Evidence-based Review of the Black-box Warning for Droperidol

Cherry W. Jackson; Amy Heck Sheehan; Jennifer G. Reddan

Am J Health Syst Pharm. 2007;64(11):1174-1186.

Conclusion

Studies show that there is a dose-dependent increase in the rate of adverse cardiovascular events when droperidol is used either alone or in combination with other medications that cause Q-T interval prolongation. At this time, there does not appear to be significant evidence to suggest that 5-HT₃ antagonists are safer than droperidol with regard to Q-T interval prolongation. More studies are needed to determine the safety and efficacy of droperidol when used in doses of 0.625-1.25 mg compared with the 5-HT₃ antagonists.

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Acknowledgments

Cynthia LaCivita, Pharm.D., is acknowledged for her assistance in the preparation of this manuscript.

Reprint Address

Cherry W. Jackson, Harrison School of Pharmacy Auburn University, 217 Walker Building, Auburn, AL 36849-8353. E-mail: cwj0002@auburn.edu .

Cite this: Evidence-based Review of the Black-box Warning for Droperidol - Medscape - Jun 01, 2007.

Table 1. Case Reports Involving at Least One Cardiac Manifestation in Patients Receiving Droperidol
Case No. (Date)	Age in yr, Sex	Medications^a	Symptom(s)^b	Outcome
1(11/06/1997)	Not provided, M	Droperidol 0.5 mg i.v., clindamycin, bupropion	Atrial fibrillation, cardiac arrest	Death
2(12/08/1997)	23, M	Droperidol 50 mg i.m., haloperidol 10 mg i.m., levomerpromethazine, zuclopenthixol	Cardiopulmonary arrest	Death
3(06/25/1998)	48, M	Droperidol 25 mg i.m.	Cardiac arrest	Death
4(06/25/1998)	26, M	Droperidol 50 mg	Cardiac arrest	Death
5(06/25/1998)	43, M	Droperidol 50 mg i.m., lactulose	Cardiopulmonary arrest	Death
6(06/25/1998)	77, F	Droperidol (no dosage information), haloperidol	Cardiac arrest	Death
7(06/25/1998)	80, M	Droperidol 0.25 mg oral, furosemide 40 mg oral	Atrioventricular block	Death
8(06/25/1998)	77, F	Droperidol, haloperidol	Cardiac arrest	Death
9(06/25/1998)	80, M	Droperidol 0.25 mg oral, furosemide 40 mg oral	Atrioventricular block	Death
10 (06/25/1998)	48, M	Droperidol 50 mg i.m.	Cardiac arrest	Death
11 (06/25/1998)	77, F	Droperidol oral, haloperidol oral, enalapril oral	Cardiac arrest	Death
12 (06/25/1998)	24, M	Droperidol 100 mg oral, levomepromazine, haloperidol 50 mg oral, pimozide, oxazepam, valpromide, chlorpromazine, trihexyphenidyl, zolpidem	Cardiac arrest, overdose	Death
13 (09/30/1998)	63, F	Droperidol 0.625 mg	Cardiac failure	Hospitalization
14 (10/07/1998)	59, F	Droperidol 0.625 mg i.v., cyclobenzaprine 10 mg po, fluoxetine, HCTZ/triamterene, amlodipine, diclofenac, simvastatin, anesthesia, atracurium, bupivacaine, cefazolin, fentanyl, ketorolac, lidocaine, metoclopramide, midazolam, nitrous oxide	Torsades de pointes	Hospitalization
15 (10/08/1998)	59, F	Droperidol 0.625 mg i.v., cyclobenzaprine 10 mg oral, fluoxetine, HCTZ/ triamterene, amlodipine, diclofenac, simvastatin, anesthesia, atracurium, bupivacaine, cefazolin, fentanyl, ketorolac, lidocaine, metoclopramide, midazolam, nitrous oxide	Torsades de pointes	Hospitalization
16 (12/03/1998)	53, M	Droperidol 0.625 mg i.v. x 1, dolasetron, 12.5 mg i.v., midazolam, ceftriaxone, propofol, lidocaine, fentanyl, vecuronium, oxygen, ketorolac, tromethamine, ondansetron, ephedrine, glucopyrronium, neostigmine, sevoflurane, sodium amidotrizoate	ECG T-wave inversion, ventricular tachycardia	Hospitalization
17 (01/27/1999)	53, M	Droperidol 0.625 mg, dolasetron, midazolam, ceftriaxone, propofol, lidocaine, fentanyl, vercuronium, oxygen, ketorolac, tromethamine, ondansetron, ephedrine, glucopyrronium, neostigmine, sevoflurane, sodium amidotrizoate (Hyopaque)	ECG T-wave inversion, ventricular tachycardia	Hospitalization
18 (06/16/1999)	53, M	Droperidol 0.625 mg, dolasetron, midazolam, ceftriaxone, propofol, lidocaine, fentanyl, vecuronium, oxygen, ketorolac, tromethamine, ondansetron, ephedrine, glucopyrronium, neostigmine, sevoflurane, sodium amidotrizoate (Hyopaque)	ECG T-wave inversion, ventricular tachycardia	Hospitalization
19 (05/24/1999)	Not provided, M	Droperidol 10 mg i.m. x 1, lorazepam 2 mg i.m. x 1	Cardiac arrest	Death
20 (06/28/1999)	41, M	Droperidol, oxacillin inj 6 gm i.v., metronidazole, fentanyl, dopamine, Nesdonal	Tachycardia	Death
21 (07/08/1999)	26, M	Droperidol 10 mg i.m. x 1, lorazepam 2 mg i.m. x 1, olanzapine	Cardiac arrest	Death
22 (07/27/1999)	30, M	Droperidol, venlafaxine 900 mg, diazepam 100 mg, paracetamol	Bradycardia, hypotension	Hospitalization
23 (08/27/1999)	No information provided	Droperidol i.v.	Blood pressure decreased	Life threatening
24 (09/02/1999)	21, F	Droperidol 30 mg i.m. x 1, procyclidine, diazepam 20 mg i.m. x 2, alcohol, flumazenil, naloxone	Tachycardia, neuroleptic malignant syndrome	Death
25 (10/04/1999)	Not provided, F	Droperidol 1 mg i.v., cyclophosphamide 510 mg i.v., warfarin, Niferex, alprazolam, Desogen, acetaminophen, mesna, dexamethasone, granisetron	Cardiopulmonary arrest	Hospitalization
26 (01/20/2000)	66, M	Droperidol 1.25 mg i.v.	Blood pressure decreased, ventricular tachycardia	Life threatening
27 (03/16/2000)	Not provided, F	Droperidol	Tachycardia not otherwise specified	Hospitalization
28 (03/20/2000)	36, M	Droperidol 5 mg t.i.d., clozapine 450 mg daily, cefuroxime, metronidazole, heparin, calcium	Cardiac disorder, not otherwise specified; conduction disorder, not otherwise specified	Death
29 (04/07/2000)	36, M	Droperidol 5 mg t.i.d., clozapine 450 mg daily, cefuroxime, metronidazole, heparin, calcium	Conduction disorder, not otherwise specified	Death
30 (04/13/2000)	35, M	Droperidol 5 mg t.i.d., clozapine, cefuroxime, metronidazole, heparin, calcium	Cardiac disorder, not otherwise specified	Death
31 (06/30/2000)	23, F	Droperidol i.v., metoclopramide i.v.	Tachycardia, not otherwise specified; neuroleptic malignant syndrome	Other
32 (07/05/2000)	32, M	Droperidol i.m., diazepam, lorazepam 10 mg po, thioridazine, flurazepam 250 mg po, benztropine, haloperidol	Cardiac arrest	Death
33 (07/21/2000)	81, F	Droperidol 2.5 mg q 5 min x 2, albumin, milrinone, vasopressin, norepinephrine, esmolol, dobutamine, dopamine, metoclopramide 25 mg x 3 doses	Hypotension, hyperpyrexia	Death
34 (07/21/2000)	Not provided, F	Droperidol 25 mg po, meclizine, valsartan, alendronate, conjugated estrogens/ progesterone	Torsades de pointes	Life threatening
35 (08/14/2000)	Not provided, F	Droperidol 25 mg po, valsartan, alendronate, conjugated estrogens/progesterone, meclizine	Torsades de pointes	Life threatening
36 (09/08/2000)	71, F	Droperidol 25 mg po, meclizine, valsartan, alendronate, conjugated estrogens/ progesterone	Torsades de pointes, cardiomegaly, myocardial infarction, ventricular tachycardia, ventricular fibrillation, atrial fibrillation	Life threatening
37 (08/30/2000)	76, M	Droperidol 5 mg inj	Hypertension, not otherwise specified; hypertensive crisis	Life threatening
38 (12/14/2000)	79, M	Droperidol 1.25 mg i.v.	Tachycardia, not otherwise specified; hypertension, not otherwise specified; hypotension, not otherwise specified; perforated appendix	Life threatening
39 (12/18/2000)	18, F	Droperidol 1 mg/hr i.v., metoclopramide 10 mg po x 1	Tachycardia, not otherwise specified	Hospitalization
40 (03/06/2001)	63, M	Droperidol, aspirin, potassium, nitroglycerin SL, dalteparin, morphine, atorvastatin, diphenhydramine, valsartan, hydrocodon/acetaminophen, piperacillin/tazobactam, clindamycin, cefazolin, tobramycin, lisinopril, insulin, metoprolol, digoxin, acetaminophen, clonazepam, NTG infusion, furosemida	Cardiopulmonary arrest	Death
41 (06/28/2001)	20, not provided	Droperidol 5 mg i.v.	Cardiopulmonary arrest	Death
42 (06/28/2001)	45, not provided	Droperidol i.v. drip	Cardiac arrest	Death
43 (07/09/2001)	53, M	Droperidol 10 mg i.v. x 1, chlorpromazine, antibiotic	Cardiovascular disorder, not otherwise specified	Death
44 (07/09/2001)	61, M	Droperidol 8 mg i.v./hr, piracetam 12 g i.v. daily, isosorbide, heparin	Ventricular fibrillation, ventricular tachycardia, atrial fibrillation, myocardial infarction	Life threatening
45 (07/09/2001)	65, F	Droperidol 240 mL i.v. daily, heparin	Torsades de pointes	Death
46 (07/09/2001)	38, F	Droperidol 240 mL i.v. daily, heparin, diazepam, vitamin E	Torsades de pointes	Life threatening
47 (07/09/2001)	48, F	Droperidol 240 mL i.v. daily, heparin, somatostatin, nitroglycerin, furosemide	Torsades de pointes	Death
48 (07/09/2001)	62, M	Droperidol 240 mL daily for several days, heparin	Torsades de pointes	Death
49 (07/09/2001)	51, M	Droperidol 200 mg daily infusion, midazolam, nitroglycerin	Ventricular fibrillation, cardiac arrest, myocardial infarction, cardiomegaly, arrhythmia	Death
50 (07/09/2001)	74, M	Droperidol 25 mg i.v. x 1	Ventricular fibrillation, ventricular extrasystoles	Life threatening
51 (07/09/2001)	69, F	Droperidol 5 mg, fentanyl 100 µg, vecuronium, thiopental, lidocaine, nitrous oxide	Cardiac arrest, bradycardia	Death
52 (07/09/2001)	56, F	Droperidol epidural, famotidine i.v., bupivacaine, bupreorphine, Minophagen C, cefmetazole, Nitroderm TTS	Prolonged Q-T interval, myocardial infarction	Other
53 (07/09/2001)	29, M	Droperidol 10 mg i.m. x 1, haloperidol, procyclidine, diazepam	Cardiac arrest	Death
54 (07/09/2001)	36, M	Droperidol 15 mg i.v. x 1, haloperidol, chlorpromazine	Cardiac arrest, coronary artery disease, hypertensive crisis	Death
55 (07/09/2001)	69, F	Droperidol, phenoperidine 0.5 mg i.v. x 1, halothane, chlordiazepoxide	Cardiac arrest	Unknown
56 (07/09/2001)	34, F	Droperidol 90 mg i.m., zuclopenthixol	Cardiac failure	Death
57 (07/09/2001)	54, M	Droperidol 50 mg i.v. x 1	Cardiac failure, not otherwise specified	Death
58 (07/09/2001)	23, F	Droperidol 2 mg i.v., alfentanil, propofol, midazolam, atropine, oxygen, nitrous oxide	Cardiac arrest	Death
59 (07/09/2001, given 06/1988)	77, F	Droperidol 20 drops, haloperidol 30 drops, enalapril ½ tablet x 3 mos	Cardiac arrest, bundle branch block, epilepsy, respiratory arrest	Death
60 (07/09/2001, given 06/15/1988)	75, M	Droperidol 25 mg daily	Torsades de pointes, atrial fibrillation, atrioventricular block, cardiac failure, prolonged Q-T interval	Life threatening
61 (07/09/2001)	40, M	Droperidol 25 mg i.m. x 1 dose, mianserin, flunitrazepam, atrium, alimemazine, chlorpromazine, heptaminol	Systolic blood pressure decreased	Death
62 (07/09/2001)	Not available, not available	Droperidol 25 mg i.m. x 1	Torsades de pointes	Death
63 (07/09/2001)	32, M	Droperidol , thioridazine i.m., lorazepam 250 mg po, diazepam po, flurazepam 10 mg po, haloperidol, benztropine	Cardiac arrest	Death
64 (07/09/2001)	21, F	Droperidol, olanzapine i.m., fluoxetine 20 mg daily, mefenamic acid po, lorazepam	Cardiac arrest	Hospitalization
65 (07/09/2001, given 06/11/1993)	24, F	Droperidol 3.75 mg i.v. daily, Dilaudid 1.5 mg daily, midazolam 4 mg daily	Cardiac arrest, cardiomyopathy, ventricular arrhythmia	Hospitalization
66 (07/09/2001)	41, M	Droperidol 2.5 mg i.m. daily, theophylline, terbutaline, metaproterenol, beclomethasone, prednisone	Torsades de pointes, ventricular arrhythmia, drug level above therapeutic, asthma aggravated	Hospitalization
67 (07/09/2001)	49, F	Droperidol 1.25 mg i.v., metoclopramide, ranitidine	Bradycardia, not otherwise specified; sinus arrest	Hospitalization
68 (07/09/2001)	22, M	Droperidol 5 mg i.m. x 1 dose, lithium, perphenazine, propranolol	Cardiac arrest, hypotension	Death
69 (07/09/2001)	39, F	Droperidol, Dilaudid 1.5 x 1, fentanyl, midazolam, morphine, ampicillin/ sulbactam, edrophonium, atropine, ketorolac, propofol, vercuronium, bupivacaine	Cardiopulmonary arrest	Death
70 (07/09/2001)	35, F	Droperidol 0.75 mg total, chlordiazepoxide, diazepam, antihistamines, antitussive, acetaminophen, aspirin	Cardiac arrest, ventricular fibrillation	Hospitalization
71 (07/09/2001)	70, F	Droperidol 2.5 mg i.v., metoclopramide	Bundle branch block, prolonged Q-T interval, torsades de pointes	Hospitalization
72 (07/09/2001)	52, M	Droperidol 3.75 mg i.v., vasopressin, nitroglycerin	Cardiac arrest, hypokalemia, ventricular fibrillation, torsades de pointes	Death
73 (07/09/2001)	39, M	Droperidol 10 mg i.m.	Bradycardia, cardiac arrest	Death
74 (07/09/2001)	47, F	Droperidol i.v.	Torsades de pointes	Death
75 (07/09/2001)	36, M	Droperidol 20 mg daily, chlorpromazine 1400 mg, fluvoxamine 200 mg, procyclidine 5 mg	Cardiopulmonary arrest	Death
76 (07/09/2001)	28, F	Droperidol 5 mg, alfentanil, lorazepam, propofol, lidocaine, succinylcholine, isoflurane, atracurium	Mitral valve prolapse, supraventricular tachycardia, ventricular bigeminy, ventricular extrasystoles	Required intervention
77 (07/09/2001)	23, M	Droperidol 50 mg i.m., haloperidol 10 mg i.m., levomepromazine, zuclopenthixol, valproate	Cardiopulmonary arrest	Death
78 (07/09/2001)	77, F	Droperidol 30 drops daily, haloperidol 30 drops daily, enalapril	Bundle branch block, cardiac arrest	Death
79 (07/09/2001)	56, F	Droperidol 250 mg x 1, antidepressants (?)	Prolonged Q-T interval	Hospitalization
80 (07/09/2001, occurred 9/27/1991)	37, M	Droperidol 125 mg, ranitidine, clomeiethiazole, nifedipine, metoprolol, potassium chloride	Ventricular fibrillation	Life threatening
81 (07/09/2001)	57, not reported	Droperidol 0.25 mg/kg, fentanyl, methohexital 0.2 mg i.v.	Cardiac arrest, prolonged Q-T interval, increased heart rate	Unkown
82 (07/09/2001)	23, M	Droperidol 50 mg i.m., haloperidol 10 mg i.m., levomepromazine, zuclopenthixol, valproate	Cardiopulmonary arrest	Death
83 (07/09/2001)	24, M	Droperidol 100 mg i.m., haloperidol 50 mg i.m., levomepromazine, valproate, pimozide, oxazepam, chlorpromazine, trihexyphenidyl, zolpidem	Cardiac arrest	Death
84 (07/09/2001)	43, M	Droperidol 50 mg i.m., lactulose, charbon powder	Atrioventricular block, bradycardia, cardiac arrest, tachycardia, ventricular extrasystoles, ventricular tachycardia	Death
85 (07/09/2001)	48, M	Droperidol 50 mg i.m.	Cardiac arrest	Death
86 (08/02/2001)	53, M	Droperidol 0.625 mg i.v.	Cardiac arrest	Death
87 (08/15/2001)	53, F	Droperidol i.v. drip, famotidine, thiamine, Coumadin, pacemone, Lanoxin, furosemide	Cardiopulmonary arrest	Death
88 (08/15/2001)	60, F	Droperidol 1.25 mg i.v., fentanyl 2 mL i.v., cefotetan 2 g i.v., tubocurare 3 mg i.v., Robinul 0.2 mg i.v., midazolam 2.5 mg i.v., atorvastatin, omeprazole, sucralfate, conjugated estrogen/progesterone	Myocardial infarction, ventricular bigeminy	Other
89 (09/04/2001)	60, F	Droperidol 1.25 mg i.v., fentanyl 2 mL i.v., cefotetan 2 gm i.v., tubocurare tubocurarine 3 mg i.v., glycopyrrolate 0.2 mg i.v., midazolam 2.5 mg i.v., atorvastatin, omeprazole, sucralfate, conjugated estrogen/progesterone	Myocardial infarction, myocardial ischemia, ventricular bigeminy	Other
90 (09/17/2001)	39, F	Droperidol 10 mg i.m., Ativan 2 mg i.m.	Cardiac arrest	Hospitalization
91 (09/21/2001)	60, F	Droperidol 1.25 mg i.v., fentanyl 2 mL i.v., cefotetan 2 gm i.v., tubocurare 3 mg i.v., glycopyrrolate 0.2 mg i.v., midazolam 2.5 mg i.v., atorvastatin, omeprazole, sucralfate, conjugated estrogen/progesterone	Myocardial infarction, ventricular bigeminy	Other
92 (10/05/2001)	60, F	Droperidol 1.25 mg i.v., fentanyl 2 mL i.v., cefotetan 2 gm i.v., Tubocurare 3 mg i.v., glycopyrrolate 0.2 mg i.v., midazolam 2.5 mg i.v., atorvastatin, omeprazole, sucralfate, conjugated estrogen/progesterone	Myocardial infarction, ventricular bigeminy	Other
93 (11/16/2001)	39, F	Droperidol i.m., lorazepam i.m.	Cardiac arrest	Life threatening
94 (12/19/2001)	38, F	Droperidol 5 mg i.m., diphenhydramine 50 mg i.m., benztropine, valproic acid	Cardiac arrest	Death
95 (01/14/2002)	36, M	Droperidol 20 mg i.m., fluvoxamine 100 mg b.i.d., chlorpromazine, procyclidine 1150 mg	Arrhythmia	Death
96 (01/23/2002)	77, F	Droperidol 2.5 mg i.v.	Bradycardia, prolonged ECG, ventricular tachycardia	Life threatening
97 (01/29/2002)	Not provided, M	Droperidol 2.5 mg i.m., lorazepam 2 mg i.m.	Cardiopulmonary arrest	Death

^aMedications are listed as transcribed from the report received from the Food and Drug Administration.
^bECG = electrocardiogram.

Table 2. Duplicated Cases from Reports in Table 1
Duplicated Case Numbers	Outcomes
2, 12, 77, 82	Death, cardiac arrest
3, 10, 85	Death, cardiac arrest
5, 84	Death, cardiac arrest
6, 8, 11, 59, 78	Death, cardiac arrest
7, 9	Death, atrioventricular block
14, 15	Hospitalization, torsades de pointes
16-18, 43, 86	Hospitalization, torsades de pointes
19, 21	Death, cardiac arrest
24, 27, 31	Hospitalization, death, tachycardia, neuroleptic malignant syndrome
28-30	Death, cardiac arrest
32, 63	Death, cardiac arrest
34-36	Life-threatening torsades de pointes
47, 74	Death, torsades de pointes
88, 89, 91, 92	Other, myocardial infarction, ventricular bigeminy
54, 75, 95	Death, arrhythmia
90, 93	Life-threatening cardiac arrest

Table 3. Summary of Manifestations and Outcomes
Primary Manifestations	Outcome
Primary Manifestations	Death	Hospitalization	Life Threatening	Other	Total
Cardiac arrest	25	6	0	2	33
Torsades de pointes	5	3	3	0	11
Atrioventricular block	1	0	0	0	1
Tachycardia	2	1	0	0	3
Conduction disorder	1	0	0	0	1
Hypotension	1	1	0	0	2
Cardiac failure	0	1	0	0	1
Ventricular tachycardia	0	1	0	0	1
Prolonged Q-T interval	0	1	0	1	2
Decreased blood pressure	0	0	1	0	1
Hypertension	0	0	2	0	2
Ventricular fibrillation	0	0	3	0	3
Ventricular bigeminy	0	0	1	1	2
Bradycardia	0	0	1	0	1
Myocardial infarction	0	0	0	1	1
Total	35	14	11	5	65

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Evidence-based Review of the Black-box Warning for Droperidol

Conclusion

Tables

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

Appendix

Appendix: Cardiovascular Effects Potentially Associated With Droperidol

Appendix

Appendix: Risk Factors for Q-T Interval Prolongation, Torsades de Pointes, and Sudden Death[22,23,29]

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Appendix: Risk Factors for Q-T Interval Prolongation, Torsades de Pointes, and Sudden Death^[22,23,29]