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Droperidol Study Proposals

Droperidol Study Proposals. ANESTHETIC & LIFE SUPPORT DRUGS ADVISORY COMMITTEE November 18-19, 2003 Lex Schultheis, M.D., Ph.D. Medical Officer Division of Anesthetic, Critical Care & Addition Drug Products. Center for Drug Evaluation and Research.

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Droperidol Study Proposals

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  1. Droperidol Study Proposals ANESTHETIC & LIFE SUPPORT DRUGS ADVISORY COMMITTEE November 18-19, 2003 Lex Schultheis, M.D., Ph.D. Medical Officer Division of Anesthetic, Critical Care & Addition Drug Products Center for Drug Evaluation and Research

  2. Challenge to the Scientific Advisory Committee • Weigh the value of performing additional studies to assess the risk of dysrhythmias that may be related to droperidol. • Consider alternative study designs, outcomes and resources required.

  3. Summary of Findings • What do we know about droperidol and QTc prolongation? • Droperidol seems to prolong QTc in a dose-dependent fashion • There appear to be outlier responders

  4. What Additional Data Will Improve Safe Use of Droperidol for PONV? • The incidence of serious cardiac dysrhythmias related to droperidol. • Particular patient populations who may be at risk. • The dose-response of QTc prolongation associated with droperidol.

  5. Additional Data: continued • Interaction of droperidol with other drugs that may affect dysrhythmic properties. • The type of patient assessment needed to insure the safest use of droperidol.

  6. Three Approaches to Gather More Data • Registry of serious dysrhythmias comparing patients who receive droperidol to patients who do not receive droperidol for treatment of PONV. • Randomized trial of QTc prolongation in a patient population comparing treatment/prophylaxis with low-dose droperidol to placebo for PONV. • Thorough QTc study in volunteers. Dose-ranging, randomized, placebo controlled.

  7. Registry of Patients Managed for PONV • Estimates incidence of serious dysrhythmias • Includes all patients managed for PONV, regardless of agent used. • Captures all serious dysrhythmias in a standardized fashion. • To relate serious dysrhythmias to droperidol, large numbers of patients would have to be enrolled.

  8. Registry: Advantages • Examines incidence of serious dysrhythmias, not biomarkers. • Wide spectrum of patients and comorbidities are evaluated.

  9. Registry: Disadvantages • No randomization • High level of patient variability • Data acquisition and management nightmare • Potential to miss significant QTc prolongation without an adverse event (near miss)

  10. Randomized Trial: Design • Randomized, blinded • Droperidol (PONV doses) vs control • Treatment or prophylaxis • Enriched population to reflect actual use • Main outcomes: QTc values, serious dysrhythmias

  11. Randomized Trial: Patient Population Considerations Patients at particular risk for PONV Patients at particular risk for prolonged QTc

  12. Randomized Trial: Patient Factors Factors that may increase QTc/TdP Patients managed with droperidol • Female, young outpatients • Elderly, eye surgery • Female • Elderly • Electrolyte imbalance • Cardiac disease • P-450 inhibition • Autonomic dysfunction • Congenital long QT syndrome

  13. Randomized Trial: Advantages • Randomization • Clinically relevant population • Manageable size of dataset

  14. Randomized Trial: Disadvantages • Recruitment may be difficult. • Practical data collection requirements may reduce data completeness. • Rare events may be missed.

  15. Thorough QTc Study: Design • Expansion of crossover volunteer study • Focus on lower (PONV) doses • Consider controlled heart rate study in patients with atrial pacing • Outcome measures: QTc, dose-response

  16. Thorough QTc Study: Advantage • Complete control over randomization and dosing • Complete ECG data

  17. Thorough QTc Study: Disadvantages • Little to no benefit to participants despite potential risk • Reduced chance of detecting outliers • May be difficult to apply results to clinical practice

  18. Other Steps That May Reduce the Risk to Vulnerable Patients • Estimate interaction of droperidol with other drugs that may affect QTc prolongation. • Determine the type of patient assessment needed to insure the safest use of droperidol (screening and monitoring).

  19. Some Other QTc Prolonging Drugs • Anesthetic vapors • Other drugs used to treat PONV • Antiarrythmics • Antibiotics: erythromycin • Antimalarial or antiprotozoal: chloroquine, quinine, mefloquine, pentamidine • Gastrointestinal prokinetic: cisapride • Psychoactive, haloperidol, phenothiazines, tricyclic antidepressants • Miscellaneous: amantadine, vasopressin • Many others

  20. Can We Reduce the Risk When We Treat Patients With Droperidol? • Improve patient selection based on comorbidities or other risk factors • Improve our understanding of the role of ECG as a preadministration screen and monitor • Define the risk period after administration

  21. Summary • Each of our presented study designs is limited. • The Scientific Advisory Committee is invited to comment on the value of additional studies to understanding the potential risk of cardiac dysrhythmias that may be related to droperidol. • Elucidation of the relationship of QTc prolongation to droperidol should consider the Agency white paper (working document) on the study of QTc prolonging drugs.

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