4.2 Posology and method of administration – the following paragraph has been changed:
Protopic can be used for short-term and intermittent long-term treatment. Treatment should not be continuous.
The following paragraph has been deleted:
Each affected region of the skin should be treated with Protopic until clearance occurs and then treatment should be discontinued. Generally, improvement is seen within one week of starting treatment. If no signs of improvement are seen after two weeks of treatment, further treatment options should be considered. Protopic can be used for short term and intermittent long term treatment. At the first signs of recurrence (flares) of the disease symptoms, treatment should be re-initiated.
The following paragraph has been added:
Treatment
Protopic treatment should begin at the first appearance of signs and symptoms. Each affected region of the skin should be treated with Protopic until lesions are cleared, almost cleared or mildly affected. Thereafter, patients are considered suitable for maintenance treatment (see below). At the first signs of recurrence (flares) of the disease symptoms, treatment should be re-initiated.
The following paragraphs have also been added:
Generally, improvement is seen within one week of starting treatment. If no signs of improvement are seen after two weeks of treatment, further treatment options should be considered.
Maintenance
Patients who are responding to up to 6 weeks treatment using tacrolimus ointment twice daily (lesions cleared, almost cleared or mildly affected) are suitable for maintenance treatment.
Protopic ointment should be applied once a day twice weekly (e.g. Monday and Thursday) to areas commonly affected by atopic dermatitis to prevent progression to flares. Between applications there should be 2–3 days without Protopic treatment.
Adult patients (16 years of age and above) should use Protopic 0.1% ointment, children (2 years of age and above) should use the lower strength Protopic 0.03% ointment.
If signs of a flare reoccur, twice daily treatment should be re-initiated (see treatment section above).
After 12 months, a review of the patient`s condition should be conducted by the physician and a decision taken whether to continue maintenance treatment in the absence of safety data for maintenance treatment beyond 12 months. In children, this review should include suspension of treatment to assess the need to continue this regimen and to evaluate the course of the disease.
The following paragraph has been deleted:
As clinical efficacy studies were performed with abrupt cessation of treatment, no information is available on whether tapering of the dosage would reduce recurrence rate.
4.4 Special warnings and precautions for use – the following paragraph has been added:
The development of any new change different from previous eczema within a treated area should be reviewed by the physician.
4.8 Undesirable effects – the following paragraph has been added:
In a study of maintenance treatment (twice weekly treatment) in adults and children with moderate and severe atopic dermatitis the following adverse events were noted to occur more frequently than in the control group: application site impetigo (7.7% in children) and application site infections (6.4% in children and 6.3% in adults).
5.1 Pharmacodynamic properties – the following paragraphs and Table 4 have been added:
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 (³ 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%
Twice weekly
(N=80)
|
Vehicle
Twice weekly
(N=73)
|
Tacrolimus 0.03%
Twice weekly
(N=78)
|
Vehicle
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
