Topical Calcineurin Inhibitors

Atopic Dermatitis—Indications in Various Countries

Q48.2 In the United States, the only indication for topical tacrolimus is as follows: ‘Protopic (trade name Protopic is no longer available in the US) ointment, both 0.03% and 0.1% for adults, and only 0.03% for children aged 2-15 years, is indicated as second-line therapy for the short-term and noncontinuous chronic treatment of moderate to severe AD in nonimmunocompromised adults and children who have failed to respond adequately to other topical prescription treatments for AD, or when those treatments are not advisable’. It is classified as pregnancy category C. See Chapter 65 Drugs in Pregnancy and Lactation for FDA narrative classification.

Q48.2 In Canada, topical tacrolimus, both 0.03% and 0.1% for adults and only 0.03% for children aged 2 to 15 years, is indicated as a second-line therapy for short- and long-term intermittent treatment of moderate to severe AD in nonimmunocompromised patients, in whom the use of conventional therapies are deemed inadvisable because of potential risks, or who are not adequately responsive to or intolerant of conventional therapies. Additionally, topical tacrolimus is indicated for maintenance therapy: ‘Protopic is also indicated for maintenance therapy to prevent flares and prolong flare-free intervals in patients with moderate to severe AD experiencing a high frequency of flares (occurring five or more times per year) who have had an initial response (lesions cleared, almost cleared or mildly affected) with up to 6 weeks of treatment with twice-daily Protopic.’

Q48.2 In Europe, topical tacrolimus is indicated as follows: ‘Treatment of moderate to severe AD for the prevention of flares and the prolongation of flare-free intervals in patients experiencing a high frequency of disease exacerbations (i.e., occurring four or more times per year) who have had an initial response to a maximum of 6 weeks treatment of twice daily tacrolimus ointment (lesions cleared, almost cleared or mildly affected).’

Atopic Dermatitis—Meta-analyses

Q48.3 Numerous double-blind and open studies have shown that topical tacrolimus is safe and effective in the treatment of AD in children and adults. These results are well documented in four meta-analyses of topical tacrolimus and pimecrolimus; hence, both agents will be discussed together to some extent in this section.

• 1.

  In one meta-analysis of eight randomized controlled trials of tacrolimus involving 1781 pediatric patients, investigators showed that tacrolimus ointment therapy resulted in the remission of AD, and the effects of tacrolimus ointment 0.03% and 0.1% were better than those of 1% hydrocortisone acetate and 1% pimecrolimus. The difference between the 0.03% and the 0.1% tacrolimus ointment groups was not statistically significant.

• 2.

  A second meta-analysis of 20 clinical trials involving 6288 infants and children with AD showed that patients using tacrolimus had a better response than those in control groups, including vehicle, 1% hydrocortisone acetate ointment, and 1% pimecrolimus cream. The results of the analysis showed that, although pimecrolimus and tacrolimus were effective in the treatment of AD in pediatric patients, tacrolimus was superior to pimecrolmus. The effect difference between 0.03% tacrolimus and 0.1% tacrolimus ointments was not statistically significant.

• 3.

  A third meta-analysis concluded that topical calcineurin inhibitors (TCI) were more effective than placebo in AD. Pimecrolimus was less effective than TCS, but had value in long-term maintenance and as a CS-sparing agent when used at the first appearance of erythema and/or itching. Topical tacrolimus was as effective as a moderately potent TCS. Chronic lesions of the face and flexures are most justified for treatment with TCI.

• 4.

  A fourth meta-analysis evaluated 17 trials comparing tacrolimus 0.03% and 0.1% ointment with TCS in pediatric ( n = 2328) and adult ( n = 2849) patients, and concluded that tacrolimus 0.1% ointment is similar in efficacy to TCS of class I/II and class III potency.

Atopic Dermatitis—Additional Reviews and Studies

Q48.3 In 2010, Fleischer and colleagues reviewed 52 articles concerning the use of tacrolimus in AD and other conditions and concluded that tacrolimus ointment is effective in reducing pruritus in both adult and pediatric patients with a wide range of disease severity, and is significantly better than treatment with vehicle alone.

In one double-blind study of adults with moderate to severe AD, tacrolimus was superior for all efficacy scores at month 6, and in the head and neck area at month 12.

In adults with AD, tacrolimus has a rapid onset of action and sustains therapeutic effect. Studies in Japanese adult patients have shown that tacrolimus has similar efficacy to mid-potency TCS betamethasone valerate when applied to the trunk and extremities, and is superior to the mild-potency CS alclometasone dipropionate when applied to the face and neck. In addition, tacrolimus and pimecrolimus are superior to vehicles for quality of life with active AD.

Another review concluded that tacrolimus and pimecrolimus have been extensively evaluated in the management of pediatric AD. Trials comparing them with placebo, TCS, and each other have shown them to be effective and safe for continuous short-term use, and for noncontinuous use for up to 4 years. The long-term safety of TCI is not known, as they have been in clinical use just since 2000.

In a 2018 review article that included the combined results of 19 studies of the use of calcineurin inhibitors in patients with AD, tacrolimus 0.03% and 0.01% were more effective than mild TCS and similar efficacy to that of medium-potency TCS. The review included a recent analysis of calcineurin inhibitor and concluded the overall efficacy of tacrolimus 0.1% was at least as good as that of medium-potency TCS. The review article from 2018 reported a favorable tolerability profile for tacrolimus and found that AE were quite rare. The most common AE in adults and children were found to be application site reactions, including burning and pruritus, although these were transient and decreased in severity after the first few days of treatment. Lastly, the Boxed Warning regarding the risk of skin cancer or lymphoma is currently not supported by strong evidence, indicating that these warnings themselves actually state that a causal relationship between malignancy and TCI has not been entirely established. However, until this relationship is entirely disproven clinicians should be cautious.

Atopic Dermatitis—Maintenance Therapy

Q48.3 Several large-scale double-blind studies have shown that once AD has stabilized, proactive treatment with tacrolimus two or three times weekly as maintenance can significantly prevent flares in pediatric and adult patients.

In one study, 267 children with mild to severe AD underwent twice-daily treatment with tacrolimus 0.03% ointment until an Investigator Global Assessment score of ≤2 was achieved. Patients were then randomized to 0.03% tacrolimus ointment or vehicle, twice weekly for 12 months. Disease flares were treated with open-label tacrolimus 0.03% ointment twice daily. Tacrolimus treatment reduced the number of flares compared with standard therapy ( P < .001), and prolonged time to first flare (146 vs. 17 days, P < .001)

In another study, 206 patients aged 2 to 15 years with moderate to severe AD were randomly assigned to 4 days of twice-daily double-blind therapy with alclometasone ointment 0.05% or tacrolimus ointment 0.03%, followed by up to 16 weeks of twice-daily open-label tacrolimus ointment 0.03%. Tacrolimus-treated patients had significantly more disease-free days, significantly longer time to first relapse, and significantly fewer disease relapse days.

Brenemen and coworkers evaluated 197 adult and pediatric patients with moderate to severe AD who were clear of disease after up to 16 weeks treatment with tacrolimus ointment, and then randomized to double-blind treatment three times weekly with either tacrolimus ointment (0.03% or 0.1%) or vehicle, for 40 weeks. Medication was applied to previously involved skin. The mean number of flare-free treatment days was 177 for tacrolimus and 134 for vehicle ( P = .003), and median time to first relapse was 169 days for tacrolimus and 43 for vehicle ( P = .037).

In one study, 257 adult patients with AD were treated with tacrolimus 0.1% ointment twice daily for up to 6 weeks; when an Investigator Global Assessment score of 2 or less was achieved, patients were randomized to either proactive tacrolimus or vehicle ointment twice weekly for 12 months. Tacrolimus treatment significantly reduced the number of disease exacerbations (median difference: 15.2%, P < .001).

One meta-analysis concluded that vehicle-controlled trials indicate efficacy of proactive treatment with tacrolimus, fluticasone propionate, and methylprednisolone aceponate to prevent flares, and that indirect evidence from vehicle-controlled trials suggest that twice-weekly application of the potent TCS fluticasone propionate may be more efficacious in preventing flares than tacrolimus ointment.

Atopic Dermatitis—Tacrolimus Versus Pimecrolimus

Q48.3 Two randomized studies showed that tacrolimus is more effective than pimecrolimus in adult AD patients. Results from three randomized control trials that included 1655 patients (adults and infants) treated with tacrolimus ointment and pimecrolimus cream for AD for 6 weeks showed that tacrolimus ointment was more effective than pimecrolimus cream at the end of the combined analysis. The difference in incidence of AE between the two treatments was not statistically significant, including application site reactions. The conclusion was that the tacrolimus ointment was more effective and had a faster onset of action than pimecrolimus cream in adults and children. One review, however, concluded that pimecrolimus cream showed similar efficacy to topical tacrolimus 0.03% ointment in a short-term, continuous-use trial, and the two agents had a generally similar tolerability profile.

Lichen Planus

Investigators have extensively studied tacrolimus in LP, especially oral erosive LP. There is strong evidence from both double-blind and open studies of efficacy in oral LP, with results at least equal to those of topical clobetasol propionate 0.05% ointment. However, use of tacrolimus ointment in oral LP can result in systemic absorption, with detectable blood levels in 27 of 50 patients, with mean maximum blood level of 2.7 ng/mL (range up to 11 ng/mL). (Note: In this chapter, articles that report ‘μg/L’ will for consistency be listed as the equivalent unit ‘ng/mL’.) This compares with target trough levels for solid organ transplant patients of 5 to 10 ng/mL. Clinically significant AE associated with systemic absorption have not been reported.

There are two reported cases of oral squamous cell carcinoma after treatment with tacrolimus ointment, but it is uncertain if there a causal relationship. Open studies and case reports have demonstrated efficacy in vulvovaginal LP and cutaneous LP, respectively. Favorable results were reported in an open study of five patients with nail LP.

Vitiligo

Q48.4 A most recent Cochrane Database Systematic Review of 96 studies, totaling 4512 participants aimed to assess the effects of all therapeutic interventions used in the management of vitiligo. Although the study had found some evidence from individual studies to support current existing therapies for vitiligo, the applicability of these outcomes is limited in the different designs and outcome measures.

Double-blind, randomized controlled studies of vitiligo have shown tacrolimus 0.1% ointment to be superior to placebo, especially for facial lesions, and almost as efficacious as clobetasol propionate 0.05% ointment (which is contraindicated for use on the face). Tacrolimus 0.1% ointment plus excimer laser was superior to excimer laser alone in one double-blind study and one randomized prospective study, especially for traditionally ultraviolet (UV)-resistant areas such as bony prominences and extremities. Additional double-blind studies showed that tacrolimus 0.1% ointment plus narrowband UVB (NB-UVB) was equal to placebo plus NB-UVB, and that twice-daily application was optimal for facial lesions.

In one open prospective study comparing tacrolimus and UVB therapy, UVB monotherapy, and vitamin E, results demonstrated that the combination treatment of 0.1% tacrolimus ointment plus UVB light and UVB light monotherapy was efficacious and safe compared with vitamin E.

Psoriasis

Q48.5 Tacrolimus 0.1% ointment has a defined role in psoriasis, especially in facial, inverse, and genital psoriasis. Three double-blind studies have shown that tacrolimus was superior to placebo or vehicle. One of these studies evaluated patients with facial or intertriginous psoriasis, with improvement as early as day 8 ( P = .004). Another double-blind study of facial/genital–femoral psoriasis showed that tacrolimus 0.03% ointment was superior to calcitriol, a natural bioactive 1,25-dihydroxyvitamin D ₃ , available as an ointment in Europe and Canada.

A randomized double-blind study of 16 patients which chronic plaque psoriasis demonstrated that sites treated with tacrolimus ointment showed a significant reduction in erythema and infiltration ( P < .001), a significant reduction in superficial blood flow ( P < .01) and a decrease in epidermal thickness ( P < .001). Efficacy and safety of tacrolimus on the face, intertriginous areas, or both were evaluated in an open-label, clinical trial of 121 patients; 98 of those patients experienced complete clearance by day 57 (end of treatment), showing that topical tacrolimus is effective and safe in these subtypes of psoriasis, proving to be a good alternative to TCS. This is especially so for those with inverse psoriasis who, because of the sensitive nature of their skin, are more prone to AE from TCS, including cutaneous atrophy, telangiectasia, and striae.

Lupus Erythematosus

One double-blind study showed that tacrolimus was equal to clobetasol propionate 0.05% ointment in facial lupus erythematosus (LE), especially malar rash, and lesions of discoid LE and subacute cutaneous LE. Favorable results were also reported in open studies and case reports. One open study showed that topical tacrolimus, either as monotherapy or combined with oral hydroxychloroquine, is effective in cutaneous LE.

Seborrheic Dermatitis

Open studies have shown favorable results with tacrolimus 0.1%.

Cutaneous Crohn Disease

One double-blind study showed tacrolimus 0.1% to be superior to placebo in patients with perianal or anal ulcerative Crohn disease, but it is unlikely to be efficacious if there are fistulae. One open study showed that tacrolimus 0.5% was effective in oral and perianal Crohn disease, but in one patient with orofacial Crohn disease treated with 0.05% in Orabase, systemic absorption was documented, with blood levels of 9 ng/mL.

Lichen Sclerosus

Favorable results with tacrolimus were reported in open studies and case reports, especially for anogenital lesions.

Pyoderma Gangrenosum

Small open studies have demonstrated that tacrolimus monotherapy was effective in five patients. A case report also showed favorable results.

Granuloma Faciale

Case reports have shown favorable results.

Contact Dermatitis

For nickel-induced allergic contact dermatitis, double-blind studies showed that tacrolimus is superior to placebo. In one double-blind study of contact dermatitis, there was no difference between tacrolimus 0.1% cream, pimecrolimus 1% cream, clobetasol propionate 0.05% ointment, triamcinolone acetonide 0.1% ointment, and placebo, but there was a clear trend in favor of active drug treatment.

Additional studies and case reports have shown favorable results for tacrolimus in allergic contact dermatitis.

Rosacea

Open studies have shown favorable results.

Tacrolimus: Lack of Efficacy

In one open study and three case reports, investigators showed that tacrolimus 0.1% is not effective in alopecia areata. One double-blind study of 22 patients with hemodialysis-related pruritus showed that tacrolimus was not superior to vehicle. Additional studies showed lack of efficacy in frontal fibrosing alopecia, factitial panniculitis, and UV-induced erythema.