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Criteria for Outpatient Use Guidelines

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Topical Calcineurin Inhibitors - Pimecrolimus (Elidel®), Tacrolimus (Protopic®)

[Developed, October 2006; Revised, December 2006; May 2010]

Information on indications for use or diagnosis is assumed to be unavailable. All criteria may be applied retrospectively; prospective application is indicated with [*].

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1.* Dosage

Topical calcineurin inhibitors are FDA-approved as second-line agents for the management of atopic dermatitis in non-immunocompromised adults and children greater than 2 years of age who have not responded to other available therapies for atopic dermatitis. Pimecrolimus (Elidel®) is indicated for short-term, intermittent treatment of mild to moderate atopic dermatitis, while tacrolimus (Protopic®) is indicated for short-term, intermittent therapy of moderate to severe atopic dermatitis. Dosage recommendations for available calcineurin inhibitors are summarized in Table 1.

Table 1
Recommended Adult Dosages for Topical Calcineurin Inhibitors
Drug Name Dosage Strength Recommended Dose/Directions
Pimecrolimus (Elidel®) cream 1% - 30 g, 60g, 100 g tube

Apply thin layer of cream to affected area twice daily until symptoms resolve; use should be confined only to areas affected by atopic dermatitis; should not be used with occlusive dressings.
Tacrolimus (Protopic®) ointment 0.03% - 30 g, 60 g, 100 g tube 0.1% - 30 g, 60 g, 100 g tube Apply thin layer of 0.03% or 0.1% ointment to affected area twice daily, rubbing in completely, and continue until symptoms resolve; use should be confined only to areas affected by atopic dermatitis.

Patient profiles documenting prescriptions for greater than the equivalent of one 60 g tube of pimecrolimus cream or tacrolimus ointment per 30 day time period will be reviewed.

Pediatrics
A potential cancer risk has been associated with use of pimecrolimus cream and tacrolimus ointment based on information from animal studies, a small number of case reports as well as the proposed mechanism of action of calcineurin inhibitors.  Therefore, topical calcineurin inhibitor use should be avoided in children under 2 years of age as the effect on the developing immune system is not known.  Recommended pediatric dosages for topical calcineurin inhibitors are summarized in Table 2.

Table 2
Recommended Pediatric Dosages for Topical Calcineurin Inhibitors
Drug Name/Strength Recommended Dose/Directions

Pimecrolimus 1% cream

Children > 2 years of age:  apply thin layer of cream to affected area twice daily until symptoms resolve; use should be confined only to areas affected by atopic dermatitis; should not be used with occlusive dressings

Tacrolimus 0.03% ointment and Tacrolimus 0.1% ointment

Children 2-15 years of age:  use only 0.03% strength; apply thin layer of ointment to affected layer twice daily, rubbing in completely, and continue until symptoms resolve; use should be confined only to areas affected by atopic dermatitis; should not be used with occlusive dressings

Children 15-17 years of age:  apply thin layer of 0.03% or 0.1% ointment to affected area twice daily, rubbing in completely, and continue until symptoms resolve; use should be confined only to areas affected by atopic dermatitis; should not be used with occlusive dressings

Patient profiles documenting prescriptions for greater than the equivalent of one 60 g tube of pimecrolimus cream or tacrolimus ointment per 30 day time period will be reviewed.

2. Duration of Therapy

Continuous, long-term use of topical calcineurin inhibitors should be avoided, and use should be confined only to areas affected by atopic dermatitis.  Patients whose symptoms do not resolve following six weeks of calcineurin inhibitor therapy should be re-evaluated by their health care provider to confirm the diagnosis of atopic dermatitis. 

Patients with a confirmed diagnosis of atopic dermatitis will require chronic, intermittent therapy for this condition.  Patient profiles with either excessive prescriptions for calcineurin inhibitors during a 30-day time period (> 1 x 60 g tube) or without a definitive diagnosis of atopic dermatitis while prescribed a topical calcineurin inhibitor during a 90-day time period will be reviewed. 

3.* Duplicative Therapy

Concurrent administration of two or more topical calcineurin inhibitors does not provide enhanced therapeutic benefit and may result in additive adverse effects. Concurrent administration of pimecrolimus cream and tacrolimus ointment is not recommended and will be reviewed.

References

  1. Pimecrolimus (Elidel®) package insert.  Novartis Pharmaceuticals Corp., May 2009.
  2. Tacrolimus (Protopic®) package insert.  Astellas Pharma US, Inc., June 2009.
  3. Drug Facts and Comparisons.  Clin-eguide [database online].  St. Louis, MO:  Wolters Kluwer Health, Inc; 2010.  Available at:  http://clineguide.com.  Accessed May 7th, 2010.
  4. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc; 2010. Available at: http://www.clinicalpharmacology.com. Accessed May 7th, 2010.
  5. AHFS Drug Information 2010 [book online].  Jackson, WY:  Teton Data Systems, Version 6.7.3, 2009.  Based on:  McEvoy GK, editor.  AHFS drug information 2010.  Bethesda (MD):  American Society of Health-System Pharmacists; 2010.  Stat!Ref Electronic Medical Library.
  6. DRUGDEX® System (electronic version). Thomson Reuters (Healthcare) Inc., Greenwood Village, Colorado, USA. Available at: http://www.thomsonhc.com.libproxy.uthscsa.edu.  Accessed May 7th, 2010.
  7. U.S. Food and Drug Administration. Center for Drug Evaluation and Research.  FDA Public Health Advisory.  Elidel (pimecrolimus) cream and Protopic (tacrolimus) ointment.  March 10, 2005.  http://www.fda.gov/cder/drug/advisory/elidel_protopic.htm.  Accessed October 11th, 2006.
  8. Berger TG, Duvic M, Van Voorhees AS, Frieden IJ.  The use of topical calcineurin inhibitors in dermatology: safety concerns.  Report of the American Academy of Dermatology Association Task Force.  J Am Acad Dermatol. 2006;54:818-23.
  9. Qureshi AA, Fischer MA.  Topical calcineurin inhibitors for atopic dermatitis: balancing clinical benefit and possible risks.  Arch Dermatol. 2006;142:633-7.
  10. Reitamo S, Wollenberg A, Schopf E, Perrot JL, Marks R, Ruzicka T, et al. Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis. The European Tacrolimus Ointment Study Group.  Arch Dermatol. 2000;136:999-1006.
  11. Papp K, Staab D, Harper J, Potter P, Puig L, Ortonne J-P, et al.  Effect of pimecrolimus cream 1% on the long-term course of pediatric atopic dermatitis.  Int J Dermatol. 2004;43:978-83.
  12. Reitamo S, Van Leent EJ, Ho V, Harper J, Ruzicka T, Kalimo K, et al. Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone acetate ointment in children with atopic dermatitis. J Allergy Clin Immunol. 2002;109:539-46.
  13. Luger TA, Lahfa M, Folster-Holst R, Gulliver WP, Allen R, Molloy S, et al.  Long-term safety and tolerability of pimecrolimus cream 1% and topical corticosteroids in adults with moderate to severe atopic dermatitis.  J Dermatolog Treat. 2004;15:169-78.
  14. Reitamo S, Harper J, Bos JD, Cambazard F, Bruijnzeel-Koomen C, Valk P, et al. 0.03% Tacrolimus ointment applied once or twice daily is more efficacious than 1% hydrocortisone acetate in children with moderate to severe atopic dermatitis: results of a randomized double-blind controlled trial. Br J Dermatol. 2004;150:554-62.
  15. Trammell S, Shakil A, Wilder L, Daugird A. Clinical inquiries. What is the role of tacrolimus and pimecrolimus in atopic dermatitis?  J Fam Pract. 2005;54:714-6.
  16. Arellano FM, Wentworth CE, Arana A, et al.  Risk of lymphoma following exposure to calcineurin inhibitors and topical steroids in patients with atopic dermatitis. J Invest Dermatol. 2007;127(4):808-16.
  17. Langley RG, Eichenfield LF, Lucky AW, et al. Sustained efficacy and safety of pimecrolimus cream 1% when used long-term (up to 26 weeks) to treat children with atopic dermatitis.  Pediatr Dermatol. 2008;25(3):301-7.
  18. Hui RL, Lide W, Chan J, et al.  Association between exposure to topical tacrolimus or pimecrolimus and cancers. Ann Pharmacother. 2009;43(12):1956-63.
  19. Ruer-Mulard M, Aberer W, Gunstone A, et al.  Twice-daily versus once-daily applications of pimecrolimus cream 1% for the prevention of disease relapse in pediatric patients with atopic dermatitis. Pediatr Dermatol. 2009;26(5):551-8.
  20. Paller AS, Eichenfield LF, Kirsner RS, et al for the US Tacrolimus Ointment Study Group.  Three times weekly tacrolimus ointment reduces relapse in stabilized atopic dermatitis: a new paradigm for use. Pediatrics. 2008;122(6):e1210-8.
  21. Thaci D, Salgo R Malignancy concerns of topical calcineurin inhibitors for atopic dermatitis: facts and controversies.  Clin Dermatol. 2010;28(1):52-6.
  22. U.S. Department of Health and Human Services.  U.S. Food and Drug Administration. FDA approves updated labeling with boxed warning and medication guide for two eczema drugs, Elidel and Protopic. (January 19, 2006)  Available at:  http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm153941.htm.  Accessed May 7th, 2010.

Prepared by: Drug Information Service, The University of Texas Health Science Center at San Antonio, and the College of Pharmacy, The University of Texas at Austin.