Diprivan (Propofol)

DIPRIVAN®

Zeneca

Propofol

I.V. Emulsion – Anesthetic – Sedative

Action And Clinical Pharmacology: Propofol is an i.v. hypnotic agent for use in the induction and maintenance of general anesthesia or sedation. The drug, an alkylphenol formulated in an oil-in-water emulsion, is chemically distinct from currently available i.v. anesthetic agents. I.V. injection of a therapeutic dose of propofol produces hypnosis rapidly and smoothly, usually within 40 seconds from the start of an injection (one arm-brain circulation time), although induction times >60 seconds have been observed.

Pharmacokinetics in Adults: The pharmacokinetic profile of propofol can be described by a 3-compartment open model. After a single bolus dose, there is fast distribution from blood into tissues (t1/2a: 1.8 to 8.3 min), high metabolic clearance (t1/2b: 34 to 66 min) and a terminal slow elimination from poorly perfused tissues (t1/2g: 184 to 480 min). With 12- and 24-hour samplings, t1/2g values of 502 and 674 min, respectively, were observed.

Propofol has large volumes of distribution as would be expected with a highly lipophilic anesthetic agent. The volume of central compartment (Vc) is between 21 and 56 L (0.35 to 0.93 L/kg based on a 60 kg patient), and the volume of distribution at steady state (Vss) is between 171 and 364 L (2.85 to 6.07 L/kg). Values for volume of distribution during the terminal phase (Vd) are 2 to 3 times the corresponding Vss values.

The termination of the anesthetic or sedative effects of propofol after a single i.v. bolus or a maintenance infusion is due to extensive redistribution from the CNS to other tissues and high metabolic clearance, both of which will decrease blood concentrations. The mean propofol concentration at time of awakening is 1 µg/mL (range: 0.74 to 2.2 µg/mL). Recovery from anesthesia or sedation is rapid. When propofol is used for both induction (2.0 to 2.5 mg/kg) and maintenance (0.1 to 0.2 mg/kg/min) of anesthesia, the majority of patients are generally awake, responsive to verbal command and oriented in approximately 7 to 8 minutes. Recovery from the effects of propofol occurs due to rapid metabolism and is not dependent on the terminal elimination half-life since the blood levels achieved in this phase are not clinically significant. A study in 6 subjects showed that 72 and 88% of the administered radio-labeled dose was recovered in the urine within 24 hours and 5 days, respectively. Less than 2% was excreted in the feces. Unchanged drug was less than 0.3%. Propofol is chiefly metabolized by conjugation in the liver to inactive metabolites which are excreted by the kidney. Propofol glucuronide accounts for about 50% of the administered dose. The remainder consists of the 1- and 4-glucuronide and 4-sulfate conjugates of 2,6-diisopropyl-1,4-quinol.

The total body clearance (Cl) of propofol ranges from 1.6 L/min to 2.3 L/min (0.026 to 0.038 L/min/kg based on a 60 kg patient). This clearance exceeds estimates of hepatic blood flow, suggesting possible extrahepatic metabolism.

The pharmacokinetics of propofol do not appear to be altered by gender or chronic hepatic cirrhosis. The effects of acute hepatic failure on the pharmacokinetics of propofol have not been studied. In renal failure, the data is based on very limited findings. There was a trend towards longer half-lives, although the differences versus control patients did not reach statistical significance. With increasing age, the dose of propofol needed to achieve a defined anesthetic endpoint (dose-requirement) decreases. Elderly patients had higher propofol blood concentrations at 2 minutes than young ones (6.07 versus 4.15 µg/mL), probably due to a significantly lower initial distribution volume (20 versus 26 L). The relatively high blood concentrations during the first few minutes can predispose elderly patients to cardiorespiratory effects including hypotension, apnea, airway obstruction and/or oxygen desaturation. The clearance of propofol also decreased from a mean±S.D. of 1.8±0.4 L/min in young patients (18 to 35 years) to 1.4±0.4 L/min in elderly patients (65 to 80 years). The reduced clearance could decrease maintenance propofol requirements and prolong recovery if inappropriate infusions are used. Obesity is associated with significantly larger volumes of distribution (399 L versus 153 L) and clearance rates (2.8 L/min versus 1.8 L/min) but there is no change in the elimination half-life.

When given by an infusion for up to 2 hours, the pharmacokinetics of propofol appear to be independent of dose (0.05 to 0.15 mg/kg/min; 3 to 9 mg/kg/hour) and similar to i.v. bolus pharmacokinetics. The steady-state propofol blood concentrations are proportional to the rate of administration.

Propofol is highly protein-bound (97 to 99%); the degree of binding seems to be unrelated to either sex or age.

In the presence of propofol, alfentanil concentrations were higher than expected based upon the rate of infusion. However, alfentanil did not affect the pharmacokinetics of propofol.

Pharmacokinetics in Adult Patients in Intensive Care Unit (ICU): Regarding most parameters, the pharmacokinetics of propofol in these patients are similar to those of patients undergoing anesthesia/sedation for short surgical procedures. However, the terminal half-life (t1/2g) is substantially prolonged after long-term infusion, reflecting extensive tissue distribution.

Pharmacokinetics in Children: The results were obtained in ASA I children, ranging in age from 3 to 10 years, who received a single bolus dose of propofol, 2.5 mg/kg. Propofol was rapidly distributed from blood into tissue (t1/2a: 1.5 to 4.1 min), metabolic clearance was high (t1/2b: 9.3 to 56.1 min) and terminal elimination slow (t1/2g: 209 to 735 min). The volume of central compartment (Vc) ranged between 0.53 to 0.72 L/kg, the volume of distribution at steady state (Vss) was between 2.1 to 10.9 L/kg and clearance (Cl) ranged between 0.032 to 0.040 L/min/kg. The mean plasma concentration of propofol at awakening was 2.3 µg/mL.

Propofol induces anesthesia in a dose-dependent manner. In unpremedicated, ASA I or II patients, propofol induced anesthesia in 87% and 95% of patients at doses of 2.0 and 2.5 mg/kg, respectively. Elderly patients require lower doses; for unpremedicated patients older than 55 years of age, the mean dose requirement was 1.66 mg/kg. Premedication profoundly alters dose requirements; at 1.75 mg/kg, propofol induced anesthesia in 65% of patients who had no premedication and in 85% and 100% of patients who received diazepam or papaveretum-hyoscine premedication, respectively.

During induction of anesthesia, the hemodynamic effects of propofol 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. Maximal fall in blood pressure occurs within the first few minutes of the administration of a bolus dose. The fall in arterial pressure is greater under propofol anesthesia than under anesthesia induced by thiopental or methohexital. Increases in heart rate with propofol are generally less pronounced or absent after an induction dose, than after equivalent doses of these other 2 agents.

During maintenance of anesthesia with propofol, systolic and diastolic blood pressures generally remain below pre-anesthetic levels, although the depth of anesthesia, the rate of maintenance infusion as well as stimulation from tracheal intubation and/or surgery may increase or decrease blood pressure. Heart rate may also vary as a function of these factors but will generally remain below preanesthetic levels.

In the presence of a potent opioid (e.g., fentanyl), the blood pressure lowering effect of propofol is substantially increased. Fentanyl also decreases heart rate and this might lead to a significant decrease in cardiac output.

Age is highly correlated with the fall in blood pressure. In elderly subjects, both the incidence and degree of hypotension are greater than in younger subjects. Thus, a lower induction dose and a slower maintenance rate of administration should be used in the elderly (see Dosage). Particular caution should be exercised in elderly patients with severe coronary and/or cerebral arteriosclerosis; reduction in perfusion pressure may impair adequate blood supply to these organs.

Insufficient data are available regarding the cardiovascular effects of propofol when used for induction and/or maintenance of anesthesia or sedation in elderly, hypotensive, debilitated or other ASA III and IV patients. However, limited information suggests that these patients may have more profound cardiovascular responses. It is recommended that if propofol is used in these patients, a lower induction dose and a slower maintenance rate of administration of the drug be used (see Warnings and Dosage).

The first respiratory disturbance after a bolus dose of propofol is a profound fall in tidal volume leading to apnea in many patients. There has been no accompanying cough or hiccough and otherwise anesthesia is smooth. However, there might be some difficulty in uptake of volatile agents if respiration is not assisted.

In unpremedicated, healthy patients, there is a steep dose-response relationship regarding apnea; 0% and 44% of patients had apnea after receiving 2.0 and 2.5 mg/kg of propofol, respectively. Fentanyl enhanced both the incidence and the onset of apnea and the episode lasted for >60 seconds in the majority of patients.

Opioid premedication – in the presence of hyoscine – affected respiratory function (rate of respiration and minute volume) substantially more than atropine premedication. Respiratory function was more depressed when these premedicants were combined with propofol than when they were combined with thiopental. Enhanced respiratory depression with propofol and an opioid have been observed in the postoperative period.

During maintenance, propofol (0.1 to 0.2 mg/kg/min; 6 to 12 mg/kg/hour) caused 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 medication (e.g., narcotics, sedatives, etc.). Propofol was not evaluated in patients with any respiratory dysfunction.

During sedation, attention must be given to the cardiorespiratory effects of propofol. Hypotension, apnea, airway obstruction, and/or oxygen desaturation can occur, especially with a rapid bolus injection. During initiation of sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration, and during maintenance of sedation, a variable rate infusion is preferable over intermittent bolus administration in order to minimize undesirable cardiorespiratory effects. In the elderly, debilitated and ASA III or IV patients, rapid (single or repeated) bolus dose administration should not be used for sedation (see Warnings).

Clinical and preclinical studies suggest that propofol is rarely associated with elevation of plasma histamine levels and does not cause signs of histamine release.

Clinical and preclinical studies show that propofol does not suppress the adrenal response to ACTH.

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

Propofol is devoid of analgesic or antanalgesic activity.

Indications And Clinical Uses: A short-acting i.v. general anesthetic agent that can be used for both induction and maintenance of anesthesia as part of a balanced anesthesia technique, including total i.v. anesthesia (TIVA), for inpatient and outpatient surgery.

Also indicated for pediatric anesthesia in children 3 years of age and older.

Propofol, when administered i.v. as directed, can be used to initiate and maintain sedation in conjunction with local/regional anesthesia in patients undergoing surgical procedures. Propofol may also be used for sedation during diagnostic procedures (see Warnings and Precautions).

Propofol 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 should be administered only by persons trained in general anesthesia or critical care medicine.

Propofol is not recommended for sedation in children under the age of 18, either during surgical/diagnostic procedures or in the Intensive Care Unit (ICU), as safety and efficacy have not been established.

Contra-Indications: When general anesthesia or sedation are contraindicated or in patients with a known allergy and/or hypersensitivity to Diprivan or its components.

Manufacturers’ Warnings In Clinical States: For general anesthesia or sedation for surgical/diagnostic procedures, propofol should be administered only by persons trained in the administration of general anesthesia and not involved in the conduct of surgical/diagnostic procedures. Patients should be continuously monitored and facilities for maintenance of a patent airway, artificial ventilation, and oxygen enrichment and circulatory resuscitation must be immediately available.

For sedation of intubated, mechanically ventilated, adult patients in the Intensive Care Unit (ICU), propofol should be administered only by persons trained in general anesthesia or critical care medicine.

In the elderly, debilitated and ASA III or IV patients, rapid (single or repeated) bolus administration should not be used during general anesthesia or sedation in order to minimize undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction and/or oxygen desaturation.

Propofol should not be coadministered through the same i.v. catheter with blood or plasma because compatibility has not been established. In vitro tests have shown that aggregates of the globular component of the emulsion vehicle have occurred with blood/plasma/serum from humans and animals. The clinical significance is not known.

Propofol should not be used in obstetrics including Cesarean section deliveries, because propofol crosses the placenta and may be associated with neonatal depression.

Propofol should not be used for Intensive Care Unit (ICU) sedation in patients who have severely disordered fat metabolism because the vehicle of propofol is similar to that of Intralipid 10%. The restrictions that apply to Intralipid 10% should also be considered when using propofol in the ICU.

Extreme care should be used in administering propofol in patients with impaired left ventricular function because propofol may produce a negative inotropic effect.

Extreme care should be used in administering propofol in patients who are hypotensive, hypovolemic or in shock because propofol may cause excessive arterial hypotension.

Extreme care should be used in administering propofol in elderly, debilitated or other ASA III or IV patients.

Strict aseptic techniques must always be maintained during handling as propofol is a single-use parenteral product and contains no antimicrobial preservatives. The vehicle is capable of supporting rapid growth of microorganism (see Precautions and Dosage). Failure to follow aseptic handling procedures may result in microbial contamination causing fever/infection/sepsis which could lead to life-threatening illness.

Propofol lacks vagolytic activity and has been associated with reports of bradycardia (occasionally profound) and also asystole. The i.v. administration of an anticholinergic agent before induction, or during maintenance of anesthesia should be considered, especially in situations where vagal tone is likely to predominate or when propofol is used in conjunction with other agents likely to cause a bradycardia.

Since various manifestations of seizures have been reported during propofol anesthesia, special care should be taken when giving the drug to epileptic patients.

Occupational Hazards: Patients receiving propofol on an outpatient basis should not engage in hazardous activities requiring complete mental alertness such as driving a motor vehicle or operating machinery until the effects of propofol have completely subsided.

Precautions: General: Patients should be continuously monitored for early signs of significant hypotension and/or bradycardia. Treatment may include increasing the rate of i.v. fluid, elevation of lower extremities, use of pressor agents or administration of anticholinergic agents (e.g., atropine). Apnea often occurs during induction and may persist for more than 60 seconds. Ventilatory support may be required. Because propofol is an emulsion, caution should be exercised in patients with disorders of lipid metabolism such as primary hyperlipoproteinemia, diabetic hyperlipemia and pancreatitis.

When propofol is administered as a sedative for surgical or diagnostic procedures, patients should be continuously monitored by persons not involved in the conduct of the surgical/diagnostic procedure. Oxygen supplementation should be immediately available and provided where clinically indicated; and oxygen saturation should be monitored in all patients. Patients should be continuously monitored for early signs of hypotension, apnea, airway obstruction and/or oxygen desaturation. These cardiorespiratory effects are more likely to occur following rapid initiation (loading) boluses or during supplemental maintenance boluses, especially in the elderly, debilitated and ASA III or IV patients.

Since propofol is rarely used alone, an adequate period of evaluation of the awakened patient is indicated to ensure satisfactory recovery from general anesthesia or sedation prior to discharge of the patient from the recovery room or to home.

Intensive Care Unit (ICU) Sedation: Strict aseptic techniques must be followed when handling propofol as the vehicle is capable of supporting rapid growth of microorganisms (see Warnings and Dosage).

The administration of propofol should be initiated as a continuous infusion and changes in the rate of administration made slowly (>5 min) in order to minimize hypotension and avoid acute overdosage.

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, i.v. fluid administration, and/or vasopressor therapy.

As with other sedative medications, there is wide interpatient variability in propofol dosage requirements, and these requirements may change with time.

Patients who receive large doses of narcotics during surgery may require very small doses of propofol for appropriate sedation.

Abrupt discontinuation of propofol infusion prior to weaning should be avoided since, due to the rapid clearance of propofol, it may result in rapid awakening with associated anxiety, agitation and resistance to mechanical ventilation. Infusions of propofol should be adjusted to maintain a light level of sedation throughout the weaning process.

Since propofol is formulated in an oil-water emulsion, patients should be monitored for lipemia. Administration of propofol 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 formulation; 1 mL of propofol contains approximately 0.1 g of fat (1.1 kcal).

The long-term administration of propofol to patients with renal failure and/or hepatic insufficiency has not been evaluated.

Pregnancy: Propofol should not be used in pregnancy. Propofol has been used during termination of pregnancy in the first trimester. Teratology studies in rats and rabbits show some evidence of delayed ossification or abnormal cranial ossification; however, such developmental delays are not considered indicative of a teratogenic effect. Reproductive studies in rats suggest that administration of propofol to the dam adversely affects perinatal survival of the offspring.

Lactation: Propofol is not recommended for use in nursing mothers because preliminary findings indicate that it is excreted in human milk and the effects of oral absorption of small amounts of propofol are not known.

Children: General Anesthesia: In the absence of sufficient clinical experience, propofol is not recommended for anesthesia in children less than 3 years of age (see Indications and Dosage).

Sedation: Propofol is not recommended for sedation in children under the age of 18, either during surgical/diagnostic procedures or in the Intensive Care Unit (ICU), as safety and efficacy have not been established.

Although no causal relationship has been established, serious adverse events (including fatalities) have been reported in children given propofol for ICU sedation. These events were seen most often in children with respiratory tract infections given doses in excess of those recommended for adults.

Geriatrics: Elderly patients may be more sensitive to the effects of propofol; therefore, the dosage of propofol should be reduced in these patients according to their condition and clinical response (see Pharmacology, Pharmacokinetics and Dosage).

Cardiac Anesthesia: Propofol was evaluated in 328 patients undergoing coronary artery bypass graft (CABG). Of these patients 85% were males (mean age 61, range 32 to 83) and 15% were females (mean age 65, range 42 to 86).

The majority of patients undergoing CABG had good left ventricular function. Experience in patients with poor left ventricular function, as well as, in patients with hemodynamically significant valvular or congenital heart disease is limited.

Slower rates of administration should be utilized in premedicated patients, geriatric patients, patients with recent fluid shift, or patients who are hemodynamically unstable. Any fluid deficits should be corrected prior to administration of propofol. In those patients where additional fluid therapy may be contraindicated, other measures, e.g., elevation of lower extremities, or use of pressor agents, may be useful to offset the hypotension which is associated with the induction of anesthesia with propofol.

Neurosurgical Anesthesia: When using propofol in patients with increased intracranial pressure (ICP) or impaired cerebral circulation, significant decreases in mean arterial pressure should be avoided because of the resultant decreases in cerebral perfusion pressure. When increased ICP is suspected, hyperventilation and hypocarbia should accompany the administration of propofol (see Dosage).

Drug Interactions: Propofol has been used in association with spinal and epidural anesthesia and with a range of premedicants, muscle relaxants, inhalational agents, analgesic agents and with local anesthetic agents; no significant adverse interactions have been observed.

Adverse Reactions: Anesthesia and Sedation for Surgical/Diagnostic Procedures: During induction of anesthesia in clinical trials, hypotension and apnea occurred in the majority of patients. The incidence of apnea varied considerably, occurring in between 30 and 100% of patients depending upon premedication, speed of administration and dose (see Pharmacology). Decreases in systolic and diastolic pressures ranged between 10 and 28%, but were more profound in the elderly and in ASA III and IV patients. Excitatory phenomena occurred in up to 14% of adult patients and in 33 to 90% of pediatric patients; they consisted most frequently of spontaneous musculoskeletal movements and twitching and jerking of the hands, arms, feet or legs. Epileptiform movements including convulsions and opisthotonus have occurred rarely, but a causal relationship with propofol has not been established. Flushing and rash have occurred in 10 to 25% of pediatric patients. Local pain occurred during i.v. injection of propofol at an incidence of 28% when veins of the dorsum of the hand were used and 5% when the larger veins of the forearm and the antecubital fossa were used. Propofol increased plasma glucose concentrations significantly, but no other significant changes in hematological or biochemical values were observed.

In the sedation clinical trials, the adverse reaction profile of propofol was similar to that seen during anesthesia. The most common adverse reactions included hypotension, nausea, pain and/or hotness at injection site and headache. Respiratory events included upper airway obstruction, apnea, hypoventilation, dyspnea and cough.

Rarely, clinical features of anaphylaxis, which may include bronchospasm, erythema and hypotension, occur following propofol administration.

There have been reports of fever.

Pulmonary edema may be a potential side effect associated with the use of propofol.

As with other anesthetics, sexual disinhibition may occur during recovery.

Intensive Care Unit (ICU) Sedation: The most frequent adverse reactions during Intensive Care Unit (ICU) sedation were hypotension (31.5%), hypoxia (6.3%), and hyperlipemia (5.5%). In some patients, hypotension was severe. Other reactions considered severe were observed in single patients and included ventricular tachycardia, decreased cardiac output, decrease in vital capacity and negative inspiratory force, increase in triglycerides, and agitation. Two patients with head injury suffered renal failure with severe increases in BUN accompanied in one patient by an increase in creatinine.

Adverse reactions reported at an incidence of 1% or less during anesthesia and sedation for surgical/diagnostic procedures: Cardiovascular: significant hypotension, premature atrial contractions, premature ventricular contractions, tachycardia, syncope, abnormal ECG, bigeminy, edema.

Respiratory: burning in throat, tachypnea, dyspnea, upper airway obstruction, wheezing, bronchospasm, laryngospasm, hypoventilation, hyperventilation, sneezing.

Excitatory: hypertonia, dystonia, rigidity, tremor.

CNS: confusion, dizziness, paresthesia, somnolence, shivering, abnormal dreams, agitation, delirium, euphoria, fatigue.

Injection Site: phlebitis, hives/itching, redness/discoloration.

Digestive: hypersalivation, dry mouth.

Skin and Appendages: flushing/rash (for incidence in children, see above), urticaria, pruritus.

Special Senses: diplopia, amblyopia, tinnitus.

Musculoskeletal: myalgia.

Urogenital: urine retention.

Adverse reactions reported at an incidence of 1% or less during ICU sedation: Cardiovascular: arrhythmia, extrasystole, heart block, right heart failure, bigeminy, ventricular fibrillation, heart failure, myocardial infarction.

Respiratory: lung function decreased, respiratory arrest.

CNS: seizure, thinking abnormal, akathisia, chills, anxiety, confusion, hallucinations.

Digestive: ileus, hepatomegaly.

Metabolic/Nutritional: osmolality increased.

Urogenital: green urine, urination disorder, oliguria.

Body as a Whole: sepsis, trunk pain, whole body weakness.

Drug Abuse and Dependence: Rare cases of self-administration of propofol by health care professionals have been reported, including some fatalities.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: To date, there is no known case of acute overdosage, and no specific information on emergency treatment of overdosage is available. If accidental overdosage occurs, propofol 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 i.v. fluids and administering pressor agents.

Dosage And Administration: Strict aseptic techniques must always be maintained during handling as propofol is a single-use parenteral product and contains no antimicrobial preservatives. The vehicle is capable of supporting rapid growth of microorganisms. Failure to follow aseptic handling procedures may result in microbial contamination causing fever/infection/sepsis which could lead to life-threatening illness.

Propofol should be shaken well before use.

General: Dosage and rate of administration should be individualized and titrated to the desired effect according to clinically relevant factors including preinduction and concomitant medications, age, ASA status and level of debilitation of the patient. In heavily premedicated patients, both the induction and maintenance doses should be reduced.

Induction of General Anesthesia: Most adult patients under 55 years of age and classified ASA I and II are likely to require 2 to 2.5 mg/kg of propofol for induction when unpremedicated or when premedicated with oral benzodiazepines or i.m. narcotics. For induction, it is recommended that propofol should be titrated (approximately 40 mg every 10 seconds) against the response of the patient until the clinical signs show the onset of general anesthesia.

It is important to be familiar and experienced with the appropriate i.v. use of propofol before treating elderly, debilitated and/or adult patients in ASA Physical Status Classes III and IV. These patients may be more sensitive to the effects of propofol; therefore, the dosage of propofol should be reduced in these patients by approximately 50% (20 mg every 10 seconds) according to their condition and clinical response. A rapid bolus should not be used as this will increase the likelihood of undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction and/or oxygen desaturation (see Warnings, Precautions and Dosage Guide).

During cardiac anesthesia, a rapid bolus induction should be avoided. A slow rate of approximately 20 mg every 10 seconds until induction onset (0.5 to 1.5 mg/kg) should be used.

Most children over 8 years of age require approximately 2.5 mg/kg of propofol for induction of anesthesia. Children 3 to 8 years of age may require somewhat higher doses, however the dose should be titrated by administering propofol slowly until the clinical signs show the onset of anesthesia. Propofol is not recommended for induction of anesthesia in children less than 3 years of age. There is no experience in children in ASA Classes III and IV.

Additionally, as with most anesthetic agents, the effects of propofol may be potentiated in patients who have received i.v. sedative or narcotic premedications shortly prior to induction.

Maintenance of General Anesthesia: Anesthesia can be maintained by administering propofol by infusion or intermittent i.v. bolus injection. The patient’s clinical response will determine the infusion rate or the amount and frequency of incremental injections.

When administering propofol by infusion, drop counters, syringe pumps or volumetric pumps must be used to provide controlled infusion rates.

Continuous Infusion: Propofol 0.1 to 0.2 mg/kg/min (6 to 12 mg/kg/h) administered in a variable rate infusion with 60 to 70% nitrous oxide and oxygen provides anesthesia for patients undergoing general surgery. Maintenance by infusion of propofol should immediately follow the induction dose in order to provide satisfactory or continuous anesthesia during the induction phase. During this initial period following the induction injection higher rates of infusion are generally required (0.15 to 0.20 mg/kg/min; 9 to 12 mg/kg/h) for the first 10 to 15 minutes. Infusion rates should subsequently be decreased by 30 to 50% during the first half-hour of maintenance. Changes in vital signs (increases in pulse rate, blood pressure, sweating and/or tearing) that indicate a response to surgical stimulation or lightening of anesthesia may be controlled by the administration of propofol 25 mg (2.5 mL) to 50 mg (5.0 mL) incremental boluses and/or by increasing the infusion rate. If vital sign changes are not controlled after a 5-minute period, other means such as a narcotic, barbiturate, vasodilator or inhalation agent therapy should be initiated to control these responses.

For minor surgical procedures (i.e., body surface) 60 to 70% nitrous oxide can be combined with a variable rate propofol infusion to provide satisfactory anesthesia. With more stimulating surgical procedures (i.e., intra-abdominal) supplementation with i.v. analgesic agents should be considered to provide a satisfactory anesthetic and recovery profile. When supplementation with nitrous oxide is not provided, administration rate(s) of propofol and/or opioids should be increased in order to provide adequate anesthesia.

Infusion rates should always be titrated downward in the absence of clinical signs of light anesthesia until a mild response to surgical stimulation is obtained in order to avoid administration of propofol at rates higher than are clinically necessary. Generally, rates of 0.05 to 0.1 mg/kg/min should be achieved during maintenance in order to optimize recovery times.

During cardiac anesthesia, when propofol is used as the primary agent, maintenance infusion rates should not be less than 0.1 mg/kg/min and should be supplemented with analgesic levels of continuous opioid administration. When an opioid is used as the primary agent, propofol maintenance rates should not be less than 0.05 mg/kg/min. Higher doses of propofol will reduce the opioid requirements.

For children, the average rate of administration varies considerably, but rates between 0.10 to 0.25 mg/kg/min (6 to 15 mg/kg/h) should achieve satisfactory anesthesia. These infusion rates may be subsequently reduced depending on patient response and concurrent medication.

Intermittent Bolus: Increments of propofol 25 mg (2.5 mL) to 50 mg (5.0 mL) may be administered with nitrous oxide in patients undergoing general surgery. The incremental boluses should be administered when changes in vital signs indicate a response to surgical stimulation or light anesthesia.

Propofol has been used in conjunction with a wide variety of agents commonly used in anesthesia such as atropine, scopolamine, glycopyrrolate, diazepam, depolarizing and nondepolarizing muscle relaxants, and narcotic analgesics, as well as with inhalational and regional anesthetic agents. No pharmacological incompatibilities have been encountered.

Sedation During Surgical or Diagnostic Procedures: When propofol is administered for sedation, rates of administration should be individualized and titrated to clinical response. In most patients, the rates of propofol administration will be approximately 25 to 30% of those used for maintenance of general anesthesia.

During initiation of sedation, slow injection or slow infusion techniques are preferable over rapid bolus administration. During maintenance of sedation, a variable rate infusion is preferable over intermittent bolus dose administration.

Initiation of Sedation: Slow Injection: Most adult patients will generally require 0.5 to 1 mg/kg administered over 3 to 5 minutes and titrated to clinical response.

In the elderly, debilitated, hypovolemic and ASA III or IV patients, the dosage of propofol should be reduced to approximately 70 to 80% of the adult dosage and administered over 3 to 5 minutes.

Infusion: Sedation may be initiated by infusing propofol at 0.066 to 0.100 mg/kg/min (4 to 6 mg/kg/h) and titrating to the desired level of sedation while closely monitoring respiratory function.

Maintenance of Sedation: Patients will generally require maintenance rates of 0.025 to 0.075 mg/kg/min (1.5 to 4.5 mg/kg/h) during the first 10 to 15 minutes of sedation maintenance.

Infusion rates should always be titrated downward in the absence of clinical signs of light sedation until mild responses to stimulation are obtained in order to avoid sedative administration of propofol at rates higher than are clinically necessary.

In addition to the infusion, bolus administration of 10 to 15 mg may be necessary if a rapid increase in sedation depth is required.

In the elderly, debilitated, hypovolemic and ASA III or IV patients, the rate of administration and the dosage of propofol should be reduced to approximately 70 to 80% of the adult dosage according to their condition, responses, and changes in vital signs. Rapid (single or repeated) bolus dose administration should not be used for sedation in these patients (see Warnings).

Intensive Care Unit (ICU) Sedation: Propofol should be individualized according to the patient’s condition and response, blood lipid profile, and vital signs.

For intubated, mechanically ventilated, adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension. When indicated, initiation of sedation should begin at 0.005 mg/kg/min (0.3 mg/kg/h). The infusion rate should be increased by increments of 0.005 to 0.010 mg/kg/min (0.3 to 0.6 mg/kg/h) until the desired level of sedation is achieved. A minimum period of 5 minutes between adjustments should be allowed for onset of peak drug effect.

Most adult patients require maintenance rates of 0.005 to 0.050 mg/kg/min (0.3 to 3 mg/kg/h). Dosages of propofol should be reduced in patients who have received large dosages of narcotics. As with other sedative medications, there is interpatient variability in dosage requirements and these requirements may change with time (see Dosage Guide, Table II).

Bolus administration of 10 to 20 mg should only be used to rapidly increase sedation depth in patients where hypotension is not likely to occur. A rapid bolus should not be used as this will increase the likelihood of hypotension. Patients with compromised myocardial function, intravascular volume depletion or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension.

Compatibility and Stability: Propofol injection should not be mixed with other therapeutic agents prior to administration.

Dilution Prior to Administration: When propofol is diluted prior to administration, it should only be diluted with 5% Dextrose Injection, USP, and it should not be diluted to a concentration less than 2 mg/mL because it is an emulsion. Dilutions should be prepared aseptically immediately before administration and should not be used beyond 6 hours of preparation. In diluted form it has been shown to be more stable when in contact with glass than with plastic (95% potency after 2 hours of running infusion in plastic).

Administration into a Running I.V. Catheter: Compatibility of propofol with the coadministration of blood/serum/plasma has not been established (see Warnings). Propofol has been shown to be compatible with the following i.v. fluids when administered into a running i.v. catheter: 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.

Handling Procedures: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Do not freeze.

Do not use if there is evidence of separation of the phases of the emulsion.

Aseptic techniques must be applied to the handling of the drug. Propofol contains no antimicrobial preservatives and the vehicle supports growth of microorganisms. When propofol is to be aspirated it should be drawn into a sterile syringe immediately after breaking the ampul or breaking the vial seal. Administration should commence without delay. Asepsis must be maintained for both propofol and the infusion equipment throughout the infusion period. Any drugs or fluids added to the infusion line must be administered close to the cannula site. Propofol must not be administered via a microbiological filter.

Propofol and any syringe containing propofol are for use in a single patient only. The contents of a propofol ampul must be used within 6 hours of opening or discarded thereafter. If a vial is utilized for infusion, both the reservoir of propofol and the infusion line must be discarded and replaced as appropriate at the end of the procedure or at 12 hours, whichever is sooner (when using diluted propofol see Dilution Prior to Administration).

Since propofol contains no preservative or bacteriostatic agents, any unused portions of propofol or solutions containing propofol should be discarded at the end of the surgical procedure.

Availability And Storage: Each mL of white, oil in water emulsion contains: propofol 10 mg for i.v. administration. Nonmedicinal ingredients: egg lecithin, glycerol, soybean oil and water for injection with sodium hydroxide to adjust pH. It is isotonic with a pH of 6.5 to 8.5. Cartons of 5´20 mL ready-to-use ampuls. Glass vials of 50 and 100 mL for single infusion only. Store between 2 and 25°C; do not freeze. The emulsion should be visually inspected for particulate matter, emulsion separation and discoloration prior to use. Any unused portions of propofol or solutions containing propofol should be discarded at the end of the surgical procedure.

DIPRIVAN® Zeneca Propofol I.V. Emulsion – Anesthetic – Sedative

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