451094A/Issued: February 2008
(propofol) Injectable Emulsion
FOR IV ADMINISTRATION
Injectable Emulsion is a single-use parenteral product which contains 0.005% disodium
edetate to inhibit the rate of growth of microorganisms, for up to 12 hours, 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
(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 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.
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 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.
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 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-
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, 30-60 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
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.
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.
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..
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.
hours. The observed distribution and clearance of propofol in these children were similar to
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.
Anesthesia and Monitored Anesthesia Care (MAC) Sedation
Birth through 16 years
TABLE 2. PEDIATRIC MAINTENANCE OF ANESTHESIA
2 months to 2 years
2 to 12 years
>12 through 16 years
199 (82 – 394)
188 (12 – 1041)
161 (84 – 359)
65 (12 - 282)
69 (23 – 374)
69 (26 – 251)
DIPRIVAN Injectable Emulsion was studied in patients undergoing craniotomy for
supratentorial tumors in two clinical trials. The mean lesion size (anterior/posterior x lateral)
was 31 mm x 32 mm in one trial and 55 mm x 42 mm in the other trial respectively.
Anesthesia was induced with a median Diprivan dose of 1.4 mg/kg (range: 0.9-6.9 mg/kg)
and maintained with a median maintenance Diprivan dose of 146 mcg/kg/min (range: 68-425
mcg/kg/min). The median duration of the Diprivan maintenance infusion was 285 minutes
(range: 48-622 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.
DIPRIVAN Injectable Emulsion was compared to benzodiazepines and opioids in clinical
trials involving ICU patients. Of these, 302 received DIPRIVAN Injectable Emulsion and
comprise the overall safety database for ICU sedation.
Across all clinical studies, the mean infusion maintenance rate for all DIPRIVAN Injectable
Emulsion patients was 27 ± 21 mcg/kg/min. The maintenance infusion rates required to
maintain adequate sedation ranged from 2.8 mcg/kg/min to 130 mcg/kg/min. The infusion
rate was lower in patients over 55 years of age (approximately 20 mcg/kg/min) compared to
patients under 55 years of age (approximately 38 mcg/kg/min). Although there are reports of
reduced analgesic requirements, most patients received opioids for analgesia during
maintenance of ICU sedation. In these studies, morphine or fentanyl was used as needed for
analgesia. Some patients also received benzodiazepines and/or neuromuscular 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 19-43 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.
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.
DIPRIVAN Injectable Emulsion was evaluated in clinical trials involving patients
undergoing coronary artery bypass graft (CABG).
In post-CABG (coronary artery bypass graft) patients, the maintenance rate of propofol
administration was usually low (median 11 mcg/kg/min) due to the intraoperative
administration of high opioid doses. Patients receiving DIPRIVAN Injectable Emulsion
required 35% less nitroprusside than midazolam patients. During initiation of sedation in
post-CABG patients, a 15% to 20% decrease in blood pressure was seen in the first 60
minutes. It was not possible to determine cardiovascular effects in patients with severely
compromised ventricular function.