# Presentation: 804313

## 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

**History of droperidol approval**
**Regulatory **
**Clinical**
**Safety**
**Post-marketing surveillance**
**European experience**
**American experience**

## 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**

## 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.**

## 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.**

## 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**

## 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.**

## 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**

## Dosing in Part I Studies

| Period | No. of Patients | Dose Range
(mg) | Mean Dose
Range
(mg) | Incidents 
of route 
“Not Reported” |
| --- | --- | --- | --- | --- |
| Pre-Op | 853 | 0.2-20.0 | 5.0-7.0 | 273 |
| Induction | 1032 | 0.4-35.0 | 4.8-16.9 | 38 |
| Maintenance | 505 | 1.0-35.0 | 4.2-16.9 | 15 |
| Post-Op | 2 | 5 | 5 | 0 |

## 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.**

## 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.**

## 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**

## 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%**

## 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.**

## Safety (during post-op period only)

| Adverse Event | Droperidol Alone | w/ Innovar | w/ Fentanyl | w/ both agents |
| --- | --- | --- | --- | --- |
| Tachycardia | 1 |  | 2 |  |
| Irregular Pulse | 1 |  |  |  |
| Hypertension |  |  | 1 |  |
| C-V Depression | 28 | 3 | 9 | 2 |
| Fibrillation |  |  | 1 |  |
| Pulmonary Edema | 1 |  |  |  |
| Embolism | 1 |  |  |  |

## Cardio-Vascular Events

| Event | Number |
| --- | --- |
| Hypotension | 61+ |
| Hypertension | 26+ |
| Bradycardia | 83 |
| Tachycardia | 39 |
| Arrhythmia | 5 |
| Myocardial Infarct/Arrest | 1 prob./1 |

## Patient Fatalities

| Time of Death | Number |
| --- | --- |
| Pre-operative | 0 |
| Intra-operative | 6 |
| Immediate Post-operative   [1st 24hrs.] | 3 |
| Post-operative            [25th hr - 4th day] | 19 |
| Late Post-operative       [5th – 21st day] | 9 |
| Remote Post-operative       [≥22nd day] | 5 |
| Not Reported | 5 |
| Total | 47 |

## 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.**

## 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.**

## 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 1****st**** 4 days post-op; 0.3% within 1****st**** 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**

## 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**

## 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**

## 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.**

## 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.**

## 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.**