# Presentation: 662252

## Efficacy and Safetyof TacrolimusOintmentIra D. Lawrence, M.D., F.A.C.P.Senior Vice PresidentResearch and DevelopmentFujisawa Healthcare, Inc.

## Five Core Phase III Studies

**Study**
**12-Week,**
**   ****Double Blind**
**(12W, DB)**
**12-Month**
**Open-Label ****(OL)**

**Age**
**Group**
**Pediatric**
**Adult**
**Adult**
**Pediatric**
**Adult**

**#**
**Patients**
**351**
**304**
**328**
**255**
**316**

**Study**
**#**
**#37**
**#35**
**#36**
**#25**
**FG-12**

## Five Core Phase III Studies

## 12W, DB Studies - Adult (35/36) / Pediatric (37)Controlled Study Design

**BL**

**W1**

**W2**

**W3**

**W6**

**W9**

**W12**

**2W**
**F/U**

**Randomization**

**Vehicle Ointment (twice daily)**

**0.03% Tacrolimus Ointment (twice daily)**

**0.1% Tacrolimus Ointment (twice daily)**

## 12W, DB Studies - Adult (35/36) / Pediatric (37)Eligibility Criteria

**Atopic dermatitis: moderate to severe, **_**>**_** 10% BSA**
**Concomitant therapy restrictions and washout requirements:**
**Emollients to treatment area**
**Topical antihistamines and antimicrobials**
**Topical or systemic corticosteroids**
**Non-sedating systemic antihistamines**
**Light treatments**
**Non-steroidal immunosuppressants**

## Results

## 12W, DB Studies - Adult (35/36) / Pediatric (37) CombinedPatient Disposition

** **
**Intent-to-Treat**
**Completed Treatment**
**Discontinued**
**   ****Lack of Efficacy**
**   ****Adverse Event**
**   ****Administrative    **
**      ****Reason **‡

**Vehicle**
**328**
**	****36%**
**	****64%**
**	****	****43%**
**	****	****11%**
**	****	****10%**

**Concentration of**
**Tacrolimus Ointment**

**0.03%**
**328**
**	****74%**
**26%**
** ****	****	**** ****9%**
** ****	****	**** ****6%**
**	****	****11%**

**0.1%**
**327**
**	**
**	****79%**
**21%**
**	**** ****	**** ****7%**
**	**** ****	**** ****4%**
**	****	****10%**

- ‡** ****Lost to follow-up, treatment noncompliance, patient refusal, etc.**

## 12W, DB Studies - Adult (35/36) / Pediatric (37) Combined Patient Demographics

** **
**Gender:****	****Female**
**	****Male**
**Race:****	****Caucasian**
**	****African American**
**	****Other**
**Age:****	****  2 -   6**
**	****  ****7 - 15**
**	****16 - 79**

**Vehicle**
**n=328**
**55%**
**45%**
**66%**
**26%**
**8%**
**22%**
**13%**
**65%**

**Total**
**n=983**
**55%**
**45%**
**66%**
**27%**
**7%**
**22%**
**14%**
**64%**

**0.03%**
**n=328**
**54%**
**46%**
**67%**
**27%**
**6%**
**23%**
**13%**
**64%**

**0.1%**
**n=327**
**57%**
**43%**
**65%**
**27%**
**7%**
**21%**
**15%**
**64%**

**Concentration of**
**Tacrolimus Ointment**

**No statistically significant differences among groups.**

**36%**

## 12W, DB Studies - Adult (35/36) / Pediatric (37) Combined Baseline Disease Characteristics

** **
**% BSA Affected**
**    **_**>**_**10 - **_**<**_** 25**
**    ****>25 - **_**<**_** 50**
**    ****>50 - **_**<**_** 75**
**    ****>75 - **_**<**_** 100**
**    ****Mean **_**+**_** SD**

**Vehicle**
**n=328**
**29%**
**30%**
**20%**
**21%**
**47 **_**+**_** 27**

**Total**
**n=983**
**30%**
**29%**
**21%**
**20%**
**46 **_**+**_** 27**

**0.03%**
**n=328**
**33%**
**28%**
**21%**
**18%**
**45 **_**+**_** 27**

**0.1%**
**n=327**
**28%**
**30%**
**22%**
**20%**
**46 **_**+**_** 26**

**Concentration of**
**Tacrolimus Ointment**

**41%**

## 12W, DB Studies - Adult (35/36) / Pediatric (37) Combined Baseline Disease Characteristics

** **
**Severity**
**    ****Moderate**
**    ****Severe**
**With Head/Neck Involvement**

**Vehicle**
**n=328**
**44%**
**56%**
**88%**

**Total**
**n=983**
**42%**
**58%**
**86%**

**0.03%**
**n=328**
**42%**
**58%**
**86%**

**0.1%**
**n=327**
**39%**
**61%**
**83%**

**Concentration of**
**Tacrolimus Ointment**

## Three, identically designed, 12 week, randomized, double-blind studies

**Efficacy**

## 12W, DB Studies - Adult (35/36) / Pediatric (37)Primary Efficacy Endpoint

**Physician’s Global Evaluation of****Clinical Response at End of Treatment**** **

**Assessment**
**Cleared**
**Excellent Improvement**
**Marked Improvement**
**Moderate Improvement**
**Slight Improvement**
**No Appreciable Improvement**
**Worse**

**% Improvement**
**100**
**90 - 99**
**75 - 89**
**50 - 74**
**30 - 49**
**0 - 29**
**< 0**

## 12W, DB Studies - Adult (35/36) / Pediatric (37) Analyses Performedfor Success

**In each of the three pivotal studies, overall tests of equal proportions were performed**
**Since overall test (among three treatments) was significant in each of the three studies, each pairwise comparison was performed.**** **
**  ****	****	****First comparisons**** **
**	****	****	****0.03% tacrolimus ointment vs. vehicle**
**	****	****	****0.1% tacrolimus ointment vs. vehicle**
**	****	**
**	****	****Second comparison**
**	****	****	****0.1% vs. 0.03% tacrolimus ointment**

## 12W, DB Studies - Adult (35/36) / Pediatric (37) Analyses Performedfor Success

**Analyses were performed**
**For each individual study**
**For data from the three studies combined**
**Intent-to-treat population**
**Last observation carried forward**

## 12W, DB Studies - Adult (35/36) / Pediatric (37)Success(>90% improvement)

*****p < 0.001 for either concentration of tacrolimus **
**  ****ointment compared with vehicle in all 3 studies.**

*******

*******

*******

*******

*******

*******

**%  Patients**

**N = 351**

**N = 304**

**N = 328**

## 12W, DB Studies - Adult (35/36) / Pediatric (37)Combined Success(>90% improvement)

**% Patients**

**Vehicle**

**0.03%**

**0.1%**

**7%**

**12W, DB Studies - Adult (35/36) / Pediatric (37)****Combined Success****(**_**>**_**90% improvement)**

*******

**N = 328**

**N = 327**

**N = 328**

*****p < 0.001 for either concentration of tacrolimus **
**  ****ointment compared with vehicle**

*******

**30%**

**38%**

## 12W, DB Studies - Adult (35/36) / Pediatric (37)> 50% Improvement

*****p < 0.001 for either concentration of tacrolimus ointment compared with vehicle**

**% Patients**

**Vehicle**

**0.03%**

**0.1%**

**22%**

**66%**

**75%**

*******

*******

**Cleared/Excellent**
**(**_**>**_** 90%)**

**Marked/Moderate**
**(**_**>**_** 50%)**

## 12W, DB Studies - Adult (35/36) / Pediatric (37)> 50% Improvement at Week 1 and End of Treatment (EOT)

**% Patients**

**wk1**

**wk1**

**wk1**

**EOT**

**EOT**

**EOT**

## Efficacy Confirmation:Secondary Endpoints

**Eczema Area and Severity Index (EASI)**
**Percent Body Surface Area (%BSA) affected**
**Physician’s Assessment of Signs of Atopic Dermatitis**
**Patient’s Assessment of Pruritus**

## Comparison of 0.1% versus 0.03% Tacrolimus Ointment

## 12W, DB Studies - Adult (35/36) / Pediatric (37)Success(>90% improvement)

**  **
**Pediatric (37)**
**Adult (35)**
**Adult (36)**
**Adult Studies Combined**
**All Studies Combined**

**0.03%**
**36%**
**29%**
**26%**
**27%**
**30%**

**0.1%**
**	****41%**
**35%**
**38%**
**37%**
**38%**

**p-value**
**0.03% vs.0.1%**
**0.401**
**0.369**
**0.060**
**0.041**
**0.038 **

**Concentration of**
**Tacrolimus Ointment**

## 12W, DB Studies - Adult (35/36)Success in Adults by Concentrationby Baseline Disease Severity

**% Patients**

**38%**

**40%**

**19%**

**35%***

***  Significantly (p = 0.009) greater improvement - 0.1% vs 0.03%**

## 12W, DB Studies - Adult (35/36)Success in Adults by Concentration by %BSA Affected at Baseline

**10 -  **_**<**_** 25%**
**BSA**

**>25 - **_**<**_** 50%**
**BSA**

**>50 -  **_**<**_** 75%**
**BSA**

**>75 -  **_**<**_** 100%**
**BSA**

**% Patients**

**45%**

**28%**

**34%**

**19%**

**31%**

**5%**

**30%***

**48%**

***  Significantly (p = 0.004) greater improvement - 0.1% vs 0.03%**

## 12W, DB Studies - Adult (35/36)Success in Adults

**% Patients**

**27%**

**16%**

**29%**

**40%***

*** Significantly (p = 0.029) greater improvement - 0.1% vs 0.03%**

## Efficacy Summary

**Both concentrations of tacrolimus ointment are effective**
**Rapid improvement (1 week)**
**In adults, 0.1% concentration more effective than 0.03%**
**Effectiveness is maintained for periods up to 1 year**

## Three 12 week, randomized, double-blind studies
Each concentration versus vehicle
Between two concentrations
Two (up to 1 year) open-label safety studies
Five core studies
Hazard rates
Laboratory profile data

**Each concentration versus vehicle**
**Between two concentrations**
**Two (up to 1 year) open-label safety studies**
**Five core studies**
**Hazard rates**
**Laboratory profile data**

**Safety Presentation**

## Five Core Phase III Studies

**Study**
**12-Week,**
**   ****Double Blind**
**(12W, DB)**
**12 Month,**
**  ****Open-Label**
**  ****(OL)**

**Age**
**Group**
**Pediatric**
**Adult**
**Adult**
**Pediatric**
**Adult**
**    **

**#**
**Patients**
**351**
**304**
**328**
**255**
**316**
**    **

**Study**
**#**
**37**
**35**
**36**
**25**
**FG-12**

**983**

**571**

## 12W, DB Studies - Adult (35/36) / Pediatric (37) CombinedMedian Treatment Days

**Median Days**

## 12W, DB Studies - Adult (35/36) / Pediatric (37) CombinedAdverse EventsAdjusted Incidence Rates ‡

**Overall AE**
**Application Site AE**
**Non-applications Site AE**
**Infections**
**AE Resulting in **
**  ****Discontinuation**

**Vehicle**
**n=328**
**84%**
**60%**
**68%**
**54%**
**13%**

**0.03%**
**n=328**
**90%**
**75%**
**70% **
**56%**
**  ****7%**

**‡**** ****Adjusted incidence rates based on Kaplan-Meier estimates at week 12.**

**0.1%**
**n=327**
**89%**
**72%**
**68% **
**58%**
**  ****5%**

**0.03% **
**vs vehicle**
**0.065**
**<0.001**
**0.766 **
**0.670**
**0.019**

**Treatment Group**

**0.1% **
**vs vehicle**
**0.158**
**0.001**
**0.880 **
**0.522**
**0.002**

** ****p - value**

**12W, DB Studies - Adult (35/36) / Pediatric (37) Combined****Adverse Events****Adjusted Incidence Rates **‡

## Comparison of Active and VehicleUsing 95% Confidence Interval

**Active > Vehicle****   (significant)**

**(not significant)**

**Active < Vehicle**
**    ****(significant)    **

**-15**

**-10**

**-5**

**0**

**5**

**10**

**15**

**Comparison of Active and Vehicle****Using 95% Confidence Interval**

**No Apparent**
**Difference**

## 12W, DB Studies - Adult (35/36) / Pediatric (37) CombinedCommon Adverse Events (> 5%) ‡  Treatment Difference with 95% CI 

**‡ ****Adjusted incidence rates based on Kaplan-Meier estimates at week 12.**

**Accidental Injury**

**Allergic Reaction**

**Skin Burning**

**Skin Erythema**

**Skin Infection**

**Fever**

**Flu- like Symptoms**

**Headache**

**Asthma**

**Cough Increased**

**Pharyngitis**

**Pruritus**

**-15**

**-5**

**5**

**15**

**25**

**35**

## 12W, DB Studies - Adult (35/36) / Pediatric (37) CombinedSkin Burning Prevalence

**% Patients**

**D4**

**W1**

**W2**

**W6**

**W9**

**W12**

**W3**

## 12W, DB Studies - Adult (35/36) / Pediatric (37)Adverse Events of Clinical InterestAdjusted Incidence Rates ‡ 

**  **
**Overall Infections**
**Flu-like Symptoms**
**Headache**
**Fever**
**Cough Increased**
**Pharyngitis**

**Vehicle**
**(n=328)**
**54%**
**22%**
**10%**
**  ****8%**
**  ****7%**
**  ****6%**

**0.03%**
**(n=328)**
**56%**
**25%**
**14%**
**10%**
**  ****7%**
**  ****4%**

**0.1%**
**(n=327)**
**58%**
**31%**
**17%**
**  ****7%**
**  ****6%**
**  ****5%**

**Concentration of**
**Tacrolimus Ointment**

**‡ ****Adjusted incidence rates based on Kaplan-Meier estimates at week 12.**

## 12W, DB Studies - Adult (35/36) / Pediatric (37)Cutaneous Events of Clinical InterestAdjusted Incidence Rates ‡ 

**  **
**Skin Infection ****+**
**Folliculitis**
**Herpes Simplex**
**Skin Tingling**
**Alcohol Intolerance**
**Hyperesthesia**

**Vehicle**
**(n=328)**
**12%**
**<1%**
**  ****3%**
**  ****2%**
**  ****0%**
**<1%**

**0.03%**
**(n=328)**
**12%**
**  ****5%**
**  ****4%**
**  ****3%**
**  ****2%**
**  ****2%**

**0.1%**
**(n=327)**
**7%**
**3%**
**4%**
**5%**
**4%**
**4%**

**Concentration of**
**Tacrolimus Ointment**

- ‡** ****Adjusted incidence rates based on Kaplan-Meier estimates at week 12.**
**+**** Majority presumed bacterial.**

## 12W, DB Studies - Pediatric (37)Common Adverse Events in Children‡  Treatment Difference with 95% CI

- ‡** ****Adjusted incidence rates based on Kaplan-Meier estimates at week 12.**

**Skin Burning**

**Skin Erythema**

**Skin Infection**

**Pharyngitis**

**Pruritus**

**Otitis Media**

**Cough Increased**

**Fever**

**Flu-like Symptoms**

**Headache**

**-20**

**-10**

**0**

**10**

**20**

**30**

## 12W, DB Studies - Pediatric (37)Common Adverse Events in Children‡  Treatment Difference with 95% CI

- ‡** ****Adjusted incidence rates based on Kaplan-Meier estimates at week 12.**

**Sinusitis**

**Pustular Rash**

**Rhinitis**

**Accidental Injury**

**Allergic Reaction**

**Asthma**

**Abdominal Pain**

**Infection**

**Vomiting**

**Bronchitis**

**-20**

**-15**

**-10**

**-5**

**0**

**5**

**10**

**15**

## 12W, DB Studies - Pediatric (37)Adverse Event of Clinical Interest in ChildrenAdjusted Incidence Rates ‡ 

**  **
**Overall Infections **
**Flu-like Symptoms**
**Skin Infections**
**Sinusitis**
**Herpes Simplex**
**Chicken Pox ****+**

**Vehicle**
**(n=116)**
**48%**
**25%**
**14%**
**  ****8%**
**  ****2%**
**  ****0%**

**0.03%**
**(n=118)**
**57%**
**28%**
**10%**
**  ****3%**
**  ****2%**
**  ****5%**

**0.1%**
**(n=118)**
**55%**
**32%**
**11%**
**  ****1%**
**  ****5%**
**  ****1%**

**Concentration of**
**Tacrolimus Ointment**

**+**** COSTART term Herpes Zoster.**

- ‡** ****Adjusted incidence rates based on Kaplan-Meier estimates at week 12.**

## 12W, DB Studies - Pediatric (37)Adverse Event Profile inYoung Pediatric Patients -- Age 2-6(n=215)

**Similar profile to overall pediatric patient population**
**No apparent difference in the 0.1% tacrolimus ointment and vehicle groups**
**Only statistically significant difference in 0.03% tacrolimus ointment group, versus vehicle**
**Pruritus**
**Chicken Pox (normal clinical course) **

## 12W, DB Studies - Adult (35/36) / Pediatric (37) Combined 0.1% minus 0.03% with 95% CI Common Adverse Events‡

- ‡** ****Adjusted incidence rates based on Kaplan-Meier estimates at week 12.**

## 12W, DB Studies - Adult (35/36) / Pediatric (37)Adverse Events Summary

**No apparent difference**
**Overall incidence adverse events**
**Overall non-application site events**
**Infections**
**Higher incidence of local irritation events**
**Short duration**
**Occur early in treatment**
**Both 0.03% and 0.1% concentrations are safe**

## Open-Label StudiesAdult (FG-12) / Pediatric (25)

**Applied 0.1% tacrolimus ointment for 87% of days on study**
**Severe disease****	****48% children****	****53% adults**
**Head/Neck****	****80% children****	****95% adults**
_**>**_** 6 months on study****	****465 patients**_**>**_** 12 months on study****	****248 patients**

## OL Studies - Adult (FG-12) / Pediatric (25)Summary of Raw Incidence ofAdverse Events

**Number of Patients**
**Overall Adverse Event AE**
**Application Site AE**
**    **
**Non-Application Site AE**
**    **
**AE Resulting - D/C**

**Pediatric**
**n=255**
**87%**
**    **
**54%**
**    **
**77%**
**      **
**4%**

**Adult**
**n=316**
**92%**
**    **
**78%**
**   **
**75%**
**     **
** ****9%**

## OL Studies - Adult (FG-12) / Pediatric (25)Common (>10%) ApplicationSite Events*

** **
**Skin Burning**
**Pruritus**
**Skin Infection**
**Skin Erythema**

**Pediatric**
**n=255**
**26%**
**23%**
**11%**
**  ****9%**

**Adult**
**n=316**
**	**** ****47%**
**24%**
**11%**
**12%**

******* **_**>**_** 5% incidence in both studies (also occurring at **_**>**_** 5% -10% incidence in FG-12:  **
**  ****folliculitis, herpes simplex)**

## OL Studies - Adult (FG-12) / Pediatric (25)Common (>10%) Non-ApplicationSite Adverse Events

**Flu-Like Symptoms**
**Headache**
**Fever**
**Asthma**
**Allergic Reaction**
**Increased Cough**
**Accidental Injury**
**Infection**

**Pediatric**
**n=255**
**35%**
**18%**
**18%**
**16%**
**15%**
**15%**
**11%**
**  ****8%**

**Adult**
**n=316**
**22%**
**10%**
**  ****2%**
**  ****5%**
**21%**
**  ****3%**
**  ****4%**
**14%**

**Occurring **_**>**_** 5% to <10%:  in 25, pharyngitis, sinusitus, bronchitis, diarrhea, vomiting, otitis media;  in FG-12, pharyngitis, rhinitis, herpes simplex. **

## OL Studies - Adult (FG-12) / Pediatric (25)Non-Application SiteAdverse Events

**No increase in non-application site adverse events with **
**cumulative length of exposure**
**cumulative ointment use**

## Open-Label Safety Studies

**Tacrolimus 0.1% ointment is safe in the long-term treatment of atopic dermatitis when used for up to 1 year in children and adults.**

## Five Core StudiesHazard Rates

**5 core studies **
**898 patients - 0.1% tacrolimus ointment**
**Local irritation events excluded**
**All 898 patients included  days 1- 89**
**Only long-term patients included  **_**>**_** 90 days**

## Five Core StudiesDaily Hazard Rates+ (SE) Over Time0.1% Tacrolimus Ointment 

**Flu-like Symptoms**
**Headache**
**Herpes Simplex**
**Folliculitus**
**Lymphadenopathy**

**Day 1-90**
**2.792 (0.211)**
**1.687 (0.163)**
**0.710 (0.105)**
**0.537 (0.091)**
**0.075 (0.034)**

**Day 91-182**
**0.986 (0.169)**
**0.292 (0.088)**
**0.248 (0.079)**
**0.219 (0.073)**
**0.093 (0.047)**

**Day 183-366**
**0.999 (0.173)**
**0.183 (0.069)**
**0.191 (0.068)**
**0.093 (0.047)**
**0.111 (0.050)**

**+**** Rate (SE) should be multiplied by 10 ****–3**** to get actual rate.**

## OL Study – Pediatric (25)Lymphadenopathy Hazard Rates+ (SE)Over Time0.1% Tacrolimus Ointment - Pediatrics 

**Hazard Rate**
**  ****(SE)**

**Wks 0-12**
**0.133**
**(0.0769)**

**Wks 12-26**
**0.048**
**(0.048)**

**Wks 26-52**
**0.147**
**(0.0737)**

**+**** Rate (SE) should be multiplied by 10 ****–3**** to get actual rate.**

## COSTART Code“Lymphadenopathy”

**Most are secondary to concurrent inflammatory processes (tonsillitis, skin infections)**
**Short-lived enlargements**
**Shotty cervical lymph node**
**Small cervical enlargement**
**Common in atopic dermatitis**
**Not associated with significant pathology**

## Lymphoma

**2 cases of lymphoma reported in global development program**
**B Cell lymphoma in 68 year old patient, presenting in parotid (low grade follicular; predated enrollment)**
**CTCL in 60 year old patient with 7 year history of eczematous dermatitis**

## Five Core StudiesClinical Laboratory Evaluation

**No observed trends in laboratory profiles suggestive of safety concern**** **

## Safety Summary - Tacrolimus Ointment0.03% & 0.1% Concentrations

**Adverse events do not increase with long term use (0.1% tacrolimus)**
**Adverse events are generally local irritation events (skin burning, pruritus)**
**Short duration**
**Occur early in treatment**

## Safety Summary - Tacrolimus Ointment0.03% & 0.1% Concentrations

**Overall - no difference in tacrolimus****vs. vehicle**
**Non-application site events**
**Infection cluster (predefined)**** **
**No trends in laboratory profile**** **
**Adverse event profiles consistent  between global and 5 core studies**

## Advisory Committee Questions

**Is Protopic 0.03% effective in the treatment of atopic dermatitis?****Yes.****In three 12-week double blind****vehicle-controlled trials involving over 300 patients in each study, 0.03% tacrolimus ointment was significantly superior to vehicle.**

## Advisory Committee Questions

**Is Protopic 0.1% more effective than Protopic 0.03% in adults? ****Yes.****In two double-blind vehicle-controlled studies involving 632 adults, 0.1% tacrolimus ointment was significantly more effective, particularily evident in patients with severe disease or extensive body surface area involvement. **

## Advisory Committee Questions

**Is Protopic 0.1% more effective than Protopic 0.03% in children?****No.****In our pediatric trials involving 351 children, there was no significant difference in efficacy between the two concentrations.**

## Advisory Committee Questions

**Is Protopic safe for unrestricted chronic therapy as a first-line treatment in adults for both concentrations? ****Yes.****The safety of the 0.1% concentration of tacrolimus ointment in adults has been established for up to 1 year and thus, established safety in 0.03% tacrolimus ointment.**

## Advisory Committee Questions

**Is Protopic safe for unrestricted chronic therapy as a first-line treatment in children for both concentrations?****Yes.****The safety of the 0.1% concentration of tacrolimus ointment in children has been established for up to 1 year and thus, established safety in 0.03% tacrolimus ointment.**

## Advisory Committee Questions

**Unrestriced Chronic Therapy vs.**
**Time-Limited Acute Therapy**

**Unrestricted chronic intermittent therapy-patient should treat each episode of atopic dermatitis until clearing, plus seven days.**

## Advisory Committee Questions

**First-Line vs.**
**Second-Line Treatment**

**Adults**

**Children**
**(**_**>**_** 2 years old)**

**First line therapy in adults and children 2 years of age and older.**

## Advisory Committee Questions

**0.03%, 0.1%,**
**Both, or Neither**

**Adults**
**0.03% & 0.1%**

**Children**
**(**_**>**_** 2 years old)**
**0.03%**

## Advisory Committee Questions

**Are there additional studies needed for the labeling of Protopic and what are they?****The NDA data summarized today clearly demonstrates the efficacy and safety of tacrolimus ointment and is sufficient to provide clear labeling for Protopic.**

## Tacrolimus OintmentFurther Recommendations

**Patients should minimize or avoid unprotected exposure to natural or artificial sunlight during therapy**
**Patients with unexplained fever or unexplained lymphadenopathy or suspected/proven infectious mononucleosis should delay or interrupt tacrolimus ointment therapy **

## Tacrolimus Ointment0.03%, 0.1%

**Novel, safe, and effective nonsteroidal topical therapy for the management of atopic dermatitis**