# Presentation: 069281

## Droperidol Since 2001FDA Risk Assessment

**Anesthetic and Life Support Drugs **
**Advisory Committee **
**November 18, 2003**
**Nancy Chang, M.D.**
**Lead Medical Officer**
**Division of Anesthetic, Critical Care and**
**Addiction Drug Products**

**Center for Drug Evaluation and Research**** **

## Droperidol - revised data sheet : cardiac arrhythmias

- France. The Medicines Agency has revised the data sheet for pharmaceutical products containing droperidol ... following a national enquiry that examined 26 reports of sudden deaths and cardiac arrhythmias associated with its use since ... 1967. The deaths occurred within 15 minutes of administration in 10 cases, and acute alcoholism was reported in 11 cases.
- The dosage used was 15 ml at 100 mg (intramuscular), whereas the dosage currently prescribed for agitation is 10 mg to be repeated every 4 to 6 hours as necessary.
- The incidence of sudden deaths is estimated as **1 per 55,000 vials.**
- A "Dear Doctor" letter has also been sent to prescribers.
*Reference: Communication from the Agence du Médicament, 7 May 1997.*

## Droleptan medicinal products will be discontinued from 31 March 2001.... This action has been taken by ... Janssen-Cilag Ltd, who has chosen to voluntarily discontinue Droleptan following an extensive risk-benefit assessment. The company concluded that the oral formulations should be discontinued to prevent use in chronic conditions and that the injectable form would no longer be commercially viable. The Medicines Control Agency (MCA) had raised concerns about the potential effect of droperidol on the cardiac QT interval and requested the risk-benefit assessment.

- ---MCA,  Jan 2001

## Postmarketing spontaneous reports

**	**

**Postmarketing spontaneous reports**

**QT prolongation, torsades, cardiac arrest, ventricular tachycardia, ventricular fibrillation, ventricular arrythmia, sudden death**
**89 events, 46 fatal**

## QT and/or Torsadespostmarketing events

**22 cases, at least 5 fatal **
**14 torsades (incl 6 with QT)**
**Route: injection (n=20) oral (n=1); unk (n=1) **
**Dose for single inj. (N=13): **
**0.625 (n=2); 1.25 (n=2); 2.5 (n=3)**
**3.75-5 (n=2); 12.5 (n=1); 21-25 (n=3)**
**Onset (N=14): immed-several minutes (n=4); 10 min (n=3); 4-12 hours (n=3); same day (n=2); in ER (n=1). **

## Dose  2.5 mgpostmarketing events(events are not mutually exclusive)

## Case Example #1

**60 yo F**
**Droperidol 0.625 mg for nausea, had QT interval prolongation**

## Case Example #2

**44 yo F, 115#**
**Droperidol 1.25 mg for nausea in ER (UTI)**
**“****then suffered adverse side effects including qt prolongation, chest pain, difficulty breathing, dizziness, extreme agitation, etc.”**
**PMH: none**
**Meds: Levaquin 500 mg**

## Case Example #3

**52 yo M, Transjugular intrahepatic PSS; 6/10/94**
**IV Droperidol****	****1.25 mg 10:30, SR**
**	****	****	****	****1.25 mg 11:26, SR w/ PVC’s**
**	****	****	****	****1.25 mg 12:06, SR**
**Procedure complete 15:06, to unit 16:30**
**19:15****	****Torsades, VF, then cardiac arrest, successfully defibrillated x2 (200, 300J), no evid ischemia, expired 6/18 unrelated**
**PMH:  ETOH, cirrhosis/ascites, varices, Tob, COPD**
**Meds: Gent/Vanco, fent 550 mg total, versed 4mg total, KCl 40mEq, heparin 3000U IV****	**

## Literature

**Lischke et al, 1994: 0.1, 0.175, 0.25 mg/kg**
**	****median QTc increases: 37, 44, 58 msec**
**Guy et al 1991: **
**Case: 12.5 mg IV => TdP; rechallenge**
**Study, 55 pts, 0.25 mg/kg: QT 387  =>  423 ms**
**Reilly et al 2000:  Psych pts**
**6/37 with QTc > 456 msec**
**Droperidol signif predictor of abnl QTc**
**Frye et al 1995: 2 case reports**
**	****ICU 5-20 mg/hr, QTc 400=>476; 437=>560**

## GP hearts, GP ventric myocytes, HERG/HEK293

- Significant effect down to 10 nM (4 ng/mL) (IC50 30nM)
- Peak 60 ng/mL 1 hr after 5-mg IM (Cressman et al, 1973)
- > 11 ug/mL peak after 10 mg IV (Lehman et al, 1988)
- J. Cardiovasc Electrophys 1999; 10

## Summary

**There is good evidence of a causal relationship between droperidol and QTc prolongation/TdP.**
**QTc effect at low doses is not known.**
**QTc effect appears to be dose dependent.**
**Serious cardiac AE’s have occurred at doses at and below the lowest labeled dose – no clear safety margin**

## Risk-Benefit Analysis

**Benefits**
**Disease/symptoms being treated**
**Alternative therapies (availability, safety and efficacy)**
**Risks**
**Patient population **
**Predictability (dose, population, setting, interactions)**
**Safety margin**
**Manageability (role of labeling)**
**Reversibility**
**Nature/consequence of adverse events (TdP)**
**Incidence of adverse events**

## Incidence of adverse events (pre-approval)

**Small numbers**
**Limited population**
**Changes in clinical practice standards over time**
**Changes in regulatory standards over time**
**47 fatalities**

## Incidence of adverse events(post-marketing)

**What is the denominator?**
**Peak sales: 10 million vials in 2001**
**Moving target**
**# of exposures?  # of patients?**
**Dose/duration/setting/concomitants?**

## What is the numerator?

**Polling - what is the right question?**

## What is the numerator? (cont)

**Amar et al, Anesth Analg 2002:  412 thoracic**
**	****15% with ********1 episode VT postop (to 3-4 d)**
**O’Kelly et al, JAMA 1992**
**230 major noncardiac surgery (CAD/CAD risk)**
**44% periop freq/major V arrhyth (>30 VEB/hr, VT)**
**Forrest et al, Anesth 1992: 17,201 gen healthy**
**	****6.3% periop V dysrhyth**
**Lagasse 2002: 2 university-based practices**
**	****1:532 periop mortality (232 deaths/2 yrs)**
**Newland et al 2002:  10 yr., teaching hospital**
**	****0.2% incidence cardiac arrests (144 cases)**

## Under-reporting is expected

**Postmarketing safety reporting is **_**voluntary**_
**Approved 1970**
**Anesthesiologists do not routinely monitor QT**
**High incidence of perioperative dysrhythmias**
**Complex setting - multiple concomitants**
**Submitted reports are often incomplete**
**QT/torsades were not in AE lexicons until 1980’s**

## Probability of at least 1 event

**Incidence 1/1000**
**50 cases:  5%**
**1000 cases:  63%**
**Incidence 1/10,000**
**50 cases: 0.5%**
**1000 cases: 9.5%**
**6000 cases: 45%**

## Rule of 3	

**If no events are observed, upper bound for incidence is ******** 3/n (95% confidence).**
**To rule out events of 1/10,000 incidence with 95% confidence, a clinical trial of 30,000 would be required.**

## Alternatives

**Alternatives available from multiple drug classes**
**Different uses with regard to dose/setting/population and limitations in safety analyses make direct comparisons difficult**
**No clear safety or efficacy advantage of droperidol **

## Immediate Interventions

**Discussions with Akorn**
**Risk assessment of alternatives**
**Label changes (in cooperation with sponsor)**
**Boxed warning (second line, patient population, monitoring)**
**Indications**
**Dosage**
**DHCP letter; FDA Talk Paper**

## Importance of the label

**Regulations/FDA mandate**
**Implications of labeling**
**marketing**
**evidence of safety and effectiveness**
**safe use**
**medical liability**

## 21 CFR §201.57

## The disconnect between clinical practice and labeling

**Clinicians don’t practice according to labeling.**
**dosing and indications examples**
**cisapride example**
**How to convey new information that may call for changes in practice?**

## Ongoing/future interventions

**Ongoing risk assessment of droperidol and alternatives**
**Clinical stud(ies)**
**ALSDAC meeting**
**Dialog with practitioner community **

## Might the setting of use reduce risk?

**Monitored patients**
**Trained personnel **
**Resources for rapid intervention**
**Acute, generally single dosing**

## Factors that may increase risk in the perioperative setting

**Co-morbidities**
**Ubiquitous co-medication**
**QT monitoring is not part of routine practice**
**Use in other settings**
**fast track outpatient procedures**
**non-OR procedures (e.g. GI, cardiac, radiology)**
**unmonitored inpatient**

## Miscellaneous Issues

**Alternative drugs that prolong QT**
**Use of lower doses**
**The boxed warning is NOT about doses of droperidol <2.5 mg. **
**The use of droperidol doses less than 2.5 mg is considered OFF LABEL use**
**Adequate data have not been submitted to the Agency to make a determination of safety and efficacy at < 2.5 mg**
**The Agency is making no statement about the safety or lack of safety at these doses**

## Miscellaneous Issues (cont.)

**Emphasis on case reports**
**point:counterpoint (predisposing factors, timing, etc.)**
**The case reports were only considered to be supportive of the boxed warning.  They were not the basis for it.**
**Emphasis on lower doses**
**Significance of boxed warnings**

## Ongoing Concerns

**There is strong evidence that droperidol can cause QTc prolongation and TdP in humans**
**Outlier responses may occur down to 2.5 mg**
**Outlier responses may be associated with silent mutations and be apparently idiosyncratic**
**Predisposing mutations/polymorphisms may be as prevalent as several %**
**Difficulties in obtaining definitive safety data**