Topical Calcineurin Inhibitors

What Are Topical Calcineurin Inhibitors?

Topical calcineurin inhibitors are a group of topical medications used to treat inflammatory skin conditions. There are two types of topical calcineurin inhibitors, tacrolimus (0.1% and 0.03% ointment) and pimecrolimus (1% cream). Both are by prescription only. Tacrolimus is a compound naturally produced by a soil bacterium called Stretomyces tsukubaensis. Pimecrolimus is a semi-synthetic molecule derived from a bacterium called Streptomyces hydroscpicus var. Ascomyceticus.^[1]

Brand names that are associated with topical calcineurin inhibitors are:

Protopic (0.1 and 0.03% tacrolimus ointment)

Elidel (1% pimecrolimus cream)

How Do They Work?

Topical calcineurin inhibitors work by binding to an enzyme called FK506 binding protein (FKBP) inside a type of immune cell (T-cell). This binding affects the function of FK506, which prevents activation of T-cells and reduces production of inflammatory molecules.^[1] The end result is a localized suppression of immune function and a decrease in skin inflammation.

What Conditions Do Topical Calcineurin Inhibitors Treat? 

Both topical calcineurin inhibitors are approved by the FDA for the treatment of atopic dermatitis (eczema) in people who are 2 years or older.^[2] Tacrolimus 0.03% ointment is approved for children 2 to 15 years old, whereas both the 0.03% and 0.1% ointments are approved for adults.^[1,2] Tacrolimus is also indicated as a second-line treatment for short-term, non-continuous, chronic treatment of moderate to severe atopic dermatitis in adults and children with normal functioning immune systems who do not have a satisfactory response to topical prescription medication for atopic dermatitis, or when these other medications are not able to be used.^[2]

Both medications are also prescribed by practitioners off-label for a number of other skin conditions. Some of them include cutaneous lupus,^[3] psoriasis,^[4] lichen planus,^[5] vitiligo,^[6] rosacea,^[7] perioral dermatitis,^[8] seborrheic dermatitis,^[9] and contact dermatitis.^[10] Unlike topical steroids, topical calcineurin inhibitors do not cause thinning of the skin; therefore they can be used as alternatives to topical steroids when treatment is needed for longer than two weeks or for use in areas with naturally thin skin (eyelids, face, neck, skin folds such as armpits, below the breasts, and groin).

How Are Topical Calcineurin Inhibitors Used?

Hands should be washed before applying topical calcineurin inhibitors, and you may be directed to apply a thin layer up to twice daily to affected skin. If a caregiver is applying the medication for the patient, he/she should wear gloves or wash hands with soap and water after applying topical calcineurin inhibitors.^[2] Proper use should be discussed with a medical professional. 

What Are The Potential Side Effects and Risks of Topical Calcineurin Inhibitors?

The most common side effect of topical calcineurin inhibitors is local skin irritation, such as burning and stinging when applied to the skin. This is usually temporary and typically goes away within one month when the inflamed skin improves.^[11] Other potential side effects include the development of freckles^[12] and benign (non-cancerous) brown spots on the lips,^[13] flushing of the face after drinking alcohol,^[14] acne,^[15] rosacea-like rash,^[16] and infection and/or reactivation of certain virus infections such as the human papillomavirus (HPV)^[17,18] and molluscum contagiosum.^[19] 

In 2006, the FDA issued an updated labeling on both topical calcineurin inhibitors (tacrolimus and pimecrolimus) that include a boxed warning about a possible risk of skin cancer.^[20] The FDA suggests that other prescription topical medications should be tried first for atopic dermatitis (eczema). There is still controversy regarding the need for this boxed-warning for topical calcineurin inhibitors. Several clinical studies are ongoing to evaluate the long-term safety of these medications.

For prescription based drugs discussed here, please consult the drug package insert for complete prescribing information and for complete information regarding side effects.

1. Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd Ed. . 2012.
2. Link to research. January 05, 2017.
3. Kreuter A, Gambichler T, Breuckmann F, et al. Pimecrolimus 1% cream for cutaneous lupus erythematosus. J Am Acad Dermatol.2004;51(3):407-410; PMID: 15337984.
4. Liao YH, Chiu HC, Tseng YS, et al. Comparison of cutaneous tolerance and efficacy of calcitriol 3 microg g(-1) ointment and tacrolimus 0.3 mg g(-1) ointment in chronic plaque psoriasis involving facial or genitofemoral areas: a double-blind, randomized controlled trial. Br J Dermatol.2007;157(5):1005-1012; PMID: 17935517.
5. Hodgson TA, Sahni N, Kaliakatsou F, et al. Long-term efficacy and safety of topical tacrolimus in the management of ulcerative/erosive oral lichen planus. Eur J Dermatol.2003;13(5):466-470; PMID: 14693491.
6. Lin AN. Innovative use of topical calcineurin inhibitors. Dermatol Clin.2010;28(3):535-545; PMID: 20510763.
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8. Schwarz T, Kreiselmaier I, Bieber T, et al. A randomized, double-blind, vehicle-controlled study of 1% pimecrolimus cream in adult patients with perioral dermatitis. J Am Acad Dermatol.2008;59(1):34-40; PMID: 18462835.
9. Warshaw EM, Wohlhuter RJ, Liu A, et al. Results of a randomized, double-blind, vehicle-controlled efficacy trial of pimecrolimus cream 1% for the treatment of moderate to severe facial seborrheic dermatitis. J Am Acad Dermatol.2007;57(2):257-264; PMID: 17188780.
10. Queille-Roussel C, Graeber M, Thurston M, et al. SDZ ASM 981 is the first non-steroid that suppresses established nickel contact dermatitis elicited by allergen challenge. Contact Dermatitis.2000;42(6):349-350; PMID: 10871099.
11. Fleischer AB, Jr., Boguniewicz M. An approach to pruritus in atopic dermatitis: a critical systematic review of the tacrolimus ointment literature. J Drugs Dermatol.2010;9(5):488-498; PMID: 20480792.
12. Hickey JR, Robson A, Barker JN, et al. Does topical tacrolimus induce lentigines in children with atopic dermatitis? A report of three cases. Br J Dermatol.2005;152(1):152-154; PMID: 15656817.
13. Shi VY, Joo JS, Sharon VR. Multiple labial melanotic macules occurring after topical application of calcineurin inhibitors. Dermatol Online J.2014;20(8)PMID: 25148283.
14. Stinco G, Piccirillo F, Sallustio M, et al. Facial flush reaction after alcohol ingestion during topical pimecrolimus and tacrolimus treatment. Dermatology.2009;218(1):71-72; PMID: 18832812.
15. Bakos L, Bakos RM. Focal acne during topical tacrolimus therapy for vitiligo. Arch Dermatol.2007;143(9):1223-1224; PMID: 17875902.
16. Fujiwara S, Okubo Y, Irisawa R, et al. Rosaceiform dermatitis associated with topical tacrolimus treatment. J Am Acad Dermatol.2010;62(6):1050-1052; PMID: 20466178.
17. Bilenchi R, Poggiali S, De Padova LA, et al. Human papillomavirus reactivation following topical tacrolimus therapy of anogenital lichen sclerosus. Br J Dermatol.2007;156(2):405-406; PMID: 17223903.
18. Kimata H. Kaposi's varicelliform eruption associated with the use of tacrolimus ointment in two neonates. Indian J Dermatol Venereol Leprol.2008;74(3):262-263; PMID: 18583800.
19. Goksugur N, Ozbostanci B, Goksugur SB. Molluscum contagiosum infection associated with pimecrolimus use in pityriasis alba. Pediatr Dermatol.2007;24(5):E63-65; PMID: 17958783.
20. Link to research. January 04, 2017.