DIPRIVAN (Propofol) INJECTABLE EMULSION, USP - Food and Drug Administration
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451094F/Revised: February 2014
2 DIPRIVAN? 3 (Propofol) INJECTABLE EMULSION, USP
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FOR INTRAVENOUS ADMINISTRATION
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Rx only
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Strict aseptic technique must always be maintained during handling. DIPRIVAN
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Injectable Emulsion is a single access parenteral product (single patient infusion vial)
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which contains 0.005% disodium edetate (EDTA) to inhibit the rate of growth of
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microorganisms, for up to 12 hours, in the event of accidental extrinsic contamination.
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However, DIPRIVAN Injectable Emulsion can still support the growth of
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microorganisms, as it is not an antimicrobially preserved product under USP standards.
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Do not use if contamination is suspected. Discard unused drug product as directed
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within the required time limits. There have been reports in which failure to use aseptic
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technique when handling DIPRIVAN Injectable Emulsion was associated with microbial
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contamination of the product and with fever, infection/sepsis, other life-threatening
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illness, and/or death.
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There have been reports, in the literature and other public sources, of the
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transmission of bloodborne pathogens (such as Hepatitis B, Hepatitis C, and HIV) from
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unsafe injection practices, and use of propofol vials intended for single use on multiple
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persons. DIPRIVAN Injectable Emulsion vials are never to be accessed more than once
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or used on more than one person.
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Reference ID: 3520825
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(See WARNINGS and DOSAGE AND ADMINISTRATION, Handling
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Procedures).
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DESCRIPTION:
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DIPRIVAN? (Propofol) Injectable Emulsion, USP is a sterile, nonpyrogenic emulsion
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containing 10 mg/mL of propofol suitable for intravenous administration. Propofol is
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chemically described as 2,6 diisopropylphenol. The structural formula is:
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C12H18O
M.W. 178.27
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Propofol is slightly soluble in water and, thus, is formulated in a white, oil-in-water
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emulsion. The pKa is 11. The octanol/water partition coefficient for propofol is 6761:1 at a
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pH of 6 to 8.5. In addition to the active component, propofol, the formulation also contains
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soybean oil (100 mg/mL), glycerol (22.5 mg/mL), egg lecithin (12 mg/mL); and disodium
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edetate (0.005%); with sodium hydroxide to adjust pH. DIPRIVAN Injectable Emulsion,
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USP is isotonic and has a pH of 7 to 8.5.
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CLINICAL PHARMACOLOGY:
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General
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DIPRIVAN Injectable Emulsion is an intravenous sedative-hypnotic agent for use in the
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induction and maintenance of anesthesia or sedation. Intravenous injection of a therapeutic
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Reference ID: 3520825
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dose of propofol induces hypnosis, with minimal excitation, usually within 40 seconds from
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the start of injection (the time for one arm-brain circulation). As with other rapidly acting
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intravenous anesthetic agents, the half-time of the blood-brain equilibration is approximately
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1 to 3 minutes, accounting for the rate of induction of anesthesia. The mechanism of action,
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like all general anesthetics, is poorly understood. However, propofol is thought to produce its
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sedative/anesthetic effects by the positive modulation of the inhibitory function of the
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neurotransmitter GABA through the ligand-gated GABAA receptors.
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Pharmacodynamics
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Pharmacodynamic properties of propofol are dependent upon the therapeutic blood propofol
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concentrations. Steady-state propofol blood concentrations are generally proportional to
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infusion rates. Undesirable side effects, such as cardiorespiratory depression, are likely to
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occur at higher blood concentrations which result from bolus dosing or rapid increases in
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infusion rates. An adequate interval (3 to 5 minutes) must be allowed between dose
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adjustments in order to assess clinical effects.
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The hemodynamic effects of DIPRIVAN Injectable Emulsion during induction of
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anesthesia vary. If spontaneous ventilation is maintained, the major cardiovascular effect is
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arterial hypotension (sometimes greater than a 30% decrease) with little or no change in heart
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rate and no appreciable decrease in cardiac output. If ventilation is assisted or controlled
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(positive pressure ventilation), there is an increase in the incidence and the degree of
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depression of cardiac output. Addition of an opioid, used as a premedicant, further decreases
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cardiac output and respiratory drive.
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If anesthesia is continued by infusion of DIPRIVAN Injectable Emulsion, the
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stimulation of endotracheal intubation and surgery may return arterial pressure towards
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Reference ID: 3520825
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normal. However, cardiac output may remain depressed. Comparative clinical studies have
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shown that the hemodynamic effects of DIPRIVAN Injectable Emulsion during induction of
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anesthesia are generally more pronounced than with other intravenous (IV) induction agents.
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Induction of anesthesia with DIPRIVAN Injectable Emulsion is frequently associated
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with apnea in both adults and pediatric patients. In adult patients who received DIPRIVAN
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Injectable Emulsion (2 to 2.5 mg/kg), apnea lasted less than 30 seconds in 7% of patients, 30
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to 60 seconds in 24% of patients, and more than 60 seconds in 12% of patients. In pediatric
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patients from birth through 16 years of age assessable for apnea who received bolus doses of
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DIPRIVAN Injectable Emulsion (1 to 3.6 mg/kg), apnea lasted less than 30 seconds in 12% of
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patients, 30 to 60 seconds in 10% of patients, and more than 60 seconds in 5% of patients.
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During maintenance of general anesthesia, DIPRIVAN Injectable Emulsion causes a
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decrease in spontaneous minute ventilation usually associated with an increase in carbon
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dioxide tension which may be marked depending upon the rate of administration and
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concurrent use of other medications (e.g., opioids, sedatives, etc.).
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During monitored anesthesia care (MAC) sedation, attention must be given to the
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cardiorespiratory effects of DIPRIVAN Injectable Emulsion. Hypotension, oxyhemoglobin
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desaturation, apnea, and airway obstruction can occur, especially following a rapid bolus of
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DIPRIVAN Injectable Emulsion. During initiation of MAC sedation, slow infusion or slow
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injection techniques are preferable over rapid bolus administration. During maintenance of
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MAC sedation, a variable rate infusion is preferable over intermittent bolus administration in
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order to minimize undesirable cardiorespiratory effects. In the elderly, debilitated, or ASA
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PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used
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for MAC sedation (see WARNINGS).
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Reference ID: 3520825
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Clinical and preclinical studies suggest that DIPRIVAN Injectable Emulsion is rarely
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associated with elevation of plasma histamine levels.
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Preliminary findings in patients with normal intraocular pressure indicate that
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DIPRIVAN Injectable Emulsion produces a decrease in intraocular pressure which may be
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associated with a concomitant decrease in systemic vascular resistance.
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Clinical studies indicate that DIPRIVAN Injectable Emulsion when used in
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combination with hypocarbia increases cerebrovascular resistance and decreases cerebral
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blood flow, cerebral metabolic oxygen consumption, and intracranial pressure. DIPRIVAN
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Injectable Emulsion does not affect cerebrovascular reactivity to changes in arterial carbon
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dioxide tension (see Clinical Trials, Neuroanesthesia).
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Clinical studies indicate that DIPRIVAN Injectable Emulsion does not suppress the
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adrenal response to ACTH.
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Animal studies and limited experience in susceptible patients have not indicated any
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propensity of DIPRIVAN Injectable Emulsion to induce malignant hyperthermia.
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Hemosiderin deposits have been observed in the livers of dogs receiving DIPRIVAN
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Injectable Emulsion containing 0.005% disodium edetate over a four-week period; the clinical
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significance of this is unknown.
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Pharmacokinetics
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The pharmacokinetics of propofol are well described by a three compartment linear model
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with compartments representing the plasma, rapidly equilibrating tissues, and slowly
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equilibrating tissues.
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Following an IV bolus dose, there is rapid equilibration between the plasma and the
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brain, accounting for the rapid onset of anesthesia. Plasma levels initially decline rapidly as a
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Reference ID: 3520825
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