Generic Name: propofol

Brand Names: Diprivan

Uses

Induction and Maintenance of Anesthesia

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Induction and/or maintenance of anesthesia as the sedative and hypnotic component of balanced anesthesia (benzodiazepines, anticholinergic agents, depolarizing and nondepolarizing skeletal muscle relaxants, opiate analgesics, inhalation and/or regional anesthetic) or total IV anesthesia (balanced anesthesia in which the IV anesthetic completely replaces the inhalation anesthetic) in patients undergoing inpatient or outpatient surgery.

Produces adequate general anesthesia in patients undergoing various types of surgery, including neurosurgery (e.g., craniotomy, intracranial aneurysm); cardiovascular (e.g., CABG); abdominal; ocular; ear, nose, and throat (ENT); orthopedic; and general surgery.

Considered the hypnotic of choice by some clinicians for patients undergoing outpatient surgery. Usually is associated with similar or faster early recovery (time to awakening and eye opening) from anesthesia, more rapid recovery of psychomotor performance and time to discharge, and lower incidence of adverse effects (e.g., nausea, vomiting, cough, hiccups) compared with other IV anesthetic agents (e.g., etomidate, methohexital, thiopental) or conventional combinations (e.g., an IV induction agent and an inhalation anesthetic).

Monitored Anesthesia Care (MAC)

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Initiation and maintenance of MAC sedation (alone or in combination with an opiate analgesic and/or a benzodiazepine) in adults undergoing diagnostic procedures or in conjunction with local or regional anesthesia for surgical procedures.

Provides sedation, analgesia, anxiolysis, and/or amnesia without assisted respiration or loss of consciousness when administered prior to and/or during dental, endoscopic (e.g., gastroscopy, bronchoscopy, colonoscopy), diagnostic, oral, or other procedures such as extracorporeal lithotripsy, transvaginal oocyte retrieval, central venous catheter placement, herniorrhaphy, and electrical cardioversion.

Used in conjunction with local or regional anesthesia for surgical procedures, including orthopedic (hip or knee arthoplasty), abdominal, or urologic surgery.

Produces less postoperative sedation, drowsiness, confusion, clumsiness, and nausea and a more rapid recovery of psychomotor performance than IV midazolam; however, midazolam has been associated with less pain at the injection site, less frequent oxygen requirements for decreased oxygen saturation, and more effective intraoperative amnesia. Quality of intraoperative sedation and time to discharge appear to be similar.

Sedation in Critical Care Settings

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Short-term sedation and control of stress responses in intubated and mechanically ventilated adults in a critical care setting when used alone or in combination with an opiate analgesic (e.g., morphine, fentanyl, hydromorphone) and/or peridural analgesia with local anesthetics.

Some experts state that midazolam or diazepam should be used for rapid sedation in acutely agitated patients, while propofol is the preferred sedative when rapid awakening (e.g., for neurologic assessment or extubation) is important.

Seizures

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Has been used in patients with refractory status epilepticus†.

Nausea and Vomiting

Has been used for the management of postoperative nausea and vomiting†.

Has been used in combination with conventional antiemetics for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy†.

Pruritus

Has been used effectively for relief of pruritus† associated with use of spinal opiates or with cholestasis.

Dosage and Administration

Administration

IV Administration

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Administer by IV infusion or IV injection.

For IV infusion, use a controlled-infusion device (pump), preferably a volumetric pump. In patients undergoing magnetic resonance imaging (MRI), use metered controlled devices when mechanical pumps are not suitable.

Use the larger veins of the forearm or antecubital fossa (rather than hand veins) in adults and children to minimize pain at the injection site; may also administer IV lidocaine prior to administration of propofol to minimize pain. (See Local Effects under Cautions.)

Transfer contents of the vial into a sterile, single-use syringe immediately after cleaning the rubber stopper with 70% isopropyl alcohol; use a sterile venting spike when withdrawing propofol from vials.

Alternatively, assemble the prefilled syringes according to the manufacturer’s instructions.

Shake well just prior to administration.

Clinical experience with use of inline filters for administration during general anesthesia, MAC sedation, or sedation in critical care settings is limited. An inline membrane filter may be used; however, the mean pore diameter of the filter should be ≥5 mcm unless it has been demonstrated that the filter does not restrict the flow and/or cause breakdown of the emulsion.

Stability and Sterility Considerations

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

For solution and drug compatibility, see Compatibility under Stability.

Manufacturers state that propofol should not be admixed with other therapeutic agents prior to administration. Do not administer through the same catheter as blood, serum, or plasma.

Observe strict aseptic technique. Although commercially available preparations contain ingredients that retard the rate of growth of microorganisms (i.e., Diprivan^® [AstraZeneca] contains edetate disodium 0.005%; Baxter preparation contains sodium metabisulfite 0.25 mg/mL), the emulsion still may support growth of microorganisms. Do not use the emulsion if contamination is suspected.

General anesthesia or MAC sedation: Start administration promptly and complete within 6 hours after opening the vials or syringes. Discard any unused portion, reservoirs, dedicated administration tubing, and/or solutions containing propofol injectable emulsion at the end of the anesthetic procedure or after 6 hours (whichever occurs sooner). Flush the IV line every 6 hours (one manufacturer recommends flushing with 5% dextrose) and at the end of the procedure to remove residual propofol emulsion.

Sedation in critical care settings: Minimize manipulations of IV lines; start administration promptly and complete within 12 hours after spiking the vial. Discard any unused portion and the IV tubing at the end of the procedure or after 12 hours (within 6 hours if the drug has been transferred prior to administration).

Dilution

May administer as a 1% (10 mg/mL) emulsion without dilution.

If dilution is necessary, the emulsion should be diluted only with 5% dextrose injection; concentration should be ≥0.2% (2 mg/mL) in order to maintain the emulsion. Discard if there is evidence of separation of the emulsion.

Rate of Administration

Administer slowly to minimize adverse effects (e.g., hypotension, respiratory depression). (See Respiratory and Cardiovascular Effects under Cautions.)

For IV injection, administer in incremental doses. (See Dosage.)

Adjust rate of continuous IV infusions according to individual requirements. (See Dosage.) In the absence of clinical signs indicating light anesthesia and until a mild response to surgical stimulation develops, titrate infusion rate downward to avoid administration at rates higher than clinically necessary.

Allow sufficient time between dosage adjustments for onset of peak response. (See Dosage.)

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Individual response to propofol is variable; therefore, adjust dosage (including infusion rate or amount and frequency of incremental doses) according to individual requirements and response, age, weight, clinical status (e.g., ASA physical status, degree of debilitation), blood lipid profile, underlying pathologic conditions (e.g., shock, intestinal obstruction, malnutrition, anemia, burns, advanced malignancy, ulcerative colitis, uremia, alcoholism), and type and amount of premedication or concomitant medication(s) used. Use the smallest effective dosage.

Pediatric Patients

Induction and Maintenance of General Anesthesia

IV

Induction of anesthesia in children 3–16 years of age (following no premedication or premedication with oral benzodiazepines or IM opiate agonists): 2.5–3.5 mg/kg over 20–30 seconds in those with ASA physical status of I or II. Within this dosage range, younger patients may require higher induction dosages than older patients. A lower dosage is recommended for induction of anesthesia in patients with ASA physical status of III or IV.

Maintenance of anesthesia in children 2 months to 16 years of age: Initially, 125–300 mcg/kg per minute (7.5–18 mg/kg per hour) administered concomitantly with inhaled 60–70% nitrous oxide and oxygen in those with ASA physical status of I or II. Dosage of 200–300 mcg/kg per minute may be required for the first 30 minutes after induction, then decrease dosage to 125–150 mcg/kg per minute (unless clinical signs of light anesthesia develop) by titration, according to the patient’s response. Within this dosage range, younger patients may require higher infusion rates than older patients.

Adults

Induction and Maintenance of General Anesthesia

General Surgery

IV

Induction of anesthesia (following no premedication or premedication with oral benzodiazepines or IM opiate agonists) in adults <55 years of age with ASA physical status of I or II: 40 mg (2–2.5 mg/kg) every 10 seconds according to the patient’s response until the onset of induction.

Maintenance of anesthesia in adults <55 years of age: Initially, 100–200 mcg/kg per minute (6–12 mg/kg per hour) administered concomitantly with inhaled 60–70% nitrous oxide and oxygen. Higher IV infusion rates of 150–200 mcg/kg per minute may be required for the first 10–15 minutes after induction, then decrease the infusion rate by 30–50% during the first 30 minutes of maintenance anesthesia.

Alternatively, for maintenance of anesthesia in adults <55 years of age: 20–50 mg by intermittent IV injection in combination with inhaled nitrous oxide. Additional IV doses of 20–50 mg may be given, if necessary, as determined by changes in vital signs (increases in pulse rate, BP, sweating, and/or lacrimation) indicating response to surgical stimulation or lightening of anesthesia.

Cardiac Anesthesia

IV

Induction of anesthesia: 20 mg (0.5–1.5 mg/kg) every 10 seconds, administered by slow IV injection until the onset of induction. Dosage of 25 mcg/kg per minute may be used for management of anxiolysis prior to induction.

Maintenance of anesthesia: 100–150 mcg/kg per minute as a continuous IV infusion when used as the primary agent and supplemented with a continuous infusion of an opiate agonist (e.g., alfentanil, fentanyl, sufentanil) administered to provide analgesia. Higher propofol dosages will reduce opiate analgesic dosage requirements.

When an opiate agonist is used as the primary agent for maintenance of anesthesia, administer propofol at a rate of 50–100 mcg/kg per minute in conjunction with a benzodiazepine to ensure adequate amnesia.

Neurosurgery

IV

Induction of anesthesia: 20 mg (1–2 mg/kg) every 10 seconds until the onset of induction.

Maintenance of anesthesia: 100–200 mcg/kg per minute (6–12 mg/kg per hour).

Monitored Anesthesia Care

IV

Initiation of MAC sedation in adults <55 years of age: Infusion of 100–150 mcg/kg per minute (6–9 mg/kg per hour) for 3–5 minutes; alternatively, injection of 0.5 mg/kg over 3–5 minutes. Slow rate of infusion or injection recommended to reduce the risk of apnea and hypotension.

Maintenance dosage in adults <55 years of age: Infusion of 25–75 mcg/kg per minute (1.5–4.5 mg/kg per hour) for the first 10–15 minutes, then decrease the infusion rate to 25–50 mcg/kg per minute. Adjust dosage according to clinical effect, allowing approximately 2 minutes for onset of peak drug response.

Alternatively, for maintenance therapy, administer intermittent IV injections of 10 or 20 mg; however, a variable-rate IV infusion is preferred. (See Monitored Anesthesia Care under Cautions.)

In neurosurgical patients, reduce maintenance dosage by 20%. Rapid IV injection is not recommended in these patients because of an increased risk of adverse cardiorespiratory effects.

Sedation in Critical Care Settings

IV

Initially, 5 mcg/kg per minute (0.3 mg/kg per hour) for ≥5 minutes in patients with residual effects from anesthetic or sedative drugs. Increase the infusion rate slowly in increments of 5–10 mcg/kg per minute (0.3–0.6 mg/kg per hour) over 5–10 minutes until desired sedation is achieved. Initiate and increase the infusion rate slowly in these patients to minimize the risk of hypotension or acute overdosage.

For maintenance of sedation: 5–50 mcg/kg per minute (0.3–3 mg/kg per hour); higher maintenance infusion rates occasionally required. Rapid IV (“bolus”) administration of 10- or 20-mg doses may be used to rapidly increase depth of sedation in patients in whom development of hypotension is unlikely.

Use the lowest effective dosage in patients with residual effects from anesthetic drugs or in those currently receiving other sedatives or opiates.

Assess level of sedation and CNS function at regular intervals (at least daily during maintenance sedation); adjust infusion rate accordingly to ensure adequate titration of the sedation level.

Do not administer Diprivan^® injectable emulsion as a continuous IV infusion for >5 days without a drug-free interval to allow replacement of estimated or measured urinary zinc losses. (See Edetate Disodium Content under Cautions.)

Some tolerance to the drug’s sedative effects may occur during long-term (>7 days) therapy; increasing the infusion rate may be necessary. However, such effects also may be associated with changes in drug elimination or an improved health status of the patient.

Seizures

Refractory Status Epilepticus

IV

Initially, 1- to 2-mg/kg doses by IV injection over 5 minutes; repeat when seizure activity no longer is adequately controlled. Maintenance infusion of 2–10 mg/kg per hour; adjust the infusion rate until the lowest rate of infusion needed to suppress epileptiform activity is achieved. Gradually decrease the dosage to prevent withdrawal seizures.†

Nausea and Vomiting

Postoperative Nausea and Vomiting

IV

Doses of 10–15 mg have been used.†

Prevention of Nausea and Vomiting Associated with Emetogenic Cancer Chemotherapy

IV

Dosage of 1 mg/kg per hour as a continuous IV infusion has been used.†

Pruritus

Pruritus Associated with Use of Spinal Opiates

IV

Doses of 10 mg administered by direct IV injection have been used; alternatively, IV infusions of 0.5–1 mg/kg per hour have been used.†

Pruritus Associated With Cholestasis

IV

Doses of 15 mg administered by direct IV injection have been used; alternatively, IV infusions of 1–1.5 mg/kg per hour have been used.†

Special Populations

Geriatric Patients (≥55 Years of Age), Debilitated Patients, and Patients with ASA Physical Status of III or IV

Induction and Maintenance of General Anesthesia

Induction of anesthesia: 20 mg (1–1.5 mg/kg) every 10 seconds according to the individual patient’s condition and response until the onset of induction.

Maintenance of anesthesia: 50–100 mcg/kg per minute (3–6 mg/kg per hour) administered concomitantly with inhaled 60–70% nitrous oxide and oxygen.

Monitored Anesthesia Care

Initiation of MAC sedation: Dosages similar to those for healthy adults are required.

Maintenance of MAC sedation: Reduce dosage by 20%. Rapid IV injection is not recommended because of an increased risk of adverse cardiorespiratory effects.

Cautions

Contraindications

• Known hypersensitivity to propofol or any ingredient in the formulation.
• When general anesthesia or sedation is contraindicated.

Warnings/Precautions

Warnings

Respiratory and Cardiovascular Effects

Can depress respiration; apnea occurs frequently during induction of anesthesia.

Cardiovascular depressant with effects greater than or equal to those associated with other IV anesthetic induction agents. The main adverse cardiovascular effect during induction of anesthesia is hypotension, with ≥30% decreases in systolic and diastolic BP.

Patients with impaired myocardial function, intravascular volume depletion, or abnormally low vascular tone (sepsis) may be more susceptible to hypotension.

Management of hypotension may include discontinuance of propofol, increasing the rate of IV fluid administration (except when additional fluid therapy is contraindicated), elevation of the lower extremities, and/or use of vasopressors.

Possible bradycardia, asystole, and rarely, cardiac arrest, especially in pediatric patients receiving fentanyl concomitantly. (See Specific Drugs under Interactions.) Consider intervention with anticholinergic agents (e.g., atropine, glycopyrrolate) to modify potential increases in vagal tone associated with surgical stimuli or concomitant use of certain drugs (e.g., succinylcholine).

Pulmonary edema reported rarely; causal relationship not established.

Monitor patients continuously for early signs of hypotension and bradycardia; also monitor for adverse respiratory effects (e.g., apnea, airway obstruction, oxygen desaturation), especially in those undergoing MAC sedation.

Cardiorespiratory effects are more likely to occur following rapid IV administration of loading doses or during supplemental maintenance rapid IV (“bolus”) injections, especially in patients with ASA physical status of III or IV and in geriatric or debilitated patients. (See Special Populations under Dosage and Administration.)

Facilities necessary for intubation, assisted respiration, administration of oxygen, and cardiopulmonary resuscitation should be readily available.

Supervised Administration

Should be administered for general anesthesia or MAC sedation only by individuals experienced in the use of general anesthesia who are not involved in the conduct of the surgical and/or diagnostic procedure.

Should be administered for sedation of intubated, mechanically ventilated patients in critical care settings only by individuals qualified in the management of patients in these settings and trained in cardiovascular resuscitation and airway management.

Potential for Microbial Contamination

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Potential for microbial contamination of the injection and consequent development of fever, infection, sepsis, other life-threatening illness, or death with improper aseptic technique.

Although commercially available preparations contain ingredients that retard the rate of growth of microorganisms (i.e., Diprivan^® [AstraZeneca] contains 0.005% of edetate disodium; Baxter preparation contains sodium metabisulfite 0.25 mg/mL), the manufacturers state that strict aseptic technique must be observed when handling the drug, because the emulsion still may support growth of microorganisms.

Do not use the emulsion if contamination is suspected; discard unused portions as recommended by the manufacturers. (See Stability and Sterility Considerations under Dosage and Administration.)

Sensitivity Reactions

Sulfite Sensitivity

Some formulations contain sulfites that may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.

Hypersensitivity Reactions

Anaphylactoid and/or anaphylactic reactions (e.g., angioedema, bronchospasm, erythema, hypotension) and flushing, possibly related to propofol, reported in <1% of adults undergoing anesthesia or MAC sedation with the drug.

General Precautions

Local Effects

Pain at the injection site occurs in up to 70% of patients following peripheral IV administration. Thrombosis or phlebitis reported rarely.

Pain, but no evidence of major sequelae, reported following inadvertent intra-arterial injection. Local pain, swelling, blisters and/or tissue necrosis reported rarely following inadvertent extravasation.

To minimize pain at the injection site, use the larger veins of the forearm or antecubital fossa rather than hand veins; may also administer 1 mL of 1% lidocaine hydrochloride solution 30–120 seconds prior to IV administration of propofol. Other methods have been used: prior administration of opiates or metoclopramide, prior application of a tourniquet, topical nitroglycerin or a local anesthetic cream, or administration of propofol at low temperatures (4–5°C).

Effects on Lipids

Commercial propofol preparations are oil-in-water emulsions; use with caution in patients with disorders of lipid metabolism (e.g., primary hyperlipoproteinemia, diabetic hyperlipemia, pancreatitis).

Prolonged administration may result in increased serum lipid concentrations (e.g., hypertriglyceridemia); monitor patients undergoing sedation in a critical care setting who are at risk of developing hyperlipidemia for increases in serum triglyceride concentrations or serum turbidity.

Reduce the quantity of concurrently administered lipids (e.g., fat emulsions for parenteral nutrition) in these patients in order to compensate for the amount of lipids contained in the propofol formulation (1 mL of propofol injectable emulsion contains 0.1 g of fat [1.1 kcal]).

Edetate Disodium Content

Certain formulations (Diprivan^®) contain 0.005% of edetate disodium, a heavy metal antagonist that can chelate many divalent and trivalent cations.

Patients receiving continuous infusions for sedation in critical care settings should not receive formulations containing edetate disodium for >5 days without a drug-free interval to allow replacement of estimated or measured urinary zinc losses.

In patients who are predisposed to zinc deficiency (e.g., those with burns, diarrhea, major sepsis), consider the need for supplemental zinc during prolonged therapy with edetate disodium-containing formulations.

Renal toxicity reported rarely in patients receiving high dosages (2–3 g daily) of edetate disodium; however, decreased renal function has not been observed in clinical studies to date in patients with normal or impaired renal function receiving propofol (Diprivan^®). Manufacturer of Diprivan^® recommends that laboratory analysis of urine (including urine sediment) be performed prior to sedation and every other day during therapy in patients at risk for developing renal impairment.

Seizures

Appears to be associated with both anticonvulsant activity and excitatory effects (e.g., seizures, myoclonus, opisthotonos) on the nervous system.

Patients with a history of seizure disorders who are receiving propofol are at increased risk of developing seizures during the recovery phase of anesthesia.

Postoperative Effects

Associated rarely with a period of postoperative unconsciousness (sometimes preceded by a brief period of wakefulness), which may be accompanied by increased muscle tone; recovery has been spontaneous.

Clinical criteria for discharge from recovery or outpatient surgery (including care of an anesthesiologist) varies among institutions; the respective institution’s guidelines should be satisfied before patients leave the facilities.

Pancreatitis

Pancreatitis (sometimes requiring hospitalization) reported in adults undergoing induction of anesthesia or prolonged sedation with propofol in a critical care setting. Causal relationship with propofol not established; consider the possibility of pancreatitis in patients receiving propofol.

CNS Effects

Performance of activities requiring mental alertness (e.g., driving, operating machinery, signing legal documents) may be impaired for some time after general anesthesia or sedation with propofol.

Neurosurgical Anesthesia

Avoid substantial decreases in mean arterial pressure (because of the resultant decreases in cerebral perfusion pressure) in patients with increased intracranial pressure or impaired cerebral circulation who are undergoing neurosurgery. To avoid substantial hypotension and decreases in cerebral perfusion pressure, administer by IV infusion or slow IV injection. (See Dosage under Dosage and Administration.)

If increased intracranial pressure is suspected, administer in combination with hyperventilation and hypocarbia.

Monitored Anesthesia Care

A variable infusion rate is preferred to intermittent bolus administration for maintenance of MAC sedation in healthy adults because the risk of hypotension may be lower. If intermittent IV injections are given, consider the possibility of respiratory depression, transient increases in sedation depth, and/or prolongation of recovery.

Cardiac Anesthesia

Use slower rates of IV administration in patients undergoing cardiac surgery who received premedication and in those with recent fluid imbalance or those who are hemodynamically unstable. Correct fluid depletion prior to administration of propofol.

If additional fluid therapy is contraindicated, management of hypotension may include discontinuance of propofol, elevation of the lower extremities, and/or use of vasopressors.

Studied extensively in patients with CAD, but experience in those with valvular or congenital heart disease is limited.

Critical Care Sedation

Failure to reduce the infusion rate during prolonged therapy may result in excessively high blood concentrations of propofol; titrate dosage downward according to individual clinical response. Evaluate sedation levels at least daily.

Prior to weaning patients from mechanical ventilator assistance, discontinue neuromuscular blocking agents or reverse neuromuscular blockade and discontinue opiate therapy or adjust the dosage to optimize respiratory function and/or to maintain a light level of sedation. If respiratory depression does not develop, maintain this level of sedation during the weaning process since abrupt withdrawal has been associated with rapid awakening accompanied by anxiety, agitation, and resistance to mechanical ventilation, thus making the weaning process difficult. Therefore, the manufacturers recommend that administration of propofol be continued until about 10–15 minutes prior to extubation.

Musculoskeletal Effects

Rhabdomyolysis reported rarely in patients receiving propofol for sedation in critical care settings.

Specific Populations

Pregnancy

Category B.

Not recommended for obstetric surgery (e.g., cesarean section).

Lactation

Distributed into milk; use not recommended by manufacturers.

Some clinicians state that nursing women undergoing surgery may receive usual anesthetic induction doses of propofol; however, since trace amounts of the drug may be present in milk, drowsiness of nursing infants may occur on the day of the procedure.

Pediatric Use

Safety and efficacy for induction of general anesthesia not established in children <3 years of age. Safety and efficacy of Diprivan^® (AstraZeneca) for maintenance of general anesthesia not established in children <2 months of age; Baxter states that safety and efficacy of propofol injectable emulsion not established in children <3 years of age.

The manufacturers state that propofol is not recommended for sedation in critical care settings in children <16 years of age because safety for this use in this patient population has not been established. Severe, progressive metabolic (e.g., lactic) acidosis syndrome (that may progress to death) has been reported in several ventilated children (mainly with respiratory infections) receiving propofol for sedation in critical care settings; acidosis sometimes was accompanied or followed by hypocalcemia, hypoglycemia, high serum lipid concentrations (hypertriglyceridemia), elevated serum liver enzyme concentrations, enlarged liver, oliguria, myoglobinuria, fever, multisystem organ failure, cardiac failure, bradycardia, hypotension, AV block of varying degrees, bundle branch block, asystole, and death. The mechanism of this syndrome is not known; the possibility that causes other than propofol administration may be involved has been suggested. In 1 study in pediatric patients (excluding those with upper respiratory infection) undergoing sedation in critical care settings, increased incidence of mortality reported in patients receiving propofol compared with those receiving standard sedative agents.

Has been used in children undergoing MAC sedation for surgical, diagnostic, and other procedures (e.g., lumbar puncture with intrathecal chemotherapy, bone marrow aspiration and biopsy, central venous catheter placement, transesophageal echocardiogram, cardiac catheterization, radiologic examinations, orthopedic manipulations); however, the manufacturers state that propofol should not be used for MAC sedation in children because safety and efficacy have not been established.

Abrupt discontinuance following prolonged IV infusion in children may result in flushing of the hands and feet, agitation, tremulousness, hyperirritability, increased incidence of bradycardia, agitation, or jitteriness.

Geriatric Use

Lower dosages may be required for anesthesia and other indications. (See Special Populations under Dosage and Administration.)

Avoid rapid (single or repeated) IV (“bolus”) administration during general anesthesia or MAC sedation to minimize the risk of adverse effects, including cardiorespiratory depression (e.g., hypotension, apnea, airway obstruction, oxygen desaturation).

Hepatic Impairment

Long-term propofol therapy not evaluated to date.

Renal Impairment

Long-term propofol therapy not evaluated to date.

Common Adverse Effects

Use for anesthesia or MAC sedation: Bradycardia, arrhythmia, tachycardia, hypotension, hypertension, movement, burning/stinging, pain at injection site, apnea, rash, pruritus.

Use for critical care setting sedation: Bradycardia, decreased cardiac output, hypotension, hyperlipidemia, respiratory acidosis (during weaning).

Interactions

Metabolized mainly by CYP2B6 and to a lesser extent by CYP2C9.

Inhibits CYP isoenzymes 1A1, 1A2, 2B1, 2C9, 2D6, 2E1, and 3A4.

Drugs Metabolized by or Affecting Hepatic Microsomal Enzymes

Possibility of interactions; however, because of the increased value for hepatic extraction (50 mcM) of propofol, there have been relatively few clinically important interactions with drugs metabolized by or affecting CYP isoenzymes.

Specific Drugs

Pharmacokinetics

Absorption

Onset

Following a single IV injection, onset as determined by time to unconsciousness (i.e., loss of response to voice command) usually ranges from 15–30 seconds and depends on the administration rate.

Duration

Following a single rapid IV injection, duration of action usually is about 5–10 minutes.

Plasma Concentrations

Following a single rapid IV injection, most patients will awaken as blood propofol concentrations decline to approximately 1 mcg/mL; improvement of psychomotor performance (as measured by patient response to verbal command) usually occurs at concentrations of 0.5–0.6 mcg/mL.

Distribution

Extent

Highly lipophilic; rapidly distributed from plasma into body tissues, including the CNS. Following IV administration, widely distributed, initially to highly perfused tissues (e.g., brain), then to lean muscle tissue, and finally to fat tissue. Equilibration between blood and CSF occurs within about 2–3 minutes.

Readily crosses the placenta.

Distributed into milk in low concentrations.

Plasma Protein Binding

Approximately 95–99% (mainly albumin and hemoglobin). Binding appears to be independent of plasma propofol concentration.

Elimination

Metabolism

Rapidly and extensively metabolized in the liver by CYP2B6 and to a lesser extent by CYP2C9.

Elimination Route

Excreted mainly in urine, principally as sulfate and/or glucuronide conjugates; <0.3% of a dose is eliminated unchanged in urine, and <2% of a dose is eliminated in feces.

Half-life

Triphasic; following a single rapid injection or a continuous infusion, half-life averages 1.8–9.5 minutes in the initial distribution phase, 21–70 minutes in the second redistribution phase, and 1.5–31 hours in the terminal elimination phase.

Terminal plasma half-life may not affect clinical outcome as substantially as the distribution half-life does, since rapid awakening from anesthesia occurs once blood propofol concentrations decrease below the range required for hypnosis.

Special Populations

In geriatric patients, clearance may be reduced substantially, possibly because of decreased hepatic metabolism resulting from decreased hepatic blood flow.

Obese patients have a substantially higher clearance than leaner individuals; mean total body clearance appears to be proportional to body weight.

Chronic renal failure or chronic hepatic cirrhosis does not appear to affect pharmacokinetics of propofol; not studied in patients with acute renal or hepatic failure.

Stability

Storage

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Parenteral

Injectable Emulsion

4–22°C. Do not freeze.

Emulsions are packaged under nitrogen to prevent oxidative degradation in the presence of oxygen.

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Solution Compatibility

Propofol emulsion diluted with 5% dextrose injection: More stable in glass than in plastic containers. Potency of diluted emulsions may decrease by about 5–8% after continuous IV infusion through PVC tubing for 2 hours and by up to 35% when diluted solution is left stationary in PVC tubing.

Compatibility with blood, serum, or plasma not established.

Y-Site Compatibility

Drug Compatibility

Formulation differences (e.g., pH, ingredients [see Preparations]) exist between the commercially available propofol preparations. Most of the compatibility information for propofol was obtained from tests using Diprivan^®; results of compatibility tests may not be applicable to propofol preparations other than the one(s) tested.

Y-Site Compatibility (Diprivan^®)

Y-Site Compatibility (Propofol Injectable Emulsion [Baxter])

Actions

• Effects appear to be related, at least partially, to propofol’s ability to enhance the activity of GABA by interacting with the GABA_A receptor complex at spinal and supraspinal synapses. Also may interact with other neurotransmitter sites (e.g., glycine, nicotinic, glutamate, G-protein coupled receptors) and inhibit sodium channels.
• Capable of producing all levels of CNS depression—from light sleep to deep coma—depending on the dosage.
• Associated with both anticonvulsant activity and excitatory effects on the nervous system.
• Anesthetic doses may increase cerebral vascular resistance and decrease cerebral blood flow and cerebral metabolic rate for oxygen and glucose. May slightly decrease intracranial pressure in patients undergoing intracranial surgery or in those undergoing sedation in a critical care setting.
• Hypnotic doses may be associated with analgesic effects; responses to subhypnotic doses vary from analgesia to hyperalgesia. Subhypnotic doses may have anxiolytic effects comparable to those of midazolam or methohexital. Amnesic effects are less than those of the benzodiazepines.
• Propofol anesthesia associated with substantial (30–60%) reductions in intraocular pressure in patients undergoing ophthalmic surgery.
• May have direct antiemetic properties; however, mechanism not established.

Advice to Patients

• Importance of informing patients that their ability to perform activities requiring mental alertness (e.g., driving, operating machinery, signing legal documents) may be impaired for some time after undergoing general anesthesia or sedation.
• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.
• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

AHFS Drug Information. © Copyright, 1959-2009, Selected Revisions August 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.