# Presentation: 403350

## Elidel® (pimecrolimus) Cream 1%Safety Update Feb, 2005

**Thomas Hultsch, MD**
**Senior Medical Director**
**Novartis Pharmaceuticals Corporation**

## Overview

**No clinical evidence for increased risk of malignancies**
**No evidence for systemic immunosuppression**
**Pharmacokinetics**
**Immunocompetence in children **
**Infections rates in children**
**Ongoing safety monitoring programs **
**Conclusions**

## Is there clinical evidence of increased risk of malignancies?

**Is there clinical evidence of increased risk of malignancies?**

## Elidel®—The Clinical Experience

**In clinical studies > 19,000 patients since 1996**
**~ 3,000 infants (3 - 24 mo)**
**> 7,000 children (2 - 17 yr)**
**In clinical practice > 5 million patients since Dec 2001**
**~ 2.7 million patients < 10 years of age**
**Average Elidel usage**
**Intermittently, 45 days/year**
**~ 1.6 grams/day **

## Reports of Malignancies—Clinical Trials 

**Novartis data as of January 15, 2005.**

***Clinical studies show no evidence of an increased risk of malignancies***

**Clinical trials**
** ****(n = 7)**

## Reports of Malignancies—Spontaneous Reporting

**Male, 2.5 yr**

**Male, 53 yr**

**Unknown****†**

**Basal cell carcinoma**
**male, 53 yr**

**Squamous****cell carcinoma**
**female, 71 yr**

**Female, 61 yr**

**Spontaneous****reports****n = 6**

**Lymphoma ****n = 4**

**Skin tumors ****n = 2**

**† ****Unconfirmed, poorly documented case, non-US.**
**Novartis data as of January 15, 2005.**

## Non-Hodgkin Lymphomas—Spontaneous Reports 

**Novartis data as of January 15, 2005.**

| 
Treatment duration and regimen | 

Extent of Elidel® use |
| --- | --- |
| A few weeks, “continuously”
 | ~ 5% TBSA

 |
| ~ 6 months
intermittent use

 | ~ 60% TBSA

  |
| ~ 6 monthsintermittent use

 | ~ 20% TBSA  |

| Independentexpert assessmentof causality |
| --- |
| Unlikely
 |
| Unlikely

 |
| Unlikely

 |

| 

Sex/age |
| --- |
| Female61 yr
 |
| Male 53 yr

 |
| Male2.5 yr

 |

| 
Lymphoma histology(localization) |
| --- |
| Histiocytic lymphoma (neck) |
| Subcutaneous panniculitis like T-cell lymphoma (trunk, limbs) |
| Lymphoblastic lymphoma (T cell)(mediastinum)
 |

**TBSA = Total body surface area.**

## No Evidence of Increased Incidence of NHL in Any Age Group

|  | < 5 | 5 - 9 | 10 - 14  | 15 - 19  | Totalchildren | Adults | Total(US) |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Person-years of exposure  | 278,842 | 118,196  | 65,224  | 33,431  | 495,694 | 237,030  | 732,724 |

| Expected no of cases (SEER), general population | 1.8 | 1.0 | 0.7 | 0.5 | 4.0 | 42.1 | 46.1 |
| --- | --- | --- | --- | --- | --- | --- | --- |

**SEER = Surveillance, epidemiology, and end result.**

## No Evidence of Immunosuppression

**Pharmacokinetics**
**Objective measures of the immune response**
**Vaccination responses (B-cell dependent)**
**Delayed hypersensitivity (T-cell dependent)**
**Infection rates**

## Pharmacokinetics—Topical

**Skin surface**

**Stratum Corneum**

**Dermis**

**Blood ****circulation**

**Stratum Reticularis**

**Basal cell layer**

**Elidel****® ****Cream 1%**

**10,000 μg/g**

**~700 μg/g**

**~30 μg/g**

**~2 μg/g**

**~0.0005 μg/g**

**Pediatric PK studies, moderate to severe AD, up to 92% TBSA (75 pts/366 samples)**
**68% of samples < [0.5] ng/mL**
**99% of samples < [2.0] ng/mL**
**10 patients with measurable AUCs 11 - 38 ng·h/mL**

## Toxicology Study—Dermal 

**Highest exposure, topical, ****human ****adult patients**

**23**

**Highest exposure, topical, ****human ****pediatric patients**

**38**

**0**

**200**

**400**

**600**

**800**

**1000**

**1200**

**AUC****(0-24h)**** ng· h/mL**

***No malignancies in mice exposed for 104 weeks ***
***at 27× the single highest AUC in pediatric patients***

## Beyond Topical Application— Oral Dosing in Monkey Toxicology Study

**0**

**200**

**400**

**600**

**800**

**1000**

**1200**

**AUC****(0-24h)**** ng· h/mL**

**27× highest human AUC**

## Vaccination Response (B-cell Mediated)No Effect of Elidel® Treatment

**Elidel**

**Range in general population **
**according to literature**

**Patients with protective antibody titre levels, %**

**61 - 80**

**76 - 82**

**79 - 92**

**92**

**91**

**83**

**89**

**82**

**0**

**20**

**40**

**60**

**80**

**100**

**Tetanus**

**Diphtheria**

**Measles**

**Rubella**

**92**

**Papp K, et al. *****J Am Acad Dermatol*****. 2005;52:247-253.**

## Delayed Type Hypersensitivity (T-cell Mediated)No Effect of Elidel® Treatment

**Children treated for 1 year (****n = 112)**

## No Imbalance in Systemic Infections in Children

**Log relative risk (Elidel****®****/vehicle) with 95% CI**

**-4**

**-2**

**0**

**2**

**4**

**CS-**

**Pyrexia**

**Viral infection**

**Urinary tract infection**

**Upper respiratory tract infection**

**Tracheitis**

**Tooth abscess**

**Tonsillitis**

**Sinusitis**

**Rhinitis**

**Respiratory tract infection**

**Pneumonia**

**Pharyngitis streptococcal**

**Pharyngitis**

**Otitis media**

**Otitis externa**

**Nasopharyngitis**

**Lower respiratory tract infection**

**Laryngitis**

**Influenza**

**Gastroenteritis viral**

**Gastroenteritis**

**Enterobiasis**

**Ear infection**

**Conjunctivitis**

**Bronchitis**

**Decreased**

**Increased**

**No Imbalance in Systemic Infections in Children**

**based on incidence density;**
**Elidel (n = 1135), vehicle (n = 707)**

## Skin Infections in Children 

**Skin Infections in Children **

**Log relative risk (Elidel****®****/vehicle) with 95% CI**

**-4**

**-2**

**0**

**2**

**4**

**Viral**

**Skin infection non specified**

**Parasitic**

**Fungal**

**Bacterial**

**based on incidence density;**
**Elidel (n = 1135), vehicle (n = 707)**

**Decreased**

**Increased**

## Extensive Clinical Program Further Monitor Elidel® Safety

**Controlled safety and efficacy study in HIV-positive patients**
**Case control study to assess the risk of non-****melanoma skin cancer in adults**
**6.****	****C****ase control study to assess the risk of melanoma skin cancer in adults**

**6-year safety and efficacy study in infants 3 - 18 mo, started Sep 2003 (n = 1,100)**
**5-year safety study in infants 3 - < 12 mo, started ****Apr 2004 (n = 2,400) **
**10-year, prospective registry to assess risk of malignancies  in children 2 - 17 yr, started Nov 2004 ****(n = 4,000)**

## Elidel® Cream—Conclusion

**Clinical data do not show evidence for an increased risk of malignancies**
**Systemic immunosuppression is clinically implausible based on**
**Pharmacokinetics (minimal blood levels)**
**Maintained immunocompetence**
**No increased risk of systemic infections**

**Extensive clinical program further monitor Elidel safety**