1. 1 Advisory Committee Meeting, 15 February, 2005. 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

2. 2 Advisory Committee Meeting, 15 February, 2005. IntroductionIntroduction Topical immunosuppressants are the newest class of drugs to be approved for atopic dermatitis (AD) They belong to a class of drugs known as macrolactam immunosuppressants, 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) Topical immunosuppressants are the newest class of drugs to be approved for atopic dermatitis (AD) They belong to a class of drugs known as macrolactam immunosuppressants, 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)

3. 3 Advisory Committee Meeting, 15 February, 2005. 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 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

4. 4 Advisory Committee Meeting, 15 February, 2005. TacrolimusTacrolimus 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 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

5. 5 Advisory Committee Meeting, 15 February, 2005. TacrolimusTacrolimus 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 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

6. 6 Advisory Committee Meeting, 15 February, 2005. PimecrolimusPimecrolimus 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. 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.

7. 7 Advisory Committee Meeting, 15 February, 2005. 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 (%) 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 (%)

8. 8 Advisory Committee Meeting, 15 February, 2005. 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 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

9. 9 Advisory Committee Meeting, 15 February, 2005. 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 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

10. 10 Advisory Committee Meeting, 15 February, 2005. 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 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

11. 11 Advisory Committee Meeting, 15 February, 2005. PharmacokineticsPharmacokinetics 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 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

12. 12 Advisory Committee Meeting, 15 February, 2005. 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 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

13. 13 Advisory Committee Meeting, 15 February, 2005. 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 * 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

14. 14 Advisory Committee Meeting, 15 February, 2005. 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. ** 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.

15. 15 Advisory Committee Meeting, 15 February, 2005. 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) 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)

16. 16 Advisory Committee Meeting, 15 February, 2005. 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 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

17. 17 Advisory Committee Meeting, 15 February, 2005. 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. 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.

18. 18 Advisory Committee Meeting, 15 February, 2005. 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. 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.

19. 19 Advisory Committee Meeting, 15 February, 2005. 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 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

20. 20 Advisory Committee Meeting, 15 February, 2005. 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 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

21. 21 Advisory Committee Meeting, 15 February, 2005. 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 * 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

22. 22 Advisory Committee Meeting, 15 February, 2005. 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. 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.

23. 23 Advisory Committee Meeting, 15 February, 2005. 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 ? 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 ?

24. 24 Advisory Committee Meeting, 15 February, 2005. 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 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

25. 25 Advisory Committee Meeting, 15 February, 2005. 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 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

26. 26 Advisory Committee Meeting, 15 February, 2005. 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? 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?

27. 27 Advisory Committee Meeting, 15 February, 2005. 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 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

28. 28 Advisory Committee Meeting, 15 February, 2005. 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 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

29. 29 Advisory Committee Meeting, 15 February, 2005. 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 AERS malignancy related reports for tacrolimus and pimecrolimus since approval 21 with tacrolimus 9 with pimecrolimus Confounding factors not unusual for AERS events

30. 30 Advisory Committee Meeting, 15 February, 2005. 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 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