For intravenous administration



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451094F/Revised: February 2014 



DIPRIVAN

® 



(Propofol) INJECTABLE EMULSION, USP





FOR INTRAVENOUS ADMINISTRATION 

Rx only 





Strict aseptic technique must always be maintained during handling.  DIPRIVAN 



Injectable Emulsion is a single access parenteral product (single patient infusion vial) 

10 

which contains 0.005% disodium edetate (EDTA) to inhibit the rate of growth of 

11 


microorganisms, for up to 12 hours, in the event of accidental extrinsic contamination.  

12 


However, DIPRIVAN Injectable Emulsion can still support the growth of 

13 


microorganisms, as it is not an antimicrobially preserved product under USP standards.  

14 


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

15 


within the required time limits.  There have been reports in which failure to use aseptic 

16 


technique when handling DIPRIVAN Injectable Emulsion was associated with microbial 

17 


contamination of the product and with fever, infection/sepsis, other life-threatening 

18 


illness, and/or death. 

19 


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

20 


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

21 


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

22 


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

23 


or used on more than one person. 

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Reference ID: 3520825 



(See WARNINGS and DOSAGE AND ADMINISTRATION, Handling 



Procedures). 



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: 





C

12

H



18

O   M.W. 

178.27 

10 


11 

Propofol is slightly soluble in water and, thus, is formulated in a white, oil-in-water 

12 

emulsion.  The pKa is 11.  The octanol/water partition coefficient for propofol is 6761:1 at a 



13 

pH of 6 to 8.5.  In addition to the active component, propofol, the formulation also contains 

14 

soybean oil (100 mg/mL), glycerol (22.5 mg/mL), egg lecithin (12 mg/mL); and disodium 



15 

edetate (0.005%); with sodium hydroxide to adjust pH.  DIPRIVAN Injectable Emulsion, 

16 

USP is isotonic and has a pH of 7 to 8.5. 



17 

CLINICAL PHARMACOLOGY: 

18 


General 

19 


DIPRIVAN Injectable Emulsion is an intravenous sedative-hypnotic agent for use in the 

20 


induction and maintenance of anesthesia or sedation.  Intravenous injection of a therapeutic 

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Reference ID: 3520825 

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

A

 receptors. 





Pharmacodynamics 

Pharmacodynamic properties of propofol are dependent upon the therapeutic blood propofol 



10 

concentrations.  Steady-state propofol blood concentrations are generally proportional to 

11 

infusion rates.  Undesirable side effects, such as cardiorespiratory depression, are likely to 



12 

occur at higher blood concentrations which result from bolus dosing or rapid increases in 

13 

infusion rates.  An adequate interval (3 to 5 minutes) must be allowed between dose 



14 

adjustments in order to assess clinical effects. 

15 

The hemodynamic effects of DIPRIVAN Injectable Emulsion during induction of 



16 

anesthesia vary.  If spontaneous ventilation is maintained, the major cardiovascular effect is 

17 

arterial hypotension (sometimes greater than a 30% decrease) with little or no change in heart 



18 

rate and no appreciable decrease in cardiac output.  If ventilation is assisted or controlled 

19 

(positive pressure ventilation), there is an increase in the incidence and the degree of 



20 

depression of cardiac output.  Addition of an opioid, used as a premedicant, further decreases 

21 

cardiac output and respiratory drive. 



22 

If anesthesia is continued by infusion of DIPRIVAN Injectable Emulsion, the 

23 

stimulation of endotracheal intubation and surgery may return arterial pressure towards 



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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 

10 

patients, 30 to 60 seconds in 10% of patients, and more than 60 seconds in 5% of patients. 



11 

During maintenance of general anesthesia, DIPRIVAN Injectable Emulsion causes a 

12 

decrease in spontaneous minute ventilation usually associated with an increase in carbon 



13 

dioxide tension which may be marked depending upon the rate of administration and 

14 

concurrent use of other medications (e.g., opioids, sedatives, etc.). 



15 

During monitored anesthesia care (MAC) sedation, attention must be given to the 

16 

cardiorespiratory effects of DIPRIVAN Injectable Emulsion.  Hypotension, oxyhemoglobin 



17 

desaturation, apnea, and airway obstruction can occur, especially following a rapid bolus of 

18 

DIPRIVAN Injectable Emulsion.  During initiation of MAC sedation, slow infusion or slow 



19 

injection techniques are preferable over rapid bolus administration.  During maintenance of 

20 

MAC sedation, a variable rate infusion is preferable over intermittent bolus administration in 



21 

order to minimize undesirable cardiorespiratory effects.  In the elderly, debilitated, or ASA­

22 

PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used 



23 

for MAC sedation (see WARNINGS). 

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Reference ID: 3520825 



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 

10 

dioxide tension (see Clinical Trials, Neuroanesthesia). 



11 

Clinical studies indicate that DIPRIVAN Injectable Emulsion does not suppress the 

12 

adrenal response to ACTH. 



13 

Animal studies and limited experience in susceptible patients have not indicated any 

14 

propensity of DIPRIVAN Injectable Emulsion to induce malignant hyperthermia. 



15 

Hemosiderin deposits have been observed in the livers of dogs receiving DIPRIVAN 

16 

Injectable Emulsion containing 0.005% disodium edetate over a four-week period; the clinical 



17 

significance of this is unknown. 

18 

Pharmacokinetics 

19 


The pharmacokinetics of propofol are well described by a three compartment linear model 

20 


with compartments representing the plasma, rapidly equilibrating tissues, and slowly 

21 


equilibrating tissues. 

22 


Following an IV bolus dose, there is rapid equilibration between the plasma and the 

23 


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

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Reference ID: 3520825 

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 

10 

of propofol, such that the reduction in circulating propofol is slowed and the time to 



11 

awakening is increased. 

12 

By daily titration of DIPRIVAN Injectable Emulsion dosage to achieve only the 



13 

minimum effective therapeutic concentration, rapid awakening within 10 to 15 minutes can 

14 

occur even after long-term administration.  If, however, higher than necessary infusion levels 



15 

have been maintained for a long time, propofol redistribution from fat and muscle to the 

16 

plasma can be significant and slow recovery. 



17 

The figure below illustrates the fall of plasma propofol levels following infusions of 

18 

various durations to provide ICU sedation. 



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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. 

10 

Adults 

11 


Propofol clearance ranges from 23 to 50 mL/kg/min (1.6 to 3.4 L/min in 70 kg adults).  It is 

12 


chiefly eliminated by hepatic conjugation to inactive metabolites which are excreted by the 

13 


kidney.  A glucuronide conjugate accounts for about 50% of the administered dose.  Propofol 

14 


has a steady-state volume of distribution (10-day infusion) approaching 60 L/kg in healthy 

15 


adults.  A difference in pharmacokinetics due to gender has not been observed.  The terminal 

16 


half-life of propofol after a 10-day infusion is 1 to 3 days. 

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18 

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Reference ID: 3520825 



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 

10 

distribution and intercompartmental clearance.  Lower doses are therefore recommended for 



11 

initiation and maintenance of sedation and anesthesia in elderly patients (see DOSAGE AND 

12 

ADMINISTRATION). 

13 


Pediatrics 

14 


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

15 


who received DIPRIVAN Injectable Emulsion for periods of approximately 1 to 2 hours.  The 

16 


observed distribution and clearance of propofol in these children were similar to adults. 

17 


Organ Failure 

18 


The pharmacokinetics of propofol do not appear to be different in people with chronic hepatic 

19 


cirrhosis or chronic renal impairment compared to adults with normal hepatic and renal 

20 


function.  The effects of acute hepatic or renal failure on the pharmacokinetics of propofol 

21 


have not been studied. 

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23 

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Reference ID: 3520825 



Clinical Trials 



Anesthesia and Monitored Anesthesia Care (MAC) Sedation 



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. 




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) 

10 


11 

12 


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) 

13 


14 

Neuroanesthesia 

15 


DIPRIVAN Injectable Emulsion was studied in patients undergoing craniotomy for 

16 


supratentorial tumors in two clinical trials.  The mean lesion size (anterior/posterior x lateral) 

17 


was 31 mm x 32 mm in one trial and 55 mm x 42 mm in the other trial respectively.  

18 


Anesthesia was induced with a median DIPRIVAN dose of 1.4 mg/kg (range: 0.9 to  

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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 

10 

changes in arterial pressure. 



11 

Intensive Care Unit (ICU) Sedation 

12 


Adult Patients 

13 


DIPRIVAN Injectable Emulsion was compared to benzodiazepines and opioids in clinical 

14 


trials involving ICU patients.  Of these, 302 received DIPRIVAN Injectable Emulsion and 

15 


comprise the overall safety database for ICU sedation.   

16 


Across all clinical studies, the mean infusion maintenance rate for all DIPRIVAN 

17 


Injectable Emulsion patients was 27 ± 21 mcg/kg/min.  The maintenance infusion rates 

18 


required to maintain adequate sedation ranged from 2.8 mcg/kg/min to 130 mcg/kg/min.  The 

19 


infusion rate was lower in patients over 55 years of age (approximately 20 mcg/kg/min) 

20 


compared to patients under 55 years of age (approximately 38 mcg/kg/min).  Although there 

21 


are reports of reduced analgesic requirements, most patients received opioids for analgesia 

22 


during maintenance of ICU sedation.  In these studies, morphine or fentanyl was used as 

23 


needed for analgesia.  Some patients also received benzodiazepines and/or neuromuscular 

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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. 

10 

In hemodynamically stable head trauma patients ranging in age from 19 to 43 years, 



11 

adequate sedation was maintained with DIPRIVAN Injectable Emulsion or morphine.  There 

12 

were no apparent differences in adequacy of sedation, intracranial pressure, cerebral perfusion 



13 

pressure, or neurologic recovery between the treatment groups.  In literature reports of 

14 

severely head injured patients in Neurosurgical ICUs, DIPRIVAN Injectable Emulsion 



15 

infusion and hyperventilation, both with and without diuretics, controlled intracranial pressure 

16 

while maintaining cerebral perfusion pressure.  In some patients, bolus doses resulted in 



17 

decreased blood pressure and compromised cerebral perfusion pressure.  

18 

DIPRIVAN Injectable Emulsion was found to be effective in status epilepticus which 



19 

was refractory to the standard anticonvulsant therapies.  For these patients, as well as for 

20 

ARDS/respiratory failure and tetanus patients, sedation maintenance dosages were generally 



21 

higher than those for other critically ill patient populations.  

22 

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Reference ID: 3520825 





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 

10 

compared to SSAs.  Of the 25 patients who died during the trial or within the 28-day follow­



11 

up period: 12 (11% were) in the DIPRIVAN Injectable Emulsion 2% treatment group, 9 (8% 

12 

were) in the DIPRIVAN Injectable Emulsion 1% treatment group, and 4% were (4%) in the 



13 

SSA treatment group.  The differences in mortality rate between the groups were not 

14 

statistically significant.  Review of the deaths failed to reveal a correlation with underlying 



15 

disease status or a correlation to the drug or a definitive pattern to the causes of death. 

16 



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