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Drug Interaction Report

24 potential interactions and/or warnings found for the following 6 drugs:

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Major

traZODone venlafaxine

Applies to: trazodone, Effexor (venlafaxine)

MONITOR CLOSELY: Concomitant use of agents with serotonergic activity such as serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, 5-HT1 receptor agonists, ergot alkaloids, cyclobenzaprine, 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. 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. For example, some experts suggest a 5-week washout period following use of fluoxetine and 3 weeks following the use of vortioxetine before administering another serotonergic agent. Individual product labeling for washout periods should be consulted for current recommendations. 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 (100)
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  2. Achamallah NS (1992) "Visual hallucinations after combining fluoxetine and dextromethorphan ." Am J Psychiatry, 149, p. 1406
  3. Nierenberg DW, Semprebon M (1993) "The central nervous system serotonin syndrome." Clin Pharmacol Ther, 53, p. 84-8
  4. Metz A (1990) "Interaction between fluoxetine and buspirone." Can J Psychiatry, 35, p. 722-3
  5. Goldberg RJ, Huk M (1992) "Serotonin syndrome from trazodone and buspirone." Psychosomatics, 33, p. 235-6
  6. (2002) "Product Information. D.H.E. 45 (dihydroergotamine)." Sandoz Pharmaceuticals Corporation
  7. Sternbach H (1991) "The serotonin syndrome." Am J Psychiatry, 148, p. 705-13
  8. Ciraulo DA, Shader RI (1990) "Fluoxetine drug-drug interactions. II." J Clin Psychopharmacol, 10, p. 213-7
  9. Ciraulo DA, Shader RI (1990) "Fluoxetine drug-drug interactions: I. Antidepressants and antipsychotics." J Clin Psychopharmacol, 10, p. 48-50
  10. (2001) "Product Information. Zoloft (sertraline)." Roerig Division
  11. (2001) "Product Information. Prozac (fluoxetine)." Dista Products Company
  12. Noble WH, Baker A (1992) "MAO inhibitors and coronary artery surgery: a patient death." Can J Anaesth, 39, p. 1061-6
  13. Insel TR, Roy BF, Cohen RM, Murphy DL (1982) "Possible development of the serotonin syndrome in man." Am J Psychiatry, 139, p. 954-5
  14. (2001) "Product Information. Effexor (venlafaxine)." Wyeth-Ayerst Laboratories
  15. Gilman AG, eds., Nies AS, Rall TW, Taylor P (1990) "Goodman and Gilman's the Pharmacological Basis of Therapeutics." New York, NY: Pergamon Press Inc.
  16. (2001) "Product Information. Paxil (paroxetine)." GlaxoSmithKline
  17. (2001) "Product Information. Flexeril (cyclobenzaprine)." Merck & Co., Inc
  18. Insler SR, Kraenzler EJ, Licina MG, Savage RM, Starr NJ (1994) "Cardiac surgery in a patient taking monoamine oxidase inhibitors - an adverse fentanyl reaction." Anesth Analg, 78, p. 593-7
  19. (2001) "Product Information. Imitrex (sumatriptan)." Glaxo Wellcome
  20. Ruiz F (1994) "Fluoxetine and the serotonin syndrome." Ann Emerg Med, 24, p. 983-5
  21. (2001) "Product Information. Luvox (fluvoxamine)." Solvay Pharmaceuticals Inc
  22. Reeves RR, Bullen JA (1995) "Serotonin syndrome produced by paroxetine and low-dose trazodone." Psychosomatics, 36, p. 159-60
  23. Harvey AT, Preskorn SH (1995) "Interactions of serotonin reuptake inhibitors with tricyclic antidepressants." Arch Gen Psychiatry, 52, p. 783-4
  24. Baetz M, Malcolm D (1995) "Serotonin syndrome from fluvoxamine and buspirone." Can J Psychiatry, 40, p. 428-9
  25. Fischer P (1995) "Serotonin syndrome in the elderly after antidepressive monotherapy." J Clin Psychopharmacol, 15, p. 440-2
  26. Corkeron MA (1995) "Serotonin syndrome - a potentially fatal complication of antidepressant therapy." Med J Aust, 163, p. 481-2
  27. George TP, Godleski LS (1996) "Possible serotonin syndrome with trazodone addition to fluoxetine." Biol Psychiatry, 39, p. 384-5
  28. Skop BP, Finkelstein JA, Mareth TR, Magoon MR, Brown TM (1994) "The serotonin syndrome associated wtih paroxetine, an over-the-counter cold remedy, and vascular disease." Am J Emerg Med, 12, p. 642-4
  29. Mason BJ, Blackburn KH (1997) "Possible serotonin syndrome associated with tramadol and sertraline coadministration." Ann Pharmacother, 31, p. 175-7
  30. John L, Perreault MM, Tao T, Blew PG (1997) "Serotonin syndrome associated with nefazodone and paroxetine." Ann Emerg Med, 29, p. 287-9
  31. (2001) "Product Information. Zomig (zolmitriptan)." Astra-Zeneca Pharmaceuticals
  32. (2001) "Product Information. Meridia (sibutramine)." Knoll Pharmaceutical Company
  33. Mills KC (1997) "Serotonin syndrome: A clinical update." Crit Care Clin, 13, p. 763
  34. Bhatara VS, Magnus RD, Paul KL, Preskorn SH (1998) "Serotonin syndrome induced by venlafaxine and fluoxetine: a case study in polypharmacy and potential pharmacodynamic and pharmacokinetic mechanisms." Ann Pharmacother, 32, p. 432-6
  35. (2001) "Product Information. Maxalt (rizatriptan)." Merck & Co., Inc
  36. (2001) "Product Information. Celexa (citalopram)." Forest Pharmaceuticals
  37. Gardner DM, Lynd LD (1998) "Sumatriptan contraindications and the serotonin syndrome." Ann Pharmacother, 32, p. 33-8
  38. Mathew NT, Tietjen GE, Lucker C (1996) "Serotonin syndrome complicating migraine pharmacotherapy." Cephalalgia, 16, p. 323-7
  39. Chan BSH, Graudins A, Whyte IM, Dawson AH, Braitberg G, Duggin GG (1998) "Serotonin syndrome resulting from drug interactions." Med J Aust, 169, p. 523-5
  40. Egberts AC, ter Borg J, Brodie-Meijer CC (1997) "Serotonin syndrome attributed to tramadol addition to paroxetine therapy." Int Clin Psychopharmacol, 12, p. 181-2
  41. Weiner AL (1999) "Meperidine as a potential cause of serotonin syndrome in the emergency department." Acad Emerg Med, 6, p. 156-8
  42. Miller LG (1998) "Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions." Arch Intern Med, 158, p. 2200-11
  43. Gordon JB (1998) "SSRI's and St. John's Wort: possible toxicity?" Am Fam Physician, 57, 950,953
  44. Lantz MS, Buchalter E, Giambanco V (1999) "St. John's wort and antidepressant drug interactions in the elderly." J Geriatr Psychiatr Neurol, 12, p. 7-10
  45. Fugh-Berman A (2000) "Herb-drug interactions." Lancet, 355, p. 134-8
  46. (2001) "Product Information. Zyvox (linezolid)." Pharmacia and Upjohn
  47. Perry NK (2000) "Venlafaxine-induced serotonin syndrome with relapse following amitriptyline." Postgrad Med J, 76, p. 254-6
  48. Manos GH (2000) "Possible serotonin syndrome associated with buspirone added to fluoxetine." Ann Pharmacother, 34, p. 871-4
  49. Nijhawan PK, Katz G, Winter S (1996) "Psychiatric illness and the serotonin syndrome: an emerging adverse drug effect leading to intensive care unit admission." Crit Care Med, 24, p. 1086-9
  50. Laird LK (1996) "Issues in the monopharmacotherapy and polypharmacotherapy of obsessive-compulsive disorder." Psychopharmacol Bull, 32, p. 569-78
  51. Margolese HC, Chouinard G (2000) "Serotonin syndrome from addition of low-dose trazodone to nefazodone." Am J Psychiatry, 157, p. 1022
  52. Mackay FJ, Dunn NR, Mann RD (1999) "Antidepressants and the serotonin syndrome in general practice." Br J Gen Pract, 49, p. 871-4
  53. Smith DL, Wenegrat BG (2000) "A case report of serotonin syndrome associated with combined nefazodone and fluoxetine." J Clin Psychiatry, 61, p. 146
  54. Rosebraugh CJ, floxkhart DA, Yasuda SU, Woosley RL (2001) "Visual hallucination and tremor induced by sertraline and oxycodone in a bone marrow transplant patient." J Clin Pharmacol, 41, p. 224-7
  55. Izzo AA, Ernst E (2001) "Interactions between herbal medicines and prescribed drugs: a systematic review." Drugs, 61, p. 2163-75
  56. Duggal HS, Fetchko J (2002) "Serotonin syndrome and atypical antipsychotics." Am J Psychiatry, 159, p. 672-3
  57. Wigen CL, Goetz MB (2002) "Serotonin syndrome and linezolid." Clin Infect Dis, 34, p. 1651-2
  58. Hammerness P, Parada H, Abrams A (2002) "Linezolid: MAOI Activity and Potential Drug Interactions." Psychosomatics, 43, p. 248-9
  59. (2002) "Product Information. Lexapro (escitalopram)." Forest Pharmaceuticals
  60. Dougherty JA, Young H, Shafi T (2002) "Serotonin syndrome induced by amitriptyline, meperidine, and venlafaxine." Ann Pharmacother, 36, p. 1647-1648
  61. Turkel SB, Nadala JG, Wincor MZ (2001) "Possible serotonin syndrome in association with 5-HT3 antagonist agents." Psychosomatics, 42, p. 258-60
  62. Martin TG (1996) "Serotonin syndrome." Ann Emerg Med, 28, p. 520-6
  63. Lavery S, Ravi H, McDaniel WW, Pushkin YR (2001) "Linezolid and serotonin syndrome." Psychosomatics, 42, p. 432-4
  64. Lane R, Baldwin D (1997) "Selective serotonin reuptake inhibitor--induced serotonin syndrome: review." J Clin Psychopharmacol, 17, p. 208-21
  65. Bernard L, Stern R, Lew D, Hoffmeyer P (2003) "Serotonin syndrome after concomitant treatment with linezolid and citalopram." Clin Infect Dis, 36, p. 1197
  66. Dannawi M (2002) "Possible serotonin syndrome after combination of buspirone and St John's Wort." J Psychopharmacol, 16, p. 401
  67. Tissot TA (2003) "Probable meperidine-induced serotonin syndrome in a patient with a history of fluoxetine use." Anesthesiology, 98, p. 1511-1512
  68. Hachem RY, Hicks K, Huen A, Raad I (2003) "Myelosuppression and serotonin syndrome associated with concurrent use of linezolid and selective serotonin reuptake inhibitors in bone marrow transplant recipients." Clin Infect Dis, 37, E8-E11
  69. Gillman PK (2003) "Linezolid and serotonin toxicity." Clin Infect Dis, 37, p. 1274-5
  70. Roy S, Fortier LP (2003) "Fentanyl-induced rigidity during emergence from general anesthesia potentiated by venlafexine." Can J Anaesth, 50, p. 32-5
  71. Giese SY, Neborsky R (2001) "Serotonin syndrome: potential consequences of Meridia combined with Demerol or fentanyl." Plast Reconstr Surg, 107, p. 293-4
  72. Jones SL, Athan E, O'Brien D (2004) "Serotonin syndrome due to co-administration of linezolid and venlafaxine." J Antimicrob Chemother, 54, p. 289-90
  73. Tahir N (2004) "Serotonin syndrome as a consequence of drug-resistant infections: an interaction between linezolid and citalopram." J Am Med Dir Assoc, 5, p. 111-3
  74. (2004) "Product Information. Cymbalta (duloxetine)." Lilly, Eli and Company
  75. Thomas CR, Rosenberg M, Blythe V, Meyer WJ 3rd (2004) "Serotonin syndrome and linezolid." J Am Acad Child Adolesc Psychiatry, 43, p. 790
  76. Boyer EW, Shannon M (2005) "The serotonin syndrome." N Engl J Med, 352, p. 1112-20
  77. Bergeron L, Boule M, Perreault S (2005) "Serotonin toxicity associated with concomitant use of linezolid." Ann Pharmacother, 39, p. 956-61
  78. Morales N, Vermette H (2005) "Serotonin syndrome associated with linezolid treatment after discontinuation of fluoxetine." Psychosomatics, 46, p. 274-5
  79. Morales-Molina JA, Mateu-de Antonio J, Marin-Casino M, Grau S (2005) "Linezolid-associated serotonin syndrome: what we can learn from cases reported so far." J Antimicrob Chemother, 56, p. 1176-8
  80. DeBellis RJ, Schaefer OP, Liquori M, Volturo GA (2005) "Linezolid-associated serotonin syndrome after concomitant treatment with citalopram and mirtazepine in a critically ill bone marrow transplant recipient." J Intensive Care Med, 20, p. 351-3
  81. Hunter B, Kleinert MM, Osatnik J, Soria E (2006) "Serotonergic syndrome and abnormal ocular movements: worsening of rigidity by remifentanil?" Anesth Analg, 102, p. 1589
  82. Taylor JJ, Wilson JW, Estes LL (2006) "Linezolid and serotonergic drug interactions: a retrospective survey." Clin Infect Dis, 43, p. 180-7
  83. Strouse TB, Kerrihard TN, Forscher CA, Zakowski P (2006) "Serotonin syndrome precipitated by linezolid in a medically ill patient on duloxetine." J Clin Psychopharmacol, 26, p. 681-683
  84. Keegan MT, Brown DR, Rabinstein AA (2006) "Serotonin syndrome from the interaction of cyclobenzaprine with other serotoninergic drugs." Anesth Analg, 103, p. 1466-8
  85. Paruchuri P, Godkar D, Anandacoomarswamy D, Sheth K, Niranjan S (2006) "Rare case of serotonin syndrome with therapeutic doses of paroxetine." Am J Ther, 13, p. 550-552
  86. Steinberg M, Morin AK (2007) "Mild serotonin syndrome associated with concurrent linezolid and fluoxetine." Am J Health Syst Pharm, 64, p. 59-62
  87. Packer S, Berman SA (2007) "Serotonin syndrome precipitated by the monoamine oxidase inhibitor linezolid." Am J Psychiatry, 164, p. 346-7
  88. Shapiro RE, Tepper SJ (2007) "The serotonin syndrome, triptans, and the potential for drug-drug interactions." Headache, 47, p. 266-9
  89. Ailawadhi S, Sung KW, Carlson LA, Baer MR (2007) "Serotonin syndrome caused by interaction between citalopram and fentanyl." J Clin Pharm Ther, 32, p. 199-202
  90. (2008) "Product Information. Pristiq (desvenlafaxine)." Wyeth Laboratories
  91. Rang ST, Field J, Irving C (2008) "Serotonin toxicity caused by an interaction between fentanyl and paroxetine." Can J Anaesth, 55, p. 521-5
  92. (2009) "Product Information. Savella (milnacipran)." Forest Pharmaceuticals
  93. (2009) "Product Information. Nucynta (tapentadol)." PriCara Pharmaceuticals
  94. Lee J, Franz L, Goforth HW (2009) "Serotonin syndrome in a chronic-pain patient receiving concurrent methadone, ciprofloxacin, and venlafaxine." Psychosomatics, 50, p. 638-9
  95. (2011) "Product Information. Viibryd (vilazodone)." Trovis Pharmaceuticals LLC
  96. Mugele J, Nanagas KA, Tormoehlen LM (2012) "Serotonin Syndrome Associated With MDPV Use: A Case Report." Ann Emerg Med
  97. (2012) "Product Information. Oleptro (trazodone)." Labopharm Inc
  98. (2013) "Product Information. Fetzima (levomilnacipran)." Forest Pharmaceuticals
  99. (2013) "Product Information. Brintellix (vortioxetine)." Takeda Pharmaceuticals America
  100. (2023) "Product Information. Exxua (gepirone)." Mission Pharmacal Company, 1
Major

traZODone escitalopram

Applies to: trazodone, escitalopram

MONITOR CLOSELY: Escitalopram can cause dose-dependent 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 such as torsade de pointes and sudden death. In a double-blind, placebo-controlled ECG study consisting of 113 healthy subjects, the change from baseline in QTc (Fridericia-corrected) was 4.3 msec for escitalopram 10 mg/day and 10.7 msec for the supratherapeutic dosage of 30 mg/day. Based on the established exposure-response relationship, the predicted QTc change from placebo under the Cmax for 20 mg/day is 6.6 msec. Cases of QT interval prolongation and torsade de pointes have been reported during postmarketing use. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). Also, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MONITOR CLOSELY: Concomitant use of escitalopram with agents that possess or enhance serotonergic activity may potentiate the risk of a potentially life-threatening condition called serotonin syndrome. The exact mechanism by which serotonin syndrome occurs may differ based on the agent(s) involved. It is thought to result from the hyperstimulation of postsynaptic 5-HT receptors and while postsynaptic 5-HT1A and 5-HT2A receptors are usually implicated, it is more likely that no single receptor is solely responsible. In addition, when two or more medications with similar adverse effect profiles are given concurrently, the likelihood of experiencing these adverse reactions may be increased. For example, the risk of experiencing central nervous system (CNS) and/or respiratory depressant effects may be increased when escitalopram is combined with another agent that also has these adverse reactions, particularly in patients who are already at an increased risk, such as debilitated or elderly patients.

MANAGEMENT: If coadministration of escitalopram with other agents that both prolong the QT interval and possess or enhance serotonergic activity is required, caution and close clinical monitoring are advised. Some authorities consider the use of escitalopram with other agents that prolong the QT interval or in patients with known QT interval prolongation to be contraindicated. Patients should be monitored closely for and counseled to seek immediate medical attention should they experience any signs and symptoms of serotonin syndrome (e.g., altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor) or prolonged QT interval (e.g., irregular heartbeat, dizziness, lightheadedness, fainting). Additional monitoring for CNS and/or respiratory depression may be advisable if the concurrent medication could also cause these side effects. In this situation, ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their doctor if they experience excessive or prolonged CNS effects that interfere with their normal activities. The product labeling of the concomitant medication should be consulted for further guidance, such as specific dosage adjustment and/or management recommendations should serious adverse reactions occur.

References (39)
  1. Nierenberg DW, Semprebon M (1993) "The central nervous system serotonin syndrome." Clin Pharmacol Ther, 53, p. 84-8
  2. Metz A (1990) "Interaction between fluoxetine and buspirone." Can J Psychiatry, 35, p. 722-3
  3. Goldberg RJ, Huk M (1992) "Serotonin syndrome from trazodone and buspirone." Psychosomatics, 33, p. 235-6
  4. Sternbach H (1991) "The serotonin syndrome." Am J Psychiatry, 148, p. 705-13
  5. Ciraulo DA, Shader RI (1990) "Fluoxetine drug-drug interactions. II." J Clin Psychopharmacol, 10, p. 213-7
  6. Ciraulo DA, Shader RI (1990) "Fluoxetine drug-drug interactions: I. Antidepressants and antipsychotics." J Clin Psychopharmacol, 10, p. 48-50
  7. (2001) "Product Information. Zoloft (sertraline)." Roerig Division
  8. (2001) "Product Information. Prozac (fluoxetine)." Dista Products Company
  9. Insel TR, Roy BF, Cohen RM, Murphy DL (1982) "Possible development of the serotonin syndrome in man." Am J Psychiatry, 139, p. 954-5
  10. Gilman AG, eds., Nies AS, Rall TW, Taylor P (1990) "Goodman and Gilman's the Pharmacological Basis of Therapeutics." New York, NY: Pergamon Press Inc.
  11. (2001) "Product Information. Paxil (paroxetine)." GlaxoSmithKline
  12. Ruiz F (1994) "Fluoxetine and the serotonin syndrome." Ann Emerg Med, 24, p. 983-5
  13. (2001) "Product Information. Luvox (fluvoxamine)." Solvay Pharmaceuticals Inc
  14. Reeves RR, Bullen JA (1995) "Serotonin syndrome produced by paroxetine and low-dose trazodone." Psychosomatics, 36, p. 159-60
  15. Harvey AT, Preskorn SH (1995) "Interactions of serotonin reuptake inhibitors with tricyclic antidepressants." Arch Gen Psychiatry, 52, p. 783-4
  16. Fischer P (1995) "Serotonin syndrome in the elderly after antidepressive monotherapy." J Clin Psychopharmacol, 15, p. 440-2
  17. Corkeron MA (1995) "Serotonin syndrome - a potentially fatal complication of antidepressant therapy." Med J Aust, 163, p. 481-2
  18. George TP, Godleski LS (1996) "Possible serotonin syndrome with trazodone addition to fluoxetine." Biol Psychiatry, 39, p. 384-5
  19. Skop BP, Finkelstein JA, Mareth TR, Magoon MR, Brown TM (1994) "The serotonin syndrome associated wtih paroxetine, an over-the-counter cold remedy, and vascular disease." Am J Emerg Med, 12, p. 642-4
  20. John L, Perreault MM, Tao T, Blew PG (1997) "Serotonin syndrome associated with nefazodone and paroxetine." Ann Emerg Med, 29, p. 287-9
  21. Mills KC (1997) "Serotonin syndrome: A clinical update." Crit Care Clin, 13, p. 763
  22. Bhatara VS, Magnus RD, Paul KL, Preskorn SH (1998) "Serotonin syndrome induced by venlafaxine and fluoxetine: a case study in polypharmacy and potential pharmacodynamic and pharmacokinetic mechanisms." Ann Pharmacother, 32, p. 432-6
  23. (2001) "Product Information. Celexa (citalopram)." Forest Pharmaceuticals
  24. Chan BSH, Graudins A, Whyte IM, Dawson AH, Braitberg G, Duggin GG (1998) "Serotonin syndrome resulting from drug interactions." Med J Aust, 169, p. 523-5
  25. Manos GH (2000) "Possible serotonin syndrome associated with buspirone added to fluoxetine." Ann Pharmacother, 34, p. 871-4
  26. Nijhawan PK, Katz G, Winter S (1996) "Psychiatric illness and the serotonin syndrome: an emerging adverse drug effect leading to intensive care unit admission." Crit Care Med, 24, p. 1086-9
  27. Margolese HC, Chouinard G (2000) "Serotonin syndrome from addition of low-dose trazodone to nefazodone." Am J Psychiatry, 157, p. 1022
  28. Mackay FJ, Dunn NR, Mann RD (1999) "Antidepressants and the serotonin syndrome in general practice." Br J Gen Pract, 49, p. 871-4
  29. Smith DL, Wenegrat BG (2000) "A case report of serotonin syndrome associated with combined nefazodone and fluoxetine." J Clin Psychiatry, 61, p. 146
  30. Dougherty JA, Young H, Shafi T (2002) "Serotonin syndrome induced by amitriptyline, meperidine, and venlafaxine." Ann Pharmacother, 36, p. 1647-1648
  31. Martin TG (1996) "Serotonin syndrome." Ann Emerg Med, 28, p. 520-6
  32. Lane R, Baldwin D (1997) "Selective serotonin reuptake inhibitor--induced serotonin syndrome: review." J Clin Psychopharmacol, 17, p. 208-21
  33. Paruchuri P, Godkar D, Anandacoomarswamy D, Sheth K, Niranjan S (2006) "Rare case of serotonin syndrome with therapeutic doses of paroxetine." Am J Ther, 13, p. 550-552
  34. Health Canada (2012) Antidepressant Cipralex (escitalopram): Updated information regarding dose-related heart risk. http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2012/2012_63-eng.php
  35. Castro VM, Clements CC, Murphy SN, et al. (2013) "QT interval and antidepressant use: a cross sectional study of electronic health records." BMJ, 346, f288
  36. (2023) "Product Information. Escitalopram (Apo) (escitalopram)." Arrotex Pharmaceuticals Pty Ltd
  37. (2024) "Product Information. Escitalopram (escitalopram)." Milpharm Ltd
  38. (2024) "Product Information. Escitalopram Oxalate (escitalopram)." Aurobindo Pharma USA Inc
  39. (2024) "Product Information. ACH-Escitalopram (escitalopram)." Accord Healthcare
Major

venlafaxine escitalopram

Applies to: Effexor (venlafaxine), escitalopram

MONITOR CLOSELY: Escitalopram can cause dose-dependent 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 such as torsade de pointes and sudden death. In a double-blind, placebo-controlled ECG study consisting of 113 healthy subjects, the change from baseline in QTc (Fridericia-corrected) was 4.3 msec for escitalopram 10 mg/day and 10.7 msec for the supratherapeutic dosage of 30 mg/day. Based on the established exposure-response relationship, the predicted QTc change from placebo under the Cmax for 20 mg/day is 6.6 msec. Cases of QT interval prolongation and torsade de pointes have been reported during postmarketing use. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). Also, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MONITOR CLOSELY: Concomitant use of escitalopram with agents that possess or enhance serotonergic activity may potentiate the risk of a potentially life-threatening condition called serotonin syndrome. The exact mechanism by which serotonin syndrome occurs may differ based on the agent(s) involved. It is thought to result from the hyperstimulation of postsynaptic 5-HT receptors and while postsynaptic 5-HT1A and 5-HT2A receptors are usually implicated, it is more likely that no single receptor is solely responsible. In addition, when two or more medications with similar adverse effect profiles are given concurrently, the likelihood of experiencing these adverse reactions may be increased. For example, the risk of experiencing central nervous system (CNS) and/or respiratory depressant effects may be increased when escitalopram is combined with another agent that also has these adverse reactions, particularly in patients who are already at an increased risk, such as debilitated or elderly patients.

MANAGEMENT: If coadministration of escitalopram with other agents that both prolong the QT interval and possess or enhance serotonergic activity is required, caution and close clinical monitoring are advised. Some authorities consider the use of escitalopram with other agents that prolong the QT interval or in patients with known QT interval prolongation to be contraindicated. Patients should be monitored closely for and counseled to seek immediate medical attention should they experience any signs and symptoms of serotonin syndrome (e.g., altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor) or prolonged QT interval (e.g., irregular heartbeat, dizziness, lightheadedness, fainting). Additional monitoring for CNS and/or respiratory depression may be advisable if the concurrent medication could also cause these side effects. In this situation, ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their doctor if they experience excessive or prolonged CNS effects that interfere with their normal activities. The product labeling of the concomitant medication should be consulted for further guidance, such as specific dosage adjustment and/or management recommendations should serious adverse reactions occur.

References (39)
  1. Nierenberg DW, Semprebon M (1993) "The central nervous system serotonin syndrome." Clin Pharmacol Ther, 53, p. 84-8
  2. Metz A (1990) "Interaction between fluoxetine and buspirone." Can J Psychiatry, 35, p. 722-3
  3. Goldberg RJ, Huk M (1992) "Serotonin syndrome from trazodone and buspirone." Psychosomatics, 33, p. 235-6
  4. Sternbach H (1991) "The serotonin syndrome." Am J Psychiatry, 148, p. 705-13
  5. Ciraulo DA, Shader RI (1990) "Fluoxetine drug-drug interactions. II." J Clin Psychopharmacol, 10, p. 213-7
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  29. Smith DL, Wenegrat BG (2000) "A case report of serotonin syndrome associated with combined nefazodone and fluoxetine." J Clin Psychiatry, 61, p. 146
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  32. Lane R, Baldwin D (1997) "Selective serotonin reuptake inhibitor--induced serotonin syndrome: review." J Clin Psychopharmacol, 17, p. 208-21
  33. Paruchuri P, Godkar D, Anandacoomarswamy D, Sheth K, Niranjan S (2006) "Rare case of serotonin syndrome with therapeutic doses of paroxetine." Am J Ther, 13, p. 550-552
  34. Health Canada (2012) Antidepressant Cipralex (escitalopram): Updated information regarding dose-related heart risk. http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2012/2012_63-eng.php
  35. Castro VM, Clements CC, Murphy SN, et al. (2013) "QT interval and antidepressant use: a cross sectional study of electronic health records." BMJ, 346, f288
  36. (2023) "Product Information. Escitalopram (Apo) (escitalopram)." Arrotex Pharmaceuticals Pty Ltd
  37. (2024) "Product Information. Escitalopram (escitalopram)." Milpharm Ltd
  38. (2024) "Product Information. Escitalopram Oxalate (escitalopram)." Aurobindo Pharma USA Inc
  39. (2024) "Product Information. ACH-Escitalopram (escitalopram)." Accord Healthcare
Major

QUEtiapine escitalopram

Applies to: Seroquel (quetiapine), escitalopram

MONITOR CLOSELY: Escitalopram can cause dose-dependent 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. In a double-blind, placebo-controlled ECG study consisting of 113 healthy subjects, the change from baseline in QTc (Fridericia-corrected) was 4.3 msec for escitalopram 10 mg/day and 10.7 msec for the supratherapeutic dosage of 30 mg/day. Based on the established exposure-response relationship, the predicted QTc change from placebo under the Cmax for 20 mg/day is 6.6 msec. Cases of QT interval prolongation and torsade de pointes have been reported during postmarketing use. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). Also, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s). In addition, when two or more medications with similar adverse effect profiles are given concurrently, the likelihood of experiencing these adverse reactions may be increased. For example, the risk of experiencing central nervous system (CNS) and/or respiratory depressant effects may be increased when escitalopram is combined with another agent that also has these adverse reactions, particularly in patients who are already at an increased risk, such as debilitated or elderly patients.

MANAGEMENT: Caution is recommended if escitalopram is used in combination with other drugs that can prolong the QT interval. Some authorities consider the concomitant use of these agents to be contraindicated. 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. When escitalopram is used in combination with other drugs that cause CNS and/or respiratory depression, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their doctor if they experience excessive or prolonged CNS effects that interfere with their normal activities. The product labeling of the concomitant medication should be consulted for further guidance, such as specific dosage adjustment and/or management recommendations should serious adverse reactions occur

References (7)
  1. Health Canada (2012) Antidepressant Cipralex (escitalopram): Updated information regarding dose-related heart risk. http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2012/2012_63-eng.php
  2. Castro VM, Clements CC, Murphy SN, et al. (2013) "QT interval and antidepressant use: a cross sectional study of electronic health records." BMJ, 346, f288
  3. EMA. European Medicines Agency. European Union (2013) EMA - List of medicines under additional monitoring. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000366.jsp&mid=WC0b01ac058067c852
  4. (2023) "Product Information. Escitalopram (Apo) (escitalopram)." Arrotex Pharmaceuticals Pty Ltd
  5. (2024) "Product Information. Escitalopram (escitalopram)." Milpharm Ltd
  6. (2024) "Product Information. Escitalopram Oxalate (escitalopram)." Aurobindo Pharma USA Inc
  7. (2024) "Product Information. ACH-Escitalopram (escitalopram)." Accord Healthcare
Moderate

traZODone divalproex sodium

Applies to: trazodone, Depakote (divalproex sodium)

MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

References (36)
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  14. Tverskoy M, Fleyshman G, Ezry J, Bradley EL, Jr Kissin I (1989) "Midazolam-morphine sedative interaction in patients." Anesth Analg, 68, p. 282-5
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  17. Greb WH, Buscher G, Dierdorf HD, Koster FE, Wolf D, Mellows G (1989) "The effect of liver enzyme inhibition by cimetidine and enzyme induction by phenobarbitone on the pharmacokinetics of paroxetine." Acta Psychiatr Scand, 80 Suppl, p. 95-8
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  22. (2001) "Product Information. Seroquel (quetiapine)." Astra-Zeneca Pharmaceuticals
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  24. (2001) "Product Information. Tasmar (tolcapone)." Valeant Pharmaceuticals
  25. Miller LG (1998) "Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions." Arch Intern Med, 158, p. 2200-11
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  33. Cerner Multum, Inc. "Australian Product Information."
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Moderate

traZODone OLANZapine

Applies to: trazodone, Zyprexa (olanzapine)

MONITOR: It is uncertain whether olanzapine causes clinically significant prolongation of the QT interval. In pooled studies of adults as well as pooled studies of adolescents, there were no significant differences between olanzapine and placebo in the proportion of patients experiencing potentially important changes in ECG parameters, including QT, QTcF (Fridericia-corrected), and PR intervals. In clinical trials, clinically meaningful QTc prolongations (QTcF >=500 msec at any time post-baseline in patients with baseline QTcF <500 msec) occurred in 0.1% to 1% of patients treated with olanzapine, with no significant differences in associated cardiac events compared to placebo. Published studies have generally reported no significant effect of olanzapine on QTc interval, although both QTc prolongation and QTc shortening have also been reported. There have been a few isolated case reports of QT prolongation in patients receiving olanzapine. However, causality is difficult to establish due to confounding factors such as concomitant use of drugs that cause QT prolongation and underlying conditions that may predispose to QT prolongation (e.g., hypokalemia, congenital long QT syndrome, preexisting conduction abnormalities).

MANAGEMENT: Some authorities recommend caution when olanzapine is used with drugs that are known to cause QT prolongation. ECG monitoring may be advisable in some cases, such as in patients with a history of cardiac arrhythmias or congenital or family history of long QT syndrome. 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.

References (3)
  1. (2001) "Product Information. Zyprexa (olanzapine)." Lilly, Eli and Company
  2. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  3. Cerner Multum, Inc. "Australian Product Information."
Moderate

traZODone QUEtiapine

Applies to: trazodone, Seroquel (quetiapine)

GENERALLY AVOID: There is some concern that quetiapine may have additive cardiovascular effects in combination with other drugs that are known to prolong the QT interval of the electrocardiogram. In clinical trials, quetiapine was not associated with a persistent increase in QT intervals, and there was no statistically significant difference between quetiapine and placebo in the proportions of patients experiencing potentially important changes in ECG parameters including QT, QTc, and PR intervals. However, QT prolongation and torsade de pointes have been reported during post marketing use in cases of quetiapine overdose and in patients with risk factors such as underlying illness or concomitant use of drugs known to cause electrolyte imbalance or increase QT interval. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). The extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s). In addition, certain agents with anticholinergic properties (e.g., sedating antihistamines; antispasmodics; neuroleptics; phenothiazines; skeletal muscle relaxants; tricyclic antidepressants) may have additive parasympatholytic and central nervous system-depressant effects when used in combination with quetiapine. Excessive parasympatholytic effects may include paralytic ileus, hyperthermia, mydriasis, blurred vision, tachycardia, urinary retention, psychosis, and seizures.

MONITOR: Coadministration of quetiapine with drugs that possess serotonergic activity (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), etc.) may increase the risk of serotonin syndrome, a rare but serious and potentially fatal condition. Combining quetiapine with other serotonergic drugs may increase the risk of serotonin syndrome by relatively enhancing 5-HT1A receptor activity. However, data are currently limited to case reports. In one case report, an 85-year-old woman developed serotonin syndrome within hours of increasing quetiapine from 12.5 mg to 25 mg/day while also taking escitalopram, mirtazapine, sulpiride, and olanzapine; symptoms resolved within 48 hours after the discontinuation of all serotonergic medications. Symptoms of 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: Coadministration of quetiapine with other drugs that can prolong the QT interval should generally be avoided. Caution and clinical monitoring are recommended if concomitant use of quetiapine with other agents that both prolong the QT interval and possess or enhance serotonergic activity is required. 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. Patients should also be monitored closely for, and counseled about the signs and symptoms of serotonin syndrome (e.g., altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor), especially during initiation and dose escalations. Due to variability and occasionally prolonged half-lives of these coadministered agents, consulting individual product labeling for specific guidance is advised.

References (7)
  1. (2023) "Product Information. Aliquen (QUETIAPine)." Pharmacor Limited
  2. (2024) "Product Information. Mintreleq XL (quetiapine)." Aristo Pharma Ltd
  3. (2025) "Product Information. QUEtiapine Fumarate (QUEtiapine)." XLCare Pharmaceuticals, Inc
  4. (2024) "Product Information. QUEtiapine Fumarate ER (QUEtiapine)." ScieGen Pharmaceuticals, Inc.
  5. (2025) "Product Information. Apo-Quetiapine (quetiapine)." Apotex Inc
  6. Miyamatsu, Y., Tanizaki, R. (2021) "Serotonin syndrome triggered by increasing the dose of quetiapine" Clinical practice and cases in emergency medicine, 5, p. 365-366
  7. Kohen, I., Gordon, M.L., Manu, P. (2007) "Serotonin syndrome in elderly patients treated for psychotic depression with atypical antipsychotics and antidepressants: two case reports" CNS Spectr, 12, p. 596-8
Moderate

venlafaxine divalproex sodium

Applies to: Effexor (venlafaxine), Depakote (divalproex sodium)

MONITOR: The efficacy of anticonvulsants may be diminished during coadministration with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitor (SNRIs). Antidepressants including SSRIs and SNRIs can reduce seizure threshold. In clinical trials, convulsions have typically been reported in 0.1% to 0.3% of patients receiving SSRIs for major depressive disorders. There have been rare reports of prolonged seizures in patients on fluoxetine receiving electroconvulsive therapy (ECT).

MONITOR: Coadministration of SSRIs or SNRIs may potentiate the central nervous system (CNS) adverse effects of anticonvulsants such as somnolence and cognitive and psychomotor impairment.

MONITOR: Coadministration of SSRIs or SNRIs with some anticonvulsants, particularly carbamazepine, eslicarbazepine, oxcarbazepine and valproic acid, may increase the risk of hyponatremia. Treatment with SSRIs or SNRIs has been associated with hyponatremia, which may be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) in many cases. While generally reversible following discontinuation of SSRI/SNRI treatment, cases with serum sodium lower than 110 mmol/L have been reported. Hyponatremia and SIADH may also result from treatment with some anticonvulsants. The risk appears to be dose-related, and elderly patients and patients who are volume depleted (e.g., diuretic use) may be at greater risk.

MANAGEMENT: SSRIs and SNRIs should be avoided in patients with unstable epilepsy, and used cautiously in patients with epilepsy controlled with anticonvulsant medications. Treatment with SSRIs and SNRIs should be discontinued if seizures develop or seizure frequency increases. Patients receiving SSRIs or SNRIs with anticonvulsants, particularly carbamazepine, eslicarbazepine, oxcarbazepine and/or valproic acid, should also have serum sodium levels measured regularly and monitored for development of hyponatremia, particularly when higher dosages of these medications are used. Signs and symptoms of hyponatremia include nausea, vomiting, headache, difficulty concentrating, memory impairment, confusion, malaise, lethargy, muscle weakness or spasms, and unsteadiness. In more severe and/or acute cases, hallucination, syncope, seizure, coma, respiratory arrest, and death may occur. Discontinuation of SSRIs and SNRIs should be considered in patients who develop symptomatic hyponatremia, and appropriate medical intervention instituted. All patients receiving concomitant therapy with SSRIs or SNRIs and anticonvulsants should be counseled against driving, operating machinery, or engaging in potentially hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

References (20)
  1. (2002) "Product Information. Tegretol (carbamazepine)." Novartis Pharmaceuticals
  2. (2001) "Product Information. Zoloft (sertraline)." Roerig Division
  3. (2001) "Product Information. Prozac (fluoxetine)." Dista Products Company
  4. (2001) "Product Information. Effexor (venlafaxine)." Wyeth-Ayerst Laboratories
  5. (2001) "Product Information. Paxil (paroxetine)." GlaxoSmithKline
  6. (2001) "Product Information. Luvox (fluvoxamine)." Solvay Pharmaceuticals Inc
  7. (2001) "Product Information. Celexa (citalopram)." Forest Pharmaceuticals
  8. (2001) "Product Information. Trileptal (oxcarbazepine)." Novartis Pharmaceuticals
  9. (2002) "Product Information. Lexapro (escitalopram)." Forest Pharmaceuticals
  10. (2004) "Product Information. Cymbalta (duloxetine)." Lilly, Eli and Company
  11. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  12. (2008) "Product Information. Pristiq (desvenlafaxine)." Wyeth Laboratories
  13. (2009) "Product Information. Savella (milnacipran)." Forest Pharmaceuticals
  14. (2013) "Product Information. Fetzima (levomilnacipran)." Forest Pharmaceuticals
  15. (2013) "Product Information. Aptiom (eslicarbazepine)." Sunovion Pharmaceuticals Inc
  16. Belcastro V, Costa C, Striano P (2008) "Levetiracetam-associated hyponatremia." Seizure, 17, p. 389-90
  17. Bavbek N, Alkan R, Uz E, Kaftan O, Akcay A (2008) "Hyponatremia associated with sodium valproate in a 22-year-old male." Nephrol Dial Transplant, 23, epub
  18. Patel KR, Meesala A, Stanilla JK (2010) "Sodium valproate-induced hyponatremia: a case report." Prim Care Companion J Clin Psychiatry, 12, epub
  19. Gandhi S, McArthur E, Mamdani MM, et al. (2016) "Antiepileptic drugs and hyponatremia in older adults: Two population-based cohort studies." Epilepsia, 57, p. 2067-79
  20. Falhammar H, Lindh JD, Calissendorff J, et al. (2018) "Differences in associations of antiepileptic drugs and hospitalization due to hyponatremia: A population-based case-control study." Seizure, 59, p. 28-33
Moderate

venlafaxine OLANZapine

Applies to: Effexor (venlafaxine), Zyprexa (olanzapine)

MONITOR: It is uncertain whether olanzapine causes clinically significant prolongation of the QT interval. In pooled studies of adults as well as pooled studies of adolescents, there were no significant differences between olanzapine and placebo in the proportion of patients experiencing potentially important changes in ECG parameters, including QT, QTcF (Fridericia-corrected), and PR intervals. In clinical trials, clinically meaningful QTc prolongations (QTcF >=500 msec at any time post-baseline in patients with baseline QTcF <500 msec) occurred in 0.1% to 1% of patients treated with olanzapine, with no significant differences in associated cardiac events compared to placebo. Published studies have generally reported no significant effect of olanzapine on QTc interval, although both QTc prolongation and QTc shortening have also been reported. There have been a few isolated case reports of QT prolongation in patients receiving olanzapine. However, causality is difficult to establish due to confounding factors such as concomitant use of drugs that cause QT prolongation and underlying conditions that may predispose to QT prolongation (e.g., hypokalemia, congenital long QT syndrome, preexisting conduction abnormalities).

MANAGEMENT: Some authorities recommend caution when olanzapine is used with drugs that are known to cause QT prolongation. ECG monitoring may be advisable in some cases, such as in patients with a history of cardiac arrhythmias or congenital or family history of long QT syndrome. 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.

References (3)
  1. (2001) "Product Information. Zyprexa (olanzapine)." Lilly, Eli and Company
  2. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  3. Cerner Multum, Inc. "Australian Product Information."
Moderate

venlafaxine QUEtiapine

Applies to: Effexor (venlafaxine), Seroquel (quetiapine)

GENERALLY AVOID: There is some concern that quetiapine may have additive cardiovascular effects in combination with other drugs that are known to prolong the QT interval of the electrocardiogram. In clinical trials, quetiapine was not associated with a persistent increase in QT intervals, and there was no statistically significant difference between quetiapine and placebo in the proportions of patients experiencing potentially important changes in ECG parameters including QT, QTc, and PR intervals. However, QT prolongation and torsade de pointes have been reported during post marketing use in cases of quetiapine overdose and in patients with risk factors such as underlying illness or concomitant use of drugs known to cause electrolyte imbalance or increase QT interval. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). The extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s). In addition, certain agents with anticholinergic properties (e.g., sedating antihistamines; antispasmodics; neuroleptics; phenothiazines; skeletal muscle relaxants; tricyclic antidepressants) may have additive parasympatholytic and central nervous system-depressant effects when used in combination with quetiapine. Excessive parasympatholytic effects may include paralytic ileus, hyperthermia, mydriasis, blurred vision, tachycardia, urinary retention, psychosis, and seizures.

MONITOR: Coadministration of quetiapine with drugs that possess serotonergic activity (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), etc.) may increase the risk of serotonin syndrome, a rare but serious and potentially fatal condition. Combining quetiapine with other serotonergic drugs may increase the risk of serotonin syndrome by relatively enhancing 5-HT1A receptor activity. However, data are currently limited to case reports. In one case report, an 85-year-old woman developed serotonin syndrome within hours of increasing quetiapine from 12.5 mg to 25 mg/day while also taking escitalopram, mirtazapine, sulpiride, and olanzapine; symptoms resolved within 48 hours after the discontinuation of all serotonergic medications. Symptoms of 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: Coadministration of quetiapine with other drugs that can prolong the QT interval should generally be avoided. Caution and clinical monitoring are recommended if concomitant use of quetiapine with other agents that both prolong the QT interval and possess or enhance serotonergic activity is required. 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. Patients should also be monitored closely for, and counseled about the signs and symptoms of serotonin syndrome (e.g., altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor), especially during initiation and dose escalations. Due to variability and occasionally prolonged half-lives of these coadministered agents, consulting individual product labeling for specific guidance is advised.

References (7)
  1. (2023) "Product Information. Aliquen (QUETIAPine)." Pharmacor Limited
  2. (2024) "Product Information. Mintreleq XL (quetiapine)." Aristo Pharma Ltd
  3. (2025) "Product Information. QUEtiapine Fumarate (QUEtiapine)." XLCare Pharmaceuticals, Inc
  4. (2024) "Product Information. QUEtiapine Fumarate ER (QUEtiapine)." ScieGen Pharmaceuticals, Inc.
  5. (2025) "Product Information. Apo-Quetiapine (quetiapine)." Apotex Inc
  6. Miyamatsu, Y., Tanizaki, R. (2021) "Serotonin syndrome triggered by increasing the dose of quetiapine" Clinical practice and cases in emergency medicine, 5, p. 365-366
  7. Kohen, I., Gordon, M.L., Manu, P. (2007) "Serotonin syndrome in elderly patients treated for psychotic depression with atypical antipsychotics and antidepressants: two case reports" CNS Spectr, 12, p. 596-8
Moderate

divalproex sodium OLANZapine

Applies to: Depakote (divalproex sodium), Zyprexa (olanzapine)

MONITOR: Concurrent use of olanzapine and valproic acid may potentiate the risk of hepatotoxicity. The exact mechanism of interaction is unknown. In a retrospective study of 52 children, combined treatment with olanzapine and divalproex was associated with more frequent elevations of hepatic enzymes than either agent alone, and mean and peak hepatic enzyme levels during the observed course of treatment were also higher. All 12 patients who received combined treatment had at least one peak enzyme elevation above the normal range, versus 10 of 17 who received olanzapine alone and 6 of 23 who received divalproex alone. With the exception of 2 patients who required discontinuation of combination treatment (due to development of pancreatitis in one and steatohepatitis in the other), the observed peak and mean enzyme levels were less than 3 times the upper limit of normal (ULN) and were asymptomatic. The long-term significance of these findings is unknown.

MANAGEMENT: The authors of the study recommend monitoring liver function tests every 3 to 4 months during the first year of treatment with either olanzapine or valproic acid, at least in pediatric patients. If no elevations of liver enzymes or marked weight gain occur after one year, a decrease in frequency of monitoring to every 6 months can be considered. Patients should be advised to notify their physician if they experience signs and symptoms of hepatotoxicity such as fever, rash, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, and jaundice.

References (1)
  1. Gonzalez-Heydrich J, Raches D, Wilens TE, Leichtner A, Mezzacappa E (2003) "Retrospective study of hepatic enzyme elevations in children treated with olanzapine, divalproex, and their combination." J Am Acad Child Adolesc Psychiatry, 42, p. 1227-33
Moderate

divalproex sodium QUEtiapine

Applies to: Depakote (divalproex sodium), Seroquel (quetiapine)

MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

References (36)
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  2. Stambaugh JE, Lane C (1983) "Analgesic efficacy and pharmacokinetic evaluation of meperidine and hydroxyzine, alone and in combination." Cancer Invest, 1, p. 111-7
  3. Sotaniemi EA, Anttila M, Rautio A, et al. (1981) "Propranolol and sotalol metabolism after a drinking party." Clin Pharmacol Ther, 29, p. 705-10
  4. Grabowski BS, Cady WJ, Young WW, Emery JF (1980) "Effects of acute alcohol administration on propranolol absorption." Int J Clin Pharmacol Ther Toxicol, 18, p. 317-9
  5. Lemberger L, Rowe H, Bosomworth JC, Tenbarge JB, Bergstrom RF (1988) "The effect of fluoxetine on the pharmacokinetics and psychomotor responses of diazepam." Clin Pharmacol Ther, 43, p. 412-9
  6. MacLeod SM, Giles HG, Patzalek G, Thiessen JJ, Sellers EM (1977) "Diazepam actions and plasma concentrations following ethanol ingestion." Eur J Clin Pharmacol, 11, p. 345-9
  7. Divoll M, Greenblatt DJ, Lacasse Y, Shader RI (1981) "Benzodiazepine overdosage: plasma concentrations and clinical outcome." Psychopharmacology (Berl), 73, p. 381-3
  8. Naylor GJ, McHarg A (1977) "Profound hypothermia on combined lithium carbonate and diazepam treatment." Br Med J, 2, p. 22
  9. Stovner J, Endresen R (1965) "Intravenous anaesthesia with diazepam." Acta Anaesthesiol Scand, 24, p. 223-7
  10. Driessen JJ, Vree TB, Booij LH, van der Pol FM, Crul JF (1984) "Effect of some benzodiazepines on peripheral neuromuscular function in the rat in-vitro hemidiaphragm preparation." J Pharm Pharmacol, 36, p. 244-7
  11. Feldman SA, Crawley BE (1970) "Interaction of diazepam with the muscle-relaxant drugs." Br Med J, 1, p. 336-8
  12. Ochs HR, Greenblatt DJ, Verburg-Ochs B (1984) "Propranolol interactions with diazepam, lorazepam and alprazolam." Clin Pharmacol Ther, 36, p. 451-5
  13. Desager JP, Hulhoven R, Harvengt C, Hermann P, Guillet P, Thiercelin JF (1988) "Possible interactions between zolpidem, a new sleep inducer and chlorpromazine, a phenothiazine neuroleptic." Psychopharmacology (Berl), 96, p. 63-6
  14. Tverskoy M, Fleyshman G, Ezry J, Bradley EL, Jr Kissin I (1989) "Midazolam-morphine sedative interaction in patients." Anesth Analg, 68, p. 282-5
  15. "Product Information. Iopidine (apraclonidine ophthalmic)." Alcon Laboratories Inc
  16. Greiff JMC, Rowbotham D (1994) "Pharmacokinetic drug interactions with gastrointestinal motility modifying agents." Clin Pharmacokinet, 27, p. 447-61
  17. Greb WH, Buscher G, Dierdorf HD, Koster FE, Wolf D, Mellows G (1989) "The effect of liver enzyme inhibition by cimetidine and enzyme induction by phenobarbitone on the pharmacokinetics of paroxetine." Acta Psychiatr Scand, 80 Suppl, p. 95-8
  18. Markowitz JS, Wells BG, Carson WH (1995) "Interactions between antipsychotic and antihypertensive drugs." Ann Pharmacother, 29, p. 603-9
  19. (2001) "Product Information. Ultram (tramadol)." McNeil Pharmaceutical
  20. (2001) "Product Information. Artane (trihexyphenidyl)." Lederle Laboratories
  21. (2001) "Product Information. Ultiva (remifentanil)." Mylan Institutional (formally Bioniche Pharma USA Inc)
  22. (2001) "Product Information. Seroquel (quetiapine)." Astra-Zeneca Pharmaceuticals
  23. (2001) "Product Information. Meridia (sibutramine)." Knoll Pharmaceutical Company
  24. (2001) "Product Information. Tasmar (tolcapone)." Valeant Pharmaceuticals
  25. Miller LG (1998) "Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions." Arch Intern Med, 158, p. 2200-11
  26. (2001) "Product Information. Precedex (dexmedetomidine)." Abbott Pharmaceutical
  27. (2001) "Product Information. Trileptal (oxcarbazepine)." Novartis Pharmaceuticals
  28. Ferslew KE, Hagardorn AN, McCormick WF (1990) "A fatal interaction of methocarbamol and ethanol in an accidental poisoning." J Forensic Sci, 35, p. 477-82
  29. Plushner SL (2000) "Valerian: valeriana officinalis." Am J Health Syst Pharm, 57, p. 328-35
  30. (2002) "Product Information. Xatral (alfuzosin)." Sanofi-Synthelabo Canada Inc
  31. (2002) "Product Information. Lexapro (escitalopram)." Forest Pharmaceuticals
  32. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  33. Cerner Multum, Inc. "Australian Product Information."
  34. (2012) "Product Information. Fycompa (perampanel)." Eisai Inc
  35. (2014) "Product Information. Belsomra (suvorexant)." Merck & Co., Inc
  36. (2015) "Product Information. Rexulti (brexpiprazole)." Otsuka American Pharmaceuticals Inc
Moderate

divalproex sodium escitalopram

Applies to: Depakote (divalproex sodium), escitalopram

MONITOR: The efficacy of anticonvulsants may be diminished during coadministration with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitor (SNRIs). Antidepressants including SSRIs and SNRIs can reduce seizure threshold. In clinical trials, convulsions have typically been reported in 0.1% to 0.3% of patients receiving SSRIs for major depressive disorders. There have been rare reports of prolonged seizures in patients on fluoxetine receiving electroconvulsive therapy (ECT).

MONITOR: Coadministration of SSRIs or SNRIs may potentiate the central nervous system (CNS) adverse effects of anticonvulsants such as somnolence and cognitive and psychomotor impairment.

MONITOR: Coadministration of SSRIs or SNRIs with some anticonvulsants, particularly carbamazepine, eslicarbazepine, oxcarbazepine and valproic acid, may increase the risk of hyponatremia. Treatment with SSRIs or SNRIs has been associated with hyponatremia, which may be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) in many cases. While generally reversible following discontinuation of SSRI/SNRI treatment, cases with serum sodium lower than 110 mmol/L have been reported. Hyponatremia and SIADH may also result from treatment with some anticonvulsants. The risk appears to be dose-related, and elderly patients and patients who are volume depleted (e.g., diuretic use) may be at greater risk.

MANAGEMENT: SSRIs and SNRIs should be avoided in patients with unstable epilepsy, and used cautiously in patients with epilepsy controlled with anticonvulsant medications. Treatment with SSRIs and SNRIs should be discontinued if seizures develop or seizure frequency increases. Patients receiving SSRIs or SNRIs with anticonvulsants, particularly carbamazepine, eslicarbazepine, oxcarbazepine and/or valproic acid, should also have serum sodium levels measured regularly and monitored for development of hyponatremia, particularly when higher dosages of these medications are used. Signs and symptoms of hyponatremia include nausea, vomiting, headache, difficulty concentrating, memory impairment, confusion, malaise, lethargy, muscle weakness or spasms, and unsteadiness. In more severe and/or acute cases, hallucination, syncope, seizure, coma, respiratory arrest, and death may occur. Discontinuation of SSRIs and SNRIs should be considered in patients who develop symptomatic hyponatremia, and appropriate medical intervention instituted. All patients receiving concomitant therapy with SSRIs or SNRIs and anticonvulsants should be counseled against driving, operating machinery, or engaging in potentially hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

References (20)
  1. (2002) "Product Information. Tegretol (carbamazepine)." Novartis Pharmaceuticals
  2. (2001) "Product Information. Zoloft (sertraline)." Roerig Division
  3. (2001) "Product Information. Prozac (fluoxetine)." Dista Products Company
  4. (2001) "Product Information. Effexor (venlafaxine)." Wyeth-Ayerst Laboratories
  5. (2001) "Product Information. Paxil (paroxetine)." GlaxoSmithKline
  6. (2001) "Product Information. Luvox (fluvoxamine)." Solvay Pharmaceuticals Inc
  7. (2001) "Product Information. Celexa (citalopram)." Forest Pharmaceuticals
  8. (2001) "Product Information. Trileptal (oxcarbazepine)." Novartis Pharmaceuticals
  9. (2002) "Product Information. Lexapro (escitalopram)." Forest Pharmaceuticals
  10. (2004) "Product Information. Cymbalta (duloxetine)." Lilly, Eli and Company
  11. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  12. (2008) "Product Information. Pristiq (desvenlafaxine)." Wyeth Laboratories
  13. (2009) "Product Information. Savella (milnacipran)." Forest Pharmaceuticals
  14. (2013) "Product Information. Fetzima (levomilnacipran)." Forest Pharmaceuticals
  15. (2013) "Product Information. Aptiom (eslicarbazepine)." Sunovion Pharmaceuticals Inc
  16. Belcastro V, Costa C, Striano P (2008) "Levetiracetam-associated hyponatremia." Seizure, 17, p. 389-90
  17. Bavbek N, Alkan R, Uz E, Kaftan O, Akcay A (2008) "Hyponatremia associated with sodium valproate in a 22-year-old male." Nephrol Dial Transplant, 23, epub
  18. Patel KR, Meesala A, Stanilla JK (2010) "Sodium valproate-induced hyponatremia: a case report." Prim Care Companion J Clin Psychiatry, 12, epub
  19. Gandhi S, McArthur E, Mamdani MM, et al. (2016) "Antiepileptic drugs and hyponatremia in older adults: Two population-based cohort studies." Epilepsia, 57, p. 2067-79
  20. Falhammar H, Lindh JD, Calissendorff J, et al. (2018) "Differences in associations of antiepileptic drugs and hospitalization due to hyponatremia: A population-based case-control study." Seizure, 59, p. 28-33
Moderate

OLANZapine QUEtiapine

Applies to: Zyprexa (olanzapine), Seroquel (quetiapine)

GENERALLY AVOID: There is some concern that quetiapine may have additive cardiovascular effects in combination with other drugs that are known to prolong the QT interval of the electrocardiogram. In clinical trials, quetiapine was not associated with a persistent increase in QT intervals, and there was no statistically significant difference between quetiapine and placebo in the proportions of patients experiencing potentially important changes in ECG parameters including QT, QTc, and PR intervals. However, QT prolongation and torsade de pointes have been reported during post marketing use in cases of quetiapine overdose and in patients with risk factors such as underlying illness or concomitant use of drugs known to cause electrolyte imbalance or increase QT interval. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). The extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s). In addition, certain agents with anticholinergic properties (e.g., sedating antihistamines; antispasmodics; neuroleptics; phenothiazines; skeletal muscle relaxants; tricyclic antidepressants) may have additive parasympatholytic and central nervous system-depressant effects when used in combination with quetiapine. Excessive parasympatholytic effects may include paralytic ileus, hyperthermia, mydriasis, blurred vision, tachycardia, urinary retention, psychosis, and seizures.

MONITOR: Coadministration of quetiapine with drugs that possess serotonergic activity (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), etc.) may increase the risk of serotonin syndrome, a rare but serious and potentially fatal condition. Combining quetiapine with other serotonergic drugs may increase the risk of serotonin syndrome by relatively enhancing 5-HT1A receptor activity. However, data are currently limited to case reports. In one case report, an 85-year-old woman developed serotonin syndrome within hours of increasing quetiapine from 12.5 mg to 25 mg/day while also taking escitalopram, mirtazapine, sulpiride, and olanzapine; symptoms resolved within 48 hours after the discontinuation of all serotonergic medications. Symptoms of 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: Coadministration of quetiapine with other drugs that can prolong the QT interval should generally be avoided. Caution and clinical monitoring are recommended if concomitant use of quetiapine with other agents that both prolong the QT interval and possess or enhance serotonergic activity is required. 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. Patients should also be monitored closely for, and counseled about the signs and symptoms of serotonin syndrome (e.g., altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor), especially during initiation and dose escalations. Due to variability and occasionally prolonged half-lives of these coadministered agents, consulting individual product labeling for specific guidance is advised.

References (7)
  1. (2023) "Product Information. Aliquen (QUETIAPine)." Pharmacor Limited
  2. (2024) "Product Information. Mintreleq XL (quetiapine)." Aristo Pharma Ltd
  3. (2025) "Product Information. QUEtiapine Fumarate (QUEtiapine)." XLCare Pharmaceuticals, Inc
  4. (2024) "Product Information. QUEtiapine Fumarate ER (QUEtiapine)." ScieGen Pharmaceuticals, Inc.
  5. (2025) "Product Information. Apo-Quetiapine (quetiapine)." Apotex Inc
  6. Miyamatsu, Y., Tanizaki, R. (2021) "Serotonin syndrome triggered by increasing the dose of quetiapine" Clinical practice and cases in emergency medicine, 5, p. 365-366
  7. Kohen, I., Gordon, M.L., Manu, P. (2007) "Serotonin syndrome in elderly patients treated for psychotic depression with atypical antipsychotics and antidepressants: two case reports" CNS Spectr, 12, p. 596-8
Moderate

OLANZapine escitalopram

Applies to: Zyprexa (olanzapine), escitalopram

MONITOR: It is uncertain whether olanzapine causes clinically significant prolongation of the QT interval. In pooled studies of adults as well as pooled studies of adolescents, there were no significant differences between olanzapine and placebo in the proportion of patients experiencing potentially important changes in ECG parameters, including QT, QTcF (Fridericia-corrected), and PR intervals. In clinical trials, clinically meaningful QTc prolongations (QTcF >=500 msec at any time post-baseline in patients with baseline QTcF <500 msec) occurred in 0.1% to 1% of patients treated with olanzapine, with no significant differences in associated cardiac events compared to placebo. Published studies have generally reported no significant effect of olanzapine on QTc interval, although both QTc prolongation and QTc shortening have also been reported. There have been a few isolated case reports of QT prolongation in patients receiving olanzapine. However, causality is difficult to establish due to confounding factors such as concomitant use of drugs that cause QT prolongation and underlying conditions that may predispose to QT prolongation (e.g., hypokalemia, congenital long QT syndrome, preexisting conduction abnormalities).

MANAGEMENT: Some authorities recommend caution when olanzapine is used with drugs that are known to cause QT prolongation. ECG monitoring may be advisable in some cases, such as in patients with a history of cardiac arrhythmias or congenital or family history of long QT syndrome. 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.

References (3)
  1. (2001) "Product Information. Zyprexa (olanzapine)." Lilly, Eli and Company
  2. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  3. Cerner Multum, Inc. "Australian Product Information."

No other interactions were found between your selected drugs. However, this does not necessarily mean no other interactions exist. Always consult your healthcare provider.

Drug and food/lifestyle interactions

Moderate

traZODone food/lifestyle

Applies to: trazodone

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

References (4)
  1. Warrington SJ, Ankier SI, Turner P (1986) "Evaluation of possible interactions between ethanol and trazodone or amitriptyline." Neuropsychobiology, 15, p. 31-7
  2. Gilman AG, eds., Nies AS, Rall TW, Taylor P (1990) "Goodman and Gilman's the Pharmacological Basis of Therapeutics." New York, NY: Pergamon Press Inc.
  3. (2012) "Product Information. Fycompa (perampanel)." Eisai Inc
  4. (2015) "Product Information. Rexulti (brexpiprazole)." Otsuka American Pharmaceuticals Inc
Moderate

venlafaxine food/lifestyle

Applies to: Effexor (venlafaxine)

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

References (4)
  1. Warrington SJ, Ankier SI, Turner P (1986) "Evaluation of possible interactions between ethanol and trazodone or amitriptyline." Neuropsychobiology, 15, p. 31-7
  2. Gilman AG, eds., Nies AS, Rall TW, Taylor P (1990) "Goodman and Gilman's the Pharmacological Basis of Therapeutics." New York, NY: Pergamon Press Inc.
  3. (2012) "Product Information. Fycompa (perampanel)." Eisai Inc
  4. (2015) "Product Information. Rexulti (brexpiprazole)." Otsuka American Pharmaceuticals Inc
Moderate

divalproex sodium food/lifestyle

Applies to: Depakote (divalproex sodium)

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

References (4)
  1. Warrington SJ, Ankier SI, Turner P (1986) "Evaluation of possible interactions between ethanol and trazodone or amitriptyline." Neuropsychobiology, 15, p. 31-7
  2. Gilman AG, eds., Nies AS, Rall TW, Taylor P (1990) "Goodman and Gilman's the Pharmacological Basis of Therapeutics." New York, NY: Pergamon Press Inc.
  3. (2012) "Product Information. Fycompa (perampanel)." Eisai Inc
  4. (2015) "Product Information. Rexulti (brexpiprazole)." Otsuka American Pharmaceuticals Inc
Moderate

OLANZapine food/lifestyle

Applies to: Zyprexa (olanzapine)

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

References (4)
  1. Warrington SJ, Ankier SI, Turner P (1986) "Evaluation of possible interactions between ethanol and trazodone or amitriptyline." Neuropsychobiology, 15, p. 31-7
  2. Gilman AG, eds., Nies AS, Rall TW, Taylor P (1990) "Goodman and Gilman's the Pharmacological Basis of Therapeutics." New York, NY: Pergamon Press Inc.
  3. (2012) "Product Information. Fycompa (perampanel)." Eisai Inc
  4. (2015) "Product Information. Rexulti (brexpiprazole)." Otsuka American Pharmaceuticals Inc
Moderate

QUEtiapine food/lifestyle

Applies to: Seroquel (quetiapine)

GENERALLY AVOID: Grapefruit juice and/or grapefruit may increase the plasma concentrations of quetiapine. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice but has been reported for other CYP450 3A4 inhibitors. For example, in 12 healthy volunteers, administration of a single 25 mg dose of quetiapine with the potent CYP450 3A4 inhibitor ketoconazole (200 mg once daily for 4 days) increased mean quetiapine peak plasma concentration (Cmax) and systemic exposure (AUC) by 3.4- and 6.2-fold, respectively, and decreased mean oral clearance by 84%. In general, the effects of grapefruit products are concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. High plasma levels of quetiapine may increase the risk and/or severity of serious adverse effects such as extrapyramidal symptoms, tardive dyskinesia, hyperglycemia, dyslipidemia, hyperprolactinemia, orthostatic hypotension, blood pressure increases (in children and adolescents), priapism, QT prolongation, cognitive and motor impairment, dysphagia, heat-related illnesses due to disruption of body temperature regulation, and symptoms of serotonin syndrome (e.g., 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).

Food may have varying effects on the absorption of quetiapine from immediate-release versus prolonged-release formulations. In a study examining the effects of food on the bioavailability of quetiapine, a high-fat meal was found to produce statistically significant increases in the quetiapine prolonged release Cmax and AUC of approximately 50% and 20%, respectively. It cannot be excluded that the effect of a high fat meal on the formulation may be larger. In comparison, a light meal had no significant effect on the Cmax or AUC of quetiapine.

Quetiapine may potentiate the cognitive and motor effects of alcohol. The mechanism is likely related to the primary central nervous system effects of quetiapine.

MANAGEMENT: According to the manufacturer, consumption of grapefruit juice should be avoided during treatment with quetiapine. Quetiapine immediate-release tablets may be taken with or without food. It is recommended that quetiapine prolonged release is taken once daily without food or with a light meal. Consumption of alcohol should be limited and used with caution while taking quetiapine.

References (10)
  1. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  2. Cerner Multum, Inc. "Australian Product Information."
  3. Agencia Española de Medicamentos y Productos Sanitarios Healthcare (2008) Centro de información online de medicamentos de la AEMPS - CIMA. https://cima.aemps.es/cima/publico/home.html
  4. (2023) "Product Information. Aliquen (QUETIAPine)." Pharmacor Limited
  5. (2024) "Product Information. Mintreleq XL (quetiapine)." Aristo Pharma Ltd
  6. (2025) "Product Information. QUEtiapine Fumarate (QUEtiapine)." XLCare Pharmaceuticals, Inc
  7. (2024) "Product Information. QUEtiapine Fumarate ER (QUEtiapine)." ScieGen Pharmaceuticals, Inc.
  8. (2025) "Product Information. Apo-Quetiapine (quetiapine)." Apotex Inc
  9. Miyamatsu, Y., Tanizaki, R. (2021) "Serotonin syndrome triggered by increasing the dose of quetiapine" Clinical practice and cases in emergency medicine, 5, p. 365-366
  10. Kohen, I., Gordon, M.L., Manu, P. (2007) "Serotonin syndrome in elderly patients treated for psychotic depression with atypical antipsychotics and antidepressants: two case reports" CNS Spectr, 12, p. 596-8
Moderate

escitalopram food/lifestyle

Applies to: escitalopram

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

References (4)
  1. Warrington SJ, Ankier SI, Turner P (1986) "Evaluation of possible interactions between ethanol and trazodone or amitriptyline." Neuropsychobiology, 15, p. 31-7
  2. Gilman AG, eds., Nies AS, Rall TW, Taylor P (1990) "Goodman and Gilman's the Pharmacological Basis of Therapeutics." New York, NY: Pergamon Press Inc.
  3. (2012) "Product Information. Fycompa (perampanel)." Eisai Inc
  4. (2015) "Product Information. Rexulti (brexpiprazole)." Otsuka American Pharmaceuticals Inc

Therapeutic duplication warnings

Therapeutic duplication is the use of more than one medicine from the same drug category or therapeutic class to treat the same condition. This can be intentional in cases where drugs with similar actions are used together for demonstrated therapeutic benefit. It can also be unintentional in cases where a patient has been treated by more than one doctor, or had prescriptions filled at more than one pharmacy, and can have potentially adverse consequences.

Duplication

CNS drugs

Therapeutic duplication

The recommended maximum number of medicines in the 'CNS drugs' category to be taken concurrently is usually three. Your list includes six medicines belonging to the 'CNS drugs' category:

  • trazodone
  • Effexor (venlafaxine)
  • Zyprexa (olanzapine)
  • Seroquel (quetiapine)
  • escitalopram
  • Depakote (divalproex sodium)

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.

Duplication

Psychotropic agents

Therapeutic duplication

The recommended maximum number of medicines in the 'psychotropic agents' category to be taken concurrently is usually three. Your list includes five medicines belonging to the 'psychotropic agents' category:

  • trazodone
  • Effexor (venlafaxine)
  • Zyprexa (olanzapine)
  • Seroquel (quetiapine)
  • escitalopram

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.

Duplication

Antipsychotics

Therapeutic duplication

The recommended maximum number of medicines in the 'antipsychotics' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'antipsychotics' category:

  • Zyprexa (olanzapine)
  • Seroquel (quetiapine)

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.


Report options

Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

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Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.