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01-03-2008 | Current Opinion

The US FDA ‘Black Box’ Warning for Topical Calcineurin Inhibitors

An Ongoing Controversy

Authors: Johannes Ring, Dr Matthias Möhrenschlager, Verena Henkel

Published in: Drug Safety | Issue 3/2008

Abstract

Atopic dermatitis is a chronic inflammatory skin disease characterized by recurrent intense pruritus and a distinctive distribution of skin lesions. The topical calcineurin inhibitors tacrolimus and pimecrolimus were approved in the USA, as an ointment and a cream, respectively, for the treatment of atopic dermatitis in 2000 and 2001, respectively. In 2005, the Pediatric Advisory Committee of the US FDA implemented a ‘black box’ warning for tacrolimus ointment and pimecrolimus cream due to the lack of long-term safety data and the potential risk of the development of malignancies. This article focuses on the safety aspects of these agents by discussing the findings from preclinical and clinical studies and postmarketing reports with regard to malignancies occurring after the use of tacrolimus ointment and pimecrolimus cream.

Aoki T, Fukuzumi T, Adachi J, et al. Re-evaluation of skin lesion distribution in atopic dermatitis: analysis of cases 0 to 9 years of age. Acta Derm Venereol 1992; 176 Suppl.: 19–23

Flohr C, Johansson SGO, Wahlgren CF, et al. How atopic is atopic dermatitis? Allergy Clin Immunol 2004; 114: 150–8CrossRef

Williams HC. Atopic dermatitis: the epidemiology, causes, and prevention of atopic eczema. Cambridge: University Press, 2000CrossRef

Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol 1980; 114: 146–8

Williams HC, Burney PGJ, Pembroke AC, et al. Validation of the UK diagnostic criteria for atopic dermatitis in a population setting. Br J Dermatol 1996; 135: 12–7PubMedCrossRef

Ring J. Allergy in practice. Berlin: Springer, 2005

Ring J, Krämer U, Schäfer T, et al. Why are allergies increasing? Curr Opinion Immunol 2001; 13: 701–8CrossRef

Schäfer T, Vieluf D, Behrendt H, et al. Atopic eczema and other manifestations of atopy: results of a study in East and West Germany. Allergy 1996; 51: 532–9PubMed

Thesdrup-Pedersen K, Ring J. Atopic dermatitis: summary of the 1st Georg Rajka symposium 1998 and a literature review. Acta Dermatol Venereol 1999; 79: 257–64CrossRef

10.

Williams H. Epidemiology of atopic dermatitis: recent advances and future predictions. Curr Probl Dermatol 1999; 28: 5–17

11.

Wüthrich B. Epidemiology and natural history of atopic dermatitis. ACI Int 1996; 8: 77–82

12.

Schultz-Larsen F, Hanifin JM. Epidemiology of atopic dermatitis. Immunol Allergy Clin North Am 2002; 22: 1–24CrossRef

13.

Ring J, Przybilla B, Ruzicka T, editors. Handbook of atopic dermatitis. 2nd ed. Berlin: Springer, 2006

14.

Ring J, Brockow K, Abeck D. The therapeutic concept of “patient management” in atopic eczema. Allergy 1996; 51: 206–15PubMed

15.

Morman MR. Possible side effects of topical steroids. Am Fam Physician 1981; 23: 171–4PubMed

16.

Bode HH. Dwarfism following long-term topical corticosteroid therapy. JAMA 1980; 244: 813–4PubMedCrossRef

17.

Turpeinen M, Salo OP, Leisti S. Effects of percutaneous absorption of hydrocortisone on adrenocortical responsiveness in infants with severe skin disease. Br J Dermatol 1986; 115: 475–84PubMedCrossRef

18.

du Vivier A, Stoughton RB. Tachyphylaxis to the action of topical applied corticosteroids. Arch Dermatol 1975; 111: 581–3PubMedCrossRef

19.

Protopic®. Tacrolimus ointment [prescribing information]. Deerfield (IL): Astellas Pharma US, Inc., 2006 Jan

20.

Elidel®. Pimecrolimus 1% cream [prescribing information]. East Hanover (NJ): Novartis Pharmaceuticals Corp., 2006 Jan

21.

Wollenberg A, Sharma S, von Bubnoff D, et al. Topical tacrolimus (FK 506) leads to profound phenotypic alterations of epidermal antigen-presenting dendritic cells in atopic dermatitis. J Allergy Clin Immunol 2001; 107: 519–25PubMedCrossRef

22.

Panhans-Gross A, Novak N, Kraft S, et al. Human epidermal Langerhans’ cells are targets for the immunosuppressive macrolide tacrolimus (FK506). J Allergy Clin Immunol 2001; 107: 345–52PubMedCrossRef

23.

Zuberbier T, Chong SU, Grunow K, et al. The ascomycin macrolactam pimecrolimus (Elidel, SDZ ASM 981) is a potent inhibitor of mediator release from human dermal mast cells and peripheral blood basophils. J Allergy Clin Immunol 2001; 108: 275–80PubMedCrossRef

24.

Bos JD. Non-steroidal topical immunomodulators provide skin-selective, self-limiting treatment in atopic dermatitis. Eur J Dermatol 2003; 13: 455–61PubMed

25.

Kempers S, Boguniewcz M, Carter E, et al. A randomized investigator-blinded study comparing pimecrolimus cream 1 % with tacrolimus ointment 0.03% in the treatment of pediatric patients with moderate atopic dermatitis. J Am Acad Dermatol 2004; 49: 515–25CrossRef

26.

Queille-Roussel C, Paul C, Duteil L, et al. The new topical ascomycin derivative SDZ ASM 981 does not induce skin atrophy when applied to normal skin for 4 weeks: a randomized, double-blind controlled study. Br J Dermatol 2001; 144: 507–13PubMedCrossRef

27.

Kyllonen H, Remitz A, Mandelin JM, et al. Effects of 1-year intermittent treatment with topical tacrolimus monotherapy on skin collagen synthesis in patients with atopic dermatitis. Br J Dermatol 2004; 150: 1174–81PubMedCrossRef

28.

Reitamo S, Rissanene J, Remitz A, et al. Tacrolimus ointment does not affect collagen synthesis: results of a single-center randomized trial. J Invest Dermatol 1998; 111: 396–8PubMedCrossRef

29.

Qureshi AA, Fischer MA. Topical calcineurin inhibitors for atopic dermatitis. Arch Dermatol 2006; 142: 633–7PubMedCrossRef

30.

Fonacier L, Spergel J, Charlesworth EN, et al. Report of the Calcineurin Inhibitor Task Force of the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immonolgy. J Allergy Clin Immunol 2005; 115: 1249–53PubMedCrossRef

31.

Fonacier L, Charlesworth EN, Spergel J, et al. The black box warning for topical calcineurin inhibitors: looking outside the box. Ann Allergy Asthma Immunol 2006; 97: 117–20PubMedCrossRef

32.

Yarosh DB, Pena AV, Nay SL, et al. Calcineurin inhibitors decrease DNA repair and apoptosis in human keratinocytes following ultraviolet B (UVB) irradiation. J Invest Dermatol 2005; 125: 1020–5PubMedCrossRef

33.

Forbes PD. Relevance of animal models of photocarcinogenesis to humans. Photochem Photobiol 1996; 63: 357–62PubMedCrossRef

34.

Tran C, Lübbe J, Sorg O, et al. Topical tacrolimus decreases UVB-induced DNA damage in mouse skin [abstract]. J Invest Dermatol 2003; 121: 1072

35.

Tran C, Liibbe J, Sorg O, et al. Topical calcineurin inhibitors decrease the production of UVB-induced thymine dimers from hairless mouse epidermis. Dermatology 2005; 211: 341–7PubMedCrossRef

36.

Ring J, Barker J, Behrendt H, et al. Review of the potential photo-cocarcinogenicity of topical calcineurin inhibitors. J Eur Acad Dermatol Venereol 2005; 19: 663–71PubMedCrossRef

37.

Fitzsimmons W. Pharmacology of tacrolimus ointment. Deerfield (IL): Fujisawa Healthcare Inc, 2000

38.

Warren BS, Slaga TJ. Mechanisms of inhibition of tumor progression. Basic Life Sci 1993; 61: 279–89PubMed

39.

Jiang H, Yamamoto S, Nishikawa K, et al. Anti-tumor promoting action of FK506, a potent immunosuppressive agent. Carcinogenesis 1993; 14: 67–71PubMedCrossRef

40.

Niwa Y, Terashima T, Sumi H. Topical application of the immunosuppressant tacrolimus accelerates carcinogenesis in mouse skin. Br J Dermatol 2004; 149: 960–7CrossRef

41.

Liibbe J, Sorg O. Tacrolimus ointment and skin carcinogenesis in the DMBA/TPA model in mice. Br J Dermatol 2004; 151: 1275–6CrossRef

42.

Enzmann H, Bomhard E, Iatropoulos M, et al. Short- and intermediate-term carcinogenicity testing: a review. Food Chem Toxicol 1998; 36: 979–95PubMedCrossRef

43.

Simon GA, Maibach HI. Relevance of hairless mouse as an experimental model of percutaneous penetration in man. Skin Pharmacol Appl Skin Physiol 1998; 11: 80–6PubMedCrossRef

44.

Halliday GM, Robertson BO, Barnetson RS. Topical retinoic acid enhances, and a dark tan protects, from subdermal solar-simulated photocarcinogenesis. J Invest Dermatol 2000; 114: 923–7PubMedCrossRef

45.

Bhawan J, Olsen E, Lufrano L, et al. Histologic evaluation of the long-term effects of tretinoin on photodamaged skin. J Dermatol Sci 1996; 11: 117–82CrossRef

46.

Jacobs J, Avalos J, Brown P, et al. Does photosensitivity predict photo-cocarcinogenicity? Int J Toxicology 1999; 18: 191–8CrossRef

47.

Peterson JK, Houghton PJ. Integrating pharmacology and in vivo cancer models in preclinical and clinical drug development. Eur J Cancer 2004; 40: 837–44PubMedCrossRef

48.

Marks F, Furstenberger G. Proliferative responses of the skin to external stimuli. Environ Health Perspect 1993; 101 Suppl. 5: 95–101PubMedCrossRef

49.

Kraus AL, Munro IC, Orr JC, et al. Benzoyl peroxide: an integrated human safety assessment for carcinogenicity. Regul Toxicol Pharmacol 1995; 21: 87–107PubMedCrossRef

50.

Siegsmund M, Wayss K, Amtmann E. Activation of latent papillomavirus genomes by chronic mechanical irritation. J Gen Virol 1991; 72: 2787–9PubMedCrossRef

51.

Callen J, Chamlin S, Eichenfield LF, et al. A systematic review of the safety of topical therapies for atopic dermatitis. Br J Dermatol 2007; 156: 203–11PubMedCrossRef

52.

Hirai O, Miyamae Y, Izumi H, et al. Mutagenicity test of tacrolimus (FK506) [in Japanese]. Kiso to Rinsho 1992; 26: 989–1001

53.

Hoetzenecker W, Meingassner JG, Ecker R, et al. Corticosteroids but not pimecrolimus affect viability, maturation and immune function of murine epidermal Langerhans cells. J Invest Dermatol 2004; 122: 673–84PubMedCrossRef

54.

Woltmann AM, de Fijter JW, Kamerling SW, et al. The effect of calcineurin inhibitors and corticosteroids on the differentiation of human dendritic cells. Eur J Immunol 2000; 30: 1807–12CrossRef

55.

Cos J, Villalba T, Parra R, et al. FK506 in the maturation of dendritic cells. Haematologica 2002; 87: 679–87PubMed

56.

Harper J, Green A, Scott G, et al. First experience of topical SDZ ASM 981 in children with atopic dermatitis. Br J Dermatol 2001; 144: 781–7PubMedCrossRef

57.

van Leent EJ, Ebelin ME, Burtin B, et al. Low systemic exposure after repeated topical application of pimecrolimus (Elidel, SDZ ASM 981) in patients with atopic dermatitis. Dermatology 2002; 204: 63–8PubMedCrossRef

58.

Harper J, Smith C, Rubins A, et al. Multicenter study of the pharmacokinetics of tacrolimus ointment after first and repeated application to children with atopic dermatitis. J Invest Dermatol 2005; 124: 695–9PubMedCrossRef

59.

Paul C, Cork MJ, Rossi AB, et al. Safety and tolerability of pimecrolimus 1% in infants: experience in 1133 patients treated for up to 2 years. Pediatrics 2006; 117: el 18–28CrossRef

60.

Alaiti S, Kang S, Fiedler VC, et al. Tacrolimus (FK 506) ointment for atopic dermatitis; a phase I study in adults and children. J Am Acad Dermatol 1998; 38: 69–76PubMedCrossRef

61.

Allen A, Siegfried E, Silverman R, et al. Significant absorption of topical tacrolimus in 3 patients with Netherton syndrome. Arch Dermatol 2001; 137: 747–50PubMed

62.

Doelker L, Tran C, Gkomouzas A, et al. Production and clearance of cyclobutane dipyrimidine dimers in UV-irradiated skin pretreated with 1% pimecrolimus or 0.1% triamcinolone acetonide creams in normal and atopic patients. Exp Dermatol 2006; 15: 342–6PubMedCrossRef

63.

Naylor N, Elmets C, Jaracz E, et al. Non-melanoma skin cancer in patients with atopic dermatitis treated with topical tacrolimus. J Dermatol Treatment 2005; 16: 149–53CrossRef

64.

Margolis DJ, Hoffstad O, Bilker W. Lack of association between exposure to topical calcineurin inhibitors and skin cancer in adults. Dermatology 2007; 214: 289–95PubMedCrossRef

65.

Ring J, Abraham A, De Cuyper C, et al. Control of atopic eczema with pimecrolimus cream 1% under daily practice conditions: results of a >2000 patient study. J Eur Acad Dermatol Venereol 2008; 22: 195–203PubMed

66.

Opelz G, Henderson R. Incidence of non-Hodgkin lymphoma in kidney and heart transplant recipients. Lancet 1993; 342: 1514–6PubMedCrossRef

67.

Opelz G, Döhler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transpl 2003; 4: 222–30CrossRef

68.

Bernhard SM, Cartwright RA, Bird CC, et al. Aetologic factors in lymphoid malignancies: a case-control epidemiological study. Leuk Res 1984; 8: 681–9CrossRef

69.

Eriksson NE, Holmen A, Hogstedt B, et al. A prospective study of cancer incidence in a cohort examined for allergy. Allergy 1995; 50: 718–22PubMedCrossRef

70.

Bernstein L, Ross RK. Prior medication use and health history as risk factors for non-Hodgkin’s lymphoma: preliminary results from a case-control epidemiological study in Los Angeles county. Cancer Res 1992; 52 Suppl. 19: 5510–5s

71.

Fabbro-Peray P, Daures JP, Rossi JF. Environmental risk factors for non-Hodgkin’s lymphoma: a population-based case-control study in Languedoc-Rousillon, France. Cancer Causes Control 2001; 12: 201–12PubMedCrossRef

72.

Söderberg KC, Hagmar L, Schwartzbaum J, et al. Allergic conditions and risk of hematological malignancies in adults: a cohort study. BMC Public Health 2004; 4: 51PubMedCrossRef

73.

Zhang Y, Holford TR, Leaderer B, et al. Prior medical conditions and medication use and risk of non-Hodgkin lymphoma in Connecticut, United States women. Cancer Causes Control 2004; 15: 419–28PubMedCrossRef

74.

Arellano FM, Wentworth CE, Arana A, et al. Risk of lymphoma following exposure to calcineurin inhibitors and topical steroids in patients with atopic dermatitis. J Invest Dermatol 2007; 127: 808–16PubMedCrossRef

75.

Ormerod AD. Topical tacrolimus and pimecrolimus and the risk of cancer: how much cause for concern? Br J Dermatol 2005; 153: 701–5PubMedCrossRef

76.

Cohen DE, Heidary N. Treatment of irritant and allergic contact dermatitis. Dermatol Ther 2004; 17: 334–40PubMedCrossRef

77.

Crutchfield CE III. Pimecrolimus: new treatment for seborrheic dermatitis. Cutis 2002; 70: 207–8PubMed

78.

Rallis E, Nasiopoulou A, Kousloukis C, et al. Pimecrolimus cream 1 % can be an effective treatment for seborrheic dermatitis of the face and trunk. Drugs Exp Clin Res 2004; 30: 191–5PubMed

79.

Rigopoulos D, Ionnides D, Kalogeromitros D, et al. Pimecrolimus cream 1% vs. bethamethasone 17-valerate 0,1% cream in the treatment of seborrheic dermatitis. Br J Dermatol 2004; 151: 1071–5PubMedCrossRef

80.

Schnopp C, Remling R, Möhrenschlager M, et al. Topical tacrolimus (FK506) and mometasone furoate in treatment of dyshidrotic palmar eczema: a randomized, observer-blinded trial J Am Acad Dermatol 2002; 46: 73–7PubMedCrossRef

81.

Black RJ. Vulval eczema associated with propolis sensitization from topical therapies treated successfully with pimecrolimus cream. Clin Exp Dermatol 2005; 30: 91–2PubMedCrossRef

82.

Warshew EM. Therapeutic options for chronic hand dermatitis. Dermatol Therapy 2004; 17: 240–50CrossRef

83.

Wollina U, Abdel-Naser MB. Pharmacotherapy of pompholyx. Exp Opin Pharmacother 2004; 5: 1517–22CrossRef

84.

Kreutter A, Hochdorfer B, Altmeyer B, et al. Pimecrolimus 1% cream for perianal atopic dermatitis. Br J Dermatol 2005; 152: 186–7CrossRef

85.

Gribetz C, Ling M, Lebwohl M, et al. Pimecrolimus cream 1% in the treatment of intertriginous psoriasis: a double-blind randomized study. J Am Acad Dermatol 2004; 51: 731–8PubMedCrossRef

86.

Tan JKL, Morneau K, Fung K. Randomized controlled trial of pimecrolimus 1 % cream for treatment of facial acne vulgaris. J Am Acad Dermatol 2005; 52: 738–9PubMedCrossRef

87.

Kreuter A, Gambichler T, Breuckmann F, et al. Pimecrolimus 1% cream for cutaneous lupus erythematosus. J Am Acad Dermatol 2004; 51: 888–9

88.

Chu C-Y. The use of 1% pimecrolimus cream for the treatment of steroid-induced rosacea. Br J Dermatol 2005; 152: 396–9PubMedCrossRef

89.

Almeida Jr HL, Oliveira Filho UL. Topical pimecrolimus is an effective treatment for balanitis circinata erosive. Int J Dermatol 2005; 44: 888–98PubMedCrossRef

90.

Goldstein AT, Merinoff SC, Christopher K. Pimecrolimus for the treatment of vulvar lichen sclerosus: a report of 4 cases. J Reprod Med 2004; 49: 778–80PubMed

91.

Coskun B, Saral Y, Turgut D. Topical 0.05% clobetasol propionate versus 1% pimecrolimus ointment in vitiligo. Eur J Dermatol 2005; 15: 88–91PubMed

92.

Oji V, Beljan G, Beier K, et al. Topical pimecrolimus: a novel therapeutic option for Netherton syndrome. Br J Dermatol 2005; 153: 1067–8PubMedCrossRef

93.

Ziemer M, Gruhn M, Thiele JJ, et al. Treatment of extensive chronic graft-versus-host disease in an infant with topical pimecrolimus. J Am Acad Dermatol 2004; 50: 946–8PubMedCrossRef

94.

Almeida Jr HL. Successful treatment of chronic actinic dermatitis with topical pimecrolimus. Int J Dermatol 2005; 44: 343–4CrossRef

95.

Böhm M, Bonsmann G, Luger TA. Resolution of lichen aureus in a 10-year-old child after topical pimecrolimus. Br J Dermatol 2004; 150: 519–20CrossRef

96.

Rigopoulos D, Prantsidis A, Christofideou E, et al. Pimecrolimus 1% cream in the treatment of disseminated granuloma annulare. Br J Dermatol 2005; 152: 1364–5PubMedCrossRef

97.

Häfner C, Hohenleutner U, Babilas P, et al. Targeting T cells to hit B cells: successful treatment of cutaneous plasmocytosis with topical pimecrolimus. Dermatology 2006; 213: 163–5PubMedCrossRef

98.

Fischer G, Bradford J. Topical immunosuppressants, genital lichen sclerosus and risk of squamous cell carcinoma. J Reprod Med 2007; 52: 329–31PubMed

99.

Langeland T, Engh V. Topical use of tacrolimus and squamous cell carcinoma on the penis. Br J Dermatol 2005; 152: 176–98

100.

Becker J, Houben R, Vetter CS, et al. The carcinogenic potential of tacrolimus ointment beyond immunosuppression: a hypothesis creating case report. BMC Cancer 2006; 6: 7PubMedCrossRef

101.

Palier A, Brinkmann W, Rico J. Apples: a prospective pediatric longitudinal evaluation to assess the long-term safety of tacrolimus ointment for the treatment of atopic dermatitis [abstract]. J Am Acad Dermatol 2007; 56 Suppl. 2: AB3

Title: The US FDA ‘Black Box’ Warning for Topical Calcineurin Inhibitors
An Ongoing Controversy
Authors: Johannes Ring
Dr Matthias Möhrenschlager
Verena Henkel
Publication date: 01-03-2008
Publisher: Springer International Publishing
Published in: Drug Safety / Issue 3/2008
Print ISSN: 0114-5916
Electronic ISSN: 1179-1942
DOI: https://doi.org/10.2165/00002018-200831030-00001

Keynote webinar | Spotlight on medication adherence

Springer Medicine

The US FDA ‘Black Box’ Warning for Topical Calcineurin Inhibitors

An Ongoing Controversy

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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