Basic Information
ID DDInter388 and DDInter527
Interaction Concomitant use of agents with serotonergic activity such as serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, 5-HT1 receptor agonists, ergot alkaloids, lithium, St. John's wort, phenylpiperidine opioids, dextromethorphan, and tryptophan may potentiate the risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A receptors. Symptoms of the serotonin syndrome may include mental status changes such as irritability, altered consciousness, confusion, hallucination, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea.
Management In general, the concomitant use of multiple serotonergic agents should be avoided if possible, or otherwise approached with caution if potential benefit is deemed to outweigh the risk. If concomitant therapy is necessary, patients should be closely monitored for symptoms of the serotonin syndrome during treatment. Particular caution is advised when increasing the dosages of these agents. The potential risk for serotonin syndrome should be considered even when administering serotonergic agents sequentially, as some agents may demonstrate a prolonged elimination half-life (e.g., fluoxetine). If serotonin syndrome develops or is suspected during the course of therapy, all serotonergic agents should be discontinued immediately and supportive care rendered as necessary. Moderately ill patients may also benefit from the administration of a serotonin antagonist (e.g., cyproheptadine, chlorpromazine). Severe cases should be managed under consultation with a toxicologist and may require sedation, neuromuscular paralysis, intubation, and mechanical ventilation in addition to the other measures.
References [1] "Product Information. Zyvox (linezolid)" Pharmacia and Upjohn, Kalamazoo, MI. [2] DeBellis RJ, Schaefer OP, Liquori M, Volturo GA "Linezolid-associated serotonin syndrome after concomitant treatment with citalopram and mirtazepine in a critically ill bone marrow transplant recipient." J Intensive Care Med 20 (2005): 351-3 [3] Turkel SB, Nadala JG, Wincor MZ "Possible serotonin syndrome in association with 5-HT3 antagonist agents." Psychosomatics 42 (2001): 258-60 [4] Taylor JJ, Wilson JW, Estes LL "Linezolid and serotonergic drug interactions: a retrospective survey." Clin Infect Dis 43 (2006): 180-7 [5] Fischer P "Serotonin syndrome in the elderly after antidepressive monotherapy." J Clin Psychopharmacol 15 (1995): 440-2 [6] Margolese HC, Chouinard G "Serotonin syndrome from addition of low-dose trazodone to nefazodone." Am J Psychiatry 157 (2000): 1022 [7] Mills KC "Serotonin syndrome: A clinical update." Crit Care Clin 13 (1997): 763 [8] "Product Information. Luvox (fluvoxamine)." Solvay Pharmaceuticals Inc, Marietta, GA. [9] Steinberg M, Morin AK "Mild serotonin syndrome associated with concurrent linezolid and fluoxetine." Am J Health Syst Pharm 64 (2007): 59-62 [10] "Product Information. Prozac (fluoxetine)." Dista Products Company, Indianapolis, IN. [11] Bhatara VS, Magnus RD, Paul KL, Preskorn SH "Serotonin syndrome induced by venlafaxine and fluoxetine: a case study in polypharmacy and potential pharmacodynamic and pharmacokinetic mechanisms." Ann Pharmacother 32 (1998): 432-6 [12] Jones SL, Athan E, O'Brien D "Serotonin syndrome due to co-administration of linezolid and venlafaxine." J Antimicrob Chemother 54 (2004): 289-90 [13] Lantz MS, Buchalter E, Giambanco V "St. John's wort and antidepressant drug interactions in the elderly." J Geriatr Psychiatr Neurol 12 (1999): 7-10 [14] "Product Information. Paxil (paroxetine)." GlaxoSmithKline, Research Triangle Park, NC. [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] Packer S, Berman SA "Serotonin syndrome precipitated by the monoamine oxidase inhibitor linezolid." Am J Psychiatry 164 (2007): 346-7 [17] Weiner AL "Meperidine as a potential cause of serotonin syndrome in the emergency department." Acad Emerg Med 6 (1999): 156-8 [18] Lavery S, Ravi H, McDaniel WW, Pushkin YR "Linezolid and serotonin syndrome." Psychosomatics 42 (2001): 432-4 [19] Hachem RY, Hicks K, Huen A, Raad I "Myelosuppression and serotonin syndrome associated with concurrent use of linezolid and selective serotonin reuptake inhibitors in bone marrow transplant recipients." Clin Infect Dis 37 (2003): E8-E11 [20] Harvey AT, Preskorn SH "Interactions of serotonin reuptake inhibitors with tricyclic antidepressants." Arch Gen Psychiatry 52 (1995): 783-4 [21] Goldberg RJ, Huk M "Serotonin syndrome from trazodone and buspirone." Psychosomatics 33 (1992): 235-6 [22] Hansen TE, Dieter K, Keepers GA "Interaction of fluoxetine and pentazocine." Am J Psychiatry 147 (1990): 949-50 [23] Egberts AC, ter Borg J, Brodie-Meijer CC "Serotonin syndrome attributed to tramadol addition to paroxetine therapy." Int Clin Psychopharmacol 12 (1997): 181-2 [24] "Product Information. Savella (milnacipran)." Forest Pharmaceuticals, St. Louis, MO. [25] Noble WH, Baker A "MAO inhibitors and coronary artery surgery: a patient death." Can J Anaesth 39 (1992): 1061-6 [26] Achamallah NS "Visual hallucinations after combining fluoxetine and dextromethorphan ." Am J Psychiatry 149 (1992): 1406 [27] 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 [28] Shapiro RE, Tepper SJ "The serotonin syndrome, triptans, and the potential for drug-drug interactions." Headache 47 (2007): 266-9 [29] Mathew NT, Tietjen GE, Lucker C "Serotonin syndrome complicating migraine pharmacotherapy." Cephalalgia 16 (1996): 323-7 [30] Thomas CR, Rosenberg M, Blythe V, Meyer WJ 3rd "Serotonin syndrome and linezolid." J Am Acad Child Adolesc Psychiatry 43 (2004): 790 [31] Paruchuri P, Godkar D, Anandacoomarswamy D, Sheth K, Niranjan S "Rare case of serotonin syndrome with therapeutic doses of paroxetine." Am J Ther 13 (2006): 550-552 [32] Dougherty JA, Young H, Shafi T "Serotonin syndrome induced by amitriptyline, meperidine, and venlafaxine." Ann Pharmacother 36 (2002): 1647-1648 [33] "Product Information. D.H.E. 45 (dihydroergotamine)." Sandoz Pharmaceuticals Corporation, East Hanover, NJ. [34] "Product Information. Brintellix (vortioxetine)." Takeda Pharmaceuticals America, Lincolnshire, IL. [35] "Product Information. Viibryd (vilazodone)." Trovis Pharmaceuticals LLC, New Haven, CT. [36] Gardner DM, Lynd LD "Sumatriptan contraindications and the serotonin syndrome." Ann Pharmacother 32 (1998): 33-8 [37] "Product Information. Celexa (citalopram)." Forest Pharmaceuticals, St. Louis, MO. [38] Rang ST, Field J, Irving C "Serotonin toxicity caused by an interaction between fentanyl and paroxetine." Can J Anaesth 55 (2008): 521-5 [39] Tissot TA "Probable meperidine-induced serotonin syndrome in a patient with a history of fluoxetine use." Anesthesiology 98 (2003): 1511-1512 [40] Hammerness P, Parada H, Abrams A "Linezolid: MAOI Activity and Potential Drug Interactions." Psychosomatics 43 (2002): 248-9 [41] "Product Information. Zomig (zolmitriptan)." Zeneca Pharmaceuticals, Wilmington, DE. [42] "Product Information. Effexor (venlafaxine)." Wyeth-Ayerst Laboratories, Philadelphia, PA. [43] "Product Information. Fetzima (levomilnacipran)." Forest Pharmaceuticals, St. Louis, MO. [44] Metz A "Interaction between fluoxetine and buspirone." Can J Psychiatry 35 (1990): 722-3 [45] Ciraulo DA, Shader RI "Fluoxetine drug-drug interactions: I. Antidepressants and antipsychotics." J Clin Psychopharmacol 10 (1990): 48-50 [46] Duggal HS, Fetchko J "Serotonin syndrome and atypical antipsychotics." Am J Psychiatry 159 (2002): 672-3 [47] "Product Information. Pristiq (desvenlafaxine)." Wyeth Laboratories, Philadelphia, PA. [48] "Product Information. Imitrex (sumatriptan)." Glaxo Wellcome, Research Triangle Park, NC. [49] "Product Information. Cymbalta (duloxetine)." Lilly, Eli and Company, Indianapolis, IN. [50] Martin TG "Serotonin syndrome." Ann Emerg Med 28 (1996): 520-6 [51] "Product Information. Nucynta (tapentadol)." PriCara Pharmaceuticals, Raritan, NJ. [52] Morales-Molina JA, Mateu-de Antonio J, Marin-Casino M, Grau S "Linezolid-associated serotonin syndrome: what we can learn from cases reported so far." J Antimicrob Chemother 56 (2005): 1176-8 [53] 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 [54] Manos GH "Possible serotonin syndrome associated with buspirone added to fluoxetine." Ann Pharmacother 34 (2000): 871-4 [55] Wigen CL, Goetz MB "Serotonin syndrome and linezolid." Clin Infect Dis 34 (2002): 1651-2 [56] Ciraulo DA, Shader RI "Fluoxetine drug-drug interactions. II." J Clin Psychopharmacol 10 (1990): 213-7 [57] "Product Information. Lexapro (escitalopram)." Forest Pharmaceuticals, St. Louis, MO. [58] Sternbach H "The serotonin syndrome." Am J Psychiatry 148 (1991): 705-13 [59] Gillman PK "Linezolid and serotonin toxicity." Clin Infect Dis 37 (2003): 1274-5 [60] Mason BJ, Blackburn KH "Possible serotonin syndrome associated with tramadol and sertraline coadministration." Ann Pharmacother 31 (1997): 175-7 [61] "Product Information. Meridia (sibutramine)." Knoll Pharmaceutical Company, Whippany, NJ. [62] Roy S, Fortier LP "Fentanyl-induced rigidity during emergence from general anesthesia potentiated by venlafexine." Can J Anaesth 50 (2003): 32-5 [63] George TP, Godleski LS "Possible serotonin syndrome with trazodone addition to fluoxetine." Biol Psychiatry 39 (1996): 384-5 [64] Nierenberg DW, Semprebon M "The central nervous system serotonin syndrome." Clin Pharmacol Ther 53 (1993): 84-8 [65] John L, Perreault MM, Tao T, Blew PG "Serotonin syndrome associated with nefazodone and paroxetine." Ann Emerg Med 29 (1997): 287-9 [66] Mackay FJ, Dunn NR, Mann RD "Antidepressants and the serotonin syndrome in general practice." Br J Gen Pract 49 (1999): 871-4 [67] Giese SY, Neborsky R "Serotonin syndrome: potential consequences of Meridia combined with Demerol or fentanyl." Plast Reconstr Surg 107 (2001): 293-4 [68] Gilman AG, Rall TW, Nies AS, Taylor P, eds. "Goodman and Gilman's the Pharmacological Basis of Therapeutics. 8th ed." New York, NY: Pergamon Press Inc. (1990): [69] Nijhawan PK, Katz G, Winter S "Psychiatric illness and the serotonin syndrome: an emerging adverse drug effect leading to intensive care unit admission." Crit Care Med 24 (1996): 1086-9 [70] Smith DL, Wenegrat BG "A case report of serotonin syndrome associated with combined nefazodone and fluoxetine." J Clin Psychiatry 61 (2000): 146 [71] Insel TR, Roy BF, Cohen RM, Murphy DL "Possible development of the serotonin syndrome in man." Am J Psychiatry 139 (1982): 954-5 [72] Bernard L, Stern R, Lew D, Hoffmeyer P "Serotonin syndrome after concomitant treatment with linezolid and citalopram." Clin Infect Dis 36 (2003): 1197 [73] 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 [74] Reeves RR, Bullen JA "Serotonin syndrome produced by paroxetine and low-dose trazodone." Psychosomatics 36 (1995): 159-60 [75] Miller LG "Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions." Arch Intern Med 158 (1998): 2200-11 [76] "Product Information. Zoloft (sertraline)." Roerig Division, New York, NY. [77] Fugh-Berman A "Herb-drug interactions." Lancet 355 (2000): 134-8 [78] Ruiz F "Fluoxetine and the serotonin syndrome." Ann Emerg Med 24 (1994): 983-5 [79] Bergeron L, Boule M, Perreault S "Serotonin toxicity associated with concomitant use of linezolid." Ann Pharmacother 39 (2005): 956-61 [80] Morales N, Vermette H "Serotonin syndrome associated with linezolid treatment after discontinuation of fluoxetine." Psychosomatics 46 (2005): 274-5 [81] Skop BP, Finkelstein JA, Mareth TR, Magoon MR, Brown TM "The serotonin syndrome associated wtih paroxetine, an over-the-counter cold remedy, and vascular disease." Am J Emerg Med 12 (1994): 642-4 [82] Laird LK "Issues in the monopharmacotherapy and polypharmacotherapy of obsessive-compulsive disorder." Psychopharmacol Bull 32 (1996): 569-78 [83] Izzo AA, Ernst E "Interactions between herbal medicines and prescribed drugs: a systematic review." Drugs 61 (2001): 2163-75 [84] "Product Information. Maxalt (rizatriptan)." Merck & Co, Inc, West Point, PA. [85] Tahir N "Serotonin syndrome as a consequence of drug-resistant infections: an interaction between linezolid and citalopram." J Am Med Dir Assoc 5 (2004): 111-3 [86] Perry NK "Venlafaxine-induced serotonin syndrome with relapse following amitriptyline." Postgrad Med J 76 (2000): 254-6 [87] Corkeron MA "Serotonin syndrome - a potentially fatal complication of antidepressant therapy." Med J Aust 163 (1995): 481-2 [88] Strouse TB, Kerrihard TN, Forscher CA, Zakowski P "Serotonin syndrome precipitated by linezolid in a medically ill patient on duloxetine." J Clin Psychopharmacol 26 (2006): 681-683 [89] Gordon JB "SSRI's and St. John's Wort: possible toxicity?" Am Fam Physician 57 (1998): 950,953 [90] Lane R, Baldwin D "Selective serotonin reuptake inhibitor--induced serotonin syndrome: review." J Clin Psychopharmacol 17 (1997): 208-21 [91] Divoll M, Greenblatt DJ, Lacasse Y, Shader RI "Benzodiazepine overdosage: plasma concentrations and clinical outcome." Psychopharmacology (Berl) 73 (1981): 381-3 [92] "Product Information. Belsomra (suvorexant)." Merck & Company Inc, Whitehouse Station, NJ. [93] Lemberger L, Rowe H, Bosomworth JC, Tenbarge JB, Bergstrom RF "The effect of fluoxetine on the pharmacokinetics and psychomotor responses of diazepam." Clin Pharmacol Ther 43 (1988): 412-9 [94] Grabowski BS, Cady WJ, Young WW, Emery JF "Effects of acute alcohol administration on propranolol absorption." Int J Clin Pharmacol Ther Toxicol 18 (1980): 317-9 [95] Feldman SA, Crawley BE "Interaction of diazepam with the muscle-relaxant drugs." Br Med J 1 (1970): 336-8 [96] Driessen JJ, Vree TB, Booij LH, van der Pol FM, Crul JF "Effect of some benzodiazepines on peripheral neuromuscular function in the rat in-vitro hemidiaphragm preparation." J Pharm Pharmacol 36 (1984): 244-7 [97] Miller LG "Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions." Arch Intern Med 158 (1998): 2200-11 [98] MacLeod SM, Giles HG, Patzalek G, Thiessen JJ, Sellers EM "Diazepam actions and plasma concentrations following ethanol ingestion." Eur J Clin Pharmacol 11 (1977): 345-9 [99] Hamilton MJ, Bush M, Smith P, Peck AW "The effects of bupropion, a new antidepressant drug, and diazepam, and their interaction in man." Br J Clin Pharmacol 14 (1982): 791-7 [100] Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0 [101] Sotaniemi EA, Anttila M, Rautio A, et al "Propranolol and sotalol metabolism after a drinking party." Clin Pharmacol Ther 29 (1981): 705-10 [102] "Product Information. Rexulti (brexpiprazole)." Otsuka American Pharmaceuticals Inc, Rockville, MD. [103] "Product Information. Tasmar (tolcapone)." Valeant Pharmaceuticals, Costa Mesa, CA. [104] Plushner SL "Valerian: valeriana officinalis." Am J Health Syst Pharm 57 (2000): 328-35 [105] "Product Information. Lexapro (escitalopram)." Forest Pharmaceuticals, St. Louis, MO. [106] Greb WH, Buscher G, Dierdorf HD, Koster FE, Wolf D, Mellows G "The effect of liver enzyme inhibition by cimetidine and enzyme induction by phenobarbitone on the pharmacokinetics of paroxetine." Acta Psychiatr Scand 80 Suppl (1989): 95-8 [107] "Product Information. Fycompa (perampanel)." Eisai Inc, Teaneck, NJ. [108] "Product Information. Meridia (sibutramine)." Knoll Pharmaceutical Company, Whippany, NJ. [109] "Product Information. Ultiva (remifentanil)." Mylan Institutional (formally Bioniche Pharma USA Inc), Canonsburg, PA. [110] Markowitz JS, Wells BG, Carson WH "Interactions between antipsychotic and antihypertensive drugs." Ann Pharmacother 29 (1995): 603-9 [111] Ferslew KE, Hagardorn AN, McCormick WF "A fatal interaction of methocarbamol and ethanol in an accidental poisoning." J Forensic Sci 35 (1990): 477-82 [112] Greiff JMC, Rowbotham D "Pharmacokinetic drug interactions with gastrointestinal motility modifying agents." Clin Pharmacokinet 27 (1994): 447-61 [113] Stambaugh JE, Lane C "Analgesic efficacy and pharmacokinetic evaluation of meperidine and hydroxyzine, alone and in combination." Cancer Invest 1 (1983): 111-7 [114] "Product Information. Seroquel (quetiapine)." Zeneca Pharmaceuticals, Wilmington, DE. [115] Cerner Multum, Inc. "Australian Product Information." O 0 [116] "Product Information. Iopidine (apraclonidine)." Alcon Laboratories Inc, Fort Worth, TX. [117] Naylor GJ, McHarg A "Profound hypothermia on combined lithium carbonate and diazepam treatment." Br Med J 2 (1977): 22 [118] Tverskoy M, Fleyshman G, Ezry J, Bradley EL, Jr Kissin I "Midazolam-morphine sedative interaction in patients." Anesth Analg 68 (1989): 282-5 [119] Desager JP, Hulhoven R, Harvengt C, Hermann P, Guillet P, Thiercelin JF "Possible interactions between zolpidem, a new sleep inducer and chlorpromazine, a phenothiazine neuroleptic." Psychopharmacology (Berl) 96 (1988): 63-6 [120] "Product Information. Artane (trihexyphenidyl)." Lederle Laboratories, Wayne, NJ. [121] "Product Information. Ultram (tramadol)." McNeil Pharmaceutical, Raritan, NJ. [122] Stovner J, Endresen R "Intravenous anaesthesia with diazepam." Acta Anaesthesiol Scand 24 (1965): 223-7 [123] "Product Information. Trileptal (oxcarbazepine)" Novartis Pharmaceuticals, East Hanover, NJ. [124] Ochs HR, Greenblatt DJ, Verburg-Ochs B "Propranolol interactions with diazepam, lorazepam and alprazolam." Clin Pharmacol Ther 36 (1984): 451-5 [125] "Product Information. Precedex (dexmedetomidine)" Abbott Pharmaceutical, Abbott Park, IL. [126] "Product Information. Xatral (alfuzosin)." Sanofi-Synthelabo Canada Inc, Markham, ON. [127] Warrington SJ, Ankier SI, Turner P "Evaluation of possible interactions between ethanol and trazodone or amitriptyline." Neuropsychobiology 15 (1986): 31-7 [128] "Product Information. Fycompa (perampanel)." Eisai Inc, Teaneck, NJ. [129] "Product Information. Rexulti (brexpiprazole)." Otsuka American Pharmaceuticals Inc, Rockville, MD. [130] Gilman AG, Rall TW, Nies AS, Taylor P, eds. "Goodman and Gilman's the Pharmacological Basis of Therapeutics. 8th ed." New York, NY: Pergamon Press Inc. (1990): [131] Warrington SJ, Ankier SI, Turner P "Evaluation of possible interactions between ethanol and trazodone or amitriptyline." Neuropsychobiology 15 (1986): 31-7 [132] "Product Information. Fycompa (perampanel)." Eisai Inc, Teaneck, NJ. [133] "Product Information. Rexulti (brexpiprazole)." Otsuka American Pharmaceuticals Inc, Rockville, MD. [134] Gilman AG, Rall TW, Nies AS, Taylor P, eds. "Goodman and Gilman's the Pharmacological Basis of Therapeutics. 8th ed." New York, NY: Pergamon Press Inc. (1990):
Alternative for Citalopram -
Alternative for Dextromethorphan R05D

N07X
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.