INFORMATION FOR HEALTH PROFESSIONALS
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Propofol injection is a sterile, nonpyrogenic emulsion containing 20 mg/mL of propofol suitable for intravenous administration. The emulsion is isotonic and has a pH of 6.0 to 8.5. In addition to the active component, propofol, the formulation also contains soybean oil (100 mg/mL), glycerol (22.5 mg/mL) and egg phosphatide (12 mg/mL); with sodium hydroxide to adjust pH (6 to 8.5) and water for injection qs.
Propofol injection is a short-acting intravenous sedative hypnotic agent for use in the induction and maintenance of anaesthesia or continuous sedation during mechanical ventilation. Intravenous injection of a therapeutic dose of propofol produces hypnosis rapidly and smoothly with minimal excitation, usually within 40 seconds from the start of an injection (the time for one arm-brain circulation). As with other rapidly acting intravenous anaesthetic agents, the half-time of the blood-brain equilibration is approximately 1 to 3 minutes, and this accounts for the rapid induction of anaesthesia.
Pharmacodynamic properties of propofol are dependent upon the therapeutic blood propofol concentrations. Steady state propofol blood concentrations are generally proportional to infusion rates, especially within an individual patient.
The haemodynamic effects of propofol injection during induction of anaesthesia vary. If spontaneous ventilation is maintained, the major cardiovascular effects are arterial hypotension (sometimes greater than a 30% decrease) with little or no change in heart rate and no appreciable decrease in cardiac output. If ventilation is assisted or controlled (positive pressure ventilation), the degree and incidence of decrease in cardiac output are accentuated. These effects are probably attributable to a central vagotonic effect or an inhibition of activity of the sympathetic nervous system. Addition of a potent opioid (e.g. fentanyl) when used as a premedicant further decreases cardiac output and respiratory drive. If anaesthesia is continued by infusion of propofol injection, the stimulation of endotracheal intubation and surgery may return arterial pressure towards normal. However, cardiac output may remain depressed.
Insufficient data are available regarding the cardiovascular effects of propofol injection when used for induction and/or maintenance of anaesthesia or sedation in elderly, hypotensive, debilitated patients, patients with severe cardiac disease (ejection fraction <50%) or other ASA III/IV patients. However, limited information suggests that these patients may have more profound adverse cardiovascular responses. It is recommended that if propofol injection is used in these patients, a lower induction dose and a slower maintenance rate of administration of the medicine be used (see DOSAGE AND ADMINISTRATION).
Induction of anaesthesia with propofol injection is frequently associated with apnoea in both adults and children.
During maintenance, propofol injection causes a decrease in ventilation usually associated with an increase in carbon dioxide tension which may be marked depending upon the rate of administration and other concurrent medications (e.g., opioids, sedatives, etc.).
Preliminary findings in patients with normal intraocular pressure indicate that propofol injection anaesthesia produces a decrease in intraocular pressure which may be associated with a concomitant decrease in systemic vascular resistance.
Studies to date indicate that propofol injection when used in combination with hypocarbia increases cerebrovascular resistance and decreases cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure. Propofol injection does not affect cerebrovascular reactivity to changes in arterial carbon dioxide tension.
Animal studies and limited experience in susceptible patients have not indicated any propensity of propofol injection to induce malignant hyperthermia.
Clinical and preclinical studies suggest that propofol injection is rarely associated with elevation of plasma histamine levels.
In vitro studies have shown that at the clinical concentrations likely to occur, propofol does not inhibit the synthesis of adrenocortical hormones.
The proper use of propofol injection requires an understanding of the disposition and elimination characteristics of propofol.
Propofol is highly lipophilic, and is 97 to 98% protein bound.
The pharmacokinetics of propofol are well described by a three compartment linear model with compartments representing the plasma, rapidly equilibrating tissues, and slowly equilibrating tissues. Following an IV bolus dose, plasma levels initially decline rapidly due to rapid medicine distribution into tissues (half-life 2 to 4 minutes) and rapid elimination (half-life 30 to 60 minutes). Distribution accounts for about half of this decline following a bolus of propofol. After longer infusions, the return to the plasma of the medicine accumulated in the tissues causes plasma levels to fall more slowly. Plasma levels fall to about 50% of peak levels in about 5 minutes following a 1 hour infusion and in about 7 minutes following a 10 hour infusion. Titration of infusion to clinical response in ICU sedation corresponds to a plasma level of about 1 mcg/mL. A fall in plasma level of about 50% (0.5 mcg/mL) generally corresponds to patient awakening.
Propofol is extensively distributed and rapidly cleared from the body (total body clearance 1.5 to 2 litres/minute). Clearance occurs principally via the liver to form inactive glucuronide conjugates of propofol and its corresponding quinol which are excreted in the urine.
Pharmacokinetics are linear over the recommended range of infusion rates. No accumulation of propofol has been seen using normal maintenance rates.
With increasing age, the dose of propofol needed to achieve a defined anaesthetic endpoint (dose-requirement) decreases. This does not appear to be an age related change to pharmacodynamics or brain sensitivity, as measured by EEG burst suppression. With increasing age pharmacokinetic changes are such that for a given IV bolus dose, higher peak plasma concentrations occur, which can explain the decreased dose requirement. These higher peak plasma concentrations in the elderly can predispose patients to cardiorespiratory effects including hypotension, apnea, airway obstruction and/or oxygen desaturation. The higher plasma levels reflect an age-related decrease in volume of distribution and reduced intercompartmental clearance. Lower doses are thus recommended for initiation and maintenance of sedation/anaesthesia in elderly patients (see DOSAGE AND ADMINISTRATION).
The pharmacokinetics of propofol in children between the ages of 3 and 12 years are also best described as a three-compartment pharmacokinetic model. A study of children undergoing general surgeries lasting approximately 1 to 2 hours, with less than 8 hours of plasma sampling, showed an elimination half-life of 250 to 400 minutes, steady state distributional volumes of 7 to 10 L/kg, and clearances of approximately 35 mL/kg/min. These estimates are consistent with the known high clearance and high lipid solubility of propofol injection. The observed differences between paediatric patients and adults in terms of elimination phase and distributional volume are related to the much longer duration of propofol administration in adults. Clearance in children is 50% higher than in adults.
The pharmacokinetics of propofol do not appear to be different in people with chronic hepatic cirrhosis or chronic renal impairment compared to adults with normal hepatic and renal function. The effects of acute hepatic or renal failure on the pharmacokinetics of propofol have not been studied.
Propofol injection is an IV anesthetic agent that can be used for both induction and/or maintenance of anaesthesia as part of a balanced anaesthetic technique for inpatient and outpatient surgery in adults and in children age 3 years or older.
Propofol injection should only be administered to intubated, mechanically ventilated adult patients in the Intensive Care Unit (ICU) to provide continuous sedation and control of stress responses. In this setting, propofol injection should be administered only by persons skilled in the medical management of critically ill patients and trained in cardiovascular resuscitation and airway management.
Dosage and rate of administration should be individualised and titrated to the desired effect according to clinically relevant factors including preinduction and concomitant medications, age, ASA physical classification and level of debilitation of the patient. It is recommended that the dose of propofol should not exceed 4mg/kg/hr when used for prolonged sedation (greater than 24 hours).
Propofol blood concentrations at steady state are generally proportional to infusion rates, especially within an individual patient. Undesirable side effects such as cardiorespiratory depression are likely to occur at higher blood levels which result from bolus dosing or rapid increase in infusion rate. An adequate interval (3 to 5 minutes) must be allowed between clinical dosage adjustments in order to assess medicine effects. No comparable data are available for children.
Supplemental analgesic agents are normally needed during propofol administration. For minor surgical procedures (e.g. body surface) nitrous oxide (60% to 70%) can be combined with a variable rate propofol injection infusion to provide satisfactory anaesthesia. With more stimulating surgical procedures (e.g. intra-abdominal), or if supplementation with nitrous oxide is not provided, administration rate(s) of propofol injection and/or opioids should be increased in order to provide adequate anaesthesia.
Propofol injection has been used with a variety of agents commonly used in anaesthesia such as atropine, scopolamine, glycopyrrolate, diazepam, depolarizing and nondepolarizing muscle relaxants, and opioid analgesics, as well as with inhalational and regional anaesthetic agents.
Lower doses of propofol may be required where general anaesthesia is used as an adjunct to regional anaesthetic techniques.
Induction
Propofol may be used to induce anaesthesia by slow bolus injection or infusion. Most adult patients under 55 years of age and classified ASA I or II require 1.5 to 2.5 mg/kg (0.15 to 0.25 ml/kg) of propofol injection for induction when unpremedicated or when premedicated with oral benzodiazepines or intramuscular opioids. For induction, propofol injection should be titrated (approximately 40 mg every 10 seconds) against the response of the patient until the clinical signs show the onset of anaesthesia. As with other sedative hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of propofol injection.
The total dose required can be reduced by lower rates of administration (20 to 50mg/min). Over this age, the requirement will generally be less. In patients of ASA Grades 3 and 4, lower rates of administration should be used (approximately 2mL (20mg) every 10 seconds).
Maintenance
In adults, anaesthesia can be maintained by administering propofol injection by infusion. Administration by bolus injection is not recommended for Propofol 20mg/mL. The patient's clinical response will determine the infusion rate or the amount and frequency of incremental injections.
Continuous Infusion
Maintenance by infusion of propofol injection should immediately follow the induction dose in order to provide satisfactory or continuous anaesthesia during the induction phase. The maintenance dose for propofol via continuous infusion in adults is 4 to 12 mg/kg/hr. During this initial period following the induction dose higher rates of infusion are generally required for the first 10 to 15 minutes. Infusion rates should subsequently be decreased 30 to 50% during the first half-hour of maintenance.
Intermittent Bolus
Bolus doses of propofol injection ranging from 25 mg (2.5 mL) to 50 mg (5.0 mL) may be administered to adult patients undergoing general surgery. The incremental boluses should be administered when changes in vital signs indicate a response to surgical stimulation or light anaesthesia.
Intensive Care Unit Sedation
Propofol injection should be individualised according to the patient's condition and response, blood lipid profile, and vital signs. For intubated, mechanically ventilated adult patient, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimise hypotension.
Evaluation of the level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of propofol injection required for sedation. Abrupt discontinuation of propofol injection prior to weaning or for daily evaluation of sedation levels should be avoided. This may result in rapid awakening with associated anxiety, agitation and resistance to mechanical ventilation. Infusions of propofol injection should be adjusted to maintain a light level of sedation through the weaning process or evaluation of sedation level (see WARNINGS & PRECAUTIONS).
Initiation of sedation should begin at 0.3 mg/kg/h (5 mcg/kg/min). The infusion rate should be increased by increments of 0.3 to 0.6 mg/kg/h (5 to 10 mcg/kg/min) until the desired level of sedation is achieved. A minimum period of 5 minutes between adjustments should be allowed for onset of peak medicine effect. Most adult patients require maintenance rates of 0.3 to 4.0 mg/kg/h. There are limited data on propofol safety at high dosage (> 4mg/kg/h) for extended periods of greater than 48 hours (see Warnings and Precautions).
Monitored Anaesthesia Care Sedation for Surgical and Diagnostic Procedures
To provide sedation for surgical and diagnostic procedures rates of administration should be individualised and titrated to clinical response. Most patients will require 0.5 to 1 mg/kg over 1 to 5 minutes for onset of sedation. Maintenance of sedation may be accomplished by titrating propofol infusion to the desired level of sedation - most patients will require 1.5 to 4.5 mg/kg/h. In addition to the infusion, bolus administration of 10 to 20mg may be used if a rapid increase in the depth of sedation is required. In patients in ASA grades 3 and 4 the rate of administration and dosage may need to be reduced.
In the elderly, debilitated and ASA III or IV patients, rapid bolus doses should not be used in the methods of administration described below (See WARNINGS & PRECAUTIONS).
Induction
Due to the reduced clearance and higher blood levels, most elderly patients require approximately 1.0 to 1.5 mg/kg (approximately 20 mg every 10 seconds) of propofol injection for induction of anaesthesia according to their condition and responses.
Maintenance
Lower maintenance infusion rates may be required as compared to healthy adults.
To avoid significant hypotension and decreases in cerebral perfusion pressure, an infusion or slow bolus of approximately 20 mg every 10 seconds should be utilised instead of rapid and large boluses of propofol injection. Slower induction titrated to clinical responses, will generally result in reduced induction dosage requirements (1.0 to 2.0 mg/kg).
Propofol must not be used in children under 3 years of age.
Induction
Propofol must be administered slowly until clinical signs of anaesthesia are observed. The dose should be corrected with respect to age/weight. Children greater than 8 years of age normally need about 2.5 mg/kg. Younger children may require higher doses. No experience is available in children of ASA classes 3 or 4.
Maintenance
The anaesthesia could be maintained through continuous infusion of repeated bolus injections. The required infusion rate greatly varies between patients. 9 to 15 mg/kg/hr normally gives a satisfactory anaesthesia.
Sedation
Propofol must not be administered for sedation in children under 16 years of age.
Monitored Anaesthesia Care Sedation for Surgical and Diagnostic Procedures
Propofol is not recommended for sedation in children as safety and efficacy have not been demonstrated.
Propofol injection should be prepared for single use in an individual patient.
Shake well before use.
Propofol 20mg/mL (2%) should only be given nondiluted as an infusion. The product should not be administered as a bolus injection.
Propofol injection must not be administered through a microbiological filter because this could restrict the flow of propofol injection and/or cause the breakdown of the emulsion.
The dilution should be prepared aseptically immediately prior to administration and used within 6 hours of preparation. When preparing diluted propofol, 5% Dextrose Injection should be withdrawn from the infusion container and replaced with an equivalent amount of propofol injection.
The tubing and any unused, undiluted propofol injection should be discarded after 12 hours because propofol injection contains no preservatives and is capable of supporting rapid growth of microorganisms (see WARNINGS & PRECAUTIONS).
Diluted propofol may be used with a variety of infusion control techniques, but an infusion set used alone will not avoid the risk of accidental uncontrolled infusion of propofol. A burette, drop counter, or volumetric pump must be included in the infusion line. The risk of uncontrolled infusion must be taken into account when deciding the maximum amount of propofol injection in the burette. When infusing propofol injection to patients undergoing magnetic resonance imaging, metered control devices may be utilised if mechanical pumps are impractical.
Compatibility of propofol injection with the coadministration of blood/serum/plasma has not been established (see WARNINGS & PRECAUTIONS).
Propofol injection may be mixed with preservative free lidocaine 0.5% or 1% immediately prior to administration to reduce pain on initial injection (20 parts propofol to 1 part lidocaine). Propofol injection should not be mixed with other therapeutic agents prior to administration.
Any medicines or fluids added to the propofol line must be administered close to the cannula site.
Propofol can be given via a Y to set at the site of injection into compatible IV fluids.
Propofol injection is compatible when administered with the following intravenous fluids:
5% Dextrose Injection, USP
Lactated Ringers Injection, USP
Lactated Ringers and 5% Dextrose Injection
5% Dextrose and 0.45% Sodium Chloride Injection, USP
5% Dextrose and 0.2% Sodium Chloride Injection, USP
0.9% Sodium Chloride Injection
When propofol is used undiluted to maintain anaesthesia, it is recommended that equipment such as syringe pumps or volumetric infusion pumps should always be used to control infusion rates.
HANDLING PROCEDURES
Parenteral medicine products should be inspected visually for particulate matter and discolouration prior to administration whenever solution and container permit.
Do not use if there is evidence of separation of the phases of the emulsion.
Propofol contains no antimicrobial preservatives and supports the growth of microorganisms. Aspiration, eventual mixture and administration of propofol should be done aseptically immediately after opening the ampoule or breaking the vial seal. Asepsis must be maintained for both propofol and infusion equipment throughout the infusion period.
Propofol injection is contraindicated in patients with a known hypersensitivity to propofol injection or its components, or when general anaesthesia or sedation is contraindicated.
Propofol injection is also contraindicated in children under three years of age, in pregnancy, for obstetric anaesthesia and for sedation in children under 16 years of age (see WARNINGS & PRECAUTIONS).
Strict aseptic technique must always be maintained during handling. Propofol injection is a single-use parenteral product, containing no antimicrobial preservatives and is able to support rapid growth of microorganisms. Discard unused portions as directed within the required time limits (see DOSAGE AND ADMINISTRATION, handling procedures). There have been reports in which failure to use aseptic technique when handling propofol injection was associated with microbial contamination of the product and resulted in fever, infection/sepsis, other life threatening illness, and/or death. Do not use if contamination is suspected.
For general anaesthesia and ICU sedation, propofol injection should be administered only by persons trained in the administration of general anaesthesia and/or management of critically ill patients who are trained in cardiovascular resuscitation and airway management and not involved in the conduct of the surgical procedure. Patients should be continuously monitored.
As with other intravenous anaesthetic agents, caution should be applied in patients with cardiac, respiratory, renal or hepatic impairment or in hypovolaemic or debilitated patients.
In the elderly, debilitated and ASA III or IV patients, rapid (single or repeated) bolus administration should not be used during general anaesthesia to minimise undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction and/or oxygen desaturation.
Perioperative myoclonia, rarely including convulsions and opisthotonos, has occurred in temporal relationship to cases in which propofol injection has been administered.
Clinical features of anaphylaxis, which may include bronchospasm, erythema and hypotension, occur rarely following propofol injection administration.
Apnea often occurs during induction and may persist for more than 60 seconds; ventilatory support may be required.
There have been rare reports of pulmonary oedema and cardiac arrest in temporal relationship to the administration of propofol injection, although a causal relationship is unknown.
When propofol injection is administered to an epileptic patient, there may be a risk of seizure during the recovery phase.
Propofol injection has no vagolytic activity. Associated cases of bradycardia ranging from mild to severe (asystole) have been reported. In situations where high vagal tone is present or when propofol is given with other substances that may trigger bradycardia, pretreatment with an anticholinergic agent may be considered before induction or during maintenance of anaesthesia. Patients should be monitored for signs of hypotension and/or bradycardia.
Propofol injection is not indicated for use in ECT.
Special caution should be exercised if infusion rates in prolonged sedation (>48 hours) exceed 4mg/kg/h. In severely head injured patients also receiving incremental inotropic support, fatal metabolic acidosis or cardiac failure have been reported in association with propofol infusion rates >5mg/kg/h for >58 hours. Review of the sedation regime should be conducted in the presence of unexplained acidosis or cardiovascular compromise.
(See DOSAGE AND ADMINISTRATION, HANDLING PROCEDURES). The administration of propofol injection should be initiated as a continuous infusion and changes in the rate of administration made slowly (>5 minutes between dosage adjustments) in order to minimise hypotension and avoid acute overdosage. As with other sedative medications, there is wide interpatient variability in propofol injection dosage requirements, and these requirements may change with time.
Patients should be monitored for early signs of significant hypotension and/or cardiovascular depression, which may be profound. These effects are responsive to discontinuation of propofol injection, IV fluid administration, and/or vasopressor therapy.
Abrupt discontinuation of a patient's propofol infusion may result in rapid awakening of the patient with associated anxiety, agitation, and resistance to mechanical ventilation, making weaning from mechanical ventilation difficult. It is therefore recommended that administration of propofol injection be continued in order to maintain a light level of sedation throughout the weaning process until 10 to 15 minutes prior to extubation at which time the infusion can be discontinued.
Since propofol injection is formulated in an oil-in-water emulsion, elevations in serum triglycerides may occur when propofol injection is administered for extended periods of time. Patients at risk of hyperlipidemia should be monitored for increases in serum triglycerides or serum turbidity. Administration of propofol injection should be adjusted if fat is being inadequately cleared from the body. A reduction in the quantity of concurrently administered lipids is indicated to compensate for the amount of lipid infused as part of the propofol injection formulation; 1.0 mL of propofol injection contains approximately 0.1 g of fat.
For sedation of intubated mechanically ventilated adult patients in the Intensive Care Unit (ICU), Propofol Injectable Emulsion should be administered only by persons skilled in the management of critically ill patients and trained in cardiovascular resuscitation and airway management.
Patients should be advised that performance of activities requiring mental alertness, such as operating a motor vehicle, or hazardous machinery or signing legal documents may be impaired for some time after general anaesthesia or sedation. Alcohol must be avoided.
Animal carcinogenicity studies have not been performed with propofol.
In vitro and in vivo animal tests failed to show any potential for mutagenicity by propofol.
Studies in female rats at intravenous doses up to 15 mg/kg/day (6 times the maximum recommended human induction dose) for 2 weeks before pregnancy to day 7 of gestation did not show impaired fertility. Male fertility in rats was not affected in a dominant lethal study at intravenous doses up to 15 mg/kg/day for 5 days.
Propofol should not be used in pregnancy.
Teratology studies in rats and rabbits showed no teratogenic effects. There are no well controlled studies in pregnant women.
Propofol should not be used as it passes the placental barrier and may cause neonatal depression.
Propofol injection is contraindicated for use in nursing mothers because propofol injection has been reported to be excreted in human milk and the effects of oral absorption of small amounts of propofol are not known.
Propofol injection for anesthesia is not recommended for use in children below the age of 3 years because safety and effectiveness have not been established. Propofol injection for ICU sedation use is not recommended for use in children because safety and effectiveness have not been established.
The long term administration of propofol injection to patients with renal failure and/or hepatic insufficiency has not been evaluated.
When propofol injection is used in patients with increased intracranial pressure or impaired cerebral circulation, significant decreases in mean arterial pressure should be avoided because of the resultant decreases in cerebral perfusion pressure. Rapid and large boluses of propofol should be avoided in this population (see DOSAGE AND ADMINISTRATION).
When increased ICP is suspected, hyperventilation and hypocarbia should accompany the administration of propofol injection.
Adverse event information is derived from controlled clinical trials and worldwide marketing experience. Most adverse events were mild and transient.
Local pain at the injection site may be minimized by coadministration with lidocaine and by the use of larger veins in the arm. Thrombosis and phlebitis are rare. Accidental clinical extravasation and animal studies showed minimal tissue reaction. Intra-arterial injection in animals has not caused tissue complications either locally or distally.
Induction of anaesthesia is generally smooth with minimal evidence of excitation, although spontaneous movements, hiccups and coughing may be seen in some patients.
As is the case with other intravenous anesthetics, hypotension and transient apnoea may occur during induction with the degree depending on the dosage and use of premedications. Occasionally, hypotension may require use of intravenous fluids and, if necessary, vasoconstricting agents and/or decreased administration rate of propofol.
The airway should be closely monitored at all times since coughing, regurgitation and vomiting have been reported in a few patients during clinical trials.
Anaphylaxis including bronchospasm, erythema and hypotension very rarely occur following propofol administration.
Less common circulatory effects include bradycardia, tachycardia and extrasystole.
Pulmonary oedema has been observed.
Very rarely, pancreatitis has been reported, but a causal relationship to propofol is unclear.
Convulsion, myoclonus and opisthotonos rarely occur usually after termination of administration of propofol and may occasionally be delayed.
Rarely, discoloration of urine has been reported following prolonged administration of propofol.
Propofol may produce sexual disinhibition upon recovery.
During the recovery phase, nausea, vomiting and headache occur in a small portion of patients.
There have been reports of post-operative fever.
Very rarely with prolonged sedation, metabolic acidosis and cardiac failure.
Other adverse events reported during induction and maintenance of anaesthesia are noted below:
Body as a Whole: Asthenia, Awareness, Chest Pain, Extremity Pain, Increased Medicine Effect, Neck Rigidity/Stiffness, Perinatal Disorder, Trunk Pain. Cardiovascular: Arrhythmia, Atrial Fibrillation, Atrioventricular Heart Block, Bigeminy, Bleeding, Bundle Branch Block, Cardiac Arrest, ECG Abnormal, Oedema, Hypertension, Myocardial Infarction, Myocardial Ischaemia, Premature Atrial Contractions, Premature Ventricular Contractions, ST segment Depression, Superventricular Tachycardia, Syncope, Ventricular Fibrillation. Central Nervous System: Abnormal Dreams, Agitation, Amorous Behaviour, Anxiety, Bucking/Jerking/Thrashing, Chills/Shivering, Combativeness, Confusion, Delirium, Depression, Dizziness, Emotional Lability, Euphoria, Fatigue, Hallucinations, Hypertonia/Dystonia, Hypotonia, Hysteria, Insomnia, Moaning, Neuropathy, Paresthesia, Somnolence, Tremor, Twitching. Digestive: Cramping, Diarrhoea, Dry Mouth, Enlarged Parotid, Hypersalivation, Swallowing. Hematologic/Lymphatic: Coagulation Disorder, Leukocytosis. Injection Site: Hives/Itching, Redness/Discoloration. Metabolic/Nutritional: Hyperkalemia, Hyperlipemia. Musculoskeletal: Myalgia. Respiratory: Burning in Throat, Dyspnea, Hyperventilation, Hypoxia, Laryngospasm, Pharyngitis, Sneezing, Tachypnoea, Upper Airway Obstruction, Wheezing. Skin and Appendages: Conjunctival Hyperaemia, Diaphoresis, Flushing, Pruritus, Rash, Urticaria. Special Senses: Amblyopia, Diplopia, Ear Pain, Eye Pain, Nystagmus, Taste Perversion, Tinnitus. Urogenital: Oliguria, Urine Retention.
Other adverse events reported during ICU Sedation are noted below:
Body as a Whole: Sepsis, Rhabdomyolysis, Whole Body Weakness. Cardiovascular: Decreased Cardiac Output, Right Heart Failure, Ventricular Tachycardia. Central Nervous System: Intracranial Hypertension, Thinking Abnormal. Digestive: Ileus, Liver Function Abnormal. Metabolic Nutritional: BUN Increased, Creatinine Increased, Dehydration, Hyperglycemia, Hyperlipemia, Metabolic Acidosis, Osmolality Increased. Respiratory: Decreased Lung Function, Respiratory Acidosis during Weaning. Urogenital: Kidney Failure.
The induction dose requirements of propofol injection may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (e.g. morphine, meperidine and fentanyl, etc.) and combinations of opioids and sedatives (e.g. benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anaesthetic or sedative effects of propofol and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output.
During maintenance of anaesthesia or sedation, the rate of propofol injection administration should be adjusted according to the desired level of anaesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (e.g. nitrous oxide or opioids). The concurrent administration of potent inhalational agents (e.g. isoflurane, enflurane, sevoflurane, and halothane) during maintenance with propofol injection has not been extensively evaluated. These inhalational agents can also be expected to increase the anaesthetic or sedative and cardiorespiratory effects of propofol injection.
Other medicines that cause CNS depression (hypnotics/sedatives, inhalational anaesthetics and opioids) can increase CNS depression induced by propofol. Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary propofol injection maintenance infusion rate and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication.
Propofol injection does not cause a clinically significant change in onset, intensity or duration of action of the commonly used neuromuscular blocking agents (e.g. succinylcholine and nondepolarizing muscle relaxants).
Propofol injection is compatible with spinal and epidural anaesthesia, commonly used premedicates, neuromuscular blocking agents, inhalation agents and analgesics.
After suxamethonium and neostigmine bradycardia and cardiac arrest may occur.
Leukoencephalopathy has been reported with administration of lipid emulsions such as propofol in patients on cyclosporine.
If overdosage occurs, propofol injection administration should be discontinued immediately. Overdosage is likely to cause cardiorespiratory depression. Respiratory depression should be treated by artificial ventilation with oxygen. Cardiovascular depression may require repositioning of the patient by raising the patient's legs, increasing the flow rate of intravenous fluids and administering pressor agents and/or anticholinergic agents.
Store below 25°C. Do not refrigerate or freeze.
Containers should be shaken before use. Any portion of the contents remaining after use should be discarded. Propofol should not be mixed prior to administration with injections or infusion fluids other than those listed in the administration section of this document. The neuromuscular blocking agents, atracurium and mivacurium should not be given through the same IV line as propofol without prior flushing.
Prescription Medicine
Propofol injection is supplied as a 20mg/mL preparation in 50 mL glass vials.
Propofol is chemically described as 2,6-diisopropylphenol and has a molecular weight of 178.27.
Propofol is very slightly soluble in water and, thus, is formulated in a white, oil-in-water emulsion. The pKa is 11.03. The octanol/water partition coefficient for propofol at physiological pH is 6761:1.
Propofol undergoes oxidative degradation in the presence of oxygen, and it is therefore packaged under nitrogen to eliminate the degradation path.
InterMed Medical Ltd
P O Box 33268
Takapuna
AUCKLAND
20 March 2006