Propofol (Systemic)


VA CLASSIFICATION
Primary: CN203
Secondary: CN206; CN309

Commonly used brand name(s): Diprivan.

Another commonly used name is
disoprofol {03} {06} .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Anesthetic, general—

anesthesia adjunct—

sedative-hypnotic—

Indications

Accepted

Anesthesia, general or
Anesthesia, general, adjunct—Propofol is indicated for the induction of general anesthesia in adults and in pediatric patients greater than 3 years of age.{57}{01}{04}{09}{10}It is also indicated for maintenance of anesthesia utilizing balanced techniques with other appropriate agents such as opioids and inhalation anesthetics in adults and pediatric patients greater than 2 months of age.{57}{01}

Sedation—Propofol is indicated for sedation in critically ill patients confined to intensive care units {04} {06} {08} {10} {13}.
—Propofol is indicated to produce sedation or amnesia as a supplement to local or regional anesthetics {04} {10}, and in diagnostic procedures, such as endoscopy {06} {10} {15} (i.e., Monitored Anesthesia Care [MAC]).
—Although cardiovascular, respiratory, and sedative effects must be carefully monitored {04} {06}, propofol provides good control of depth of sedation {10}, and the rapid return of spontaneous ventilation following discontinuation of propofol infusion allows early extubation {13} {14} {41}. Tachyphylaxis, delayed awakening, or cumulative effects have not been reported after prolonged administration of propofol as they have with prolonged infusion of thiopental, diazepam, or midazolam. In addition, propofol does not suppress adrenocortical function {06} {11} {13} {16} as does etomidate {04} {10}.

Unaccepted
Propofol is not indicated in pediatric patients for monitored anesthesia care (MAC) sedation or for sedation in intensive care.{57}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    178.28 {02}


pH
    Propofol emulsion: 7 to 8.5 {01} {04}.

Mechanism of action/Effect:

Propofol is a short-acting hypnotic {01} {04} {09} {12} {15}. Its mechanism of action has not been well-defined {11}.


Other actions/effects:


Hemodynamic effects:

Propofol's hemodynamic effects are generally more pronounced than those of other intravenous anesthetic agents {01} {06} {08}. Arterial hypotension, with readings decreased by as much as 30% or more {01} {04} {06} {08} {15}, has been reported, possibly due to inhibition of sympathetic vasoconstrictor nerve activity {42}. Hypotensive effects are generally proportional to dose and rate of administration of propofol {04} {08} {09}, and may be potentiated by opioid analgesics {01} {04} {08}. Endotracheal intubation and surgical stimulation may increase arterial pressure {01} {06} {10} {11}; increases in heart rate and/or blood pressure to greater than baseline values, which occur frequently with other agents, are not as significant with propofol, possibly due to central sympatholytic and/or vagotonic effects {04}. Propofol may also decrease systemic vascular resistance {04} {06} {08} {10} {11} {24}, myocardial blood flow, and oxygen consumption {04}. The mechanism of these effects may involve direct vasodilation {04} {06} {10} and negative inotropy {04} {10}. Effects such as decreased stroke volume and cardiac output have been demonstrated in some studies {01} {04} {06} {10}.



Respiratory effects:

Propofol is a respiratory depressant, frequently producing apnea that may persist for longer than 60 seconds {01} {06} {08} {10} {11} {15}, depending on factors such as premedication {04} {08} {10}, rate of administration {10}, dose administered {04} {10}, and presence of hyperventilation or hyperoxia {10}. In addition, propofol may produce significant decreases in respiratory rate {10}, minute volume {06} {10}, tidal volume {06} {10}, mean inspiratory flow rate {06}, and functional residual capacity {06}. These respiratory depressant effects may be the result of depression of the central inspiratory drive as opposed to a change in central timing {06}. The ventilatory depressant effects of propofol may be counteracted by painful surgical stimulation {06}.



Cerebral effects:

Propofol decreases cerebral blood flow {01} {06} {10} {36}, cerebral metabolic oxygen consumption {01} {10} {36}, and intracranial pressure {01} {10}, and increases cerebrovascular resistance {01} {06} {10}. It does not appear to affect cerebrovascular reactivity to changes in arterial carbon dioxide tension {01} {06} {10} {39}.



Other effects:

Preliminary findings suggest that in patients with normal intraocular pressure, propofol decreases intraocular pressure {01} {10} {11} by as much as 30 to 50% {04} {06}. This decrease may be associated with a concomitant decrease in systemic vascular resistance {01}.

Clinical studies have shown that propofol does not cause significant signs of histamine release {01} {04} {06} {08} {16} or significant increases in plasma immunoglobulin or complement C 3 levels {06}. Respiratory resistance after tracheal intubation is lower when propofol is used for induction of anesthesia than when thiopental or high-dose etomidate is used for induction of anesthesia {48}.

Although propofol has the potential for affecting adrenal steroidogenesis {06}, it does not appear to block cortisol and aldosterone secretion in response to surgical stress or adrenocorticotropic hormone (ACTH) in clinical practice {01} {06} {08} {10} {11} {13} {16} {24}. Although transient decreases in plasma cortisol concentrations have occurred, these reductions have not been sustained {08} {10}.

Propofol appears to have no analgesic activity {06}. In addition, animal studies have demonstrated no significant effect on coagulation profiles {06} {08} {24}.

Limited experience with propofol in susceptible patients and animal studies has not demonstrated a propensity to induce malignant hyperthermia {01}.

Propofol has antiemetic properties {10} {43} {47}. Anesthesia with propofol results in less nausea and vomiting than anesthesia with desflurane, enflurane, isoflurane, methohexital, nitrous oxide, or thiopental {10} {16} {44} {45} {46}.


Distribution:

Propofol is rapidly {08} {10} {12} {14} and extensively {04} {10} {12} {14} distributed in the body. It crosses the blood-brain barrier quickly {09}, and its short duration of action is due to rapid redistribution from the CNS to other tissues {01} {09} {12}, high metabolic clearance {01} {04}, and high lipophilicity {04} {10} {11} {12} {14}.


Volumes of distribution:

Initial apparent (Vol D): 13 to 76 liters (L) {04} {10} {11} {12}.

Steady-state (Vol DSS): 171 to 349 L {10} {12}.

Elimination (Vol D): 209 to 1008 L {10} {11}.

Steady-state (Vol DSS) in pediatric patients: 9.5 ± 3.71 liters per kg of body weight (L/kg) {54}.


Protein binding:

Very high (95 to 99%) {04} {12}.

Biotransformation:

Hepatic {01} {04} {08} {11} {12} {22}; rapidly undergoes glucuronide conjugation to inactive metabolites {01} {04} {08} {10}. An unidentified route of extrahepatic metabolism may also exist, suggested by the fact that propofol clearance exceeds estimated hepatic blood flow {01} {04} {06} {10} {11} {12} {14}.

Half-life:


Distribution:


Two distribution phases—

Rapid—2 to 4 minutes {04} {10}.

Slower—30 to 64 minutes {01} {04} {12}.




Elimination:

Terminal elimination half-life is 3 to 12 hours {01} {09} {10} {11} {12}; prolonged administration of propofol may result in a longer duration {01} {09}.

Note: The long terminal elimination half-life of propofol does not reflect elimination, as more than 70% is eliminated during the first 2 phases {12}. Some investigators believe that the second exponential phase half-life (30 to 64 minutes) best explains the properties of propofol in clinical practice {12}.




Other:

Blood-brain equilibration half-life: 2.9 minutes {04} {10} {12}.


Onset of action:

Loss of consciousness occurs rapidly and smoothly, usually within 40 seconds (one arm-brain circulation time) from the start of intravenous injection of propofol {01} {04} {06} {08} {09} {10} {12}. Loss of consciousness is dependent on the dose administered, the rate of administration, and the extent of premedication {04} {10}.

Plasma concentrations

Propofol concentrations of 1.5 to 6 mcg per mL (8.42 to 33.66 micromoles per liter [micromoles/L]) will maintain hypnosis, although needs vary with type of surgery and use of other anesthetic agents {04}.

Duration of action:

Mean duration following a single bolus dose of 2 to 2.5 mg per kg of body weight is 3 to 5 minutes {04} {09}.

Time to recovery

Recovery from anesthesia with propofol is rapid {01} {06} {08} {09} {10} {11} {12} {15}, with minimal psychomotor impairment {10}. Emergence following induction (with 2 to 2.5 mg of propofol per kg) and maintenance (with 0.1 to 0.2 mg of propofol per kg per minute) for up to 2 hours occurs in most patients within 8 minutes {01} {04} {11}. If an opioid has been used, recovery may take up to 19 minutes {06}.

Recovery occurs faster than recovery following the use of etomidate {20}, methohexital {04}, midazolam {21}, or thiopental {04} {20}. When anesthesia has included use of an opioid with propofol, recovery has occurred more quickly than with similar use of etomidate {06}, midazolam {08}, or thiopental {09}.

Many investigators have noted clearheadedness in patients emerging from propofol anesthesia {04} {06} {08} {09} {15}, and less residual impairment of performance than in patients who received methohexital has been reported {10}.

Elimination:
    Renal {01} {22}; approximately 70% of a dose is excreted in the urine within 24 hours after administration, and 90% is excreted within 5 days {01}. Clearance of propofol ranges from 1.6 to 3.4 liters per minute in healthy 70 kg patients {01}. As the age of the patient increases, total body clearance of propofol may decrease {01} {04} {06} {10} {11} {12}. Clearance rates ranging from 1.4 to 2.2 liters per minute in patients 18 to 35 years of age have been reported, in contrast to clearance rates of 1 to 1.8 liters per minute in patients 65 to 80 years of age {01}.

Note: Pharmacokinetic parameters of propofol appear to be unaffected by gender {01} {10} {12}, obesity {12}, chronic hepatic cirrhosis {01} {25}, and chronic renal failure {01} {12} {22}.



Precautions to Consider

Carcinogenicity

Studies have not been done {01}.

Mutagenicity

The Ames mutation test using Salmonella species, gene mutation/gene conversion using Saccharomyces cerevisiae , cytogenetic studies in Chinese hamsters, and a mouse micronucleus test have failed to demonstrate mutagenic potential by propofol {01}.

Pregnancy/Reproduction
Fertility—
Studies in rats given doses up to 6 times the human dose for varying lengths of time have shown no evidence of impaired fertility {01}.

Pregnancy—
Propofol crosses the placenta. Adequate and well-controlled studies in humans have not been done.

Studies in animals have shown propofol to cause increased maternal deaths in rats and rabbits and decreased pup survival during the lactating period when the dams received 6 times the recommended human dose {01}.

FDA Pregnancy Category B {01}.


Labor and delivery—

A study was conducted in 74 patients comparing the use of propofol with that of thiamylal-isoflurane for induction and maintenance of anesthesia during cesarean section. The study did not show any problems in the mothers or in the neonates with the use of propofol {55}. There was no difference between the neonates in the two groups in Apgar scores or the neurological and adaptive capacity scores (NACS) {55}. However, the manufacturer states that use of propofol is not recommended since data are insufficient to support its use in obstetrics, including cesarean section deliveries {01}.

Breast-feeding

Propofol is distributed into breast milk {01} {06}. However, the effects of oral administration of small amounts of propofol are not known {01}.

Pediatrics

Appropriate studies with propofol for sedation have not been performed in the pediatric population. There are case reports in the medical literature of pediatric patients developing metabolic acidosis after receiving propofol for sedation in the intensive care unit (ICU) {01} {30} {56}. Rarely, deaths have occurred {01} {30} {56}. The role of propofol in these deaths is controversial {01}. Other causes of metabolic acidosis could not be ruled out, and a causal relationship could not be established {01}.

Note: Propofol is approved by the FDA for use in pediatric patients 3 years of age and older for induction of anesthesia and as a component of balanced anesthesia {01}, and in pediatric patients 2 months of age and older for maintenance of anesthesia and as a component of balanced anesthesia{57}.



Geriatrics


Dosage requirements are lower in geriatric patients than in younger adult patients, probably due to pharmacokinetic differences rather than pharmacodynamic differences in geriatric patients {01} {12}. Lower induction doses and a slower maintenance infusion rate should be used in geriatric patients {01} {12}, due to reduced total body clearance {04} {06} {10} {11} and volume of distribution {04} {10} {23} in these patients.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Alcohol or
» CNS depression–producing medications, other, including those commonly used for preanesthetic medication or induction or supplementation of anesthesia (see Appendix II )    (concurrent administration may increase the CNS-depressant, respiratory-depressant, or hypotensive effects of propofol, as well as decreasing anesthetic requirements and prolonging recovery from anesthesia; dosage adjustments may be required {01} {06} {10} {12} {13} {33} {34} {40}; propofol may also decrease the emetic effects of some opioid drugs {33})


Droperidol    (droperidol may compete with propofol for binding sites in the chemoreceptor trigger zone; concurrent use of propofol and droperidol to control nausea and vomiting is less effective than using propofol alone{17})


Fentanyl    (concomitant administration of fentanyl in pediatric patients may result in serious bradycardia{57})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Circulatory disorders {01} or
Compromised cardiovascular function {04} {06} {10} {11}    (may be aggravated by cardiovascular-depressant and hypotensive effects )


Disorders of lipid metabolism, such as primary hyperlipoproteinemia, diabetic hyperlipemia, or pancreatitis {01}    (may be aggravated by emulsion vehicle of propofol)


Increased intracranial pressure {01} {06} or
Impaired cerebral circulation {01}    (substantial decreases in mean arterial pressure and cerebral perfusion may occur)


Sensitivity to propofol or its emulsion vehicle {01}
Caution is also recommended in geriatric, debilitated, and/or hypovolemic patients, because they may require lower induction and maintenance doses {01} {04} {06} {10} .


Side/Adverse Effects

Note: Postoperative infections and subsequent deaths have been reported following the use of propofol that was not administered using strict aseptic technique {19} {26}.
Rarely, a clinical syndrome including bronchospasm, erythema, and hypotension has occurred shortly after administration of propofol {01}, and sequelae including anoxic brain damage and death have been reported {31}; concurrent use of other agents makes a causal relationship unclear {01}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Apnea{01}{08}{09}{10}{11}{23}
    
bradycardia{01}{06}{09}{10}
    
hypotension{01}{04}{06}{09}{10}

Incidence less frequent or rare
    
Hypertension{01}
    
perioperative myoclonia, rarely including opisthotonus{01}
    
pancreatitis{01}{35} (abdominal pain)—symptoms may not occur until after discharge from medical care following use of propofol



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Involuntary muscle movements, temporary{01}{06}{08}{10}{11}{15}{16}
    
nausea and/or vomiting{01}{06}{15}{16}
    
pain, burning, or stinging at injection site{01}{04}{06}{08}{09}{10}{11}{15}{16}{23}

Note: Excitatory movements reportedly occur more often than with thiopental {04} {08} {16} but less often than with etomidate {08} or methohexital {04} {08} {10} {16}.
Pain is usually mild and short-lived {04}, and may be decreased by using the larger veins of the forearm or the antecubital fossa {01} {04} {06} {09} {10} {11} {15} {16} or a dedicated intravenous catheter {01}. Pain may be decreased by prior intravenous injection of 10 to 20 mg of lidocaine {01} {04} {09} {16}. Post-injection thrombosis or phlebitis is rare {01} {04} {06} {08} {11}.


Incidence less frequent or rare
    
Abdominal cramping{01}
    
cough{01}{15}{16}
    
dizziness{01}
    
fever{01}
    
flushing{01}{16}
    
headache{01}{06}{15}{16}
    
hiccups{01}{06}
    
tingling, numbness, or coldness at injection site{01}{15}





Overdose
For specific information on the management of a propofol overdose, see:    • Atropine in Anticholinergics/Antispasmodics monograph; and/or
   • Sympathomimetic Agents—Cardiovascular Use (Parenteral-Systemic) monograph.


For more information on the management of overdose, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
    
Cardiovascular depression
    
respiratory depression


Treatment of overdose


Specific treatment:
Discontinuation of propofol {01}.

For respiratory depression: artificial ventilation with oxygen {01}.

For cardiovascular depression: elevation of legs, increasing flow rate of intravenous fluids, and administration of pressor agents and/or anticholinergic agents {01}.



Monitoring:
Patients should be continuously monitored for signs of significant hypotension and/or bradycardia.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Anesthetics, General (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to propofol or its emulsion vehicle

Pregnancy—Propofol crosses the placenta

Use of propofol is not recommended in labor and delivery because data are insufficient to support its use in obstetrics




Use in children—Propofol should not be used for sedation in pediatric intensive care unit patients or for monitored anesthesia care (MAC) sedation in pediatric patients because safety and efficacy have not been established






Use in the elderly—Lower induction and maintenance doses are recommended
Other medications, especially other CNS depressants

Proper use of this medication

Proper dosing

Precautions after receiving this medication
Possibility of psychomotor impairment following use of anesthetics; for about 24 hours following anesthesia, using added caution in driving or performing other tasks requiring alertness and coordination

Avoiding use of alcohol or other CNS depressants within 24 hours following anesthesia except as directed by physician or dentist


Side/adverse effects
Signs of potential side effects, especially pancreatitis


General Dosing Information
Propofol should be administered only by individuals qualified in the use of general anesthetics. Appropriate resuscitative and endotracheal intubation equipment, oxygen, and medications for prevention and treatment of anesthetic emergencies must be immediately available. Airway patency must be maintained at all times.

Propofol emulsion is for intravenous administration only. Although clinical experience and animal studies have shown that inadvertent intra-arterial injection of propofol usually produces minimal tissue reaction, intra-arterial injection of propofol is not recommended {01}.

To minimize the pain, burning, or stinging patients may experience at the site of injection of propofol, a larger vein of the forearm or the antecubital fossa may be used as the infusion site {01}. Pretreatment of the injection site with one mL of 1% lidocaine may also decrease the incidence of this side effect {01}.

Dosage of propofol must be individualized for each patient {01}, with the dose titrated to achieve the desired clinical effect {01} {04} {09} {10}. Lower doses are usually required for elderly, debilitated, or higher risk surgical patients, or those with circulatory disorders {01} {10}. The dosage of intravenously administered propofol should be adjusted according to the type and amount of premedication used {01}.

Rapid intravenous injection of propofol should not be used in elderly, debilitated, hypovolemic, or higher risk surgical patients. Rapid intravenous injection of propofol in these patients may result in cardiopulmonary depression including hypotension, apnea, airway obstruction and/or oxygen desaturation {01}.

When propofol is administered by infusion, it is recommended that drop counters, syringe pumps, or volumetric pumps be utilized to control infusion rates {01}.

When nitrous oxide, oxygen, and propofol are used for maintenance of general anesthesia, supplemental analgesic agents are generally required; neuromuscular blocking agents may also be required {01}. Concurrent use of propofol with neuromuscular blocking agents does not significantly alter the onset, intensity, or duration of action of these agents {01}.

Propofol injection contains 0.005% disodium edetate, but it is not an antimicrobially preserved product under USP standards. The vehicle is capable of supporting the rapid growth of microorganisms {01} {19}, and particulate or bacterial contamination may be difficult to detect because propofol injection is opaque {27}. Rarely, failure to use strict aseptic technique has resulted in sepsis in patients to whom contaminated solution was administered. Therefore, strict aseptic technique must be maintained {01} {19}, and propofol injection should be administered promptly after opening {01}. Unused portions of the injection, as well as reservoirs, intravenous lines, or solutions containing propofol injection, must be discarded at the end of the procedure or within 12 hours (6 hours if propofol was transferred from the original container) {01}.

Propofol should not be infused through filters with pore size smaller than 5 microns because infusion through a smaller filter may cause breakdown of the emulsion {01}.


Parenteral Dosage Forms

PROPOFOL INJECTABLE EMULSION

Usual adult and adolescent dose
Dosage must be individualized and titrated to the desired clinical effect {01}; however, as a general guideline


Anesthesia, general (induction):


Adults up to 55 years of age and/or American Society of Anesthesiologists (ASA) I or II patients—
Intravenous, 2 to 2.5 mg per kg of body weight (approximately 40 mg every ten seconds until onset of induction) {01}.



Cardiac patients—
Intravenous, 0.5 to 1.5 mg per kg of body weight (approximately 20 mg every ten seconds until onset of induction) {01}.



Elderly, debilitated, hypovolemic, and/or ASA III or IV patients—
Intravenous, 1 to 1.5 mg per kg of body weight (approximately 20 mg every ten seconds until onset of induction) {01}.



Neurosurgical patients—
Intravenous, 1 to 2 mg per kg of body weight (approximately 20 mg every ten seconds until onset of induction) {01}.


Note: Slow injection of the induction dose of propofol may result in longer induction times and a lower percentage of successful inductions, probably due to rapid redistribution from the CNS {12}; however, slow injection of doses is preferable, in order to diminish some of the cardiovascular effects {01} {12} {23}.
Rapid intravenous injection of propofol should not be used in elderly, debilitated, hypovolemic, or higher-risk surgical patients. Rapid intravenous injection of propofol in these patients may result in cardiopulmonary depression including hypotension, apnea, airway obstruction and/or oxygen desaturation {01}.




Anesthesia, general, adjunct (maintenance):


Adults up to 55 years of age and/or ASA I or II patients—
Intravenous infusion, 100 to 200 mcg (0.1 to 0.2 mg) per kg of body weight per minute (6 to 12 mg per kg of body weight per hour), with 60 to 70% nitrous oxide and oxygen {01}.
Note: During the initial ten to fifteen minutes following induction, higher infusion rates of 150 to 200 mcg (0.15 to 0.2 mg) per kg of body weight per minute are generally required {01}. Infusion rates should subsequently be decreased by 30 to 50% during the first half-hour of maintenance {01}.
Infusion rates should always be titrated downward in the absence of light anesthesia to avoid administration of propofol at rates higher than clinically necessary {01}. In general, rates of 50 to 100 mcg (0.05 to 0.1 mg) per kg of body weight per minute should be achieved during maintenance to optimize recovery times {01}.



Intravenous intermittent injection, 20 to 50 mg increments, administered as needed {01}. Alternatively, some clinicians recommend increments of 500 mcg (0.5 mg) per kg of body weight {04}.



Adults receiving propofol for maintenance of general anesthesia for cardiac surgery—
Intravenous infusion, 50 to 150 mcg (0.05 to 0.15 mg) per kg of body weight per minute (3 to 9 mg per kg of body weight per hour) {01}. The use of an opioid as the primary anesthetic will result in a need for dosing of propofol at the lower end of this range, and the use of low-dose opioid as a secondary agent will result in a need for dosing of propofol at the higher end of this range {01}.



Adults receiving propofol for maintenance of general anesthesia for neurosurgery—
Intravenous infusion, 100 to 200 mcg (0.1 to 0.2 mg) per kg of body weight per minute (6 to 12 mg per kg of body weight per hour) {01}.



Elderly, debilitated, hypovolemic, and/or ASA III or IV patients—
Intravenous infusion, 50 to 100 mcg (0.05 to 0.1 mg) per kg of body weight per minute (3 to 6 mg per kg of body weight per hour) {01}.




Sedation:


Intensive care—
Individualize dose by titrating to unconsciousness with minimal hypotension:

• Initiation: Intravenous infusion, 5 mcg (0.005 mg) per kg of body weight per minute (0.3 mg per kg of body weight per hour) for at least 5 minutes.{57}{59}


• Titrate: Intravenous infusion, increments of 5 to 10 mcg (0.005 to 0.010 mg) per kg of body weight per minute (0.3 to 0.6 mg per kg of body weight per hour) over 5 to 10 minutes.{57}{59}


• Maintenance: Intravenous infusion, 5 to 50 mcg (0.005 to 0.050 mg) per kg of body weight per minute (0.3 to 3 mg per kg of body weight per hour). or higher may be required.{57}{59}


• Daily reassessment of level of sedation and CNS function should be carried out during maintenance dosing of propofol to determine the minimum dose of propofol injectable emulsion required for sedation.{57}{59}
.
Note: The mean requirement for sedation in the intensive care unit is 27 mcg per kg of body weight per minute, but the requirements vary widely, from 2.8 to 130 mcg per kg of body weight per minute. Lower rates of administration may be sufficient for patients receiving benzodiazepines or opioid analgesics. Older patients (i.e., those 55 years of age and older) require less propofol for sedation than younger patients (i.e., those up to 55 years of age) (20 and 38 mcg per kg of body weight per minute, respectively). In all cases, the infusion should be initiated slowly and titrated to effect. {01}





Monitored Anesthesia Care (MAC)—
Initiation: Intravenous infusion, 100 to 150 mcg (0.1 to 0.15 mg) per kg of body weight per minute (6 to 9 mg per kg of body weight per hour) for three to five minutes; or slow intravenous injection over three to five minutes, 0.5 mg per kg of body weight {01}.

Maintenance: Intravenous infusion, 25 to 50 mcg (0.025 to 0.05 mg) per kg of body weight per minute (1.5 to 3 mg per kg of body weight per hour) {01}.
Note: During the initial ten to fifteen minutes following induction, higher infusion rates of 25 to 75 mcg (0.025 to 0.075 mg) per kg of body weight per minute (1.5 to 4.5 mg per kg of body weight per hour) may be needed {01}.
In titrating to clinical effect, two minutes should be allowed to observe effects after an adjustment in dose. When propofol is used to provide MAC for elderly, debilitated, or ASA III or IV patients, the rate of administration and dose should be reduced to eighty percent of the usual adult dose {01}.






Usual pediatric dose
Anesthesia, general (induction)
Pediatric patients (ASA I or II) 3 years of age or older: Intravenous, 2.5 to 3.5 mg per kg of body weight {01}.

Note: Propofol is approved for induction of anesthesia in pediatric patients 3 years of age and older. However, propofol has been used in pediatric patients younger than 3 years of age for induction of anesthesia. In one study, infants 1 to 6 months of age required 3 mg per kg of body weight for induction of anesthesia {53}.
A lower dosage is recommended in pediatric patients classified as ASA III or IV.{57}


Anesthesia, general, adjunct (maintenance)
Pediatric patients (ASA I or II) 2 months of age to 16 years of age: Intravenous infusion, 125 to 300 mcg (0.125 to 0.3 mg) per kg of body weight per minute (7.5 to 18 mg per kg of body weight per hour), titrated to achieve the desired clinical effect.{57}

Note: During the initial one-half hour following induction, higher infusion rates of 200 to 300 mcg (0.2 to 0.3 mg) per kg of body weight per minute (12 to 18 mg per kg of body weight per hour) may be needed{01}. After one-half hour, the dose may be decreased to 125 to 150 mcg (0.125 to 0.15 mg) per kg of body weight per minute (7.5 to 9 mg per kg of body weight per hour) in most cases{01}. Following the first half hour of maintenance, if clinical signs of light anesthesia are not present, the infusion rate should be decreased.{57}
Children 5 years of age and younger may require larger weight-adjusted maintenance doses than older children{01}.



Strength(s) usually available
U.S.—


10 mg per mL (Rx) [Diprivan (soybean oil 10% w/v) (glycerol 2.25% w/v) (purified egg phosphatide [lecithin] 1.2% w/v) (disodium edetate 0.005%)]

Canada—


10 mg per mL (Rx) [Diprivan (soybean oil 10% w/v) (glycerol 2.25% w/v) (purified egg phosphatide [lecithin] 1.2% w/v) (disodium edetate 0.005%)]

Packaging and storage:
Store between 4 and 22 °C (40 and 72 °F). Refrigeration is not recommended. Protect from light {01}.

Preparation of dosage form:
Propofol is compatible with 5% dextrose in water, lactated Ringer's solution, lactated Ringer's and 5% dextrose in water, and combinations of 5% dextrose with 0.45% or 0.2% sodium chloride {01}.

If propofol is diluted prior to administration, only 5% Dextrose Injection USP should be used as a diluent, and the final concentration should not be less than 2 mg per mL to preserve the emulsion base {01}. The dilution is more stable in glass than in plastic {01}.

Stability:
Propofol injection contains 0.005% disodium edetate, but it is not an antimicrobially preserved product under USP standards. The vehicle is capable of supporting the rapid growth of microorganisms {01} {19}, and particulate or bacterial contamination may be difficult to detect because propofol injection is opaque {27}. Therefore, strict aseptic technique must be maintained {01} {19}. Propofol injection should be administered promptly after opening {01}. Unused portions of the injection, as well as reservoirs, IV lines, or solutions containing propofol injection, must be discarded at the end of the procedure or within 12 hours (6 hours if propofol was transferred from the original container) {01}.

Propofol should not be used if there is evidence of separation of the emulsion phases {01}.

Incompatibilities:
The manufacturer states that propofol emulsion should not be mixed with other therapeutic agents prior to administration {01}. In addition, propofol should not be coadministered through the same IV catheter with blood or plasma; although the clinical significance is not known, in vitro studies have shown that the globular component of the emulsion vehicle has formed aggregates when in contact with human and animal blood, plasma, and serum {01}.

Auxiliary labeling:
   • Shake well before use.
   • Protect from light.



Revised: 08/30/2002



References
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  1. USP Nomenclature committee comment, 09/2001.
  1. Expert Committee comment, 08/17/02.
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