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 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.
| ||
| Adverse Reaction | EUCRISA | Vehicle |
|---|---|---|
| Application site paina | 45 (4.45%) | 6 (1.20%) |
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.
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.
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.
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.
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
)EUCRISA (crisaborole ointment, 2 %) is indicated for:
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.
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.
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.
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.
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.
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 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.
| Route of Administration | Dosage Form / Strength/Composition | Non-medicinal Ingredients |
|---|---|---|
| Topical | Ointment: 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.
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.
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).
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 (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.
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.
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 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.
| ||
| Adverse Reaction | EUCRISA | Vehicle |
|---|---|---|
| Application site paina | 45 (4.45%) | 6 (1.20%) |
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.
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.
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.
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.
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
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.
Drug-behavioural interactions have not been established.
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.
Interactions with food have not been established, as not applicable for topical products.
Interactions with herbal products have not been established.
Interactions with laboratory tests have not been established.
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.
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.
| 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) |
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 (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.
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 Cmax and AUC0-12 for crisaborole were 188 ± 100 ng/mL and 1164 ± 550 ng∙h/mL, respectively.
Based on an in vitro study, crisaborole is 97% bound to human plasma proteins.
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.
Renal excretion of metabolites is the major route of elimination.
Store below 25°C.
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
*Contact Medical Information. 9AM-5PM ET Monday to Friday; excluding holidays.
Submit a medical question for Pfizer prescription products.
Contact Pfizer Safety to report an adverse event, side effect or concern about the quality of a Pfizer product:
1 866 723-7111.
To report an adverse event related to the Pfizer-BioNTech COVID-19 Vaccine, and you are not part of a clinical trial* for this product, click the link below to submit your information:
*If you are involved in a clinical trial for this product, adverse events should be reported to your coordinating study site.
You may also contact the Canada Vigilance Program directly to report adverse events or product quality concerns at 1-866-234-2345 or www.healthcanada.gc.ca/medeffect.