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Tacrolimus

Authors: Vanessa Ngan, Staff Writer, 2004. Updated: Dr Kelvin Truong, Dermatology Research Fellow, Westmead Hospital, Sydney, Australia; Dr Martin Keefe, Dermatologist, Christchurch, New Zealand. Copy edited by Gus Mitchell. September 2021.


Tacrolimus — codes and concepts
open

What is tacrolimus?

Tacrolimus is a macrolide calcineurin inhibitor immunosuppressant drug available as a topical ointment, oral capsule, and intravenous injection. It was initially isolated from the soil fungus Streptomyces tsukabaenis.

Who uses tacrolimus?

Systemic tacrolimus

Tacrolimus may be used to treat these skin conditions

Topical tacrolimus

Topical tacrolimus may be used to treat these skin conditions

What are the contraindications with tacrolimus?

Contraindications to systemic and topical tacrolimus

Additional contraindications to topical tacrolimus

  • Children under the age of 2 years
  • Immunocompromised adults and children
  • Active bacterial skin infection
  • Application to malignant or premalignant skin lesions
  • Netherton syndrome due to significant percutaneous absorption

Tell me more about tacrolimus.

Tacrolimus is a lipophilic molecule; for topical use it is formulated as an ointment. Percutaneous absorption is minimal except where there is an epidermal barrier defect such as in active atopic dermatitis. As disease activity settles, absorption through the skin reduces.

Tacrolimus is metabolised by cytochrome P450 in the liver. Tacrolimus is not metabolised in the skin.

Polymorphisms in the CYP3A5 gene affect the bioavailability of systemic tacrolimus with CYP3A5 non-expressors requiring a higher dose of systemic tacrolimus post-transplant.

Mechanism of action of tacrolimus

Tacrolimus suppresses the cell-mediated immune response.

  • Tacrolimus binds to FKBP-12 (an intracellular protein) preventing activation of calcineurin phosphatase, thus inhibiting dephosphorylation of nuclear factor of activated T-cells (NFAT) and suppressing activity of genes that code for IL-2.
  • Tacrolimus also inhibits transcription of genes which encode IL-3, IL-4, IL-8, GM-CSF, and TNF-α, all of which are involved in the early stages of T-cell activation.
  • Tacrolimus inhibits the release of preformed mediators from skin mast cells and basophils, and downregulates the expression of the IgE receptor FcεRI on Langerhans cells.

How to use tacrolimus

Systemic tacrolimus

  • Following a solid organ transplant, tacrolimus is initially given as an intravenous continuous infusion until able to swallow.
  • Oral tacrolimus is available as a twice daily immediate-release, a once-daily extended-release capsule, or granule.

Topical tacrolimus

  • A thin layer of tacrolimus ointment is applied to the affected areas twice each day. It can be used on any affected skin site, including the face and folds, but mucous membranes should be avoided.
  • Topical steroids may be better for an acute flare with topical tacrolimus introduced as the dermatitis improves.
  • Emollients are usually prescribed concurrently, with tacrolimus applied at least two hours later.
  • Topical tacrolimus can be continued twice each week for maintenance.

What are the benefits of tacrolimus?

Systemic tacrolimus

Topical tacrolimus

  • Efficacy is equivalent to moderate-to-potent topical steroids
  • Does not cause skin atrophy so can be used on the face and skin folds
  • No association with glaucoma or cataracts
  • Response is usually seen within one week

What are the disadvantages of tacrolimus?

Systemic tacrolimus

  • Narrow therapeutic range
  • Risk of toxicity and requirement for monitoring of serum levels
  • May unmask latent Lynch syndrome
  • Drug interactions include posaconazole and erythromycin — tacrolimus dose must be reduced if these are prescribed to avoid toxicity
  • Atypical haemolytic uraemic syndrome

Topical tacrolimus

What are the side effects and risks of tacrolimus?

The Food and Drug Administration (FDA) has a black box warning for a possible increase in cancer risk including skin cancers and lymphoma. Evidence is conflicting with topical use so the risk, if any, is probably very small.

Systemic tacrolimus

Topical tacrolimus

  • Mucocutaneous
  • Other
    • Flu-like symptoms including headache and fever
    • Application site redness following alcohol ingestion

New Zealand approved datasheets are the official source of information for prescription medicines, including approved uses and risk information. Check the individual New Zealand datasheet on the Medsafe website.

If you are not based in New Zealand, we suggest you refer to your national drug approval agency for further information about medicines (eg, the Australian Therapeutic Goods Administration and the US Food and Drug Administration) or a national or state-approved formulary (eg, the New Zealand Formulary and New Zealand Formulary for Children and the British National Formulary and British National Formulary for Children).

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Related information

 

Bibliography

  • Ali FR, Lyon CC. Tacrolimus toxicity following topical treatment of perianal Crohn disease: an admonitory anecdote. J Crohns Colitis. 2013; 7(12): e713. Journal
  • Cury Martins J, Martins C, Aoki V, Gois AF, Ishii HA, da Silva EM. Topical tacrolimus for atopic dermatitis. Cochrane Database Syst Rev. 2015;2015(7):CD009864. doi:10.1002/14651858.CD009864.pub2. Journal
  • Elmets CA, Korman NJ, Prater EF, et al. Joint AAD-NPF Guidelines of care for the management and treatment of psoriasis with topical therapy and alternative medicine modalities for psoriasis severity measures. J Am Acad Dermatol. 2021;84(2):432-70. doi:10.1016/j.jaad.2020.07.087. Journal
  • Ghislain PD, De Decker I, Lachapelle JM. Efficacy and systemic absorption of topical tacrolimus used in pyoderma gangrenosum. Br J Dermatol. 2004;150(5):1052–3. doi:10.1111/j.1365-2133.2004.05914.x. PubMed
  • Madan V, Griffiths CE. Systemic ciclosporin and tacrolimus in dermatology. Dermatol Ther. 2007;20(4):239–50. doi:10.1111/j.1529-8019.2007.00137.x. PubMed
  • Malecic N, Young H. Tacrolimus for the management of psoriasis: clinical utility and place in therapy. Psoriasis (Auckl). 2016;6:153-63. doi:10.2147/PTT.S101233. Journal
  • Ponte GM, Baidal DA, Romanelli P, et al. Resolution of severe atopic dermatitis after tacrolimus withdrawal. Cell Transplant. 2007;16(1):23-30. doi:10.3727/000000007783464524. Journal
  • Sun SL, Liu JJ, Zhong B, et al. Topical calcineurin inhibitors in the treatment of oral lichen planus: a systematic review and meta-analysis. Br J Dermatol. 2019;181(6):1166–76. doi:10.1111/bjd.17898. PubMed
  • Taieb A, Alomar A, Böhm M, et al. Guidelines for the management of vitiligo: the European Dermatology Forum consensus. Br J Dermatol. 2013;168(1):5-19. doi:10.1111/j.1365-2133.2012.11197.x. Journal
  • Tavira B, Coto E, Díaz-Corte C, et al. Pharmacogenetics of tacrolimus after renal transplantation: analysis of polymorphisms in genes encoding 16 drug metabolizing enzymes [published correction appears in Clin Chem Lab Med. 2011 Jun;49(6):1087. Garciá, Eliecer Coto [corrected to Coto, Eliecer]; Alvarezca, Victoria [corrected to Alvarez, Victoria]]. Clin Chem Lab Med. 2011;49(5):825-33. doi:10.1515/CCLM.2011.143. PubMed

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