- 207 Downloads
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.
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.
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.
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.
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.
KeywordsTacrolimus Atopic Dermatitis Topical Corticosteroid Pimecrolimus Rosacea
- 8.Boucher M. Tacrolimus ointment for the treatment of atopic dermatitis. Issues Emerg Health Technol 2001 Jul; (19): 1–4Google Scholar
- 12.Lawrence I. Tacrolimus (FK506): experience in dermatology. Dermatol Ther 1998; 5: 74–84Google Scholar
- 18.Leung DY, Hanifin JM, Charlesworth EN, et al. Disease management of atopic dermatitis: a practice parameter. Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma and Immunology, the American College of Allergy, Asthma and Immunology, and the Joint Council of Allergy, Asthma and Immunology. Work Group on Atopic Dermatitis. Ann Allergy Asthma Immunol 1997 Sep; 79(3): 197–211Google Scholar
- 31.Eberlein-Konig B, Ruzicka T, Michel G, et al. Inhibition of in vitro histamine release (HR) from human basophils by the immunosuppressive drug FK 506. J Invest Dermatol 1993; 100: 446Google Scholar
- 35.Fujii Y, Sakuma S, Senoh H, et al. Topical tacrolimus is more efficacious than pimecrolimus in inhibiting acute contact dermatitis in a rat model. J Invest Dermatol 2002 Sep; 119: 727Google Scholar
- 55.Wollenberg A, Regele D, Sharma S, et al. Topical tacrolimus treatment leads to profound alterations of the antigen presenting cells in lesional atopic dermatitis skin. J Invest Dermatol 1996 Sep; 107: 468Google Scholar
- 57.Toyoda M. Antipruritic mechanism of tacrolimus ointment for atopic dermatitis: consideration of dermatoneuronal factors. Clin Dermatol 2003; 57(5): 45–50Google Scholar
- 63.Wollenberg A, for the European Tacrolimus Multicenter Atopic Dermatitis Study Group. Long-term efficacy and safety of tacrolimus ointment in adult patients with atopic dermatitis [abstract no. 013]. 58th Annual Meeting of the American Academy of Dermatology; 2000 Mar 10–15; San FranciscoGoogle Scholar
- 65.National Institute for Clinical Excellence. Atopic eczema in primary care. Merec Bull 2003 Jul; 14(1): 1–4Google Scholar
- 67.Food and Drug Administration Center for Drug Evaluation and Research. Pharmacologist’s view of new drug application 50777 [Protopic (Tacrolimus ointment) approval online; online]. Available from URL: http://www.fda.gov/cder [Accessed 2005 Feb 5]
- 71.Naylor MF, Elmets C, Satoi Y, et al. Treatment with topical tacrolimus is not associated with an increase in non-melanoma skin cancers [abstract no. P18]. 60th Annual Meeting of the American Academy of Dermatology; 2002 Feb 22–27; New OrleansGoogle Scholar
- 73.Rico MJ, Naylor M, Elmets CA, et al. Treatment with tacrolimus ointment is not associated with an increase in nonmelanoma skin cancer [abstract no. PP1-30]. 1st EADV International Spring Symposium; 2003 Feb 27–Mar 1; St Julian’s, MaltaGoogle Scholar
- 83.Soter N, Ling M, Fleischer A, et al. Topically applied tacrolimus ointment vs vehicle ointment in adult patients with atopic dermatitis [poster no. 109]. 58th Annual Meeting of the American Academy of Dermatology; 2000 Mar 10–15; San FranciscoGoogle Scholar
- 84.Hanifin J, Sober A, Lawrence I, et al. Comparison of topically applied tacrolimus ointment vs. vehicle ointment in adult patients with atopic dermatitis [abstract no. 16]. 58th Annual Meeting of the American Academy of Dermatology; 2000 Mar 10–15; San FranciscoGoogle Scholar
- 87.Fujisawa. Protopic® (tacrolimus) ointment 0.03% and 0.1% prescribing information. Deerfield (IL): Fujisawa, 2000Google Scholar
- 88.Undre N, Rubins A, Gutmane R, et al. Pharmacokinetics of tacrolimus ointment in adult patients with moderate to severe atopic dermatitis. Ann Dermatol Venereol 2002 Jul; 129 Suppl.: 425Google Scholar
- 89.Undre N, Green A, Harper J, et al. Tacrolimus pharmacokinetics in paediatric patients with moderate to severe atopic dermatitis after single and repeated application. Ann Dermatol Venereol 2002 Jul; 129 Suppl.: 424Google Scholar
- 96.Ohtsuki M. Tacrolimus ointment is effective and safe in Japanese atopic dermatitis children. Ann Dermatol Venereol 2002 Jul; 129 Suppl.: 418Google Scholar
- 97.Reitamo S, for the European Tacrolimus Ointment Study group. 0.1% Tacrolimus ointment is significantly more efficacious than a steroid regimen in adults with moderate to severe topic dermatitis [abstract no. 129055 plus poster]. 1st EADV International Spring Symposium; 2003 Feb 27–Mar 1; St Julian’s, MaltaGoogle Scholar
- 98.Palier AS, Lebwohl M, Fleishcher AB, et al. Tacrolimus ointment is more effective than pimecrolimus cream with a similar safety profile in the treatment of atopic dermatitis: results from three randomized, comparative studies. J Am Acad Dermatol. In PressGoogle Scholar
- 99.Reitamo S, Harper J, Bos JD, et al. 0.03% Tacrolimus ointment applied once or twice daily is more efficacious than 1% hydrocortisone acetate in children with moderate to severe atopic dermatitis: results of a randomized double-blind controlled trial. Br J Dermatol 2004 Mar; 150(3): 554–62PubMedCrossRefGoogle Scholar
- 100.FK506 Ointment Study Group. Phase III comparative study of FK506 ointment. Group comparison study with betametasone valerate in atopic dermatitis: trunk and extremities. Nishi Nihon J Dermatol 1997; 59: 870–9Google Scholar
- 101.FK506 Ointment Study Group. Phase III comparative study of FK506 ointment. Group comparison study with alclometasone dipropionate in atopic dermatitis: face and neck. Acta Dermatologica (Kyoto) 1997; 92(3): 277–88Google Scholar
- 103.Kawashima M, FK506 Ointment Study Group. Long-term study of FK506 (tacrolimus) ointment in patients with atopic dermatitis. Analysis at the time of completion of 2-year observation. Rinsho Iyaku 2001; 17: 705–26Google Scholar
- 105.Palier A, Hanifin J, Eichenfield L, et al. Tacrolimus ointment monotherapy is a safe and effective treatment for atopic dermatitis long-term (more than 3 years) [abstract no. P24]. 61st Annual Meeting of the Am Academy of Dermatology; 2003 Mar 21–26; San FranciscoGoogle Scholar
- 106.Rajka G, Langeland T. Grading of the severity of atopic dermatitis. Acta Derm Venereol Suppl (Stoch) 1989; 144: 13–4Google Scholar
- 107.Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol 1980; 92 Suppl.: 22–47Google Scholar
- 109.Ruzicka T. Efficacy and safety of tacrolimus ointment (Protopic) versus a mid-potent to potent corticosteroid in adults with moderate to severe atopic dermatitis. Ann Dermatol Venereol 2002 Jul; 129 Suppl.: 421Google Scholar
- 111.Koo JYM, Fleischer A, Pariser D, et al. Tacrolimus ointment 0.1% is safe and effective in the treatment for atopic dermatitis: final results of a large (over 7000 patients) open-label study [abstract no. P22]. 61st Annual Meeting of the American Academy of Dermatology; 2003 Mar 21–26; San FranciscoGoogle Scholar
- 112.Remitz A, The European Tacrolimus Ointment Study Group. Flare prevention and clinical changes with long-term use of tacrolimus ointment in adults with moderate to severe atopic dermatitis. 1 lth Annual Congress of the European Academy of Dermatology and Venereology; 2002 Oct 2–6; PragueGoogle Scholar
- 116.Nakagawa H, Etoh T, Ishibashi Y, et al. Effects of tacrolimus (FK506) ointment for facial atopic dermatitis [abstract no. P-0860]. Eur J Allergy Clin Immunol 1995; 50 Suppl. 26: 683Google Scholar
- 118.Krupnick Freeman A, Serie J, Van Veldhuisen P, et al. Tacrolimus ointment in the treatment of eyelid dermatitis. Therapeutics Clinician 2004 Apr; 73: 267–71Google Scholar
- 120.Nakata Y, Toyoda M,. Practical use of tacrolimus with steroidbased conventional therapy [abstract and oral presentation]. Japn J Dermatol 2004; 114(3): 130Google Scholar
- 121.Nakahara T, Koga T, Fukagawa S, et al. Intermittent topical corticosteroid/tacrolimus sequential therapy improves lichenification and chronic papules more efficiently than intermittent topical corticosteroid/emollient sequential therapy in patients with atopic dermatitis. J Dermatol 2004 Jul; 31(7): 524–8PubMedGoogle Scholar
- 123.Reitamo S. Quality of life improved in adults with moderate to severe atopic dermatitis with 0.1% tacrolimus ointment [abstract plus poster]. Congress of the European Academy of Dermatology and Venereology; 2004 29 Apr–1 May; BudapestGoogle Scholar
- 141.Alomar A, Puig L, Gallardo CM, et al. Topical tacrolimus 0.1 % ointment (Protopic®) reverses nickel contact dermatitis elicited by allergen challenge to a similar degree to mometasone furoate 0.1% with greater suppression of late erythema. Contact Dermatitis 2003 Oct; 49(4): 185–8PubMedCrossRefGoogle Scholar
- 159.Goldman D, Gruchalla D, Shull T. Tacrolimus ointment for the treatment of steroid-induced rosacea [abstract no. P311]. 61st Annual Meeting of the American Academy of Dermatology; 2003 Mar 21–26; San FranciscoGoogle Scholar
- 166.Koo J, Abramovits W, Fivenson D, et al. The experience of tacrolimus ointment in adult atopic dermatitis patients: results of two large open-label studies [abstract no. PI05 plus poster]. 60th Annual Meeting of the American Academy of Dermatology; 2002 Feb 22–27; New Orleans, 42Google Scholar
- 167.Rico MJ, Koo J, Fleischer A, et al. Long-term tacrolimus ointment monotherapy effectively controls atopic dermatitis: results in 8000 patients [abstract no. plus poster]. 12th Annual Congress of the European Academy of Dermatology and Venereology; 2003 Oct 15–18; BarcelonaGoogle Scholar
- 168.Milingou M, Antille C, Saurat JH, et al. Alcohol intolerance in adult patients with atopic dermatitis treated with 0.1% topical tacrolimus ointment [abstract no. SSS 10–8]. J Eur Acad Dermatol Venereol 2003; 17 Suppl. 3: 462Google Scholar
- 186.National Institute for Clinical Excellence. Tacrolimus and pimecrolimus for atopic eczema. Technology Appraisal Guidance 82. London: National Institute for Clinical Excellence, 2004 AugGoogle Scholar
- 187.Rustin M, The UK Tacrolimus Ointment Study group. Costeffectiveness of tacrolimus ointment in the treatment of adults and children with moderate to severe atopic dermatitis in the UK [poster]. Congress of the European Academy of Dermatology and Venereology; 2004 29 Apr–lMay; BudapestGoogle Scholar
- 188.Abramovits W, Boguniewicz M, Prendergast MM, et al. Comparisons of efficacy and cost-effectiveness of topical immunomodulators in the management of atopic dermatitis. J Drug Assess 2003; 6: 13–26Google Scholar
- 189.Fujisawa GmbH. Protopic® 0.03% ointment. Summary of product characteristics. Munich: Fujisawa GmbH, 2002 Feb 28Google Scholar
- 190.Fujisawa GmbH. Protopic® 0.1% ointment. Munich: Fujisawa GmbH, 2002 Feb 28Google Scholar
- 191.Hoare C, Li Wan Po. A., Williams H. Systematic review of treatments for atopic eczema. Health Technol Assess 2000; 4 (37)Google Scholar
- 193.Atopic Dermatitis Guidelines/Outcomes Task Force. Guidelines of care for atopic dermatitis [online]. Available from URL: http://www.aadassociation.org [Accessed 2005 Feb 2]
- 196.Novartis Pharma GmbH. Elidel® (pimecrolimus) cream 1%. Prescribing information. Novartis Pharma GmbH, 2003Google Scholar
- 198.Housman TS, Norton AB, Feldman SR, et al. Tacrolimus ointment: utilization patterns in children under age 2 years. Dermatol Online J [online]. Available from URL: http://dermatology.cdlib.org/ [Accessed 2004 Aug 27]
- 199.Wahn U, Bos JD, Goodfield M, et al. Efficacy and safety of pimecrolimus cream in the long-term management of atopic dermatitis in children. Pediatrics 2002 Jul; 110 (1)Google Scholar