EUCRISA

Topical Phosphodiesterase-4 (PDE-4) Inhibitors

Apply thin layer to affected areas.
For external use only. Avoid administering via the ophthalmic, oral, or vaginal routes.

contact dermatitis / Delayed / Incidence not known

skin irritation / Early / 4.0-4.0
urticaria / Rapid / 0-1.0

EUCRISA

Rx

Topical phosphodiesterase 4 inhibitor
For treatment of mild to moderate atopic dermatitis in patients 3 months and older
Most common adverse reaction is application site pain

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.

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.

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

There are no drug interactions associated with Crisaborole products.

EUCRISA Topical Ointment: 2%

Specific maximum dosage information not available.

Specific maximum dosage information not available.

Specific maximum dosage information not available.

Specific maximum dosage information not available.

3 months and older: Specific maximum dosage information not available.
Younger than 3 months: Safety and efficacy have not been established.

Safety and efficacy have not been established.

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.[61575]
 
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.[61575]

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.

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.