Crisaborole is a phosphodiesterase 4 (PDE-4) inhibitor indicated for the topical treatment of mild to moderate atopic dermatitis in adult and pediatric patients 3 months of age and older. Because crisaborole is administered topically, it avoids the gastrointestinal side effects that are associated with apremilast, an orally administered PDE-4 inhibitor. The most commonly reported adverse event with crisaborole is application site pain, which frequently develops after the first dose and resolves within 1 day.
Approval was based on the results of 2 double-blinded, vehicle-controlled trials involving 1,522 patients (ages 2 to 79 years) with mild to moderate atopic dermatitis. The primary endpoint, defined as an Investigator's Static Global Assessment score of clear (0) or almost clear (1) with a 2-grade or greater improvement from baseline, was achieved by more crisaborole-treated patients (31.4% to 32.8%) than those receiving vehicle ointment (18% to 25.4%). In addition, the time to reach the primary endpoint occurred earlier in patients treated with crisaborole than in those treated with the vehicle.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Topical Administration
Cream/Ointment/Lotion Formulations
-Apply thin layer to affected areas.
-For external use only. Avoid administering via the ophthalmic, oral, or vaginal routes.
During clinical trials, application site skin irritation (defined as pain, burning, or stinging) was reported by 4% of patients treated with crisaborole (n = 45 of 1,012) and 1% of patients receiving the vehicle (n = 6 of 499). Of the crisaborole recipients who experienced application site skin irritation, 76.7% reported the adverse event on the first treatment day, and 77.6% had resolution within 1 day of onset. In addition, less than 1% of patients receiving crisaborole during clinical trials developed contact urticaria. Cases of allergic contact dermatitis have been reported during postmarketing use of the drug. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established.
Use of crisaborole is contraindicated in patients with a known hypersensitivity to the active ingredient or any component of the formulation. A hypersensitivity reaction should be suspected in any drug recipient who develops severe pruritus, swelling, and erythema at the application site or at a distant site. Instruct patients to immediately discontinue use of the drug and seek medical care if signs and symptoms of a hypersensitivity reaction develop during treatment.
Crisaborole is only approved for external use on the skin; it is not for ophthalmic administration, oral administration, or vaginal administration. During topical application, take care to avoid accidental ocular exposure.
No data are available regarding use of crisaborole during human pregnancy. In animal studies, no adverse developmental effects were observed when oral doses of 3- and 2-times the maximum recommended human dose, were administered during organogenesis to pregnant rats and rabbits, respectively. Administer during pregnancy only if the potential benefits to the mother justify the potential risks to the fetus.
Data are limited regarding use of crisaborole during breast-feeding, and its' excretion into human milk is unknown. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.
For the treatment of mild to moderate atopic dermatitis (eczema):
Topical dosage:
Adults: Apply a thin layer topically to the affected skin area(s) 2 times daily. Once clinical effect is achieved, consider reducing application to once daily.
Infants, Children, and Adolescents 3 months to 17 years: Apply a thin layer topically to the affected skin area(s) 2 times daily. Once clinical effect is achieved, consider reducing application to once daily.
Maximum Dosage Limits:
-Adults
Specific maximum dosage information not available.
-Geriatric
Specific maximum dosage information not available.
-Adolescents
Specific maximum dosage information not available.
-Children
Specific maximum dosage information not available.
-Infants
3 months and older: Specific maximum dosage information not available.
Younger than 3 months: Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Crisaborole products.
The specific mechanisms by which crisaborole exerts its therapeutic effect in patients with atopic dermatitis has not been fully defined; however, the drug has been found to increase intracellular concentrations of cyclic adenosine monophosphate (cAMP) by inhibiting phosphodiesterase-4 (PDE-4). Phosphodiesterase-4 is an enzyme that regulates production of inflammatory cytokines through the degradation of cAMP. In patients with atopic dermatitis, PDE-4 activity is enhanced in circulating inflammatory cells resulting in increased cytokine production. By inhibiting the ability of PDE-4 to degrade cAMP, crisaborole suppresses the release of pro-inflammatory cytokines.
Crisaborole is administered topically. Once absorbed into systemic circulation, 97% of the drug is bound to human plasma proteins. Crisaborole is substantially metabolized into 2 inactive metabolites. Initially, the drug undergoes hydrolysis to form 5-(4-cyanophenoxy)-2-hydroxyl benzylalcohol (metabolite 1). Metabolite 1 is subsequently oxidized to form 5-(4-cyanophenoxy)-2-hydroxyl benzoic acid (metabolite 2). These metabolites are primarily eliminated via renal excretion.
Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, CYP2B6, CYP2C8, CYP2C9, uridine diphosphate glucuronosyltransferase (UGT), and breast cancer resistance protein (BCRP)
Based on data from in vitro studies in human hepatocytes, crisaborole and the 2 inactive metabolites are not expected to induce CYP enzymes. In addition, CYP enzymes, UGT, P-glycoprotein (P-gp), and organic anion or cationic transporters are not expected to be inhibited by crisaborole or metabolite 1. However, metabolite 2 was found to be a weak inhibitor of CYP1A2 and CYP2B6, as well as a moderate inhibitor of CYP2C8 and CYP2C9. Further evaluation of the most sensitive enzyme (CYP2C9), showed no drug interaction potential between metabolite 2 and a CYP2C9 substrate (warfarin). Metabolite 2 also showed weak inhibition of UGT1A1, moderate inhibition of UGT1A9, and is expected to inhibit BCRP at therapeutic concentrations. Sensitive substrates of UGT1A9 may have their concentrations moderately increased by metabolite 2.
-Route-Specific Pharmacokinetics
Topical Route
Due to a low molecular weight (251 daltons), crisaborole effectively penetrates through human skin and is systemically absorbed following topical administration. During clinical trials, quantifiable systemic drug concentrations were identified in all drug recipients. Steady state drugs concentrations are reached by treatment day 8; and based on the ratio of concentrations between day 8 and day 1, the mean accumulation factor for crisaborole is 1.9. Accumulation factors for metabolite 1 and metabolite 2 are 1.7 and 6.3, respectively.
-Special Populations
Pediatrics
A pharmacokinetic study of 13 subjects (age 4 to less than 24 months) found the mean Cmax (188 +/- 100 ng/mL) and mean systemic exposure (1,164 +/- 550 ng x hour/mL) of crisaborole to be similar to those observed in patients 2 to 17 years of age (127 +/- 196 ng/mL and 949 +/- 1,240 ng x hour/mL, respectively).