Propofol-lipuro

Overdose

Accidental overdosage is likely to cause cardiorespiratory depression. Respiratory depression should be treated by artificial ventilation with oxygen. Cardiovascular depression would require lowering of the patient's head and, if severe, use of plasma expanders and pressor agents.

If overdosage occurs, Propofol-Lipuro injectable emulsion 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.

If overdosage occurs, DIPRIVAN Injectable Emulsion 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.

Incompatibilities

The neuromuscular blocking agents, atracurium and mivacurium should not be given through the same intravenous line as Propofol-Lipuro 1% without prior flushing.

Undesirable effects

General

Induction and maintenance of anaesthesia or sedation is generally smooth with minimal evidence of excitation. The most commonly reported ADRs are pharmacologically predictable side effects of an anaesthetic/sedative agent, such as hypotension. The nature, severity and incidence of adverse events observed in patients receiving Propofol-Lipuro 1% may be related to the condition of the recipients and the operative or therapeutic procedures being undertaken.

The following definitions of frequencies are used:

Very common (>1/10), common (>1/100 to <1/10), uncommon ((>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).

Table of Adverse Drug Reactions

(1) Serious bradycardias are rare. There have been isolated reports of progression to asystole.

(2) Occasionally, hypotension may require use of intravenous fluids and reduction of the administration rate of Propofol-Lipuro.

(3) Very rare reports of rhabdomyolysis have been received where Propofol-Lipuro has been given at doses greater than 4 mg/kg/hr for ICU sedation.

(4) May be minimised by using the larger veins of the forearm and antecubital fossa. With Propofol-Lipuro 1% local pain can also be minimised by the co-administration of lidocaine.

(6) Brugada-type ECG - elevated ST-segment and coved T-wave in ECG.

(7) Rapidly progressive cardiac failure (in some cases with fatal outcome) in adults. The cardiac failure in such cases was usually unresponsive to inotropic supportive treatment.

(8) Abuse of and drug dependence on propofol, predominantly by health care professionals.

(9) Not known as it cannot be estimated from the available clinical trial data.

(10) Necrosis has been reported where tissue viability has been impaired.

Dystonia/dyskinesia have been reported.

Local

The local pain which may occur during the induction phase of Propofol-Lipuro 1% anaesthesia can be minimised by the co-administration of lidocaine (see "Dosage and Administration") and by the use of the larger veins of the forearm and antecubital fossa. Thrombosis and phlebitis are rare. Accidental clinical extravasation and animal studies showed minimal tissue reaction. Intra-arterial injection in animals did not induce local tissue effects.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard.

Adverse event information is derived from controlled clinical trials and worldwide marketing experience. In the description below, rates of the more common events represent US/Canadian clinical study results. Less frequent events are also derived from publications and marketing experience in over 8 million patients; there are insufficient data to support an accurate estimate of their incidence rates. These studies were conducted using a variety of premedicants, varying lengths of surgical/diagnostic procedures, and various other anesthetic/sedative agents. Most adverse events were mild and transient.

The following estimates of adverse events for Propofol-Lipuro injectable emulsion include data from clinical trials in general anesthesia/MAC sedation (N=2889 adult patients). The adverse events listed below as probably causally related are those events in which the actual incidence rate in patients treated with Propofol-Lipuro injectable emulsion was greater than the comparator incidence rate in these trials. Therefore, incidence rates for anesthesia and MAC sedation in adults generally represent estimates of the percentage of clinical trial patients which appeared to have probable causal relationship.

The adverse experience profile from reports of 150 patients in the MAC sedation clinical trials is similar to the profile established with Propofol-Lipuro during anesthesia (see below). During MAC sedation clinical trials, significant respiratory events included cough, upper airway obstruction, apnea, hypoventilation, and dyspnea.

Generally the adverse experience profile from reports of 506 Propofol-Lipuro injectable emulsion pediatric patients from 6 days through 16 years of age in the US/Canadian anesthesia clinical trials is similar to the profile established with Propofol-Lipuro injectable emulsion during anesthesia in adults (see Pediatric percentages [Peds %] below). Although not reported as an adverse event in clinical trials, apnea is frequently observed in pediatric patients.

The following estimates of adverse events include data from clinical trials in ICU sedation (N=159 adult patients). Probably related incidence rates for ICU sedation were determined by individual case report form review. Probable causality was based upon an apparent dose response relationship and/or positive responses to rechallenge. In many instances the presence of concomitant disease and concomitant therapy made the causal relationship unknown. Therefore, incidence rates for ICU sedation generally represent estimates of the percentage of clinical trial patients which appeared to have a probable causal relationship.

Incidence greater than 1% - Probably Causally Related

Adverse event information is derived from controlled clinical trials and worldwide marketing experience. In the description below, rates of the more common events represent US/Canadian clinical study results. Less frequent events are also derived from publications and marketing experience in over 8 million patients; there are insufficient data to support an accurate estimate of their incidence rates. These studies were conducted using a variety of premedicants, varying lengths of surgical/diagnostic procedures, and various other anesthetic/sedative agents. Most adverse events were mild and transient.

The following estimates of adverse events for DIPRIVAN Injectable Emulsion include data from clinical trials in general anesthesia/MAC sedation (N=2889 adult patients). The adverse events listed below as probably causally related are those events in which the actual incidence rate in patients treated with DIPRIVAN Injectable Emulsion was greater than the comparator incidence rate in these trials. Therefore, incidence rates for anesthesia and MAC sedation in adults generally represent estimates of the percentage of clinical trial patients which appeared to have probable causal relationship.

The adverse experience profile from reports of 150 patients in the MAC sedation clinical trials is similar to the profile established with DIPRIVAN Injectable Emulsion during anesthesia (see below). During MAC sedation clinical trials, significant respiratory events included cough, upper airway obstruction, apnea, hypoventilation, and dyspnea.

Generally the adverse experience profile from reports of 506 DIPRIVAN Injectable Emulsion pediatric patients from 6 days through 16 years of age in the US/Canadian anesthesia clinical trials is similar to the profile established with DIPRIVAN Injectable Emulsion during anesthesia in adults (see Pediatric percentages [Peds %] below). Although not reported as an adverse event in clinical trials, apnea is frequently observed in pediatric patients.

The following estimates of adverse events include data from clinical trials in ICU sedation (N=159 adult patients). Probably related incidence rates for ICU sedation were determined by individual case report form review. Probable causality was based upon an apparent dose response relationship and/or positive responses to rechallenge. In many instances the presence of concomitant disease and concomitant therapy made the causal relationship unknown. Therefore, incidence rates for ICU sedation generally represent estimates of the percentage of clinical trial patients which appeared to have a probable causal relationship.

Incidence greater than 1% - Probably Causally Related

Incidence less than 1% - Probably Causally Related

Incidence less than 1% - Causal Relationship Unknown

There are reports of the abuse of propofol for recreational and other improper purposes, which have resulted in fatalities and other injuries. Instances of self-administration of DIPRIVAN Injectable Emulsion by health care professionals have also been reported, which have resulted in fatalities and other injuries. Inventories of DIPRIVAN Injectable Emulsion should be stored and managed to prevent the risk of diversion, including restriction of access and accounting procedures as appropriate to the clinical setting.

Preclinical safety data

Propofol is a drug on which extensive clinical experience has been obtained. All relevant information for the prescriber is provided elsewhere in the Summary of Product Characteristics.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Other general anaesthetics

ATC code: N01AX10

Mechanism of action

Propofol (2, 6-diisopropylphenol) is a short-acting general anaesthetic agent with a rapid onset of action of approximately 30 seconds. Recovery from anaesthesia is usually rapid. The mechanism of action, like all general anaesthetics, is poorly understood. However, propofol is thought to produce its sedative/anaesthetic effects by the positive modulation of the inhibitory function of the neurotransmitter GABA through the ligand-gated GABAA receptors.

Pharmacodynamic properties

In general, falls in mean arterial blood pressure and slight changes in heart rate are observed when Propofol-Lipuro 1% is administered for induction and maintenance of anaesthesia. However, the haemodynamic parameters normally remain relatively stable during maintenance and the incidence of untoward haemodynamic changes is low.

Although ventilatory depression can occur following administration of Propofol-Lipuro 1%, any effects are qualitatively similar to those of other intravenous anaesthetic agents and are readily manageable in clinical practice.

Propofol-Lipuro 1% reduces cerebral blood flow, intracranial pressure and cerebral metabolism. The reduction in intracranial pressure is greater in patients with an elevated baseline intracranial pressure.

Clinical efficacy and safety

Recovery from anaesthesia is usually rapid and clear headed with a low incidence of headache and post-operative nausea and vomiting.

In general, there is less post-operative nausea and vomiting following anaesthesia with Propofol-Lipuro 1% than following anaesthesia with inhalational agents. There is evidence that this may be related to a reduced emetic potential of propofol.

Propofol-Lipuro 1%, at the concentrations likely to occur clinically, does not inhibit the synthesis of adrenocortical hormones.

Paediatric population

Limited studies on the duration of propofol based anaesthesia in children indicate safety and efficacy is unchanged up to duration of 4 hours. Literature evidence of use in children documents use for prolonged procedures without changes in safety or efficacy.

Pharmacodynamic properties of Propofol-Lipuro are dependent upon the therapeutic blood Propofol-Lipuro concentrations. Steady-state Propofol-Lipuro blood concentrations are generally proportional to infusion rates. Undesirable side effects such as cardiorespiratory depression are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in infusion rates. An adequate interval (3 to 5 minutes) must be allowed between dosage adjustments in order to assess clinical effects.

The hemodynamic effects of Propofol-Lipuro injectable emulsion during induction of anesthesia vary. If spontaneous ventilation is maintained, the major cardiovascular effect is 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), there is an increase in the incidence and the degree of depression of cardiac output. Addition of an opioid, used as a premedicant, further decreases cardiac output and respiratory drive.

If anesthesia is continued by infusion of Propofol-Lipuro injectable emulsion, the stimulation of endotracheal intubation and surgery may return arterial pressure towards normal. However, cardiac output may remain depressed. Comparative clinical studies have shown that the hemodynamic effects of Propofol-Lipuro injectable emulsion during induction of anesthesia are generally more pronounced than with other intravenous (I.V.) induction agents.

Induction of anesthesia with Propofol-Lipuro injectable emulsion is frequently associated with apnea in both adults and pediatric patients. In adult patients who received Propofol-Lipuro injectable emulsion (2 to 2.5 mg/kg), apnea lasted less than 30 seconds in 7% of patients, 30 to 60 seconds in 24% of patients, and more than 60 seconds in 12% of patients. In pediatric patients from birth through 16 years of age assessable for apnea who received bolus doses of Propofol-Lipuro injectable emulsion (1 to 3.6 mg/kg), apnea lasted less than 30 seconds in 12% of patients, 30 to 60 seconds in 10% of patients, and more than 60 seconds in 5% of patients.

During maintenance of general anesthesia, Propofol-Lipuro injectable emulsion causes a decrease in spontaneous minute ventilation usually associated with an increase in carbon dioxide tension which may be marked depending upon the rate of administration and concurrent use of other medications (e.g., opioids, sedatives, etc.).

During monitored anesthesia care (MAC) sedation, attention must be given to the cardiorespiratory effects of Propofol-Lipuro injectable emulsion. Hypotension, oxyhemoglobin desaturation, apnea, and airway obstruction can occur, especially following a rapid bolus of Propofol-Lipuro injectable emulsion. During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration. During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus administration in order to minimize undesirable cardiorespiratory effects. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).

Clinical and preclinical studies suggest that Propofol-Lipuro injectable emulsion is rarely associated with elevation of plasma histamine levels.

Preliminary findings in patients with normal intraocular pressure indicate that Propofol-Lipuro injectable emulsion produces a decrease in intraocular pressure which may be associated with a concomitant decrease in systemic vascular resistance.

Clinical studies indicate that Propofol-Lipuro injectable emulsion when used in combination with hypocarbia increases cerebrovascular resistance and decreases cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure. Propofol-Lipuro injectable emulsion does not affect cerebrovascular reactivity to changes in arterial carbon dioxide tension (see Clinical Trials - Neuroanesthesia).

Clinical studies indicate that Propofol-Lipuro injectable emulsion does not suppress the adrenal response to ACTH.

Animal studies and limited experience in susceptible patients have not indicated any propensity of Propofol-Lipuro injectable emulsion to induce malignant hyperthermia.

Hemosiderin deposits have been observed in the livers of dogs receiving Propofol-Lipuro injectable emulsion containing 0.005% disodium edetate over a four-week period; the clinical significance of this is unknown.

Pharmacodynamic properties of propofol are dependent upon the therapeutic blood propofol concentrations. Steady-state propofol blood concentrations are generally proportional to infusion rates. Undesirable side effects, such as cardiorespiratory depression, are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in infusion rates. An adequate interval (3 to 5 minutes) must be allowed between dose adjustments in order to assess clinical effects.

The hemodynamic effects of DIPRIVAN Injectable Emulsion during induction of anesthesia vary. If spontaneous ventilation is maintained, the major cardiovascular effect is 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), there is an increase in the incidence and the degree of depression of cardiac output. Addition of an opioid, used as a premedicant, further decreases cardiac output and respiratory drive.

If anesthesia is continued by infusion of DIPRIVAN Injectable Emulsion, the stimulation of endotracheal intubation and surgery may return arterial pressure towards normal. However, cardiac output may remain depressed. Comparative clinical studies have shown that the hemodynamic effects of DIPRIVAN Injectable Emulsion during induction of anesthesia are generally more pronounced than with other intravenous (IV) induction agents.

Induction of anesthesia with DIPRIVAN Injectable Emulsion is frequently associated with apnea in both adults and pediatric patients. In adult patients who received DIPRIVAN Injectable Emulsion (2 to 2.5 mg/kg), apnea lasted less than 30 seconds in 7% of patients, 30 to 60 seconds in 24% of patients, and more than 60 seconds in 12% of patients. In pediatric patients from birth through 16 years of age assessable for apnea who received bolus doses of DIPRIVAN Injectable Emulsion (1 to 3.6 mg/kg), apnea lasted less than 30 seconds in 12% of patients, 30 to 60 seconds in 10% of patients, and more than 60 seconds in 5% of patients.

During maintenance of general anesthesia, DIPRIVAN Injectable Emulsion causes a decrease in spontaneous minute ventilation usually associated with an increase in carbon dioxide tension which may be marked depending upon the rate of administration and concurrent use of other medications (e.g., opioids, sedatives, etc.).

During monitored anesthesia care (MAC) sedation, attention must be given to the cardiorespiratory effects of DIPRIVAN Injectable Emulsion. Hypotension, oxyhemoglobin desaturation, apnea, and airway obstruction can occur, especially following a rapid bolus of DIPRIVAN Injectable Emulsion. During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration. During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus administration in order to minimize undesirable cardiorespiratory effects. In the elderly, debilitated, or ASAPS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).

Clinical and preclinical studies suggest that DIPRIVAN Injectable Emulsion is rarely associated with elevation of plasma histamine levels.

Preliminary findings in patients with normal intraocular pressure indicate that DIPRIVAN Injectable Emulsion produces a decrease in intraocular pressure which may be associated with a concomitant decrease in systemic vascular resistance.

Clinical studies indicate that DIPRIVAN Injectable Emulsion when used in combination with hypocarbia increases cerebrovascular resistance and decreases cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure. DIPRIVAN Injectable Emulsion does not affect cerebrovascular reactivity to changes in arterial carbon dioxide tension (see Clinical Trials, Neuroanesthesia).

Clinical studies indicate that DIPRIVAN Injectable Emulsion does not suppress the adrenal response to ACTH.

Animal studies and limited experience in susceptible patients have not indicated any propensity of DIPRIVAN Injectable Emulsion to induce malignant hyperthermia.

Hemosiderin deposits have been observed in the livers of dogs receiving DIPRIVAN Injectable Emulsion containing 0.005% disodium edetate over a four-week period; the clinical significance of this is unknown.

Pharmacokinetic properties

Absorption

When Propofol-Lipuro 1% is used to maintain anaesthesia, blood concentrations asymptotically approach the steady-state value for the given administration rate.

Distribution

Propofol is extensively distributed and rapidly cleared from the body (total body clearance 1.5-2 litres/minute).

Elimination

The decline in propofol concentrations following a bolus dose or following the termination of an infusion can be described by a three compartment open model with very rapid distribution (half-life 2 -4 minutes), rapid elimination (half-life 30 - 60 minutes), and a slower final phase, representative of redistribution of propofol from poorly perfused tissue.

Clearance occurs by metabolic processes, mainly in the liver where it is blood flow dependent, to form inactive conjugates of propofol and its corresponding quinol, which are excreted in urine.

After a single dose of 3 mg/kg intravenously, propofol clearance/kg body weight increased with age as follows: Median clearance was considerably lower in neonates <1 month old (n=25) (20 ml/kg/min) compared to older children (n= 36, age range 4 months-7 years). Additionally inter-individual variability was considerable in neonates (range 3.7-78 ml/kg/min). Due to this limited trial data that indicates a large variability, no dose recommendations can be given for this age group.

Median propofol clearance in older aged children after a single 3 mg/kg bolus was 37.5 ml/min/kg (4-24 months) (n=8), 38.7 ml/min/kg (11-43 months) (n=6), 48 ml/min/kg (1-3 years)(n=12), 28.2 ml/min/kg (4-7 years)(n=10) as compared with 23.6 ml/min/kg in adults (n=6).

Linearity

The pharmacokinetics are linear over the recommended range of infusion rates of Propofol-Lipuro 1%.

In pediatric patients, abrupt discontinuation following prolonged infusion may result in flushing of the hands and feet, agitation, tremulousness and hyperirritability. Increased incidences of bradycardia (5%), agitation (4%), and jitteriness (9%) have also been observed.

Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome,” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.

Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome,” the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.

The effect of age on induction dose requirements for Propofol-Lipuro was assessed in an open-label study involving 211 unpremedicated patients with approximately 30 patients in each decade between the ages of 16 and 80. The average dose to induce anesthesia was calculated for patients up to 54 years of age and for patients 55 years of age or older. The average dose to induce anesthesia in patients up to 54 years of age was 1.99 mg/kg and in patients above 54 it was 1.66 mg/kg. Subsequent clinical studies have demonstrated lower dosing requirements for subjects greater than 60 years of age.

A lower induction dose and a slower maintenance rate of administration of Propofol-Lipuro injectable emulsion should be used in elderly patients. In this group of patients, rapid (single or repeated) bolus administration should not be used in order to minimize undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation. All dosing should be titrated according to patient condition and response. (See DOSAGE AND ADMINISTRATION – Elderly, debilitated or ASA-PS III or IV patients and CLINICAL PHARMACOLOGY – Geriatrics.)

If overdosage occurs, Propofol-Lipuro injectable emulsion 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.

Propofol-Lipuro injectable emulsion is contraindicated in patients with a known hypersensitivity to Propofol-Lipuro injectable emulsion or any of its components.

Propofol-Lipuro injectable emulsion is contraindicated in patients with allergies to eggs, egg products, soybeans or soy products.

Propofol-Lipuro is an intravenous sedative-hypnotic agent for use in the induction and maintenance of anesthesia or sedation. Intravenous injection of a therapeutic dose of Propofol-Lipuro induces hypnosis with minimal excitation, usually within 40 seconds from the start of injection (the time for one arm-brain circulation). As with other rapidly acting intravenous anesthetic agents, the half-time of the blood-brain equilibration is approximately 1 to 3 minutes, accounting for the rate of induction of anesthesia.

Pharmacodynamic properties of Propofol-Lipuro are dependent upon the therapeutic blood Propofol-Lipuro concentrations. Steady-state Propofol-Lipuro blood concentrations are generally proportional to infusion rates. Undesirable side effects such as cardiorespiratory depression are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in infusion rates. An adequate interval (3 to 5 minutes) must be allowed between dosage adjustments in order to assess clinical effects.

The hemodynamic effects of Propofol-Lipuro injectable emulsion during induction of anesthesia vary. If spontaneous ventilation is maintained, the major cardiovascular effect is 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), there is an increase in the incidence and the degree of depression of cardiac output. Addition of an opioid, used as a premedicant, further decreases cardiac output and respiratory drive.

If anesthesia is continued by infusion of Propofol-Lipuro injectable emulsion, the stimulation of endotracheal intubation and surgery may return arterial pressure towards normal. However, cardiac output may remain depressed. Comparative clinical studies have shown that the hemodynamic effects of Propofol-Lipuro injectable emulsion during induction of anesthesia are generally more pronounced than with other intravenous (I.V.) induction agents.

Induction of anesthesia with Propofol-Lipuro injectable emulsion is frequently associated with apnea in both adults and pediatric patients. In adult patients who received Propofol-Lipuro injectable emulsion (2 to 2.5 mg/kg), apnea lasted less than 30 seconds in 7% of patients, 30 to 60 seconds in 24% of patients, and more than 60 seconds in 12% of patients. In pediatric patients from birth through 16 years of age assessable for apnea who received bolus doses of Propofol-Lipuro injectable emulsion (1 to 3.6 mg/kg), apnea lasted less than 30 seconds in 12% of patients, 30 to 60 seconds in 10% of patients, and more than 60 seconds in 5% of patients.

During maintenance of general anesthesia, Propofol-Lipuro injectable emulsion causes a decrease in spontaneous minute ventilation usually associated with an increase in carbon dioxide tension which may be marked depending upon the rate of administration and concurrent use of other medications (e.g., opioids, sedatives, etc.).

During monitored anesthesia care (MAC) sedation, attention must be given to the cardiorespiratory effects of Propofol-Lipuro injectable emulsion. Hypotension, oxyhemoglobin desaturation, apnea, and airway obstruction can occur, especially following a rapid bolus of Propofol-Lipuro injectable emulsion. During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration. During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus administration in order to minimize undesirable cardiorespiratory effects. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).

Clinical and preclinical studies suggest that Propofol-Lipuro injectable emulsion is rarely associated with elevation of plasma histamine levels.

Preliminary findings in patients with normal intraocular pressure indicate that Propofol-Lipuro injectable emulsion produces a decrease in intraocular pressure which may be associated with a concomitant decrease in systemic vascular resistance.

Clinical studies indicate that Propofol-Lipuro injectable emulsion when used in combination with hypocarbia increases cerebrovascular resistance and decreases cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure. Propofol-Lipuro injectable emulsion does not affect cerebrovascular reactivity to changes in arterial carbon dioxide tension (see Clinical Trials - Neuroanesthesia).

Clinical studies indicate that Propofol-Lipuro injectable emulsion does not suppress the adrenal response to ACTH.

Animal studies and limited experience in susceptible patients have not indicated any propensity of Propofol-Lipuro injectable emulsion to induce malignant hyperthermia.

Hemosiderin deposits have been observed in the livers of dogs receiving Propofol-Lipuro injectable emulsion containing 0.005% disodium edetate over a four-week period; the clinical significance of this is unknown.

The pharmacokinetics of Propofol-Lipuro are well described by a three compartment linear model with compartments representing the plasma, rapidly equilibrating tissues, and slowly equilibrating tissues.

Following an I.V. bolus dose, there is rapid equilibration between the plasma and the brain, thus accounting for the rapid onset of anesthesia. Plasma levels initially decline rapidly as a result of both distribution and metabolic clearance. Distribution accounts for about half of this decline following a bolus of Propofol-Lipuro.

However, distribution is not constant over time, but decreases as body tissues equilibrate with plasma and become saturated. The rate at which equilibration occurs is a function of the rate and duration of the infusion. When equilibration occurs there is no longer a net transfer of Propofol-Lipuro between tissues and plasma.

Discontinuation of the recommended doses of Propofol-Lipuro injectable emulsion after the maintenance of anesthesia for approximately one hour, or for sedation in the ICU for one day, results in a prompt decrease in blood Propofol-Lipuro concentrations and rapid awakening. Longer infusions (10 days of ICU sedation) result in accumulation of significant tissue stores of Propofol-Lipuro, such that the reduction in circulating Propofol-Lipuro is slowed and the time to awakening is increased.

By daily titration of Propofol-Lipuro injectable emulsion dosage to achieve only the minimum effective therapeutic concentration, rapid awakening within 10 to 15 minutes can occur even after long-term administration. If, however, higher than necessary infusion levels have been maintained for a long time, Propofol-Lipuro redistribution from fat and muscle to the plasma, can be significant and slow recovery.

The figure below illustrates the fall of plasma Propofol-Lipuro levels following infusions of various durations to provide ICU sedation.

The large contribution of distribution (about 50%) to the fall of Propofol-Lipuro plasma levels following brief infusions means that after very long infusions a reduction in infusion rate is appropriate by as much as half the initial infusion rate in order to maintain a constant plasma level. Therefore, failure to reduce the infusion rate in patients receiving Propofol-Lipuro injectable emulsion for extended periods may result in excessively high blood concentrations of the drug. Thus, titration to clinical response and daily evaluation of sedation levels are important during use of Propofol-Lipuro injectable emulsion infusion for ICU sedation.

Propofol-Lipuro clearance ranges from 23 to 50 mL/kg/min (1.6 to 3.4 L/min in 70 kg adults). It is chiefly eliminated by hepatic conjugation to inactive metabolites which are excreted by the kidney. A glucuronide conjugate accounts for about 50% of the administered dose. Propofol-Lipuro has a steady state volume of distribution (10-day infusion) approaching 60 L/kg in healthy adults. A difference in pharmacokinetics due to gender has not been observed. The terminal half-life of Propofol-Lipuro after a 10-day infusion is 1 to 3 days.

With increasing patient age, the dose of Propofol-Lipuro needed to achieve a defined anesthetic endpoint (dose-requirement) decreases. This does not appear to be an age-related change in pharmacodynamics or brain sensitivity, as measured by EEG burst suppression. With increasing patient age, pharmacokinetic changes are such that for a given I.V. 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 arterial oxygen desaturation. The higher plasma levels reflect age-related decrease in volume of distribution and intercompartmental clearance. Lower doses are therefore recommended for initiation and maintenance of sedation and anesthesia in elderly patients. (See DOSAGE AND ADMINISTRATION.)

The pharmacokinetics of Propofol-Lipuro were studied in children between 3 and 12 years of age who received Propofol-Lipuro injectable emulsion for periods of approximately 1 to 2 hours. The observed distribution and clearance of Propofol-Lipuro in these children were similar to adults.

The pharmacokinetics of Propofol-Lipuro 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-Lipuro have not been studied.

Propofol-Lipuro injectable emulsion was studied in clinical trials which included cardiac surgical patients. Most patients were 3 years of age or older. The majority of the patients were healthy ASA-PS I or II patients. The range of doses in these studies are described in Tables 1 and 2.

TABLE 1: PEDIATRIC INDUCTION OF ANESTHESIA

TABLE 2: PEDIATRIC MAINTENANCE OF ANESTHESIA

Propofol-Lipuro injectable emulsion was studied in patients undergoing craniotomy for supratentorial tumors in two clinical trials. The mean lesion size (anterior/posterior x lateral) was 31 mm x 32 mm in one trial and 55 mm x 42 mm in the other trial respectively. Anesthesia was induced with a median Propofol-Lipuro dose of 1.4 mg/kg (range: 0.9 to 6.9 mg/kg) and maintained with a median maintenance Propofol-Lipuro dose of 146 mcg/kg/min (range: 68 to 425 mcg/kg/min). The median duration of the Propofol-Lipuro maintenance infusion was 285 minutes (range: 48 to 622 minutes).

Propofol-Lipuro injectable emulsion was administered by infusion in a controlled clinical trial to evaluate its effect on cerebrospinal fluid pressure (CSFP). The mean arterial pressure was maintained relatively constant over 25 minutes with a change from baseline of -4% ± 17% (mean ± SD). The change in CSFP was -46% ± 14%. As CSFP is an indirect measure of intracranial pressure (ICP), Propofol-Lipuro injectable emulsion, when given by infusion or slow bolus in combination with hypocarbia, is capable of decreasing ICP independent of changes in arterial pressure.

Propofol-Lipuro injectable emulsion was compared to benzodiazepines and opioids in clinical trials involving ICU patients. Of these, 302 received Propofol-Lipuro injectable emulsion and comprise the overall safety database for ICU sedation.

Across all clinical studies, the mean infusion maintenance rate for all Propofol-Lipuro injectable emulsion patients was 27 ± 21 mcg/kg/min. The maintenance infusion rates required to maintain adequate sedation ranged from 2.8 mcg/kg/min to 130 mcg/kg/min. The infusion rate was lower in patients over 55 years of age (approximately 20 mcg/kg/min) compared to patients under 55 years of age (approximately 38 mcg/kg/min). Although there are reports of reduced analgesic requirements, most patients received opioids for analgesia during maintenance of ICU sedation. In these studies, morphine or fentanyl was used as needed for analgesia. Some patients also received benzodiazepines and/or neuromuscular blocking agents. During long-term maintenance of sedation, some ICU patients were awakened once or twice every 24 hours for assessment of neurologic or respiratory function.

In Medical and Postsurgical ICU studies comparing Propofol-Lipuro injectable emulsion to benzodiazepine infusion or bolus, there were no apparent differences in maintenance of adequate sedation, mean arterial pressure, or laboratory findings. Like the comparators, Propofol-Lipuro injectable emulsion reduced blood cortisol during sedation while maintaining responsivity to challenges with adrenocorticotropic hormone (ACTH). Case reports from the published literature generally reflect that Propofol-Lipuro injectable emulsion has been used safely in patients with a history of porphyria or malignant hyperthermia.

In hemodynamically stable head trauma patients ranging in age from 19 to 43 years, adequate sedation was maintained with Propofol-Lipuro injectable emulsion or morphine. There were no apparent differences in adequacy of sedation, intracranial pressure, cerebral perfusion pressure, or neurologic recovery between the treatment groups. In literature reports of severely head-injured patients in Neurosurgical ICUs, Propofol-Lipuro injectable emulsion infusion and hyperventilation, both with and without diuretics, controlled intracranial pressure while maintaining cerebral perfusion pressure. In some patients, bolus doses resulted in decreased blood pressure and compromised cerebral perfusion pressure.

Propofol-Lipuro injectable emulsion was found to be effective in status epilepticus which was refractory to the standard anticonvulsant therapies. For these patients, as well as for ARDS/respiratory failure and tetanus patients, sedation maintenance dosages were generally higher than those for other critically ill patient populations.

A single, randomized, controlled, clinical trial that evaluated the safety and effectiveness of Propofol-Lipuro versus standard sedative agents (SSA) was conducted on 327 pediatric ICU patients. Patients were randomized to receive either Propofol-Lipuro 2% (113 patients), Propofol-Lipuro 1% (109 patients), or an SSA (e.g., lorazepam, chloral hydrate, fentanyl, ketamine, morphine, or phenobarbital). Propofol-Lipuro therapy was initiated at an infusion rate of 5.5 mg/kg/hr and titrated as needed to maintain sedation at a standardized level. The results of the study showed an increase in the number of deaths in patients treated with Propofol-Lipuro as compared to SSAs. Of the 25 patients who died during the trial or within the 28-day follow-up period: 12 (11% were) in the Propofol-Lipuro 2% treatment group, 9 (8% were) in the Propofol-Lipuro 1% treatment group, and 4% were (4%) in the SSA treatment group. The differences in mortality rate between the groups were not statistically significant. Review of the deaths failed to reveal a correlation with underlying disease status or a correlation to the drug or a definitive pattern to the causes of death.

Propofol-Lipuro injectable emulsion was evaluated in clinical trials involving patients undergoing coronary artery bypass graft (CABG).

In post-CABG (coronary artery bypass graft) patients, the maintenance rate of Propofol-Lipuro administration was usually low (median 11 mcg/kg/min) due to the intraoperative administration of high opioid doses. Patients receiving Propofol-Lipuro injectable emulsion required 35% less nitroprusside than midazolam patients. During initiation of sedation in post-CABG patients, a 15% to 20% decrease in blood pressure was seen in the first 60 minutes. It was not possible to determine cardiovascular effects in patients with severely compromised ventricular function.

In pediatric patients, abrupt discontinuation of DIPRIVAN Injectable Emulsion following prolonged infusion may result in flushing of the hands and feet, agitation, tremulousness and hyperirritability. Increased incidences of bradycardia (5%), agitation (4%), and jitteriness (9%) have also been observed.

The effect of age on induction dose requirements for propofol was assessed in an open-label study involving 211 unpremedicated patients with approximately 30 patients in each decade between the ages of 16 and 80. The average dose to induce anesthesia was calculated for patients up to 54 years of age and for patients 55 years of age or older. The average dose to induce anesthesia in patients up to 54 years of age was 1.99 mg/kg and in patients above 54 it was 1.66 mg/kg. Subsequent clinical studies have demonstrated lower dosing requirements for subjects greater than 60 years of age.

A lower induction dose and a slower maintenance rate of administration of DIPRIVAN Injectable Emulsion should be used in elderly patients. In this group of patients, rapid (single or repeated) bolus administration should not be used in order to minimize undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation. All dosing should be titrated according to patient condition and response (see DOSAGE AND ADMINISTRATION, Elderly, Debilitated or ASA-PS III or IV Patients and CLINICAL PHARMACOLOGY, Geriatrics).

If overdosage occurs, DIPRIVAN Injectable Emulsion 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.

DIPRIVAN Injectable Emulsion is contraindicated in patients with a known hypersensitivity to propofol or any of DIPRIVAN Injectable Emulsion components.

DIPRIVAN Injectable Emulsion is contraindicated in patients with allergies to eggs, egg products, soybeans or soy products.

DIPRIVAN Injectable Emulsion is an intravenous sedative-hypnotic agent for use in the induction and maintenance of anesthesia or sedation. Intravenous injection of a therapeutic dose of propofol induces hypnosis, with minimal excitation, usually within 40 seconds from the start of injection (the time for one arm-brain circulation). As with other rapidly acting intravenous anesthetic agents, the half-time of the blood-brain equilibration is approximately 1 to 3 minutes, accounting for the rate of induction of anesthesia. The mechanism of action, like all general anesthetics, is poorly understood. However, propofol is thought to produce its sedative/anesthetic effects by the positive modulation of the inhibitory function of the neurotransmitter GABA through the ligand-gated GABAa receptors.

Pharmacodynamic properties of propofol are dependent upon the therapeutic blood propofol concentrations. Steady-state propofol blood concentrations are generally proportional to infusion rates. Undesirable side effects, such as cardiorespiratory depression, are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in infusion rates. An adequate interval (3 to 5 minutes) must be allowed between dose adjustments in order to assess clinical effects.

The hemodynamic effects of DIPRIVAN Injectable Emulsion during induction of anesthesia vary. If spontaneous ventilation is maintained, the major cardiovascular effect is 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), there is an increase in the incidence and the degree of depression of cardiac output. Addition of an opioid, used as a premedicant, further decreases cardiac output and respiratory drive.

If anesthesia is continued by infusion of DIPRIVAN Injectable Emulsion, the stimulation of endotracheal intubation and surgery may return arterial pressure towards normal. However, cardiac output may remain depressed. Comparative clinical studies have shown that the hemodynamic effects of DIPRIVAN Injectable Emulsion during induction of anesthesia are generally more pronounced than with other intravenous (IV) induction agents.

Induction of anesthesia with DIPRIVAN Injectable Emulsion is frequently associated with apnea in both adults and pediatric patients. In adult patients who received DIPRIVAN Injectable Emulsion (2 to 2.5 mg/kg), apnea lasted less than 30 seconds in 7% of patients, 30 to 60 seconds in 24% of patients, and more than 60 seconds in 12% of patients. In pediatric patients from birth through 16 years of age assessable for apnea who received bolus doses of DIPRIVAN Injectable Emulsion (1 to 3.6 mg/kg), apnea lasted less than 30 seconds in 12% of patients, 30 to 60 seconds in 10% of patients, and more than 60 seconds in 5% of patients.

During maintenance of general anesthesia, DIPRIVAN Injectable Emulsion causes a decrease in spontaneous minute ventilation usually associated with an increase in carbon dioxide tension which may be marked depending upon the rate of administration and concurrent use of other medications (e.g., opioids, sedatives, etc.).

During monitored anesthesia care (MAC) sedation, attention must be given to the cardiorespiratory effects of DIPRIVAN Injectable Emulsion. Hypotension, oxyhemoglobin desaturation, apnea, and airway obstruction can occur, especially following a rapid bolus of DIPRIVAN Injectable Emulsion. During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration. During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus administration in order to minimize undesirable cardiorespiratory effects. In the elderly, debilitated, or ASAPS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).

Clinical and preclinical studies suggest that DIPRIVAN Injectable Emulsion is rarely associated with elevation of plasma histamine levels.

Preliminary findings in patients with normal intraocular pressure indicate that DIPRIVAN Injectable Emulsion produces a decrease in intraocular pressure which may be associated with a concomitant decrease in systemic vascular resistance.

Clinical studies indicate that DIPRIVAN Injectable Emulsion when used in combination with hypocarbia increases cerebrovascular resistance and decreases cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure. DIPRIVAN Injectable Emulsion does not affect cerebrovascular reactivity to changes in arterial carbon dioxide tension (see Clinical Trials, Neuroanesthesia).

Clinical studies indicate that DIPRIVAN Injectable Emulsion does not suppress the adrenal response to ACTH.

Animal studies and limited experience in susceptible patients have not indicated any propensity of DIPRIVAN Injectable Emulsion to induce malignant hyperthermia.

Hemosiderin deposits have been observed in the livers of dogs receiving DIPRIVAN Injectable Emulsion containing 0.005% disodium edetate over a four-week period; the clinical significance of this is unknown.

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, there is rapid equilibration between the plasma and the brain, accounting for the rapid onset of anesthesia. Plasma levels initially decline rapidly as a result of both distribution and metabolic clearance. Distribution accounts for about half of this decline following a bolus of propofol. However, distribution is not constant over time, but decreases as body tissues equilibrate with plasma and become saturated. The rate at which equilibration occurs is a function of the rate and duration of the infusion. When equilibration occurs there is no longer a net transfer of propofol between tissues and plasma.

Discontinuation of the recommended doses of DIPRIVAN Injectable Emulsion after the maintenance of anesthesia for approximately one hour, or for sedation in the ICU for one day, results in a prompt decrease in blood propofol concentrations and rapid awakening. Longer infusions (10 days of ICU sedation) result in accumulation of significant tissue stores of propofol, such that the reduction in circulating propofol is slowed and the time to awakening is increased.

By daily titration of DIPRIVAN Injectable Emulsion dosage to achieve only the minimum effective therapeutic concentration, rapid awakening within 10 to 15 minutes can occur even after long-term administration. If, however, higher than necessary infusion levels have been maintained for a long time, propofol redistribution from fat and muscle to the plasma can be significant and slow recovery.

The figure below illustrates the fall of plasma propofol levels following infusions of various durations to provide ICU sedation.

The large contribution of distribution (about 50%) to the fall of propofol plasma levels following brief infusions means that after very long infusions a reduction in the infusion rate is appropriate by as much as half the initial infusion rate in order to maintain a constant plasma level. Therefore, failure to reduce the infusion rate in patients receiving DIPRIVAN Injectable Emulsion for extended periods may result in excessively high blood concentrations of the drug. Thus, titration to clinical response and daily evaluation of sedation levels are important during use of DIPRIVAN Injectable Emulsion infusion for ICU sedation.

Propofol clearance ranges from 23 to 50 mL/kg/min (1.6 to 3.4 L/min in 70 kg adults). It is chiefly eliminated by hepatic conjugation to inactive metabolites which are excreted by the kidney. A glucuronide conjugate accounts for about 50% of the administered dose. Propofol has a steady-state volume of distribution (10-day infusion) approaching 60 L/kg in healthy adults. A difference in pharmacokinetics due to gender has not been observed. The terminal half-life of propofol after a 10-day infusion is 1 to 3 days.

With increasing patient age, the dose of propofol needed to achieve a defined anesthetic end point (dose-requirement) decreases. This does not appear to be an age-related change in pharmacodynamics or brain sensitivity, as measured by EEG burst suppression. With increasing patient 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 arterial oxygen desaturation. The higher plasma levels reflect an age-related decrease in volume of distribution and intercompartmental clearance. Lower doses are therefore recommended for initiation and maintenance of sedation and anesthesia in elderly patients (see DOSAGE AND ADMINISTRATION).

The pharmacokinetics of propofol were studied in children between 3 and 12 years of age who received DIPRIVAN Injectable Emulsion for periods of approximately 1 to 2 hours. The observed distribution and clearance of propofol in these children were similar to 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.

DIPRIVAN Injectable Emulsion was studied in clinical trials which included cardiac surgical patients. Most patients were 3 years of age or older. The majority of the patients were healthy ASA-PS I or II patients. The range of doses in these studies are described in Tables 1 and 2.

TABLE 1: PEDIATRIC INDUCTION OF ANESTHESIA

TABLE 2: PEDIATRIC MAINTENANCE OF ANESTHESIA

DIPRIVAN Injectable Emulsion was studied in patients undergoing craniotomy for supratentorial tumors in two clinical trials. The mean lesion size (anterior/posterior x lateral) was 31 mm x 32 mm in one trial and 55 mm x 42 mm in the other trial respectively. Anesthesia was induced with a median DIPRIVAN dose of 1.4 mg/kg (range: 0.9 to 6.9 mg/kg) and maintained with a median maintenance DIPRIVAN dose of 146 mcg/kg/min (range: 68 to 425 mcg/kg/min). The median duration of the DIPRIVAN Injectable Emulsion maintenance infusion was 285 minutes (range: 48 to 622 minutes).

DIPRIVAN Injectable Emulsion was administered by infusion in a controlled clinical trial to evaluate its effect on cerebrospinal fluid pressure (CSFP). The mean arterial pressure was maintained relatively constant over 25 minutes with a change from baseline of -4% ± 17% (mean ± SD). The change in CSFP was -46% ± 14%. As CSFP is an indirect measure of intracranial pressure (ICP), DIPRIVAN Injectable Emulsion, when given by infusion or slow bolus in combination with hypocarbia, is capable of decreasing ICP independent of changes in arterial pressure.

DIPRIVAN Injectable Emulsion was compared to benzodiazepines and opioids in clinical trials involving ICU patients. Of these, 302 received DIPRIVAN Injectable Emulsion and comprise the overall safety database for ICU sedation.

Across all clinical studies, the mean infusion maintenance rate for all DIPRIVAN Injectable Emulsion patients was 27 ± 21 mcg/kg/min. The maintenance infusion rates required to maintain adequate sedation ranged from 2.8 mcg/kg/min to 130 mcg/kg/min. The infusion rate was lower in patients over 55 years of age (approximately 20 mcg/kg/min) compared to patients under 55 years of age (approximately 38 mcg/kg/min). Although there are reports of reduced analgesic requirements, most patients received opioids for analgesia during maintenance of ICU sedation. In these studies, morphine or fentanyl was used as needed for analgesia. Some patients also received benzodiazepines and/or neuromuscular blocking agents. During long-term maintenance of sedation, some ICU patients were awakened once or twice every 24 hours for assessment of neurologic or respiratory function.

In Medical and Postsurgical ICU studies comparing DIPRIVAN Injectable Emulsion to benzodiazepine infusion or bolus, there were no apparent differences in maintenance of adequate sedation, mean arterial pressure, or laboratory findings. Like the comparators, DIPRIVAN Injectable Emulsion reduced blood cortisol during sedation while maintaining responsivity to challenges with adrenocorticotropic hormone (ACTH). Case reports from the published literature generally reflect that DIPRIVAN Injectable Emulsion has been used safely in patients with a history of porphyria or malignant hyperthermia.

In hemodynamically stable head trauma patients ranging in age from 19 to 43 years, adequate sedation was maintained with DIPRIVAN Injectable Emulsion or morphine. There were no apparent differences in adequacy of sedation, intracranial pressure, cerebral perfusion pressure, or neurologic recovery between the treatment groups. In literature reports of severely head injured patients in Neurosurgical ICUs, DIPRIVAN Injectable Emulsion infusion and hyperventilation, both with and without diuretics, controlled intracranial pressure while maintaining cerebral perfusion pressure. In some patients, bolus doses resulted in decreased blood pressure and compromised cerebral perfusion pressure.

DIPRIVAN Injectable Emulsion was found to be effective in status epilepticus which was refractory to the standard anticonvulsant therapies. For these patients, as well as for ARDS/respiratory failure and tetanus patients, sedation maintenance dosages were generally higher than those for other critically ill patient populations.

A single, randomized, controlled, clinical trial that evaluated the safety and effectiveness of DIPRIVAN Injectable Emulsion versus standard sedative agents (SSA) was conducted on 327 pediatric ICU patients. Patients were randomized to receive either DIPRIVAN Injectable Emulsion 2%, (113 patients), DIPRIVAN Injectable Emulsion 1%, (109 patients), or an SSA (eg, lorazepam, chloral hydrate, fentanyl, ketamine, morphine, or phenobarbital). DIPRIVAN Injectable Emulsion therapy was initiated at an infusion rate of 5.5 mg/kg/hr and titrated as needed to maintain sedation at a standardized level. The results of the study showed an increase in the number of deaths in patients treated with DIPRIVAN Injectable Emulsion as compared to SSAs. Of the 25 patients who died during the trial or within the 28-day followup period: 12 (11% were) in the DIPRIVAN Injectable Emulsion 2% treatment group, 9 (8% were) in the DIPRIVAN Injectable Emulsion 1% treatment group, and 4% were (4%) in the SSA treatment group. The differences in mortality rate between the groups were not statistically significant. Review of the deaths failed to reveal a correlation with underlying disease status or a correlation to the drug or a definitive pattern to the causes of death.

DIPRIVAN Injectable Emulsion was evaluated in clinical trials involving patients undergoing coronary artery bypass graft (CABG).

In post-CABG (coronary artery bypass graft) patients, the maintenance rate of propofol administration was usually low (median 11 mcg/kg/min) due to the intraoperative administration of high opioid doses. Patients receiving DIPRIVAN Injectable Emulsion required 35% less nitroprusside than midazolam patients. During initiation of sedation in post-CABG patients, a 15% to 20% decrease in blood pressure was seen in the first 60 minutes. It was not possible to determine cardiovascular effects in patients with severely compromised ventricular function.

Effects on ability to drive and use machines

Propofol-Lipuro 1% has moderate influence on the ability to drive and use machines. Patients should be advised that performance at skilled tasks, such as driving and operating machinery, may be impaired for some time after general anaesthesia.

Special precautions for disposal and other handling

In-use precautions

Containers should be shaken before use.

Any portion of the contents remaining after use should be discarded.

Propofol-Lipuro 1% should not be mixed prior to administration with injections or infusion fluids other than 5% Dextrose or Lidocaine Injection.