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Tacrolimus and Pimecrolimus and Risk Of Malignancy

Elizabeth Gorevski Kingsbrook Jewish Medical Center Brooklyn, NY. Tacrolimus and Pimecrolimus and Risk Of Malignancy. Uses of Tacrolimus and Pimecrolimus. Munzenberger P et al Pharmacotherapy 2007; 27(7). Treating Atopic Dermatitis.

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Tacrolimus and Pimecrolimus and Risk Of Malignancy

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  1. Elizabeth Gorevski Kingsbrook Jewish Medical Center Brooklyn, NY Tacrolimus and Pimecrolimus and Risk Of Malignancy

  2. Uses of Tacrolimus and Pimecrolimus 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 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 Arellano F. et al J Invest Derm 2007; 127

  13. Risk of Lymphoma According to Age Arellano F. et al J Invest Derm 2007; 127

  14. International Consensus

  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

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