1. Pediatric Subcommittee of the AIDAC October 29-30, 2003 1 Topical Immunosuppressants (Calcineurin Inhibitors) - Animal Toxicology October 30, 2003 Barbara Hill, Ph.D. Division of Dermatologic and Dental Drug Products

2. Pediatric Subcommittee of the AIDAC October 29-30, 2003 2 Overall Objective Compare the animal toxicology data available for two topical immunosuppressants (Calcineurin Inhibitors) that have recently been approved for the topical treatment of atopic dermatitis Protopic (tacrolimus) ointment (12-8- 00) and Elidel (pimecrolimus) cream (12-13-01) Compare the animal toxicology data available for two topical immunosuppressants (Calcineurin Inhibitors) that have recently been approved for the topical treatment of atopic dermatitis Protopic (tacrolimus) ointment (12-8- 00) and Elidel (pimecrolimus) cream (12-13-01)

3. Pediatric Subcommittee of the AIDAC October 29-30, 2003 3 OutlineOutline StructuresStructures General ToxicologyGeneral Toxicology Genetic Toxicology StudiesGenetic Toxicology Studies Photoco-carcinogenicity StudiesPhotoco-carcinogenicity Studies Carcinogenicity StudiesCarcinogenicity Studies Overall SummaryOverall Summary StructuresStructures General ToxicologyGeneral Toxicology Genetic Toxicology StudiesGenetic Toxicology Studies Photoco-carcinogenicity StudiesPhotoco-carcinogenicity Studies Carcinogenicity StudiesCarcinogenicity Studies Overall SummaryOverall Summary

4. Pediatric Subcommittee of the AIDAC October 29-30, 2003 4 StructuresStructures Tacrolimus Pimecrolimus

5. Pediatric Subcommittee of the AIDAC October 29-30, 2003 5 General Toxicology Potential immune target organs of toxicity identified in chronic rodent and nonrodent toxicology studies include thymus, lymph nodes and spleen Nonclinical toxicology study results indicate both compounds are classic immunosuppressive agents Potential immune target organs of toxicity identified in chronic rodent and nonrodent toxicology studies include thymus, lymph nodes and spleen Nonclinical toxicology study results indicate both compounds are classic immunosuppressive agents

6. Pediatric Subcommittee of the AIDAC October 29-30, 2003 6 Genetic Toxicology Tacrolimus Conducted an appropriate battery of in vitro and in vivo genotoxicity tests Non-genotoxic Tacrolimus Conducted an appropriate battery of in vitro and in vivo genotoxicity tests Non-genotoxic Pimecrolimus Conducted an appropriate battery of in vitro and in vivo genotoxicity tests Non-genotoxic

7. Pediatric Subcommittee of the AIDAC October 29-30, 2003 7 Carcinogenic Mechanisms Not all carcinogens are direct acting genotoxic (DNA reactive) agents Indirect-acting carcinogens – Do not interact directly with DNA – Carcinogenesis is based on another mechanism – e.g., hormones, immunosuppressants Not all carcinogens are direct acting genotoxic (DNA reactive) agents Indirect-acting carcinogens – Do not interact directly with DNA – Carcinogenesis is based on another mechanism – e.g., hormones, immunosuppressants

8. Pediatric Subcommittee of the AIDAC October 29-30, 2003 8 Photoco-carcinogenicity Study Objective:Objective: –To determine in a hairless mouse model if dermal test article application combined with simulated sunlight exposure can reduce the time to formation of skin papillomas compared to simulated sunlight exposure alone Objective:Objective: –To determine in a hairless mouse model if dermal test article application combined with simulated sunlight exposure can reduce the time to formation of skin papillomas compared to simulated sunlight exposure alone

9. Pediatric Subcommittee of the AIDAC October 29-30, 2003 9 Photoco-carcinogenicity Study A positive effect in this assay is referred to as an enhancement of the UV skin photo-carcinogenic effect, which is defined as shortening the time to skin tumor formation

10. Pediatric Subcommittee of the AIDAC October 29-30, 2003 10 Photoco-carcinogenicity Study Tacrolimus Vehicle ointment enhanced UV photo- carcinogenesisVehicle ointment enhanced UV photo- carcinogenesis Tacrolimus ointment had an additional small effectTacrolimus ointment had an additional small effect Tacrolimus Vehicle ointment enhanced UV photo- carcinogenesisVehicle ointment enhanced UV photo- carcinogenesis Tacrolimus ointment had an additional small effectTacrolimus ointment had an additional small effect Pimecrolimus Vehicle cream enhanced UV photo- carcinogenesisVehicle cream enhanced UV photo- carcinogenesis Pimecrolimus cream had no additional effectPimecrolimus cream had no additional effect

11. Pediatric Subcommittee of the AIDAC October 29-30, 2003 11 Photoco-carcinogenicity Study Result of nonclinical finding: –a precaution was included in the label of each drug product advising patients to minimize or avoid exposure to natural or artificial sunlight while using the drug product Result of nonclinical finding: –a precaution was included in the label of each drug product advising patients to minimize or avoid exposure to natural or artificial sunlight while using the drug product

12. Pediatric Subcommittee of the AIDAC October 29-30, 2003 12 Carcinogenicity Studies Tacrolimus Oral rat Oral mouse Dermal mouse (marketed formulation) Tacrolimus Oral rat Oral mouse Dermal mouse (marketed formulation) Pimecrolimus Oral rat Oral mouse Dermal rat (marketed formulation) Dermal mouse (ethanol - 13 week; special high dose studies)

13. Pediatric Subcommittee of the AIDAC October 29-30, 2003 13 Carcinogenicity Studies A treatment related tumor is identified as a statistically significant increase in the incidence of the tumor in treated animals compared to vehicle control animals Treatment related tumors are expressed in both labels as a multiple of human exposure based on AUC comparisons to the maximum recommended human dose (MRHD) A treatment related tumor is identified as a statistically significant increase in the incidence of the tumor in treated animals compared to vehicle control animals Treatment related tumors are expressed in both labels as a multiple of human exposure based on AUC comparisons to the maximum recommended human dose (MRHD)

14. Pediatric Subcommittee of the AIDAC October 29-30, 2003 14 Oral Carcinogenicity Studies - Lymphoma Signal

15. Pediatric Subcommittee of the AIDAC October 29-30, 2003 15 Dermal Carcinogenicity Studies - Lymphoma Signal

16. Pediatric Subcommittee of the AIDAC October 29-30, 2003 16 Carcinogenicity Studies - Other Tumor Signal

17. Pediatric Subcommittee of the AIDAC October 29-30, 2003 17 Overall Summary Protopic (tacrolimus) ointment and Elidel (pimecrolimus) cream are topical immunosuppressants Neither tacrolimus or pimecrolimus exhibited a genotoxic signal Both Protopic ointment and Elidel cream contain cautionary wording in the labels to avoid sunlight exposure Protopic (tacrolimus) ointment and Elidel (pimecrolimus) cream are topical immunosuppressants Neither tacrolimus or pimecrolimus exhibited a genotoxic signal Both Protopic ointment and Elidel cream contain cautionary wording in the labels to avoid sunlight exposure

18. Pediatric Subcommittee of the AIDAC October 29-30, 2003 18 Overall Summary A lymphoma signal was evident in a dermal mouse carcinogenicity study conducted with tacrolimus ointment A lymphoma signal was evident in an oral mouse carcinogenicity study conducted with pimecrolimus A lymphoma signal was evident in the 13 week dermal mouse study conducted with pimecrolimus dissolved in ethanol A lymphoma signal was evident in a dermal mouse carcinogenicity study conducted with tacrolimus ointment A lymphoma signal was evident in an oral mouse carcinogenicity study conducted with pimecrolimus A lymphoma signal was evident in the 13 week dermal mouse study conducted with pimecrolimus dissolved in ethanol

19. Pediatric Subcommittee of the AIDAC October 29-30, 2003 19 Overall Summary body surface area that is treated in an atopic dermatitis patientThe estimates of human systemic exposure data are highly variable and are dependent on the maximum body surface area that is treated in an atopic dermatitis patient It is acknowledged that demonstrating this effect could be technically challenging)Biologic plausibility of lymphoma formation in local lymph nodes can not be ruled out at this time (It is acknowledged that demonstrating this effect could be technically challenging) body surface area that is treated in an atopic dermatitis patientThe estimates of human systemic exposure data are highly variable and are dependent on the maximum body surface area that is treated in an atopic dermatitis patient It is acknowledged that demonstrating this effect could be technically challenging)Biologic plausibility of lymphoma formation in local lymph nodes can not be ruled out at this time (It is acknowledged that demonstrating this effect could be technically challenging)

20. Pediatric Subcommittee of the AIDAC October 29-30, 2003 20 Overall Summary Other tumor signals included: –Benign thymoma noted in the oral rat carcinogenicity study conducted with pimecrolimus –Follicular cell adenoma of the thyroid noted in the dermal rat carcinogenicity study conducted with pimecrolimus cream Other tumor signals included: –Benign thymoma noted in the oral rat carcinogenicity study conducted with pimecrolimus –Follicular cell adenoma of the thyroid noted in the dermal rat carcinogenicity study conducted with pimecrolimus cream

21. Pediatric Subcommittee of the AIDAC October 29-30, 2003 21 Overall Summary Based on the carcinogenic signals noted in nonclinical studies, registry studies were recommended as a phase 4 commitment for both Protopic (tacrolimus) ointment and Elidel (pimecrolimus) cream