451094F/Revised: February 2014
(Propofol) INJECTABLE EMULSION, USP
Injectable Emulsion is a single access parenteral product (single patient infusion vial)
which contains 0.005% disodium edetate (EDTA) to inhibit the rate of growth of
(Propofol) Injectable Emulsion, USP is a sterile, nonpyrogenic emulsion
containing 10 mg/mL of propofol suitable for intravenous administration. Propofol is
chemically described as 2,6 diisopropylphenol. The structural formula is:
Propofol is 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 to 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. DIPRIVAN Injectable Emulsion,
USP is isotonic and has a pH of 7 to 8.5.
dose of propofol induces hypnosis, with minimal excitation, usually within 40 seconds from
the start of 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, accounting for the rate of induction of anesthesia. The mechanism of action,
like all general anesthetics, is poorly understood. However, propofol is thought to produce its
sedative/anesthetic effects by the positive modulation of the inhibitory function of the
neurotransmitter GABA through the ligand-gated GABA
Pharmacodynamic properties of propofol are dependent upon the therapeutic blood propofol
concentrations. Steady-state propofol blood concentrations are generally proportional to
infusion rates. Undesirable side effects, such as cardiorespiratory depression, are likely to
occur at higher blood concentrations which result from bolus dosing or rapid increases in
infusion rates. An adequate interval (3 to 5 minutes) must be allowed between dose
adjustments in order to assess clinical effects.
The hemodynamic effects of DIPRIVAN Injectable Emulsion during induction of
anesthesia vary. If spontaneous ventilation is maintained, the major cardiovascular effect is
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), there is an increase in the incidence and the degree of
depression of cardiac output. Addition of an opioid, 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
Reference ID: 3520825
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 intravenous (IV) induction agents.
Induction of anesthesia with DIPRIVAN Injectable Emulsion is frequently associated
with apnea in both adults and pediatric patients. In adult patients who received DIPRIVAN
Injectable Emulsion (2 to 2.5 mg/kg), apnea lasted less than 30 seconds in 7% of patients, 30
to 60 seconds in 24% of patients, and more than 60 seconds in 12% of patients. In 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 to 60 seconds in 10% of patients, and more than 60 seconds in 5% of patients.
During maintenance of general anesthesia, DIPRIVAN Injectable Emulsion causes a
decrease in spontaneous minute ventilation usually associated with an increase in carbon
dioxide tension which may be marked depending upon the rate of administration and
concurrent use of other 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, and airway obstruction 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. 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
PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used
for MAC sedation (see WARNINGS).
Clinical and preclinical studies suggest that DIPRIVAN Injectable Emulsion is rarely
associated with elevation of plasma histamine levels.
Preliminary findings in patients with normal intraocular pressure indicate that
DIPRIVAN Injectable Emulsion produces a decrease in intraocular pressure which may be
associated with a concomitant decrease in systemic vascular resistance.
Clinical studies 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).
Clinical studies indicate that DIPRIVAN Injectable Emulsion does not suppress the
adrenal response to ACTH.
Animal studies and limited experience in susceptible patients have not indicated any
propensity of DIPRIVAN Injectable Emulsion to induce malignant hyperthermia.
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 of this is unknown.
result of both distribution and 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 can
occur even after long-term administration. If, however, higher than necessary infusion levels
have been maintained for a long time, propofol redistribution from fat and muscle to the
plasma can be significant and slow recovery.
The figure below illustrates the fall of plasma propofol levels following infusions of
various durations to provide ICU sedation.
following brief infusions means that after very long infusions a reduction in the infusion rate
is appropriate by as much as half the initial infusion rate in order to maintain a constant
plasma level. Therefore, 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 evaluation of sedation levels are
important during use of DIPRIVAN Injectable Emulsion infusion for ICU sedation.
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 in
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 arterial
oxygen desaturation. The higher plasma levels reflect an age-related decrease in volume of
distribution and intercompartmental clearance. Lower doses are therefore recommended for
initiation and maintenance of sedation and anesthesia in elderly patients (see DOSAGE AND
Anesthesia and Monitored Anesthesia Care (MAC) Sedation
DIPRIVAN Injectable Emulsion was studied in clinical trials which included cardiac surgical
patients. Most patients were 3 years of age or older. The majority of the patients were
healthy ASA-PS I or II patients. The range of doses in these studies are described in Tables 1
TABLE 1. PEDIATRIC INDUCTION OF ANESTHESIA
Birth through 16 years
(1 to 3.6)
2 months to 2 years
199 (82 to 394)
65 (12 to 282)
2 to 12 years
188 (12 to 1041)
69 (23 to 374)
12 through 16 years
161 (84 to 359)
69 (26 to 251)
6.9 mg/kg) and maintained with a median maintenance DIPRIVAN dose of 146 mcg/kg/min
(range: 68 to 425 mcg/kg/min). The median duration of the DIPRIVAN Injectable Emulsion
maintenance infusion was 285 minutes (range: 48 to 622 minutes).
DIPRIVAN Injectable Emulsion was administered by infusion in a controlled clinical
trial to evaluate its effect on cerebrospinal fluid pressure (CSFP). The mean arterial pressure
was maintained relatively constant over 25 minutes with a change from baseline of -4% ±
17% (mean ± SD). The change in CSFP was -46% ± 14%. As CSFP is an indirect measure
of intracranial pressure (ICP), DIPRIVAN Injectable Emulsion, when given by infusion or
slow bolus in combination with hypocarbia, is capable of decreasing ICP independent of
changes in arterial pressure.
blocking agents. During long-term maintenance of sedation, some ICU patients were
awakened once or twice every 24 hours for assessment of neurologic or respiratory function.
In Medical and Postsurgical ICU studies comparing DIPRIVAN Injectable Emulsion
to benzodiazepine infusion or bolus, there were no apparent differences in maintenance of
adequate sedation, mean arterial pressure, or laboratory findings. Like the comparators,
DIPRIVAN Injectable Emulsion reduced blood cortisol during sedation while maintaining
responsivity to challenges with adrenocorticotropic hormone (ACTH). Case reports from the
published literature generally reflect that DIPRIVAN Injectable Emulsion has been used
safely in patients with a history of porphyria or malignant hyperthermia.
In hemodynamically stable head trauma patients ranging in age from 19 to 43 years,
adequate sedation was maintained with DIPRIVAN Injectable Emulsion or morphine. There
were no apparent differences in adequacy of sedation, intracranial pressure, cerebral perfusion
pressure, or neurologic recovery between the treatment groups. In literature reports of
severely head injured patients in Neurosurgical ICUs, DIPRIVAN Injectable Emulsion
infusion and hyperventilation, both with and without diuretics, controlled intracranial pressure
while maintaining cerebral perfusion pressure. In some patients, bolus doses resulted in
decreased blood pressure and compromised cerebral perfusion pressure.
DIPRIVAN Injectable Emulsion was found to be effective in status epilepticus which
was refractory to the standard anticonvulsant therapies. For these patients, as well as for
ARDS/respiratory failure and tetanus patients, sedation maintenance dosages were generally
higher than those for other critically ill patient populations.
A single, randomized, controlled, clinical trial that evaluated the safety and effectiveness of
DIPRIVAN Injectable Emulsion versus standard sedative agents (SSA) was conducted on 327
pediatric ICU patients. Patients were randomized to receive either DIPRIVAN Injectable
Emulsion 2%, (113 patients), DIPRIVAN Injectable Emulsion 1%, (109 patients), or an SSA
(eg, lorazepam, chloral hydrate, fentanyl, ketamine, morphine, or phenobarbital). DIPRIVAN
Injectable Emulsion therapy was initiated at an infusion rate of 5.5 mg/kg/hr and titrated as
needed to maintain sedation at a standardized level. The results of the study showed an
increase in the number of deaths in patients treated with DIPRIVAN Injectable Emulsion as
compared to SSAs. Of the 25 patients who died during the trial or within the 28-day follow
up period: 12 (11% were) in the DIPRIVAN Injectable Emulsion 2% treatment group, 9 (8%
were) in the DIPRIVAN Injectable Emulsion 1% treatment group, and 4% were (4%) in the
SSA treatment group. The differences in mortality rate between the groups were not
statistically significant. Review of the deaths failed to reveal a correlation with underlying
disease status or a correlation to the drug or a definitive pattern to the causes of death.