Tacrolimus (Page 2 of 6)

CLINICAL STUDIES

Three randomized, double-blind, vehicle-controlled, multi-center, phase 3 studies were conducted to evaluate Tacrolimus Ointment for the treatment of patients with moderate to severe atopic dermatitis. One (Pediatric) study included 351 patients 2-15 years of age, and the other two (Adult) studies included a total of 632 patients 15-79 years of age. Fifty-five percent (55%) of the patients were women and 27% were black. At baseline, 58% of the patients had severe disease and the mean body surface area (BSA) affected was 46%. Over 80% of patients had atopic dermatitis affecting the face and/or neck region. In these studies, patients applied either Tacrolimus Ointment 0.03%, Tacrolimus Ointment 0.1%, or vehicle ointment twice daily to 10% — 100% of their BSA for up to 12 weeks.

In the pediatric study, a significantly greater (p < 0.001) percentage of patients achieved at least 90% improvement based on the physician’s global evaluation of clinical response (the pre-defined primary efficacy endpoint) in the Tacrolimus Ointment 0.03% treatment group compared to the vehicle treatment group, but there was insufficient evidence that Tacrolimus Ointment 0.1% provided more efficacy than Tacrolimus Ointment 0.03%.

In both adult studies, a significantly greater (p < 0.001) percentage of patients achieved at least 90% improvement based on the physician’s global evaluation of clinical response in the Tacrolimus Ointment 0.03% and Tacrolimus Ointment 0.1% treatment groups compared to the vehicle treatment group. There was evidence that Tacrolimus Ointment 0.1% may provide more efficacy than Tacrolimus Ointment 0.03%. The difference in efficacy between Tacrolimus Ointment 0.1% and 0.03% was particularly evident in adult patients with severe disease at baseline, adults with extensive BSA involvement, and black adults. Response rates for each treatment group are shown below by age groups. Because the two adult studies were identically designed, the results from these studies were pooled in this table.

Table 1
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A statistically significant difference in the percentage of adult patients with ≥ 90% improvement was achieved by week 1 for those treated with Tacrolimus Ointment 0.1%, and by week 3 for those treated with Tacrolimus Ointment 0.03%. A statistically significant difference in the percentage of pediatric patients with ≥ 90% improvement was achieved by week 2 for those treated with Tacrolimus Ointment 0.03%.

In adult patients who had achieved ≥ 90% improvement at the end of treatment, 35% of those treated with Tacrolimus Ointment 0.03% and 41% of those treated with Tacrolimus Ointment 0.1%, regressed from this state of improvement at 2 weeks after end-of-treatment. In pediatric patients who had achieved ≥ 90% improvement, 54% of those treated with Tacrolimus Ointment 0.03% regressed from this state of improvement at 2 weeks after end-of-treatment. Because patients were not followed for longer than 2 weeks after end-of-treatment, it is not known how many additional patients regressed at periods longer than 2 weeks after cessation of therapy.

In both Tacrolimus Ointment treatment groups in adults and in the Tacrolimus Ointment 0.03% treatment group in pediatric patients, a significantly greater improvement compared to vehicle (p < 0.001) was observed in the secondary efficacy endpoints of percent body surface area involved, patient evaluation of pruritus, erythema, edema, excoriation, oozing, scaling, and lichenification. The following two graphs depict the time course of improvement in the percent body surface area affected in adult and in pediatric patients as a result of treatment.

Figures 1 and 2
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The following two graphs depict the time course of improvement in erythema in adult and in pediatric patients as a result of treatment.

Figures 3 and 4
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The time course of improvement in the remaining secondary efficacy variables was similar to that of erythema, with improvement in lichenification slightly slower.

INDICATIONS AND USAGE

Tacrolimus Ointment, both 0.03% and 0.1% for adults, and only 0.03% for children aged 2 to 15 years, is indicated as second-line therapy for the short-term and non-continuous chronic treatment of moderate to severe atopic dermatitis in non-immunocompromised adults and children who have failed to respond adequately to other topical prescription treatments for atopic dermatitis, or when those treatments are not advisable.

Tacrolimus Ointment is not indicated for children younger than 2 years of age (see boxed WARNING, WARNINGS and PRECAUTIONS: Pediatric Use).

CONTRAINDICATIONS

Tacrolimus Ointment is contraindicated in patients with a history of hypersensitivity to tacrolimus or any other component of the ointment.

WARNINGS

WARNING

Long-term Safety of Topical Calcineurin Inhibitors Has Not Been Established

Although a causal relationship has not been established, rare cases of malignancy (e.g., skin and lymphoma) have been reported in patients treated with topical calcineurin inhibitors, including Tacrolimus Ointment.

Therefore:

  • Continuous long-term use of topical calcineurin inhibitors, including Tacrolimus Ointment, in any age group should be avoided, and application limited to areas of involvement with atopic dermatitis.
  • Tacrolimus Ointment is not indicated for use in children less than 2 years of age. Only 0.03% Tacrolimus Ointment is indicated for use in children 2-15 years of age.

Prolonged systemic use of calcineurin inhibitors for sustained immunosuppression in animal studies and transplant patients following systemic administration has been associated with an increased risk of infections, lymphomas, and skin malignancies. These risks are associated with the intensity and duration of immunosuppression.

Based on the information above and the mechanism of action, there is a concern about potential risk with the use of topical calcineurin inhibitors, including Tacrolimus Ointment. While a causal relationship has not been established, rare cases of skin malignancy and lymphoma have been reported in patients treated with topical calcineurin inhibitors, including Tacrolimus Ointment. Therefore:

  • Tacrolimus Ointment should not be used in immunocompromised adults and children.
  • If signs and symptoms of atopic dermatitis do not improve within 6 weeks, patients should be re-examined by their healthcare provider and their diagnosis be confirmed (see PRECAUTIONS: General).
  • The safety of Tacrolimus Ointment has not been established beyond one year of non-continuous use.

(See CLINICAL PHARMACOLOGY , boxed WARNING , INDICATIONS AND USAGE , and DOSAGE AND ADMINISTRATION).

PRECAUTIONS

General

The use of Tacrolimus Ointment should be avoided on pre-malignant and malignant skin conditions. Some malignant skin conditions, such as cutaneous T-cell lymphoma (CTCL), may mimic atopic dermatitis.

The use of tacrolimus ointment is not recommended in patients having skin conditions with a skin barrier defect where there is the potential for increased systemic absorption of tacrolimus, including but not limited to, Netherton’s syndrome, lamellar ichthyosis, generalized erythroderma or cutaneous Graft Versus Host Disease. Oral application is also not recommended. Post-marketing cases of increased tacrolimus blood level have been reported in these conditions.

The use of Tacrolimus Ointment may cause local symptoms such as skin burning (burning sensation, stinging, soreness) or pruritus. Localized symptoms are most common during the first few days of Tacrolimus Ointment application and typically improve as the lesions of atopic dermatitis resolve. With Tacrolimus Ointment 0.1%, 90% of the skin burning events had a duration between 2 minutes and 3 hours (median 15 minutes). 90% of the pruritus events had a duration between 3 minutes and 10 hours (median 20 minutes) (see ADVERSE REACTIONS).

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