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Cutaneous adverse reactions to calcineurin inhibitors

Author: Dr Jacqueline Deen, Dermatology Principal House Officer, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia. DermNet NZ Editor in Chief: Adjunct A/Prof. Amanda Oakley, Dermatologist, Hamilton, New Zealand. Copy edited by Gus Mitchell. November 2019.

Cutaneous adverse reactions to calcineurin inhibitors — codes and concepts

What are calcineurin inhibitors?

Calcineurin inhibitors are drugs that work by inhibiting the calcium-dependent protein phosphatase calcineurin, an enzyme that results in activation of T lymphocytes through the upregulation of interleukin-2 and related cytokines, and leads to immunosuppression [1].

What are topical calcineurin inhibitors used for?

The topical calcineurin inhibitors tacrolimus and pimecrolimus are approved for the treatment of atopic dermatitis.

They are commonly used off-label in dermatology for:

Topical calcineurin inhibitors do not cause many of the possible adverse effects of topical corticosteroids, such as striae, cutaneous atrophy, glaucoma, rebound flares, and systemic absorption, or the potential for hypothalamic pituitary–adrenal axis (HPA) suppression.

Indications for topical calcineurin inhibitors

What are oral calcineurin inhibitors used for?

Oral calcineurin inhibitors are commonly used for immunosuppression after solid organ transplantation. Occasionally, systemic ciclosporin and tacrolimus may also be used to treat immune-mediated diseases including psoriasis and atopic dermatitis; however, their use is mainly restricted to patients who have failed to respond to conventional therapy [3].

What are the cutaneous side effects of topical calcineurin inhibitors?

The most commonly reported side effect of topical calcineurin inhibitors is local skin irritation (burning, pruritus, and erythema) at the application site. However, this is usually transient and decreases over time (usually within one month).

Other adverse effects may include:

There is no evidence to support the theoretical concern that topical calcineurin inhibitors may increase the risk of malignancy, such as basal cell carcinoma, cutaneous squamous cell carcinoma, melanoma and cutaneous lymphoma. Information reporting this risk is based on data from animal studies, case reports in a small number of patients, and knowledge of how these drugs work [2,4,5].

Potential adverse effects of topical calcineurin inhibitors

What are the mucocutaneous side effects of oral calcineurin inhibitors?

The adverse effects of tacrolimus and ciclosporin are generally similar. These include:

Adverse effects of oral calcineurin inhibitors

What are the non-cutaneous side effects of calcineurin inhibitors?

Calcineurin inhibitors can cause non-cutaneous side effects.

Oral calcineurin inhibitors

Oral calcineurin inhibitors can cause the following side effects:

  • Nephrotoxicity (the most common adverse effect)
  • Hypertension
  • Neurotoxicity (tremors, severe headache, visual abnormalities, seizures, encephalopathy, and coma)
  • Metabolic abnormalities (glucose intolerance, hyperlipidaemia, hyperuricaemia, hyperkalaemia, hypomagnesaemia, liver dysfunction with jaundice)
  • Infections (bacterial, viral, and fungal)
  • Increased risk of neoplasia (benign and malignant lymphoproliferative disorders including lymphoma)
  • Gastrointestinal side effects (nausea, vomiting, diarrhoea, and abdominal discomfort) [1,3].

Topical calcineurin inhibitors

Topically applied calcineurin inhibitors do not cause significant systemic side effects as less than 0.1% of the applied dose is absorbed except in conditions with severe skin barrier defects. Large epidemiological studies have not found topical calcineurin inhibitors to be correlated with an increased risk of lymphoma or other malignancies, however a Cochrane review noted such conclusions are affected by lack of reliable data [6, 7].

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Related information



  1. Malvezzi P, Rostaing L. The safety of calcineurin inhibitors for kidney-transplant patients. Expert Opin Drug Saf 2015; 14: 1531–46. PubMed
  2. Sehgal VN, Srivastava G, Dogra S. Tacrolimus in dermatology- pharmacokinetics, mechanism of action, drug interactions, dosages, and side effects: part I. Skinmed 2008; 7: 27–30. PubMed
  3. Azzi JR, Sayegh MH, Mallat SG. Calcineurin Inhibitors: 40 Years Later, Can’t Live Without. J Immunol 2013; 191: 5785–91. PubMed
  4. 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: 488–98. PubMed
  5. Undre NA, Moloney FJ, Ahmadi S. Skin and systemic pharmacokinetics of tacrolimus following topical application of tacrolimus ointment in adults with moderate to severe atopic dermatitis. Br J Dermatol 2009; 160: 665–9. PubMed
  6. Thaci D, Salgo R. Malignancy concerns of topical calcineurin inhibitors for atopic dermatitis: facts and controversies. Clin Dermatol 2010; 28: 52–6. PubMed
  7. Cury Martins J, Martins C, Aoki V, Gois AF, Ishii HA, da Silva EM. Topical tacrolimus for atopic dermatitis. Cochrane Database Syst Rev. 2015 Jul 1;2015(7):CD009864. doi: 10.1002/14651858.CD009864.pub2. PMID: 26132597; PMCID: PMC6461158.

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