Indication:

Treatment:

Protopic®, 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 atopic dermatitis in non-immunocompromised 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.

TCI=topical calcineurin inhibitor; AD=Atopic Dermatitis
*Comparative clinical significance unknown

Maintenance:

Protopic® is also indicated for maintenance therapy to prevent flares and prolong flare-free intervals in patients with moderate to severe atopic dermatitis experiencing a high frequency of flares (i.e., occurring 5 or more times per year) who have had an initial response (i.e., lesions cleared, almost cleared or mildly affected) with up to 6 weeks of treatment with twice-daily Protopic®.

In adult and pediatric patients with moderate/severe AD, how did Protopic® compare to hydrocortisone acetate and hydrocortisone butyrate treatment?

Results observed in pediatric patients (2-16 years) after 3 weeks of twice-daily treatment:1

2-fold
decrease

in mEASI score in patients treated with Protopic® 0.03% and 0.1% (0.1% is not indicated for pediatric use) vs. hydrocortisone acetate 1%.

~50%
more patients

in the Protopic® group experienced >moderate improvement in severity and completed the study vs. the hydrocortisone group.

Greater
improvement

in all symptoms (except lichenification which was similar for all treatment groups) observed for Protopic® vs. hydrocortisone groups.

Results observed
in adult patients
after 3 weeks
of twice-daily
treatment:1

Effectiveness
within 1 week

was evident for adult (and pediatric) patients treated with Protopic®.

63-75%
reduction

in mean mEASI from baseline for adult (and pediatric) patients treated with Protopic®.

Symptom improvement

observed in patients treated with Protopic® 0.1% vs. hydrocortisone butyrate 0.1% was not significantly different.

How was the primary
endpoint defined?

The primary endpoint of the above studies was decrease in modified Eczema Area and Severity Index (mEASI), which is a composite score that includes the physician assessment of individual signs and symptoms, affected body surface area (BSA), and the patients’ assessment of itch.1

Study Design

Pediatric: A 3-week, multi-centre, randomized, double-blind, active-comparator study to evaluate the effect of Protopic® 0.03% (n=189) and 0.1% (n=186; not indicated for pediatric use) concentrations compared to hydrocortisone acetate 1% (n=185), applied twice daily for 3 weeks, in pediatric patients (2-15 years old) with moderate to severe atopic dermatitis.1

Adult: A 3-week, multi-centre, randomized, double-blind, active-comparator study to evaluate the effect of Protopic® 0.03% (n=193) and 0.1% (n=191) concentrations compared to hydrocortisone butyrate 0.1% (n=186; not available in Canada), applied twice daily for 3 weeks, in adult patients with moderate to severe atopic dermatitis.1

See Clinical Trial Cases

Swipe to reveal cases of patients with moderate to severe AD treated with Protopic® 0.1% twice daily for 3 weeks. Please note these are real patient cases and individual results may vary.1

Before/After (Baseline/Week 3)

16-year-old female patient
with severe AD

Photo courtesy of Dr. Bourcier.

16-year-old female patient with severe AD16-year-old female patient with severe AD afer 3 weeks

27-year-old female patient with
moderate AD

Photo courtesy of Dr. B. Barakin.

27-year-old female patient with moderate AD27-year-old female patient with moderate AD after 3 weeks

47-year-old male patient
with severe AD

Photo courtesy of Adrian Azim.

47-year-old male patient with severe AD47-year-old male patient with severe AD after 3 weeks

Protopic® helped control AD flares with twice-weekly maintenance therapy1

In 12-month maintenance studies in pediatric (2-15 years) and adult patients, twice-weekly treatment with Protopic® (0.1% adults, 0.03% pediatrics) significantly reduced the occurrence of AD flares.1

Number of AD flares in pediatrics1
  • 1.0 Protopic® 0.03% (n=78)*
  • 2.9 vehicle control (n=75)
  • p<0.001*
Number of AD flares in adults1
  • 1.0 Protopic® 0.1% (n=80)*
  • 5.3 vehicle control (n=73)
  • p<0.001*

How were AD flares defined?
Flares were defined as disease exacerbations (DE) requiring substantial therapeutic intervention, defined as a DE with an Investigator’s Global Assessment (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.1

Protopic® maintenance therapy prolonged time to first AD flare in a secondary endpoint analysis:

Days to first AD flare in pediatrics1

217-36 days pediatrics” width=

Days to first AD flare in adults1

142-15 days adults

Study Design1

Two similar phase 3, 12-month, multi-centre, randomized, vehicle-controlled studies evaluating the efficacy of twice-weekly maintenance application of Protopic® ointment for moderate to severe eczema; one in adult patients (≥16 years) and one in pediatric patients (2–15 years).

In both studies, patients with active disease entered an open-label period during which they treated affected lesions with Protopic® ointment twice daily until improvement had reached a predefined score (IGA ≤2, i.e., clear, almost clear, or mild disease) for a maximum of 6 weeks. If patients did not respond to treatment, they were discontinued from the studies.

Thereafter, patients entered a double-blind disease control period for up to 12 months.

Patients were randomized to receive either Protopic® 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 Protopic® ointment twice daily for a maximum of 6 weeks until the IGA score returned to ≤2. Patients who did not achieve an IGA score of ≤2 were withdrawn from the study.

Vehicle-Controlled Studies of Protopic®
with Quality of Life Questionnaires1

As a result of the significant impact atopic dermatitis can have on a patient’s life,

  • hindering social interaction, lowering self-esteem, leading to work/school absenteeism, negatively affecting family interactions, producing sleep disturbances and emotional distress

A quality of life (QoL) questionnaire was completed by patients/parents/guardians in five pivotal studies

  • The pediatric patients in these studies treated with Protopic® 0.03% or 0.1% (Protopic® 0.1% is not indicated for use in pediatric patients) had statistically significant improvement in their QoL compared with vehicle-treated patients or those treated with hydrocortisone acetate1
  • In adults, statistically significant improvements in the QoL were observed in patients treated with
    Protopic® 0.1% compared with those treated with the 0.03% Protopic® concentration1

In a secondary endpoint analysis vs. vehicle
Protopic® significantly decreased itch in pediatric patients1,3*

Significant improvements in itch with Protopic 0.03% were
observed at Week 12 in the secondary endpoint analysis3

improvements with protopic

iimprovements with protopic

Patients applied Protopic® twice daily to 10-100% of their BSA for up to 12 weeks.

Study Design3

Protopic® was evaluated for the treatment of pediatric patients (2-15 years of age) with moderate to severe atopic dermatitis in a randomized, double-blind, vehicle-controlled, multicentre, phase 3 study.

In this study, patients applied either Protopic® 0.03% (n=117), Protopic® 0.1% (n=118; not indicated for pediatric use) or vehicle ointment (n=116) twice-daily to 10-100% of their BSA for up to 12 weeks.

The primary endpoint was the incidence of success (≥90% improvement) based on the Physician’s Global Evaluation of clinical response. The patient’s assessment of overall response and pruritus was also evaluated.

Available in two dosage strengths for moderate
to severe AD treatment and maintenance1

Tube image of 0.3% Protopic® LEO Pharma

Protopic® 0.03%

for patients age 2 and over

Protopic® tube 60g 0.1%

Protopic® 0.1%

for patients age 16 and over

Available in 60 g and 30 g pack sizes

Treatment1

  • A thin layer of Protopic® should be applied topically twice daily (morning and evening) to the affected areas of the skin, which can include the face, neck and eyelids
  • If no improvement occurs after 6 weeks of therapy or in case of disease exacerbation, Protopic® should be discontinued

Maintenance1

  • Patients who have a high frequency of flares (≥5 times per year) and are responding to up to 6 weeks of acute twice-daily treatment with Protopic® are suitable for Protopic® maintenance therapy twice weekly
  • A thin layer of Protopic® should be applied once daily, twice a week to areas of the skin normally affected by AD. There should be 2 to 3 days between applications (ex. Monday and Thursday)

Reinitiate twice-daily treatment if signs of flare reoccur1 

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.

Safety profile established in Protopic®
treatment studies1

In open-label, long-term safety studies of up to 4 years duration, the adverse event profile of Protopic® was similar to that seen in pivotal phase 3 studies:1

  • In vehicle-controlled phase 3 studies, the most common adverse events (>40%) experienced were: skin burning (58% for Protopic® 0.1% and 46% for Protopic® 0.03% in adults; 43% for Protopic® 0.03% in children), and pruritus (46% for Protopic® 0.1%, and 46% for Protopic® 0.03% in adults; and 41% for Protopic® 0.03% in children). Both skin burning and pruritus tended to be brief; the occurrence of which decreased with time, lasting approximately 4-7 days.
  • Localized symptoms, such as skin burning (burning sensation, stinging, soreness) or pruritus, are most common during the first few days of Protopic® application and typically resolve as the lesions of AD heal.

Pharmacodynamic effect of Protopic® vs. vehicle and betamethasone valerate ointment on collagen synthesis1*

When Protopic® was applied for 7 days to the unaffected skin of AD patients and healthy volunteers:1

Protopic® did not
reduce collagen
synthesis vs. vehicle

Protopic® did not
reduce skin thickness
vs. vehicle

Protopic® did not
produce skin atrophy
vs. vehicle

Similar exposure to the steroid ointment significantly reduced collagen synthesis and skin thickness relative to both Protopic® and vehicle1*

Study Design

A pharmacodynamic (PD) study of the effects of 0.1% and 0.3% Protopic® (0.3% Protopic® is not available in Canada), vehicle, and 0.1% betamethasone valerate ointment (a known atrophogenic corticosteroid, not available in Canada) on collagen synthesis in unaffected skin of AD patients and in healthy volunteers under occlusion over 7 days. Note: The use of Protopic® under occlusion has not been studied and occlusive dressings are therefore not recommended.

*Clinical significance has not been established. Comparative clinical significance is unknown

How does Protopic® work?*

While the exact mechanism of action of Protopic in AD is not known, the active ingredient (tacrolimus) has been shown to inhibit T-lymphocyte activation.1

Tacrolimus inhibits transcription of genes encoding IL-3, IL-4, IL-5, GM-CSF, and TNFα – factors involved in early-stage T-cell activation and postulated to play significant roles in AD pathogenesis.1

Need a refresher?

Review pathophysiology here

*Clinical significance has not been established.

Trust in the experience of Protopic®

Trust in the experience of Protopic®

The first and only TCI for AD maintenance therapy1*

Protopic Safety Information

Most serious warning and precautions:
Risk of skin malignancy and lymphoma: Long-term safety of topical calcineurin inhibitors has not been established. Although causal relationship has not been established, rare cases of skin malignancy and lymphoma have been reported in patients treated with topical calcineurin inhibitors, including Protopic® ointment 0.1% and 0.03%. Therefore:

● Continuous long-term use of Protopic® ointment should be avoided and application limited to areas of involvement with atopic dermatitis
● Protopic® ointment is not indicated in children less than 2 years of age. Only 0.03% Protopic® ointment is indicated for use in children 2-15 years of age

Other relevant warnings and precautions:
● Risk of skin burning (burning sensation, stinging, soreness) or pruritus
● Risk of infections
● Avoid use on pre-malignant and malignant skin conditions
● Do not use in immunocompromised adults and children
● Discontinue use in patients who do not improve within 6 weeks of twice-daily treatment
● Risk of lymphadenopathy
● Risk of acute renal failure
● Risk of varicella zoster virus infection (chickenpox or shingles), herpes simplex virus infection or eczema herpeticum
● Minimize or avoid natural or artificial sunlight exposure
● Risk of increased systemic absorption in patients with a skin barrier defect
● Use in pregnant and nursing women

For more information:
Please consult the Product Monograph at https://health-products.canada.ca/dpd-bdpp/index-eng.jsp for more important information relating to adverse reactions, drug interactions, and dosing/administration information which have not been discussed in this piece. The Product Monograph is also available by calling LEO Pharma Medical Information at 1-800-263-4218.

Is Protopic® covered?

See Local Coverage

© 2020 LEO Pharma Inc. All rights reserved.
® Registered trademark of LEO Pharma A/S used under license and distributed by LEO Pharma Inc.
www.leo-pharma.ca

References:
1. Protopic® Product Monograph. LEO Pharma Inc. June 21, 2016.
2. Health Canada. Protopic® Notice of Compliance. 2001. Available at: https://health-products.canada.ca/noc-ac/index-eng.jsp. Retrieved Aug 14, 2019.
3. Paller A, Eichenfield LF, Leung DY, Stewart D, Appell M. A 12-week study of tacrolimus ointment for the treatment of atopic dermatitis in pediatric patients. J Am Acad Dermatol. 2001;44(1 Suppl):S47-57.