Tacrolimus Ointment (Protopic—Fujisawa)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
The fda recently approved a topical preparation of the immunosuppressant tacrolimus for the treatment of atopic dermatitis. Tacrolimus was originally developed as an immunosuppressant for preventing allograft rejection in organ transplantation and is currently in wide usage in this role, along with cyclosporine. But unlike cyclosporine, tacrolimus is active topically and may represent the first in an important new class of drugs for the treatment of inflammatory skin disorders. Tacrolimus ointment is marketed as Protopic by Fujisawa Healthcare, Inc.
Tacrolimus is indicated for short-term and intermittent long-term therapy in the treatment of patients with moderate to severe atopic dermatitis in whom the use of alternative, conventional therapies are deemed inadvisable because of potential risks, or in the treatment of patients who are not adequately responsive to or are intolerant of alternative conventional therapies.1
Tacrolimus ointment is available in two strengths for adults, 0.03% and 0.1%, and one strength for children 2-15 years of age, 0.03%. A thin layer is applied to the clear, dry, affected skin twice daily and should be rubbed in gently and completely. Treatment should be continued for one week after the clearing of signs and symptoms of atopic dermatitis.1 The 0.1% strength may be more appropriate in patients with severe disease and/or extensive body surface involvement or in African Americans.1,4,6
Tacrolimus is supplied as 0.03% and 0.1% ointment as 30 g or 60 g.
Tacrolimus offers an alternative to corticosteroids for the treatment of atopic dermatitis. In contrast to corticosteroids, atrophogenic effects have not been reported with tacrolimus, thus the drug can be used safely on the face and neck.
Side effects include burning (47%), pruritus (24%), and erythema (12%). The frequency of side effects tends to decline over time.1,3 Topical tacrolimus may be associated with increased risk of chicken pox or shingles (eczema herpeticum), although the latter is a recognized complication of atopic dermatitis. The drug should not be used in patients who are pregnant, breast feeding, or have on-site infections. Lymphadenopathy has been reported in a small percent (0.8%) of patients. Exposure to ultraviolet radiation of natural or artificial sources should be minimized as tacrolimus has been shown to shorten the time to skin tumor development in animals.1 Tacrolimus can be absorbed after topical application of the 0.1% strength, although levels are at least 30-fold less than levels achieved with oral administration.1
The topical mechanism of action of tacrolimus is not known but may involve interference of the epidermal cytokine networks, suppression of T-cell activation, and inhibition of the release of preformed mediators from skin mast cells and basophils.1,2 Tacrolimus has been studied in adults and children in vehicle-controlled trials in subjects with moderate to severe atopic dermatitis and percent of body surface involvement of 45-48%.
Twelve-week randomized, double blind, vehicle-controlled, efficacy trials were conducted in pediatric (n = 351) and adult patients (n = 632).4-6 Primary efficacy end point was the Physician’s Global Evaluation of Clinical Response at the end of treatment. This was defined as a rating of cleared or excellent improvement (at least 90%) compared to baseline. Tacrolimus treated subjects had a success rate of 27.5-35.9% for the 0.03% ointment, 36.8-40.7% for the 0.1% ointment, and 6.6- 6.9% for vehicle. Results may be achieved during the first week and maximized at three months.3 Success will begin to regress about two weeks after discontinuation of treatment.1
One-year open-label studies in adults (n = 316) and children (n = 255) reported that tacrolimus was generally safe and well tolerated.3,7 Quantifiable blood tacrolimus levels were considered transient and isolated, although Fujisawa is required by the FDA to conduct pediatric pharmacokinetic studies. Skin atrophy was not reported and some authors reported reversal of skin atrophy, although this may also be attributed to discontinuation of topical corticosteroids. These studies suggest that efficacy was maintained for at least the 12-month period. However, a long-term efficacy study in patients with atopic dermatitis and recalcitrant facial erythema resistant to topical corticosteroids did show tachyphylaxis.8
Atopic dermatitis is a chronic relapsing inflammatory skin disease that affects up to 15% of children. In about 50% of these children, the disease persists into adulthood. Moderate to severe disease can have a significant effect on the patient’s quality of life. Topical cortico-steroids are the mainstay of therapy; however, these drugs are plagued with the problem of skin atrophy, striae, and even systemic effects. High potency corticosteroids are indicated for limited areas, for short periods, and cannot be used on the face and other sensitive skin at all. Tacrolimus appears modestly effective as about one-fourth to two-fifths of patients achieve excellent improvement (³ 90%) and two-thirds to three-fourths of patients achieve moderate success (³ 50% improvement).
The relative efficacy of tacrolimus vs. corticosteroids is not clear as results from comparative trials are not available. Tacrolimus provides an alternative to corticosteroids for moderate to severe atopic dermatitis and represents the first topical immunosuppressants for the treatment of inflammatory skin diseases. Tacrolimus is expensive, the cost is about $50 for 30 g and about $100 for 60 g.
1. Protopic Product Information. Fujisawa Healthcare, Inc. December 2000.
2. Ruzicka T, et al. Arch Dermatol 1999;135:574-580.
3. Reitamo S, et al. Arch Dermatol 2000;136:999-1006.
4. Hanifin JM, et al. J Am Acad Dermatol 2001;44 (1 pt 2):S28-38.
5. Paller A, et al. J Am Acad Dermatol 2001;44 (1 pt 2):S47-57.
6. Soter N, et al. J Am Acad Dermatol 2001;44 (1 pt 2):S39-46.
7. Kang S, et al. J Am Acad Dermatol 2001;44 (1 pt 2):S58-64.
8. Sugiura H, et al. Arch Dermatol 2000;136:1062-1063.