Propofol

Pharmacologic Category

General Anesthetic

Dosing: Adult

Consult local regulations and individual institutional policies and procedures. Dosage must be individualized based on total body weight and titrated to the desired clinical effect. Wait at least 3 to 5 minutes between dosage adjustments to clinically assess drug effects. Smaller doses are required when used with opioids; the following are general dosing guidelines (see “Abbreviations, Acronyms, and Symbols” for explanation of ASA-PS classes):

General anesthesia: Note: Increase dose in patients with chronic alcoholism (Fassoulaki 1993); decrease dose with acutely intoxicated (alcoholic) patients.

Induction of general anesthesia:

Healthy adults, ASA-PS 1 or 2, <55 years: IV: 2 to 2.5 mg/kg (~40 mg every 10 seconds until onset of induction)

Debilitated, ASA-PS 3 or 4: Refer to geriatric dosing.

Maintenance of general anesthesia:

Healthy adults, ASA-PS 1 or 2, <55 years:

IV infusion: Initial: 100 to 200 mcg/kg/minute (or 6 to 12 mg/kg/hour) for 10 to 15 minutes; usual maintenance infusion rate: 50 to 100 mcg/kg/minute (or 3 to 6 mg/kg/hour) to optimize recovery time.

IV intermittent bolus: 25 to 50 mg increments as needed

Debilitated, ASA-PS 3 or 4: IV Infusion: Refer to geriatric dosing.

Monitored anesthesia care sedation:

Healthy adults, ASA-PS 1 or 2, <55 years: Slow IV infusion: 100 to 150 mcg/kg/minute (or 6 to 9 mg/kg/hour) for 3 to 5 minutes or slow injection: 0.5 mg/kg over 3 to 5 minutes followed by IV infusion of 25 to 75 mcg/kg/minute (or 1.5 to 4.5 mg/kg/hour) or incremental bolus doses: 10 mg or 20 mg

Debilitated or ASA-PS 3 or 4 patients: Use 80% of healthy adult dose

ICU sedation in intubated mechanically ventilated patients: Avoid rapid bolus injection; individualize dose and titrate to response.

Continuous infusion: Initial: 5 mcg/kg/minute (or 0.3 mg/kg/hour); increase by 5 to 10 mcg/kg/minute (or 0.3 to 0.6 mg/kg/hour) every 5 to 10 minutes until desired sedation level is achieved; usual maintenance: 5 to 50 mcg/kg/minute (or 0.3 to 3 mg/kg/hour); reduce dose after goal sedation established and adjust to response (eg, evaluate frequently to minimize dose for sedation). Daily interruption with retitration to a light target level of sedation is recommended to minimize prolonged sedative effects (SCCM [Barr 2013]; SCCM [Devlin 2018]).

Elderly, debilitated, or ASA-PS 3 or 4 patients: Refer to geriatric dosing.

Postoperative nausea and vomiting (PONV), rescue therapy (off-label use): IV: 15 to 20 mg, may be repeated (SAA [Gan 2014]; Unlugenc 2003).

Status epilepticus, refractory (off-label use): IV: Note: Mechanical ventilation and cardiovascular monitoring required; titrate dose to cessation of electrographic seizures or burst suppression (NCS [Brophy, 2012]).

Neurocritical Care Society recommendations (NCS [Brophy 2012]):

Loading dose: 1 to 2 mg/kg with initiation of a continuous infusion.

Continuous infusion: Initial: 20 mcg/kg/minute (1.2 mg/kg/hour). If the patient experiences breakthrough status epilepticus while on continuous infusion, increase infusion rate by 5 to 10 mcg/kg/minute (0.3 to 0.6 mg/kg/hour) every 5 minutes (may also administer a 1 mg/kg bolus dose with continuous infusion titration); dosage range: 30 to 200 mcg/kg/minute (1.8 to 12 mg/kg/hour). Note: Use caution with doses >80 mcg/kg/minute (>4.8 mg/kg/hour) for >48 hours. Prior to withdrawal, a period of at least 24 to 48 hours of electrographic control is recommended; withdraw gradually to prevent recurrent status epilepticus.

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Consult local regulations and individual institutional policies and procedures. Dosage must be individualized based on total body weight and titrated to the desired clinical effect. Wait at least 3 to 5 minutes between dosage adjustments to clinically assess drug effects. Smaller doses are required when used with opioids; the following are general dosing guidelines (see “Abbreviations, Acronyms, and Symbols” for explanation of ASA-PS classes):

General anesthesia: Note: Increase dose in patients with chronic alcoholism (Fassoulaki, 1993); decrease dose with acutely intoxicated (alcoholic) patients.

Induction of general anesthesia: Elderly, debilitated, ASA-PS 3 or 4: IV: 1 to 1.5 mg/kg (~20 mg every 10 seconds until onset of induction)

Maintenance of general anesthesia: Elderly, debilitated, ASA-PS 3 or 4: IV infusion: 50 to 100 mcg/kg/minute (or 3 to 6 mg/kg/hour)

Monitored anesthesia care sedation: Elderly, debilitated, ASA-PS 3 or 4: IV: Use 80% of healthy adult dose

ICU sedation in intubated mechanically-ventilated patients: Avoid rapid bolus injection; individualize dose and titrate to response:

Continuous infusion: Elderly, debilitated, ASA-PS 3 or 4: Use 80% of healthy adult dose; reduce dose after adequate sedation established and adjust to response (eg, evaluate frequently to use minimum dose for sedation). Daily interruption with retitration to a light target level of sedation is recommended to minimize prolonged sedative effects (SCCM [Barr 2013]; SCCM [Devlin 2018]).

Dosing: Renal Impairment: Adult

No dosage adjustment necessary.

Dosing: Hepatic Impairment: Adult

No dosage adjustment necessary.

Dosing: Pediatric

Note: Consult local regulations and individual institutional policies and procedures; should only be used by experienced personnel who are not actively engaged in the procedure or surgery; if used in a nonintubated and/or nonmechanically ventilated patient, qualified personnel and appropriate equipment for rapid institution of respiratory and/or cardiovascular support must be immediately available.

Dosage must be individualized based on total body weight and titrated to the desired clinical effect; wait at least 3 to 5 minutes between dosage adjustments to clinically assess drug effects; smaller doses are required when used with opioids; the following are general dosing guidelines (see "Abbreviations, Acronyms, and Symbols" section in front section for explanation of ASA-PS classes).

Anesthesia, general: Note: Increase dose in patients with chronic alcoholism (Fassoulaki 1993); decrease dose with acutely intoxicated (alcoholic) patients.

Induction of general anesthesia: Children and Adolescents (healthy) 3 to 16 years, ASA-PS 1 or 2: IV: 2.5 to 3.5 mg/kg over 20 to 30 seconds; use a lower dose for ASA-PS 3 or 4

Maintenance of general anesthesia: Infants ≥2 months, Children, and Adolescents (healthy), ASA-PS 1 or 2: IV infusion: General range: 125 to 300 mcg/kg/minute (7.5 to 18 mg/kg/hour); Initial dose immediately following induction: 200 to 300 mcg/kg/minute; then decrease dose after 30 minutes if clinical signs of light anesthesia are absent; usual infusion rate after initial 30 minutes: 125 to 150 mcg/kg/minute (7.5 to 9 mg/kg/hour); younger pediatric patients may need higher infusion rates than older pediatric patients.

Procedural sedation: Limited data available: Infants, Children, and Adolescents: IV:

Repeated bolus method: Usual initial dose: 1 mg/kg; reported range for initial dose: 1 to 2 mg/kg; follow initial dose with 0.5 mg/kg every 3 to 5 minutes as needed until adequate level of sedation achieved (ACEP [Godwin 2014]; Bedirli 2012; Cho 2010; Ince 2013; Krauss 2006).

IV bolus followed by continuous infusion: Initial bolus: 1 to 2 mg/kg; continuous infusion: Reported initial rate and titration are variable (Machata 2010; Srinivasan 2012; Vespasiano 2007). In a large report of a pediatric sedation program in >4,000 patients (age range: 1 month to 21 years), after an initial bolus of at least 2 mg/kg, an infusion was started at an initial rate of 9 mg/kg/hour (150 mcg/kg/minute) and titrated as required; supplemental doses of 1 to 2 mg/kg were used as needed; however, hypotension occurred in up to 42.5% of patients undergoing MRI and 23.2% of patients undergoing other procedures (Vespasiano 2007). In a smaller trial of 138 young pediatric patients (age range: 3 months to 6 years), after a 1 mg/kg bolus, an infusion was initiated at an initial rate of 5 mg/kg/hour (83 mcg/kg/minute) and then titrated upward in 1 mg/kg/hour increments (to a maximum of 8 mg/kg/hour [133 mcg/kg/minute]) with additional boluses of 0.5 mg/kg given as needed to achieve adequate sedation level (Machata 2010).

Propofol with concurrent ketamine; emergency department procedures: IV: 0.5 to 0.75 mg/kg (ACEP [Godwin 2014])

Note: When utilized by an organized service with trained and credentialed personnel, propofol use for procedural sedation outside of the operating room was shown to have low risk for serious adverse outcomes (Cravero 2009; Kamat 2015).

Status epilepticus; refractory: Limited data available: Children and Adolescents: Note: Several experts have expressed concern when using propofol for this indication in infants and children due to the risk for propofol-related infusion syndrome, particularly when administered in conjunction with a ketogenic diet or when given at high doses for prolonged periods of time (Baumeister 2004; Iyer 2009). Neurocritical Care Society guidelines for status epilepticus state that use of propofol in young children is contraindicated (NCS [Brophy 2010]):

Initial propofol infusion: IV: Loading dose 1 to 2 mg/kg, then initiate continuous IV infusion at 1.2 mg/kg/hour (20 mcg/kg/minute); titrate to desired effect (eg, burst suppression on EEG); usual range: 1.8 to 12 mg/kg/hour (30 to 200 mcg/kg/minute) (NCS [Brophy 2012]). Note: Use caution when administering high doses (>4 mg/kg/hour [>65 mcg/kg/minute]) for extended periods of time (>48 hours); monitor closely for adverse effects (eg, PRIS) (NCS [Brophy 2012]).

Breakthrough seizure while on propofol infusion: IV: Increase infusion rate by 0.3 to 0.6 mg/kg/hour (5 to 10 mcg/kg/minute) every 5 minutes with or without an additional 1 mg/kg bolus (NCS [Brophy 2012])

Dosing: Renal Impairment: Pediatric

No dosage adjustment necessary.

Dosing: Hepatic Impairment: Pediatric

No dosage adjustment necessary.

Calculations

• Propofol

Use: Labeled Indications

Induction of anesthesia in patients ≥3 years of age; maintenance of anesthesia in patients >2 months of age; in adults, for monitored anesthesia care sedation during procedures; in adults, for sedation in intubated, mechanically-ventilated ICU patients

Note: Consult local regulations and individual institutional policies and procedures.

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

Postoperative nausea and vomiting (PONV), rescue therapyLevel of Evidence [B, G]

Data from a randomized, blinded study supports the use of propofol in the treatment of postoperative nausea and vomiting ^Ref. Additional trials may be necessary to further define the role of propofol in this condition.

Based on the Society for Ambulatory Anesthesia Guidelines for the Management of Postoperative Nausea and Vomiting, propofol is effective and may be considered for postoperative nausea and vomiting rescue therapy in patients still in the post anesthesia care unit ^Ref.

Status epilepticus, refractoryLevel of Evidence [C, G]

Data from two retrospective chart reviews and one small, mixed prospective/retrospective study in patients with refractory status epilepticus treated with propofol suggests that propofol may be beneficial for the treatment of this condition ^Ref.

Based on the Neurocritical Care Society Guidelines for the Evaluation and Management of Status Epilepticus, the use of propofol is an effective and recommended treatment for refractory status epilepticus in adults.

Level of Evidence Definitions

Level of Evidence Scale

Clinical Practice Guidelines

Critical Care:

ACCM/SCCM, "Clinical Practice Guidelines for the Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU,” September 2018

ACCM/SCCM, “Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU,” August 2018

ACCM/SCCM, "Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit,” January 2013

Status Epilepticus:

EFNS 2010, “EFNS Guideline on the Management of Status Epilepticus in Adults,” December 2009

Neurocritical Care Society (NCS), “Guidelines for the Evaluation and Management of Status Epilepticus,” April 2012

Administration: IV

Administer IVP or by continuous IV infusion. Consult local regulations and individual institutional policies and procedures. Strict aseptic technique must be maintained in handling although a preservative has been added. Do not use if contamination is suspected. Do not administer through the same IV catheter with blood or plasma. Tubing and any unused portions of propofol vials should be discarded after 12 hours.

To reduce pain associated with injection, use larger veins of forearm or antecubital fossa; lidocaine IV (1 mL of a 1% solution) may also be used prior to administration or it may be added to propofol immediately before administration in a quantity not to exceed 20 mg lidocaine per 200 mg propofol. Do not use filter <5 micron for administration.

Administration: Injectable Detail

pH: 7 to 8.5

Administration: Pediatric

Note: Consult local regulations and individual institutional policies and procedures.

Parenteral: IV: Strict aseptic technique must be maintained in handling. Shake emulsion well before use. May be administered undiluted or may be further diluted with D5W. Do not administer via filter with <5-micron pore size. Do not administer through the same IV catheter with blood or plasma. Tubing and any unused portions of propofol vials should be discarded after 12 hours.

To reduce pain associated with injection, use larger veins of forearm or antecubital fossa; lidocaine IV (1 mL of a 1% solution) may also be used prior to administration or lidocaine may be added to propofol immediately before administration.

Induction: Administer pediatric induction doses over 20 to 30 seconds

Maintenance: Administer at a concentration of 2 to 10 mg/mL at prescribed rate

Dietary Considerations

Propofol is formulated in an oil-in-water emulsion. If on parenteral nutrition, may need to adjust the amount of lipid infused. Propofol emulsion contains 1.1 kcal/mL. Soybean fat emulsion is used as a vehicle for propofol. Formulations also contain egg phospholipids (egg lecithin) and glycerol.

Storage/Stability

Store between 4°C to 22°C (40°F to 72°F); refrigeration is not required. Do not freeze. Shake well before use. Withdraw from vial into a syringe immediately after sterile vented spike inserted. Administration should begin immediately and completed within 12 hours after the vial has been opened. Do not use if there is evidence of separation of phases of emulsion.

Preparation for Administration: Adult

Does not need to be diluted; however, propofol may be further diluted in 5% dextrose in water to a concentration of ≥2 mg/mL.

Preparation for Administration: Pediatric

Parenteral: IV: May be further diluted in D5W to a concentration of ≥2 mg/mL; diluted emulsion is more stable in glass (stability in plastic: 95% potency after 2 hours). To reduce pain associated with administration, may add lidocaine to propofol immediately before administration in a quantity not to exceed 20 mg lidocaine per 200 mg propofol. Strict aseptic technique must be maintained in handling. Prepare drug for single-patient use only. Shake emulsion well before use.

Compatibility

See Trissel’s IV Compatibility Database

Open Trissel's IV Compatibility

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to put you to sleep for surgery.

• It is used to calm you before a procedure.

• It is used to cause sleep during a procedure.

• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Fatigue

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Pancreatitis like severe abdominal pain, severe back pain, severe nausea, or vomiting.

• Severe dizziness

• Passing out

• Severe headache

• Difficulty breathing

• Slow breathing

• Shallow breathing

• Slow heartbeat

• Abnormal movements

• Twitching

• Change in balance

• Difficulty swallowing

• Difficulty speaking

• Vision changes

• Severe injection site pain, redness, burning, edema, blistering, or irritation

• Propofol infusion syndrome like dark urine or unable to pass urine; fast breathing; fast heartbeat or abnormal heartbeat; severe fatigue; nausea or vomiting; severe muscle pain or weakness; or shortness of breath, excessive weight gain, or swelling of the arms or legs.

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Safety Issues

Sound-alike/look-alike issues:

High alert medication:

Administration issues:

Contraindications

Hypersensitivity to propofol or any component of the formulation; hypersensitivity to eggs, egg products, soybeans, or soy products; when general anesthesia or sedation is contraindicated.

Note: Although the manufacturer's labeling lists egg allergy as a contraindication, available studies (mostly retrospective) and an American Academy of Allergy, Asthma, and Immunology statement have suggested that propofol may be used safely in soy- or egg-allergic patients (AAAAI [Lieberman 2015]; AAAAI 2019; Asserhoj 2016; Dziedzic 2016; Murphy 2011). In patients with more severe soy or egg allergy, some experts recommend the use of an alternative anesthetic or a small trial dose of propofol prior to full dose administration (Sicherer 2020).

Canadian labeling: Additional contraindication (not in US labeling): Hypersensitivity to lipid emulsions; sedation of children ≤18 years of age receiving intensive care.

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylaxis/hypersensitivity reactions: May rarely cause hypersensitivity, anaphylaxis, anaphylactoid reactions, angioedema, bronchospasm, and erythema; medications for the treatment of hypersensitivity reactions should be available for immediate use. Use with caution in patients with history of hypersensitivity/anaphylactic reaction to peanuts; a low risk of cross-reactivity between soy and peanuts may exist. According to the manufacturer, use is contraindicated in patients who are hypersensitive to eggs, egg products, soybeans, or soy products. However, available studies (mostly retrospective) and an American Academy of Allergy, Asthma, and Immunology statement have suggested that propofol may be used safely in soy- or egg-allergic patients (AAAAI [Lieberman 2015]; AAAAI 2019; Asserhoj 2016; Dziedzic 2016; Murphy 2011). In patients with more severe soy or egg allergy, some experts recommend the use of an alternative anesthetic or a small trial dose of propofol prior to full dose administration (Sicherer 2020).

• ECG effects: In most cases, propofol does not significantly affect the QT interval (Staikou 2014). However, prolongation of the QT interval, usually within normal limits, has occurred in case reports and small prospective studies and may be dose dependent (Hume-Smith 2008; Kim 2008; McConachie 1989; Saarnivaara 1990; Saarnivaara 1993; Sakabe 2002). Shortening of the QT interval has also occurred (Erdil 2009; Tanskanen 2002).

• Hypertriglyceridemia: Because propofol is formulated within a 10% fat emulsion, hypertriglyceridemia is an expected side effect. Patients who develop hypertriglyceridemia (eg, >500 mg/dL) are at risk of developing pancreatitis. Serum triglyceride levels should be obtained prior to initiation of therapy and every 3 to 7 days thereafter. Monitoring of serum triglycerides should especially be considered with therapy >48 hours with doses exceeding 50 mcg/kg/minute (Devlin 2005). An alternative sedative agent should be employed if significant hypertriglyceridemia occurs. Use with caution in patients with preexisting hyperlipidemia as evidenced by increased serum triglyceride levels or serum turbidity.

• Hypotension: The major cardiovascular effect of propofol is hypotension especially if patient is hypovolemic or if bolus dosing is used. Hypotension may be substantial with a reduction in mean arterial pressure occasionally exceeding 30%. Use with caution in patients who are hemodynamically unstable, hypovolemic, or have abnormally low vascular tone (eg, sepsis).

• Injection-site reaction: Transient local pain may occur during IV injection; lidocaine 1% solution may be administered prior to administration or may be added to propofol immediately prior to administration to reduce pain associated with injection (see Administration).

• Myoclonus: Perioperative myoclonus (eg, convulsions and opisthotonos) has occurred with administration.

• Propofol-related infusion syndrome (PRIS): PRIS is a serious side effect with a high mortality rate (up to 33%) characterized by dysrhythmia (eg, bradycardia or tachycardia), heart failure, hyperkalemia, lipemia, metabolic acidosis, and/or rhabdomyolysis or myoglobinuria with subsequent renal failure. Risk factors include poor oxygen delivery, sepsis, serious cerebral injury, and the administration of high doses of propofol (usually doses >83 mcg/kg/minute or >5 mg/kg/hour for >48 hours), but has also been reported following large dose, short-term infusions during surgical anesthesia. PRIS has also been reported with lower-dose infusions (Chukwuemeka 2006; Merz 2006). The onset of the syndrome is rapid, occurring within 4 days of initiation. The mechanism of the syndrome has yet to be determined. Alternate sedative therapy should be considered for patients with escalating doses of vasopressors or inotropes, when cardiac failure occurs during high-dose propofol infusion, when metabolic acidosis is observed, or in whom lengthy and/or high-dose sedation is needed (Corbett 2008; SCCM [Barr 2013]).

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with severe cardiac disease (ejection fraction <50%) or hypotension; may have more profound adverse cardiovascular responses to propofol. In a scientific statement from the American Heart Association, propofol has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: moderate) (AHA [Page 2016]).

• Increased intracranial pressure: Use with caution in patients with increased intracranial pressure or impaired cerebral circulation; substantial decreases in mean arterial pressure and subsequent decreases in cerebral perfusion pressure may occur; consider continuous infusion or administer as a slow bolus.

• Infection risk: Propofol vials and prefilled syringes have the potential to support the growth of various microorganisms despite product additives intended to suppress microbial growth. To limit the potential for contamination, strictly adhere to recommendations in product labeling for handling and administering propofol.

• Pancreatitis: Use with caution in patients with preexisting pancreatitis; use of propofol may exacerbate this condition.

• Respiratory disease: Use with caution in patients with respiratory disease.

• Seizure disorder: Use with caution in patients with a history of epilepsy or seizures; seizure may occur during recovery phase.

Concurrent drug therapy issues:

• Opioids: Concomitant use may lead to increased sedative or anesthetic effects of propofol, more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output; lower doses of propofol may be needed. In addition, fentanyl may cause serious bradycardia when used with propofol in pediatric patients. Alfentanil use with propofol has precipitated seizure activity in patients without any history of epilepsy.

Special populations:

• ASA-PS (American Society of Anesthesiologists - Physical Status) 3/4 patients: Use a lower induction dose, a slower maintenance rate of administration, and avoid rapidly delivered boluses in ASA-PS 3/4 patients to reduce the incidence of unwanted cardiorespiratory depressive events.

• Debilitated patients: Use a lower induction dose, a slower maintenance rate of administration, and avoid rapidly delivered boluses in debilitated patients to reduce the incidence of unwanted cardiorespiratory depressive events.

• Elderly: Use a lower induction dose, a slower maintenance rate of administration, and avoid rapidly delivered boluses in elderly patients to reduce the incidence of unwanted cardiorespiratory depressive events.

• Pediatric neurotoxicity: In pediatric and neonatal patients <3 years and patients in third trimester of pregnancy (ie, times of rapid brain growth and synaptogenesis), the repeated or lengthy exposure to sedatives or anesthetics during surgery/procedures may have detrimental effects on child or fetal brain development and may contribute to various cognitive and behavioral problems. Epidemiological studies in humans have reported various cognitive and behavioral problems including neurodevelopmental delay (and related diagnoses), learning disabilities, and ADHD. Human clinical data suggest that single, relatively short exposures are not likely to have similar negative effects. No specific anesthetic/sedative has been found to be safer. For elective procedures, risk vs benefits should be evaluated and discussed with parents/caregivers/patients; critical surgeries should not be delayed (FDA 2016).

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.

• Edetate disodium: Some formulations contain edetate disodium which may lead to decreased zinc levels in patients with prolonged therapy (>5 days) or a predisposition to zinc deficiency (eg, burns, diarrhea, or sepsis). A holiday from propofol infusion should take place after 5 days of therapy to allow for evaluation and necessary replacement of zinc.

• Sulfites: Some formulations may contain sulfites.

Other warnings/precautions:

• Abrupt discontinuation: Avoid abrupt discontinuation prior to weaning or daily wake up assessments. Abrupt discontinuation can result in rapid awakening, anxiety, agitation, and resistance to mechanical ventilation; wean the infusion rate so the patient awakens slowly. Discontinue opioids and paralytic agents prior to weaning. Long-term infusions can result in some tolerance; taper propofol infusions to prevent withdrawal.

• Analgesic supplementation: Propofol lacks analgesic properties; pain management requires specific use of analgesic agents, at effective dosages, propofol must be titrated separately from the analgesic agent.

• Experienced personnel: Use requires careful patient monitoring, should only be used by experienced personnel who are not actively engaged in the procedure or surgery. If used in a nonintubated and/or nonmechanically ventilated patient, qualified personnel and appropriate equipment for rapid institution of respiratory and/or cardiovascular support must be immediately available. Use to induce moderate (conscious) sedation in patients warrants monitoring equivalent to that seen with deep anesthesia. Consult local regulations and individual institutional policies and procedures.

* See Cautions in AHFS Essentials for additional information.

Warnings: Additional Pediatric Considerations

In pediatric and neonatal patients <3 years of age and patients in third trimester of pregnancy (ie, times of rapid brain growth and synaptogenesis), the repeated or lengthy exposure to sedatives or anesthetics during surgery/procedures may have detrimental effects on the child’s or fetus’ brain development and may contribute to various cognitive and behavioral problems; the FDA is requiring warnings be included in the manufacturer’s labeling for all general anesthetic/sedative drugs. Multiple animal species studies have shown adverse effects on brain maturation; in juvenile animals, drugs that potentiate GABA activity and/or block NMDA receptors for >3 hours demonstrated widespread neuronal and oligodendrocyte cell loss along with alteration in synaptic morphology and neurogenesis. Epidemiological studies in humans have reported various cognitive and behavioral problems including neurodevelopmental delay (and related diagnoses), learning disabilities, and ADHD. Human clinical data suggest that single, relatively short exposures are not likely to have similar negative effects. Further studies are needed to fully characterize findings and ensure that these findings are not related to underlying conditions or the procedure itself. No specific anesthetic/sedative has been found to be safer. For elective procedures, risk vs benefits should be evaluated and discussed with parents/caregivers/patients; critical surgeries should not be delayed (FDA 2016).

Metabolic acidosis with fatal cardiac failure has occurred in several infants and children (4 weeks to 11 years of age) who received propofol infusions at average rates of infusion of 4.5 to 10 mg/kg/hour for 66 to 115 hours (maximum rates of infusion: 6.2 to 11.5 mg/kg/hour) (Bray 1995; Parke 1992; Strickland 1995). Anecdotal reports of serious adverse events, including death, have been reported in pediatric patients with upper respiratory tract infections receiving propofol for ICU sedation. Not recommended for ICU sedation of pediatric patients; an increased number of deaths was observed in a multicenter clinical trial of pediatric ICU patients who received propofol (9% mortality) versus patients who received other sedative agents (4% mortality); although causality was not established, propofol is not indicated for sedation in PICU patients until further studies can document its safety in this population.

Use extreme caution when using for refractory status epilepticus because higher doses are often required to control seizures for an extended period of time (in pediatric patients: doses >65 mcg/kg/minute (4 mg/kg/hour) for >48 hours) which may increase risk for PRIS (NCS [Brophy 2012]). Fatal cardiac failure has also been reported with concurrent ketogenic diet and propofol therapy (Baumeister 2004).

In neonates, decreased mean arterial pressure (MAP) is frequently observed with propofol administration. Significantly decreased MAP (<25 mm Hg) were reported in a trial of premature neonates (n=13, GA: 29 to 32 weeks) receiving propofol (1 mg/kg) with atropine at PNA <8 hours. The 1 mg/kg dose decreased the mean MAP from 38 mm Hg to 24 mm Hg; investigators ended the trial early as a result. Previous experience by these investigators had similar findings of hypotension, sometimes refractory to fluid therapy, when a dose of 2.5 mg/kg was used (Welzing 2010). In the largest reported experience from a prospective observational study (n=44; 62 intubation procedures; GA: 24 to 40 weeks), 39% of patients experienced hypotension after receiving propofol and were treated with additional intravascular fluid; two patients (5%) required the use of dobutamine to treat their hypotension (Simons 2013); use extreme caution with use in neonates; monitor hemodynamic status closely.

Propofol use for procedural sedation outside of the operating room was shown to have low risk for serious adverse outcomes when utilized by an organized service with trained and credentialed personnel. Data was collected by the Pediatric Sedation Research Consortium from 37 institutions including 49,836 encounters. There were no deaths, two cardiopulmonary resuscitations, and four aspiration events. Less serious events included central apnea/airway obstruction (5.7%), excessive secretions (3.4%), other respiratory events (0.5% to 1.5%, eg, desaturation, stridor, laryngospasm) and vomiting (0.5%). The pulmonary adverse effects were similar to expected values (Cravero 2009). The same study group reported an additional 5 years of data with an additional 91,189 encounters and showed similar findings. In comparison to the earlier time period, the incidence of airway obstruction was lower (1.6%). Risk factors for adverse reaction included: primary diagnosis of respiratory infection, prematurity, concomitant medications, and certain procedure locations (eg, dental clinic, catheter lab) (Kamat 2015).

Acute febrile reactions: In June 2007, the FDA alerted clinicians of several reports of chills, fever, and body aches occurring in clusters of patients after administration of propofol for sedation in gastrointestinal suites. These reports were received from several facilities and involved multiple vials and lots. Symptoms appeared 6 to 18 hours following propofol therapy and persisted for ≤3 days. There is no evidence that any patient had sepsis or that the vials were contaminated. The FDA has tested multiple propofol vials and lots used in these patients and presently have found no evidence of bacterial contamination. Regardless, propofol vials and prefilled syringes have the potential to support the growth of various microorganisms despite product additives intended to suppress microbial growth. To limit the potential for contamination, the FDA is reminding healthcare professionals to strictly adhere to recommendations in product labeling for handling and administering propofol. Clinicians should also be vigilant for signs and symptoms of acute febrile reactions and evaluate patients for bacteremia. The FDA is continuing to work with the Centers for Disease Control and Prevention to investigate factors contributing to these occurrences. Additional information is available at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm109357.htm.

Pregnancy Considerations

Propofol crosses the placenta and may be associated with neonatal CNS and respiratory depression.

Based on animal data, repeated or prolonged use of general anesthetic and sedation medications that block N-methyl-D-aspartate (NMDA) receptors and/or potentiate gamma-aminobutyric acid (GABA) activity may affect brain development. Evaluate benefits and potential risks of fetal exposure to propofol when duration of surgery is expected to be >3 hours (Olutoye 2018).

Propofol is not recommended by the manufacturer for obstetrical use, including cesarean section deliveries. However, in cases where general anesthesia is needed for cesarean delivery, propofol has been used as an induction agent (ACOG 209 2019; Devroe 2015).

The ACOG recommends that pregnant women should not be denied medically necessary surgery, regardless of trimester. If the procedure is elective, it should be delayed until after delivery (ACOG 775 2019).

Breast-Feeding Considerations

Propofol is present in breast milk.

In studies where propofol is used prior to cesarean delivery, exposure to the infant is low due to low concentrations in breast milk and low volume of breast milk produced within 24 hours' postpartum. When measurable, concentrations decrease quickly over time (Dailland 1989). Studies conducted in nine lactating women undergoing general surgery where propofol was used to induce anesthesia report propofol milk concentrations that are <1% of the total maternal dose. Except in one case where age was not clearly specified, infants in these studies were between 6 weeks and 15 months of age (Nitsun 2006; Stuttmann 2010).

A green discoloration to the breast milk was noted in a woman following administration of propofol during surgery for removal of an ectopic pregnancy. Although other medications were also administered, propofol was detected in the milk and assumed to be the cause; resolution of this effect occurred within 48 hours after surgery (Birkholz 2009). Dizziness or drowsiness were not observed in four breastfed infants. One was a 3-month old infant fed as early as ~90 minutes after maternal surgery (Stuttmann 2010).

Breastfeeding is not recommended by the manufacturer. The Academy of Breast Feeding Medicine recommends postponing elective surgery until milk supply and breastfeeding are established. Milk should be expressed ahead of surgery when possible. In general, when the child is healthy and full term, breastfeeding may resume, or milk may be expressed once the mother is awake and in recovery. For children who are at risk for apnea, hypotension, or hypotonia, milk may be saved for later use when the child is at lower risk (ABM [Reece-Stremtan 2017]).

Briggs' Drugs in Pregnancy & Lactation

• Propofol

Adverse Reactions

>10%:

Cardiovascular: Hypotension (adults: 3% to 26%; children: 17%)

Central nervous system: Involuntary body movements (children: 17%; adults: 3% to 10%)

Local: Burning sensation at injection site (adults: ≤18%; children: ≤10%), pain at injection site (includes stinging; adults: ≤18%; children: ≤10%)

Respiratory: Apnea (30 to 60 seconds duration: adults: 24%, children: 10%; >60 seconds duration: adults: 12%, children: 5%)

1% to 10%:

Cardiovascular: Hypertension (children: 8%), bradycardia (1% to 3%), cardiac arrhythmia (1% to 3%), low cardiac output (1% to 3%; concurrent opioid use increases incidence), tachycardia (1% to 3%)

Dermatologic: Skin rash (children: 5%; adults: 1% to 3%), pruritus (1% to 3%)

Endocrine & metabolic: Hypertriglyceridemia (3% to 10%), respiratory acidosis (during weaning; 3% to 10%)

<1%, postmarketing, and/or case reports: Agitation, amblyopia, anaphylaxis, anaphylactoid reaction, anticholinergic syndrome, asystole, atrial arrhythmia, atrial premature contractions, bigeminy, chills, cloudy urine, cough, decreased lung function, delirium, dizziness, drowsiness, fever, flushing, hair discoloration (green), hemorrhage, hypertonia, hypomagnesemia, hypoxia, infusion-related reaction (propofol-related infusion syndrome), infusion site reaction (including pain, swelling, blisters and/or tissue necrosis following accidental extravasation), laryngospasm, leukocytosis, limb pain, loss of consciousness (postoperative; with or without increased muscle tone), myalgia, myoclonus (rarely including seizure and opisthotonos), nail discoloration (nailbeds green), nausea, pancreatitis, paresthesia, phlebitis, pulmonary edema, rhabdomyolysis, sialorrhea, syncope, thrombosis, urine discoloration (green), ventricular premature contractions, visual disturbance, wheezing

* See Cautions in AHFS Essentials for additional information.

Allergy and Idiosyncratic Reactions

• Propofol Allergy

Metabolism/Transport Effects

Substrate of CYP1A2 (minor), CYP2A6 (minor), CYP2B6 (major), CYP2C19 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP2E1 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP3A4 (weak)

Drug Interactions Open Interactions

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alfentanil: May enhance the adverse/toxic effect of Propofol. Specifically the development of opisthotonus (severe hyperextension and spasticity resulting in arching or bridging position) and/or tonic clonic seizures. Risk C: Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Risk D: Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy

ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Risk C: Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Risk X: Avoid combination

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Risk D: Consider therapy modification

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromperidol: Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents. Risk X: Avoid combination

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Risk C: Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Risk C: Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Risk D: Consider therapy modification

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy

EPHEDrine (Systemic): Propofol may enhance the therapeutic effect of EPHEDrine (Systemic). Risk C: Monitor therapy

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Risk C: Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Risk D: Consider therapy modification

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

Lemborexant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lemborexant. Management: The maximum recommended dosage of lemborexant is 5 mg, no more than once per night, when coadministered with weak CYP3A4 inhibitors. Risk D: Consider therapy modification

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification

Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Risk C: Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Risk C: Monitor therapy

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Risk D: Consider therapy modification

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy

Midazolam: May increase the serum concentration of Propofol. Propofol may increase the serum concentration of Midazolam. Risk C: Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP2B6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Risk C: Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Risk D: Consider therapy modification

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Risk D: Consider therapy modification

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Risk X: Avoid combination

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

RifAMPin: May enhance the hypotensive effect of Propofol. Management: Note that use of propofol in a patient who has been taking rifampin may result in clinically significant hypotension. If possible, avoid use of this combination. Risk D: Consider therapy modification

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

Ropivacaine: Propofol may increase the serum concentration of Ropivacaine. Risk C: Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Risk C: Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Risk D: Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Thiotepa: May increase the serum concentration of CYP2B6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Triazolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Triazolam. Management: Consider triazolam dose reduction in patients receiving concomitant weak CYP3A4 inhibitors. Risk D: Consider therapy modification

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Ubrogepant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Ubrogepant. Management: In patients taking weak CYP3A4 inhibitors, the initial and second dose (if needed) of ubrogepant should be limited to 50 mg. Risk D: Consider therapy modification

Valproate Products: May enhance the therapeutic effect of Propofol. Risk C: Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification

Food Interactions

Edetate disodium, an ingredient of propofol emulsion, may lead to decreased zinc levels in patients on prolonged therapy (>5 days) or those predisposed to deficiency (burns, diarrhea, and/or major sepsis). Management: Zinc replacement therapy may be needed.

Genes of Interest

• Cytochrome P450 2B6

Monitoring Parameters

Cardiac monitor, blood pressure, oxygen saturation (during monitored anesthesia care sedation), arterial blood gas (with prolonged infusions). With prolonged infusions (eg, ICU sedation), monitor for signs and symptoms of propofol-related infusion syndrome (PRIS): Metabolic acidosis, hyperkalemia, rhabdomyolysis or elevated CPK, hepatomegaly, and progression of cardiac and renal failure.

ICU sedation: Assess and adjust sedation according to scoring system (Richmond Agitation-Sedation Scale or Sedation-Agitation Scale) (SCCM [Devlin 2018]); assess CNS function daily. Serum triglyceride levels should be obtained prior to initiation of therapy and every 3 to 7 days thereafter, especially if receiving for >48 hours with doses exceeding 50 mcg/kg/minute (Devlin 2005); use IV port opposite propofol infusion or temporarily suspend infusion and flush port prior to blood draw.

Diprivan: Monitor zinc levels in patients predisposed to deficiency (burns, diarrhea, major sepsis) or after 5 days of treatment.

Advanced Practitioners Physical Assessment/Monitoring

An imported product, Fresenius Propoven, that has been used to deal with the U.S. propofol shortage, is contraindicated in patients with a peanut allergy. Dosage and rate of administration should be individualized and titrated to the desired effect, according to relevant clinical factors, premedication, concomitant medications, age, and general condition of patient. Continuous monitoring of vital signs, cardiac and respiratory status, and level of sedation is mandatory during infusion and until full consciousness is regained. Safety precautions must be maintained until patient is fully alert. Propofol is an anesthetic; pain must be treated with appropriate analgesic agents. Do not discontinue abruptly (may result in rapid awakening associated with anxiety, agitation, and resistance to mechanical ventilation). Titrate infusion rate so patient awakes slowly. After long-term administration, it will take longer for reduction of propofol levels than if propofol is used for short-term anesthesia. Reposition patient and provide appropriate skin care, mouth care, and care of patient's eyes every 2 to 3 hours while sedated. Provide appropriate emotional and sensory support (auditory and environmental).

Nursing Physical Assessment/Monitoring

An imported product, Fresenius Propoven, being used temporarily in the U.S. should not be used in patients with a peanut allergy. Continuous monitoring of vital signs, cardiac and respiratory status, and level of sedation is mandatory during infusion and until full consciousness is regained. Safety precautions must be maintained until patient is fully alert. Propofol is an anesthetic; pain must be treated with appropriate analgesic agents. Do not discontinue abruptly (may result in rapid awakening associated with anxiety, agitation, and resistance to mechanical ventilation); titrate infusion rate so patient awakes slowly. After long-term administration, it will take longer for reduction of propofol levels than if propofol is used for short-term anesthesia. Reposition patient and provide appropriate skin care, mouth care, and care of patient's eyes every 2 to 3 hours while sedated. Provide appropriate emotional and sensory support (auditory and environmental).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Emulsion, Intravenous:

Diprivan: 100 mg/10 mL (10 mL); 200 mg/20 mL (20 mL); 500 mg/50 mL (50 mL); 1000 mg/100 mL (100 mL) [contains edetate disodium, egg phospholipids (egg lecithin), glycerin, soybean oil]

Generic: 1000 mg/100 mL (100 mL); 200 mg/20 mL (20 mL); 500 mg/50 mL (50 mL)

Emulsion, Intravenous [preservative free]:

Fresenius Propoven: 200 mg/20 mL (20 mL); 500 mg/50 mL (50 mL); 1000 mg/100 mL (100 mL) [contains egg phosphatides, soybean oil]

Generic: 1000 mg/100 mL (100 mL); 200 mg/20 mL (20 mL); 500 mg/50 mL (50 mL)

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Emulsion, Intravenous:

Diprivan: 10 mg/mL (20 mL, 50 mL, 100 mL) [contains edetate disodium, egg phosphatides, soybean oil]

Generic: 10 mg/mL (20 mL, 50 mL, 100 mL)

Anatomic Therapeutic Chemical (ATC) Classification

• N01AX10

Generic Available (US)

Yes

Pricing: US

Emulsion (Diprivan Intravenous)

100 mg/10 mL (per mL): $0.36

200 mg/20 mL (per mL): $0.14

500 mg/50 mL (per mL): $0.14

1000 mg/100 mL (per mL): $0.14

Emulsion (Propofol Intravenous)

200 mg/20 mL (per mL): $0.26 - $0.35

500 mg/50 mL (per mL): $0.26 - $0.35

1000 mg/100 mL (per mL): $0.26 - $0.35

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

Propofol is a short-acting, lipophilic intravenous general anesthetic. The drug is unrelated to any of the currently used barbiturate, opioid, benzodiazepine, arylcyclohexylamine, or imidazole intravenous anesthetic agents. Propofol causes global CNS depression, presumably through agonism of GABA_A receptors and perhaps reduced glutamatergic activity through NMDA receptor blockade.

Pharmacodynamics/Kinetics

Onset of action: Anesthetic: Bolus infusion (dose dependent): 9 to 51 seconds (average 30 seconds)

Duration: 3 to 10 minutes depending on the dose, rate and duration of administration; with prolonged use (eg, 10 days ICU sedation), propofol accumulates in tissues and redistributes into plasma when the drug is discontinued, so that the time to awakening (duration of action) is increased; however, if dose is titrated on a daily basis, so that the minimum effective dose is utilized, time to awakening may be within 10 to 15 minutes even after prolonged use

Distribution: Large volume of distribution; highly lipophilic ; V_d:

Children 4 to 12 years: 5 to 10 L/kg

Adults: 2 to 10 L/kg; after a 10-day infusion, V_d approaches 60 L/kg; decreased in the elderly

Protein binding: 97% to 99%

Metabolism: Hepatic to water-soluble sulfate and glucuronide conjugates (~50%)

Half-life elimination: Biphasic: Initial: 40 minutes; Terminal: 4 to 7 hours (after 10-day infusion, may be up to 1 to 3 days)

Excretion: Urine (~88% as metabolites, 40% as glucuronide metabolite); feces (<2%)

Pharmacodynamics/Kinetics: Additional Considerations

Geriatric: With increasing age, the dose requirement decreases because of occurrence of higher peak plasma concentrations.

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

No significant effects or complications reported

Effects on Bleeding

No information available to require special precautions

Related Information

• Anesthetic Agents
• Dosing Considerations for the Critically Ill Patient With Morbid Obesity

FDA Approval Date

October 02, 1989

References

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Brand Names: International

Anepol (KR, TH); Anesia (LK); Anesticap (ID); Aquafol (KR); Diprivan (AE, AR, AT, AU, BB, BE, BF, BG, BH, BJ, BM, BR, BS, BZ, CI, CL, CN, CO, CR, CU, CY, CZ, DE, DK, DO, EE, EG, ES, ET, FI, FR, GB, GH, GM, GN, GR, GT, GY, HK, HN, HR, HU, IE, IN, IQ, IR, IT, JM, JO, KE, KW, LB, LR, LU, LV, LY, MA, ML, MR, MT, MU, MW, MX, MY, NE, NG, NI, NL, NZ, OM, PA, PE, PH, PK, PL, PR, PT, QA, RU, SA, SC, SD, SE, SI, SK, SL, SN, SR, SV, SY, TN, TR, TT, TW, TZ, UA, UG, UY, VE, VN, YE, ZA, ZM, ZW); Diprofen (TW); Diprofol (IL, UA); Disoprivan (CH, HR); Dormifor (LB); Emifol (BD); Fresofol (AU, CR, DO, GT, HN, KR, MY, NI, NZ, PA, PH, SV, TW); Fresofol MCT/LCT (HK, ID, TH); Gobbifol (AR, PY); Indofol (MX); Lexofol (PH); Lipofol (TW); Neorof (ET, PH); Nirfol (LK, ZW); Operol (PH); Pofol (BD, EG, KR, TH); Proanes (ID); Profast (RO); Profosol (PH); Propofol-Lipuro (EC); Propovan (LK, PY); Propoven (EE, IE, LV); Provive (AU, BH, HK, KR, LB, NZ, QA, ZW); Recofol (AE, BH, CH, CY, ES, HU, ID, JO, MX, QA, SG, TH); Recofol N (MT, SG); Ripol (IL); Safol (ID); Spiva with MCT-LCT (PH); Trivam (ID); Troyppofol (TZ); Ufol (BD)

Last Updated 2/20/20