Basic Information
ID DDInter1607 and DDInter884
Interaction Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of hydrocodone, which is substantially metabolized by the isoenzyme. Increased hydrocodone concentrations could conceivably increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Because hydrocodone is also partially metabolized by CYP450 2D6, the magnitude of interaction may be even greater with concomitant use of a CYP450 3A4 and a CYP450 2D6 inhibitor, or concomitant use of a drug that is a dual inhibitor of both isoenzymes.
Management Extreme caution is advised if hydrocodone is prescribed with CYP450 3A4 inhibitors, particularly potent and moderate inhibitors (e.g., azole antifungal agents, protease inhibitors, aprepitant, ceritinib, ciprofloxacin, chloramphenicol, clarithromycin, cobicistat, conivaptan, crizotinib, delavirdine, diltiazem, dronedarone, erythromycin, fusidic acid, idelalisib, imatinib, letermovir, mibefradil, mifepristone, nefazodone, netupitant, quinupristin-dalfopristin, telithromycin, verapamil) or weak inhibitors that also inhibit CYP450 2D6 (e.g., abiraterone, amiodarone, cimetidine, pazopanib, ranolazine). A fatal overdose may occur following the initiation of a CYP450 3A4 inhibitor in patients already receiving hydrocodone. Patients should be closely monitored for signs and symptoms of sedation, respiratory depression, and hypotension. Following discontinuation of the CYP450 3A4 inhibitor, patients should be monitored for reduced efficacy of hydrocodone or development of withdrawal symptoms due to reduced plasma hydrocodone levels.
References [1] "Product Information. Zohydro ER (HYDROcodone)." Zogenix, Inc, San Diego, CA. [2] Hutchinson MR, Menelaou A, Foster DJ, Coller JK, Somogyi AA "CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes." Br J Clin Pharmacol 57 (2004): 287-97 [3] Vizcaychipi MP, Walker S, Palazzo M "Serotonin syndrome triggered by tramadol." Br J Anaesth 99 (2007): 919 [4] Das PK, Warkentin DI, Hewko R, Forrest DL "Serotonin syndrome after concomitant treatment with linezolid and meperidine." Clin Infect Dis 46 (2008): 264-5 [5] Mittino D, Mula M, Monaco F "Serotonin syndrome associated with tramadol-sertraline coadministration." Clin Neuropharmacol 27 (2004): 150-1 [6] Gillman PK "Possible serotonin syndrome with moclobemide and pethidine." Med J Aust 162 (1995): 554 [7] Mason BJ, Blackburn KH "Possible serotonin syndrome associated with tramadol and sertraline coadministration." Ann Pharmacother 31 (1997): 175-7 [8] Dougherty JA, Young H, Shafi T "Serotonin syndrome induced by amitriptyline, meperidine, and venlafaxine." Ann Pharmacother 36 (2002): 1647-1648 [9] Kesavan S, Sobala GM "Serotonin syndrome with fluoxetine plus tramadol." J R Soc Med 92 (1999): 474-5 [10] Insler SR, Kraenzler EJ, Licina MG, Savage RM, Starr NJ "Cardiac surgery in a patient taking monoamine oxidase inhibitors - an adverse fentanyl reaction." Anesth Analg 78 (1994): 593-7 [11] Hansen TE, Dieter K, Keepers GA "Interaction of fluoxetine and pentazocine." Am J Psychiatry 147 (1990): 949-50 [12] Noble WH, Baker A "MAO inhibitors and coronary artery surgery: a patient death." Can J Anaesth 39 (1992): 1061-6 [13] Rang ST, Field J, Irving C "Serotonin toxicity caused by an interaction between fentanyl and paroxetine." Can J Anaesth 55 (2008): 521-5 [14] Martin TG "Serotonin syndrome." Ann Emerg Med 28 (1996): 520-6 [15] Ailawadhi S, Sung KW, Carlson LA, Baer MR "Serotonin syndrome caused by interaction between citalopram and fentanyl." J Clin Pharm Ther 32 (2007): 199-202 [16] Meyer D, Halfin V "Toxicity secondary to meperidine in patients on monoamine oxidase inhibitors: a case report and critical review." J Clin Psychopharmacol 1 (1981): 319-21 [17] Mills KC "Serotonin syndrome: A clinical update." Crit Care Clin 13 (1997): 763 [18] Gillman PK "Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity." Br J Anaesth (2005): [19] US Food and Drug Administration (FDA) "FDA Drug Safety Communication: FDA warns about several safety issues with opioid pain medicines; requires label changes. Available from: URL: https://www.fda.gov/downloads/Drugs/DrugSafety/UCM491302.pdf." ([2016, Mar 22]): [20] Lange-Asschenfeldt C, Weigmann H, Hiemke C, Mann K "Serotonin syndrome as a result of fluoxetine in a patient with tramadol abuse: plasma level-correlated symptomatology." J Clin Psychopharmacol 22 (2002): 440-1 [21] Gonzalez-Pinto A, Imaz H, De Heredia JL, Gutierrez M, Mico JA "Mania and tramadol-fluoxetine combination." Am J Psychiatry 158 (2001): 964-5 [22] Chan BSH, Graudins A, Whyte IM, Dawson AH, Braitberg G, Duggin GG "Serotonin syndrome resulting from drug interactions." Med J Aust 169 (1998): 523-5 [23] Abadie D, Rousseau V, Logerot S, Cottin J, Montastruc JL, Montastruc F "Serotonin Syndrome: Analysis of Cases Registered in the French Pharmacovigilance Database." J Clin Psychopharmacol (2015): [24] Rosebraugh CJ, floxkhart DA, Yasuda SU, Woosley RL "Visual hallucination and tremor induced by sertraline and oxycodone in a bone marrow transplant patient." J Clin Pharmacol 41 (2001): 224-7 [25] Egberts AC, ter Borg J, Brodie-Meijer CC "Serotonin syndrome attributed to tramadol addition to paroxetine therapy." Int Clin Psychopharmacol 12 (1997): 181-2 [26] Davis JJ, Buck NS, Swenson JD, Johnson KB, Greis PE "Serotonin syndrome manifesting as patient movement during total intravenous anesthesia with propofol and remifentanil." J Clin Anesth 25 (2013): 52-4 [27] Shakoor M, Ayub S, Ahad A, Ayub Z "Transient serotonin syndrome caused by concurrent use of tramadol and selective serotonin reuptake inhibitor." Am J Case Rep 15 (2014): 562-4 [28] Lantz MS, Buchalter EN, Giambanco V "Serotonin syndrome following the administration of tramadol with paroxetine." Int J Geriatr Psychiatry 13 (1998): 343-5 [29] Tissot TA "Probable meperidine-induced serotonin syndrome in a patient with a history of fluoxetine use." Anesthesiology 98 (2003): 1511-1512 [30] "Venlafaxine + tramadol: serotonin syndrome." Prescrire Int 13 (2004): 57 [31] Gnanadesigan N, Espinoza RT, Smith R, Israel M, Reuben DB "Interaction of serotonergic antidepressants and opioid analgesics: Is serotonin syndrome going undetected?" J Am Med Dir Assoc 6 (2005): 265-9 [32] Houlihan DJ "Serotonin syndrome resulting from coadministration of tramadol, venlafaxine, and mirtazapine." Ann Pharmacother 38 (2004): 411-3 [33] Hillman AD, Witenko CJ, Sultan SM, Gala G "Serotonin syndrome caused by fentanyl and methadone in a burn injury." Pharmacotherapy 35 (2015): 112-7 [34] Sternbach H "The serotonin syndrome." Am J Psychiatry 148 (1991): 705-13 [35] Roy S, Fortier LP "Fentanyl-induced rigidity during emergence from general anesthesia potentiated by venlafexine." Can J Anaesth 50 (2003): 32-5 [36] Guo SL, Wu TJ, Liu CC, Ng CC, Chien CC, Sun HL "Meperidine-induced serotonin syndrome in a susceptible patient." Br J Anaesth (2009): [37] Mateo-Carrasco H, Munoz-Aguilera EM, Garcia-Torrecillas JM, Abu Al-Robb H "Serotonin Syndrome Probably Triggered by a Morphine-Phenelzine Interaction." Pharmacotherapy (2015): [38] Hunter B, Kleinert MM, Osatnik J, Soria E "Serotonergic syndrome and abnormal ocular movements: worsening of rigidity by remifentanil?" Anesth Analg 102 (2006): 1589 [39] Kitson R, Carr B "Tramadol and severe serotonin syndrome." Anaesthesia 60 (2005): 934-5 [40] Zornberg GL, Bodkin JA, Cohen BM "Severe adverse interaction between pethidine and selegiline." Lancet 337 (1991): 246 [41] Mahlberg R, Kunz D, Sasse J, Kirchheiner J "Serotonin syndrome with tramadol and citalopram." Am J Psychiatry 161 (2004): 1129 [42] Larson KJ, Wittwer ED, Nicholson WT, Weingarten TN, Price DL, Sprung J "Myoclonus in patient on fluoxetine after receiving fentanyl and low-dose methylene blue during sentinel lymph node biopsy." J Clin Anesth 27 (2015): 247-51 [43] "Product Information. Zohydro ER (HYDROcodone)." Zogenix, Inc, San Diego, CA.
Alternative for Ritonavir J05A
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Alternative for Hydrocodone R05D
Benzonatate Clofedanol Pentoxyverine
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.