1. Postoperative Nausea and Vomiting Prophylaxis with Antipsychotic Agents Should we or should we not? Natalie Clavel October 8, 2008

2. Overview Pathophysiology of nausea / vomiting PONV Overview PONV prophylaxis guidelines (2007) Droperidol What happened to it? Evidence for and against its use for PONV prophylaxis Ondansetron Evidence for and against its use for PONV prophylaxis Haloperidol Evidence for and against its use for PONV prophylaxis

3. Pathophysiology of Nausea and Vomiting

4. Why should we care?  Approximately 75 million surgeries performed (in patient and ambulatory) annually in the USA  If untreated, PONV occurs in 20-30% of the general surgical population and in 70-80% of high-risk surgical patients  Vomiting increases the risk of : aspiration, suture dehiscence, esophageal rupture, subcutaneous emphysema, and pneumothorax  Annual cost of PONV in the United States is thought to be $ 200 million  PONV in ambulatory patients accounts for 0.1- 0.2% of unanticipated hospital admissions  Approx 35% of patients will not experience PONV before discharge form PACU and may onset within the first 24-48 hrs postoperatively

5. SAMBA Guidelines for Management of PONV Anesth Analg 2007 ; 105 : 1615-28

6. PONV Prophylaxis : Cost Effectiveness Anesthesiology 2000 ; 92 : 958-67 Each episode of emesis is thought to delay discharge from PACU by 20 min Costs associated with PONV in patients not receiving prophylaxis were 100x more than the cost of prophylaxis with a generic agent. Costs of treating vomiting were shown to be 3x that of treating nausea

7. Droperidol A Butyrophenone & derivative of haldoperidol Antiemetic, sedative, antipuritic, pain adjunct Acts at dopamine > NorAd + 5HT Anti-emetic effects thought to be due to a triggered imbalance in dopamine in the chemoreceptor trigger zone Biotranformation occurs in the liver. T 1/2 = 103-134 minutes CNS – NMS, movement disorder, extrapyrimidal signs, drowsiness CVS – prolongation of QT interval (delays repolarization by inhibiting cardiac K+ channels). Vasodilation via A-adrenergic blockade

8. Droperidol : Is it Effective ? IMPACT TRIAL Compared effectiveness of droperidol (1.25mg IV), dexamethasone (4mg IV), and ondansetron (4mg IV) All reduced the incidence of PONV by 26% Multimodal prophylaxis resulted in additive reduction in the incidence of PONV 0 agent = 52% risk of PONV 1 agent = 37% risk of PONV 2 agent = 28% risk of PONV 3 agent = 22% risk of PONV N EGNL J MED 2004; 350: 2441-51

9. NNT to prevent an episode of PONV compared to placebo is 5 (0-24hrs) Side effects are dose dependant. Below 2.5 mg extra- pyramidal signs and sedation were extremely rare. Incidentally found to decrease the incidence of headache Can J Anaesth 2000; 47 : 537-51 NNT to prevent an episode of NV associated with morphine PCA is 3 Anesth Analg 1999; 88: 1354-61 Effective against established PONV in PACU. Anesth 2005; 102:1094-100

10. What Happened to Droperidol? 1991 : FDA approval of Ondansetron 2001 : FDA Issues Black Box Warning against use of Droperidol (30% of market shares) 2001 : Production shortage of prochlorperazine. Consequential increase in use of 5HT agents for PONV prophylaxis 2002 : 10-fold decrease in sales of droperidol in USA 2004 : Droperidol no longer manufactured in Europe 2005 : SAMBA survey (25% resp rate) Droperidol use for prophylaxis decreased from 47% to 5%. 92% of respondents felt black box warning unjustified Dec 24, 2006 : Ondansetron patent expired (GSK) 2007 : Ondansetron leading first-line agent of choice in PONV prophylaxis (>30% of market share) Presently : Waiting for FDA internal review of droperidol and possible withdrawal or modification of black box warning

11. Black box warning is the most serious warning that the FDA can require on a drug’s labeling There is significant medical liability associated with use of a medication with a black box warning

12. Droperidol: The Black Box Warning Estimated >11 million ampules of droperidol sold in USA in 2001 Nov 1,1997 – Jan 2, 2001 : 273 adverse events reported to the FDA regarding droperidol 74/273 = cardiac event / torsades 17/273 = prolonged QT interval In patients that received 0.625-1.25mg droperidol IV : 10 experienced adverse cardiac events (1 torsades) J Clin Anesth 2008: 20: 35-39

13. Anesth Analg 2003; 96: 1377-9

15. Does droperidol cause arrhythmias ? RCT, 1028 pts received droperidol 0.625 or 1.25 mg IV. No reports of cardiovascular events or sudden deaths Anesth Analg 1998; 86: 731-8 Meta-Analysis of 76 trials involving 5351 pts receiving 0.625-5mg IV did not report an increased risk of arrhythmias or sudden death Can J Anaesth 2000; 47: 537-51 Retrospective study of 16790 pts who were exposed to droperidol. No torsades/ arrythmias noted. 1 episode of arrhythmia documented to have occurred 2 hrs post administration of 0.625mg droperidol. Pt had baseline QT prolongation (chronic cyclobenzaprine tx) w concurrent fluoxetine tx (P450 inhib) Anesth 2007;107:531-6

16. Does droperidol cause QT prolongation ? Rapid Onset, Dose dependent increase in QT interval with 0.1-0.25 mg/kg Max prolongation occurred within 60s of administration and decreased over the following 10 min (no arrhythmias) Anesth Analg 1994; 79: 983-6

17. Can we blame the droperidol ? RCT using low dose droperidol (0.625 and 1.25mg IV) in 120 ASA I-III, healthy 0.625 mg increased QT by 15 +/- 40 msec 1.25 mg increased QT by 22+/-41 msec QT Interval returned to baseline 2 hrs post- op No arrhythmias documented Placebo increased QTc by 12 +/-35 msec GA alone assoc with 14-16 msec prolongation of QTc postoperatively (not explained by droperidol) Anesth 2005; 102:1101-5

18. Routinely Used Drugs that prolong QT Interval in Anesthesia ThiopentalSuccinylcholine IsofluraneNeostigmine SevofluraneAtropine DesfluraneGlycopyrrolate Anesth Analg 2008; 106: 1414-17

19. Drugs that prolong QT Interval Antibiotics Clarithromycin, erythromycin, gatifloxacin, levofloxacin, moxifloxacin Antiarrythmics Amiodarone, Procainamide Antidepressants Fluoxetine, Paroxetine, Sertraline Antipsychotics Chlorpromazine, Droperidol, Haloperidol, Seroquel, Risperidone Other Indapamide, Nicardipine, Octreotide, Sumitriptan

20. Conclusion Droperidol has a long-established safety record when used in antiemetic dosages No evidence suggesting an increased risk of arrhythmia when using dosages <1.25mg QTc is prolonged in a dose-dependent fashion after administration of droperidol. Prolongation is modest and transient. A product warning would likely have been sufficient. A black box warning is excessive for use of droperidol at <1.25mg dosages and is not evidence based.

21. 2003 Consensus Guidelines for the Management of PONV Anesth Analg 2003; 97: 62-71

22. Ondansetron : Better Safety Profile? “ setrons” share with droperidol the ability to block the HERG cardiac potassium channel Anesth 2007; 106: 967-76 RCT (16 healthy pts) showed 1mg droperidol and 4mg ondansetron increased QTc by 25+/-8ms and 17+/- 10ms respectively. Together QTc increased by 28+/-10ms. Anesth 2008; 109: 206-212 Droperidol 0.75mg vs. ondansetron 4mg for established PONV in PACU. QTc was prolonged in 21% pts before anti-emetic administration. Max prolongation occurred 2-3 min after administration and returned to below baseline 90 min after administration. SVT in 1 pt receiving ondansetron Anesth 2005; 102:1094-100

23. Ondansetron : Better efficacy ? Meta-analysis confirmed that 1.25mg droperidol was found to possess greater antinausea efficacy that ondansetron(4mg). There was no increase in sedation or other side effects. Can J Anaesth 2000; 47: 537-51 Droperidol and ondansetron have been shown to be similarly effective against established PONV Anesth 2005; 102:1094-100

24. What about Haloperidol? A Butyrophenone Obtained FDA approval in 1967 for use as an antipsychotic/ neuroleptic/ tranquilizer Metabolized in liver via CYP450 Mechanism of action via D2 (low dose) 5-HT2 (high dose) CNS – EPS, NMS, extrapyramidal, tardive dyskinesia CVS – QT interval prolongation Established use in treatment of chemotx / XRTx / and opioid- related N/V (1.5-3mg po) Palliat Med 2004; 18: 195-201 Systematic review (1962-1988) suggested that haloperidol at 1- 2 mg might be effective against PONV NNT to prevent an episode of PONV compared to placebo determined to be 4-6 Anesth 2004; 101:1454-63

25. Haloperidol as a safer alternative to Droperidol? Haloperidol 1mg and droperidol 0.625mg were better than placebo for PONV prophylaxis. Both equally effective. No difference in QTc prologation. Acta Anaesthesiol Scand 2007; Epub Haloperidol (1mg) was as effective as ondansetron (4mg). No difference in QTc prolongation Anesth Analges 2006; 106 : 1407-9

26. . Haloperidol was not more effective in reducing incidence of late onset PONV than droperidol (T1/2 18 hr vs. 2hr) No increase in sedation, extrapyrimidal symptoms, of clinically significant prolongation of QTc was observed at anti- emetic dosages Anesth Analg 2008; 106: 1402-6

27. Future Concerns In September 2007, the FDA issued an alert regarding the updated labeling for haloperidol. Warning states: Risk of QT prolongation / torsades Haldol not approved for IV use EKG monitoring required if given IV Administration Dosage, Timing, Safety/ Side effect profile of repeated dosages of long acting drug Trials Unlikely to have large clinical trials conducted on a generic drug

28. Conclusions Available evidence suggests that small-dose haloperidol appears to be safe and effective when given as a single dose (1- 2mg) for PONV prophylaxis. Large studies are required to provide additional safety and efficacy information. In the absence of this safety data, droperidol is a better choice for PONV prophylaxis Given the FDA Black Box warning for droperidol, the anesthesia community has “reinvented the wheel”

29. Thank You

30. Antiemetic and Timing of Administration Anesth Analg 2007 ; 105 : 1615-28