dysfunction".) Multiple cardiac effects can be seen in patients taking chronic amiodarone therapy. Sinus bradycardia is an expected result from amiodarone treatment, but excessive bradycardia or AV block often represents toxicity. Amiodarone does generally lead to mild prolongation of the QT interval, but this is rarely proarrhythmic. Finally, amiodarone can alter the defibrillation thresholds for patients with an implantable cardioverter-defibrillators (ICDs). Management varies depending upon the adverse effect. (See 'Adverse cardiac effects' above.) Symptomatic hepatitis occurs in less than 3 percent of patients on amiodarone, and potential complications such as cirrhosis and hepatic failure occur very infrequently. However, a transient asymptomatic rise in serum aminotransferase concentrations occurs in approximately 25 percent of patients soon after beginning amiodarone. Although the relation of hepatotoxicity to cumulative dose and duration of therapy is uncertain, it is likely that cumulative dose correlates with overall toxicity. While patients are usually asymptomatic, the drug should be discontinued if there is more than a twofold elevation in serum aminotransferases. (See 'Adverse hepatic effects' above.) Corneal microdeposits occur in most patients receiving long-term amiodarone therapy, while some patients also develop lenticular opacities. While corneal microdeposits do not reduce visual acuity, ocular symptoms may occur, including halo vision (colored rings around lights), photophobia, and blurred vision. The presence of microdeposits is not considered a contraindication to continued amiodarone therapy since visual acuity is rarely affected. (See 'Corneal microdeposits' above.) Amiodarone is highly bound to plasma proteins (>96 percent) and can alter the plasma concentration of other highly bound drugs. Additionally, amiodarone can interfere with the hepatic metabolism of several antiarrhythmic drugs (such as quinidine, procainamide, and digoxin), possibly leading to supratherapeutic plasma concentrations if the dose is not reduced. (See 'Adverse drug interactions' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 12/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate 1. Desai AD, Chun S, Sung RJ. The role of intravenous amiodarone in the management of cardiac arrhythmias. Ann Intern Med 1997; 127:294. 2. Mason JW. Amiodarone. N Engl J Med 1987; 316:455. 3. Dusman RE, Stanton MS, Miles WM, et al. Clinical features of amiodarone-induced pulmonary toxicity. Circulation 1990; 82:51. 4. Zimetbaum P. Amiodarone for atrial fibrillation. N Engl J Med 2007; 356:935. 5. Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects of low dose amiodarone: a meta-analysis. J Am Coll Cardiol 1997; 30:791. 6. Martin WJ 2nd, Rosenow EC 3rd. Amiodarone pulmonary toxicity. Recognition and pathogenesis (Part I). Chest 1988; 93:1067. 7. Kharabsheh S, Abendroth CS, Kozak M. Fatal pulmonary toxicity occurring within two weeks of initiation of amiodarone. Am J Cardiol 2002; 89:896. 8. Mason JW. Prediction of amiodarone-induced pulmonary toxicity. Am J Med 1989; 86:2. 9. Gleadhill IC, Wise RA, Schonfeld SA, et al. Serial lung function testing in patients treated with amiodarone: a prospective study. Am J Med 1989; 86:4. 10. Martino E, Safran M, Aghini-Lombardi F, et al. Environmental iodine intake and thyroid dysfunction during chronic amiodarone therapy. Ann Intern Med 1984; 101:28. 11. Goldschlager N, Epstein AE, Naccarelli G, et al. Practical guidelines for clinicians who treat patients with amiodarone. Practice Guidelines Subcommittee, North American Society of Pacing and Electrophysiology. Arch Intern Med 2000; 160:1741. 12. Malfatto G, Zaza A, Facchini M. Different effects of antiarrhythmic drugs on the rate- dependency of QT interval: a study with amiodarone and flecainide. J Cardiovasc Pharmacol 2007; 50:535. 13. Hohnloser SH, Klingenheben T, Singh BN. Amiodarone-associated proarrhythmic effects. A review with special reference to torsade de pointes tachycardia. Ann Intern Med 1994; 121:529. 14. Hohnloser SH, Singh BN. Proarrhythmia with class III antiarrhythmic drugs: definition, electrophysiologic mechanisms, incidence, predisposing factors, and clinical implications. J Cardiovasc Electrophysiol 1995; 6:920. 15. van Opstal JM, Schoenmakers M, Verduyn SC, et al. Chronic amiodarone evokes no torsade de pointes arrhythmias despite QT lengthening in an animal model of acquired long-QT syndrome. Circulation 2001; 104:2722. 16. Makkar RR, Fromm BS, Steinman RT, et al. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA 1993; 270:2590. https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 13/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate 17. Goldschlager N, Epstein A, Friedman P, et al. Environmental and drug effects on patients with pacemakers and implantable cardioverter/defibrillators: a practical guide to patient treatment. Arch Intern Med 2001; 161:649. 18. Zhou L, Chen BP, Kluger J, et al. Effects of amiodarone and its active metabolite desethylamiodarone on the ventricular defibrillation threshold. J Am Coll Cardiol 1998; 31:1672. 19. Pelosi F Jr, Oral H, Kim MH, et al. Effect of chronic amiodarone therapy on defibrillation energy requirements in humans. J Cardiovasc Electrophysiol 2000; 11:736. 20. Nielsen TD, Hamdan MH, Kowal RC, et al. Effect of acute amiodarone loading on energy requirements for biphasic ventricular defibrillation. Am J Cardiol 2001; 88:446. 21. Brown MA, Smith WM, Lubbe WF, Norris RM. Amiodarone-induced torsades de pointes. Eur Heart J 1986; 7:234. 22. Lewis JH, Ranard RC, Caruso A, et al. Amiodarone hepatotoxicity: prevalence and clinicopathologic correlations among 104 patients. Hepatology 1989; 9:679. 23. Richer M, Robert S. Fatal hepatotoxicity following oral administration of amiodarone. Ann Pharmacother 1995; 29:582. 24. Chang CC, Petrelli M, Tomashefski JF Jr, McCullough AJ. Severe intrahepatic cholestasis caused by amiodarone toxicity after withdrawal of the drug: a case report and review of the literature. Arch Pathol Lab Med 1999; 123:251. 25. Macarri G, Feliciangeli G, Berdini V, et al. Canalicular cholestasis due to amiodarone toxicity. A definite diagnosis obtained by electron microscopy. Ital J Gastroenterol 1995; 27:436. 26. Somani P, Bandyopadhyay S, Klaunig JE, Gross SA. Amiodarone- and desethylamiodarone- induced myelinoid inclusion bodies and toxicity in cultured rat hepatocytes. Hepatology 1990; 11:81. 27. M ntyj rvi M, Tuppurainen K, Ik heimo K. Ocular side effects of amiodarone. Surv Ophthalmol 1998; 42:360. 28. Ingram DV. Ocular effects in long-term amiodarone therapy. Am Heart J 1983; 106:902. 29. Flach AJ, Dolan BJ. Progression of amiodarone induced cataracts. Doc Ophthalmol 1993; 83:323. 30. Macaluso DC, Shults WT, Fraunfelder FT. Features of amiodarone-induced optic neuropathy. Am J Ophthalmol 1999; 127:610. 31. Cheng HC, Yeh HJ, Huang N, et al. Amiodarone-Associated Optic Neuropathy: A Nationwide Study. Ophthalmology 2015; 122:2553. https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 14/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate 32. Passman RS, Bennett CL, Purpura JM, et al. Amiodarone-associated optic neuropathy: a critical review. Am J Med 2012; 125:447. 33. Mindel JS, Anderson J, Hellkamp A, et al. Absence of bilateral vision loss from amiodarone: a randomized trial. Am Heart J 2007; 153:837. 34. Jaworski K, Walecka I, Rudnicka L, et al. Cutaneous adverse reactions of amiodarone. Med Sci Monit 2014; 20:2369. 35. Enseleit F, Wyss CA, Duru F, et al. Images in cardiovascular medicine. The blue man: amiodarone-induced skin discoloration. Circulation 2006; 113:e63. 36. Alinovi A, Reverberi C, Melissari M, Gabrielli M. Cutaneous hyperpigmentation induced by amiodarone hydrochloride. J Am Acad Dermatol 1985; 12:563. 37. Delage C, Lagac R, Huard J. Pseudocyanotic pigmentation of the skin induced by amiodarone: a light and electron microscopic study. Can Med Assoc J 1975; 112:1205. 38. Kounis NG, Frangides C, Papadaki PJ, et al. Dose-dependent appearance and disappearance of amiodarone-induced skin pigmentation. Clin Cardiol 1996; 19:592. 39. Blackshear JL, Randle HW. Reversibility of blue-gray cutaneous discoloration from amiodarone. Mayo Clin Proc 1991; 66:721. 40. Orr CF, Ahlskog JE. Frequency, characteristics, and risk factors for amiodarone neurotoxicity. Arch Neurol 2009; 66:865. 41. Sanoski CA, Bauman JL. Clinical observations with the amiodarone/warfarin interaction: dosing relationships with long-term therapy. Chest 2002; 121:19. 42. Holm J, Lindh JD, Andersson ML, Mannheimer B. The effect of amiodarone on warfarin anticoagulation: a register-based nationwide cohort study involving the Swedish population. J Thromb Haemost 2017; 15:446. 43. Kurnik D, Loebstein R, Farfel Z, et al. Complex drug-drug-disease interactions between amiodarone, warfarin, and the thyroid gland. Medicine (Baltimore) 2004; 83:107. Topic 931 Version 36.0 https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 15/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate GRAPHICS Amiodarone baseline testing and monitoring for side effects Monitoring Area of interest for Possible adverse monitoring effect Baseline testing Follow-up testing Cardiac ECG (at baseline and during loading dose) Yearly QT prolongation; torsades de pointes After adding medications that interact with amiodarone or prolong Symptomatic sinoatrial or conduction system impairment the QT interval Implantable cardioverter- Defibrillation threshold testing (if clinically As needed for signs/symptoms Increased defibrillation threshold defibrillators indicated) Dermatologic Physical examination As needed for signs/symptoms Photosensitivity to UV light Blue-gray skin discoloration Endocrine TSH (with reflex testing if abnormal) 3 to 4 months after starting drug, then yearly Hyperthyroidism, hypothyroidism As needed for signs/symptoms Hepatic AST and ALT 6 months after starting drug, then yearly AST or ALT elevation 2 upper limit of reference range Ophthalmologic Eye examination Yearly Corneal microdeposits Optic neuropathy Pulmonary Chest radiograph, PFTs* Yearly for surveillance Pulmonary toxicity (cough, fever, dyspnea) Along with PFTs (including DLCO) and chest computed tomography for signs/symptoms Refer to UpToDate topics on pulmonary toxicity, thyroid toxicity, and clinical uses of amiodarone for additional information. https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 16/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate ECG: electrocardiogram; UV: ultraviolet; TSH: thyroid-stimulating hormone; AST: aspartate aminotransferase; ALT: alanine transaminase; PFTs: pulmonary function tests; DLCO: diffusing capacity of the lungs for carbon monoxide. There are differing opinions, and no concensus, of obtaining formal PFTs with assessment of diffusion capacity (ie, DLCO) as baseline testing in all patients. Some experts obtain baseline PFTs with DLCO prior to starting amiodarone, particularly among patients with underlying lung disease, while other experts rarely or never obtain baseline PFTs. Graphic 126072 Version 4.0 https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 17/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate Amiodarone-induced pigmentation Amiodarone causes a striking slate-gray pigmentation in a photodistribution of the face. The blue color (ceruloderma) is due to the deposition of melanin and lipofuscin contained in macrophages and endothelial cells in the dermis. The pigmentation is reversible, but it may take up to a year or more to complete resolution. Reproduced with permission from: Fitzpatrick TB, Johnson AB, Wol K, Suurmond D. Color Atlas and Synopsis of Clinical Dermatology: Common and Serious Diseases, 4th ed, McGraw-Hill, New York 2001. Copyright 2001 The McGraw-Hill Companies, Inc. Graphic 70419 Version 6.0 https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 18/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate Contributor Disclosures Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Rod Passman, MD, MSCE Grant/Research/Clinical Trial Support: Abbott [Ablation]; AHA [Ablation]; NIH [Stroke prevention]. Consultant/Advisory Boards: Abbott [Ablation]; iRhythm [Monitoring]; Janssen [Atrial fibrillation detection]; Medtronic [Implantable cardiac monitors]. Speaker's Bureau: iRhythm [Monitoring]. All of the relevant financial relationships listed have been mitigated. Mark S Link, MD No relevant financial relationship(s) with ineligible companies to disclose. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 19/19