Relevant BNF section: 13.5.3
Conventional treatment of atopic dermatitis includes the regular, frequent use of emollients, and intermittent application of topical corticosteroids to control acute 'flares'. ▼Tacrolimus (pronounced ta-kro-li-mus), which is available for systemic use for the prevention of organ rejection following allogenic liver and kidney transplantation, is now formulated as an immunosuppressant ointment (Protopic - Fujisawa). This is licensed for use in adults and children aged 2 years and over with moderate to severe atopic dermatitis inadequately responsive to conventional therapy. Promotion states that, in these groups, tacrolimus is "at least as effective as topical steroids" and "without the potential side effects of conventional therapy". Here we consider the place of tacrolimus ointment in the management of atopic dermatitis.
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Relevant BNF section: 13.5.3
Atopic dermatitis is a chronic relapsing inflammatory disorder of the skin characterised by an itchy red rash which favours the skin creases (e.g. folds of elbows, behind the knees, around the neck). The disorder usually presents in the first 5 years of life, and affects around 15-20% of schoolchildren and 2-3% of adults in the UK.1,2 The exact pathophysiology of atopic dermatitis is not known. However, abnormal secretion of cytokines from T-lymphocytes appears to be an important factor in the genesis of lesions in atopic dermatitis.3
What is tacrolimus?
Tacrolimus is an immunosuppressive macrolide produced by the fungus, Streptomyces tsukubaensis.4 In the skin, tacrolimus is believed to act directly on T-lymphocytes to inhibit interleukin 2 transcription, which results in decreased responsiveness of T-lymphocytes to foreign antigens.4 When applied as an ointment, systemic absorption of tacrolimus is low; the amount entering the blood is small, and depends on the percentage of body surface area treated and the quantity of ointment applied.4 With regular application of 0.03% or 0.1% ointment to around 50% of body surface area in adults and children, overall systemic exposure to the drug is approximately 30-fold less than with oral immunosuppressive doses.5,6 Any tacrolimus that enters the blood is metabolised by the liver cytochrome P450 enzyme CYP3A4.
Tacrolimus ointment is available in 0.03% and 0.1% strengths. In patients aged 16 years or older with moderate or severe atopic dermatitis, who are inadequately responsive to, or intolerant of, conventional therapies, the summary of product characteristics (SPC) advises initial twice-daily application of 0.1% ointment for up to 3 weeks, and then 0.03% ointment until clearance of the lesion(s).5,6 Only the 0.03% ointment is licensed for use in children (aged 2 years or older). In this group, the SPC advises twice-daily application for up to 3 weeks, then once-daily until clearance of the lesion (s).6 Tacrolimus ointment should not be applied under occlusion. The SPC advises that only specialists should prescribe tacrolimus ointment.
Several published double-blind randomised controlled studies have evaluated tacrolimus ointment in adults and children with moderate or severe atopic dermatitis, typically involving 15-50% of body surface area. None has addressed treatment for patients unresponsive to, or intolerant of, conventional therapy - its licensed indication.
Comparisons with vehicle
Five published trials, involving a total of 1,383 patients, have compared tacrolimus ointment with vehicle ointment. Two were brief (3-week) studies that demonstrated marked superiority of each of three strengths of tacrolimus (0.03%, 0.1%, 0.3%) over vehicle in patients aged 7-16 years7 and 13-60 years.8 In two longer (12-week) studies, published as pooled results and involving a total of 632 adults, use of 0.03% and 0.1% tacrolimus ointments brought about over 90% improvement or clearing of atopic dermatitis (based on the physician's global assessment) in 27.5% and 36.8% of patients, respectively (vs. 6.6% with vehicle; p<0.001).9 The 0.1% ointment was more effective than 0.03% tacrolimus ointment (p=0.04). In a similar study in 354 children (aged 2-15 years), 35.9% and 40.7% had over 90% improvement or clearing with 0.03% and 0.1% tacrolimus ointments, respectively (vs. 6.9% with vehicle ointment; p<0.001), with no significant difference on any outcome between the two strengths of tacrolimus.10
Comparisons with topical corticosteroid
A double-blind study in 560 children (aged 2-15 years) compared 3 weeks' treatment (twice daily) with 0.03% tacrolimus, 0.1% tacrolimus or 1.0% hydrocortisone acetate ointments (a very weak corticosteroid), using an Eczema Area and Severity Index (a composite score of typical signs of atopic dermatitis, total area of skin involved, and degree of itch) to assess the response.11 Averaged over 3 weeks, median improvement from baseline was significantly greater with both 0.03% tacrolimus (55.2% improvement) and 0.1% tacrolimus (60.2%) than with 1.0% hydrocortisone acetate (36.0%; p<0.001), and was greater with 0.1% than with 0.03% tacrolimus (p<0.006). These findings held for both younger (aged 2-6 years) and older (7-15 years) children.11 In a 3-week study in 570 adults, which used the same index, improvement was similar with 0.1% tacrolimus ointment (63.5%) and the potent topical corticosteroid 0.1% hydrocortisone butyrate (63.9%), and was greater than with 0.03% tacrolimus (53%; p=0.002).12
Other studies, published in Japanese, and read in translation, have reported no significant difference in efficacy between 0.1% tacrolimus ointment and either 0.1% betamethasone valerate or 0.1% aclometasone dipropionate ointments (both potent corticosteroids) in adults with atopic dermatitis.13
Effects on thin skin
Tacrolimus ointment does not appear to impair collagen synthesis14 and is licensed to be used on areas where skin is naturally thin, such as the face, neck and flexures, where its efficacy is comparable to that at other sites.11,12 Small, brief, uncontrolled series have reported benefit with tacrolimus when applied to facial atopic dermatitis poorly responsive to topical corticosteroid therapy.15
Effects on quality of life
We know of no study that has compared tacrolimus and corticosteroid ointments with regards to quality-of-life outcomes. In three 12-week double-blind studies, involving a total of 902 adults, school-age children and toddlers, improvement in atopic dermatitis with 0.03% and 0.1% tacrolimus ointments was accompanied by significant improvement (compared to baseline and to a vehicle control group) in total quality-of-life score (using a dermatology-specific instrument), and in scores for individual items such as symptoms, feelings, daily activity and sleep.16
Data on long-term efficacy (up to 12 months) come from two uncontrolled studies, one in 255 children (aged 2-15 years)17 and one in 316 adults.18 Both used the higher (0.1%) strength of tacrolimus as sole topical anti-inflammatory therapy during active episodes of moderate or severe atopic dermatitis. They reported marked improvement, beginning in the first week of treatment, continuing in the first 3 months, then remaining stable while treatment was maintained, with no evidence of 'rebound flare' of dermatitis when treatment was stopped. In all, 3.1% of children and 6.0% of adults stopped tacrolimus because of lack of efficacy, while around 4.0% of all patients stopped because of unwanted effects.17,18
Around half of patients experience a transient burning sensation, itching or erythema at the site of application of tacrolimus.5,6,19 This usually declines within the first few days despite continued use. Alcohol intolerance (manifesting as facial flushing or skin irritation) is also said to be common.5,6 In long-term open studies, the risk of skin infections (e.g. folliculitis, acne, herpes simplex) or non-skin infections in patients using tacrolimus ointment was reported to be consistent with that expected in patients with atopic dermatitis, and did not increase with the cumulative dose.17,18 However, no safety data are available beyond 4 years, and whether the local immunosuppressive action of tacrolimus has the potential to increase the risk of infection, or of skin and other cancers, during long-term use will require careful ongoing surveillance. Renal toxicity, which is a risk with systemic treatment in immunosuppressive doses, has not been reported with tacrolimus ointment.
Contraindications and precautions
Tacrolimus ointment is contraindicated in patients with hypersensitivity to macrolides, in pregnancy, and in women who are breast-feeding. Therefore, women and girls of childbearing age and at risk of becoming pregnant should use contraception while using the ointment. Tacrolimus ointment should be used with caution in patients receiving systemic doses of drugs that inhibit the hepatic CYP3A4 enzyme (e.g. erythromycin, ketoconazole, diltiazem) or who have liver failure.5,6 Clinically infected atopic dermatitis should be treated before starting tacrolimus ointment. Patients requiring vaccination should not apply tacrolimus ointment for 14 days (28 days for live vaccines) either side of immunisation. The SPC advises that patients using tacrolimus ointment should minimise exposure to sunlight and ultraviolet light and should use appropriate sun-protection measures,5,6 presumably as a precaution against any potential increase in the risk of skin cancers.
Place in treatment
Topical corticosteroids are the mainstay of treatment for acute 'flares' of atopic dermatitis. Treatment should be with a corticosteroid of the lowest potency and ointment strength, applied for the shortest time necessary to adequately control the episode. The more potent topical corticosteroids should generally be avoided in children (or used with caution and for short periods only). On thin skin, only weaker corticosteroids (e.g. 1.0% hydrocortisone acetate) should be used where possible. With such management, clinically significant thinning of the skin and systemic effects are extremely uncommon, and true treatment-failure rare.13 Apparent treatment-failure on a topical corticosteroid should first prompt a search for a possible cause, such as infection or non-adherence to the regimen. While the role of tacrolimus ointment within its licensed indications therefore appears limited, it may be a useful choice for facial atopic dermatitis or for atopic dermatitis at other sites where the skin is thin. Whether tacrolimus can bring about longer-lasting or better-quality remission than topical corticosteroid in difficult (chronically relapsing) atopic dermatitis is not known.
The drug costs to the NHS of tacrolimus ointment are around £62 and £68 per 100g for 0.03% and 0.1% ointments, respectively (based on a 60g tube). By comparison, 100g of 0.1% hydrocortisone butyrate ointment costs around £6 and of 0.1% betamethasone valerate around £4.
▼Tacrolimus ointment, a topically active immunosuppressive agent, is an effective novel treatment for moderate or severe atopic dermatitis. In children, the lower strength (0.03%) ointment has been shown to be more effective than the weak corticosteroid, 1.0% hydrocortisone acetate. The higher strength (0.1%) ointment, which is licensed only for patients aged 16 years or over, appears as effective as more potent corticosteroids such as 0.1% hydrocortisone butyrate. Tacrolimus costs much more than topical corticosteroid, and we have found no published randomised controlled trial of its use in patients with atopic dermatitis that has responded inadequately to such conventional therapy - the patient group for whom tacrolimus is licensed. Tacrolimus may be useful for atopic dermatitis affecting areas where skin is thin, such as on the face, where avoidance of potent corticosteroids is desirable. Short-term use of topical tacrolimus ointment appears well-tolerated and safe, but long-term safety studies are needed. Treatment with tacrolimus should be supervised by a specialist.
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