EUCRISA (crisaborole)

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 Dosage Forms, Strengths, Composition and Packaging.

Dosing Considerations

Not applicable

Recommended Dose and Dosage Adjustment

Apply a thin layer of EUCRISA twice daily to affected areas.

Administration

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

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

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.

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.

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.

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

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

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.