Introduction

  • Prolonged QT interval reflects prolonged myocyte repolarization due to ion channel malfunction and gives rise to early after-depolarizations.1
  • Prolonged QTc is defined as > 470 msec in males and > 480 msec in females.1
  • The danger of a prolonged QTc interval is a life-threatening polymorphic ventricular rhythm known as Torsades de Pointes (TdP), the risk of TdP is 2-3 times higher when QTc is > 500 msec.1
  • Multiple factors can contribute to QTc prolongation including advancing age, bradyarrhythmias, underlying cardiac disease, electrolyte abnormalities (e.g. hypokalemia, hypomagnesaemia, hypocalcemia), and medications (e.g.

    • antiarrhythmics, antidepressants, antimicrobials, antipsychotics, and many others).1-2

  • Medication induced QT prolongation is dose and route related, with higher doses and IV administration being associated with more QT prolongation

Clinical Detail

MedicationOndansetron (Zofran®)Promethazine (Phenergan®)Metoclopramide (Reglan®)Prochlorperazine (Compazine®)
Dose4 mg12.5 mg5 to 10 mg5 to 10 mg
Route of AdministrationPO (ODT + Tab), IV, IMPO, IV, IM, RectalPO, IV, IMPO, IV, IM, Rectal
PK/PDOnset: ~30 min
Half-life: 3-6 hours
Metabolism: Extensive hepatic, CYP1A2/2D6/3A4
Excretion: Urine (44-60%), feces (~25%)		Onset: PO/IM ~20 min, IV ~5 min
Duration: 4-6 hours
Metabolism: Hepatic, CYP2D6/2B6
Excretion: Urine & feces as inactive metabolites		Onset: PO 30-60 min, IV 1-3 min, IM 10-15 min
Duration: 1-2 hours
Metabolism: Hepatic, CYP2D6
Excretion: Urine (~85%), feces		Onset: PO 30-40 min, IM 10-20 min, rectal 60 min
Duration: 3-4 hours
Metabolism: Primarily hepatic
Excretion: Feces
Adverse EffectsHeadache, fatigue, malaise, constipationInjection reactions (vesicant), CNS depressionFlushing (common w/ high IV doses), injection reactions, dystonic reactions, restlessnessAnticholinergic effects, extrapyramidal symptoms, risk of aspiration
Drug Interactions and WarningsCYP3A4 inducers, QT prolongating medications, serotonin syndrome, caution in hepatic disease (Child-Pugh class C)BBW: Severe tissue injury (including gangrene) with injection administration (IM preferred over IV)
CNS depressants, anticholinergics		BBW: Tardive dyskinesia (dose & duration related), CYP2D6 inhibitors, serotonin modulators, anti-Parkinson agents, CNS depression, extrapyramidal symptomsBBW: Elderly patients with dementia (increased risk of death CNS depression), orthostatic hypotension, caution in seizure disorders
Crediblemeds ClassificationKnown risk of TdPPossible risk of TdPConditional risk of TdPNo classification

Evidence

Medications Associated with QT Prolongation
AntiarrhythmicsAntidepressantsAntimicrobialsAntipsychoticsOthers
AmiodaroneCitalopramAzithromycinChlorpromazineOndansetron
PropafenoneEscitalopramClarithromycinHaloperidolMetoclopramide
ProcainamideAmitriptylineLevofloxacinZiprasidoneSumatriptan
FlecainideSertralineCiprofloxacinOlanzapineMethadone
DronedaroneFluoxetineFluconazoleQuetiapineLoperamide
Sotalol
Author, yearDesign/sample sizeIntervention & ComparisonOutcome
Li, 2018Prospective, observational study (n=20)IV ondansetron 4 mgA single administration of ondansetron was associated with a mean QTc increase of 16.2 msec (p=0.01)
• Zero related cardiac events reported
Moffett, 2016Prospective, observational study (n=22)IV ondansetron 4 mgA single administration of ondansetron was associated with a mean QTc increase of 20 msec
• Zero related cardiac events reported
Owczuk, 2009Prospective, double-blind, randomized study (n=40)IV promethazine 25 mg
IV midazolam 2.5 mg		Promethazine had a statistically significant increase in QTc interval compared to midazolam at 5,10,15,& 20 min (p<0.001)
Promethazine is classified as Possible Risk of Torsades de Pointes (CredibleMeds/AZCERT); midazolam is not a recognized QT-prolonging agent
• No cardiac events were reported
Charbit, 2008Prospective, double-blind, randomized study (n=16)IV 1 mg droperidol
IV ondansetron 4 mg
IV droperidol 1 mg + ondansetron 4 mg
Placebo		Compared to placebo both droperidol and ondansetron significantly prolonged the QTc interval by 25 msec and 17 msec respectably (p=0.014)
Droperidol and ondansetron combined prolonged the QTc by 28 msec compared to placebo
Ellidokuz, 2003Prospective, double-blind, cross-over (n=10)IV metoclopramide 10 mgMetoclopramide administration resulted in steeper QT/RR slopes compared with the pre-drug values (0.037 ± 0.004 vs 0.064 ± 0.012, p=0.041)
The QT variance increased after metoclopramide administration (46 ± 9 vs 164 ± 27, p=0.003)
• No cardiac events were reported
Czekalla, 2001Four controlled, double-blind, randomized controlled trials (N=2700)Olanzapine 5-15 mg
Placebo		Olanzapine 15 ± 2.5 mg/day dose group had an increase of QTc of 8.44 msec (within-group p=0.038) vs a 4.71 msec decrease in the placebo group (between-group p=0.004); no difference in olanzapine group dosing < 15 mg/day
No cardiac events were reported were reported in post marketing data

Conclusions

    Kai Li, Kathy, et al. J of Health-System Pharm. 2018;

    75(5):276-282.

  • Moffett P, et al. Acad Emerg Med. 2016; 23(1):102-5.
  • Owczuk R, , et al. Anaesthesia. 2009; 64(6):609-614.
  • Charbit B, et al. Anesthesiology. 2008; 109:206-12.
  • Czekalla J et al. J Clin Psychiatry. 2001 Mar;62(3):191-8.
  • Ellidokuz E. Aliment Pharmacol Ther. 2003 Jul 1;18(1):151-5.

References

  • Drew BJ, et al. Circulation. 2010 Mar 2;121(8):1047-60
  • Viskin S et al. Lancet. 1999;354:1625-33.
  • Chan A et al. An International J of Med. 2007. 100(10)609-
  • Drew BJ, et al. Circulation. 2010; 121:1047.
  • Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc.

    • Riverwoods, IL. Available

  • at: http://online.lexi.com. Accessed May 22, 2019.
  • Kai Li, Kathy, et al. J of Health-System Pharm. 2018;

    • 75(5):276-282.

  • Moffett P, et al. Acad Emerg Med. 2016; 23(1):102-5.
  • Owczuk R, , et al. Anaesthesia. 2009; 64(6):609-614.
  • Charbit B, et al. Anesthesiology. 2008; 109:206-12.
  • Czekalla J et al. J Clin Psychiatry. 2001 Mar;62(3):191-8.
  • Ellidokuz E. Aliment Pharmacol Ther. 2003 Jul 1;18(1):151-5.
Tags:antiemetics QTc ondansetron droperidol