Basic Information
ID DDInter1166 and DDInter8
Interaction Methadone may cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. High dosages of methadone alone have been associated with QT interval prolongation and torsade de pointes.
Management Caution is recommended if methadone is used in combination with other drugs that can prolong the QT interval, particularly in the setting of chronic pain management or methadone maintenance for opioid dependency where high dosages may be employed. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope. If taking drugs that also cause CNS-depressant or orthostatic effects (e.g., sedating antihistamines, psychotropic drugs like tricyclic antidepressants, phenothiazines, and neuroleptics), patients should be made aware of the possibility of additive effects with methadone and counseled to avoid activities requiring mental alertness until they know how these agents affect them.
References [1] Krantz MJ, Mehler PS "Synthetic opioids and QT prolongation." Arch Intern Med 163 (2003): 1615; author reply 1615 [2] Mokwe EO, Ositadinma O "Torsade de pointes due to methadone." Ann Intern Med 139 (2003): W64 [3] Gil M, Sala M, Anguera I, et al. "QT prolongation and Torsades de Pointes in patients infected with human immunodeficiency virus and treated with methadone." Am J Cardiol 92 (2003): 995-7 [4] Krantz MJ, Lewkowiez L, Hays H, et al "Torsade de pointes associated with very-high-dose methadone." Ann Intern Med 137 (2002): 501-4 [5] Ehret GB, Desmeules JA, Broers B "Methadone-associated long QT syndrome: improving pharmacotherapy for dependence on illegal opioids and lessons learned for pharmacology." Expert Opin Drug Saf 6 (2007): 289-303 [6] Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0 [7] Sala M, Anguera I, Cervantes M "Torsade de pointes due to methadone." Ann Intern Med 139 (2003): W64 [8] EMA. European Medicines Agency. European Union "EMA - List of medicines under additional monitoring. Available from: URL: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000366.jsp&mid=WC0b01ac058067c852" ([2013 - ]): [9] Walker PW, Klein D, Kasza L "High dose methadone and ventricular arrhythmias: a report of three cases." Pain 103 (2003): 321-4 [10] Krantz MJ, Kutinsky IB, Robertson AD, Mehler PS "Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes." Pharmacotherapy 23 (2003): 802-5 [11] Canadian Pharmacists Association "e-CPS. Available from: URL: http://www.pharmacists.ca/function/Subscriptions/ecps.cfm?link=eCPS_quikLink." [12] De Bels D, Staroukine M, Devriendt J "Torsades de pointes due to methadone." Ann Intern Med 139 (2003): E156 [13] Cerner Multum, Inc. "Australian Product Information." O 0 [14] Martell BA, Arnsten JH, Krantz MJ, Gourevitch MN "Impact of methadone treatment on cardiac repolarization and conduction in opioid users." Am J Cardiol 95 (2005): 915-8 [15] Beauverie P, Taburet AM, Dessalles MC, Furlan V, Touzeau D "Therapeutic drug monitoring of methadone in HIV-infected patients receiving protease inhibitors." AIDS 12 (1998): 2510-1 [16] Geletko SM, Erickson AD "Decreased methadone effect after ritonavir initiation." Pharmacotherapy 20 (2000): 93-4 [17] Foster DJ, Somogyi AA, Bochner F "Methadone N-demethylation in human liver microsomes: lack of stereoselectivity and involvement of CYP3A4." Br J Clin Pharmacol 47 (1999): 403-12 [18] Benmebarek M, Devaud C, Gex-Fabry M, et al. "Effects of grapefruit juice on the pharmacokinetics of the enantiomers of methadone." Clin Pharmacol Ther 76 (2004): 55-63 [19] Oda Y, Kharasch ED "Metabolism of methadone and levo-alpha-acetylmethadol (LAAM) by human intestinal cytochrome P450 3A4 (CYP3A4): potential contribution of intestinal metabolism to presystemic clearance and bioactivation." J Pharmacol Exp Ther 298 (2001): 1021-32 [20] Iribarne C, Berthou F, Baird S, Dreano Y, Picart D, Bail JP, Beaune P, Menez JF "Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes." Chem Res Toxicol 9 (1996): 365-73 [21] "Product Information. Kaletra (lopinavir-ritonavir)" Abbott Pharmaceutical, Abbott Park, IL. [22] "Product Information. Norvir (ritonavir)." Abbott Pharmaceutical, Abbott Park, IL.
Alternative for Methadone N07B
Nicotine Nalmefene Acamprosate Disulfiram Varenicline Diamorphine

N02A
Opium Pentazocine Dihydrocodeine Butorphanol Acetaminophen
More
Alternative for Abiraterone L02B
Exemestane Darolutamide Anastrozole Letrozole Fulvestrant
Potential Metabolism Interactions
Substrate-Substrate Interaction：If more than one drug is metabolized by the same CYP, it is possible that its metabolism is inhibited because of the competition between the drugs. That means, it can be useful to lower the dosage of the drugs in the drug-cocktail because they remain longer in the organism than in monotherapy.
Inhibitor-Inhibitor Interaction：Combining two or more inhibitors of one CYP, should be compensated by lowering the dosage of these drugs because the metabolism is reduced and the drugs remain longer in the organism than in monotherapy. Not adapting the dosage bears the risk of even more side effects.
Inhibitor-Substrate Interaction：Combining drugs that have inhibitory effect and are substrates of one particular CYP, should be compensated by lowering the dosage. They rest longer in the organism than in monotherapy. Not adapting the dosage bears the risk of even more side effects.