How are calcineurin inhibitors used in the treatment of atopic dermatitis?

1.

Leung, Donald Y.M., Sicherer, Scott H. (2025). Atopic Dermatitis (Atopic Eczema). In Nelson Textbook of Pediatrics (pp. 1410). DOI: 10.1016/B978-0-323-88305-4.00186-3

The nonsteroidal topical calcineurin inhibitors are effective in reducing AD skin inflammation. Pimecrolimus cream 1% (Elidel) is indicated for mild to moderate AD. Tacrolimus ointment 0.1% and 0.03% (Protopic) is indicated for moderate to severe AD. Both are approved for short-term or intermittent long-term treatment of AD in patients ≥2 years whose disease is unresponsive to or who are intolerant of other conventional therapies or for whom these therapies are inadvisablebecause of potential risks. Topical calcineurin inhibitors may be better than topical corticosteroids in the treatment of patients whose AD is poorly responsive to topical steroids, patients with steroid phobia, and those with face and neck dermatitis, in whom ineffective, low-potency topical corticosteroids are typically used because of fears of steroid-induced skin atrophy.

2.

Elsevier ClinicalKey Drug Monograph

Content last updated: September 5, 2023.

Indications And Dosage **For the treatment of mild to moderate atopic dermatitis** NOTE: Topical pimecrolimus is indicated as a second-line therapy for short-term and non-continuous chronic treatment in non-immunocompromised persons who have failed to respond adequately to other topical treatments or when those treatments are not advisable. Topical dosage Adults: Apply a thin layer topically to the affected skin area(s) 2 times daily until symptoms resolve. If no improvement within 6 weeks, reassess diagnosis. Avoid continuous long-term use. Proactive, intermittent application of topical calcineurin inhibitors 2 to 3 times weekly to recurrent sites of disease has also been shown to be effective in reducing relapses. Children and Adolescents 2 to 17 years: Apply a thin layer topically to the affected skin area(s) 2 times daily until symptoms resolve. If no improvement within 6 weeks, reassess diagnosis. Avoid continuous long-term use. Proactive, intermittent application of topical calcineurin inhibitors 2 to 3 times weekly to recurrent sites of disease has also been shown to be effective in reducing relapses. Infants † and Children 1 year†: Apply a thin layer topically to the affected skin area(s) 2 times daily until symptoms resolve. Proactive, intermittent application of topical calcineurin inhibitors 2 to 3 times weekly to recurrent sites of disease has also been shown to be effective in reducing relapses.

Boxed Warning WARNING: LONG-TERM SAFETY OF TOPICAL CALCINEURIN INHIBITORS HAS NOT BEEN ESTABLISHED Although a causal relationship has not been established, rare cases of malignancy (e.g., skin and lymphoma) have been reported in patients treated with topical calcineurin inhibitors, including Pimecrolimus Cream, 1%. [see Warnings and Precautions (5.1) ] . Therefore: • Continuous long-term use of topical calcineurin inhibitors, including Pimecrolimus Cream, 1%, in any age group should be avoided and application limited to areas of involvement with atopic dermatitis [see Dosage and Administration (2) , Warnings and Precautions (5.1) ] . • Pimecrolimus Cream, 1% is not indicated for use in children less than 2 years of age [see Warnings and Precautions (5.1) , Use in Specific Populations (8.4) ] . WARNING: LONG-TERM SAFETY OF TOPICAL CALCINEURIN INHIBITORS HAS NOT BEEN ESTABLISHED See full prescribing information for complete boxed warning. Although a causal relationship has not been established, rare cases of malignancy (e.g., skin and lymphoma) have been reported in patients treated with topical calcineurin inhibitors, including Pimecrolimus Cream, 1%. ( 5.1 )

3.

Humphrey, Stephen R. (2025). In Nelson Textbook of Pediatrics (pp. 4038). DOI: 10.1016/B978-0-323-88305-4.00687-8

Calcineurin-inhibiting antiinflammatory agents that inhibit T-cell activation may be used instead of topical steroids for the treatment of atopic dermatitis and other inflammatory conditions. These agents are pimecrolimus and tacrolimus. They do not have the adverse local effects seen with topical steroids. Stinging with application is the most common complaint and may be lessened by mixing the medication with an ointment such as petrolatum jelly for the initial applications. These agents are only as strong as medium-potency topical steroids. In 2006, the FDA issued a boxed warning for topical calcineurin inhibitors because data from animal experiments and case reports suggested potential for an increased risk of lymphoma with systemic use. No clear link between topical calcineurin inhibitor use and lymphoma risk has been established despite multiple epidemiologic and clinical studies. Crisaborole, a novel PDE4 inhibitor, is now approved for mild to moderate atopic dermatitis, and is another option for nonsteroidal treatments.

4.

Elsevier ClinicalKey Drug Monograph

Content last updated: May 5, 2024.

Indications And Dosage Adolescents 16 to 17 years: Apply a thin layer topically to the affected skin area(s) 2 times daily until symptoms resolve. If no improvement within 6 weeks, reassess diagnosis. Avoid continuous long-term use. Proactive, intermittent application of topical calcineurin inhibitors 2 to 3 times weekly to recurrent sites of disease has also been shown to be effective in reducing relapses.

Indications And Dosage NOTE: Topical tacrolimus is indicated as a second-line therapy for short-term and non-continuous chronic treatment in non-immunocompromised persons who have failed to respond adequately to other topical treatments or when those treatments are not advisable. Topical dosage (0.03% ointment) Adults: Apply a thin layer topically to the affected skin area(s) 2 times daily until symptoms resolve. If no improvement within 6 weeks, reassess diagnosis. Avoid continuous long-term use. Proactive, intermittent application of topical calcineurin inhibitors 2 to 3 times weekly to recurrent sites of disease has also been shown to be effective in reducing relapses. Children and Adolescents 2 to 17 years: Apply a thin layer topically to the affected skin area(s) 2 times daily until symptoms resolve. If no improvement within 6 weeks, reassess diagnosis. Avoid continuous long-term use. Proactive, intermittent application of topical calcineurin inhibitors 2 to 3 times weekly to recurrent sites of disease has also been shown to be effective in reducing relapses. Infants † (off-label indication) and Children 1 year† (off-label indication): Apply a thin layer topically to the affected skin area(s) 2 times daily until symptoms resolve. Proactive, intermittent application of topical calcineurin inhibitors 2 to 3 times weekly to recurrent sites of disease has also been shown to be effective in reducing relapses. Topical dosage (0.1% ointment) Adults: Apply a thin layer topically to the affected skin area(s) 2 times daily until symptoms resolve. If no improvement within 6 weeks, reassess diagnosis. Avoid continuous long-term use. Proactive, intermittent application of topical calcineurin inhibitors 2 to 3 times weekly to recurrent sites of disease has also been shown to be effective in reducing relapses. Adolescents 16 to 17 years: Apply a thin layer topically to the affected skin area(s) 2 times daily until symptoms resolve. If no improvement within 6 weeks, reassess diagnosis.

Dosage And Administration DOSAGE AND ADMINISTRATION ADULT Tacrolimus ointment 0.03% and 0.1% • Apply a thin layer of tacrolimus ointment to the affected skin twice daily. The minimum amount should be rubbed in gently and completely to control signs and symptoms of atopic dermatitis. Stop using when signs and symptoms of atopic dermatitis resolve. • If signs and symptoms (e.g. itch, rash, and redness) do not improve within 6 weeks, patients should be re-examined by their healthcare provider to confirm the diagnosis of atopic dermatitis. • Continuous long-term use of topical calcineurin inhibitors, including tacrolimus ointment should be avoided, and application should be limited to areas of involvement with atopic dermatitis. The safety of tacrolimus ointment under occlusion, which may promote systemic exposure, has not been evaluated. Tacrolimus ointment should not be used with occlusive dressings. PEDIATRIC – FOR CHILDREN 2-15 YEARS Tacrolimus ointment 0.03% • Apply a thin layer of tacrolimus ointment, 0.03% to the affected skin twice daily. The minimum amount should be rubbed in gently and completely to control signs and symptoms of atopic dermatitis. Stop using when signs and symptoms of atopic dermatitis resolve. • If signs and symptoms (e.g. itch, rash, and redness) do not improve within 6 weeks, patients should be re-examined by their healthcare provider to confirm the diagnosis of atopic dermatitis. • Continuous long-term use of topical calcineurin inhibitors, including tacrolimus ointment should be avoided, and application should be limited to areas of involvement with atopic dermatitis. The safety of tacrolimus ointment under occlusion, which may promote systemic exposure, has not been evaluated. Tacrolimus ointment should not be used with occlusive dressings.

5.

Elsevier ClinicalKey Clinical Overview

Treatment Medium potency topical corticosteroid (eg, triamcinolone acetonide 0.1%, mometasone furoate 0.1%) applied once to twice weekly, avoiding the face and eyes Topical calcineurin inhibitor (tacrolimus or pimecrolimus) applied 2 to 3 times weekly (daily if nonresponsive) to sites of recurrent disease Choice of corticosteroid or calcineurin inhibitor is based on lesion location (topical corticosteroid use is limited in sensitive skin areas such as face and eyes), effectiveness and tolerability, patient or provider preference, and access to the medication (eg, cost, formulary status) Topical calcineurin inhibitors Effective steroid-sparing agents that do not cause skin atrophy; may actually reverse skin atrophy Approved in the United States as second line therapy for short-term or noncontinuous long-term treatment of atopic dermatitis in immunocompetent patients whose condition has not responded to other agents (ie, topical corticosteroids) or when other treatment is not recommended May be preferable to topical corticosteroids in the following situations: Lesions are recalcitrant to corticosteroids Involvement of sensitive areas (eg, face, skin folds, anogenital region) that are more susceptible to corticosteroid adverse effects Presence of steroid-induced atrophy Uninterrupted long-term corticosteroid use May be used for patients with moderate to severe disease (0.03% tacrolimus for patients aged 2 to 15 years and 0.1% for patients aged 16 years and older); 1% pimecrolimus may be used for patients aged 2 years and older with mild to severe disease

6.

Food and Drug Administration (DailyMed).

Publish date: June 2, 2022.

Dosage And Administration DOSAGE AND ADMINISTRATION ADULT Protopic (tacrolimus) ® Ointment 0.03% and 0.1% Apply a thin layer of Protopic (tacrolimus) ® Ointment to the affected skin twice daily. The minimum amount should be rubbed in gently and completely to control signs and symptoms of atopic dermatitis. Stop using when signs and symptoms of atopic dermatitis resolve. If signs and symptoms (e.g. itch, rash, and redness) do not improve within 6 weeks, patients should be re-examined by their healthcare provider to confirm the diagnosis of atopic dermatitis. Continuous long-term use of topical calcineurin inhibitors, including Protopic (tacrolimus) ® Ointment should be avoided, and application should be limited to areas of involvement with atopic dermatitis. The safety of Protopic (tacrolimus) ® Ointment under occlusion, which may promote systemic exposure, has not been evaluated. Protopic (tacrolimus) ® Ointment should not be used with occlusive dressings. PEDIATRIC – FOR CHILDREN 2-15 YEARS Protopic (tacrolimus) ® Ointment 0.03% Apply a thin layer of Protopic (tacrolimus) ® Ointment, 0.03% to the affected skin twice daily. The minimum amount should be rubbed in gently and completely to control signs and symptoms of atopic dermatitis. Stop using when signs and symptoms of atopic dermatitis resolve. If signs and symptoms (e.g. itch, rash, and redness) do not improve within 6 weeks, patients should be re-examined by their healthcare provider to confirm the diagnosis of atopic dermatitis. Continuous long-term use of topical calcineurin inhibitors, including Protopic (tacrolimus) ® Ointment should be avoided, and application should be limited to areas of involvement with atopic dermatitis. The safety of Protopic (tacrolimus) ® Ointment under occlusion, which may promote systemic exposure, has not been evaluated. Protopic (tacrolimus) ® Ointment should not be used with occlusive dressings.