Abstract

Atopic dermatitis (AD) is a common chronic inflammatory skin disease that causes significant suffering and has limited treatment options.1Leung D.Y.M. Bieber T. Atopic dermatitis.Lancet. 2003; 361: 151-160Abstract Full Text Full Text PDF PubMed Scopus (1163) Google Scholar, 2Spergel J.M. Paller A.S. Atopic dermatitis and the atopic march.J Allergy Clin Immunol. 2003; 112: S118-S127Abstract Full Text Full Text PDF PubMed Scopus (862) Google Scholar It is often the first step in the atopic march and might contribute to the severity-persistence of asthma.2Spergel J.M. Paller A.S. Atopic dermatitis and the atopic march.J Allergy Clin Immunol. 2003; 112: S118-S127Abstract Full Text Full Text PDF PubMed Scopus (862) Google Scholar, 3Miranda C. Busacker A. Balzar S. Trudeau J. Wenzel S.E. Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation.J Allergy Clin Immunol. 2004; 113: 101-108Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar, 4Illi S. von Mutius E. Lau S. Nickel R. Gruber C. Niggemann B. et al.The natural course of atopic dermatitis from birth to age 7 years and the association with asthma.J Allergy Clin Immunol. 2004; 113: 925-931Abstract Full Text Full Text PDF PubMed Scopus (593) Google Scholar On February 15, 2005, the Pediatric Advisory Committee of the US Food and Drug Administration (FDA) recommended “black box” warnings for pimecrolimus (Elidel; Novartis, Basel, Switzerland) and tacrolimus (Protopic; Astellas Pharma, Tokyo, Japan) because of a potential risk of cancer. The American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology formed a Joint Task Force to review the data and present it to their membership with the following objectives:1.to review current FDA concerns regarding the safety of the use of topical pimecrolimus (Elidel) and tacrolimus (Protopic) in patients with AD;2.to assist the allergist in providing their patients with appropriate information and to assist them in proper use of these products; and3.to address the black box warning and its effect on the treatment of AD at this time A.Because of a perception by physicians and patients that topical pimecrolimus and tacrolimus are safer than steroid preparations, they have increasingly been used as first-line therapy and off label. There were almost 2 million prescriptions written for these topical medications for children between June 2003 and May 2004, and approximately half a million were for those less than 2 years of age. There is also heavy direct-to-consumer advertising, which might be related to its increasing use.B.The FDA is investigating postmarketing reports of malignancy in children and adults who have used these medications (Table I, Table II).5Novartis and Fujisawa FDA Briefing Statements. Pediatric Advisory Committee Meeting of the US Food Drug Administration. Washington, DC, 2005. Available at: http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4089b2.htm. Accessed March 16, 2005.Google Scholar A postmarketing nonhuman primate study with an oral formulation of pimecrolimus demonstrated an occurrence of lymphoma in monkeys exposed to the lowest dose, which represented 30 times the maximum recommended human dose (MRHD).5Novartis and Fujisawa FDA Briefing Statements. Pediatric Advisory Committee Meeting of the US Food Drug Administration. Washington, DC, 2005. Available at: http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4089b2.htm. Accessed March 16, 2005.Google ScholarTable IPostmarketing total tumor adverse events as of December 31, 2004Total tumor5Novartis and Fujisawa FDA Briefing Statements. Pediatric Advisory Committee Meeting of the US Food Drug Administration. Washington, DC, 2005. Available at: http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4089b2.htm. Accessed March 16, 2005.Google ScholarTotal US cases of lymphoma5Novartis and Fujisawa FDA Briefing Statements. Pediatric Advisory Committee Meeting of the US Food Drug Administration. Washington, DC, 2005. Available at: http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4089b2.htm. Accessed March 16, 2005.Google ScholarMedian time from initial treatment until diagnosis5Novartis and Fujisawa FDA Briefing Statements. Pediatric Advisory Committee Meeting of the US Food Drug Administration. Washington, DC, 2005. Available at: http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4089b2.htm. Accessed March 16, 2005.Google ScholarPimecrolimusChildren ≤16 y1190 (7-300 d)Adult5†There is one non-US case of lymphoma that is poorly documented.3†There is one non-US case of lymphoma that is poorly documented.TacrolimusChildren ≤16 y30240 (21-940 d)Adult184† There is one non-US case of lymphoma that is poorly documented. Open table in a new tab Table IIUS FDA cases of spontaneous reports of lymphoma5Novartis and Fujisawa FDA Briefing Statements. Pediatric Advisory Committee Meeting of the US Food Drug Administration. Washington, DC, 2005. Available at: http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4089b2.htm. Accessed March 16, 2005.Google Scholar∗There is one non-US case of lymphoma.DrugAge (y)Lymphoma histologyIndependent expert assessment of causalityPimecrolimus61Histiocytic lymphomaUnlikelyPimecrolimus53Subcutaneous panniculitis like T-cell lymphomaUnlikelyPimecrolimus2.5Lymphoblastic lymphoma (T cell)UnlikelyTacrolimus52Non-Hodgkin's lymphomaInsufficient evidenceTacrolimus50Anaplastic large cell lymphoma–T-cell typeInsufficient evidenceTacrolimus40Lymphoma “possible”Insufficient evidenceTacrolimus54Non-Hodgkin's lymphomaInsufficient evidence∗ There is one non-US case of lymphoma. Open table in a new tab C.A definitive answer regarding the risk of carcinogenicity from topical pimecrolimus and tacrolimus will not be known for years, and if such a risk was real, the advisory panel was concerned that people might think they were not provided adequate information to assist them in the proper use of these products. A.After topical application of tacrolimus and pimecrolimus, serum concentrations are usually low or undetectable,5Novartis and Fujisawa FDA Briefing Statements. Pediatric Advisory Committee Meeting of the US Food Drug Administration. Washington, DC, 2005. Available at: http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4089b2.htm. Accessed March 16, 2005.Google Scholar, 6Harper J. Green A. Scott G. Gruendl E. Dorobek B. Cardno M. et al.First experience of topical SDZ ASM 981 in children with atopic dermatitis.Br J Dermatol. 2001; 144: 781-787Crossref PubMed Scopus (135) Google Scholar, 7Protopic (Tacrolimus) Ointment New Drug Application 50-777. Approval date 12/8/2000. Available at: http://www.fda.gov/cder/foi/nda/2000/50777_protopic.htm. Accessed March 16, 2005.Google Scholar, 8Van Leent E.J. Ebelin M.E. Burtin P. Dorobek B. Spuls P.I. Bos J.D. Low systemic exposure after repeated topical application of Pimecrolimus (Elidel), SD Z ASM 981) in patients with atopic dermatitis.Dermatology. 2002; 204: 63-68Crossref PubMed Scopus (109) Google Scholar and absorption decreases as dermatitis improves. Additional absorption studies are needed in infants and young children.B.Although there are animal data showing dose-dependent carcinogenicity, it should be noted that the lymphoma formation was only reported in mice with the application of tacrolimus and pimecrolimus dissolved in ethanol at 26 and 47 times the MRHD.5Novartis and Fujisawa FDA Briefing Statements. Pediatric Advisory Committee Meeting of the US Food Drug Administration. Washington, DC, 2005. Available at: http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4089b2.htm. Accessed March 16, 2005.Google ScholarC.On the basis of the malignancy rates in the general population of the United States for tacrolimus (Table III)5Novartis and Fujisawa FDA Briefing Statements. Pediatric Advisory Committee Meeting of the US Food Drug Administration. Washington, DC, 2005. Available at: http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4089b2.htm. Accessed March 16, 2005.Google Scholar, 10Ries L.A.G. Eisner M.P. Kosary C.L. Hankey B.F. Miller B.A. Clegg L. SEER cancer statistics review, 1975-2001. National Cancer Institute, Bethesda (MD)2004http://seer.cancer.gov/csr/1975_2001/Google Scholar, 11Miller D.L. Weinstock M.A. Nonmelanoma skin cancer in the United States: incidence.J Am Acad Dermatol. 1994; 30: 774-778Abstract Full Text PDF PubMed Scopus (934) Google Scholar and the incidence of non-Hodgkin's lymphoma on the basis of the person-years of exposure for pimecrolimus (Table IV),5Novartis and Fujisawa FDA Briefing Statements. Pediatric Advisory Committee Meeting of the US Food Drug Administration. Washington, DC, 2005. Available at: http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4089b2.htm. Accessed March 16, 2005.Google Scholar, 11Miller D.L. Weinstock M.A. Nonmelanoma skin cancer in the United States: incidence.J Am Acad Dermatol. 1994; 30: 774-778Abstract Full Text PDF PubMed Scopus (934) Google Scholar, 11aNational Cancer Institute. Probability of developing non-Hodgkin's lymphoma. Available at: http://seer.cancer.gov/faststats/html/dev_nhl.html.Google Scholar there is no evidence of increased incidence of lymphoma with the short-term or intermittent long-term application of topical tacrolimus and pimecrolimus at this time, despite the use of these drugs in nearly 7 million persons.Table IIITacrolimus analysis of malignancy ratesMalignancy rates in the general US populationMalignancies reported in tacrolimus-treated patients∗For the time period up to December 2004, 1,700,000 patients have been treated with tacrolimus.9 Eleven lymphomas, including 6 cutaneous T-cell lymphomas, and 16 nonmelanoma skin cancers have been reported in the United States.5Lymphoma22/100,00010†Surveillance Epidemiology and End Result (SEER).0.65/100,0005Nonmelanoma skin cancer533/100,00011‡Public Health Service (Department of Health and Human Services).0.94/100,0005∗ For the time period up to December 2004, 1,700,000 patients have been treated with tacrolimus.9Reitamo S. Wollenberg A. Schopf E. Perrot J.L. Marks R. Ruzicka T. et al.Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis. The European Tacrolimus Ointment Study Group.Arch Dermatol. 2000; 136: 999-1006Crossref PubMed Scopus (363) Google Scholar Eleven lymphomas, including 6 cutaneous T-cell lymphomas, and 16 nonmelanoma skin cancers have been reported in the United States.5Novartis and Fujisawa FDA Briefing Statements. Pediatric Advisory Committee Meeting of the US Food Drug Administration. Washington, DC, 2005. Available at: http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4089b2.htm. Accessed March 16, 2005.Google Scholar† Surveillance Epidemiology and End Result (SEER).‡ Public Health Service (Department of Health and Human Services). Open table in a new tab Table IVPimecrolimus analysis of malignancy rates5Novartis and Fujisawa FDA Briefing Statements. Pediatric Advisory Committee Meeting of the US Food Drug Administration. Washington, DC, 2005. Available at: http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4089b2.htm. Accessed March 16, 2005.Google Scholar<55-910-1415-19Total childrenTotal adultsTotal (US)Person-years of exposure278,842118,19665,22433,431495,694237,030732,724Expected no. of cases (SEER)11Miller D.L. Weinstock M.A. Nonmelanoma skin cancer in the United States: incidence.J Am Acad Dermatol. 1994; 30: 774-778Abstract Full Text PDF PubMed Scopus (934) Google Scholar, 11aNational Cancer Institute. Probability of developing non-Hodgkin's lymphoma. Available at: http://seer.cancer.gov/faststats/html/dev_nhl.html.Google Scholar1.81.00.70.54.042.146.1Reported cases5Novartis and Fujisawa FDA Briefing Statements. Pediatric Advisory Committee Meeting of the US Food Drug Administration. Washington, DC, 2005. Available at: http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4089b2.htm. Accessed March 16, 2005.Google Scholar1000123On the basis of the person-years of exposure, there is no evidence of increased incidence of non-Hodgkin's lymphoma in any age group in patients receiving pimecrolimus.SEER, Surveillance Epidemiology and End Result. Open table in a new tab D.There are features that characterize lymphomas occurring in the setting of immunomodulatory or immunosuppressive therapy. These are (1) frequent occurrence in unusual sites, including soft tissue, joint spaces, and lungs; (2) polymorphous and pleomorphic large cell or Hodgkin's-like morphology; (3) presence of the Epstein-Barr genome in lymphoma cells; (4) B-cell lymphomas developing weeks, months, or, less commonly, up to several years after receipt of immunomodulatory therapy; and (5) lymphomas spontaneously regressing after withdrawal of immunomodulatory therapy without the need for chemotherapy or radiation therapy in a significant percentage of cases (30% to 50%).None of the information provided for the cases of lymphoma associated with the use of topical pimecrolimus or tacrolimus in patients with AD indicate or suggest a causal relationship. The histology reported and the clinical presentations are not those usually associated with posttransplant lymphoproliferative disorder or of lymphoma occurring in the immunocompromised setting. Five independent external experts in the areas of dermatology, epidemiology, posttransplantation lymphoproliferative disorders–oncology, and pediatric oncology concluded that there was no clear-cut link between pimecrolimus or tacrolimus5Novartis and Fujisawa FDA Briefing Statements. Pediatric Advisory Committee Meeting of the US Food Drug Administration. Washington, DC, 2005. Available at: http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4089b2.htm. Accessed March 16, 2005.Google Scholar and increased risk of lymphoma.E.There is no evidence of systemic immunosuppression from topical pimecrolimus or tacrolimus, as measured on the basis of response to childhood immunizations (B cell)12Papp K.A. Breuer K. Meurer M. Ortonne J.P. Potter P.C. de Prost Y. et al.Long-term treatment of atopic dermatitis with pimecrolimus cream 1% in infants does not interfere with the development of protective antibodies after vaccination.J Am Acad Dermatol. 2005; 52: 247-253Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 13Stiehm E, Roberts R, Kaplan M, Corren J, Jaracz E, Rico M. Pneumococcal seroconversion after vaccination in children with atopic dermatitis treated with tacrolimus ointment. J Am Acad Dermatol. In press 2005.Google Scholar and delayed hypersensitivity (T cell).9Reitamo S. Wollenberg A. Schopf E. Perrot J.L. Marks R. Ruzicka T. et al.Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis. The European Tacrolimus Ointment Study Group.Arch Dermatol. 2000; 136: 999-1006Crossref PubMed Scopus (363) Google Scholar, 14Wahn U. Bos J.D. Goodfield M. Caputo R. Papp K. Manjra A. et al.Efficacy and safety of pimecrolimus cream in the long-term management of atopic dermatitis in children.Pediatrics. 2002; 110: e2Crossref PubMed Scopus (326) Google ScholarF.In clinical trials infants and children younger than 2 years of age treated with topical pimecrolimus were reported to have higher rates of upper respiratory tract infections than those treated with placebo cream. However, when data were adjusted for time on medication, pimecrolimus was not associated with increased prevalence of systemic infection. There was also no difference in systemic infections in children 2 to 17 years of age or adults.5Novartis and Fujisawa FDA Briefing Statements. Pediatric Advisory Committee Meeting of the US Food Drug Administration. Washington, DC, 2005. Available at: http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4089b2.htm. Accessed March 16, 2005.Google Scholar, 12Papp K.A. Breuer K. Meurer M. Ortonne J.P. 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Bone mineral density in patients with atopic dermatitis.Br J Dermatol. 1997; 136: 172-175Crossref PubMed Scopus (27) Google ScholarOral corticosteroids†Occasionally required for treatment of severe AD.Increased risk of squamous cell–basal cell carcinoma; increased risk of non-Hodgkin's lymphoma20Karagas M.R. Cushing Jr., G.L. Greenberg E.R. Mott L.A. Spencer S.K. Nierenberg D.W. Non-melanoma skin cancers and glucocorticoid therapy.Br J Cancer. 2001; 85: 683-686Crossref PubMed Scopus (126) Google Scholar, 21Sorensen H.T. Mellemkjaer L. Nielsen G.L. Baron J.A. Olsen J.H. Karagas M.R. Skin cancers and non-Hodgkin lymphoma among users of systemic glucocorticoids: a population-based cohort study.J Natl Cancer Inst. 2004; 96: 709-711Crossref PubMed Scopus (135) Google Scholar↑ infection, hypertension, myopathy, glaucoma, aseptic necrosis of the hip, cataracts, Cushing syndrome, weight gain, osteopenia44Covar R.A. Leung D.Y. McCormick D. Steelman J. Zeitler P. Spahn J.D. 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High levels of ultraviolet B exposure increase the risk of non-melanoma skin cancer in psoralen and ultraviolet a-treated patients.J Invest Dermatol. 2005; 124: 505-513Crossref PubMed Scopus (101) Google ScholarErythema, pruritis, nausea, headache, chronic actinic skin damage, dyskeratotic and precancerous skin conditions22Stern R.S. Laird N. The carcinogenic risk of treatments for severe psoriasis. Photochemotherapy Follow-up Study.Cancer. 1994; 73: 2759-2764Crossref PubMed Scopus (364) Google Scholar, 25Momtaz K. Fitzpatrick T.B. The benefits and risks of long-term PUVA photochemotherapy.Dermatol Clin. 1998; 16: 227-234Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 27van Praag M.C. Tseng L.N. Mommaas A.M. Boom B.W. Vermeer B.J. Minimising the risks of PUVA treatment.Drug Saf. 1993; 8: 340-349Crossref PubMed Scopus (16) Google Scholar, 34Sheehan M.P. Atherton D.J. Norris P. Hawk J. Oral psoralen photochemotherapy in severe childhood atopic eczema: an update.Br J Dermatol. 1993; 129: 431-436Crossref PubMed Scopus (67) Google ScholarUVA, Ultraviolet A; UVB, ultraviolet B; PUVA, psoralen plus ultraviolet A.∗ Adverse effects relate to corticosteroid potency, occlusiveness of the preparations, site of application, percentage of the body surface covered, and duration of treatment.† Occasionally required for treatment of severe AD. Open table in a new tab On the basis of the person-years of exposure, there is no evidence of increased incidence of non-Hodgkin's lymphoma in any age group in patients receiving pimecrolimus. SEER, Surveillance Epidemiology and End Result. UVA, Ultraviolet A; UVB, ultraviolet B; PUVA, psoralen plus ultraviolet A. A.Guidelines for the use of pimecrolimus cream 1% and tacrolimus ointment 0.03% and 0.1%.1.Current FDA guidelines recommend that topical pimecrolimus and tacrolimus are indicated for the short-term or intermittent long-term treatment of AD in patients 2 years of age or older who are unresponsive to or intolerant of other conventional therapies or in whom these therapies are inadvisable because of potential risks.2.The long-term effect of pimecrolimus and tacrolimus on the developing immune system in infants and children is not known. Children and adults with a compromised immune system should not use pimecrolimus or tacrolimus.3.On the basis of information available, it would be prudent to use these medications as has been previously recommended and approved and at the amount needed to control the patient's symptoms. Animal data suggest that the risk of cancer increases with increased exposure to pimecrolimus or tacrolimus. However, the doses in which cancers occur were substantially higher than the levels used in human subjects.4.It is important to reinforce the need for adjunctive treatment for AD, including liberal moisturization, evaluation for food and inhalant allergies, treatment of infections, and referral to an allergist-immunologist or a dermatologist for identification of triggers and optimal skin care.5.There is no evidence to date of systemic immunosuppression after short-term or intermittent long-term topical application of FDA-approved formulations of pimecrolimus and tacrolimus in patients with AD.B.Patient information should be adequate and must include the risks and benefits of the drug and the proper use of these products. This includes:1.addressing the chronic, relapsing nature of AD and its complications, such as infection, associated allergies, skin barrier dysfunction, and risk of asthma;2.acknowledging that topical calcineurin inhibitors have significantly improved the clinical management of patients with AD;3.discussing current product label in the use of these drugs on patients:a.younger than 2 years of age,b.with compromised immune system,c.treated with concurrent phototherapy,d.pregnant or breast-feeding, ande.with severely impaired skin barrier function (eg, Netherton syndrome) that might result in immunosuppressive blood levels of the drug;4.discussing treatment options for AD, including topical corticosteroids that might have adverse effects relating to potency, occlusiveness of the preparation, site of application, percentage of body surface covered, and duration of treatment, including skin atrophy; and5.discussing alternative treatments for moderate-to-severe AD, which include oral corticosteroids, cyclosporin A, and phototherapy, all of which have significant potential for causing serious adverse events, including malignancy.C.The Topical Calcineurin Inhibitor Task Force of the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology concludes that on the basis of current data, the risk/benefit ratios of topical pimecrolimus and tacrolimus are similar to those of most conventional therapies for the treatment of chronic relapsing eczema.

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