EUCRISA (crisaborole)

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Product Monograph

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Note: the information below includes the Part I: Health Professional Information.

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Health Professional Information

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Serious Warnings And Precautions Box

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Dosage Forms, Strengths, Composition And Packaging

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Table 1 – Dosage Forms, Strengths, Composition and Packaging.
Route of Administration	Dosage Form / Strength/Composition	Non-medicinal Ingredients
Topical	Ointment: 30g, 60g and 100g 20 mg of crisaborole per gram (2%) of white to off-white ointment	butylated hydroxytoluene, edetate calcium disodium, mono- and di-glycerides, paraffin, white petrolatum, propylene glycol.

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.

Special Populations

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).

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.

Pediatrics

Pediatrics (2 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 2 years and older. Use of EUCRISA in this age group is supported by evidence from two multicenter, randomized, double-blind, parallel-group, vehicle-controlled 28-day trials which included 1,313 pediatric patients 2 to <18 years old (see ADVERSE REACTIONS and CLINICAL TRIALS).

The safety and effectiveness of EUCRISA in pediatric patients below the age of 2 years have not been established.

Geriatrics

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

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Adverse Reactions

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Adverse Reaction Overview

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

Clinical Trial Adverse Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials 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 is useful for identifying drug-related adverse events and for approximating rates.

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.

Table 2: Adverse Reaction Occurring in ≥1% of Patients in Atopic Dermatitis Trials through Week 4
a Refers to skin sensations such as burning or stinging.
Adverse Reaction	EUCRISA N=1012 n (%)	Vehicle N=499 n (%)
Application site pain^a	45 (4.45%)	6 (1.20%)

Less Common Clinical Trial Adverse Reactions

Less common (<1%) adverse reactions in patients treated with EUCRISA included application site reactions (including contact dermatitis and pruritus) and 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.

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.

Clinical Trial Adverse Reactions (Pediatrics)

See Clinical Trial Adverse Reactions.

Post-Market Adverse Reactions

Not applicable

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Drug Interactions

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Action And Clinical Pharmacology

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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.

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.

Pharmacokinetics

Table 3 - Summary of EUCRISA Pharmacokinetic Parameters in 2 – 17 year old patients with mild to moderate atopic dermatitis and treated BSA range from 27% - 92%
	C_maxng/ml	T_max(hrs, median (range))	AUC_0-12(ng.hr/ml)
Steady State Mean (SD)	127 (196)	3.00 (3.00 – 24.0)	949 (1240)

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 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.

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).

Geriatrics
PK profiles of crisaborole and its two metabolites have not been assessed in geriatric subjects.

Renal Impairment
PK profiles of crisaborole and its two metabolites have not been assessed in patients with renal impairment.

Hepatic Impairment
PK profiles of crisaborole and its two metabolites have not been assessed in patients with hepatic impairment.

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Storage, Stability And Disposal

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Special Handling Instructions

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EUCRISA Quick Finder

Health Professional Information

INDICATIONS

Contraindications

Serious Warnings And Precautions Box

Dosage And Administration

Dosing Considerations

Recommended Dose and Dosage Adjustment

Administration

Missed Dose

Overdosage

Dosage Forms, Strengths, Composition And Packaging

Warnings And Precautions

Hypersensitivity

Special Populations

Pregnant Women

Breast-feeding

Pediatrics

Geriatrics

Adverse Reactions

Adverse Reaction Overview

Clinical Trial Adverse Reactions

Less Common Clinical Trial Adverse Reactions

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

Clinical Trial Adverse Reactions (Pediatrics)

Post-Market Adverse Reactions

Drug Interactions

Serious Drug Interactions Box

Overview

Drug-Drug Interactions

Drug-Food Interactions

Drug-Herb Interactions

Drug-Laboratory Test Interactions

Drug-Lifestyle Interactions

Action And Clinical Pharmacology

Mechanism of Action

Pharmacodynamics

Pharmacokinetics

Absorption:

Distribution:

Metabolism:

Elimination:

Special Populations and Conditions

Storage, Stability And Disposal

Special Handling Instructions

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