2018

Advise the patient or caregivers to read the Patient Medication Information.

Hypersensitivity:
Advise patients to discontinue EUCRISA and seek medical attention immediately if signs or symptoms of hypersensitivity occur (see WARNING and PRECAUTIONS).

Administration Instructions:
Advise patients or caregivers that EUCRISA is for external use only and is not for ophthalmic, oral, or intravaginal use.

Control #: 267872
AUG 29, 2023

EUCRISA is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

Hypersensitivity

Hypersensitivity reactions, including contact urticaria, have occurred in patients treated with EUCRISA. Hypersensitivity should be suspected in the event of severe pruritus, swelling and erythema at the application site or at a distant site.  If signs and symptoms of hypersensitivity occur, discontinue EUCRISA immediately and initiate appropriate therapy.

7.1 Special Populations

7.1.1 Pregnant Women

There is no available data with EUCRISA in pregnant women to inform the drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, there were no adverse developmental effects observed with oral administration of crisaborole in pregnant rats and rabbits during organogenesis at doses up to 3 and 2 times, respectively, the maximum recommended human dose (MRHD).

7.1.2 Breast-feeding

It is unknown if EUCRISA is excreted in human milk. There is no information available on the effects of the drug on the breastfed infant or the effects on milk production after topical application of EUCRISA to women who are breastfeeding.  EUCRISA is systemically absorbed.  The lack of clinical data during lactation precludes a clear determination of the risk of EUCRISA to a breastfed infant.  Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for EUCRISA and any potential adverse effects on the breastfed infant from EUCRISA or from the underlying maternal condition. Because many drugs are excreted in human milk, precaution should be exercised.

7.1.3 Pediatrics

Pediatrics (3 months to <18 years): Based on the data submitted and reviewed by Health Canada, the safety and effectiveness of EUCRISA for topical treatment of mild to moderate atopic dermatitis have been established in pediatric patients age 3 months and older.Use of EUCRISA in this age group is supported by data from two 28 day adequate, vehicle-controlled safety and efficacy trials which included 1,313 pediatric patients ages 2 to <18 years old of whom 874 received EUCRISA. The most commonly reported adverse reaction in subjects 2 years and older was application site pain.  Additionally, use of EUCRISA in pediatric patients aged 3 months to less than 2 years was supported by data from a 28-day open-label, safety and pharmacokinetics (PK) trial in 137 subjects. No new safety signals were identified in subjects 3 months to less than 2 years of age (see ADVERSE REACTIONS, ACTION AND CLINICAL PHARMACOLOGY and CLINICAL TRIALS).

The safety and effectiveness of EUCRISA in pediatric patients below the age of 3 months have not been established.

7.1.4 Geriatrics

Evidence from clinical studies of EUCRISA did not include sufficient numbers of patients 65 years of age and over to determine whether they respond differently from younger patients.

8.1 Adverse Reaction Overview

The most common adverse drug reactions reported in clinical trials among patients with mild to moderate atopic dermatitis 2 years of age and older have been application site reactions.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

In two randomized, double-blind, parallel-group, vehicle-controlled Phase 3 clinical trials (Studies AN2728-AD-301 and AN2728-AD-302), 1012 patients 2 to 79 years of age with mild to moderate atopic dermatitis were treated with EUCRISA twice daily for 4 weeks.  The adverse reaction reported by ≥1% of EUCRISA-treated patients is listed in Table 2.

In one double-blind, vehicle-controlled, maintenance trial (C3291035), 497 subjects 5 months to 79 years of age with mild to moderate atopic dermatitis entered into an open label period and were first treated with EUCRISA twice daily for up to 8 weeks. The adverse reactions observed in the open label period were consistent with the known safety profile of twice daily EUCRISA. During the double-blind maintenance period, 135 subjects out of 270 randomized subjects were treated with EUCRISA and 135 subjects received vehicle once daily for 52 weeks or until they developed a flare. The adverse reactions observed with once daily EUCRISA treatment were similar to vehicle.

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

In a multicenter, open label, uncontrolled trial, 137 pediatric subjects aged 3 months to less than 2 years were treated with EUCRISA twice daily for 4 weeks. Overall, the safety profile of EUCRISA in this age group was consistent with that of Studies AN2728-AD-301 and AN2728-AD-302 in subjects 2 years of age and older.

Use of EUCRISA twice daily in pediatric patients aged 3 months to 17 years is further supported by data from the open-label period of up to 8 weeks in C3291035, a vehicle-controlled maintenance trial in 327 pediatric subjects. Once daily use of EUCRISA in 82 pediatric subjects 3 months to 17 years is supported by data from the 52-week double-blind maintenance period of C3291035. No new safety concerns were identified in C3291035 in pediatric subjects.

8.3 Less Common Clinical Trial Adverse Reactions

The following adverse reactions were observed in <1% of patients treated with EUCRISA.

General disorders and administration site conditions: application site reactions (including contact dermatitis and pruritus)

Skin and subcutaneous tissue disorders: flare of atopic dermatitis.

In an open-label, single arm, long-term safety study, 517 patients 2 to 72 years of age (including 454 patients 2 to 17 years of age), who had completed one of the Phase 3 studies without safety issues that precluded further treatment, were treated with EUCRISA twice daily intermittently for up to 48 weeks in 28 day on-treatment or off-treatment cycles. A total of 9 (2%) patients discontinued the therapy due to adverse events. The most frequently reported adverse events included atopic dermatitis, application site pain, and application site infection.

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Results for clinical laboratory testing have not identified clinically important changes from baseline to the end of study in mean or median values for any hematology or biochemistry parameters in any of the clinical studies in patients with atopic dermatitis.

8.5 Post-Market Adverse Reactions

The following adverse reactions have been identified during post-approval use of EUCRISA. Because these 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:

Application site reactions

10.1 Mechanism of Action

Crisaborole is a phosphodiesterase 4 (PDE-4) inhibitor.  PDE-4 inhibition results in increased intracellular cyclic adenosine monophosphate (cAMP) levels.  While the specific mechanism(s) by which crisaborole exerts its therapeutic action is not well defined, crisaborole reduces the production of some inflammatory cytokines implicated in the pathophysiology of atopic dermatitis.

10.2 Pharmacodynamics

At therapeutic doses, EUCRISA ointment is not expected to prolong QTc to any clinically relevant extent. In a thorough QT/QTc study of healthy volunteers, there was no clinically important prolongation of QT/QTc interval induced by either crisaborole or its metabolites and there were no clinically significant effects on heart rate or PR or QRS intervals.

A randomized clinical study was carried out to determine the potential of EUCRISA ointment, 2%, to induce sensitization and to cause irritation by repeated topical application to normal skin of healthy volunteers (18 years of age or older) under controlled conditions. In this study, EUCRISA showed no evidence of skin sensitization potential. Some skin irritations (e.g. erythema, edema and papules) were reported.

10.3 Pharmacokinetics

Absorption:

The pharmacokinetics (pK) of EUCRISA were investigated in 33 pediatric patients 2 to 17 years of age with mild to moderate atopic dermatitis and a mean ± SD body surface area (BSA) involvement of 49 ± 20% (range 27% to 92%). In this study, patients applied approximately 3 mg/cm² of EUCRISA ointment (dose range was approximately 6 g to 30 g per application) twice daily for 8 days. The lower limit of quantification for the pK assay used to detect presence of crisaborole in plasma was 0.2 ng/mL.

Plasma concentrations were quantifiable in all the patients. The mean ± SD maximum plasma concentration (C_max) and area under the concentration time curve from 0 to 12 hours post dose (AUC_0-12) for crisaborole on Day 8 were 127 ± 196 ng/mL and 949 ± 1240 ng*h/mL, respectively (Table 3). Systemic concentrations of crisaborole were at steady state by Day 8. Based on the ratios of AUC_0-12 between Day 8 and Day 1, the mean accumulation factor for crisaborole was 1.9.

The PK of EUCRISA were investigated in 18 subjects 3 months to less than 24 months of age. Excluding outlier values from 5 subjects the mean ± SD C_max and AUC_0-12 for crisaborole were 188 ± 100 ng/mL and 1164 ± 550 ng∙h/mL, respectively.

Distribution:

Based on an in vitro study, crisaborole is 97% bound to human plasma proteins.

Metabolism:

Crisaborole is substantially metabolized into inactive metabolites. The major metabolite 5-(4-cyanophenoxy)-2-hydroxyl benzylalcohol (metabolite 1), is formed via hydrolysis; this metabolite is further metabolized into downstream metabolites, among which 5-(4-cyanophenoxy)-2-hydroxyl benzoic acid (metabolite 2), formed via oxidation, is also a major metabolite.

Pharmacokinetics of metabolites 1 and 2 were assessed in the PK study described above and the systemic concentrations were at or near steady state by Day 8. Based on the ratios of AUC_0-12 between Day 8 and Day 1, the mean accumulation factors for metabolites 1 and 2 were 1.7 and 6.3, respectively.

Elimination:

Renal excretion of metabolites is the major route of elimination.

Special Populations and Conditions

• Pediatrics
  A multicenter, open-label maximal use, systemic exposure study with a pK Phase and a non-pK Safety Phase was conducted in children and adolescents with mild to moderate AD. Based on the pK exposures, no difference was seen in pK exposures in patients between the various age cohorts (2 to <18 years old).
  A separate PK study evaluated 18 subjects aged 3 months to <2 years of age. Following EUCRISA twice daily administration, large variations in plasma concentrations of crisaborole were observed, with 5 infants exhibiting more than 2-fold higher AUC compared to adults. Sampling methodology errors may have contributed to this result. When excluding values associated with potential sampling errors, results indicated comparable systemic crisaborole exposures in infants and toddlers as observed in older patients at similar treated BSA. However, an actual increase in exposure in infants and toddlers relative to older patients cannot be excluded.
• Geriatrics
  PK profiles of crisaborole and its two metabolites have not been assessed in geriatric subjects.
• Hepatic Insufficiency
  PK profiles of crisaborole and its two metabolites have not been assessed in patients with hepatic impairment.
• Renal Insufficiency
  PK profiles of crisaborole and its two metabolites have not been assessed in patients with renal impairment.
  

9.2 Drug Interactions Overview

In vitrostudies using human liver microsomes indicated that under the conditions of clinical use, crisaborole and metabolite 1 are not expected to inhibit cytochrome P450 (CYP) 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4.

In vitro studies using human liver microsome for metabolite 2 showed that it did not inhibit activities of CYP2C19, 2D6, and 3A4; was a weak inhibitor of CYP1A2 and 2B6; and a moderate inhibitor of CYP2C8 and 2C9.

In vitrostudies in human hepatocytes showed that under the conditions of clinical use, crisaborole and metabolites 1 and 2 are not expected to induce CYP enzymes.

In vitro studies showed that crisaborole and metabolite 1 did not inhibit the activities of uridine diphosphate (UDP)‑glucuronosyltransferase (UGT) 1A1, 1A4, 1A6, 1A9, 2B7, and 2B15.  Metabolite 2 did not inhibit UGT1A4, 1A6, 2B7, and 2B15. Metabolite 2 showed weak inhibition of UGT1A1, however, no clinically significant drug interactions are expected between crisaborole (and its metabolites) and UGT1A1 substrates at therapeutic concentrations.  Metabolite 2 showed moderate inhibition of UGT1A9 and may result in a moderate increase of the concentrations of sensitive UGT1A9 substrates.

In vitro studies indicate that under the condition of clinical use, crisaborole and metabolites 1 and 2 are not expected to cause clinically significant interactions with substrates of P-glycoprotein and organic anionic or cationic transporters.  Crisaborole and metabolite 1 are not expected to inhibit breast cancer resistance protein (BCRP); metabolite 2 is expected to inhibit BCRP at therapeutic concentrations.

9.3 Drug-Behavioural Interactions

Drug-behavioural interactions have not been established.

9.4 Drug-Drug Interactions

The most sensitive enzyme, CYP2C9, was further investigated in a clinical trial with coadministration of EUCRISA with warfarin, a CYP2C9 substrate.  The results of this study showed no drug interaction potential.

9.5 Drug-Food Interactions

Interactions with food have not been established, as not applicable for topical products.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

1 INDICATIONS

EUCRISA (onguent de crisaborole à 2 %) est indiqué pour :

• le traitement topique de la dermatite atopique légère ou modérée chez les adultes et chez les enfants âgés de 3 mois ou plus. (voir 4 POSOLOGIE ET ADMINISTRATION, 4.2 Posologie recommandée et ajustement posologique).

1.1 Enfants

Enfants (âgés de 3 mois à < 18 ans) : Selon les données soumises à Santé Canada et examinées par l’organisme, l’innocuité et l’efficacité d’EUCRISA ont été établies chez les enfants âgés de 3 mois ou plus pour le traitement topique de la dermatite atopique légère ou modérée.

Enfants (< 3 mois) : Santé Canada ne dispose d’aucune donnée sur l’utilisation d’EUCRISA chez des enfants de moins de 3 mois et n’a donc pas autorisé d’indication pour cette population.

1.2 Personnes âgées

Personnes âgées (≥ 65 ans) : Les données probantes issues des études cliniques sur EUCRISA ne portent pas sur suffisamment de patients âgés de 65 ans ou plus pour qu’il soit possible de déterminer si ces derniers répondent au traitement de la même façon que les patients plus jeunes.

EUCRISA is not for oral use.

There are no data from clinical trials regarding signs and symptoms of overdose of EUCRISA. Overdosage with EUCRISA is not anticipated with dermal application. If surplus EUCRISA has been applied, the excess should be thoroughly wiped off.

EUCRISA contains 2% crisaborole (w/w) in a petrolatum-based, white to off-white ointment and is for topical use. Each gram of EUCRISA contains 20 mg of crisaborole in an ointment containing white petrolatum, propylene glycol, mono- and di-glycerides, paraffin, butylated hydroxytoluene, and edetate calcium disodium.

EUCRISA is supplied in 30g, 60g, and 100g multilaminate tubes.

4.2 Recommended Dose and Dosage Adjustment

EUCRISA should be applied topically twice daily to all affected areas of skin for management of active disease.

For maintenance, once affected areas are clear or almost clear, a layer of ointment is to be applied once daily to the most commonly affected areas. If signs and symptoms of the disease worsen, a layer of ointment is to be applied twice daily to affected areas. Patients responding to up to 8 weeks of twice daily active disease treatment (i.e., lesions cleared or almost cleared) are suitable for once daily maintenance treatment.

4.4 Administration

EUCRISA should be applied topically to all affected areas of skin.

EUCRISA is for topical use only and not for oral, ophthalmic or intravaginal use.

4.5 Missed Dose

Advise patients if they forget to use EUCRISA as directed, to apply it as soon as possible, then go back to their regular schedule.

Store below 25°C.

EUCRISA est contre-indiqué chez les patients qui présentent une hypersensibilité à ce médicament ou à l’un des composants du produit (y compris les ingrédients non médicinaux) ou du contenant.

Pour obtenir une liste complète, veuillez consulter la section 6 FORMES PHARMACEUTIQUES, TENEURS, COMPOSITION ET CONDITIONNEMENT.

4.2 Posologie recommandée et ajustement posologique

EUCRISA doit être appliqué deux fois par jour par voie topique sur toutes les zones cutanées touchées pour prendre en charge la phase active de la maladie.

Pour le traitement d’entretien, une fois les lésions complètement ou presque complètement disparues, il faut appliquer une couche d’onguent une fois par jour sur les zones qui sont le plus souvent touchées. Si les signes et les symptômes de la maladie s’aggravent, il convient d’appliquer une couche d’onguent deux fois par jour sur les zones touchées. Lorsqu’une réponse (lésions complètement ou presque complètement disparues) est obtenue après 8 semaines ou moins d’applications biquotidiennes en phase active de la maladie, les patients peuvent passer au traitement d’entretien (1 application par jour).

4.4 Administration

EUCRISA doit être appliqué par voie topique sur toutes les zones cutanées touchées par la maladie.

EUCRISA est destiné exclusivement à un usage topique et ne doit pas être administré par voie orale, ophtalmique ou intravaginale.

4.5 Dose oubliée

Préciser au patient que s’il oublie d’utiliser EUCRISA conformément aux directives reçues, il devra l’appliquer sur les zones à traiter dès que possible, puis revenir à l’horaire d’application habituel.

9.2 Aperçu des interactions médicamenteuses

Des études in vitro sur des microsomes de foie humain ont indiqué que dans les conditions d’utilisation clinique, le crisaborole et le métabolite 1 ne devraient pas inhiber les isoenzymes du cytochrome P450 suivantes : CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 et CYP3A4.

Les études in vitro réalisées surdes microsomes de foie humain pour le métabolite 2 ont démontré que celui-ci n’inhibe pas l’activité de la CYP2C19, de la CYP2D6 ou de la CYP3A4, qu’il est un faible inhibiteur de la CYP1A2 et de la CYP2B6 et un inhibiteur modéré de la CYP2C8 et de la CYP2C9.

En somme, les études in vitrosur les hépatocytes humains ont démontré que ni le crisaborole ni les métabolites 1 et 2 ne devraient induire l’activité des isoenzymes du CYP dans les conditions d’utilisation clinique.

Des études in vitro ont révélé que ni le crisaborole ni son métabolite 1 n’inhibaient les activités des isoenzymes 1A1, 1A4, 1A6, 1A9, 2B7 et 2B15 du système UGT (uridine diphosphate-glucuronosyltransférase). Le métabolite 2 n’inhibait pas les isoenzymes 1A4, 1A6, 2B7 et 2B15. Le métabolite 2 inhibait faiblement l’UGT1A1; aucune interaction médicamenteuse d’importance clinique ne devrait toutefois avoir lieu entre le crisaborole (y compris ses métabolites) et les substrats de l’UGT1A1 à des concentrations thérapeutiques. Le métabolite 2 a de plus causé une inhibition modérée de l’UGT1A9, ce qui pourrait entraîner une élévation modérée de la concentration des substrats sensibles de l’UGT1A9. 

Selon des études in vitro, ni le crisaborole ni ses métabolites 1 et 2 ne devraient être à l’origine d’interactions d’importance clinique avec des substrats de la glycoprotéine P ou des transporteurs d’anions ou de cations organiques dans les conditions d’utilisation clinique. Ni le crisaborole ni son métabolite 1 ne devraient inhiber la protéine de résistance au cancer du sein (BCRP); toutefois, le métabolite 2 devrait inhiber la BCRP aux concentrations thérapeutiques.

9.3 Interactions médicament-comportement

Les interactions avec les comportements n’ont pas été établies.

9.4 Interactions médicament-médicament 

La CYP2C9, l’isoenzyme la plus sensible, a fait l’objet d’une évaluation approfondie dans le cadre d’une étude clinique dans laquelle la warfarine, un substrat pour cette isoenzyme, était administrée avec EUCRISA. Les résultats de cette étude n’ont mis en évidence aucun risque d’interactions médicamenteuses.

9.5 Interactions médicament-aliment

Les interactions avec les aliments n’ont pas été établies, puisqu’elles ne sont pas pertinentes pour l’application topique.

9.6 Interactions médicament-plante médicinale

Les interactions avec des produits à base de plante médicinale n’ont pas été établies.

9.7 Interactions médicament-épreuves de laboratoire

Les interactions avec les épreuves de laboratoire n’ont pas été établies.

Conserver à moins de 25 ˚C.

Conseiller aux patients ou à leurs aidants de lire les Renseignements destinés aux patients.

Hypersensibilité
Recommander aux patients de cesser l’application d’EUCRISA et de consulter immédiatement un médecin en cas d’apparition de signes ou de symptômes d’hypersensibilité (voir MISES EN GARDE ET PRÉCAUTIONS).

Directives d’administration
Préciser aux patients ou à leurs aidants qu’EUCRISA est réservé à l’usage externe et qu’il ne doit pas être administré par voie ophtalmique, orale ou intravaginale.

Numéro de contrôle : 267872
29 août 2023

8.1 Aperçu des effets indésirables

Les réactions au point d’application ont été les effets indésirables du médicament signalés le plus souvent au cours des études cliniques portant sur des patients de 2 ans ou plus atteints d’une dermatite atopique légère ou modérée.

8.2 Effets indésirables observés au cours des études cliniques

Étant donné que les études cliniques sont menées dans des conditions très particulières, les taux des effets indésirables qui y sont observés peuvent ne pas refléter les taux observés dans la pratique courante et ne doivent pas être comparés aux taux observés dans le cadre des études cliniques portant sur un autre médicament. Les renseignements sur les effets indésirables provenant des études cliniques peuvent être utiles pour la détermination des effets indésirables liés aux médicaments et pour l’approximation des taux en contexte réel.

Dans le cadre de deux études cliniques de phase III à double insu, à répartition aléatoire, à groupes parallèles et comparatives avec excipient (études AN2728-AD-301 et AN2728-AD-302), 1012 patients âgés de 2 à 79 ans atteints d’une dermatite atopique légère ou modérée ont reçu EUCRISA deux fois par jour pendant 4 semaines. Les effets indésirables ayant été signalés par ≥ 1 % des patients traités par EUCRISA sont présentés au tableau 2.

Dans le cadre d’une étude à double insu et comparative avec excipient sur le traitement d’entretien (étude C3291035), 497 sujets âgés de 5 mois à 79 ans atteints d’une dermatite atopique légère ou modérée ont été admis à une période sans insu et ont d’abord reçu EUCRISA deux fois par jour pendant une durée maximale de 8 semaines. Les effets indésirables observés lors de la période sans insu concordaient avec la marge d’innocuité connue d’EUCRISA administré deux fois par jour. Au cours de la période d’entretien à double insu, 135 des 270 sujets ayant été répartis aléatoirement ont été traités par EUCRISA, et les 135 autres ont reçu l’excipient; les deux agents étaient administrés une fois par jour pendant 52 semaines ou jusqu’à la survenue d’une poussée de la maladie. Les effets indésirables observés dans le groupe EUCRISA étaient comparables à ceux observés dans le groupe excipient.

8.1.1 Effets indésirables observés au cours des études cliniques – enfants

Au cours d’une étude multicentrique sans insu et non comparative, 137 enfants âgés de 3 mois à moins de 2 ans ont été traités par EUCRISA 2 fois par jour pendant 4 semaines. Dans l’ensemble, la marge d’innocuité d’EUCRISA dans ce groupe d’âge correspondait à celle observée lors des études AN2728-AD-301 et AN2728-AD-302, menées chez des sujets de 2 ans ou plus.

L’utilisation d’EUCRISA deux fois par jour chez des enfants âgés de 3 mois à 17 ans est aussi étayée par des données provenant de la période sans insu d’une durée maximale de 8 semaines de l’étude C3291035, une étude comparative avec excipient sur le traitement d’entretien menée auprès de 327 enfants. L’utilisation d’EUCRISA une fois par jour chez 82 enfants âgés de 3 mois à 17 ans est corroborée par des données provenant de la période de traitement d’entretien à double insu de 52 semaines de l’étude C3291035. Aucun nouveau problème d’innocuité n’a été décelé chez les enfants durant cette étude.

8.3 Effets indésirables peu fréquents observés au cours des études cliniques

Les effets indésirables énumérés ci-dessous ont été observés chez < 1 % des patients traités par EUCRISA.

Troubles généraux et réactions au point d’administration : réactions au point d’application (y compris dermatite de contact et prurit)

Troubles cutanés et sous-cutanés : poussée de dermatite atopique.

Durant une étude sans insu sur l’innocuité à long terme comportant un seul groupe, 517 patients de 2 à 72 ans (dont 454 patients de 2 à 17 ans), qui avaient terminé l’une des deux études de phase III sans avoir eu de problème d’innocuité susceptible de les empêcher de poursuivre le traitement, ont reçu EUCRISA deux fois par jour de manière intermittente pendant une période maximale de 48 semaines où se sont succédé des cycles de traitement et des cycles de repos thérapeutique de 28 jours. En tout, 9 (2 %) des patients ont abandonné le traitement en raison d’effets indésirables. Les effets indésirables les plus souvent signalés étaient la dermatite atopique, la douleur au point d’application et l’infection au point d’application.

8.4 Résultats anormaux aux épreuves de laboratoire : données hématologiques, données biochimiques et autres données quantitatives

Les résultats des analyses de laboratoire n’ont pas mis en évidence de variation d’importance clinique des valeurs moyennes ou médianes des paramètres hématologiques ou biochimiques entre le début et la fin des études cliniques menées chez des patients atteints de dermatite atopique.

8.5 Effets indésirables observés après la commercialisation

Les effets indésirables suivants ont été recensés après l’autorisation de mise en marché d’EUCRISA. Comme ces effets sont déclarés volontairement par une population de taille incertaine, leur fréquence et leur lien causal avec l’exposition au médicament ne peuvent pas toujours être établis avec certitude.

Réactions au point d’application

EUCRISA ne doit pas être administré par voie orale.

Les études cliniques ne contiennent pas de données concernant les signes et les symptômes d’un surdosage d’EUCRISA. L’application cutanée d’EUCRISA ne devrait pas entraîner de surdosage de ce médicament. En cas d’application d’un surplus d’EUCRISA, il faut essuyer complètement l’excès d’onguent.

EUCRISA contient 2 % de crisaborole (p/p) dans un onguent blanc ou blanc cassé à base de gelée de pétrole et il est destiné à un usage topique. Un gramme d’EUCRISA renferme 20 mg de crisaborole dans un onguent contenant de la gelée de pétrole blanche, du propylèneglycol, des monoglycérides et diglycérides, de la paraffine, de l’hydroxytoluène butylé et de l’édétate de calcium disodique.

EUCRISA est offert dans des tubes multicouches de 30, de 60 ou de 100 g.

Hypersensibilité

Des réactions d’hypersensibilité, y compris des cas d’urticaire de contact, sont survenues chez des patients traités par EUCRISA. Il faut soupçonner une hypersensibilité en présence d’un prurit, d’un œdème et d’un érythème sévères, qu’ils se manifestent au point d’application ou dans une zone éloignée de celui-ci. En cas d’apparition de signes et de symptômes d’hypersensibilité, il faut cesser immédiatement l’application d’EUCRISA et instaurer le traitement qui s’impose.

7.1 Populations particulières

7.1.1 Femmes enceintes

Il n’existe aucune donnée sur l’emploi d’EUCRISA chez la femme enceinte qui permette d’évaluer le risque de malformation congénitale grave et de fausse couche associé à ce médicament. Dans les études sur la reproduction animale, aucun effet indésirable sur le développement n’a été observé lorsque le crisaborole a été administré à des rates et à des lapines gravides par voie orale, durant l’organogenèse, à des doses qui pouvaient atteindre respectivement le triple et le double de la dose maximale recommandée chez l’humain (DMRH).

7.1.2 Femmes qui allaitent

On ignore si EUCRISA est excrété dans le lait maternel humain. On ne dispose d’aucun élément d’information sur les effets qu’il exerce sur la lactation ou sur le nourrisson allaité après son application par voie topique chez une femme qui allaite. EUCRISA passe dans la circulation générale. En l’absence de données cliniques obtenues durant la lactation, il est impossible d’établir clairement les risques auxquels EUCRISA expose les nourrissons durant l’allaitement. Par conséquent, il convient de peser les avantages de l’allaitement pour le développement et pour la santé en regard de la nécessité clinique d’administrer EUCRISA à la mère et des effets indésirables que pourrait subir le nourrisson, qu’ils soient imputables à EUCRISA ou à l’affection sous-jacente de la mère. Comme beaucoup de médicaments sont excrétés dans le lait maternel chez l’humain, des précautions s’imposent.

7.1.3 Enfants

Enfants (âgés de 3 mois à < 18 ans) : Selon les données soumises à Santé Canada et examinées par l’organisme, l’innocuité et l’efficacité d’EUCRISA dans le traitement topique de la dermatite atopique légère ou modérée ont été établies chez les enfants âgés de 3 mois ou plus. L’utilisation d’EUCRISA chez les patients de ce groupe d’âge est étayée par les données de deux études valables de 28 jours, comparatives avec excipient, qui visaient à évaluer l’efficacité et l’innocuité du médicament chez 1313 enfants et adolescents âgés de 2 à < 18 ans; 874 d’entre eux ont reçu EUCRISA. L’effet indésirable le plus couramment signalé chez les sujets de 2 ans ou plus était la douleur au point d’application. Par ailleurs, l’utilisation d’EUCRISA chez les patients âgés de 3 mois à moins de 2 ans est étayée par les données d’une étude sans insu de 28 jours visant à établir l’innocuité et la pharmacocinétique du médicament chez 137 sujets. Aucun nouveau problème d’innocuité n’a été relevé chez les sujets âgés de 3 mois à moins de 2 ans (voir EFFETS INDÉSIRABLES, MODE D’ACTION ET PHARMACOLOGIE CLINIQUE et ÉTUDES CLINIQUES). 

L’innocuité et l’efficacité d’EUCRISA chez les enfants de moins de 3 mois n’ont pas été établies.

7.1.4 Personnes âgées

Les données probantes issues des études cliniques sur EUCRISA ne portent pas sur suffisamment de patients âgés de 65 ans ou plus pour qu’il soit possible de déterminer si ces derniers répondent au traitement de la même façon que les patients plus jeunes.

10.1 Mode d’action

Le crisaborole est un inhibiteur de la phosphodiestérase de type 4 (PDE4). L’inhibition de la PDE4 entraîne une hausse de la concentration intracellulaire d’adénosine monophosphate cyclique (AMPc). Le crisaborole réduit la production de certaines cytokines proinflammatoires impliquées dans la physiopathologie de la dermatite atopique; cela dit, on n’a pas encore tout à fait élucidé les mécanismes spécifiques suivant lesquels cet agent exerce ses effets thérapeutiques.

10.2 Pharmacodynamie

En principe, lorsqu’il est administré aux doses thérapeutiques, l’onguent EUCRISA ne devrait pas entraîner d’allongement cliniquement important de l’intervalle QTc. Au cours d’une étude approfondie ayant porté sur les effets du crisaborole sur l’intervalle QT/QTc chez des volontaires sains, ni le crisaborole ni ses métabolites n’ont induit d’allongement cliniquement important de cet intervalle, et ils n’ont pas non plus exercé d’effets cliniquement importants sur la fréquence cardiaque, l’intervalle PR ou le complexe QRS.

Une étude clinique à répartition aléatoire a été réalisée pour déterminer si l’application topique répétée de l’onguent EUCRISA à 2 % sur la peau normale de volontaires sains (âgés de 18 ans ou plus), dans des conditions contrôlées, risquait d’induire une sensibilisation et de causer une irritation. Dans cette étude, EUCRISA n’a été associé à aucun signe évocateur d’un risque de sensibilisation de la peau. Certaines irritations de la peau (érythème, œdème, papules, etc.) ont été signalées.

10.3 Pharmacocinétique

Absorption

Les paramètres pharmacocinétiques d’EUCRISA ont été évalués chez 33 enfants et adolescents âgés de 2 à 17 ans atteints d’une dermatite atopique légère ou modérée pour lesquels le pourcentage moyen de surface corporelle touchée par la maladie ± écart-type était de 49 ± 20 % (min.-max. : 27-92 %). Dans cette étude, les patients ont appliqué à peu près 3 mg/cm² d’onguent EUCRISA (min.-max. : 6-30 g approximativement par application) sur les zones à traiter deux fois par jour pendant 8 jours. Le seuil de détection du dosage pharmacocinétique utilisé pour déceler la présence du crisaborole dans le plasma était de 0,2 ng/mL.

La concentration plasmatique du crisaborole était mesurable chez tous les patients. Le 8^e jour, la concentration plasmatique maximale (C_max; moyenne ± écart-type) du crisaborole était de 127 ± 196 ng/mL, et l’aire sous la courbe de la concentration de cet agent en fonction du temps de 0 à 12 heures après administration (ASC_0-12 h; moyenne ± écart-type), de 949 ± 1240 ng·h/mL (tableau 3). La concentration du crisaborole dans la circulation générale a atteint l’état d’équilibre au bout de 8 jours. D’après le rapport des ASC_0-12 h observées le 8^e et le 1^er jour, le facteur d’accumulation moyen du crisaborole se chiffrait à 1,9. 

Les paramètres pharmacocinétiques d’EUCRISA ont été évalués chez 18 sujets âgés de 3 à moins de 24 mois. Excluant les valeurs aberrantes provenant de 5 des sujets, la C_max (moyenne ± écart-type) du crisaborole était de 188 ± 100 ng/mL, et l’ASC_0-12 h (moyenne ± écart-type), de 1164 ± 550 ng·h/mL.

Distribution

D’après une étude in vitro, le taux de liaison du crisaborole aux protéines plasmatiques s’élève à 97 % chez l’humain.

Métabolisme

Le crisaborole subit une biotransformation importante en métabolites inactifs. Le principal métabolite de cet agent, l’alcool 5-(4-cyanophénoxy)-2-hydroxybenzylique (métabolite 1), est formé par hydrolyse. Il est métabolisé à son tour en plusieurs métabolites en aval, dont un autre métabolite majeur, l’acide 5-(4-cyanophénoxy)-2-hydroxybenzoïque (métabolite 2), qui est formé par oxydation.

Les paramètres pharmacocinétiques des métabolites 1 et 2 ont été évalués dans le cadre de l’étude pharmacocinétique décrite ci-dessus : au bout de 8 jours, les concentrations de ces deux métabolites avaient atteint l’état d’équilibre dans l’organisme ou elles s’en étaient rapproché. D’après le rapport des ASC_{0-12 h} observées le 8^e et le 1^er jour, les facteurs d’accumulation moyens des métabolites 1 et 2 s’établissaient respectivement à 1,7 et à 6,3.

Élimination

L’excrétion rénale des métabolites est la principale voie d’élimination.

Populations particulières et états pathologiques

• Enfants
  Une étude sans insu et multicentrique de type MUSE (Maximal Use, Systemic Exposure; risque d’exposition générale dans des conditions d’utilisation maximales) comportant une phase d’analyse pharmacocinétique et une phase d’évaluation de l’innocuité sans analyse pharmacocinétique a été menée auprès d’enfants et d’adolescents atteints d’une dermatite atopique légère ou modérée. D’après les paramètres pharmacocinétiques d’exposition, il n’y avait aucune différence entre les divers groupes d’âge (de 2 à < 18 ans) quant à l’exposition (pharmacocinétique) au crisaborole.
  
  Une étude de pharmacocinétique distincte a été menée auprès de 18 sujets âgés de 3 mois à moins de 2 ans. Suivant l’administration d’EUCRISA deux  fois par jour, on a observé de fortes variations des concentrations plasmatiques du crisaborole; chez 5 des nourrissons, l’ASC était plus du double de celle qu’on obtient chez l’adulte. Des erreurs dans la méthode d’échantillonnage pourraient avoir contribué à ce résultat. Lorsque les valeurs associées à d’éventuelles erreurs d’échantillonnage sont exclues, les résultats indiquent que l’exposition générale au crisaborole notée chez le nourrisson et le jeune enfant se compare à celle qu’on obtient chez des patients plus âgés pour des surfaces corporelles traitées similaires. Cependant, la possibilité d’une réelle augmentation de l’exposition chez le nourrisson et le jeune enfant ne peut être écartée.
• Personnes âgées
  Les paramètres pharmacocinétiques du crisaborole et de ses deux métabolites n’ont pas été évalués chez des sujets âgés.
• Insuffisance hépatique
  Les paramètres pharmacocinétiques du crisaborole et de ses deux métabolites n’ont pas été évalués en présence d’insuffisance hépatique.
• Insuffisance rénale
  Les paramètres pharmacocinétiques du crisaborole et de ses deux métabolites n’ont pas été évalués en présence d’insuffisance rénale.

1 INDICATIONS

EUCRISA (crisaborole ointment, 2 %) is indicated for:

• topical treatment of mild to moderate atopic dermatitis in adults and pediatric patients 3 months of age and older. (see 4 DOSAGE AND ADMINISTRATION, 4.2 Recommended Dose and Dosage Adjustment)

1.1 Pediatrics

Pediatrics (3 months to <18 years): Based on the data submitted and reviewed by Health Canada, the safety and effectiveness of EUCRISA have been established in pediatric patients age 3 months and older for topical treatment of mild to moderate atopic dermatitis.

Pediatrics (< 3 months of age): No data are available to Health Canada, therefore, Health Canada has not authorized an indication for pediatric patients below the age of 3 months.

1.2 Geriatrics

Geriatrics (≥ 65 years of age): Evidence from clinical studies of EUCRISA did not include sufficient numbers of patients 65 years of age and over to determine whether they respond differently from younger patients.