Droperidol Since 2001 Droperidol Since 2001 FDA Risk Assessment FDA Risk Assessment Anesthetic and Life Support Drugs Anesthetic and Life Support Drugs Advisory Committee Advisory Committee November 18, 2003 November 18, 2003 Nancy Chang, M.D. Nancy Chang, M.D. Lead Medical Officer Lead Medical Officer Division of Anesthetic, Critical Care and Division of Anesthetic, Critical Care and Addiction Drug Products Addiction Drug Products Center for Drug Evaluation and Research Center for Drug Evaluation and Research
Transcript
Droperidol Since 2001Droperidol Since 2001FDA Risk AssessmentFDA Risk AssessmentDroperidol Since 2001Droperidol Since 2001FDA Risk AssessmentFDA Risk Assessment
Anesthetic and Life Support Drugs Anesthetic and Life Support Drugs Advisory Committee Advisory Committee
November 18, 2003November 18, 2003
Nancy Chang, M.D.Nancy Chang, M.D.Lead Medical OfficerLead Medical OfficerDivision of Anesthetic, Critical Care andDivision of Anesthetic, Critical Care andAddiction Drug ProductsAddiction Drug Products
Anesthetic and Life Support Drugs Anesthetic and Life Support Drugs Advisory Committee Advisory Committee
November 18, 2003November 18, 2003
Nancy Chang, M.D.Nancy Chang, M.D.Lead Medical OfficerLead Medical OfficerDivision of Anesthetic, Critical Care andDivision of Anesthetic, Critical Care andAddiction Drug ProductsAddiction Drug Products
Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research
2Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
Droperidol - revised data sheet : cardiac arrhythmiasDroperidol - 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.
• 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.
3Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
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
4Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
5Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
– 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).
6Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
Dose Dose 2.5 mg 2.5 mgpostmarketing eventspostmarketing events(events are not mutually exclusive)(events are not mutually exclusive)
Dose Dose 2.5 mg 2.5 mgpostmarketing eventspostmarketing events(events are not mutually exclusive)(events are not mutually exclusive)
Dose Death CardiacArrest
QT Torsades
2.5 mg(n=26)
10 18 6 3
<1 mg(n=11)
5 9 2 1
Dose Death CardiacArrest
QT Torsades
2.5 mg(n=26)
10 18 6 3
<1 mg(n=11)
5 9 2 1
7Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
Case Example #1Case Example #1Case Example #1Case Example #1
60 yo FDroperidol 0.625 mg for nausea, had
QT interval prolongation
60 yo FDroperidol 0.625 mg for nausea, had
QT interval prolongation
8Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
Case Example #2Case Example #2Case Example #2Case Example #2
• 44 yo F, 115#• Droperidol 1.25 mg for nausea in ER
9Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
Case Example #3Case Example #3Case Example #3Case Example #352 yo M, Transjugular intrahepatic PSS; 6/10/94IV Droperidol 1.25 mg 10:30, SR
1.25 mg 11:26, SR w/ PVC’s1.25 mg 12:06, SR
Procedure complete 15:06, to unit 16:3019:15 Torsades, VF, then cardiac arrest, successfully
defibrillated x2 (200, 300J), no evid ischemia, expired 6/18 unrelated
10Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
• 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 reportsICU 5-20 mg/hr, QTc 400=>476; 437=>560
11Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
•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
12Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
SummarySummarySummarySummary
• 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
• 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
13Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
– 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
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
14Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
Incidence of adverse events Incidence of adverse events (pre-approval)(pre-approval)
Incidence of adverse events Incidence of adverse events (pre-approval)(pre-approval)
• Small numbers• Limited population• Changes in clinical practice
standards over time• Changes in regulatory standards
over time• 47 fatalities
• Small numbers• Limited population• Changes in clinical practice
standards over time• Changes in regulatory standards
over time• 47 fatalities
15Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
Incidence of adverse eventsIncidence of adverse events(post-marketing)(post-marketing)
Incidence of adverse eventsIncidence of adverse events(post-marketing)(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 denominator?– Peak sales: 10 million vials in 2001– Moving target– # of exposures? # of patients?– Dose/duration/setting/concomitants?
16Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
What is the numerator?What is the numerator?What is the numerator?What is the numerator?
Polling - what is the right question?Polling - what is the right question?
17Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
What is the numerator? (cont)What is the numerator? (cont)What is the numerator? (cont)What is the numerator? (cont)
• Amar et al, Anesth Analg 2002: 412 thoracic15% 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 healthy6.3% periop V dysrhyth
• Newland et al 2002: 10 yr., teaching hospital0.2% incidence cardiac arrests (144 cases)
18Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
Under-reporting is expectedUnder-reporting is expectedUnder-reporting is expectedUnder-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
• 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
19Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
Probability of at least 1 eventProbability of at least 1 eventProbability of at least 1 eventProbability of at least 1 event
20Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
Rule of 3Rule of 3Rule of 3Rule 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.
• 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.
21Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
AlternativesAlternativesAlternativesAlternatives
• 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
• 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
22Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
Immediate InterventionsImmediate 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
23Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
Importance of the labelImportance of the labelImportance of the labelImportance of the label
• Regulations/FDA mandate• Implications of labeling
– marketing– evidence of safety and effectiveness– safe use– medical liability
• Regulations/FDA mandate• Implications of labeling
– marketing– evidence of safety and effectiveness– safe use– medical liability
24Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
FDA is compelled to use warnings in labeling to describe “serious adverse reactions and potential safety hazards, limitations in use imposed by them, and steps that should be taken if they occur. The labeling shall be revised to include a warning as soon as there is reasonable evidence of an association,… a causal relationship need not be established. …Special problems, particularly those that may lead to death or serious injury, may be required…to be placed in a prominently displayed box.”
21 CFR §201.57
25Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
The disconnect between The disconnect between clinical practice and labelingclinical practice and labeling
The disconnect between The disconnect between clinical practice and labelingclinical 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?
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?
26Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
• Ongoing risk assessment of droperidol and alternatives
• Clinical stud(ies)• ALSDAC meeting• Dialog with practitioner community
27Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
Might the setting of use Might the setting of use reduce risk?reduce risk?
Might the setting of use Might the setting of use reduce risk?reduce risk?
• Monitored patients• Trained personnel • Resources for rapid intervention• Acute, generally single dosing
• Monitored patients• Trained personnel • Resources for rapid intervention• Acute, generally single dosing
28Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
Factors that may increase risk Factors that may increase risk in the perioperative settingin the perioperative setting
Factors that may increase risk Factors that may increase risk in the perioperative settingin 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
• 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
29Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
Miscellaneous IssuesMiscellaneous IssuesMiscellaneous IssuesMiscellaneous 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
•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
30Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
• 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
• 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
31Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
