Health Professional Information
INDICATIONS
EUCRISA (crisaborole ointment, 2 %) is indicated for topical treatment of mild to moderate atopic dermatitis in patients 2 years of age and older.
Pediatrics (2 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 2 years and older for topical treatment of mild to moderate atopic dermatitis.
Pediatrics (<2 years of age): No data are available to Health Canada, therefore, Health Canada has not authorized an indication for pediatric patients below the age of 2 years.
Geriatrics (≥ 65 years of age):
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.
Contraindications
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.
Serious Warnings And Precautions Box
Not applicable
Dosage And Administration
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 ophthalmic, oral, 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.
Overdosage
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.
For management of a suspected drug overdose, contact your regional poison control centre.
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. |
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.
Warnings And Precautions
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.
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.
Adverse Reactions
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.
|
||
Adverse Reaction |
EUCRISA N=1012 n (%) |
Vehicle N=499 n (%) |
Application site paina |
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
Drug Interactions
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.
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.
Action And Clinical Pharmacology
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
Cmax ng/ml |
Tmax (hrs, median (range)) |
AUC0-12(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 (Cmax) and area under the concentration time curve from 0 to 12 hours post dose (AUC0-12) 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 AUC0-12 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 AUC0-12 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.
Storage, Stability And Disposal
Store below 25°C.
Special Handling Instructions
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 #: 206906
June 11, 2018