Atopic Dermatitis Knowledge Centre
Topical calcineurin inhibitors
PROTOPIC™ - Efficacy and Safety
Mechanism of Action | Efficacy and safety | FAQ
The efficacy and safety of PROTOPIC are supported by a substantial amount of clinical data. It has been prescribed to over 20 million patients over the last 6 years,21 and has been the subject of possibly the most extensive clinical programme conducted in dermatology to date. Comprising both short- and long-term clinical trials, PROTOPIC has been rigorously investigated in vehicle- and active-controlled trials (with other topical calcineurin inhibitors and topical corticosteroids ). The key findings of the clinical trials are presented in Table 2.
In several of the studies described below, PROTOPIC has been investigated in situations that do not fall within the current licensing restrictions. Specifically, although PROTOPIC has been administered to patients with mild atopic dermatitis in some key studies,22,23 it must be noted that it is not currently licensed for the treatment of these patients.20 Similarly, a number of trials involving paediatric patients used PROTOPIC at a concentration of 0.1%,14,24–28 whereas only the 0.03% formulation is licensed for use in children.20
| Tacrolimus ointment clinical trials - key findings |
|---|
| Tacrolimus (PROTOPIC 0.03% and 0.1%) significantly improves moderate and severe atopic dermatitis in vehicle-controlled trials.27,29,30 |
| Tacrolimus ointment is an effective treatment for moderate and severe atopic dermatitis.14,27,29–31 |
| Tacrolimus ointment is more effective than pimecrolimus cream in the treatment of moderate and severe atopic dermatitis.32 |
| Several studies have shown tacrolimus ointment to have similar or superior efficacy than the commonly prescribed topical corticosteroids, hydrocortisone butyrate, hydrocortisone acetate and betamethasone valerate.13,14,33,34 |
| Long-term use of tacrolimus ointment is an effective therapy for recurrent flare control, with an acceptable safety profile.24–26,28,35,36 |
| Twice-weekly use of tacrolimus ointment for active disease management significantly reduces the frequency of flares and helps prolong flare-free periods.22,23 |
*Some of these studies included patients with mild atopic dermatitis22,23 or paediatric patients treated with the 0.1% formulation,14,24–28 and thus relate to out of licence usage.20
In double-blind, vehicle controlled studies examining the efficacy of short-term tacrolimus treatment, PROTOPIC (0.1% and 0.03%) significantly reduced the severity of atopic dermatitis compared to the control. A range of clinical outcome measures were used in these trials. The main efficacy criteria used were:
- EASI (eczema area and severity index)
- mEAS AUC (mEASI Area Under the Curve)
- Physician’s assessment of affected BSA
- Physician’s Global Evaluation of Clinical Response
In the pivotal short-term PROTOPIC trial in adults, Hanifin et al reported that the overall success rates (≥90% improvement in Physician’s Global Evaluation of Clinical Response) was significantly (p<0.001) higher, over the 12-week study period, for patients treated with PROTOPIC, than for vehicle-treated patients.24 In addition, patients in the PROTOPIC treatment groups had significantly greater improvements in EASI, % of BSA and the patient’s own assessment of symptoms than patients treated with the vehicle control. Improvements were seen as early as 1 week after the commencement of therapy. Similar results were obtained in the key paediatric PROTOPIC study.24 Paller et al reported that up to 78% of patients, aged 2–15 years, treated with PROTOPIC had significant improvements in the Physician’s Global Evaluation of Clinical Response compared to only 26.7% of the vehicle-treated group.27
A number of comparator trials have assessed the efficacy of PROTOPIC in relation to topical corticosteroids of varying potencies, or to topical pimecrolimus. The outcomes from these comparator clinical trials are summarised in the table below. These key studies highlight the clinical efficacy of PROTOPIC treatment compared to topical corticosteroid treatments and demonstrate that topical calcineurin inhibitors are an effective alternative to conventional steroid treatments.13,14,31,32,34
| Published | Comparator | Study populations | Summary of clinical findings |
|---|---|---|---|
| Reitamo et al, 200234 | Hydrocortisone butyrate 0.1% | Adult | PROTOPIC 0.1% (but not 0.03%) was comparable in efficacy to hydrocortisone butyrate 0.1% over the three-week study period |
| Reitamo et al, 200513 | Hydrocortisone butyrate 0.1%, on the trunk and extremities and hydrocortisone acetate 1% on the face and neck | Adult | PROTOPIC 0.1% was more effective than standard corticosteroid treatment at reducing the severity of atopic dermatitis over 6 months |
| Reitamo et al, 200214 | Hydrocortisone acetate 1% | Paediatric (2–15 years) | PROTOPIC 0.03% treatment was more effective than hydrocortisone acetate 1% at improving clinical outcomes during the three-week study. |
| Reitamo et al, 200431 | Hydrocortisone acetate 1% | Paediatric (2–15 years) | PROTOPIC 0.03% administered once or twice daily was more effective than corticosteroid steroid treatment during the three-week study period |
| Paller et al, 200532 and Abramovits et al, 200837 | Pimecrolimus 1% cream | Adult and paediatric | PROTOPIC 0.1% and 0.03% was more effective for most efficacy measures than pimecrolimus 1% for treating moderate to very severe atopic dermatitis |
*Some of these studies included paediatric patients treated with PROTOPIC 0.1%14,32 and thus relate to out of licence usage.20
PROTOPIC has an acceptable tolerability profile compared to topical corticosteroid treatments as it is not associated with skin atrophy, a commonly reported adverse event associated with topical corticosteroids.9 The most frequently reported localised adverse effects are pruritis at the site of application, sometimes associated with mild burning sensations or pain. These symptoms resolve quickly and are not associated with long-term problems or increases in skin infections.20 Commonly reported systemic adverse effects include parasthaesia (pins and needles) and alcohol-related flushing. These conditions are usually mild and are, in most cases, rapidly resolved with no long-term consequences.20
A theoretical concern of using PROTOPIC, and other topical calcineurin inhibitors, was that their use could be associated with an increased risk of skin malignancies and melanomas. Oral calcineurin inhibitors have the potential to increase the risk of malignancies due to their mechanism of action, and this concern was extended to topical formulations including PROTOPIC. It should be noted however that oral calcineurin inhibitors are prescribed for long periods of time, resulting in high systemic exposure sustained over years. Studies determining the levels of PROTOPIC that are absorbed systemically suggest that this theoretical risk is unlikely when topical formulations are used and no causal link between PROTOPIC use and increased risk of malignancy has been established.38–40 Additionally, epidemiological studies have reported that there are no direct causal links between PROTOPIC use and observed rates of skin cancer.15–18
The long-term safety of PROTOPIC use has been investigated in both adult and paediatric populations. The short-term efficacy data are supported by follow-up studies, which have demonstrated that the clinical efficacy of PROTOPIC is sustained for up to 4 years with no increase in the incidence of adverse events and no indication of increased risk for cutaneous infections.24,25,28,36 These data further highlights the suitability of PROTOPIC for the long-term control of moderate to severe atopic dermatitis.
Recently, results from two important clinical trials investigating PROTOPIC use to extend the duration of flare-free periods have been published.41 Both studies were 12-month, European, multicentre, randomised trials investigating whether using twice-weekly PROTOPIC for active disease management after flare resolution successfully reduced the incidence of flares and whether twice-weekly application was effective at prolonging flare-free periods. These studies assessed two different ways of using PROTOPIC; as a standard reactive therapy (control group) or as twice-weekly proactive therapy (treatment group) in patients with moderate and severe atopic dermatitis.
Adult atopic dermatitis patients assigned to the PROTOPIC 0.1% twice-weekly treatment group had significantly fewer numbers of disease exacerbations requiring intervention, significantly shortened flare episodes where therapeutic intervention was required and significantly delayed the onset of acute atopic dermatitis manifestations (flares and pruritis) compared to the control group (p<0.001 for all measurements. No significant differences in the frequency of adverse events were reported between the treatment and control groups.41
Paediatric patients assigned to PROTOPIC 0.03% twice-weekly treatment showed significant reductions in the frequency of disease exacerbations, had significantly fewer days requiring therapeutic intervention and significantly delayed the time to the first disease exacerbation requiring treatment (p<0.001 for all measurements). As was observed in adult patients, there were no significant differences in the frequency or severity of adverse events between the PROTOPIC twice-weekly or vehicle control treatment groups.41
The data from these key clinical studies demonstrate that a twice-weekly PROTOPIC regimen is an effective approach for preventing flares over a 12 month period in adults and children, and is a valuable asset for the long-term control of atopic dermatitis. The new twice-weekly regimen also appears to be cost effective or even cost saving (in severe patients) compared to the usual way of managing the disease with PROTOPIC used solely for the treatment of acute flare episodes.42 Studies have demonstrated that the benefits of twice-weekly PROTOPIC use were achieved without significant increases in the amount of ointment used as compared to standard reactive therapy.22,23
Protopic Prescribing Information 
References:
13. Reitamo S, Ortonne JP, Sand C, et al. A multicentre, randomized, double-blind, controlled study of long-term treatment with 0.1% tacrolimus ointment in adults with moderate to severe atopic dermatitis. Br J Dermatol 2005; 152: 1282–9.
14. Reitamo S, Van Leent EJ, Ho V, et al. Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone acetate ointment in children with atopic dermatitis. J Allergy Clin Immunol 2002; 109: 539–46.
20. PROTOPIC – Summary of Product Characteristics. Available from: http:/anti-infectives/Paris-Event/Live-Webcast.cfmwww.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000374/WC500046824.pdf [Accessed July 2010].
21. Data on file: 4268/Sept08, 2008. Astellas Pharma Europe Ltd.
22. Thaci D, Reitamo S, Gonzalez Ensenat MA, et al. Proactive disease management with 0.03% tacrolimus ointment for children with atopic dermatitis: results of a randomized, multicentre, comparative study. Br J Dermatol 2008; 159: 1348–56.
23. Wollenberg A, Reitamo S, Girolomoni G, et al. Proactive treatment of atopic dermatitis in adults with 0.1% tacrolimus ointment. Allergy 2008; 63: 742–50.
24. Hanifin JM, Paller AS, Eichenfield L, et al. Efficacy and safety of tacrolimus ointment treatment for up to 4 years in patients with atopic dermatitis. J Am Acad Dermatol 2005; 53: S186–94.
25. Kang S, Lucky AW, Pariser D, et al. Long-term safety and efficacy of tacrolimus ointment for the treatment of atopic dermatitis in children. J Am Acad Dermatol 2001; 44: S58–64.
26. Koo JY, Fleischer AB, Jr., Abramovits W, et al. Tacrolimus ointment is safe and effective in the treatment of atopic dermatitis: results in 8000 patients. J Am Acad Dermatol 2005; 53: S195–205.
27. Paller A, Eichenfield LF, Leung DY, et al. A 12-week study of tacrolimus ointment for the treatment of atopic dermatitis in pediatric patients. J Am Acad Dermatol 2001; 44: S47–57.
28. Remitz A, Harper J, Rustin M, et al. Long-term safety and efficacy of tacrolimus ointment for the treatment of atopic dermatitis in children. Acta Derm Venereol 2007; 87: 54–61.
29. Hanifin JM, Ling MR, Langley R, et al. Tacrolimus ointment for the treatment of atopic dermatitis in adult patients: part I, efficacy. J Am Acad Dermatol 2001; 44: S28–38.
30. Soter NA, Fleischer AB, Jr., Webster GF, et al. Tacrolimus ointment for the treatment of atopic dermatitis in adult patients: part II, safety. J Am Acad Dermatol 2001; 44: S39–46.
31. 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; 150: 554–62.
32. Paller AS, Lebwohl M, Fleischer AB, Jr., et al. Tacrolimus ointment is more effective than pimecrolimus cream with a similar safety profile in the treatment of atopic dermatitis: results from 3 randomized, comparative studies. J Am Acad Dermatol 2005; 52: 810–22.
33. FK506 Study Group. Phase III comparative study of FK506 ointment. Group comparison with betamethasone valerate in atopic dermatitis. Nishinihon J Dermatol 1997; 59: 870–879.
34. Reitamo S, Rustin M, Ruzicka T, et al. Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone butyrate ointment in adult patients with atopic dermatitis. J Allergy Clin Immunol 2002; 109: 547–55.
35. Reitamo S, Wollenberg A, Schopf E, et al. Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis. The European Tacrolimus Ointment Study Group. Arch Dermatol 2000; 136: 999–1006.
36. Remitz A, Reitamo S. Long-term safety of tacrolimus ointment in atopic dermatitis. Expert Opin Drug Saf 2009; 8: 501–6.
37. Abramovits W, Fleischer AB, Jr., Jaracz E, et al. Adult patients with moderate atopic dermatitis: tacrolimus ointment versus pimecrolimus cream. J Drugs Dermatol 2008; 7: 1153–8.
38. Harper J, Smith C, Rubins A, et al. A multicenter study of the pharmacokinetics of tacrolimus ointment after first and repeated application to children with atopic dermatitis. J Invest Dermatol 2005; 124: 695–9.
39. Krueger GG, Eichenfield L, Goodman JJ, et al. Pharmacokinetics of tacrolimus following topical application of tacrolimus ointment in adult and pediatric patients with moderate to severe atopic dermatitis. J Drugs Dermatol 2007; 6: 185–93.
40. Rubins A, Gutmane R, Valdmane N, et al. Pharmacokinetics of 0.1% tacrolimus ointment after first and repeated application to adults with moderate to severe atopic dermatitis. J Invest Dermatol 2005; 125: 68–71.
41. Reitamo S, Allsopp R. Treatment with twice-weekly tacrolimus ointment in patients with moderate-to-severe atopic dermatitis: Results from two randomized, multicentre, comparative studies J Dermatolog Treat 2009; In press.
42. Wollenberg A, Sidhu MK, Odeyemi I, et al. Economic evaluation of maintenance treatment with tacrolimus 0.1% ointment in adults with moderate to severe atopic dermatitis. Br J Dermatol 2008; 159: 1322–30.
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