1. Pediatric Subcommittee of the AIDAC October 29-30, 2003 Topical Immunosuppressants Bindi M. Nikhar, M.D., FAAP Division of Dermatologic and Dental Drug Products, ODE V Bindi M. Nikhar, M.D., FAAP Division of Dermatologic and Dental Drug Products, ODE V

2. Pediatric Subcommittee of the AIDAC October 29-30, 2003 2 TOPICAL IMMUNOSUPPRESSANTS Newest pharmacological class for AD Introduced in this decade Direct immunosuppressive action in diseases with an immunological basis 2 currently FDA approved products Tacrolimus (FK506) (trade name Protopic) Pimecrolimus (SDZ ASM 981) (trade name Elidel) Newest pharmacological class for AD Introduced in this decade Direct immunosuppressive action in diseases with an immunological basis 2 currently FDA approved products Tacrolimus (FK506) (trade name Protopic) Pimecrolimus (SDZ ASM 981) (trade name Elidel)

3. Pediatric Subcommittee of the AIDAC October 29-30, 2003 3 BackgroundBackground Tacrolimus ointment approved on 12/08/2000, 0.03% ointment approved for children 2 to 15 years, 0.1% ointment approved for adults. Indication in both age groups is short and intermittent long term therapy of patients with moderate to severe AD. Systemic Tacrolimus (Prograf) first introduced for prevention of allograft rejection, now used in kidney, liver and heart transplantation Tacrolimus ointment approved on 12/08/2000, 0.03% ointment approved for children 2 to 15 years, 0.1% ointment approved for adults. Indication in both age groups is short and intermittent long term therapy of patients with moderate to severe AD. Systemic Tacrolimus (Prograf) first introduced for prevention of allograft rejection, now used in kidney, liver and heart transplantation

4. Pediatric Subcommittee of the AIDAC October 29-30, 2003 4 Elidel cream 1% approved on 12/13/2001. Indicated for patients 2 years of age and older for short and intermittent long term therapy in the treatment of mild to moderate atopic dermatitis. Both drugs not approved for use in children less than 2 years of age. Systemic absorption can take place in both adult and pediatric age groups from the topical application of both drugs. Currently, the effects of topical immunosuppressants on the developing immune system are unknown. Elidel cream 1% approved on 12/13/2001. Indicated for patients 2 years of age and older for short and intermittent long term therapy in the treatment of mild to moderate atopic dermatitis. Both drugs not approved for use in children less than 2 years of age. Systemic absorption can take place in both adult and pediatric age groups from the topical application of both drugs. Currently, the effects of topical immunosuppressants on the developing immune system are unknown. Background (cont’d)

5. Pediatric Subcommittee of the AIDAC October 29-30, 2003 5 Pharmacokinetic (PK) studies for Tacrolimus Pooled results from 2 PK studies in 49 adult moderate-severe AD patients indicate that tacrolimus is absorbed after the topical application of 0.1% Protopic ointment. Peak tacrolimus levels ranged from undetectable to 20 ng/ml after single or multiple doses of 0.1% Protopic ointment, 45 out of the 49 patients had peak concentrations less than 5 ng/ml. Pooled results from 2 PK studies in 49 adult moderate-severe AD patients indicate that tacrolimus is absorbed after the topical application of 0.1% Protopic ointment. Peak tacrolimus levels ranged from undetectable to 20 ng/ml after single or multiple doses of 0.1% Protopic ointment, 45 out of the 49 patients had peak concentrations less than 5 ng/ml.

6. Pediatric Subcommittee of the AIDAC October 29-30, 2003 6 Pharmacokinetic studies for Tacrolimus (cont’d) A PK study of 0.1% Protopic ointment in 20 pediatric AD patients (ages 6-13 years), showed peak tacrolimus concentrations below 1.6 ng/ml in all patients. Absolute bioavailability of topical tacrolimus is unknown. Using iv historical data for comparison, the bioavailability of tacrolimus from Protopic in AD patients is < 0.5%. Lowest tacrolimus blood level at which systemic effects can be observed is not known. A PK study of 0.1% Protopic ointment in 20 pediatric AD patients (ages 6-13 years), showed peak tacrolimus concentrations below 1.6 ng/ml in all patients. Absolute bioavailability of topical tacrolimus is unknown. Using iv historical data for comparison, the bioavailability of tacrolimus from Protopic in AD patients is < 0.5%. Lowest tacrolimus blood level at which systemic effects can be observed is not known.

7. Pediatric Subcommittee of the AIDAC October 29-30, 2003 7 Pharmacokinetic studies for Pimecrolimus In adults treated for AD with 13–62% BSA involvement for periods up to a year, detectable pimecrolimus blood concentrations were < 2 ng/ml (LOQ <0.5 ng/ml). In 26 pediatric patients between 2-14 years with AD (20-69% BSA involvement) who had b.i.d. application for 3 weeks, blood concentrations of pimecrolimus were < 3 ng/ml (LOQ < 0.5 ng/ml) In adults treated for AD with 13–62% BSA involvement for periods up to a year, detectable pimecrolimus blood concentrations were < 2 ng/ml (LOQ <0.5 ng/ml). In 26 pediatric patients between 2-14 years with AD (20-69% BSA involvement) who had b.i.d. application for 3 weeks, blood concentrations of pimecrolimus were < 3 ng/ml (LOQ < 0.5 ng/ml)

8. Pediatric Subcommittee of the AIDAC October 29-30, 2003 8 Pharmacokinetic studies for Pimecrolimus (cont’d) 20 out of 23 children investigated had at least one detectable blood level as compared to adults (13 out of 25 investigated) over a 3 week period. In 22 pediatric patients aged 3 to 23 months with 10-92% BSA involvement, a higher proportion of blood levels ranging from 0.1 to 2.6 ng/ml (LOQ 0.1 ng/ml) was seen. 20 out of 23 children investigated had at least one detectable blood level as compared to adults (13 out of 25 investigated) over a 3 week period. In 22 pediatric patients aged 3 to 23 months with 10-92% BSA involvement, a higher proportion of blood levels ranging from 0.1 to 2.6 ng/ml (LOQ 0.1 ng/ml) was seen.

9. Pediatric Subcommittee of the AIDAC October 29-30, 2003 9 Pharmacokinetic studies for Pimecrolimus (cont’d) This increase may be due to larger surface area to body mass ratio seen in younger subjects. A higher incidence of upper respiratory symptoms/infections was also seen in the 3-23 months age group relative to the older age group in PK studies. A causal relationship between these findings and Elidel use cannot be ruled out. This increase may be due to larger surface area to body mass ratio seen in younger subjects. A higher incidence of upper respiratory symptoms/infections was also seen in the 3-23 months age group relative to the older age group in PK studies. A causal relationship between these findings and Elidel use cannot be ruled out.

10. Pediatric Subcommittee of the AIDAC October 29-30, 2003 10 Pharmacokinetics (cont’d) Some factors leading to higher systemic levels include Higher body surface area Younger age groups, especially the 3 to 23 month age groups as seen with pimecrolimus, this may be due to larger surface area to body mass ratio (this age group has not had pharmacokinetic testing for tacrolimus levels) Reduced skin barrier function eg. Netherton’s syndrome Some factors leading to higher systemic levels include Higher body surface area Younger age groups, especially the 3 to 23 month age groups as seen with pimecrolimus, this may be due to larger surface area to body mass ratio (this age group has not had pharmacokinetic testing for tacrolimus levels) Reduced skin barrier function eg. Netherton’s syndrome

11. Pediatric Subcommittee of the AIDAC October 29-30, 2003 11 Pediatric clinical studies Use of Protopic 0.03% ointment was studied in children 2-15 years of age by conducting 2 Phase 3 studies. In these studies, varicella zoster and vesiculobullous rash were seen more frequently in patients treated with Protopic ointment 0.03%, compared to vehicle. Use of Protopic 0.03% ointment was studied in children 2-15 years of age by conducting 2 Phase 3 studies. In these studies, varicella zoster and vesiculobullous rash were seen more frequently in patients treated with Protopic ointment 0.03%, compared to vehicle.

12. Pediatric Subcommittee of the AIDAC October 29-30, 2003 12 Pediatric clinical studies (cont’d) Elidel cream 0.1% was studied in infants 3-23 months of age and in children 2-17 years of age. In the 2-17 years age group, nasopharyngitis, influenza, viral infections, pyrexia,cough, headache, eczema herpeticum were increased over vehicle in the 1 year safety study. Elidel cream 0.1% was studied in infants 3-23 months of age and in children 2-17 years of age. In the 2-17 years age group, nasopharyngitis, influenza, viral infections, pyrexia,cough, headache, eczema herpeticum were increased over vehicle in the 1 year safety study.

13. Pediatric Subcommittee of the AIDAC October 29-30, 2003 13 Pediatric clinical studies (cont’d) In the 3-23 months short term (6 week) infant study, pyrexia, URI, nasopharyngitis, gastroenteritis, otitis media, diarrhea seen more frequently compared to vehicle. The adverse event incidence for those in the open label phase of this study who switched over to Elidel cream from vehicle approached the incidence of those patients who remained on the cream.

14. Pediatric Subcommittee of the AIDAC October 29-30, 2003 14 Pediatric clinical studies (cont’d) In the 6 month infant study safety data, adverse events occurring more frequently in the Elidel cream group compared to vehicle included pyrexia, URI, cough, vomiting, hypersensitivity, rhinitis, viral rash, rhinorrhea, and wheezing.

15. Pediatric Subcommittee of the AIDAC October 29-30, 2003 15 Indications for use (Second-line) Both Protopic and Elidel are 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

16. Pediatric Subcommittee of the AIDAC October 29-30, 2003 16 Proposed Mechanisms of Action * Both Tacrolimus and Pimecrolimus inhibit T- cell activation by binding to the same cellular receptor, the FK-binding protein (FKBP) or macrophilin-12. * The tacrolimus/pimecrolimus-FKBP complex further binds to calcineurin, which is an enzyme vital for early activation of both T helper cell types 1 and 2. * Both Tacrolimus and Pimecrolimus inhibit T- cell activation by binding to the same cellular receptor, the FK-binding protein (FKBP) or macrophilin-12. * The tacrolimus/pimecrolimus-FKBP complex further binds to calcineurin, which is an enzyme vital for early activation of both T helper cell types 1 and 2.

17. Pediatric Subcommittee of the AIDAC October 29-30, 2003 17 Adverse Effects of Topical Immunosuppressants Local (Application site) Burning Pruritus Erythema Irritation Edema Urticaria Local (Application site) Burning Pruritus Erythema Irritation Edema Urticaria

18. Pediatric Subcommittee of the AIDAC October 29-30, 2003 18 Adverse effects of Topical Immunosuppressants (cont’d) Systemic Pyrexia Upper and lower respiratory tract infection Nasopharyngitis Viral skin rashes eg. molluscum contagiosum, herpes simplex, herpes zoster, eczema herpeticum Influenza Systemic Pyrexia Upper and lower respiratory tract infection Nasopharyngitis Viral skin rashes eg. molluscum contagiosum, herpes simplex, herpes zoster, eczema herpeticum Influenza

19. Pediatric Subcommittee of the AIDAC October 29-30, 2003 19 Adverse effects of Topical Immunosuppressants cont’d Systemic side effects cont’d Otitis media Gastroenteritis, vomiting, diarrhea Streptococcal pharyngitis, staphylococcal infection Skin infection NOS Lymphadenopathy - In absence of a clear etiology or in the presence of acute infectious mononucleosis, discontinuation recommended. Close monitoring required. Systemic side effects cont’d Otitis media Gastroenteritis, vomiting, diarrhea Streptococcal pharyngitis, staphylococcal infection Skin infection NOS Lymphadenopathy - In absence of a clear etiology or in the presence of acute infectious mononucleosis, discontinuation recommended. Close monitoring required.

20. Pediatric Subcommittee of the AIDAC October 29-30, 2003 20 Adverse effects of Prograf Patients receiving Prograf are at an increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression. A lymphoproliferative disorder (LPD) related to Epstein-Barr virus infection has been reported in immunosuppressed patients. The risk of LPD appears greatest in young children who are at risk for primary EBV infection while immunosuppressed.

21. Pediatric Subcommittee of the AIDAC October 29-30, 2003 21 Potential long-term adverse effects of topical immunosuppressants Increased incidence of malignancies in animal studies with topical tacrolimus(T) and pimecrolimus (P): –Lymphomas [P & T] –Follicular cell adenomas [P] –Skin tumors (with concurrent UV radiation exposure) [P &T] Increased incidence of malignancies in animal studies with topical tacrolimus(T) and pimecrolimus (P): –Lymphomas [P & T] –Follicular cell adenomas [P] –Skin tumors (with concurrent UV radiation exposure) [P &T]

22. Pediatric Subcommittee of the AIDAC October 29-30, 2003 22 Since systemic use of calcineurin inhibitors is associated with formation of lymphomas and skin malignancies, low systemic exposure from topical calcineurin inhibitors over a course of time leading to a cumulative dose effect may lead to melanomas, non-melanoma skin cancers, Hodgkin’s and Non- Hodgkin’s lymphomas Potential long-term adverse effects (cont’d)

23. Pediatric Subcommittee of the AIDAC October 29-30, 2003 23 Concerns about long term side effects Children from the age of 2 years and upwards (with off- label use expected in even younger children) will be using these medications on a short or intermittent long term basis About one third of children with moderate- severe AD may continue to use these drugs into teenage and adult years, thereby having a long duration of exposure. Children from the age of 2 years and upwards (with off- label use expected in even younger children) will be using these medications on a short or intermittent long term basis About one third of children with moderate- severe AD may continue to use these drugs into teenage and adult years, thereby having a long duration of exposure.

24. Pediatric Subcommittee of the AIDAC October 29-30, 2003 24 Concerns about long term side effects (cont’d) Currently, we do not have long term safety data on either Tacrolimus or Pimecrolimus. Postmarketing evaluation of topical immunosuppressants is needed to evaluate this potential risk. Means of setting up these prospective studies need to be discussed. Currently, we do not have long term safety data on either Tacrolimus or Pimecrolimus. Postmarketing evaluation of topical immunosuppressants is needed to evaluate this potential risk. Means of setting up these prospective studies need to be discussed.