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451094F/Revised: February 2014

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DIPRIVAN

®

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(Propofol) INJECTABLE EMULSION, USP

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FOR INTRAVENOUS ADMINISTRATION

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

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 under USP standards.

Do not use if contamination is suspected. Discard unused drug product as directed

within the required time limits. 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.

There have been reports, in the literature and other public sources, of the

transmission of bloodborne pathogens (such as Hepatitis B, Hepatitis C, and HIV) from

unsafe injection practices, and use of propofol vials intended for single use on multiple

persons. DIPRIVAN Injectable Emulsion vials are never to be accessed more than once

or used on more than one person.

Reference ID: 3520825

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(See WARNINGS and DOSAGE AND ADMINISTRATION, Handling

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Procedures).

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DESCRIPTION:

DIPRIVAN

(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:

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9

O M.W.

178.27

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.

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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

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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

receptors.

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Pharmacodynamics

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

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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).

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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.

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Pharmacokinetics

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

brain, accounting for the rapid onset of anesthesia. Plasma levels initially decline rapidly as a

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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.

Reference ID: 3520825

The large contribution of distribution (about 50%) to the fall of propofol plasma levels

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.

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Adults

Propofol clearance ranges from 23 to 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.

Reference ID: 3520825

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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 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

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ADMINISTRATION).

Pediatrics

The pharmacokinetics of propofol were studied in children between 3 and 12 years of age

who received DIPRIVAN Injectable Emulsion for periods of approximately 1 to 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.

Reference ID: 3520825

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Clinical Trials

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Anesthesia and Monitored Anesthesia Care (MAC) Sedation

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Pediatric Anesthesia

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

and 2.

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TABLE 1. PEDIATRIC INDUCTION OF ANESTHESIA

Age Range

Induction Dose

Median (range)

Injection Duration

Median (range)

Birth through 16 years

2.5 mg/kg

(1 to 3.6)

20 sec.

(6 to 45)

TABLE 2. PEDIATRIC MAINTENANCE OF ANESTHESIA

Age Range

Maintenance Dosage

(mcg/kg/min)

Duration

(minutes)

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)

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Neuroanesthesia

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 to

Reference ID: 3520825

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.

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Intensive Care Unit (ICU) Sedation

Adult Patients

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

Reference ID: 3520825

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.

Reference ID: 3520825

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Pediatric Patients

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.

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