1. Elizabeth Gorevski Kingsbrook Jewish Medical Center Brooklyn, NY

2. Uses of Tacrolimus and Pimecrolimus Tacrolimus Oral/injection: Potent immunosuppressant used in heart, kidney or liver transplant Topical: moderate to severe atopic dermatitis in patients not responsive to conventional therapy Pimecrolimus Topical: Mild to moderate atopic dermatitis in patient not responsive to conventional therapy Munzenberger P et al Pharmacotherapy 2007; 27(7)

3. Treating Atopic Dermatitis International Consensus Conference on Atopic Dermatitis II (ICCAD II) and American Academy of Dermatology (AAD) Pimecrolimus cream 1% - a second-line therapy of mild – moderate atopic dermatitis Tacrolimus ointment 0.03% - moderate – severe atopic dermatitis that inadequately responds to other topicals In children 3-5 only use tacrolimus 0.03% Munzenberger P et al Pharmacotherapy 2007; 27(7)

4. Mechanism of Action Mirsland A. et al Euro J Derm 2002;12(6)

5. Boxed Warning of Tacrolimus and Pimecrolimus Increased susceptibility of infection and the possible development of lymphoma may result from immunosuppression Lymphoma Have been associated with rare cases of skin malignancies, therefore it should be limited to short and intermittent treatment using the minimum amount necessary to control of symptoms and only on areas involved Skin Cancer Should be administered under the supervision of a physician experienced in immunosuppressive therapy in a facility appropriate for monitoring and managing therapy Administration Casual relationship has not been established

6. Why concerns?  Increased risk of malignancies with systemic immunosuppression after long term-high dose for graft rejection in transplant patients Oral tacrolimus associated with posttranslational lymphoproliferative disease Occurs in first 8 months after stem cell transplant in 0.7% of population receiving related donor human leukocyte antigen matched transplants  Animal studies show carcinogenicity Yarosh D, et al J Invest Dermatol 2005; 125

7. Pharmacokinetic Data for Topical Pimecrolimus and Tacrolimus Pharmacokinetic studies with PO and IV tacrolimus Concentrations achieved PO : 82.7 ng/mL (0.075 mg/kg/12 hours) IV : 3300 ng/mL (0.05 mg/kg/12 hours) Sanchez-Perez J at al. Actas Derm 2007; 98

8. Agents Plasma Concentrations Pimecrolimus – Used twice daily led to blood concentrations < 0.5 – 1 ng/mL – Higher concentrations in patients with more extensive disease  Netherton syndrome In transplant patients the systemic administrations has been increased rate of lymphomas, nonmelanoma skin cancer and melanomas in sun exposed areas Plasma concentrations are much lower with topical application then systemic when used in plasma patients Arellano F. et al J Invest Derm 2007; 127

9. Lymphomas No evidence of increased prevalence of lymphomas associated with short term, intermittent topical application According to clinical trials – No observed lymphomas in close to 10,000 patients with tacrolimus – Only 2 cases of solid tumors in 25,000 patients treated with pimecrolimus Pharmacovigilance data – Compared with general population following marketing no increased risk of lymphoma in close to 7 million prescriptions of pimecrolimus and 2 million prescriptions of topical tacrolimus Systemic administration – Posttransplant lymphoproliferative disease ranges from 2% - 60 % in patient and is most common with small intestant transplant – Lymphomas regress spontaneously upon discontinuation of therapy in 30% - 50 % of cases Arellano F. et al J Invest Derm 2007; 127

10. Skin Cancer Clinical trials – 13 cases of nonmalenoma skin cancer, 10 basal cell epithelimas and 3 sqamous cell carcinomas observed in 10,000 patients treated FDA report in December 2004 – 10 cases of skin tumors in patients treated with tacrolimus – 6 cases of basla and sqamous cell carcinomas in patients treated with pimecrolimus – In subsequent publications number increased to 21 cases Prospective study of 9813 patients with atopic dermatitis for 208 days – No increase was in nonmelanoma cancer was observed when 0.1% and 0.003% tacrolimus cream was used Arellano F. et al J Invest Derm 2007; 127

11. A Cohort Analysis  293, 253 patients 58.6% < 20 years old Almost 60% female 20% met criteria for severe atopic dermatitis  Topical agents at follow up 40% used topical steroids 7.4% pimecrolimus 13.7% tacrolimus 0.9% to pimecrolimus and tacrolimus Almost half of patients did not use medications  Most patients were enrolled in database from 2001 onward  Atopic dermatitis was diagnosed by family physician, pediatrician or dermatologist Arellano F. et al J Invest Derm 2007; 127

12. Exposure to Medication and Risk of Lymphoma MedicationCasesControlsOR95% CI Non-use1316031 Top corticosteroids (high potency) 721951.230.83 – 1.84 Top corticosteroids (low potency) 612631.060.72 – 1.57 Pimecrolimus14650.820.42 – 1.61 Pimecrolimus with TS9271.090.45 – 2.64 Pimecrolimus without TS5380.600.21 – 1.69 Tacrolimus11410.790.37 – 1.71 Tacrolumus with TS9280.930.39 – 2.22 Tacrolimus without TS2130.50.10 – 2.53 Pimecrolimus +Tacrolimus with TS 491.010.25 – 4.12 Pimecrolimus +Tacrolimus without TS 10INF Arellano F. et al J Invest Derm 2007; 127

13. Risk of Lymphoma According to Age AgeCasesControlsOR95 % CI 0 – 2241811.00 3 – 5171420.940.48 – 1.82 6 – 10101610.480.22 – 1.03 11 – 20301971.180.66 – 2.11 21 – 3011850.990.46 – 2.13 31 – 40311341.670.93 – 2.99 41 – 50651353.672.17 – 6.23 51 – 60741184.752.79 – 8.10 > 6132239.674.74 – 19.72 Arellano F. et al J Invest Derm 2007; 127

14. International Consensus European Academy of Dermatology No casual relationship between use of topical calcineurin inhibitors and cancer in humans Spanish Academy of Dermatology and Venereology Rare cases of cancer have not been associated with the use of these medications Number of cases reported with use of calcineurin inhibitors are lower than the incidence in general population American Academy of Dermatology Published declaration against the FDA’s proposal for boxed warning Data demonstrating danger of topical calcienurin inhibitors is unavailable and may cause concern among patients

15. Conclusions  Pharmacokinetics data do not suggest that TCI affect the systemic immune system, as their oral counterparts  There is no data associated with an increased risk of lymphoproliferative disease with topical tacrolimus and pimecrolimus  Short term efficacy and safety data was demonstrated in clinical trials and post-surveillance in approximately 11 million patients  Several professional and patient organization are supporting safety, with close monitoring  Box warning itself states no casual link between TCI and malignancy  Post marketing surveillance for at least 8 – 10 years is required to ensure safety

16. Application to Pharmacists Is patient > 2 years? Age Have they tried 1 st line agents? History of Therapy Do not use with occlusive dressing Have signs and symptoms improved within 6 weeks? Monitor/Administration Always dispense medication guide to patients who have a prescription for TCI Medication Guide