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?
- Solid organ transplant — kidney, heart, lung – approved for adults and children to prevent post-transplant organ rejection
- Off-label use in dermatology – graft versus host disease, hidradenitis suppurativa, paediatric systemic lupus erythematosus
Tacrolimus may be used to treat these skin conditions
- Atopic dermatitis — adults and children over the age of 2 years
- Off-label uses in dermatology include:
- Double-blind clinical trials
- Seborrhoeic dermatitis, oral lichen planus (as a mouth rinse), pruritus ani, facial psoriasis, flexural psoriasis
- Clinical trials
- Small trials of at least 20 people
- Double-blind clinical trials
Topical tacrolimus may be used to treat these skin conditions
What are the contraindications with tacrolimus?
Contraindications to systemic and topical tacrolimus
- Hypersensitivity to tacrolimus and other macrolides such as erythromycin, or product excipients
- Pregnancy and lactation – Pregnancy Category C
- Concurrent use of ciclosporin
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
- 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.
- 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?
- Less nephrotoxic than ciclosporin
- Less frequent gingival enlargement and hypertrichosis than ciclosporin
- 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?
- 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
- Enhanced absorption across mucous membranes
- Tinea incognito if applied to a dermatophyte skin infection
- Steroid rosacea-like face rash with prolonged topical application
- Toxicity can, rarely, follow topical use
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.
- Itch (36%)
- Skin rashes (24%)
- Alopecia and hypertrichosis
- Stevens/Johnson syndrome/toxic epidermal necrolysis, urticaria
- Common symptoms — diarrhoea, headache, tremor, nausea
- Symptoms of toxicity include nausea, paraesthesia, light-headedness
- Hypertension, hyperglycaemia, anaemia, renal impairment
- Application site irritation, stinging, burning, itch
- Contact dermatitis
- Focal hypertrichosis and trichomegaly at application site
- Reactivation of herpes simplex
- Increased risk of candidiasis with use in anogenital area
- Flu-like symptoms including headache and fever
- Application site redness following alcohol ingestion
We suggest you refer to your national drug approval agency such as the Australian Therapeutic Goods Administration (TGA), US Food and Drug Administration (FDA), UK Medicines and Healthcare products regulatory agency (MHRA) / emc, and NZ Medsafe, or a national or state-approved formulary eg, the New Zealand Formulary (NZF) and New Zealand Formulary for Children (NZFC) and the British National Formulary (BNF) and British National Formulary for Children (BNFC).