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Inapsine: Basis for Approval

Inapsine: Basis for Approval. Anesthetics and Life Support Drugs Advisory Committee Meeting November 18, 2002 Arthur Simone, MD, PhD Medical Officer Division of Anesthetic, Critical Care and Addiction Drug Products. Center for Drug Evaluation and Research. Overview.

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Inapsine: Basis for Approval

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  1. Inapsine: Basis for Approval Anesthetics and Life Support Drugs Advisory Committee Meeting November 18, 2002 Arthur Simone, MD, PhD Medical Officer Division of Anesthetic, Critical Care and Addiction Drug Products Center for Drug Evaluation and Research

  2. Overview • History of droperidol approval • Regulatory • Clinical • Safety • Post-marketing surveillance • European experience • American experience

  3. Initial NDA Submission • June 26, 1968 - McNeil Laboratories • Indications sought: • Sedation or tranquilization in the pre-operative, induction, maintenance, and post-operative phases of anesthesia • Neuroleptanalgesia • Prevention of nausea and vomiting

  4. Pharmacokinetic Information • No human PK data was submitted with the NDA. • Animal data was limited to an excretion study of tritiated droperidol in rats. • At 96 hours, 62% of recovered radioactive substance was found in feces; 30% in urine and 8%in the carcass and intestine; • Urinary metabolites were primarily p-fluorophenaceturic acid (60-70%) and p- fluorophenyl acetic acid (20-30%); • Fecal metabolites were not determined; • Urinary metabolites seemed to be derived from fluorobenzoyl proprionic acid that was void of tranquilizing activity.

  5. Regulatory Context • Must studies were conducted shortly after 1962 amendments to FDCA requiring demonstration of efficacy in addition to safety for approval. • Studies were completed prior to FDA publication of the Guidance on Adequate and Well-Controlled Studies.

  6. Phase II and III Trials • 54 studies, 50 investigators, 2906 patients • Used droperidol as an adjunct to anesthesia or as a component for neuroleptanalgesia • Majority of trials were uncontrolled. • Nine trials had only 1 subject. • Few trials had formal protocols

  7. Presentation of Clinical Data • Information for over-all efficacy and safety • Included tabulation and analysis of 1824/2906 patients from 44 studies • Administered during all phases of anesthesia • Special studies, e.g., otologic procedures • Included 1197 patients; some (115) were from studies included in Part I as well. • Polled opinions of investigators of studies in Parts I and II • Safety and efficacy of droperidol as a neuroleptanalgesic.

  8. Part I Studies • 44 studies/44 investigators; 1824 patients • Evaluated use pre-op, induction, maintenance, post-op • Included evaluation for prevention and treatment of nausea/vomiting • 26 studies evaluated ≤10 subjects • 5 studies had ≥70 subjects • 1470 subjects total

  9. Dosing in Part I Studies

  10. Part II Studies • “special studies” including controlled studies • 1197 patients (115 were in Part I studies) • Epinephrine Antagonism • To determine the effect of droperidol on cardiovascular alterations due to the use of epinephrine during surgical procedures. • Only BP and pulse rate were measured.

  11. Part III Studies • 50 investigators were sent questionnaires regarding the safety and efficacy of droperidol use as a pre-op med. and/or for induction phase of anesthesia. • All but one replied. • All found it to be safe and effective.

  12. Nausea/Vomiting Evidence of efficacy: • 110 patients for pneumocephalography • 11% had N/V vs. investigator’s “usual” incidence of ≥39% • Dose = 0.15 mg/kg (10.5 mg for 70 kg adult) • Average dose = 9.5 mg

  13. Nausea/Vomiting (continued) • 45 patients evaluated for quality of neuroleptanesthesia • 15 patients received 10 mg droperidol with 50-125 mg meperidine • 15 patients received 15 mg chlorpromazine with same meperidine dose; • 15 patients received 15 mg chlorpromazine with 150-250 mcg fentanyl • N/V incidences: 13% / 40% / 27%

  14. Nausea/Vomiting (continued) • Overall, 1716 patients evaluated for nausea/vomiting • Mean droperidol dose was 5-7 mg. • Incidence of nausea and/or vomiting was approximately 5%. • Only incidences in the intra- and immediate post-op periods reported.

  15. Safety (during post-op period only)

  16. Cardio-Vascular Events

  17. Patient Fatalities

  18. NDA - Amendment • April 8, 1969 • Sufficient post-operative laboratory data was submitted to satisfy the medical reviewer of safety. • Label was modified to reflect what was currently known. • Inapsine was approved by FDA as safe and effective on June 11, 1970.

  19. Approved Label • Indication: “preoperatively, during induction and during maintenance for sedation or tranquilization, for anti-anxiety activity, and for reduction of the incidence of nausea and vomiting.” • Usual Adult Dosage: • Premedication: 2.5-10.0 mg IM/IV • Induction: 2.5 mg/20-25 lbs usually IV • Maintenance: 1.25 – 2.5 mg usually IV • Dosing for nausea or vomiting was not provided.

  20. Relevance • Quality of data limited safety evaluation • Incidents of “not reported” results • Combining protocols dissimilar in terms of dose/endpoints/safety assessments/demo-graphics • 1.6% overall mortality; 1.0% within 1st 4 days post-op; 0.3% within 1st 24 hours post-op • 0.24% recorded incidence of arrhythmia/MI/ cardiac arrest • Data derived from published studies • Studies not submitted for publication generally have results not supportive of efficacy and possibly safety

  21. Relevance • Practice of medicine • Level of monitoring • Understanding of physiology • Number of drugs available • Regulation of drug development/approval • Requirements for approval • Benefit/Risk assessment

  22. Current Use Treatment of peri-operative nausea/vomiting; dose: 0.625-1.25 mg IV/IM Emergency treatment of agitated patients; dose: 2.5-10.0 mg IV/IM

  23. 2001 Labeling • Indication: Inapsine (droperidol) is indicated: • To produce tranquilization and to reduce the incidence of nausea and vomiting in surgical and diagnostic procedures. • For premedication, induction, and as an adjunct in the maintenance of general and regional anesthesia. • In neuroleptanalgesia in which Inapsine is given concurrently with an opioid analgesic, such as Sublimaze Injection, to aid in producing tranquility and decreasing anxiety and pain.

  24. 2001 Labeling • Dosage and Administration: • Adults: • Premedication – 2.5 to 10 mg IM 30-60 minutes preoperatively • Adjunct to General Anesthesia – • Induction – 2.5 mg per 20 to 25 pounds • Maintenance – 1.25 to 2.5 mg usually intravenously • Use without a general anesthetic in diagnostic procedures – 2.5 to 10 mg IM 30 – 60 minutes before the procedure. Additional 1.25 to 2.5 mg amounts may be administered • Adjunct to regional anesthesia – 2.5 to 5 mg IM or slow IV • Children, ages 2-12, 1.0 – 1.5 mg per 20-25 pounds for premedication or for induction of anesthesia.

  25. Summary • Significant data was not provided regarding absorption, distribution, metabolism or excretion of droperidol. • Cardiovascular events and mortality data from the NDA suggest possible safety concerns – not deemed significant at the time – with labeled use. • A significant portion of current use is off-label. • Dosing studies for treatment of nausea/vomiting were never performed.

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