Eucrisa Ointment

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Mechanism Of Action

Crisaborole is a phosphodiesterase 4 (PDE-4) inhibitor. PDE-4 inhibition results in increased intracellular cyclic adenosine monophosphate (cAMP) levels. The specific mechanism(s) by which crisaborole exerts its therapeutic action for the treatment of atopic dermatitis is not well defined.

Pharmacodynamics

At therapeutic doses, EUCRISA ointment is not expected to prolong QTc to any clinically relevant extent.

Pharmacokinetics

The pharmacokinetics (PK) of EUCRISA were investigated in 33 pediatric subjects 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, subjects applied approximately 3 mg/cm² of EUCRISA ointment (dose range was approximately 6 g to 30 g per application) twice daily for 8 days.

Plasma concentrations were quantifiable in all the subjects. 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. 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.

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.

PK 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.

Excretion

Renal excretion of metabolites is the major route of elimination.

Drug Interaction Studies

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 human liver microsomes studies 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. The most sensitive enzyme, CYP2C9, was further investigated in a clinical trial using warfarin as a CYP2C9 substrate. The results of this study showed no drug interaction potential.

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.

Clinical Studies

Two multicenter, randomized, double-blind, parallel-group, vehicle-controlled trials (Trials 1 and 2) treated a total of 1522 subjects 2 to 79 years of age (86.3% of subjects were 2 to 17 years of age) with a 5% to 95% treatable body surface area. At baseline, 38.5% of the subjects had an Investigator's Static Global Assessment [ISGA] score of 2 (mild), and 61.5% had an ISGA score of 3 (moderate), in the overall assessment of atopic dermatitis (erythema, induration/papulation, and oozing/crusting) on a severity scale of 0 to 4.

In both trials, subjects were randomized 2:1 to receive EUCRISA or vehicle applied twice daily for 28 days. The primary efficacy endpoint was the proportion of subjects at Day 29 who achieved success, defined as an ISGA grade of Clear (score of 0) or Almost Clear (score of 1) with a 2-grade or greater improvement from baseline, comparing EUCRISA-treated subjects to vehicle-treated subjects.

Efficacy results from the two trials are summarized in Table 2.

Table 2: Primary Efficacy Outcomes in Subjects with Mild to Moderate Atopic Dermatitis at Day 29

The success rates over time are presented in Figure 1.

Figure 1: Success in ISGAa Over Time in Subjects with Mild to Moderate Atopic Dermatitis

EUCRISA™
(you-KRIS-a)
(crisaborole) Ointment, 2%

Important information: EUCRISA is for use on skin (topical use) only. Do not use EUCRISA in your eyes, mouth, or vagina.

What is EUCRISA?

EUCRISA is a prescription medicine used on the skin (topical) to treat mild to moderate eczema (atopic dermatitis) in adults and children 2 years of age and older.

It is not known if EUCRISA is safe and effective in children under 2 years of age.

Who should not use EUCRISA?

Do not use EUCRISA if you are allergic to crisaborole or any of the ingredients in EUCRISA. See the end of this leaflet for a complete list of ingredients in EUCRISA.

Before using EUCRISA, tell your healthcare provider about all of your medical conditions, including if you:

• are pregnant or plan to become pregnant. It is not known if EUCRISA will harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if EUCRISA passes into your breast milk.

Tell your healthcare provider about all the medicines you take, including prescription and over-thecounter medicines, vitamins, and herbal supplements.

How should I use EUCRISA?

• Use EUCRISA exactly as your healthcare provider tells you to use it.
• Apply a thin layer of EUCRISA to the affected areas 2 times each day.
• Wash your hands after applying EUCRISA, unless hands are being treated. If someone else applies EUCRISA for you, they should wash their hands after applying EUCRISA.

What are the possible side effects of EUCRISA?

EUCRISA may cause side effects.

• Allergic reactions. EUCRISA may cause allergic reactions at or near the application site. These can be serious and may include hives, itching, swelling, and redness. If you have any of these symptoms, stop using EUCRISA and get medical help right away.

The most common side effect of EUCRISA is application site pain, such as burning or stinging.

This is not the only possible side effect of EUCRISA.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store EUCRISA?

• Store EUCRISA at room temperature, between 68°F and 77°F (20°C and 25°C).
• Keep the tube tightly closed.

General information about the safe and effective use of EUCRISA

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use EUCRISA for a condition for which it was not prescribed. Do not give EUCRISA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about EUCRISA that is written for healthcare professionals.

What are the ingredients in EUCRISA?

Active ingredient: crisaborole

Inactive ingredients: white petrolatum, propylene glycol, mono- and di-glycerides, paraffin, butylated hydroxytoluene, and edetate calcium disodium.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In two double-blind, vehicle-controlled clinical trials (Trial 1 and Trial 2), 1012 subjects 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 subjects is listed in Table 1.

Table 1: Adverse Reaction Occurring in ≥ 1% of Subjects in Atopic Dermatitis Trials through Week 4

Less common ( < 1%) adverse reactions in subjects treated with EUCRISA included contact urticaria [see WARNINGS AND PRECAUTIONS].

Read the entire FDA prescribing information for Eucrisa (crisaborole)

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© Eucrisa Patient Information is supplied by Cerner Multum, Inc. and Eucrisa Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.