DIPRIVAN® (propofol) Injectable Emulsion is a sterile, nonpyrogenic emulsion containing 10 mg/mL of propofol suitable for intravenous administration. Propofol is chemically described as 2,6-diisopropylphenol and has a molecular weight of 178.27. The structural and molecular formulas are:
Propofol is very slightly soluble in water and, thus, is formulated in a white, oil-in-water emulsion. The pKa is 11. The octanol/water partition coefficient for propofol is 6761:1 at a pH of 6-8.5. In addition to the active component, propofol, the formulation also contains soybean oil (100 mg/mL), glycerol (22.5 mg/mL), egg lecithin (12 mg/mL), and disodium edetate (0.005%); with sodium hydroxide to adjust pH. The DIPRIVAN Injectable Emulsion is isotonic and has a pH of 7-8.5.
STRICT ASEPTIC TECHNIQUE MUST ALWAYS BE MAINTAINED DURING HANDLING. DIPRIVAN INJECTABLE EMULSION IS A SINGLE-USE PARENTERAL PRODUCT WHICH CONTAINS 0.005% DISODIUM EDETATE TO RETARD THE RATE OF GROWTH OF MICROORGANISMS IN THE EVENT OF ACCIDENTAL EXTRINSIC CONTAMINATION. HOWEVER, DIPRIVAN INJECTABLE EMULSION CAN STILL SUPPORT THE GROWTH OF MICROORGANISMS AS IT IS NOT AN ANTIMICROBIALLY PRESERVED PRODUCT UNDER USP STANDARDS. ACCORDINGLY, STRICT ASEPTIC TECHNIQUE MUST STILL BE ADHERED TO. DO NOT USE IF CONTAMINATION IS SUSPECTED. DISCARD UNUSED PORTIONS AS DIRECTED WITHIN THE REQUIRED TIME LIMITS (SEE DOSAGE AND ADMINISTRATION, HANDLING PROCEDURES). THERE HAVE BEEN REPORTS IN WHICH FAILURE TO USE ASEPTIC TECHNIQUE WHEN HANDLING DIPRIVAN INJECTABLE EMULSION WAS ASSOCIATED WITH MICROBIAL CONTAMINATION OF THE PRODUCT AND WITH FEVER, INFECTION/SEPSIS, OTHER LIFE-THREATENING ILLNESS, AND/OR DEATH.
CLINICAL PHARMACOLOGY
General
DIPRIVAN Injectable Emulsion is an intravenous sedative-hypnotic agent for use in the induction and maintenance of anesthesia or sedation. Intravenous injection of a therapeutic dose of propofol produces hypnosis rapidly with minimal excitation, usually within 40 seconds from the start of an injection (the time for one arm-brain circulation). As with other rapidly acting intravenous anesthetic agents, the half-time of the blood-brain equilibration is approximately 1 to 3 minutes, and this accounts for the rapid induction of anesthesia.
Pharmacodynamics
Pharmacodynamic properties of propofol are dependent upon the therapeutic blood propofol concentrations. Steady state propofol blood concentrations are generally proportional to infusion rates, especially within an individual patient. Undesirable side effects such as cardiorespiratory depression are likely to occur at higher blood concentrations which result from bolus dosing or rapid increase in infusion rate. An adequate interval (3 to 5 minutes) must be allowed between clinical dosage adjustments in order to assess drug effects.
The hemodynamic effects of DIPRIVAN Injectable Emulsion during induction of anesthesia vary. If spontaneous ventilation is maintained, the major cardiovascular effects are arterial hypotension (sometimes greater than a 30% decrease) with little or no change in heart rate and no appreciable decrease in cardiac output. If ventilation is assisted or controlled (positive pressure ventilation), the degree and incidence of decrease in cardiac output are accentuated. Addition of a potent opioid (e.g., fentanyl) when used as a premedicant further decreases cardiac output and respiratory drive.
If anesthesia is continued by infusion of DIPRIVAN Injectable Emulsion, the stimulation of endotracheal intubation and surgery may return arterial pressure towards normal. However, cardiac output may remain depressed. Comparative clinical studies have shown that the hemodynamic effects of DIPRIVAN Injectable Emulsion during induction of anesthesia are generally more pronounced than with other IV induction agents traditionally used for this purpose.
Clinical and preclinical studies suggest that DIPRIVAN Injectable Emulsion is rarely associated with elevation of plasma histamine levels.
Induction of anesthesia with DIPRIVAN Injectable Emulsion is frequently associated with apnea in both adults and pediatric patients. In 1573 adult patients who received DIPRIVAN Injectable Emulsion (2 to 2.5 mg/kg), apnea lasted less than 30 seconds in 7% of patients, 30-60 seconds in 24% of patients, and more than 60 seconds in 12% of patients. In 218 pediatric patients from birth through 16 years of age assessable for apnea who received bolus doses of DIPRIVAN Injectable Emulsion (1 to 3.6 mg/kg), apnea lasted less than 30 seconds in 12% of patients, 30-60 seconds in 10% of patients, and more than 60 seconds in 5% of patients.
During maintenance, DIPRIVAN Injectable Emulsion causes a decrease in ventilation usually associated with an increase in carbon dioxide tension which may be marked depending upon the rate of administration and other concurrent medications (e.g., opioids, sedatives, etc.).
During monitored anesthesia care (MAC) sedation, attention must be given to the cardiorespiratory effects of DIPRIVAN Injectable Emulsion. Hypotension, oxyhemoglobin desaturation, apnea, airway obstruction, and/or oxygen desaturation can occur, especially following a rapid bolus of DIPRIVAN Injectable Emulsion. During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration, and during maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus administration in order to minimize undesirable cardiorespiratory effects. In the elderly, debilitated, or ASA III/IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation. (See WARNINGS.)
Clinical studies in humans and studies in animals show that DIPRIVAN Injectable Emulsion does not suppress the adrenal response to ACTH.
Preliminary findings in patients with normal intraocular pressure indicate that DIPRIVAN Injectable Emulsion anesthesia produces a decrease in intraocular pressure which may be associated with a concomitant decrease in systemic vascular resistance.
Animal studies and limited experience in susceptible patients have not indicated any propensity of DIPRIVAN Injectable Emulsion to induce malignant hyperthermia.
Studies to date indicate that DIPRIVAN Injectable Emulsion when used in combination with hypocarbia increases cerebrovascular resistance and decreases cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure. DIPRIVAN Injectable Emulsion does not affect cerebrovascular reactivity to changes in arterial carbon dioxide tension (see Clinical Trials- Neuroanesthesia).
Hemosiderin deposits have been observed in the livers of dogs receiving DIPRIVAN Injectable Emulsion containing 0.005% disodium edetate over a four-week period; the clinical significance is unknown.
Pharmacokinetics
The proper use of DIPRIVAN Injectable Emulsion requires an understanding of the disposition and elimination characteristics of propofol.
The pharmacokinetics of propofol are well described by a three compartment linear model with compartments representing the plasma, rapidly equilibrating tissues, and slowly equilibrating tissues.
Following an IV bolus dose, there is rapid equilibration between the plasma and the highly perfused tissue of the brain, thus accounting for the rapid onset of anesthesia. Plasma levels initially decline rapidly as a result of both rapid distribution and high metabolic clearance. Distribution accounts for about half of this decline following a bolus of propofol.
However, distribution is not constant over time, but decreases as body tissues equilibrate with plasma and become saturated. The rate at which equilibration occurs is a function of the rate and duration of the infusion. When equilibration occurs there is no longer a net transfer of propofol between tissues and plasma.
Discontinuation of the recommended doses of DIPRIVAN Injectable Emulsion after the maintenance of anesthesia for approximately one-hour, or for sedation in the ICU for one-day, results in a prompt decrease in blood propofol concentrations and rapid awakening. Longer infusions (10 days of ICU sedation) result in accumulation of significant tissue stores of propofol, such that the reduction in circulating propofol is slowed and the time to awakening is increased.
By daily titration of DIPRIVAN Injectable Emulsion dosage to achieve only the minimum effective therapeutic concentration, rapid awakening within 10 to 15 minutes will occur even after long-term administration. If, however, higher than necessary infusion levels have been maintained for a long time, propofol will be redistributed from fat and muscle to the plasma, and this return of propofol from peripheral tissues will slow recovery.
The figure below illustrates the fall of plasma propofol levels following ICU sedation infusions of various durations.
The large contribution of distribution (about 50%) to the fall of propofol plasma levels following brief infusions means that after very long infusions (at steady state), about half the initial rate will maintain the same plasma levels. Failure to reduce the infusion rate in patients receiving DIPRIVAN Injectable Emulsion for extended periods may result in excessively high blood concentrations of the drug. Thus, titration to clinical response and daily eva luation of sedation levels are important during use of DIPRIVAN Injectable Emulsion infusion for ICU sedation, especially of long duration.
Adults: Propofol clearance ranges from 23-50 mL/kg/min (1.6 to 3.4 L/min in 70 kg adults). It is chiefly eliminated by hepatic conjugation to inactive metabolites which are excreted by the kidney. A glucuronide conjugate accounts for about 50% of the administered dose. Propofol has a steady state volume of distribution (10-day infusion) approaching 60 L/kg in healthy adults. A difference in pharmacokinetics due to gender has not been observed. The terminal half-life of propofol after a 10-day infusion is 1 to 3 days.
Geriatrics: With increasing patient age, the dose of propofol needed to achieve a defined anesthetic end point (dose-requirement) decreases. This does not appear to be an age-related change of pharmacodynamics or brain sensitivity, as measured by EEG burst suppression. With increasing patient age pharmacokinetic changes are such that for a given IV bolus dose, higher peak plasma concentrations occur, which can explain the decreased dose requirement. These higher peak plasma concentrations in the elderly can predispose patients to cardiorespiratory effects including hypotension, apnea, airway obstruction, and/or oxygen desaturation. The higher plasma levels reflect an age-related decrease in volume of distribution and reduced intercompartmental clearance. Lower doses are thus recommended for initiation and maintenance of sedation/anesthesia in elderly patients. (See CLINICAL PHARMACOLOGY- Individualization of Dosage.)
Pediatrics: The pharmacokinetics of propofol were studied in 53 children between the ages of 3 and 12 years who received DIPRIVAN Injectable Emulsion for periods of approximately 1-2 hours. The observed distribution and clearance of propofol in these children were similar to adults.
Organ Failure: The pharmacokinetics of propofol do not appear to be different in people with chronic hepatic cirrhosis or chronic renal impairment compared to adults with normal hepatic and renal function. The effects of acute hepatic or renal failure on the pharmacokinetics of propofol have not been studied.
Clinical Trials
Anesthesia and Monitored Anesthesia Care (MAC) Sedation
DIPRIVAN Injectable Emulsion was compared to intravenous and inhalational anesthetic or sedative agents in 91 trials involving a total of 5,135 patients. Of these, 3,354 received DIPRIVAN Injectable Emulsion and comprised the overall safety database for anesthesia and MAC sedation. Fifty-five of these trials, 20 for anesthesia induction and 35 for induction and maintenance of anesthesia or MAC sedation, were carried out in the US or Canada and provided the basis for dosage recommendations and the adverse event profile during anesthesia or MAC sedation.
Pediatric Anesthesia
DIPRIVAN Injectable Emulsion was studied in 14 clinical trials involving 691 pediatric patients, including 42 cardiac surgical patients. Of the total 691 patients, 90 were less than 3 years of age and 601 were 3 years of age or older. Of these, 506 were from US/Canadian clinical trials and comprised the overall safety and efficacy database for Pediatric Anesthesia. The majority of the remaining patients were healthy ASA I/II patients. (See Table 1)
