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 (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.

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.

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Adverse Reactions

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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.

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)

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.

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

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Drug Interactions

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Serious Drug Interactions Box

Not applicable

Overview

In vitro studies 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 vitro studies 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.

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.

Drug-Food Interactions

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

Drug-Herb Interactions

Interactions with herbal products have not been evaluated.

Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been evaluated.

Drug-Lifestyle Interactions

Interactions with lifestyle have not been evaluated.

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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 (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.

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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