Colchicine in Dermatology Jeremy A. Schneider, MD Assistant Clinical Professor UC San Diego Department of Dermatology

Transcription

1 Colchicine in Dermatology Jeremy A. Schneider, MD Assistant Clinical Professor UC San Diego Department of Dermatology

2 Conflicts of interest: none. Disclosures: No personal disclosures. This presentation includes discussions of off-label uses of colchicine. Discussion of drug-drug interactions is not comprehensive. Please review potential interactions between colchicine and your patients medications prior to prescribing. Please do not take photographs of any slides containing clinical images.

3 Colchicum autumnale Gout and familial Mediterranean fever (FMF) and associated amyloidosis Colchicine (Wolverton SE, 2013, Lexicomp)

4 Uses in Dermatology (off-label) Neutrophilic inflammatory disease Chronic urticaria ** Cutaneous vasculitis * Pyoderma gangrenosum Sweet syndrome ** Relapsing polychondritis Neutrophilic infiltrative disease Palmoplantar pustulosis * Psoriasis ** Neutrophilic bullous disease Dermatitis herpetiformis ** Linear IgA Dermatosis Epidermolysis bullosa acquisita ** Mucous membrane pemphigoid ** Subcorneal pustular dermatosis (Sneddon-Wilkinson disease) Pustular appendageal disease Hidradenitis suppurativa ** Acne vulgaris ** Other Actinic keratosis * Recurrent aphthous stomatitis (including Behçet disease) * Morphea/localized scleroderma and reticulate hyperpigmented scleroderma Dermatomyositis Primary anetoderma Pachydermoperiostosis Type II lepra reaction Condyloma *prospective controlled trial(s) **retrospective trial or case series (Wolverton SE, 2013, Bhat et al. Ann N Y Acad Sci. 2009, Bibas et al. J. Drugs Dermatol , Robinson and Chan. Australas J Dermatol. 2018)

5 More recent:

6 F: ~45%; jejunum and ileum Pharmacokinetics V D : 5-8 L/kg Distribution: leukocytes (up to 10 days), kidney, spleen, liver) t 1/2 : h (2x in renal failure, 10x in cirrhosis + renal failure) t max : min (2 nd peak 6 h) Protein binding: ~39% Metabolism: Hepatic (CYP3A4) Elimination: bile in feces; 10-20% unchanged in urine (Wolverton SE, 2013 and Bhat et al., Ann N Y Acad Sci )

7 Mechanism of Action Inhibits β-tubulin polymerization into microtubules à mitotic arrest (metaphase), decreased cell motility/chemotaxis; prevents activation, degranulation, migration of neutrophils May interfere with NALp3 (cryopyrin) inflammasome activation and intracellular assembly of neutrophil and monocyte inflammasome complex (decreased activation of interleukin-1β) Inhibits synthesis of tumor necrosis factor-α, leukotriene B4, prostaglandin E2, thromboxane A2; activity of cyclooxygenase-2; release of insulin, histamine, parathyroid hormone Inhibits delayed hypersensitivity reactions Inhibits melanosome movement in melanophores (Wolverton SE, 2013, Bhat et al. Ann N Y Acad Sci. 2009, Lexicomp)

8 Contraindications P-glycoprotein or strong CYP3A4 inhibitor plus renal or hepatic impairment Leukopenia, thrombocytopenia, blood dyscrasias Known allergy/hypersensitivity (Canadian labeling) Serious gastrointestinal, renal, hepatic, cardiac disease (Canadian labeling) (Wolverton SE, 2013, Lexicomp)

9 Pregnancy Category Crosses human placenta; FDA Category C Present in sera and breast milk; administer with caution ; amount ingested by nursing baby is <10% of the weightadjusted maternal dose (Bhat et al. Ann N Y Acad Sci and Lexicomp)

10 Adverse effects GI: diarrhea (up to 77%), vomiting (17%), nausea (4-17%) CNS: fatigue (up to 4%), headache (2%) Endocrine/metabolic: gout (4%) Pulmonary: pharyngolaryngeal pain (3%) Rare: alopecia, aplastic anemia, azoospermia/oligospermia, bone marrow suppression, dermatitis, depression, DIC, granulocytopenia, hepatotoxicity, hypersensitivity reaction, increased CPK, ALT, AST, lactose intolerance, leukopenia, myalgias, myasthenia, myopathy, myotonia, neuropathy, peripheral neuritis, purpura, rhabdomyolysis, thrombocytopenia, toxic epidermal necrolysis, toxic neuromuscular disease (Bhat et al. Ann N Y Acad Sci and Lexicomp)

11 Overdose/toxicity Estimated at mg/kg Can be fatal; stop immediately when GI symptoms occur; NOT dialyzable or hemoperfusable [colchicine specific antigen-binding immunoglobulin (Fab) may be used] 24 hours: gastrointestinal symptoms +/- leukocytosis, dehydration; hypokalemia, hyponatremia, metabolic acidosis hours: bone marrow toxicity, hepatotoxicity, renal failure, DIC, cardiac arrhythmia, acute respiratory distress syndrome, neuromuscular disturbances 3rd phase (recovery): rebound leukocytosis, resolution of organ system derangement, alopecia (Wolverton SE, 2013, Bhat et al. Ann N Y Acad Sci. 2009, Lexicomp)

12 Formulations Oral Capsules and tablets Intravenous formulation (no longer available) Shorter half-life Removed from market due to toxicity FDA 2/6/2008; 23 deaths (pancytopenia, acute renal failure, disseminated intravascular coagulation) (Bhat et al. Ann N Y Acad Sci and Lexicomp)

13 Dosing Usual dose*: 0.6 mg PO BID-TID, taper as disease activity allows *Variability in dosing published in trials, series, and case reports (see handout 2 for details)

14 Interactions Risk X (do not combine): antihepaciviral combination products, conivaptan, fusidic acid, grapefruit juice, idelalisib (phosphoinositide 3- kinase inhibitor) Risk D (consider modification of therapy): P-glycoprotein/ABCB1 inhibitors (protease inhibitors, macrolide antibiotics, calcineurin inhibitors, carvedilol, reserpine, sodium channel blockers, calcium channel blockers, most azole antifungals, proton pump inhibitors, quinine, SSRIs, spironolactone, tamoxifen, ulipristal, some tyrosine kinase inhibitors, dexamethasone, mifepristone); HMG-CoA reductase inhibitors, stiripentol Risk C (monitor therapy): P-glycoprotein/ABCB1 inducers; kinase inhibitors (tropomyosin, tyrosine and CDK), digoxin, fibric acid derivatives, fosaprepitant, luliconazole, lumacaftor, choline C 11, cyanocobalamin, multivitamins, (Lexicomp)

15 Monitoring Parameters CBC, urinalysis, renal and hepatic function (baseline, monthly for first few months, then at least every 3 months) Consider CPK/CK (especially if concurrent statin or fibric acid derivative therapy) Extra vigilance in renal patients By Hans-Simon Holtzbecker - Self-scanned, Public Domain, (Wolverton SE, 2013, Lexicomp)

16 Managing adverse effects Tolerance may be enhanced by starting low, going slow Gastrointestinal symptoms: dose reduction; diarrhea can be controlled with aluminum-containing antacids or antidiarrheal medications Myelosuppression and aplastic anemia: drug discontinuation Myotoxicity/rhabdomyolysis (especially renal dysfunction, elderly, concomitant cyclosporine, diltiazem, verapamil, fibrates, statins): discontinuation (Wolverton SE, 2013, Lexicomp)

17 Key Points Colchicine primarily works by inhibiting β-tubulin polymerization, inhibiting microtubuledependent cellular functions Particular efficacy in treating diseases characterized by polymorphonuclear leukocyte infiltration/inflammation Dosing should be titrated based on tolerability and comorbidities Potential interactions with other P450 3A4 substrates, inhibitors, and inducers should be considered prior to and during therapy (Morgan AS and Yang DT. Blood )

18 References Aktulga E, AltaçM, Müftüoglu A, Ozyazgan Y, Pazarli H, Tüzün Y, Yalçin B, Yazici H, Yurdakul S. A double blind study of colchicine in Behçet's disease. Haematologica. 1980;65(3):399. Alarcon-Segovia D, Ramos-Niembro F, Ibanez de Kasep G, Alcocer J, Tamayo RP. Long-term evaluation of colchicine in the treatment of scleroderma. J Rheumatol. 1979;6(6):705. Ben-Chetrit, E. & M. Levy. Colchicine prophylaxis in familial Mediterranean fever: reappraisal after 15 years. Semin. Arthritis Rheum. 1991;20: Bhat A, Naguwa SM, Cheema GS, Gershwin ME. Colchicine revisited. Ann N Y Acad Sci Sep;1173: Bibas, R., N.K. Gaspar & M. Ramos-e-Silva. Colchicine for dermatologic diseases. J. Drugs Dermatol : Braun RP, Borradori L, Chavaz P, MasouyéI, French L, Saurat JH. Treatment of primary anetoderma with colchicine. J Am Acad Dermatol Jun;38(6 Pt 1): Callen JP, af Ekenstam E. Cutaneous leukocytoclastic vasculitis: clinical experience in 44 patients. South Med J. 1987;80(7):848. Callen JP. Colchicine is effective in controlling chronic cutaneous leukocytoclastic vasculitis. J Am Acad Dermatol. 1985;13(2 Pt 1):193. Colchicine. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: Cohen, P.R Sweet's syndrome a comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet. J. Rare Dis. 2: 34. Cozzani E, Gariazzo L, Cioni M, Parodi A. Could colchicine represent a new therapeutic approach for lichen planus pigmentosus?. Dermatologic therapy Jan 7:e Cozzani E, Basso D, Cimmino MA, Larosa M, Burlando M, Rongioletti F, Drago F, Parodi A. Generalized annular granuloma associated with crowned dens syndrome, which resolved with colchicine treatment. Clinical and experimental dermatology Aug;41(6): Cunningham BB, Kirchmann TT, Woodley D. Colchicine for epidermolysis bullosa acquisita. J Am Acad Dermatol May;34(5 Pt 1): Davatchi F, Sadeghi Abdollahi B, Tehrani Banihashemi A, Shahram F, Nadji A, Shams H, Chams-Davatchi C. Colchicine versus placebo in Behçet's disease: randomized, double-blind, controlled crossover trial. Mod Rheumatol. 2009;19(5): Epub 2009 Jul 14. Fortuna G, Marinkovich MP. Linear immunoglobulin A bullous dermatosis. Clin Dermatol. 2012;30(1):38. Fuchs, D., L. Fruchter, B. Fishel, et al. Colchicine suppression of local inflammation due to calcinosis in dermatomyositis and progressive systemic sclerosis. Clin. Rheumatol. 1986;5: Grimaitre M, Etienne A, Fathi M, et al.: Topical colchicine therapy for actinic keratoses. Dermatology. 2000;200: Hazen PG, Michel B. Management of necrotizing vasculitis with colchicine. Improvement in patients with cutaneous lesions and Behcet s syndrome. Arch Dermatol. 1979;115(11):1303. Kaidbey, K.H., J.W. Petrozzi & A.M. Kligman Topical colchicine therapy for recalcitrant psoriasis. Arch. Dermatol. 111:

19 Kaklamani VG, Kaklamanis PG. Treatment of Behçet's disease--an update. Semin Arthritis Rheum. 2001;30(5):299. Kar HK, Roy RG: Comparison of colchicine and aspirin in the treatment of type 2 lepra reaction. Lepr Rev. 59: Kazokoglu H, Saatçi O, Cuhadaroglu H, Eldem B. Long-term effects of cyclophosphamide and colchicine treatment in Behçet's disease. Ann Ophthalmol. 1991;23(4):148. Konda C, Rao AG. Colchicine in dermatology. Indian J Dermatol Venereol Leprol 2010;76: MacLeod J G, Phillips L. Hypersensitivity to colchicine. Ann Rheum Dis1947;6: Mark, K.A. & A.G. Franks, Jr. Colchicine and indomethacin for the treatment of relapsing polychondritis. J. Am. Acad. Dermatol. 2002;46: S22 S24. Martinez-Teaboada VM, Blanco R, Garcia-Fuentes M, Rodriguez-Valverde V. Clinical features and outcome of 95 patients with hypersensitivity vasculitis. Am J Med. 1997;102(2):186. Masmoudi, A., H. Chaaben, K. Hamdouni, et al Sweet syndrome: retrospective study of 54 cases. Presse Med. 36: Matucci-Cerinic M, Fattorini L, Gerini G, et al.: Colchicine treatment in a case of pachydermoperiostosis with acroosteolysis.rheumatol Int. 1988;8: Megahed M, Scharffetter-Kochanek K. Epidermolysis bullosa acquisita successful treatment with colchicine. Arch Dermatol Res. 1994;286(1): Mintz EM, Morel KD. Clinical features, diagnosis, and pathogenesis of chronic bullous disease of childhood. Dermatol Clin Jul;29(3):459-62, ix. Morgan AS, Yang DT. Neutrophil alphabet. Blood May 2;121(18): References Noh JW, Kim J, Kin JW. Localized scleroderma: a clinical study at a single center in Korea. Int J Rheum Dis Aug;16(4): Plotnick S, Huppert AS, Kantor G. Colchicine and leukocytoclastic vasculitis. Arthritis Rheum. 1989;32(11):1489. Saenz A, Ausejo M, Shea B, Wells G, Welch V, Tugwell P. Pharmacotherapy for Behcet's syndrome. Cochrane Database Syst Rev Silvers, D.N., E.A. Juhlin, P.H. Berczeller & J. McSorley. Treatment of dermatitis herpetiformis with colchicine. Arch. Dermatol. 1980; 116: Stalder, J.F., A. David, J.Y. Cohen & H. Barriere. Dermatomyositis in children. Use of colchicine in outbreaks of calcinosis. Presse Med. 1984; 13: 441. Robinson KP, Chan JJ. Colchicine in dermatology: A review. Australasian Journal of Dermatology Feb 12. Terrier B, Krastinova E, Marie I, Launay D, Lacraz A, Belenotti P, de Saint-Martin L, Quemeneur T, Huart A, Bonnet F, Le Guenno G, Kahn JE, Hinschberger O, Rullier P, Diot E, Lazaro E, Bridoux F, Zénone T, Carrat F, Hermine O, Léger JM, Mariette X, Senet P, Plaisier E, Cacoub P. Management of noninfectious mixed cryoglobulinemia vasculitis: data from 242 cases included in the CryoVas survey. Blood. 2012;1119(25):5996. Venzor J, Lee WL, Huston DP. Urticarial vasculitis. Clin Rev Allergy Immunol. 2002;23(2):201. Von Krogh G, Ruden AK: Topical treatment of penile condylomata acuminata with colchicine at hour intervals. Acta Derm Venereol. 1980; 60: Wahba, A. & H. Cohen Therapeutic trials with oral colchicine in psoriasis. Acta. Derm. Venereol. 60: Wiles JC, Hansen RC, Lynch PJ. Urticarial vasculitis treated with colchicine. Arch Dermatol. 1985;121(6):802. Wolverton, Stephen E. Comprehensive Dermatologic Drug Therapy. Edinburgh: Saunders/Elsevier, Yurdakul S, Mat C, Tüzün Y, Ozyazgan Y, Hamuryudan V, Uysal O, Senocak M, Yazici H. A double-blind trial of colchicine in Behçet's syndrome. Arthritis Rheum. 2001;44(11):2686.