, Volume 65, Issue 6, pp 827-859
Date: 19 Sep 2012

Tacrolimus Ointment

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Summary

Abstract

Tacrolimus ointment (Protopic®) is a topically applied macrolide lactone immunomodulator effective in the treatment of atopic dermatitis. Its mechanism of action primarily involves calcineurin inhibition, which interrupts cytokine gene expression and leads to the downregulation of T-cell activity.

Tacrolimus ointment (0.03% and 0.1% for adults and 0.03% for children) is an effective treatment for atopic dermatitis of the trunk and limbs, as well as sensitive skin areas such as the face. Its efficacy is similar to or greater than that of hydrocortisone acetate 1%, hydrocortisone butyrate 0.1% and betamethsone valerate 0.12% ointments and pimecrolimus 1% cream. Systemic absorption of tacrolimus from the ointment is minimal, and adverse events, which are mostly associated with the application site and include skin burning and pruritus, tend to resolve early in treatment. Unlike topical corticosteroids, tacrolimus ointment is not associated with skin atrophy, and it is a well tolerated treatment for adults or children with atopic dermatitis, particularly when long-term treatment is indicated or the face or skin-fold regions are involved.

Pharmacological Properties

Tacrolimus ointment has demonstrated immunomodulatory and anti-inflammatory properties in animal models and human studies. The primary mechanism of action of tacrolimus in the treatment of atopic dermatitis involves calcineurin inhibition, which leads to downregulation of antigen-specific T-cell reactivity and interruption of the transcription of genes for a range of proinflammatory cytokines important in the pathophysiology of the early immune response. Additional mechanisms of action may include actions on other cells (dendritic cells, mast cells, keratinocytes, basophils and eosinophils) important in the pathophysiology of atopic dermatitis.

Unlike topical corticosteroids, tacrolimus 0.1% or 0.3% ointment does not interfere with collagen synthesis or induce skin atrophy (0.3% ointment is not available commercially).

Systemic absorption of tacrolimus from the 0.03% or 0.1% ointment in adults and children with atopic dermatitis was minimal; systemic exposure following topical application of tacrolimus 0.1% ointment to atopic dermatitis lesions was approximately 1.5% (in adults) and 3% (in children) of that following oral administration of the drug (dose not specified) [body surface area treated was up to 10 000 cm2 in adults and up to 5000 cm2 in children]. Blood concentrations during studies were generally <1 ng/mL, which is well below the concentration following orally administered tacrolimus in transplant patients (5–20 ng/mL), and no adverse events have been associated with detectable blood concentrations of tacrolimus following application of the ointment. Detectable blood concentrations of tacrolimus decreased during the course of treatment.

Therapeutic Efficacy

Tacrolimus ointment (0.03% or 0.1%) applied twice daily has shown efficacy in treating the signs and symptoms of moderate-to-severe atopic dermatitis in adults and children in large, 3-week to 6-month vehicle- or comparator-controlled clinical trials. Major endpoints were the Eczema Area and Severity Index and/or the clinical improvement in the condition according to the physician’s global assessment. Beneficial effects were generally observed within a week of initiating topical tacrolimus therapy. The vast majority of patients in these trials had head and neck involvement and the efficacy of topical tacrolimus in these areas was at least similar to that in affected areas of the trunk and limbs.

In adults with moderate-to-severe atopic dermatitis, tacrolimus 0.1% ointment has shown greater efficacy than a combined regimen of topical corticosteroids (hydrocortisone acetate 1 % ointment applied to the head and neck, and hydrocortisone butyrate 0.1% ointment applied to the trunk and limbs [24-week trial]) and efficacy similar to hydrocortisone butyrate 0.1% ointment (3-week trial). Tacrolimus 0.1% ointment generally had greater efficacy than the 0.03% concentration, and the efficacy of the 0.1% ointment (0.03% not investigated) was maintained in studies of approximately 3 years’ duration.

In another well controlled clinical study in adults with mild-to-very-severe atopic dermatitis, tacrolimus 0.1% ointment was significantly more effective than pimecrolimus 1% cream.

In children with moderate-to-severe atopic dermatitis, tacrolimus 0.03% and 0.1% ointment demonstrated similar efficacy in a 12-week vehicle-controlled trial. In a 3-week study, both concentrations of tacrolimus ointment were more effective than hydrocortisone acetate 1% ointment and tacrolimus 0.1% ointment was significantly more effective than tacrolimus 0.03% ointment. Tacrolimus 0.1% (0.03% not investigated) maintained efficacy in children in a 12-month clinical trial. Tacrolimus 0.1% ointment had greater efficacy than pimecrolimus 1% cream in patients with moderate-to-severe disease, but the lesser strength 0.03% tacrolimus had similar efficacy to pimecrolimus in children with mild disease.

According to the retrospective analysis of two studies, tacrolimus ointment also showed sustained efficacy over 12 months in adults and children with either mild or severe disease.

Controlled studies have shown tacrolimus ointment to be effective in plaquetype psoriasis, and preliminary open-label studies indicate that tacrolimus ointment has potential in the treatment of contact dermatitis, seborrhoeic dermatitis, rosacea, lichen planus and vitiligo.

Tolerability

Because there is minimal systemic absorption of tacrolimus from the ointment, topical tacrolimus 0.03% or 0.1% is not associated with the adverse events that have been observed with the oral administration of the drug. Treatment with tacrolimus ointment was generally well tolerated in short-term (3- to 12-week) and long-term (12- and 24-month) clinical trials. The type, incidence and severity of adverse events were broadly similar among adults and children and irrespective of the application site or the inflammatory condition being treated.

Tacrolimus-related adverse events were mostly associated with the application site (skin burning or pruritus), were mild or moderate and tended to diminish during the first week of, or early in, treatment as the lesions healed. Transient skin burning occurred in up to approximately one-half of patients and was reported significantly more frequently with tacrolimus than with vehicle ointment or topical corticosteroids. In adults, but not children, it occurred more frequently with tacrolimus application than with pimecrolimus. Pruritus, which is also a disease event, was reported more frequently in children applying tacrolimus ointment than those applying vehicle ointment, or pimecrolimus 1 % cream (in one trial but not another). Pruritus occurred with a similar incidence in children applying tacrolimus to that in children applying hydrocortisone acetate 1% ointment. In adults, pruritus occurred more frequently with tacrolimus ointment than with hydrocortisone butyrate 0.1% but with a similar frequency to that occurring with vehicle ointment or pimecrolimus 1 % cream.

In the majority of trials, the incidence of flu-like symptoms, the most common non-application-site adverse event in tacrolimus recipients, was generally consistent with that reported in the wider population but occurred significantly more frequently with tacrolimus 0.1% than with vehicle ointment in two trials.

Headache was reported significantly more frequently with tacrolimus 0.03% and 0.1% ointment than with vehicle ointment (20% and 19% vs 11%). Other less commonly reported adverse events (incidence <8%) that were significantly more frequent with tacrolimus 0.03% or 0.1% than with vehicle ointment were skin tingling, acne, alcohol intolerance (a reaction to alcohol involving skin flushing with heat sensation), hyperesthesia, folliculitis and rash.

No skin atrophy was observed with tacrolimus treatment in trials of up to 12 months’ duration and, compared with vehicle ointment, there was no increased incidence of skin infection (other than folliculitis in adults in one trial). Although animal data concerning the risk of malignancies are conflicting, experience in human clinical trials (up to 3 years’ duration) to date has not indicated an increased risk of skin cancers in patients using tacrolimus ointment. As with all immunomodulatory treatments, vigilance in this regard is recommended.

Pharmacoeconomic Considerations

Two US studies concluded that tacrolimus was at least as cost effective as highpotency topical corticosteroids in adults with moderate-to-severe atopic dermatitis and more cost effective than pimecrolimus 1 % cream in children with assumed moderate atopic dermatitis. Two analyses by the National Institute of Clinical Excellence in the UK concluded that treatment of atopic dermatitis with topical tacrolimus was more costly than that with topical corticosteroids for similar benefits, although the manufacturer’s economic model assessed tacrolimus as being at least as cost effective as topical corticosteroids; in the latter study, tacrolimus ointment was more cost effective than topical corticosteroids in the adult model run over 27 weeks but results were not as clear in the paediatric model. Limitations and uncertainties associated with these economic models limit the interpretation of the available pharmacoeconomic data.