Droperidol Since 2001 FDA Risk Assessment

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Droperidol Since 2001FDA 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
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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.

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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
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Postmarketing spontaneous reports

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

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QT and/or Torsadespostmarketing events

• 22 cases, at least 5 fatal
• 14 torsades (incl 6 with QT)
• Route injection (n20) oral (n1) unk (n1)
• Dose for single inj. (N13)
• 0.625 (n2) 1.25 (n2) 2.5 (n3)
• 3.75-5 (n2) 12.5 (n1) 21-25 (n3)
• Onset (N14) immed-several minutes (n4) 10 min
  (n3) 4-12 hours (n3) same day (n2) in ER
  (n1).

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Dose ? 2.5 mgpostmarketing events(events are
not mutually exclusive)
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Case Example 1

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

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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

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Case Example 3

• 52 yo M, Transjugular intrahepatic PSS 6/10/94
• IV Droperidol 1.25 mg 1030, SR
• 1.25 mg 1126, SR w/ PVCs
• 1.25 mg 1206, SR
• Procedure complete 1506, to unit 1630
• 1915 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

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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 gt TdP rechallenge
• Study, 55 pts, 0.25 mg/kg QT 387 gt 423 ms
• Reilly et al 2000 Psych pts
• 6/37 with QTc gt 456 msec
• Droperidol signif predictor of abnl QTc
• Frye et al 1995 2 case reports
• ICU 5-20 mg/hr, QTc 400gt476 437gt560

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• 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)
• gt 11 ug/mL peak after 10 mg IV (Lehman et al,
  1988)
• J. Cardiovasc Electrophys 1999 10

Acrobat Document
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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 AEs have occurred at doses at
  and below the lowest labeled dose no clear
  safety margin

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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

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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

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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?

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What is the numerator?

• Polling - what is the right question?

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What is the numerator? (cont)

• Amar et al, Anesth Analg 2002 412 thoracic
• 15 with ?1 episode VT postop (to 3-4 d)
• OKelly et al, JAMA 1992
• 230 major noncardiac surgery (CAD/CAD risk)
• 44 periop freq/major V arrhyth (gt30 VEB/hr, VT)
• Forrest et al, Anesth 1992 17,201 gen healthy
• 6.3 periop V dysrhyth
• Lagasse 2002 2 university-based practices
• 1532 periop mortality (232 deaths/2 yrs)
• Newland et al 2002 10 yr., teaching hospital
• 0.2 incidence cardiac arrests (144 cases)

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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 1980s

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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

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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.

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Alternatives

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

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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

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Importance of the label

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

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21 CFR 201.57
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The disconnect between clinical practice and
labeling

• Clinicians dont practice according to labeling.
• dosing and indications examples
• cisapride example
• How to convey new information that may call for
  changes in practice?

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Ongoing/future interventions

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

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Might the setting of use reduce risk?

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

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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

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Miscellaneous Issues

• Alternative drugs that prolong QT
• Use of lower doses
• The boxed warning is NOT about doses of
  droperidol lt2.5 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 lt 2.5 mg
• The Agency is making no statement about the
  safety or lack of safety at these doses

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Miscellaneous Issues (cont.)

• Emphasis on case reports
• pointcounterpoint (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

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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