Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: LEO Pharma A/S, Industriparken 55 2750, Ballerup, Denmark
Pharmacotherapeutic group: Other dermatologicals
ATC code: D11AH01
The mechanism of action of tacrolimus in atopic dermatitis is not fully understood. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known.
Via its binding to a specific cytoplasmic immunophilin (FKBP12), tacrolimus inhibits calcium-dependent signal transduction pathways in T cells, thereby preventing the transcription and synthesis of IL-2, IL-3, IL-4, IL-5 and other cytokines such as GM-CSF, TNF-α and IFN-γ. In vitro, in Langerhans cells isolated from normal human skin, tacrolimus reduced the stimulatory activity towards T cells. Tacrolimus has also been shown to inhibit the release of inflammatory mediators from skin mast cells, basophils and eosinophils.
In animals, tacrolimus ointment suppressed inflammatory reactions in experimental and spontaneous dermatitis models that resemble human atopic dermatitis. Tacrolimus ointment did not reduce skin thickness and did not cause skin atrophy in animals.
In patients with atopic dermatitis, improvement of skin lesions during treatment with tacrolimus ointment was associated with reduced Fc receptor expression on Langerhans cells and a reduction of their hyperstimulatory activity towards T cells. Tacrolimus ointment does not affect collagen synthesis in humans.
The efficacy and safety of Protopic was assessed in more than 18,500 patients treated with tacrolimus ointment in Phase I to Phase III clinical trials. Data from six major trials are presented here.
In a six-month multicentre double-blind randomised trial, 0.1% tacrolimus ointment was administered twice-a-day to adults with moderate to severe atopic dermatitis and compared to a topical corticosteroid based regimen (0.1% hydrocortisone butyrate on trunk and extremities, 1% hydrocortisone acetate on face and neck). The primary endpoint was the response rate at month 3 defined as the proportion of patients with at least 60% improvement in the mEASI (modified Eczema Area and Severity Index) between baseline and month 3. The response rate in the 0.1% tacrolimus group (71.6%) was significantly higher than that in the topical corticosteroid based treatment group (50.8%; p<0.001; Table 1). The response rates at month 6 were comparable to the 3-month results.
Table 1. Efficacy at month 3:
| Topical corticosteroid regimen§ (N=485) | Tacrolimus 0.1% (N=487) | |
|---|---|---|
| Response rate of >60% improvement in mEASI (Primary Endpoint)§§ | 50.8% | 71.6% |
| Improvement >90% in Physician’s Global Evaluation | 28.5% | 47.7% |
§ Topical corticosteroid regimen = 0.1% hydrocortisone butyrate on trunk and extremities, 1% hydrocortisone acetate on face and neck
§§ higher values = greater improvement
The incidence and nature of most adverse events were similar in the two treatment groups. Skin burning, herpes simplex, alcohol intolerance (facial flushing or skin sensitivity after alcohol intake), skin tingling, hyperaesthesia, acne and fungal dermatitis occurred more often in the tacrolimus treatment group. There were no clinically relevant changes in the laboratory values or vital signs in either treatment group throughout the study.
In the second trial, children aged from 2 to 15 years with moderate to severe atopic dermatitis received twice daily treatment for three weeks of 0.03% tacrolimus ointment, 0.1% tacrolimus ointment or 1% hydrocortisone acetate ointment. The primary endpoint was the area-under-the-curve (AUC) of the mEASI as a percentage of baseline averaged over the treatment period. The results of this multicentre, double-blind, randomised trial showed that tacrolimus ointment, 0.03% and 0.1%, is significantly more effective (p<0.001 for both) than 1% hydrocortisone acetate ointment (Table 2).
Table 2. Efficacy at week 3:
| Hydrocortisone acetate 1% (N=185) | Tacrolimus 0.03% (N=189) | Tacrolimus 0.1% (N=186) | |
|---|---|---|---|
| Median mEASI as Percentage of Baseline mean AUC (Primary Endpoint)§ | 64.0% | 44.8% | 39.8% |
| Improvement >90% in Physician’s Global Evaluation | 15.7% | 38.5% | 48.4% |
§ lower values = greater improvement
The incidence of local skin burning was higher in the tacrolimus treatment groups than in the hydrocortisone group. Pruritus decreased over time in the tacrolimus groups but not in the hydrocortisone group. There were no clinically relevant changes in the laboratory values or vital signs in either treatment group throughout the clinical trial.
The purpose of the third multicentre, double-blind, randomised study was the assessment of efficacy and safety of 0.03% tacrolimus ointment applied once or twice a day relative to twice daily administration of 1% hydrocortisone acetate ointment in children with moderate to severe atopic dermatitis. Treatment duration was for up to three weeks.
Table 3. Efficacy at week 3:
| Hydrocortisone acetate 1% Twice daily (N=207) | Tacrolimus 0.03% Once daily (N=207) | Tacrolimus 0.03% Twice daily (N=210) | |
|---|---|---|---|
| Median mEASI Percentage Decrease (Primary Endpoint)§ | 47.2% | 70.0% | 78.7% |
| Improvement >90% in Physician’s Global Evaluation | 13.6% | 27.8% | 36.7% |
§ higher values = greater improvement
The primary endpoint was defined as the percentage decrease in mEASI from the baseline to end of treatment. A statistically significant better improvement was shown for once daily and twice daily 0.03% tacrolimus ointment compared to twice daily hydrocortisone acetate ointment (p<0.001 for both). Twice daily treatment with 0.03% tacrolimus ointment was more effective than once daily administration (Table 3). The incidence of local skin burning was higher in the tacrolimus treatment groups than in the hydrocortisone group. There were no clinically relevant changes in the laboratory values or vital signs in either treatment group throughout the study.
In the fourth trial, approximately 800 patients (aged >2 years) received 0.1% tacrolimus ointment intermittently or continuously in an open-label, long-term safety study for up to four years, with 300 patients receiving treatment for at least three years and 79 patients receiving treatment for a minimum of 42 months. Based on changes from baseline in EASI score and body surface area affected, patients regardless of age had improvement in their atopic dermatitis at all subsequent time points. In addition, there was no evidence of loss of efficacy throughout the duration of the clinical trial. The overall incidence of adverse events tended to decrease as the study progressed for all patients independent of age. The three most common adverse events reported were flu-like symptoms (cold, common cold, influenza, upper respiratory infection, etc.), pruritus and skin burning. No adverse events previously unreported in shorter duration and/or previous studies were observed in this long-term study.
The efficacy and safety of tacrolimus ointment in maintenance treatment of mild to severe atopic dermatitis was assessed in 524 patients in two Phase III multicentre clinical trials of similar design, one in adult patients (>16 years) and one in paediatric patients (2-15 years). In both studies, patients with active disease entered an open-label period (OLP) during which they treated affected lesions with tacrolimus ointment twice daily until improvement had reached a predefined score (Investigator’s Global Assessment [IGA] <2, i.e. clear, almost clear or mild disease) for a maximum of 6 weeks. Thereafter, patients entered a double-blind disease control period (DCP) for up to 12 months. Patients were randomised to receive either tacrolimus ointment (0.1% adults; 0.03% children) or vehicle, once a day twice weekly on Mondays and Thursdays. If a disease exacerbation occurred, patients were treated with open-label tacrolimus ointment twice daily for a maximum of 6 weeks until the IGA score returned to <2.
The primary endpoint in both studies was the number of disease exacerbations requiring a “substantial therapeutic intervention” during the DCP, defined as an exacerbation with an IGA of 3-5 (i.e. moderate, severe and very severe disease) on the first day of the flare, and requiring more than 7 days treatment. Both studies showed significant benefit with twice weekly treatment with tacrolimus ointment with regard to the primary and key secondary endpoints over a period of 12 months in a pooled population of patients with mild to severe atopic dermatitis. In a subanalysis of a pooled population of patients with moderate to severe atopic dermatitis these differences remained statistically significant (Table 4). No adverse events not reported previously were observed in these studies.
Table 4. Efficacy (moderate to severe subpopulation):
| Adults, >16 years | Children, 2-15 years | |||
|---|---|---|---|---|
| Tacrolimus 0.1% | Vehicle | Tacrolimus 0.03% | Vehicle | |
| Twice weekly (N=80) | Twice weekly (N=73) | Twice weekly (N=78) | Twice weekly (N=75) | |
| Median number of DEs requiring substantial intervention adjusted for time at risk (% of patients without DE requiring substantial intervention) | 1.0 (48.8%) | 5.3 (17.8%) | 1.0 (46.2%) | 2.9 (21.3%) |
| Median time to first DE requiring substantial intervention | 142 days | 15 days | 217 days | 36 days |
| Median number of DEs adjusted for time at risk (% of patients without any DE periods) | 1.0 (42.5%) | 6.8 (12.3%) | 1.5 (41.0%) | 3.5 (14.7%) |
| Median time to first DE | 123 days | 14 days | 146 days | 17 days |
| Mean (SD) percentage of days of DE exacerbation treatment | 16.1 (23.6) | 39.0 (27.8) | 16.9 (22.1) | 29.9 (26.8) |
DE: disease exacerbation
P<0.001 in favour of tacrolimus ointment 0.1% (adults) and 0.03% (children) for the primary and key secondary endpoints
A seven-month, double blind, randomised parallel group study of paediatric patients (2-11 years) with moderate to severe atopic dermatitis was performed. In one arm patients received Protopic 0.03% ointment (n=121) twice a day for 3 weeks and thereafter once a day until clearance. In the comparator arm patients received 1% hydrocortisone acetate ointment (HA) for head and neck and 0.1% hydrocortisone butyrate ointment for trunk and limbs (n=111) twice a day for 2 weeks and subsequently HA twice a day to all affected areas. During this period all patients and control subjects (n=44) received a primary immunisation and a rechallenge with a protein-conjugate vaccine against Neisseria menigitidis serogroup C.
The primary endpoint of this study was the response rate to vaccination, defined as the percentage of patients with a serum bactericidal antibody (SBA) titre >8 at the week 5 visit. Analysis of the response rate at week 5 showed equivalence between the treatment groups (hydrocortisone 98.3%, tacrolimus ointment 95.4%; 7-11 years: 100% in both arms). The results in the control group were similar. The primary response to vaccination was not affected.
Clinical data have shown that tacrolimus concentrations in systemic circulation after topical administration are low and, when measurable, transient.
Data from healthy human subjects indicate that there is little or no systemic exposure to tacrolimus following single or repeated topical application of tacrolimus ointment.
Most atopic dermatitis patients (adults and children) treated with single or repeated application of tacrolimus ointment (0.03-0.1%), and infants from age of 5 months treated with tacrolimus ointment (0.03%) had blood concentrations <1.0 ng/ml. When observed, blood concentrations exceeding 1.0 ng/ml were transient. Systemic exposure increases with increasing treatment areas. However, both the extent and the rate of topical absorption of tacrolimus decrease as the skin heals. In both adults and children with an average of 50% body surface area treated, systemic exposure (i.e. AUC) of tacrolimus from Protopic is approximately 30-fold less than that seen with oral immunosuppressive doses in kidney and liver transplant patients. The lowest tacrolimus blood concentration at which systemic effects can be observed is not known.
There was no evidence of systemic accumulation of tacrolimus in patients (adults and children) treated for prolonged periods (up to one year) with tacrolimus ointment.
As systemic exposure is low with tacrolimus ointment, the high binding of tacrolimus (>98.8%) to plasma proteins is considered not to be clinically relevant.
Following topical application of tacrolimus ointment, tacrolimus is selectively delivered to the skin with minimal diffusion into the systemic circulation.
Metabolism of tacrolimus by human skin was not detectable. Systemically available tacrolimus is extensively metabolised in the liver via CYP3A4.
When administered intravenously, tacrolimus has been shown to have a low clearance rate. The average total body clearance is approximately 2.25 l/h. The hepatic clearance of systemically available tacrolimus could be reduced in subjects with severe hepatic impairment, or in subjects who are co- treated with drugs that are potent inhibitors of CYP3A4.
Following repeated topical application of the ointment the average half-life of tacrolimus was estimated to be 75 hours for adults and 65 hours for children.
The pharmacokinetics of tacrolimus after topical application are similar to those reported in adults, with minimal systemic exposure and no evidence of accumulation (see above).
Repeated topical administration of tacrolimus ointment or the ointment vehicle to rats, rabbits and micropigs was associated with slight dermal changes such as erythema, oedema and papules. Long-term topical treatment of rats with tacrolimus led to systemic toxicity including alterations of kidneys, pancreas, eyes and nervous system. The changes were caused by high systemic exposure of rodents resulting from high transdermal absorption of tacrolimus. Slightly lower body weight gain in females was the only systemic change observed in micropigs at high ointment concentrations (3%). Rabbits were shown to be especially sensitive to intravenous administration of tacrolimus, reversible cardiotoxic effects being observed.
In vitro and in vivo tests did not indicate a genotoxic potential of tacrolimus.
Systemic carcinogenicity studies in mice (18 months) and rats (24 months) revealed no carcinogenic potential of tacrolimus.
In a 24-month dermal carcinogenicity study performed in mice with 0.1% ointment, no skin tumours were observed. In the same study an increased incidence of lymphoma was detected in association with high systemic exposure.
In a photocarcinogenicity study, albino hairless mice were chronically treated with tacrolimus ointment and UV radiation. Animals treated with tacrolimus ointment showed a statistically significant reduction in time to skin tumour (squamous cell carcinoma) development and an increase in the number of tumours. It is unclear whether the effect of tacrolimus is due to systemic immunosuppression or a local effect. The risk for humans cannot be completely ruled out as the potential for local immunosuppression with the long-term use of tacrolimus ointment is unknown.
Reproduction toxicity
h3.
Embryo/foetal toxicity was observed in rats and rabbits, but only at doses that caused significant toxicity in maternal animals. Reduced sperm function was noted in male rats at high subcutaneous doses of tacrolimus.
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