Propofol

Pronunciation

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

Warning(s)

Special Alerts:

[Posted 6/19/2012] APP issued a Dear Healthcare Professional letter regarding the continued shortage of Diprivan (propofol). The FDA will allow APP to reintroduce Fresenius Propoven 1% (propofol 1%) to the US market. This is the same anesthesia product that was imported during the 2009 and 2010 propofol drug shortage.

Fresenius Propoven 1% (propofol 1%) contains the same active ingredient, propofol, in the same concentration as APP DIPRIVAN (propofol 1%). It is important to note that there are some key differences in the formulation and labeling between the US marketed propofol products and the international Fresenius Propoven 1% (propofol 1%), that you need to be aware of. Please refer to the Dear Healthcare Professional letter available on the FDA's website at .

Warning(s)

  • Microbial Contamination
  • Propofol injectable emulsion can support microbial growth.1 (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.1 2 103 113 194 195 197 198 199

  • Discard unused portions within the required time limits.1 2 (See Stability and Sterility Considerations under Dosage and Administration.)

  • Do not use if contamination is suspected.1 2 194

Introduction

Sedative and hypnotic.1 2

Uses for Propofol

Because of a continued shortage of propofol injection, FDA announced in June 2012 that it will temporarily allow APP Pharmaceuticals to import Fresenius Propoven 1% (propofol 1%) to the US market. Key differences in the formulation and labeling (prescribing information) between the US marketed propofol preparations and the international Fresenius Propoven preparation should be considered. (See Special Alerts.)

Induction and Maintenance of Anesthesia

Induction and/or maintenance of anesthesia as the sedative and hypnotic component of balanced anesthesia (benzodiazepines, anticholinergic agents, depolarizing and nondepolarizing skeletal muscle relaxants, opiate analgesics, inhalation and/or regional anesthetic) or total IV anesthesia (balanced anesthesia in which the IV anesthetic completely replaces the inhalation anesthetic) in patients undergoing inpatient or outpatient surgery.1 2 6 7 8 9 118 192

Produces adequate general anesthesia in patients undergoing various types of surgery, including neurosurgery (e.g., craniotomy, intracranial aneurysm);1 2 6 cardiovascular (e.g., CABG);1 2 6 7 abdominal;6 ocular;6 ear, nose, and throat (ENT);8 orthopedic;8 and general surgery.1 2

Considered the hypnotic of choice by some clinicians for patients undergoing outpatient surgery.118 Usually is associated with similar or faster early recovery (time to awakening and eye opening) from anesthesia, more rapid recovery of psychomotor performance and time to discharge, and lower incidence of adverse effects (e.g., nausea, vomiting, cough, hiccups) compared with other IV anesthetic agents (e.g., etomidate, methohexital, thiopental) or conventional combinations (e.g., an IV induction agent and an inhalation anesthetic).6 7 9 10 118

Monitored Anesthesia Care (MAC)

Initiation and maintenance of MAC sedation (alone or in combination with an opiate analgesic and/or a benzodiazepine) in adults undergoing diagnostic procedures or in conjunction with local or regional anesthesia for surgical procedures.1 2 6 7 152 153 154 155 156 157 158

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Provides sedation, analgesia, anxiolysis, and/or amnesia without assisted respiration or loss of consciousness6 7 131 when administered prior to and/or during dental,6 endoscopic (e.g., gastroscopy, bronchoscopy, colonoscopy),6 7 diagnostic,7 oral,7 or other procedures such as extracorporeal lithotripsy,6 7 transvaginal oocyte retrieval,6 7 central venous catheter placement,7 herniorrhaphy,7 and electrical cardioversion.6

Used in conjunction with local or regional anesthesia for surgical procedures, including orthopedic (hip or knee arthoplasty),6 30 abdominal,6 or urologic6 surgery.

Produces less postoperative sedation, drowsiness, confusion, clumsiness, and nausea and a more rapid recovery of psychomotor performance than IV midazolam; however, midazolam has been associated with less pain at the injection site, less frequent oxygen requirements for decreased oxygen saturation, and more effective intraoperative amnesia.6 7 9 23 42 43 170 171 Quality of intraoperative sedation and time to discharge appear to be similar.6 7 23

Sedation in Critical Care Settings

Short-term sedation and control of stress responses in intubated and mechanically ventilated adults in a critical care setting1 2 5 33 34 35 36 37 39 40 41 47 69 132 133 135 when used alone or in combination with an opiate analgesic (e.g., morphine, fentanyl, hydromorphone) and/or peridural analgesia with local anesthetics.1 2 5 8 33 35 36 38 39 41 69 132 133 135 136 159 160 162

Some experts state that midazolam or diazepam should be used for rapid sedation in acutely agitated patients, while propofol is the preferred sedative when rapid awakening (e.g., for neurologic assessment or extubation) is important.136

Seizures

Has been used in patients with refractory status epilepticus.4 17 48 49 134 137 168 169

Nausea and Vomiting

Has been used for the management of postoperative nausea and vomiting.17 50

Has been used in combination with conventional antiemetics for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy.17 51 52

Pruritus

Has been used effectively for relief of pruritus associated with use of spinal opiates or with cholestasis.17 53 54 55 56

Misuse and Abuse

Abuse and dependence, sometimes resulting in death, have been reported.57 65 66 83 109 200 201 202 203 204 206 207 208 209 Most reports involved health-care professionals (principally anesthesiology personnel),57 109 201 202 203 204 209 but abuse by lay persons also reported.200 206 208 209

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).1 65 67 83 194 204 205 Prevalence of abuse and related deaths appears to be greater at institutions with no established system to control or monitor propofol use.204 205

Propofol Dosage and Administration

Administration

IV Administration

Because of a continued shortage of propofol injection, FDA announced in June 2012 that it will temporarily allow APP Pharmaceuticals to import Fresenius Propoven 1% (propofol 1%) to the US market. Key differences in the formulation and labeling (prescribing information) between the US marketed propofol preparations and the international Fresenius Propoven preparation should be considered when administering the drug. (See Special Alerts and consult the international manufacturer’s labeling for Fresenius Propoven.)

Administer by IV infusion1 2 4 6 8 9 10 102 118 or IV injection.1 2 3 4 6 8 9 10 102 118

For IV infusion, use a controlled-infusion device (pump), preferably a volumetric pump.1 2 In patients undergoing magnetic resonance imaging (MRI), use metered controlled devices when mechanical pumps are not suitable.1 2

Use the larger veins of the forearm or antecubital fossa (rather than hand veins) in adults and children to minimize pain at the injection site; may also administer IV lidocaine prior to administration of propofol to minimize pain.1 2 144 (See Local Effects under Cautions.) Administer 1 mL of 1% lidocaine hydrochloride solution 30–120 seconds prior to propofol administration or add lidocaine to propofol immediately prior to administration in quantities not exceeding 20 mg of lidocaine hydrochloride per 200 mg of propofol.1 2 4 6 8 9 144 194

Transfer contents of the vial into a sterile, single-use syringe immediately after the vial is opened and after cleaning the rubber stopper with 70% isopropyl alcohol; use a sterile venting spike when withdrawing propofol from vials.1 2 7

Prepare propofol for single patient use only.1 194 Label syringes with appropriate information, including the date and time the vial was opened.1 194

Shake well just prior to administration.1 2

Clinical experience with use of inline filters for administration during general anesthesia, MAC sedation, or sedation in critical care settings is limited.1 2 An inline membrane filter may be used; however, the mean pore diameter of the filter should be ≥5 mcm unless it has been demonstrated that the filter does not restrict the flow and/or cause breakdown of the emulsion.1 2 11 Use filters with caution and only when clinically appropriate.1 194 Monitor continuously for restricted flow and breakdown of the emulsion.1 194

Stability and Sterility Considerations

For solution and drug compatibility, see Compatibility under Stability.

Manufacturers state that propofol should not be admixed with other therapeutic agents prior to administration.1 2 12 Do not administer through the same catheter as blood, serum, or plasma.1 2

Observe strict aseptic technique.1 2 3 Although commercially available preparations contain ingredients that retard growth of microorganisms (e.g., Diprivan contains edetate disodium 0.005%), the emulsion still may support growth of microorganisms.1 3 194 Do not use the emulsion if contamination is suspected.1 2 194

General anesthesia or MAC sedation: Start administration promptly and complete within 12 hours after opening the vials or syringes.1 2 7 194 Prepare propofol for use immediately prior to initiation of each individual anesthetic/sedative procedure.1 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).1 194 FDA recommends completing administration from a single vial or syringe within 6 hours of opening when propofol is used for general anesthesia or procedural sedation (see Potential for Microbial Contamination under Cautions).195 Flush the IV line every 12 hours (one manufacturer recommends flushing with 5% dextrose)192 and at the end of the procedure to remove residual propofol emulsion.1 2 181 194

Sedation in critical care settings: Minimize manipulations of IV lines; start administration promptly and complete within 12 hours after inserting spike in vial.1 2 7 Use a sterile vent spike and sterile tubing.1 194 Discard any unused portion and the IV tubing at the end of the procedure or after 12 hours.1

Dilution

May administer as a 1% (10 mg/mL) emulsion without dilution.1 2

If dilution is necessary, the emulsion should be diluted only with 5% dextrose injection; concentration should be ≥0.2% (2 mg/mL) in order to maintain the emulsion.1 2 4 Discard if there is evidence of separation of the emulsion.1 2

Rate of Administration

Administer slowly to minimize adverse effects (e.g., hypotension, respiratory depression).1 2 (See Respiratory and Cardiovascular Effects under Cautions.)

For IV injection, administer in incremental doses.1 2 3 4 6 8 9 10 102 118 (See Dosage.)

Adjust rate of continuous IV infusions according to individual requirements.1 2 (See Dosage.) In the absence of clinical signs indicating light anesthesia and until a mild response to surgical stimulation develops, titrate infusion rate downward to avoid administration at rates higher than clinically necessary.1 2

Allow sufficient time between dosage adjustments for onset of peak response.1 2 (See Dosage.)

Dosage

Because of a continued shortage of propofol injection, FDA announced in June 2012 that it will temporarily allow APP Pharmaceuticals to import Fresenius Propoven 1% (propofol 1%) to the US market. Key differences in the formulation and labeling (prescribing information) between the US marketed propofol preparations and the international Fresenius Propoven preparation should be considered when administering the drug. (See Special Alerts and consult the international manufacturer’s labeling for Fresenius Propoven.)

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.1 2 118 Use the smallest effective dosage.1 2

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.1 2 Within this dosage range, younger patients may require higher induction dosages than older patients.1 2 A lower dosage is recommended for induction of anesthesia in patients with ASA physical status of III or IV.1 2

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.1 2 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.1 2 Within this dosage range, younger patients may require higher infusion rates than older patients.1 2

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.1 2

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.1 2 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.1 2

Alternatively, for maintenance of anesthesia in adults <55 years of age: 20–50 mg by intermittent IV injection in combination with inhaled nitrous oxide.1 2 192 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.1 2 194

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.1 2 192 Dosage of 25 mcg/kg per minute may be used for management of anxiolysis prior to induction.1 2

Maintenance of anesthesia: 100–150 mcg/kg per minute as a continuous IV infusion when used as the primary agent and supplemented with a continuous infusion of an opiate agonist (e.g., alfentanil, fentanyl, sufentanil) administered to provide analgesia.1 2 Higher propofol dosages will reduce opiate analgesic dosage requirements.1 2

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.1 2 194

Neurosurgery
IV

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

Maintenance of anesthesia: 100–200 mcg/kg per minute (6–12 mg/kg per hour).1 2

Monitored Anesthesia Care
IV

Initiation of MAC sedation in adults <55 years of age: Infusion of 100–150 mcg/kg per minute (6–9 mg/kg per hour) for 3–5 minutes; alternatively, injection of 0.5 mg/kg over 3–5 minutes.1 2 Slow rate of infusion or injection recommended to reduce the risk of apnea and hypotension.1 2

Maintenance dosage in adults <55 years of age: Infusion of 25–75 mcg/kg per minute (1.5–4.5 mg/kg per hour) for the first 10–15 minutes, then decrease the infusion rate to 25–50 mcg/kg per minute.1 2 Adjust dosage according to clinical effect, allowing approximately 2 minutes for onset of peak drug response.1 2

Alternatively, for maintenance therapy, administer intermittent IV injections of 10 or 20 mg; however, a variable-rate IV infusion is preferred.1 2 (See Monitored Anesthesia Care under Cautions.)1 2

In neurosurgical patients, reduce maintenance dosage by 20%.1 2 Rapid IV injection is not recommended in these patients because of an increased risk of adverse cardiorespiratory effects.1 2

Sedation in Critical Care Settings
IV

Initially, 5 mcg/kg per minute (0.3 mg/kg per hour) for ≥5 minutes in patients with residual effects from anesthetic or sedative drugs.1 2 5 Increase the infusion rate slowly in increments of 5–10 mcg/kg per minute (0.3–0.6 mg/kg per hour) over 5–10 minutes until desired sedation is achieved.1 2 5 Initiate and increase the infusion rate slowly in these patients to minimize the risk of hypotension or acute overdosage.1 2 5

For maintenance of sedation: 5–50 mcg/kg per minute (0.3–3 mg/kg per hour); higher maintenance infusion rates occasionally required.1 2 5 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.1 2

Use the lowest effective dosage in patients with residual effects from anesthetic drugs or in those currently receiving other sedatives or opiates.1 2 181 192

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.1 2 136 181 192

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.1 2 136 (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.5 64 However, such effects also may be associated with changes in drug elimination or an improved health status of the patient.64

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.4 137 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.4 137 Gradually decrease the dosage to prevent withdrawal seizures.137

Nausea and Vomiting
Postoperative Nausea and Vomiting
IV

Doses of 10–15 mg have been used.17 50

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.17 51 52

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.17 53 54

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.17 53 54

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.1 2

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.1 2

Monitored Anesthesia Care

Initiation of MAC sedation: Dosages similar to those for healthy adults are required.1 2 192

Maintenance of MAC sedation: Reduce dosage by 20%.1 2 Rapid IV injection is not recommended because of an increased risk of adverse cardiorespiratory effects.1 2

Cautions for Propofol

Contraindications

  • Known hypersensitivity to propofol or any ingredient in the formulation.1 194

  • Known hypersensitivity to eggs, egg products, soybeans, or soy products.1 194

  • Because of a continued shortage of propofol injection, FDA announced in June 2012 that it will temporarily allow APP Pharmaceuticals to import Fresenius Propoven 1% (propofol 1%) to the US market. Key differences in the formulation and labeling (prescribing information) between the US marketed propofol preparations and the international Fresenius Propoven preparation should be considered when administering the drug. (See Special Alerts and consult the international manufacturer’s labeling for Fresenius Propoven.)

Warnings/Precautions

Warnings

Because of a continued shortage of propofol injection, FDA announced in June 2012 that it will temporarily allow APP Pharmaceuticals to import Fresenius Propoven 1% (propofol 1%) to the US market. Key differences in the formulation and labeling (prescribing information) between the US marketed propofol preparations and the international Fresenius Propoven preparation should be considered. (See Special Alerts.)

Respiratory and Cardiovascular Effects

Can depress respiration;1 2 5 6 8 9 apnea occurs frequently during induction of anesthesia.1 2 4 6 8 9 10 118

Cardiovascular depressant1 2 4 5 6 7 8 9 10 118 with effects greater than or equal to those associated with other IV anesthetic induction agents.6 8 9 10 118 The main adverse cardiovascular effect during induction of anesthesia is hypotension, with ≥30% decreases in systolic and diastolic BP.1 2 4 6 7 118

Patients with impaired myocardial function, intravascular volume depletion, or abnormally low vascular tone (sepsis) may be more susceptible to hypotension.1 2

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.1 2

Possible bradycardia, asystole, and rarely, cardiac arrest, especially in pediatric patients receiving fentanyl concomitantly.1 2 (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).1 2

Pulmonary edema reported rarely; causal relationship not established.1 2

Monitor sedated patients continuously for early signs of hypotension and bradycardia;1 2 194 also monitor for adverse respiratory effects (e.g., apnea, airway obstruction, oxyhemoglobin desaturation), especially in those undergoing MAC sedation.1 2 194

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.1 2 194 (See Special Populations under Dosage and Administration.)

Facilities necessary for intubation, assisted respiration, administration of oxygen, and cardiopulmonary resuscitation should be readily available.1 2 6 7 130 131 192

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.1 2 6 7 130 131

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.1 2 7 192

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 in handling propofol.1 2 103 194

Although commercially available preparations contain ingredients that retard growth of microorganisms, they are not considered antimicrobially preserved products by USP standards.1 103 194 Contamination of propofol with even very small numbers of microorganisms may result in clinical disease;197 strict aseptic technique and strict adherence to the manufacturer’s preparation and handling instructions are required.1 103 113 194 195 197 198 199 (See Stability and Sterility Considerations under Dosage and Administration.)

Do not use the emulsion if contamination is suspected; discard unused portions as recommended by the manufacturers.1 2 (See Stability and Sterility Considerations under Dosage and Administration.)

Several clusters of patients experiencing chills, fever, and body aches shortly after receiving propofol for sedation or general anesthesia reported.195 Symptoms developed 6–18 hours after propofol administration and lasted up to 3 days.195 Several patients were hospitalized and one experienced seizures; all patients recovered without apparent sequelae.195 Evaluate patients who develop these symptoms shortly after receiving propofol for bacterial sepsis and report such cases to the FDA MedWatch program.195

Specific lots of propofol (Teva) were recalled secondary to the presence of elevated endotoxin levels.196

Dependence, Tolerance, and Abuse

Dependence and abuse, sometimes resulting in death, have been reported.57 83 109 200 201 202 203 204 206 207 208 209 Most reported cases have involved health-care professionals (principally anesthesiology personnel),57 65 66 109 201 202 203 204 209 but abuse by lay persons also reported.200 206 208 209

Psychological dependence (e.g., intense craving for the drug, loss of control over amount and frequency of use) reported in cases of propofol abuse.57 200 202 206 207 Withdrawal symptoms (e.g., insomnia, anxiety, difficulty concentrating), suggesting physical dependence, observed rarely.202 Signs of tolerance also observed.109 200 206

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.2 163 194

Hypersensitivity Reactions

Anaphylactoid and/or anaphylactic reactions (e.g., angioedema, bronchospasm, erythema, hypotension) and flushing, possibly related to propofol, reported in <1% of adults undergoing anesthesia or MAC sedation with the drug; may be fatal or life-threatening.1 2 4 6 194

General Precautions

Local Effects

Pain at the injection site occurs in up to 70% of patients144 following peripheral IV administration.1 4 5 6 7 8 9 89 118 144 Thrombosis or phlebitis reported rarely.1 2

Pain, but no evidence of major sequelae, reported following inadvertent intra-arterial injection.1 2 8 118 Local pain, swelling, blisters and/or tissue necrosis reported rarely following inadvertent extravasation.1 2

To minimize pain at the injection site, use the larger veins of the forearm or antecubital fossa rather than hand veins; may also administer lidocaine prior to IV administration of propofol1 2 4 6 8 9 144 (see IV Administration under Dosage and Administration). Other methods have been used: prior administration of opiates or metoclopramide, prior application of a tourniquet, topical nitroglycerin or a local anesthetic cream, or administration of propofol at low temperatures (4–5°C).6

Metabolic Effects

Propofol infusion syndrome reported in patients receiving propofol for sedation in a critical care setting.1 194 211 Characterized by severe metabolic acidosis, hyperkalemia, lipidemia, rhabdomyolysis, hepatomegaly, and cardiac, renal, or circulatory failure.1 194 211 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.1 194 211

Closely monitor patients for development of unexplained acidosis, rhabdomyolysis, and cardiac or renal failure.211 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.1 194

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).1 2

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.1 2

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]).1 2

Edetate Disodium Content

Certain formulations (Diprivan) contain 0.005% of edetate disodium, a heavy metal antagonist that can chelate many divalent and trivalent cations.1 136

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.1

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.1

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).1 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.1

Seizures

Appears to be associated with both anticonvulsant activity and excitatory effects (e.g., seizures, myoclonus, opisthotonos) on the nervous system.5 6 17 117 118

Patients with a history of seizure disorders who are receiving propofol are at increased risk of developing seizures during the recovery phase of anesthesia.1 2

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.1 2

Pancreatitis

Pancreatitis (sometimes requiring hospitalization) reported in adults undergoing induction of anesthesia1 2 85 86 87 88 167 or prolonged sedation with propofol in a critical care setting.84 87 167 Causal relationship with propofol not established; consider the possibility of pancreatitis in patients receiving propofol.85 86 181 192

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.1 2

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.1 2 To avoid substantial hypotension and decreases in cerebral perfusion pressure, administer by IV infusion or slow IV injection.1 2 (See Dosage under Dosage and Administration.)

If increased intracranial pressure is suspected, administer in combination with hyperventilation and hypocarbia.1

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.1 2 192 If intermittent IV injections are given, consider the possibility of respiratory depression, transient increases in sedation depth, and/or prolongation of recovery.1 2

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.1 2 181 192 Correct fluid depletion prior to administration of propofol.1 2

If additional fluid therapy is contraindicated, management of hypotension may include discontinuance of propofol, elevation of the lower extremities, and/or use of vasopressors.1 2

Studied extensively in patients with CAD, but experience in those with valvular or congenital heart disease is limited.1 2

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.1 2 136 181 Evaluate sedation levels at least daily.1 2 136 181

Prior to weaning patients from mechanical ventilator assistance, discontinue neuromuscular blocking agents1 2 or reverse neuromuscular blockade181 and discontinue opiate therapy1 2 or adjust the dosage181 to optimize respiratory function and/or to maintain a light level of sedation.1 2 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.1 2 Therefore, the manufacturers recommend that administration of propofol be continued until about 10–15 minutes prior to extubation.1 2

Musculoskeletal Effects

Rhabdomyolysis reported in association with propofol infusion syndrome (see Metabolic Effects under Cautions).1 194

Specific Populations

Pregnancy

Category B.1

Not recommended for obstetric surgery (e.g., cesarean section).1 2

Lactation

Distributed into milk;1 2 6 19 use not recommended by manufacturers.1 2

Some clinicians state that nursing women undergoing surgery may receive usual anesthetic induction doses of propofol;118 however, since trace amounts of the drug may be present in milk, drowsiness of nursing infants may occur on the day of the procedure.118

Pediatric Use

Safety and efficacy for induction of general anesthesia not established in children <3 years of age.1 2 Safety and efficacy of Diprivan (APP) for maintenance of general anesthesia not established in children <2 months of age; Baxter states that safety and efficacy of propofol injectable emulsion not established in children <3 years of age.1 2

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 age1 192 194 because safety for these uses in this patient population has not been established.1 2 90 146 192 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;1 2 5 90 91 140 142 143 146 147 acidosis sometimes was accompanied or followed by hypocalcemia, hypoglycemia, high serum lipid concentrations (hypertriglyceridemia), elevated serum liver enzyme concentrations, enlarged liver, oliguria, myoglobinuria, fever, multisystem organ failure, cardiac failure, bradycardia, hypotension, AV block of varying degrees, bundle branch block, asystole, and death.1 2 90 91 140 141 142 143 The mechanism of this syndrome is not known;90 the possibility that causes other than propofol administration may be involved has been suggested.91 In 1 study in pediatric patients (excluding those with upper respiratory infection) undergoing sedation in critical care settings, increased incidence of mortality reported in patients receiving propofol compared with those receiving standard sedative agents.1 146 147

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);94 95 however, the manufacturers state that propofol should not be used for MAC sedation in children because safety and efficacy have not been established.1 2

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.1

Geriatric Use

Lower dosages may be required for anesthesia and other indications.1 2 (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).1 2 194

Hepatic Impairment

Long-term propofol therapy not evaluated to date.1 2

Renal Impairment

Long-term propofol therapy not evaluated to date.1 2

Common Adverse Effects

Use for anesthesia or MAC sedation: Bradycardia, arrhythmia, tachycardia, hypotension, hypertension, movement, burning/stinging, pain at injection site, apnea, rash, pruritus.1

Use for critical care setting sedation: Bradycardia, decreased cardiac output, hypotension, hyperlipidemia, respiratory acidosis (during weaning).1

Interactions for Propofol

Metabolized mainly by CYP2B6 and to a lesser extent by CYP2C9.179

Inhibits CYP isoenzymes 1A1, 1A2, 2B1, 2C9, 2D6, 2E1, and 3A4.72 73

Drugs Metabolized by or Affecting Hepatic Microsomal Enzymes

Possibility of interactions; however, because of the increased value for hepatic extraction (50 mcM) of propofol,179 there have been relatively few clinically important interactions with drugs metabolized by or affecting CYP isoenzymes.71 192

Specific Drugs

Drug

Interaction

Comments

Anesthetics, inhalation (e.g., halothane, isoflurane)

Increased serum propofol concentrations4

Anesthetics, local (e.g., bupivacaine, lidocaine)

Reduced propofol dosage requirements for sedation or hypnosis4

Anticoagulants, coumarin-derivative (e.g., warfarin)

IV administration of lipids (e.g., those contained in the propofol emulsion) may decrease response to coumarin-derivative anticoagulants in patients with malabsorptive states secondary to disease (e.g., those with Crohn’s disease)70

Use heparin for initial anticoagulation in patients with malabsorptive states receiving high-dose lipid emulsions;70 if warfarin is given, monitor INR daily70

Clonidine

Premedication with clonidine reported to reduce intraoperative propofol dosage requirements4

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

Increased sedative, anesthetic, and cardiorespiratory depressant effects of propofol1 2 4

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).1 2 Reduce infusion rate of propofol during maintenance of anesthesia or sedation in those receiving CNS depressants concomitantly1 2

Droperidol

Increased frequency of postoperative nausea and vomiting reported74

Fentanyl

Possibility of severe bradycardia in pediatric patients1 2

Midazolam

Synergistic effect (possibly at GABAA receptors in the brain), producing induction of anesthesia and sedation4 78 79 80

Free plasma concentrations of midazolam increased by about 20%; no apparent effect on free concentrations of propofol79

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 agents1 2 8

Bradycardia and asystole have occurred in combination with atracurium or suxamethonium; causal relationship not established4

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

Blood concentrations of opiates increased by 10–20%75

Blood concentrations of propofol increased by up to 22% with alfentanil use75

Variations in blood concentrations of propofol and opiates are unlikely to be clinically important;75 however, sedation and analgesia may be greater with the combination than with either agent alone76

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.6 18 20 117

Duration

Following a single rapid IV injection, duration of action usually is about 5–10 minutes.20 117

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.9

Distribution

Extent

Highly lipophilic; rapidly distributed from plasma into body tissues, including the CNS.5 6 9 10 117 Following IV administration, widely distributed, initially to highly perfused tissues (e.g., brain), then to lean muscle tissue, and finally to fat tissue.5 6 7 9 117 Equilibration between blood and CSF occurs within about 2–3 minutes.5 6 9 10 117

Readily crosses the placenta.1 2 6 19 31 32

Distributed into milk in low concentrations.1 2 6 19

Plasma Protein Binding

Approximately 95–99% (mainly albumin and hemoglobin).5 6 9 18 Binding appears to be independent of plasma propofol concentration.6

Elimination

Metabolism

Rapidly and extensively metabolized in the liver1 2 5 6 8 9 20 179 by CYP2B6 and to a lesser extent by CYP2C9.179

Elimination Route

Excreted mainly in urine, principally as sulfate and/or glucuronide conjugates;6 9 10 20 <0.3% of a dose is eliminated unchanged in urine,5 6 9 10 and <2% of a dose is eliminated in feces.8

Half-life

Triphasic;1 2 5 6 10 45 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.5 6 8 9 45 46

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.6 7

Special Populations

In geriatric patients, clearance may be reduced substantially,5 6 8 9 10 18 106 possibly because of decreased hepatic metabolism resulting from decreased hepatic blood flow.6

Obese patients have a substantially higher clearance than leaner individuals; mean total body clearance appears to be proportional to body weight.5 6 180 192

Chronic renal failure or chronic hepatic cirrhosis does not appear to affect pharmacokinetics of propofol;1 2 5 6 7 8 9 10 not studied in patients with acute renal or hepatic failure.1

Stability

Storage

Because of a continued shortage of propofol injection, FDA announced in June 2012 that it will temporarily allow APP Pharmaceuticals to import Fresenius Propoven 1% (propofol 1%) to the US market. Key differences in the formulation and labeling (prescribing information) between the US marketed propofol preparations and the international Fresenius Propoven preparation should be considered. (See Special Alerts.)

Parenteral

Injectable Emulsion

4–22°C.1 2 Do not freeze.1

Emulsions are packaged under nitrogen to prevent oxidative degradation in the presence of oxygen.1 2

Compatibility

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

Because of a continued shortage of propofol injection, FDA announced in June 2012 that it will temporarily allow APP Pharmaceuticals to import Fresenius Propoven 1% (propofol 1%) to the US market. Key differences in the formulation and labeling (prescribing information) between the US marketed propofol preparations and the international Fresenius Propoven preparation should be considered. (See Special Alerts.)

Solution Compatibility

Propofol emulsion diluted with 5% dextrose injection: More stable in glass than in plastic containers.1 2 11 101 102 Potency of diluted emulsions may decrease by about 5–8% after continuous IV infusion through PVC tubing for 2 hours1 2 192 and by up to 35% when diluted solution is left stationary in PVC tubing.11 102

Compatibility with blood, serum, or plasma not established.1 2

Y-Site 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.1 2 HID 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.HID

Y-Site Compatibility (Diprivan)HID

Compatible

Acyclovir sodium

Alfentanil HCl

Aminophylline

Ampicillin sodium

Aztreonam

Bumetanide

Buprenorphine HCl

Butorphanol tartrate

Calcium gluconate

Carboplatin

Cefazolin sodium

Cefotaxime sodium

Cefoxitin sodium

Ceftizoxime sodium

Ceftriaxone sodium

Cefuroxime sodium

Chlorpromazine HCl

Cimetidine 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

Inamrinone lactate

Isoproterenol HCl

Labetalol HCl

Lidocaine HCl

Lorazepam

Magnesium sulfate

Mannitol

Meperidine HCl

Milrinone lactate

Nafcillin sodium

Nalbuphine HCl

Naloxone HCl

Nitroglycerin

Norepinephrine bitartrate

Ofloxacin

Paclitaxel

Pentobarbital sodium

Phenobarbital sodium

Potassium chloride

Prochlorperazine edisylate

Propranolol HCl

Ranitidine HCl

Scopolamine HBr

Sodium bicarbonate

Sodium nitroprusside

Succinylcholine chloride

Sufentanil citrate

Thiopental sodium

Ticarcillin disodium–clavulanate potassium

Vecuronium bromide

Incompatible

Amikacin sulfate

Amphotericin B

Atracurium besylate

Bretylium tosylate

Calcium chloride

Ciprofloxacin

Diazepam

Digoxin

Doxorubicin HCl

Gentamicin sulfate

Levofloxacin

Methotrexate sodium

Methylprednisolone sodium succinate

Metoclopramide HCl

Mitoxantrone HCl

Phenytoin sodium

Tobramycin sulfate

Verapamil HCl

Variable

Ascorbic acid injection

Atropine sulfate

Cefepime HCI

Ceftazidime

Midazolam HCl

Morphine sulfate

Pancuronium bromide

Phenylephrine HCl

Vancomycin HCl

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

Incompatible

Atracurium besylate

Vancomycin HCl

Actions

  • Effects appear to be related, at least partially, to propofol’s ability to enhance the activity of GABA6 116 145 by interacting with the GABAA receptor complex at spinal and supraspinal synapses.6 17 116 145 181 192 Also may interact with other neurotransmitter sites (e.g., glycine, nicotinic, glutamate, G-protein coupled receptors) and inhibit sodium channels.6 145

  • Capable of producing all levels of CNS depression—from light sleep to deep coma—depending on the dosage.5 117

  • Associated with both anticonvulsant activity and excitatory effects on the nervous system.5 6 17 117 118 210

  • Anesthetic doses may increase cerebral vascular resistance and decrease cerebral blood flow and cerebral metabolic rate for oxygen and glucose.1 2 5 6 7 8 10 117 118 May slightly decrease intracranial pressure in patients undergoing intracranial surgery6 8 10 or in those undergoing sedation in a critical care setting.5

  • Hypnotic doses may be associated with analgesic effects; responses to subhypnotic doses vary from analgesia to hyperalgesia.5 6 10 18 Subhypnotic doses may have anxiolytic effects comparable to those of midazolam or methohexital.17 192 Amnesic effects are less than those of the benzodiazepines.5 6 7 9 36 43 136

  • Propofol anesthesia associated with substantial (30–60%) reductions in intraocular pressure in patients undergoing ophthalmic surgery.1 2 6 9 10 118

  • May have direct antiemetic properties; however, mechanism not established.17

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.1 2

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

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

Because of a continued shortage of propofol injection, FDA announced in June 2012 that it will temporarily allow APP Pharmaceuticals to import Fresenius Propoven 1% (propofol 1%) to the US market. (See Special Alerts.)

* 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 infusion vials)

APP Pharmaceuticals

Propofol Injectable Emulsion (available as ready-to-use single patient infusion vials)

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 23, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

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