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9/5/2018

Kelly Murray, PharmD, BCACP Clinical Assistant Professor of Clinical Pharmacy OSU-CHS, Dept. of Emergency Medicine // September 2018

Financial Disclosures .None

1 9/5/2018

Assessment Questions 1. Which antibiotic class is most well-known for its QTc-prolonging potential?

A. Beta-lactams B. Carbapenems C. Tetracyclines D. Fluoroquinolones

Assessment Questions 2. What is the maximum single dose of recommended to help avoid QTc-prolongation?

A. 4 mg B. 8 mg C. 16 mg D. 32 mg

2 9/5/2018

Assessment Questions 3. Which of the following is a scale that can be used to help determine the risk of QT prolongation in a hospitalized patient?

A. Mayfield Risk Calculation B. Tisdale Risk Score C. Switzer Risk Scale D. Sims Risk Calculation

Objectives .Identify patients at risk for prolonged QT interval based on home medication history.

.List antibiotics most associated with a prolonged QT interval.

.Select anti-nausea medications least likely to prolong the QT interval.

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Overview .QTc prolongation .Risk factors for Long QT Syndrome

.Medications and classes .General overview .Notable medications .Anti-nausea agents .Antibiotics

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QT Length .Normal QT = <440 ms . Prolonged QT = >500 msec // >460 msec // >450 msec . Varies in literature

.Incidence of QT prolongation estimated to be 35% of ED patients . Nearly half of these patients were discharged

.AZCERT “Known Risk” medications study = . 485 msec (men), 469 msec (women)

Seftchick MW, et al. Ann Emerg Med 2009;54:763-768. Zemrak WR, et al. Am J Health-Syst Pharm. 2008; 65:1029-38. Riad FS, et al. Am J Cardiol 2017;119:280-283.

Correcting a QT Interval .Adjusts for the patient’s heart rate

https://www.uptodate.com/contents/image?topicKey=1043&imageKey=CARD%2F77018&source=outline_link &search=qt%20prolongation

5 9/5/2018

QT Prolongation

Early repolarization Action potential .Delayed plateau ventricular Initial repolarization, depolarization Terminal repolarization usually manifested in prolongation of phase 2, action potential plateau phase

Turner JR, et al. J Clin Pharmacology 2018;58(8):997-1012.

Risk Factors for QT Prolongation .Females .Elderly .Electrolyte disturbances (hypokalemia, hypomagnesemia) .Congestive heart failure, cardiac abnormalities .Drug interactions .Co-administered QT-prolonging medications .Baseline QT prolongation

Roden DM. N Engl J Med 2004;350:1013-22. Wooten JM. South Med J 2006;99:16.

6 9/5/2018

Why can QT prolongation happen? 1. Effects on ion channels

2. Genetic involvement . Congenital long-QT syndrome (CLQTS)

3. Medications . Changes to medications . Drug interactions . Cumulative effects of multiple QT-prolonging medications

Turner JR, et al. J Clin Pharmacology 2018;58(8):997-1012.

What is Torsades de Pointes (TdP)? .Rare polymorphic ventricular arrhythmia

.Occurs in self-limiting bursts

.Symptoms: dizziness, palpitations, syncope, seizures

.Can progress to ventricular fibrillation and sudden cardiac death

Turner JR, et al. J Clin Pharmacology 2018;58(8):997-1012.

7 9/5/2018

ECG Waveform of TdP

.Rapid, irregular QRS complexes “twisting” around the isoelectric baseline

Turner JR, et al. J Clin Pharmacology 2018;58(8):997-1012.

Tisdale QTc Prolongation Risk Score

Prospective, Risk Factors Points Observational Age ≥ 68 years 1 Female 1 Cardiac ICU Loop diuretic 1 Serum K+ ≤ 3.5 mEq/L 2 n= 900 (development) Admitting QTc interval ≥ 450 msec 2 n= 300 (validation) Acute myocardial infarction 2 Sepsis 3 QTc prolongation= Heart Failure with reduced EF 3 • >500 msec or One QTc-prolonging drug 3 • increase ≥ 60 msec Two or more QTc-prolonging drugs 3 from baseline Maximum score 21

Tisdale JE et al. Circ Cardiovasc Qual Outcomes 2013;6:479-487. Tomaselli et al. Pharmacotherapy 2018;38(8):813-821.

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Tisdale Risk Score

Risk Category Scoring Sensitivity Specificity PPV NPV High Risk ≥ 11 74% 77% 79% 76% Moderate Risk 7-10 67% 88% 55% 88% Low Risk < 7 ------. Identifies patients at high risk of QTc interval prolongation before developing it

Tisdale JE et al. Circ Cardiovasc Qual Outcomes 2013;6:479-487. Tomaselli et al. Pharmacotherapy 2018;38(8):813-821.

Goal .Prevent or minimize QT prolongation .Avoid Torsades de Pointes (TdP) and sudden cardiac death .Avoid codes

Google Images. “Stress Relief” Episode. The Office.

9 9/5/2018

Goals of Proarrhythmic Cardiac Safety 1. Need to determine whether a new drug has a proarrhythmic propensity

2. Implement risk management strategies and optimally safe therapeutic use of drugs known to have proarrhythmic liability

Turner JR, et al. J Clin Pharmacology 2018;58(8):997-1012.

10 9/5/2018

Drug Marketing Withdrawals due to Proarrhythmic Concerns Drug Indication Year Withdrawn Prenylamine Antianginal 1989 (UK) Terodiline Urinary incontinence 1991 (UK, US) Sparfloxacin Antibiotic 1996 (US) 1998 (UK) Terfenadine 1998 (US) Astemizole Antihistamine 1999 (US) Grepafloxacin Antibiotic 1999 (UK, US) Gastroesophageal reflux 2000 (UK, US) Levacetylmethadol addiction 2003 (UK)

Turner JR, et al. J Clin Pharmacology 2018;58(8):997-1012.

Thorough QT (TQT) Studies .Phase 2 of FDA Approval .Healthy individuals, crossover design study .4 treatment arms, randomized 1. Positive control arm, drug with known QTc prolongation (5 msec minimum comparator) 2. Placebo 3. Max recommended therapeutic dose of drug 4. Supratherapeutic dose of drug

Turner JR, et al. J Clin Pharmacology 2018;58(8):997-1012.

11 9/5/2018

Adverse Drug Event Casualty Analysis (ADECA) .Categories of certainty

.KR = .PR = .CR = .CLQT =

https://crediblemeds.org/new-drug-list/

Most Potent QT-Prolonging Medications .Antiarrhythmic agents .Ia - Quinidine* .III - Amiodarone .III - Dofetilide .III - Sotalol

*most torsadogenic potential

Ayad RF, et al. Proc (Bayl Univ Med Cent) 2010;23(3):250–255. Dipiro 2008.

12 9/5/2018

https://crediblemeds.org/files/7413/9568/0020/Antiarrhythmic_drug_actions.pdf

QT Prolonging Medication Classes

Class Risk Medications most likely… , , , , , , , , Antidepressants Citalopram, escitalopram Clomipramine desipramine, imipramine, , nortriptyline, venlafaxine Fluoxetine, fluvoxamine, paroxetine, sertraline, trazodone, ,

doxepin www.CredibleMeds.org.

13 9/5/2018

QT Prolonging Medication Classes

Class Risk Medications most likely… Pain medications , ER, Acid suppressants Famotidine Omeprazole, esomeprazole, lansoprazole, pantoprazole Antifungals Fluconazole, ketoconazole, amphotericin B

www.CredibleMeds.org.

QT Prolonging Medication Classes

Class Risk Medications most likely… Anti-nausea Droperidol, ondansetron, , , Antibiotics Azithromycin, clarithromycin, erythromycin, ciprofloxacin, levofloxacin, moxifloxacin Gemifloxacin, telavancin Metronidazole Miscellaneous Loperamide www.CredibleMeds.org.

14 9/5/2018

Other Notable Medications

COCAINE .Produces local Acts like a class I anesthetic effects via antiarrhythmic sodium channel agent blockade in the heart .Alters repolarization with QT prolongation (among other things) .Rhythm disturbances typically disappear when drug is metabolized Magnano AR, et al. Am J Cardiol 2006;97(8):1244-6.

Other Notable Medications

LOPERAMIDE .Loperamide-induced cardiac toxicity .Excessive dose .Impaired drug elimination .Present with QT prolongation, QRS widening, and ventricular dysrhythmias +/- conventional toxicity symptoms

Wu PE, et al. Ann Emerg Med 2017;pii:S0196-0644(17)30424-9. Kozak PM, et al. Journal of Electrocardiology 2017;50:355–357.

15 9/5/2018

Patient Case .A 31 year old male presents complaining of chest pain and shortness of breath. (+) for nausea/vomiting. Only medications given en route were , nitroglycerin, and ondansetron.

.PMH: major depressive disorder, HTN, dyslipidemia.

.Current meds: citalopram, lisinopril, atorvastatin.

.NKDA

16 9/5/2018

Patient Case .Focus should be on his cardiac workup. .EKG ordered. QTc = 513 msec. .Still need to address his nausea/vomiting.

.What do you order for nausea/vomiting? A. Ondansetron B. Haloperidol C. Promethazine D. Metoclopramide E. Prochlorperazine

Anti-nausea Medications .Ondansetron Serotonin receptor antagonist .Promethazine .Prochlorperazine .Chlorpromazine .Metoclopramide Benzamide .Droperidol .Haloperidol

17 9/5/2018

Ondansetron .QT increase and TdP risk ARE in label .Dose-related increase in risk

.Ondansetron IV one-time doses showed QTc changes of: .32mg = 21.8 msec .8mg = 7.4 msec

FDA Drug Safety Communication: New information regarding QT prolongation with ondansetron (Zofran). Accessed at FDA.gov. on 16 May 2017. Ondansetron Package Insert. Accessed on 16 May 2017 at https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020103s035_020605s019_020781s019lbl.pdf

“…no increased incidence of a patient developing a cardiac arrhythmia after a single oral dose of ondansetron.”

= no need for routine EKG and electrolyte screening in those without known risk factors

Freedman SB, et al. Ann Emerg Med 2014;64(1):19-25.

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STUDY DESIGN: n=22 Ondansetron EKG every 2 (Mean 32y, Baseline EKG 4mg IV x 1 min x 20 min otherwise dose healthy)

PRIMARY OUTCOME: Mean Maximal Prolongation of QTc Baseline QTc Max QT Max QTc p-value Prolongation Interval length 395 (386-404) 415 (405-425) 20 (14.0-26) <0.0001

Moffett PM, et al. Academic emergency medicine 2016;23:102–105

.Thorough QT Study Results .Ondansetron single dose vs. moxifloxacin .Maximum mean difference of: .8 mg IV dose = 10 msec .32 mg IV dose = 20 msec

Zuo P, et al. J Clin Pharmacol 2014;54(11):1221-1229.

19 9/5/2018

Ondansetron Recommendations .Avoid: . High doses (max 16mg in a single dose) . In patients with Congenital LQTS

.Monitor EKG: . Electrolyte abnormalities (low K+ or Mg+) . CHF . Bradyarrhythmias . Pt is taking other QT prolonging medications . If multiple IV doses are given within a few hours of each other

Ondansetron Package Insert. Accessed on 16 May 2017at https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020103s035_020605s019_020781s019lbl.pdf.

Phenothiazines .Known Risk - , chlorpromazine .Possible Risk - Promethazine .Risk not assessed - Prochlorperazine

.Thioridazine is most common culprit for QT prolongation .Limit dose to ≤100 mg/day

www.Crediblemeds.org. Prochlorperazine drug label. Accessed at http://www.sanofi.com.au/products/aus_pi_stemetil.pdf. Owczuk R, et al. Anaesthesia. 2009 Jun;64(6):609-14. Lexi-complete. Accessed 22 May 2017.

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Phenothiazines .Safest choices = .Prochlorperazine .Promethazine

.Proceed with caution

www.Crediblemeds.org. Prochlorperazine drug label. Accessed at http://www.sanofi.com.au/products/aus_pi_stemetil.pdf. Owczuk R, et al. Anaesthesia. 2009 Jun;64(6):609-14. Lexi-complete. Accessed 22 May 2017.

Metoclopramide .Conditional Risk =

.May cause TdP under certain circumstances:

. Low serum Mg+ or K+

. Concomitant use of QT-prolonging or TdP-causing medications

www.CredibleMeds.org.

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STUDY DESIGN: EKG before n=33 Baseline Metoclopramide 10mg discharge EKG IV x 1 dose (out of 64) (in 45%)

SECONDARY OUTCOME (Metoclopramide Data Only): Pretreatment QTc Posttreatment QTc p-value Interval length 428 msec 440 msec NS

Gaffigan ME, et al. J Emerg Med 2015;49(3):326-334.

Metoclopramide .Lexi-complete: . “…known to cause sinus arrest (with rapid IV administration or higher doses).” . “…torsadogenic potential… considered to be low.” . More common in heart failure patients with renal impairment . May shorten the QT interval - ??? . Only case reports demonstrate QT prolonging effect.

Bentsen G, et al. Anaesthesiol Scand. 2002;46(7):908-910. Siddique SM, et al. Ann Intern Med. 2009;150(7):502-504. Malkoff MD, et al. Ann Pharmacother. 1995;29(4):381-383. Ellidokuz E, et al. Aliment Pharmacol Ther. 2003;18(1):151-155. Claassen S, et al. Pharmacology. 2005;74(1):31-36.

22 9/5/2018

Butyrophenones: DROPERIDOL .Known risk –

.QT prolongation = why you don’t have this in your toolbox

.Black box warning decision may stem from post-marketing data, not peer-reviewed data

.Dose-related risk (greatest with >5mg doses)

Lexi-complete. Accessed 22 May 2017. Kao LW, et al. Ann Emerg Med. 2003;41:546-558.

Butyrophenones: HALOPERIDOL .Known risk – .Great for N/V/HA in patients with psych diagnoses . Watch for home medications as additional risk factors .Give IM . Haloperidol lactate for ED (decanoate = long acting formulation) . Limit IV dose to x1 .Get a baseline EKG and consider continuous monitoring (if baseline prolongation or ≥2mg are needed).

Lexi-complete. Accessed 22 May 2017. Kao LW, et al. Ann Emerg Med. 2003;41:546-558.

23 9/5/2018

Anti-nausea Summary .Haloperidol = high risk (especially IV) .Ondansetron ~20 msec .Consider EKG to monitor if risk factors .Promethazine/Prochlorperazine .Watch for additional risk factors and concomitant medications with QT risk .Metoclopramide .Watch for additional risk factors .Possibly the safest?

Patient Case .CP/N/V. .QTc = 513 msec.

.What do you order for nausea/vomiting?

A. Ondansetron Known QT prolongation risk - AVOID B. Haloperidol Known QT prolongation risk - AVOID C. Promethazine Possible QT prolongation risk D. Metoclopramide Conditional QT prolongation risk E. Prochlorperazine Unknown QT prolongation risk

24 9/5/2018

Patient Case .Cardiac labs came back normal. Chest infiltrates seen on x-ray.

.Dx of community-acquired pneumonia given.

.He will be treated outpatient.

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Image from https://emcrit.org/pulmcrit/myth-busting-azithromycin-does-not-cause-torsade-de-pointes-or-increase-mortality/

Antibiotics .Azithromycin .Clarithromycin Macrolides .Erythromycin .Ciprofloxacin .Levofloxacin Fluoroquinolones .Gemifloxacin .Moxifloxacin

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Macrolides .Erythromycin, azithromycin, clarithromycin .Known risk of TdP .Two major studies conflict (among others)

www.crediblemeds.org Ray WA, et al. N Engl J Med 2012;366:1881-90. Svanstrom H, et al. N Engl J Med 2013;368:1704-12.

“Ray”

Population Risk Ratios for Risk Ratios for Overall Cardiovascular Azithromycin Azithromycin Mortality Rate compared to Compared to Nonuse B-Lactam Use Tennessee 2.88, 95% CI, 2.49; 95% CI, 85.2 deaths per 1 million 1.25-2.75 1.38-4.50 azithromycin courses

Ray WA, et al. N Engl J Med 2012;366:1881-90.

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“Svanstrom”

Population Risk Ratios for Risk Ratios for Overall Cardiovascular Azithromycin Azithromycin Mortality Rate compared to Compared to Nonuse B-Lactam Use Denmark 2.85; 95% CI 0.93; 95% CI, 15.4 deaths per 1 million 1.13-7.24 0.56-1.55 azithromycin courses NS

Svanstrom H, et al. N Engl J Med 2013;368:1704-12.

Ray vs Svanstrom Population Risk Ratios for Risk Ratios for Overall + Risk Azithromycin Azithromycin Cardiovascular compared to Compared to B- Mortality Rate Nonuse Lactam Use Tennessee 2.88, 95% CI, 2.49; 95% CI, 85.2 deaths per 1 + 47 1.25-2.75 1.38-4.50 million azithromycin courses Denmark 2.85; 95% CI 0.93; 95% CI, 15.4 deaths per 1 -1 1.13-7.24 0.56-1.55 million azithromycin courses

- Lexi-complete

Giudicessi JR, et al. Cleve Clin J Med 2013;80(9): 539–544.

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Fluoroquinolones .Most associated with gatifloxacin, moxifloxacin, and withdrawn agents sparifloxacin and grepafloxacin.

.KR – levofloxacin, ciprofloxacin, moxifloxacin .PR - gemifloxacin

Knorr JP, et al. Am J Health-Syst Pharm. 2008; 65:547-51.

Fluoroquinolones .Makaryus et al. .N=38; cipro = 11 + levofloxacin = 27 . Ciprofloxacin = NS change in longest QT, mean QTc . Levofloxacin = significant increase in longest QT, but not mean .Lapi et al. .n=605,127; 1838 cases of arrhythmias identified . FQ use + arrhythmia RR=1.76; 95% CI 1.19-2.59; new current use RR=2.23;95% CI 1.31-3.80 . Ciprofloxacin RR=2.15 . Levofloxacin = “did not appear to increase rate of serious arrhythmia”

Makaryus AN, et al. South Med J. 2006; 99:52-6. Lapi F, et al. Clin Infect Dis. 2012;55(11):1457.

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.Fluoroquinolone Analysis:

“…ciprofloxacin was not associated with an increased risk of cardiovascular mortality.”

“It is unclear whether or not levofloxacin was associated with an increased risk…”

Ray WA, et al. N Engl J Med 2012;366:1881-90.

.Conclusion from the Ray study:

.Azithromycin CV risk > ciprofloxacin CV risk

.Azithromycin vs levofloxacin CV risk not statistically significantly different

Ray WA, et al. N Engl J Med 2012;366:1881-90.

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.Fluoroquinolone Analysis:

.n=909,656 courses of fluoroquinolones evaluated (ciprofloxacin = 83%)

.NO increase in risk of serious arrhythmias with FQ vs beta-lactams

Svanstrom H, et al. N Engl J Med 2013;368:1704-12.

.Levofloxacin single dose 1000 mg or 1500 mg versus moxifloxacin 400 mg

.Prolongation Potential at 3.5 h .1000 mg = 4.42 msec (2.44-6.39 msec) .1500 mg = 7.44 msec (5.47-9.42 msec)

Taubel J, et al. Br J Clin Pharmacol 2010;69(4):391-400.

31 9/5/2018

Patient Case .Dx of community-acquired pneumonia given. .He will be treated for CAP outpatient.

.What antibiotic plan should you recommend? A. Doxycycline B. Azithromycin C. Levofloxacin D. Beta lactam + doxycycline E. Levofloxacin + doxycycline

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Beta-lactam +

Macrolide vs Doxycycline

= Doxycycline

Mandell LA, et al. Clinical Infectious Diseases 2007; 44:S27–72.

Patient Case .Dx of community-acquired pneumonia given. .He will be treated for CAP outpatient.

.What antibiotic plan should you recommend? A. Doxycycline B. Azithromycin C. Levofloxacin D. Beta lactam + doxycycline E. Levofloxacin + doxycycline

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Review those medication lists… .Recommend medications that don’t pose risk of prolonging QT (if possible)

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Advocate for calculating risk scores… .Tisdale Risk Score is one option

Risk Factors Points Age ≥ 68 years 1 Female 1 Loop diuretic 1 Serum K+ ≤ 3.5 mEq/L 2 Admitting QTc interval ≥ 450 msec 2 Acute myocardial infarction 2 Sepsis 3 Heart Failure with reduced EF 3 One QTc-prolonging drug 3 Two or more QTc-prolonging drugs 3 Maximum score 21

Watch for drug interactions and multiple QTc-prolonging meds… .Amiodarone + fluoroquinolones .Increased risk of TdP/QT prolongation .Concomitant blockade of cardiac potassium channels

.CYP450 inhibitors vs substrates .1A2 – haloperidol increased when amiodarone, ciprofloxacin, or fluvoxamine given .2D6 – haloperidol, promethazine, prochlorperazine, SSRIs increased when given with amiodarone .3A4 – amiodarone, methadone, TCAs increased with azole antifungals, metronidazole, diltiazem

35 9/5/2018

Nausea .Don’t need to get an EKG on everyone .Only those with RFs .Recommend haloperidol IM .Consider EKG when redosing ondansetron .Use metoclopramide if prolonged QT at baseline or if at risk for drug-induced QT prolongation .Alternate option = promethazine

Antibiotics .Avoid QT prolonging antibiotics if possible .Options for atypical and respiratory coverage exist . Outpatient: doxycycline . Inpatient: doxycycline, tobramycin, gentamicin

.Get baseline EKG if your options are limited

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Final Thoughts .Read primary literature to form your own conclusions

.Clinical relevance may be lacking

.FDA recommendations, warnings exist

.Avoid unnecessary risk when possible

.Use caution when ordering and prescribing

But just in case…

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Resources .http://www.Crediblemeds.org .Accounts are free. .There’s an app for that.

Assessment Questions 1. Which antibiotic class is most well-known for its QTc-prolonging potential?

A. Beta-lactams B. Carbapenems C. Tetracyclines D. Fluoroquinolones

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Assessment Questions 2. What is the maximum single dose of ondansetron recommended to help avoid QTc-prolongation?

A. 4 mg B. 8 mg C. 16 mg D. 32 mg

Assessment Questions 3. Which of the following is a scale that can be used to help determine the risk of QT prolongation in a hospitalized patient?

A. Mayfield Risk Calculation B. Tisdale Risk Score C. Switzer Risk Scale D. Sims Risk Calculation

39 9/5/2018

References . Seftchick MW, Adler PH, Hsieh M, et al. The prevalence and factors associated with QTc prolongation among emergency department patients. Ann Emerg Med 2009;54:763-768. . Zemrak WR, Kenna GA. Association of antipsychotic and antidepressant drugs with Q-T interval prolongation. Am J Health-Syst Pharm 2008;65:1029-38. . Riad FS, Davis AM, Moranville MP, Beshai JF. Drug-induced QTc prolongation. Am J Cardiol 2017;119:280-283. . Single-lead electrocardiogram (ECG) showing a prolonged QT interval. UpToDate, Inc. 2018. Accessed at https://www.uptodate.com/contents/image?topicKey=1043&imageKey=CARD%2F77018&source=outline_ link&search=qt%20prolongation on 5 Sept 2018. . Turner JR, et al. Drug-induced Proarrhythmia and Torsade de Pointes: A Primer for Students and Practitioners of Medicine and Pharmacy. J Clin Pharmacology 2018;58(8):997-1012. . Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004;350:1013-22. . Wooten JM. Drug-induced QT prolongation. South Med J 2006;99:16. . Tisdale JE et al. Development and validation of a risk score to predict QT interval prolongation in hospitalized patients. Circ Cardiovasc Qual Outcomes 2013;6:479-487. . Tomaselli et al. Predictive Analytics for Identification of Patients at Risk for QT Interval Prolongation: A Systematic Review. Pharmacotherapy 2018;38(8):813-821. . CredibleMeds. Risk Categories for Drugs that Prolong QT and induce Torsades de Pointes (TdP). Accessed at https://crediblemeds.org/new-drug-list/ on 5 Sept 2018. . Ayad RF, Assar MD, Simpson L, et al. Causes and management of drug-induced long QT syndrome. Proc (Bayl Univ Med Cent) 2010;23(3):250–255. . DiPiro, Joseph T. Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw-Hill Medical, 2008. . CredibleMeds. Antiarrhythmic drug actions. Accessed at https://crediblemeds.org/files/7413/9568/0020/Antiarrhythmic_drug_actions.pdf on 5 Sept 2018.

References

. Woosley, RL, Heise, CW and Romero, KA, www.CredibleMeds.org, QTdrugs List, 19 May 2017, AZCERT, Inc. 1822 Innovation Park Dr., Oro Valley, AZ 85755. . Magnano AR, Talathoti NB, Hallur R, et al. Effect of acute cocaine administration on the QTc interval of habitual users. Am J Cardiol 2006;97(8):1244-6. . Wu PE, Juurlink DN. Clinical review: loperamide toxicity. Ann Emerg Med 2017;online. http://dx.doi.org/10.1016/j.annemergmed.2017.04.008. . Kozak PM, Harris AE, McPherson JA, Roden DM. Torsades de pointes with high-dose loperamide. J Electrocardiology 2017;50:355-357. . FDA Drug Safety Communication: New information regarding QT prolongation with ondansetron (Zofran). Accessed at FDA.gov. on 16 May 2017. . Ondansetron Package Insert. Accessed on 16 May 2017 at https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020103s035_020605s019_020781s019lbl.pdf . Freedman SB, et al. Ondansetron and the risk of cardiac arrhythmias: a systematic review and postmarketing analysis. Ann Emerg Med 2014;64(1):19-25. . Moffett PM, Cartwright L, Grossart EA, et al. Intravenous ondansetron and the QT interval in adult emergency department patients: an observational study. Academic emergency medicine 2016;23:102-105. . Zuo P, et al. Integration of modeling and simulation to support changes to ondansetron dosing following a randomized, double-blind, placebo-, and active-controlled thorough QT study. J Clin Pharmacol 2014;54(11):1221-1229. . Prochlorperazine drug label. Accessed at http://www.sanofi.com.au/products/aus_pi_stemetil.pdf on 5 Sept 2018. . Owczuk R, Twardowski P, Dylczyk-Sommer A, et al. Influence of promethazine on cardiac repolarisation: a double-blind, - controlled study. Anaesthesia. 2009 Jun;64(6):609-14. . Lexi-complete. Accessed at http://www.uptodate.com on 23 May 2017. . Gaffigan ME, Bruner DI, Wason C, et al. A randomized controlled trial of intravenous haloperidol vs. intravenous metoclopramide for acute migraine therapy in the emergency department. J Emerg Med 2015;49(3):326-334.

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References

. Bentsen G, Stubhaug A. Cardiac arrest after intravenous metoclopramide - a case of five repeated injections of metoclopramide causing five episodes of cardiac arrest. Acta Anaesthesiol Scand. 2002;46(7):908-910. . Malkoff MD, Ponzillo JJ, Myles GL, Gomez CR, Cruz-Flores S. Sinus arrest after administration of intravenous metoclopramide. Ann Pharmacother. 1995;29(4):381-383. . Claassen S, Zünkler BJ. Comparison of the effects of metoclopramide and on HERG channels. Pharmacology. 2005;74(1):31-36. . Siddique SM, Shariff N, Vesuwala N, Hafiz T. Metoclopramide as a possible cause of prolonged QT syndrome and torsade de pointes in a patient with heart failure and renal insufficiency. Ann Intern Med. 2009;150(7):502-504. . Ellidokuz E, Kaya D. The effect of metoclopramide on QT dynamicity: double-blind, placebo-controlled, cross-over study in healthy male volunteers. Aliment Pharmacol Ther. 2003;18(1):151-155. . Kao LW, Kirk MA, Evers SJ, Rosenfeld SH. Droperidol, QT prolongation, and sudden death: what is the evidence? Ann Emerg Med 2003;41:546-558. . Ray WA, Murray KT, Hall K, et al. Azithromycin and the risk of cardiovascular death. N Engl J Med 2012;366:1881-90. . Svanstrom H, Pasternak B, Hviid A. Use of azithromycin and death from cardiovascular causes. N Engl J Med 2013;368:1704-12. . Giudicessi JR, Ackerman MJ. Azithromycin and risk of sudden cardiac death: guilty as charged or falsely accused? Cleve Clin J Med 2013;80(9): 539–544. . Knorr JP, Moshfeghi M, Sokoloski MC. Ciprofloxacin-induced Q-T interval prolongation. Am J Health-Syst Pharm 2008;65:547-51. . Makaryus AN, Byrns K, Makaryus MN et al. Effect of ciprofloxacin and levofloxacin on the QT interval: is this a significant “clinical” event? South Med J 2006;99:52-6. . Lapi F, Wilchesky M, Kezouh A, Benisty JI, Ernst P, Suissa S. Fluoroquinolones and the risk of serious arrhythmia: a population-based study. Clin Infect Dis 2012;55(11):1457. . Taubel J et al. Levofloxacin can be used effectively as a positive control in thorough QT/QTc studies in healthy volunteers. Br J Clin Pharmacol 2010;69(4):391-400. . Mandell LA, Wunderink RG, Anzueto A, et al. Infectious diseases society of America/American thoracic society consensus guidelines on the management of community-acquired pneumonia in adults. Clinical Infectious Diseases 2007; 44:S27–72.

Kelly Murray, PharmD, BCACP Clinical Assistant Professor of Clinical Pharmacy OSU-CHS, Dept. of Emergency Medicine // September 2018

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