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Propofol

Class: General Anesthetics, Miscellaneous
VA Class: CN203
Chemical Name: 2,6-Bis(1-methylethyl) phenol
Molecular Formula: C12H18O
CAS Number: 2078-54-8
Brands: Diprivan

Medically reviewed by Drugs.com. Last updated on Aug 24, 2020.

Warning

Special Alerts:

Emergency Use Authorization (EUA) for Propoven: On May 8, 2020, FDA issued an Emergency Use Authorization (EUA) permitting the emergency use of the unapproved product, Fresenius Propoven 2% (propofol 20 mg/mL) Emulsion 100 mL, to maintain sedation via continuous infusion in patients older than 16 years of age who require mechanical ventilation in an intensive care unit (ICU) setting during the COVID-19 pandemic. Because Fresenius Propoven 2% (propofol 20 mg/mL) Emulsion has a concentration twice that of the FDA-approved propofol product, there is a risk of unintentional overdose. There are also important differences in the formulation and labeling between the two products. Healthcare providers should review the EUA and the differences between the two products prior to administering Propoven. Documents related to the EUA can be found on the FDA website at [Web], including the most recent letter of authorization ([Web]), a fact sheet on the EUA for healthcare providers ([Web]), and a wall chart outlining the key differences between the two products ([Web]).

Temporary Policy on Repackaging or Combining Propofol Drug Products During the COVID-19 Public Health Emergency: During the COVID-19 public health emergency, FDA has received several inquiries from healthcare professionals concerning the unavailability of propofol drug products used in the treatment and management of patients with complications related to COVID-19. FDA is issuing this guidance to communicate its temporary policy regarding the repackaging or combining of propofol drug products by a licensed pharmacist in a State licensed pharmacy, a Federal facility, or an outsourcing facility registered pursuant to section 503B of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 353b) as outlined in this guidance for the duration of the public health emergency declared by the Secretary of Health and Human Services (HHS) on January 31, 2020, or for such shorter time as FDA may announce through updated guidance. This policy is intended to remain in effect for no longer than the duration of the public health emergency related to COVID-19 declared by HHS, including any renewals made by the HHS Secretary in accordance with section 319(a)(2) of the Public Health Service Act (42 U.S.C. 247d(a)(2)). FDA is continually assessing the needs and circumstances that make issuance of this guidance appropriate. As relevant needs and circumstances evolve, FDA intends to update, modify, or withdraw policies in this guidance as appropriate. For additional information, please see the full guidance at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/temporary-policy-repackaging-or-combining-propofol-drug-products-during-covid-19-public-health.

Warning

    Microbial Contamination
  • Propofol injectable emulsion can support microbial growth. (See Potential for Microbial Contamination under Cautions.)

  • Use strict aseptic technique at all times during handling; failure to use aseptic technique may result in microbial contamination and possible fever, infection/sepsis, other life-threatening illness, and/or death.

  • Discard unused portions within the required time limits. (See Stability and Sterility Considerations under Dosage and Administration.)

  • Do not use if contamination is suspected.

Introduction

Sedative and hypnotic.

Uses for Propofol

Induction and Maintenance of Anesthesia

IV induction and maintenance of general anesthesia.

FDA-labeled for use as an IV induction agent for general anesthesia in adults and pediatric patients ≥3 years of age and for maintenance anesthesia in adults and pediatric patients ≥2 months of age.

IV induction with propofol is rapid and results in dose-related hypnotic effects (progressing from light sleep to unconsciousness) and anterograde amnesia; however, analgesic properties not conclusively demonstrated. Generally produces loss of consciousness in <1 minute (time required for one arm-brain circulation). Following induction, anesthesia can be maintained by continuous IV infusion or intermittent IV injections. Recovery from propofol anesthesia is rapid because of fast redistribution and clearance of the drug.

Usually associated with similar or faster time to recovery from anesthesia, more rapid recovery of psychomotor performance and time to discharge, and lower incidence of adverse effects (e.g., nausea, vomiting) compared with other IV anesthetic agents (e.g., etomidate, methohexital).

Compared with inhalation anesthetics (e.g., sevoflurane, desflurane, isoflurane), propofol is associated with a consistent and clinically relevant lower incidence of postoperative nausea and vomiting.

Procedural Sedation

Sedation in patients undergoing diagnostic or therapeutic procedures across various clinical settings (e.g., emergency department, cardiac catheterization laboratories, radiology suites, endoscopy suites, dental offices). A preferred drug for this use because of rapid onset of effect, short duration, and rapid recovery.

Generally used to provide moderate sedation (also referred to as conscious sedation) or deep sedation depending on the procedure, clinical setting, and patient requirements. Because propofol can produce rapid and profound changes in the depth of sedation and lacks a reversal agent, the American Society of Anesthesiologists states that even if moderate sedation is intended, patients should receive the same level of care required for deep sedation.

May be used with monitored anesthesia care (MAC) or in conjunction with local or regional anesthesia. (See Monitored Anesthesia Care under Uses.)

Although not FDA-labeled for use in children, propofol has been used widely for pediatric procedural sedation.

Monitored Anesthesia Care

Initiation and maintenance of MAC sedation (alone or in combination with an opiate analgesic and/or a benzodiazepine) in adults undergoing diagnostic or therapeutic procedures.

MAC is a specific anesthesia service performed by a qualified anesthesia provider and does not refer to a specific level of sedation. The MAC provider is focused exclusively on the patient's anesthetic needs and is prepared to manage any complications, including conversion to general anesthesia if necessary.

Factors to consider when determining whether MAC sedation is indicated include the nature of the procedure, patient's clinical condition, risk factors, and/or need for deeper levels of analgesia and sedation than can be provided by moderate sedation (including need to convert to general or regional anesthesia).

MAC sedation is distinguished from moderate sedation, which is a drug-induced depression of consciousness during which patients respond purposefully to verbal commands. (See Procedural Sedation under Uses.)

Sedation in Critical Care Settings

Sedation in intubated and mechanically ventilated adults in a critical care setting (e.g., ICU); used alone or in combination with an opiate analgesic (e.g., morphine, fentanyl).

Appears to be as effective as dexmedetomidine and benzodiazepines (e.g., midazolam, lorazepam) for ICU sedation; however, because of some modest clinical benefits (e.g., reduced duration of mechanical ventilation, shorter time to extubation, reduced risk of delirium), some experts state that nonbenzodiazepine sedatives (dexmedetomidine or propofol) may be preferred to benzodiazepines in mechanically ventilated, critically ill adults.

When selecting an appropriate sedative agent, consider patient's individual sedation goals in addition to specific drug-related (e.g., pharmacology, pharmacokinetics, adverse effects, availability, cost) and patient-related (e.g., comorbid conditions such as anxiety, seizures, or alcohol or benzodiazepine withdrawal) factors.

Because of its short duration of sedative effect, some experts state that propofol may be particularly useful in patients requiring frequent awakenings (e.g., for neurologic assessments) or undergoing daily sedation interruption protocols.

Seizures

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.

Misuse and Abuse

Abuse and dependence, sometimes resulting in death, have been reported. Most reports involved healthcare professionals (principally anesthesiology personnel), but abuse by lay persons also reported.

Currently not subject to control under the Federal Controlled Substances Act of 1970; however, some clinicians have suggested such control or some other means of ensuring greater accountability (e.g., restriction of access, drug accounting procedures, routine testing for propofol in drug screenings of at-risk individuals). Prevalence of abuse and related deaths appears to be greater at institutions with no established system to control or monitor propofol use.

Propofol Dosage and Administration

Administration

IV Administration

Administer by IV infusion or IV injection.

When administered by IV infusion, a controlled-infusion device (e.g., syringe or volumetric pump) is recommended. In patients undergoing magnetic resonance imaging (MRI), metered controlled devices may be used when mechanical pumps are not suitable.

Propofol may be transferred to a syringe prior to administration. After cleaning the rubber stopper of the vial with 70% isopropyl alcohol, transfer contents into a sterile syringe immediately after vial is opened using a sterile vented spike. Label syringes with appropriate information, including date and time vial was opened.

Shake well prior to administration. Do not use if there is evidence of excessive creaming or aggregation, if large droplets are visible, or if there are other forms of phase separation indicating that stability of the product has been compromised. Slight creaming, which may be visible upon prolonged standing, should disappear after shaking.

Filters

Clinical experience with use of inline filters is limited. An inline membrane filter may be used; however, the mean pore diameter of the filter should be ≥5 µm unless it has been demonstrated that the filter does not restrict flow and/or cause breakdown of the emulsion. Use filters with caution and only when clinically appropriate. Monitor continuously for restricted flow and breakdown of the emulsion.

Stability and Sterility Considerations

For solution and drug compatibility, see Compatibility under Stability.

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

Use strict aseptic technique during preparation and administration. Although commercially available preparations contain ingredients that retard growth of microorganisms (e.g., edetate disodium, sodium metabisulfite, sodium benzoate, benzyl alcohol), the emulsion may still support growth of microorganisms. Vials are intended for single-patient use and single access only. Discard unused drug within specified time limits. Failure to observe strict aseptic technique has resulted in microbial contamination and transmission of infections. (See Potential for Microbial Contamination under Cautions.) Do not use if contamination is suspected.

When used for general anesthesia or MAC sedation, start administration promptly and complete within 12 hours of opening vials. Prepare propofol for use immediately prior to initiation of each individual anesthetic/sedative procedure. Discard any unused portion, reservoirs, dedicated administration tubing, and/or solutions containing propofol at the end of the anesthetic procedure or after 12 hours (whichever occurs sooner). Flush the IV line every 12 hours (one manufacturer recommends flushing with 5% dextrose) and at the end of the procedure to remove residual propofol emulsion.

When used for sedation in critical care settings, minimize manipulations of IV lines; start administration promptly and complete within 12 hours after inserting spike in vial. Use a sterile vent spike and sterile tubing. Discard any unused portion and the IV tubing at the end of the procedure or after 12 hours.

Dilution

Commercially available 1% (10 mg/mL) injectable emulsion may be administered without dilution.

If dilution is necessary, dilute with 5% dextrose injection only; do not dilute to a concentration less than 0.2% (2 mg/mL) in order to maintain the emulsion. Do not use if there is evidence of separation of the emulsion.

Rate of Administration

Administer slowly to minimize adverse effects (e.g., hypotension, respiratory depression). Cardiorespiratory depression is more likely to occur at higher propofol concentrations resulting from rapid IV (“bolus”) injection or rapid increases in the rate of infusion. (See Respiratory and Cardiovascular Effects under Cautions.)

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

When administered as an IV infusion, adjust rate of infusion according to individual requirements; allow sufficient time between rate adjustments to assess clinical effect. (See Dosage.) To avoid administering the drug at rates higher than clinically necessary, always titrate infusion rates downward in the absence of clinical signs of light anesthesia until a mild response to surgical stimulation is obtained.

To optimize recovery times, manufacturers state that maintenance IV infusions usually should be administered at a rate of about 50–100 mcg/kg per minute in adults.

Injection-site Pain

Pain on injection occurs frequently. Minimize pain by using larger veins of the forearm or antecubital fossa (rather than hand veins) and administering IV lidocaine (either as pretreatment or admixed with propofol). (See Local Effects under Cautions.) Because lidocaine may cause instability of the propofol emulsion, manufacturers recommend administering 1 mL of 1% lidocaine hydrochloride solution 30–120 seconds prior to propofol administration or adding lidocaine to propofol immediately prior to administration in quantities not exceeding 20 mg of lidocaine per 200 mg of propofol.

Administration Precautions

Due to potential for rapid and profound changes in the depth of anesthesia and sedation, special precautions are required when administering propofol. The American Society of Anesthesiologists (ASA) states that even if moderate sedation is intended, patients receiving propofol should receive care consistent with that required for deep sedation.

During administration, monitor patients continuously to assess level of consciousness and identify early signs of hypotension, bradycardia, apnea, airway obstruction, and/or oxygen desaturation. There are different considerations when propofol is used for ICU sedation. Administration of propofol is regulated at the state, regional, and local levels; such guidance should be consulted.

Dosage

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.

Procedural Sedation†
IV

Various dosage regimens have been used. Individualize appropriate dose and depth of sedation based on the procedure and needs of the patient.

Has been given as an initial IV bolus injection followed by intermittent injections or by continuous IV infusion to maintain desired level of sedation.

In pediatric patients undergoing procedural sedation, an initial IV propofol dose of 1 mg/kg has been used. In one study, children 3–18 years of age undergoing an emergency orthopedic procedure received an initial IV propofol dose of 1 mg/kg, followed by smaller intermittent doses based on patient response. In another study in children ≥2 years of age who received propofol sedation for closed orthopedic reductions, the drug was given as an initial 1-mg/kg IV bolus dose over 2 minutes, followed by an IV infusion of 67–100 mcg/kg per minute until cast completion. To maintain the desired level of sedation, additional IV bolus doses of 1 mg/kg were administered and/or the infusion rate was adjusted.

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 25–50 mg may be given, if necessary, as determined by clinical signs (increases in pulse rate, BP, sweating, and/or lacrimation) indicating a stress response to surgical stimulation or emergence from 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 IV infusion of an opiate agonist (e.g., alfentanil, fentanyl, sufentanil) 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 mcg/kg per minute; 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).

Procedural Sedation
IV

Various dosage regimens have been used. Individualize appropriate dose and depth of sedation based on the procedure and needs of the patient. Usually given as an initial IV bolus injection followed by intermittent injections or continuous IV infusion to maintain desired level of sedation; also has been given by IV infusion throughout the procedure. Administration by IV infusion may allow for more precise control of the level of sedation compared with a repeated bolus technique.

In clinical studies, an IV propofol dose of 1 mg/kg was commonly used to achieve initial sedation in adults undergoing a diagnostic or therapeutic procedure; however, lower (e.g., 0.5 mg/kg) or higher (e.g., 1.5 mg/kg) initial doses also have been used. To maintain the desired level of sedation, additional doses (e.g., 0.25-0.5 mg/kg by intermittent IV injection) usually are administered as needed.

For dosages recommended by the manufacturer for MAC sedation, see Monitored Anesthesia Care under Dosage and Administration.

Monitored Anesthesia Care
IV

Initiation of MAC sedation in healthy 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 healthy 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

Individualize dosage and titrate to the desired level of sedation; in most cases, a light rather than deep level of sedation is recommended in critically ill, mechanically ventilated adults because of improved clinical outcomes (e.g., shortened duration of mechanical ventilation, reduced ICU length of stay). Assess depth and quality of sedation frequently using a validated and reliable assessment tool (e.g., Richmond Agitation-Sedation Scale [RASS], Sedation-Agitation Scale [SAS]).

Initiate slowly with a continuous IV infusion to minimize risk of hypotension. Because most patients will have residual effects from previous anesthetic or sedative agents, manufacturers recommend an initial infusion rate of 5 mcg/kg per minute (0.3 mg/kg per hour). Increase 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 level of sedation is achieved; allow a minimum period of 5 minutes between dosage adjustments to assess clinical effects.

For maintenance of sedation, most adults require 5–50 mcg/kg per minute (0.3–3 mg/kg per hour); higher maintenance infusion rates occasionally required (e.g., patients who have recovered from general anesthesia or deep sedation). However, manufacturers state that infusion rate should not exceed 4 mg/kg per hour unless benefits outweigh risks. 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.

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 for Propofol

Contraindications

  • Known hypersensitivity to propofol or any ingredient in the formulation.

  • Known hypersensitivity to eggs, egg products, soybeans, or soy products.

Warnings/Precautions

Warnings

Respiratory and Cardiovascular Effects

Risk of respiratory depression; apnea and airway obstruction can occur, especially following rapid bolus injection and/or administration of larger doses such as those used for induction of anesthesia.

Cardiovascular depressant with effects greater than or equal to those associated with other IV 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 sedated patients continuously for early signs of hypotension and bradycardia; also monitor for adverse respiratory effects (e.g., apnea, airway obstruction, oxyhemoglobin desaturation), especially in those undergoing MAC sedation.

Cardiorespiratory effects are more likely to occur following administration of 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

Potential for microbial contamination of the injection and consequent development of fever, infection, sepsis, other life-threatening illness, or death with improper aseptic technique when handling propofol. In addition, transmission of bloodborne pathogens (e.g., hepatitis B, hepatitis C, HIV) reported from unsafe injection practices and use of propofol vials intended for single use on multiple patients.

Although commercially available preparations contain ingredients that retard growth of microorganisms, they are not considered antimicrobially preserved products by USP standards. Contamination of propofol with even very small numbers of microorganisms may result in clinical disease; strict aseptic technique and strict adherence to the manufacturer’s preparation and handling instructions are required.

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

Although infections associated with propofol principally have been traced to extrinsic contamination of the drug, specific lots of propofol (Teva) were recalled secondary to the presence of elevated endotoxin levels.

Dependence, Tolerance, and Abuse

Dependence and abuse, sometimes resulting in death, have been reported. Most reported cases have involved healthcare professionals (principally anesthesiology personnel), but abuse by lay persons also reported.

Psychological dependence (e.g., intense craving for the drug, loss of control over amount and frequency of use) reported in cases of propofol abuse. Withdrawal symptoms (e.g., insomnia, anxiety, difficulty concentrating), suggesting physical dependence, observed rarely. Signs of tolerance also observed.

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. (See Contraindications under Cautions.)

Hypersensitivity Reactions

Anaphylactoid and/or anaphylactic reactions (e.g., angioedema, bronchospasm, erythema, hypotension) reported rarely following propofol administration; may be fatal or life-threatening. (See Contraindications under Cautions.)

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 larger veins of the forearm or antecubital fossa rather than hand veins; may also administer lidocaine prior to or with (premixed) propofol (see IV Administration under Dosage and Administration). Other methods that may be beneficial include prior administration of low-dose opiates or other analgesic agents and venous occlusion with a tourniquet.

Propofol Infusion Syndrome

Propofol infusion syndrome reported in patients receiving propofol for sedation in a critical care setting. Characterized by severe metabolic acidosis, hyperkalemia, lipidemia, rhabdomyolysis, hepatomegaly, and cardiac, renal, or circulatory failure. Occurs most frequently in patients receiving prolonged, high-dose infusions (>5 mg/kg per hour for >48 hours) but has occurred following short-term, high-dose infusions during surgical anesthesia.

Closely monitor patients for development of unexplained acidosis, rhabdomyolysis, and cardiac or renal failure. Consider alternate means of sedation in the setting of prolonged need for sedation, increasing propofol dosage requirements to maintain a constant level of sedation, or onset of metabolic acidosis during propofol infusion.

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 (e.g., Diprivan) contain 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

Propofol 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.

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. Concomitant use of opiate analgesics and benzodiazepines can increase the risk of CNS effects.

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 to produce a light level of sedation until about 10–15 minutes prior to extubation.

Specific Populations

Pregnancy

No adequate and controlled studies in pregnant women. Not recommended for obstetric surgery (e.g., cesarean section).

In animal reproduction studies, decreased pup survival and increased postimplantation loss observed.

Based on animal data, repeated or prolonged use of general anesthetics and sedation drugs, including propofol, during the third trimester of pregnancy may result in adverse neurodevelopmental effects in the fetus. (See Pediatric Use under Cautions and also see Advice to Patients.)

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

Manufacturer states safety and efficacy for induction of general anesthesia not established in children <3 years of age; safety and efficacy for maintenance of general anesthesia not established in children <2 months of age.

The manufacturers state that propofol is not recommended for sedation in critical care settings or for use in combination with regional anesthesia in children <16 years of age because safety for these uses 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.

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.

Repeated or prolonged use of general anesthetics and sedation drugs, including propofol, in children <3 years of age or during the third trimester of pregnancy may adversely affect neurodevelopment. In animals, use for >3 hours of anesthetic and sedation drugs that block N-methyl-d-aspartic acid (NMDA) receptors and/or potentiate GABA activity leads to widespread neuronal apoptosis in the brain and long-term deficits in cognition and behavior; clinical relevance to humans is unknown. Some evidence suggests similar deficits may occur in children following repeated or prolonged exposure to anesthesia early in life. Some evidence also indicates that a single, relatively brief exposure to general anesthesia in generally healthy children is unlikely to cause clinically detectable deficits in global cognitive function or serious behavioral disorders. Most studies to date have substantial limitations; further research needed to fully characterize effects, particularly for prolonged or repeated exposures and in more vulnerable populations (e.g., less healthy children). Consider benefits and potential risks when determining the timing of elective procedures requiring anesthesia. FDA states that medically necessary procedures should not be delayed or avoided. (See Advice to Patients.)

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, oxyhemoglobin desaturation).

Hepatic Impairment

Long-term propofol therapy not evaluated to date.

Renal Impairment

Long-term propofol therapy not evaluated to date.

Common Adverse Effects

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

ICU sedation: Bradycardia, decreased cardiac output, hypotension, hyperlipidemia, respiratory acidosis (during weaning).

Interactions for Propofol

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 µM) of propofol, there have been relatively few clinically important interactions with drugs metabolized by or affecting CYP isoenzymes.

Specific Drugs

Drug

Interaction

Comments

Anticoagulants (e.g., warfarin)

IV administration of lipids (e.g., those contained in the propofol emulsion) may decrease response to warfarin in patients with malabsorptive states (e.g., Crohn’s disease)

Use heparin for initial anticoagulation in patients with malabsorptive states receiving high-dose lipid emulsions; if warfarin is given, monitor INR daily

CNS depressants (e.g., benzodiazepines, opiates, inhalation anesthetics [e.g., nitrous oxide, isoflurane])

Increased sedative, anesthetic, and cardiorespiratory depressant effects of propofol

Reduce induction dose of propofol in patients receiving premedication with IV or IM opiates or in those receiving opiates in combination with sedatives (e.g., benzodiazepines, barbiturates, chloral hydrate, droperidol)

Reduce infusion rate of propofol during maintenance of anesthesia or sedation in those receiving CNS depressants concomitantly

Droperidol

Increased frequency of postoperative nausea and vomiting reported

Fentanyl

Possibility of severe bradycardia in pediatric patients

Midazolam

Synergistic effect (possibly at GABAA receptors in the brain), producing induction of anesthesia and sedation

Free plasma concentrations of midazolam increased by about 20%; no apparent effect on free concentrations of propofol

Neuromuscular blocking agents (e.g., succinylcholine, nondepolarizing skeletal muscle relaxants)

No clinically important changes in the onset, intensity, or duration of action of commonly used neuromuscular blocking agents

Opiate agonists (e.g., alfentanil, fentanyl, sufentanil)

Blood concentrations of opiates increased by 10–20%

Blood concentrations of propofol increased by up to 22% with alfentanil use

Variations in blood concentrations of propofol and opiates are unlikely to be clinically important; however, sedation and analgesia may be greater with the combination than with either agent alone

Propofol 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

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.

Solution Compatibility1 2

Compatible

Dextrose 5% in Ringer’s injection, lactated

Dextrose 5% in sodium chloride 0.2 or 0.45%

Dextrose 5% in water

Ringer’s injection, lactated

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)HID

Compatible

Acyclovir sodium

Alfentanil HCl

Aminophylline

Ampicillin sodium

Atropine sulfate

Aztreonam

Bumetanide

Buprenorphine HCl

Butorphanol tartrate

Calcium gluconate

Carboplatin

Cefazolin sodium

Cefotaxime sodium

Cefotetan disodium

Cefoxitin sodium

Ceftazidime

Ceftriaxone sodium

Cefuroxime sodium

Chlorpromazine HCl

Cisplatin

Clindamycin phosphate

Cyclophosphamide

Cyclosporine

Cytarabine

Dexamethasone sodium phosphate

Dexmedetomidine HCl

Diphenhydramine HCl

Dobutamine HCl

Dopamine HCl

Doxycycline hyclate

Droperidol

Enalaprilat

Ephedrine sulfate

Epinephrine HCl

Esmolol HCl

Famotidine

Fenoldopam mesylate

Fentanyl citrate

Fluconazole

Fluorouracil

Furosemide

Ganciclovir sodium

Glycopyrrolate

Granisetron HCl

Haloperidol lactate

Heparin sodium

Hydrocortisone sodium succinate

Hydromorphone HCl

Hydroxyzine HCl

Ifosfamide

Imipenem–cilastatin sodium

Insulin

Isoproterenol HCl

Ketamine HCl

Labetalol HCl

Lidocaine HCl

Lorazepam

Magnesium sulfate

Mannitol

Meperidine HCl

Midazolam HCl

Milrinone lactate

Morphine sulfate

Nafcillin sodium

Nalbuphine HCl

Naloxone HCl

Nitroglycerin

Norepinephrine bitartrate

Paclitaxel

Pancuronium bromide

Pentobarbital sodium

Phenobarbital sodium

Phenylephrine HCl

Potassium chloride

Prochlorperazine edisylate

Propranolol HCl

Ranitidine HCl

Scopolamine HBr

Sodium bicarbonate

Sodium nitroprusside

Succinylcholine chloride

Sufentanil citrate

Vancomycin HCl

Vecuronium bromide

Incompatible

Amikacin sulfate

Amphotericin B

Calcium chloride

Ceftolozane sulfate-tazobactam sodium

Diazepam

Gentamicin sulfate

Methotrexate sodium

Methylprednisolone sodium succinate

Mitoxantrone HCl

Phenytoin sodium

Tobramycin sulfate

Variable

Atracurium besylate

Cisatracurium besylate

Telavancin HCl

Actions

  • Effects appear to be related, at least partially, to propofol’s ability to enhance the activity of GABA by interacting with the GABAA 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.

  • When procedures requiring general anesthetics or sedation drugs, including propofol, are considered for young children or pregnant women, importance of discussing with the patient, parent, or caregiver the benefits, risks (including potential risk of adverse neurodevelopmental effects), and appropriate timing and duration of the procedure.

  • 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.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Propofol

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injectable emulsion, for IV use

10 mg/mL*

Diprivan Emulsion (available as ready-to-use single patient vials)

Fresenius Kabi

Propofol Injectable Emulsion

AHFS DI Essentials™. © Copyright 2021, Selected Revisions August 24, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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

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