# Presentation: 064074

##           
            FDA Perspective
  Topical Immunosuppressants

                  Bindi Nikhar, MD.
     Division of Dermatologic and Dental Drugs

**            ****FDA Perspective**
**  ****Topical Immunosuppressants**
**                **
**                  ****Bindi Nikhar, MD.**
**     ****Division of Dermatologic and Dental Drugs**

- advisory committeee

## Introduction

**Topical immunosuppressants are the newest class of drugs to be approved for atopic dermatitis (AD)**
**They belong to a class of drugs known as ma**_***crol***_**actam **_***im***_**m**_***u***_**no**_***s***_**uppressants, which were first introduced in the 1980s for prevention of graft rejection in transplant therapy**
**Tacrolimus (FK506) (trade name Protopic)**
**   ****Pimecrolimus (SDZ ASM 981) (trade name Elidel)**

- advisory committeee

## Topical Corticosteroids (TCS)

**Antiinflammatory effects**
** ****-  TCS              ****inhibit nuclear factor kappa B (NFkB)****, which upregulates cytokines. Inhibition done by increasing production of NFkB inhibitor (IkB) and directly binding & inactivating NFkB **
** ****-  Affects leukocytes, lymphocytes, monocytes, epidermal Langerhans’ cells**
** ****-  Inhibit phospholipase A2              inhibit  prostaglandins & leukotrienes**
** ****-  Vasoconstrictive**
** ****-  Antipruritic - Mast cell sensitization & IgE induced mediator release inhibited**
**Antiproliferative & Atrophogenic effects**

- advisory committeee

## Tacrolimus

**Advisory Committee meeting on 11/16/2000 **
**Second-line therapy in the treatment of atopic dermatitis (AD)**
**Not be approved in children < 2 years of age**
**Only the lower concentration be approved for 2 to 15 years **
**  ****- ****12 week study in **_**pediatric patients**_**               **
**      ****equivalent efficacy for both strengths**
**  ****-  larger BSA              more absorption**
**  ****- longer exposure & long-term safety unknown**

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## Tacrolimus

**Protopic (topical tacrolimus) approved on 12/8/2000. 0.03% ointment approved for children 2 to 15 years, 0.1% ointment approved for adults**
**Prograf (systemic tacrolimus) approved on 4/8/1994, first introduced for allograft rejection, currently used mainly in kidney and liver transplants**

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## Pimecrolimus

**Elidel (pimecrolimus) cream 1% approved on 12/13/2001 for patients 2 years of age and older **
**Phase 3 studies – higher incidence of adverse effects (%) in Elidel arm vs. vehicle arm; URI (24/14 ), pyrexia (32/13), otitis media (4/0), gastroenteritis (7/3), diarrhea (8/0)**
**Currently available only for topical use**
**Literature report * - oral formulation under development for psoriasis and atopic dermatitis**
**  ***** ****Expert Opinion on Pharmacotherapy. 2004 March;5(3):643-55, Wolf K, Stuetz A. Pimecrolimus for the treatment of inflammatory skin diseases****. **

- advisory committeee

## Clinical studies for Pimecrolimus

_**2-17 years***_** -  1 year safety study, nasopharyngitis (26/21), influenza (13/4), pharyngitis (8/3), viral infection (7/1), pyrexia (13/5), cough (16/11), headache (25/16)**
_**3-23 months***_** – 6 week study, pyrexia (32/13), URI (24/14), nasopharyngitis (15/8), gastroenteritis (7/3), otitis media (4/0), diarrhea (8/0)**
_**3-23 months***_** – 1 year study, pyrexia (30/20), URI (21/17), cough (15/9), vomiting (9/4), rhinitis (13/9), viral rash (4/0), rhinorrhea (4/0), wheezing (4/0)**
**   ***** all adverse events, Elidel vs. vehicle (%)**

- advisory committeee

## Indications for Use

**Tacrolimus – moderate to severe AD**
**Pimecrolimus – mild to moderate AD**
**Both indicated for patients ‘in whom the use of alternative, conventional therapies are deemed inadvisable because of potential risks, *****or***** in the treatment of patients who are not adequately responsive to, *****or***** are intolerant of alternative, conventional therapies’ **
**Neither drug approved for children < 2 years of age**

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## Recent Concerns

**UNCERTAIN RISK FOR CANCER**
**Biological plausibility**
**Emerging signal in AERS **
**Difficult to study and ‘answers’ would be late**
**INFORMATIONAL LANDSCAPE**
**Suggests ‘first-line’**
**‘****Steroid-free’, Direct-to-consumer advertising **
**Other indications**
**Peer and non-peer reviewed literature portrays safety**
**CURRENT PRACTICES**
**Overall use increasing**
**Use in < 2 years increasing**

- advisory committeee

## Proposed mechanisms of action

**    ****Clinical significance of these observations in atopic dermatitis are unknown.**
**T & P             bind to FK-binding protein (FKBP)**
**T/P-FKBP complex             ****inhibits calcineurin**
**                ****inhibits T cell activation**
**Both              inhibit production of pro-inflammatory cytokines from mast cells and down regulate the production of Th1 and Th2 type cytokines**** **

- advisory committeee

## Pharmacokinetics 

**Systemic absorption can take place in both adult and pediatric age groups from the topical application of both drugs**
**Factors leading to increased absorption include:**
**Larger body surface areas**
**Younger age groups, especially the 3 to 23 month age groups due to the larger body surface area to mass ratio**
**Reduced skin barrier function -Netherton’s syndrome, generalized erythrodermic skin conditions, eg. GVHD**

- advisory committeee

## AERS reports of systemic exposure

**Acute renal failure reported in a patient with Netherton’s syndrome secondary to topical absorption of tacrolimus. 0.1% ointment used**
**    ****for 1 year. On admission, tacrolimus level = 34.4 ng/ml, BUN/creatinine = 54/3.4. On discharge, tacrolimus level = 2.3 ng/ml, creatinine = 1.9**
** ****Tacrolimus 0.1% ointment was used in a 11 month old patient to treat GVHD secondary to BMT. Patient died; tacrolimus levels were 75 ng/ml at time of death **

- advisory committeee

## Cases of systemic exposure

*** Literature report  - 7 month patient with BMT secondary to SCID. At age 7 months, single application of tacrolimus 0.1% on scalp for chronic dermatitis               tacrolimus level 24 ng/ml at 20 hours after application. After 7 days, 0.03 % ointment used             level 7 ng/ml at 20 hours after application with transient tremor of the upper limbs and jaw.**
**** Increased tacrolimus levels have been reported in 3 patients with ichthyosis and Netherton’s syndrome  (3-14 years) after treatment with topical tacrolimus.**
**  ***** ****Journal of Pediatrics, August 2003, vol 143, number 2**
**** Arch Dermatology 2001, 137: 747-750**
** **

- advisory committeee

## Cases of systemic exposure

**** ****Literature report - 28 month old patient with lamellar ichthyosis, 0.1% tacrolimus ointment used over 100% of BSA. 7 weeks later            tacrolimus level = 19.3 ng/ml 3 hours after application.  2 weeks later, after **_**decreased amount**_** of use            level 7.4 ng/ml. 2 weeks later, after **_**decreased frequency**_** (twice daily every third day)        tacrolimus level = 5.8 ng/ml.**
**** ****Archives Dermatology, vol 138, Sep. 2002.**

- advisory committeee

## Adverse Effects

**Local (application site):**
**Burning, pruritus, erythema, irritation, edema, urticaria**
**Systemic: **
**Respiratory & gastrointestinal infections, viral skin rashes (herpes simplex and zoster, eczema herpeticum), lymphadenopathy, streptococcal & staphylococcal infections, leg amputation due to infection (P - no further information), septicemia (T), septic arthritis (P), renal failure (T)**

- advisory committeee

## Systemic immunosuppression and malignancies

**Patients receiving Prograf (systemic tacrolimus) are at an increased risk of developing Hodgkin’s, Non-Hodgkin’s lymphomas, Kaposi’s sarcomas, and in particular skin cancers such as squamous cell carcinomas (SCC), basal cell carcinomas (BCC) and malignant melanomas **
**Literature reports suggest a correlation between tumor regression and reduction in immunosuppression**

- advisory committeee

## Systemic immunosuppression and malignancies

**       ****Comparative incidence of de novo non-lymphoid malignancies after liver transplantation under tacrolimus protocols done using SEER data**
**1000 liver transplant patients, median follow-up 6.5 years, 57 malignancies**
**22/57 (33.3%) were skin malignancies; 50% SCC, 40.9% BCC, 9.1% melanomas **
**SEER incidence rates not available for SCC & BCC **
**Malignant melanoma - 1.94 times SEER rates**
**Oropharyngeal cancers - 7.6 times SEER rates**** **
**** Transplantation 1998;66:1193-200, Jain AB, Yee LD, Nalesnik et al.***

- advisory committeee

## Systemic immunosuppression & skin cancers*

**Squamous & basal cell carcinomas account for > 90% of all skin cancers in transplant recipients; melanomas 6.2% in adults (15% in children)**
**Cancers more aggressive, incidence increases with duration of immunosuppressive therapy; tapering therapy usually decreases rate**
**Cancers affect 50% or more of white transplant patients (genetic difference present)**
**Australian study – incidence 7% after I year of therapy, increased to 82% after 20 years **
**Dutch study – incidence 0.2% after 1 year and long-term incidence 41%.**
**   *****N Engl J Med 2003; 348:1681-91. Skin cancers after organ transplantation.**

- advisory committeee

## Systemic immunosuppression and lymphoma

**Post transplant lymphoproliferative disorder (PTLD) in immunosuppressed patients related to Epstein-Barr virus infection is a well-recognized complication **
**Risk of PTLD appears greatest in young children who are at risk for EBV infection while immunosuppressed***
**Risk appears to be related to the intensity and duration of immunosuppression**
** ***** ****Prograf label**

- advisory committeee

## Possible mechanisms of topical immunosuppressants in causing malignancy-related events

**Topical immunosuppressants may ‘break’ local immune surveillance resulting in skin cancers**
**T & P draining from atopic skin into regional lymph nodes may result in immunosuppression **
**Systemic exposure to these drugs  over a course of time could lead to the formation of lymphomas and skin cancers**

- advisory committeee

## Case report of lentigines in area of topical tacrolimus use

**   ***** 3 children with severe atopic dermatitis were noted at routine follow-up to have developed multiple small pigmented macules during long-term therapy with topical tacrolimus 0.1%. **
_**4 year old patient**_** with severe AD, tacrolimus 0.1% ointment used; 6 months after start of therapy, multiple lentigines noted over sites of continued tacrolimus use. **
_**7 year old patient**_** with severe AD, tacrolimus 0.1% ointment used; 5 months after start of therapy, multiple lentigines noted especially over area of therapy.  **
*** British journal of Dermatology 2005; 152, 152-154**

- advisory committeee

## Case report of lentigines in area of topical tacrolimus use

_**11 year old patient**_** with severe AD, tacrolimus 0.1% ointment used; after about 3 and a half years of onset of therapy, multiple lentigines noted, especially over area of therapy. **
**Histology confirmation present in 2 cases, treatment discontinued, lesions persisted.**
**Lentigines also occurred at sun-protected sites. **
**Per report, focal distribution of lentigines to sites of tacrolimus use and the temporal association between use of tacrolimus and development of lesions suggest direct etiology. **

- advisory committeee

## Case report (cont’d)

**Simple lentigines are small pigmented macules that usually appear in childhood on sun-exposed sites. **
**They represent the simplest form of melanocytic neoplasia and are one end of a spectrum of melanocytic maturation that ranges from lentigines to junctional, compound and dermal naevi. **
**Post-inflammatory changes documented in AD, but, discrete pigmented macules are not documnted.**
**Systemic immunosuppressants reported to cause an increase in melanocytic activity.**
**Does topical tacrolimus have an effect (undefined) on melanocyte biology ?**

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## Concerns in the pediatric age groups

**Long-term effects of topical immunosuppressants and their effects on the developing immune system in infants and children are unknown**
**Medications used on an intermittent, long-term basis**
**About one third of children with moderate to severe AD may continue to use these drugs into teenage and adult years**

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## Expanding use

**   ****Literature reports suggest use in following conditions:**
**Contact dermatitis, chronic hand dermatitis, seborrheic dermatitis, rosacea, psoriasis, lichen planus, lichen sclerosus et atrophicus, Graft vs. Host disease, pyoderma gangrenosum, etc  **
*** Pimecrolimus: Patients 3-18 months, ‘atopic march’ study – investigating benefits of long-term management of AD, starting in infants at first sign of disease**
**      ***** Novartis web site**

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## Use characteristics 

**Use of both drugs is increasing in the US**
**Use is increasing in the pediatric age groups**
**Substantial proportion of use is in children < 2 years of age**
**How often are they being used first-line?**

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## Concerns about long-term use

**Both drugs are being widely reported as safe and effective with some local side effects, but being ‘steroid-free’**
**In medical and non-medical journals, need for long-term safety information and larger patient numbers is often ignored**

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## October 2003 Pediatric Advisory Committee Meeting

**5 malignancy related events associated with tacrolimus and 2 non-malignant tumors with pimecrolimus**
**   ****(Newer malignancy related events have since been reported)**
**Logistics of cancer registry was to be discussed**
**Difficult to initiate, answers not available for 10 to 12 years, inconclusive**
**Label revisions, addition of a ‘black box’ and other risk management issues were discussed**

- advisory committeee

## Recent History

**                       ****AERS malignancy related reports for tacrolimus and pimecrolimus since approval**
**21 with tacrolimus **
**9 with pimecrolimus **
**   **
**   ****Confounding factors not unusual for AERS events**
**                **
**                 **

- advisory committeee

## Recent Concerns 

**UNCERTAIN RISK FOR CANCER**
**Biological plausibility**
**Emerging signal in AERS **
**Difficult to study and ‘answers’ would be late**
**INFORMATIONAL LANDSCAPE**
**Suggests ‘first-line’**
**‘****Steroid-free’, Direct-to-consumer advertising **
**Other indications**
**Peer and non-peer reviewed literature portrays safety**
**CURRENT PRACTICES**
**Overall use increasing**
**Use in < 2 years increasing**

- advisory committeee