Dosage Form: injection, emulsion
Propofol Injectable Emulsion 1%
Contains a sulfite
FOR IV ADMINISTRATION
Strict aseptic technique must always be maintained during handling. Propofol injectable emulsion is a single-use parenteral product which contains sodium metabisulfite (0.25 mg/mL) to retard the rate of growth of microorganisms in the event of accidental extrinsic contamination. However, Propofol Injectable Emulsion can still support the growth of microorganisms as it is not an antimicrobially preserved product under usp standards. Accordingly, strict aseptic technique must still be adhered to. Do not use if contamination is suspected. Discard unused portions as directed within the required time limits (see DOSAGE AND ADMINISTRATION - Handling Procedures). There have been reports in which failure to use aseptic technique when handling Propofol injectable emulsion was associated with microbial contamination of the product and with fever, infection/sepsis, other life-threatening illness, and/or death.
Propofol Description
Propofol injectable emulsion is a sterile, nonpyrogenic emulsion containing 10 mg/mL of Propofol suitable for intravenous administration. Propofol is chemically described as 2, 6-diisopropylphenol and has a molecular weight of 178.27. The structural and molecular formulas are:
Propofol is very slightly soluble in water and, thus, is formulated in a white, oil-in-water emulsion. The pKa is 11. The octanol/water partition coefficient for Propofol is 6761:1 at a pH of 6-8.5. In addition to the active component, Propofol, the formulation also contains soybean oil (100 mg/mL), glycerol (22.5 mg/mL), egg yolk phospholipid (12 mg/mL), and sodium metabisulfite (0.25 mg/mL); with sodium hydroxide to adjust pH. The Propofol injectable emulsion is isotonic and has a pH of 4.5-6.6.
Propofol - Clinical Pharmacology
General
Propofol 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.
Pharmacodynamics
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 Propofol 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 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 Injectable Emulsion during induction of anesthesia are generally more pronounced than with other intravenous (IV) induction agents.
Induction of anesthesia with Propofol Injectable Emulsion is frequently associated with apnea in both adults and pediatric patients. In adult patients who received Propofol Injectable Emulsion (2 to 2.5 mg/kg), apnea lasted less than 30 seconds in 7% of patients, 30-60 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 Injectable Emulsion (1 to 3.6 mg/kg), apnea lasted less than 30 seconds in 12% of patients, 30-60 seconds in 10% of patients, and more than 60 seconds in 5% of patients.
During maintenance of general anesthesia, Propofol 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 Injectable Emulsion. Hypotension, oxyhemoglobin desaturation, apnea, and airway obstruction can occur, especially following a rapid bolus of Propofol 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 Injectable Emulsion is rarely associated with elevation of plasma histamine levels.
Preliminary findings in patients with normal intraocular pressure indicate that Propofol 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 Injectable Emulsion when used in combination with hypocarbia increases cerebrovascular resistance and decreases cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure. Propofol Injectable Emulsion does not affect cerebrovascular reactivity to changes in arterial carbon dioxide tension (see Clinical Trials-Neuroanesthesia).
Clinical studies indicate that Propofol 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 Injectable Emulsion to induce malignant hyperthermia.
Pharmacokinetics
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 Propofol 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 Propofol 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 Propofol 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 Injectable Emulsion infusion for ICU sedation.
Adults
Propofol clearance ranges from 23-50 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.
Geriatrics
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 age-related decreased 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.)
Pediatrics
The pharmacokinetics of Propofol were studied in children between 3 and 12 years of age who received Propofol Injectable Emulsion for periods of approximately 1-2 hours. The observed distribution and clearance of Propofol in these children were similar to adults.
Organ Failure
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.
Clinical Trials
Anesthesia and Monitored Anesthesia Care (MAC) Sedation
Pediatric Anesthesia
Propofol 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.
| Age Range | Induction Dose Median (range) | Injection Duration Median (range) |
|---|---|---|
| Birth through 16 years | 2.5 mg/kg (1-3.6) | 20 sec. (6-45) |
| Age Range | Maintenance Dosage (mcg/kg/min) | Duration (minutes) |
|---|---|---|
| 2 months to 2 years | 199 (82 – 394) | 65 (12 -282) |
| 2 to 12 years | 188 (12 – 1041) | 69 (23 – 374) |
| >12 through 16 years | 161 (84 – 359) | 69 (26 – 251) |
Neuroanesthesia
Propofol Injectable Emulsion was studied in patients undergoing craniotomy for supratentorial tumors in two clinical trials. The mean lesion size (anterior/posterior × lateral) was 31 mm × 32 mm in one trial and 55 mm × 42 mm in the other trial respectively. Anesthesia was induced with a median Propofol Injectable Emulsion dose of 1.4 mg/kg (range: 0.9-6.9 mg/kg) and maintained with a median maintenance Propofol Injectable Emulsion dose of 146 mcg/kg/min (range: 68-425 mcg/kg/min). The median duration of the Propofol Injectable Emulsion maintenance infusion was 285 minutes (range: 48-622 minutes).
Propofol 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 Injectable Emulsion, when given by infusion or slow bolus in combination with hypocarbia, is capable of decreasing ICP independent of changes in arterial pressure.
Intensive Care Unit (ICU) Sedation
Adult Patients
Propofol Injectable Emulsion was compared to benzodiazepines and opioids in clinical trials involving ICU patients. Of these, 302 received Propofol Injectable Emulsion and comprise the overall safety database for ICU sedation.
Across all clinical studies, the mean infusion maintenance rate for all Propofol 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 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 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 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 19-43 years, adequate sedation was maintained with Propofol 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 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 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.
Pediatric Patients
A single, randomized, controlled, clinical trial that evaluated the safety and effectiveness of Propofol versus standard sedative agents (SSA) was conducted on 327 pediatric ICU patients. Patients were randomized to receive either Propofol 2%, (113 patients), Propofol 1%, (109 patients), or an SSA (eg, lorazepam, chloral hydrate, fentanyl, ketamine, morphine, or phenobarbital). Propofol 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 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 2% treatment group, 9 (8% were) in the Propofol 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.
Cardiac Anesthesia
Propofol 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 Propofol 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.
Indications and Usage for Propofol
Propofol Injectable Emulsion is an IV sedative-hypnotic agent that can be used as described in the table below.
| Indication | Approved Patient Population |
|---|---|
| Initiation and maintenance of Monitored Anesthesia Care (MAC) sedation | Adults only |
| Combined sedation and regional anesthesia | Adults only (See PRECAUTIONS) |
| Induction of General Anesthesia | Patients ≥ 3 years of age |
| Mainenance of General Anesthesia | Patients ≥ 2 months of age |
| Intensive Care Unit (ICU) sedation of intubated, mechanically ventilated patients | Adults only |
Safety, effectiveness and dosing guidelines for Propofol Injectable Emulsion have not been established for MAC Sedation in the pediatric population; therefore, it is not recommended for this use. (See PRECAUTIONS, Pediatric Use).
Propofol Injectable Emulsion is not recommended for induction of anesthesia below the age of 3 years or for maintenance of anesthesia below the age of 2 months because its safety and effectiveness have not been established in those populations.
In the Intensive Care Unit (ICU), Propofol Injectable Emulsion can be administered to intubated, mechanically ventilated adult patients to provide continuous sedation and control of stress responses only by persons skilled in the medical management of critically ill patients and trained in cardiovascular resuscitation and airway management.
Propofol Injectable Emulsion is not indicated for use in Pediatric ICU sedation since the safety of this regimen has not been established. (See PRECAUTIONS, Pediatric Use).
Propofol Injectable Emulsion is not recommended for obstetrics, including Cesarean section deliveries. Propofol Injectable Emulsion crosses the placenta, and as with other general anesthetic agents, the administration of Propofol Injectable Emulsion may be associated with neonatal depression. (See PRECAUTIONS.)
Propofol Injectable Emulsion is not recommended for use in nursing mothers because Propofol Injectable Emulsion has been reported to be excreted in human milk, and the effects of oral absorption of small amounts of Propofol are not known. (See PRECAUTIONS.)
Contraindications
Propofol Injectable Emulsion is contraindicated in patients with a known hypersensitivity to Propofol Injectable Emulsion or any of its components.
Propofol Injectable Emulsion is contraindicated in patients with allergies to eggs, egg products, soybeans or soy products.
Warnings
Use of Propofol Injectable Emulsion has been associated with both fatal and life-threatening anaphylactic and anaphylactoid reactions.
For general anesthesia or monitored anesthesia care (MAC) sedation, Propofol Injectable Emulsion should be administered only by persons trained in the administration of general anesthesia and not involved in the conduct of the surgical/diagnostic procedure. Sedated patients should be continuously monitored, and facilities for maintenance of a patent airway, providing artificial ventilation, administering supplemental oxygen, and instituting cardiovascular resuscitation must be immediately available. 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 bolus administration, especially in the elderly, debilitated, or ASA-PS III or IV patients.
For sedation of intubated, mechanically ventilated patients in the Intensive Care Unit (ICU), Propofol Injectable Emulsion should be administered only by persons skilled in the management of critically ill patients and trained in cardiovascular resuscitation and airway management.
Contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
Use of Propofol Injectable Emulsion infusions for both adult and pediatric ICU sedation has been associated with a constellation of metabolic derangements and organ system failures, referred to as Propofol Infusion Syndrome, that have resulted in death. The syndrome is characterized by severe metabolic acidosis, hyperkalemia, lipemia, rhabdomyolysis, hepatomegaly, cardiac and renal failure. The syndrome is most often associated with prolonged, high-dose infusions (> 5 mg/kg/h for > 48h) but has also been reported following large-dose, short-term infusions during surgical anesthesia. In the setting of prolonged need for sedation, increasing Propofol dose requirements to maintain a constant level of sedation, or onset of metabolic acidosis during administration of a Propofol infusion, consideration should be given to using alternative means of sedation.
Abrupt discontinuation of Propofol Injectable Emulsion prior to weaning or for daily evaluation of sedation levels should be avoided. This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation. Infusions of Propofol Injectable Emulsion should be adjusted to maintain a light level of sedation through the weaning process or evaluation of sedation level. (See PRECAUTIONS.)
Propofol Injectable Emulsion should not be coadministered through the same IV 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 of these findings is not known.
There have been reports in which failure to use aseptic technique when handling Propofol Injectable Emulsion was associated with microbial contamination of the product and with fever, infection, sepsis, other life-threatening illness, and death. Do not use if contamination is suspected. Discard unused portions as directed within the required time limits (see DOSAGE AND ADMINISTRATION, Handling Procedures)
Precautions
Contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
General
Adult and Pediatric Patients
A lower induction dose and a slower maintenance rate of administration should be used in elderly, debilitated, or ASA-PS III or IV patients. (See DOSAGE AND ADMINISTRATION.) Patients should be continuously monitored for early signs of hypotension and/or bradycardia. Apnea requiring ventilatory support often occurs during induction and may persist for more than 60 seconds. Propofol Injectable Emulsion use requires caution when administered to patients with disorders of lipid metabolism such as primary hyperlipoproteinemia, diabetic hyperlipemia, and pancreatitis.
Very rarely the use of Propofol Injectable Emulsion may be associated with the development of a period of postoperative unconsciousness which may be accompanied by an increase in muscle tone. This may or may not be preceded by a brief period of wakefulness. Recovery is spontaneous.
When Propofol Injectable Emulsion is administered to an epileptic patient, there is a risk of seizure during the recovery phase.
Attention should be paid to minimize pain on administration of Propofol Injectable Emulsion. Transient local pain can be minimized if the larger veins of the forearm or antecubital fossa are used. Pain during intravenous injection may also be reduced by prior injection of IV lidocaine (1 mL of a 1% solution). Pain on injection occurred frequently in pediatric patients (45%) when a small vein of the hand was utilized without lidocaine pretreatment. With lidocaine pretreatment or when antecubital veins were utilized, pain was minimal (incidence less than 10%) and well-tolerated. There have been reports in the literature indicating that the addition of lidocaine to Propofol in quantities greater than 20 mg lidocaine/200 mg Propofol results in instability of the emulsion which is associated with increases in globule sizes over time and (in rat studies) a reduction in anesthetic potency. Therefore, it is recommended that lidocaine be administered prior to Propofol administration or that it be added to Propofol immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg Propofol.
Venous sequelae, i.e., phlebitis or thrombosis, have been reported rarely (<1%). In two clinical studies using dedicated intravenous catheters, no instances of venous sequelae were observed up to 14 days following induction.
Intra-arterial injection in animals did not induce local tissue effects. Accidental intra-arterial injection has been reported in patients, and, other than pain, there were no major sequelae.
Intentional injection into subcutaneous or perivascular tissues of animals caused minimal tissue reaction. During the post-marketing period, there have been rare reports of local pain, swelling, blisters, and/or tissue necrosis following accidental extravasation of Propofol Injectable Emulsion.
Perioperative myoclonia, rarely including convulsions and opisthotonos, has occurred in association with Propofol Injectable Emulsion administration.
Clinical features of anaphylaxis, including angioedema, bronchospasm, erythema, and hypotension, occur rarely following Propofol Injectable Emulsion administration.
There have been rare reports of pulmonary edema in temporal relationship to the administration of Propofol Injectable Emulsion, although a causal relationship is unknown.
Rarely, cases of unexplained postoperative pancreatitis (requiring hospital admission) have been reported after anesthesia in which Propofol Injectable Emulsion was one of the induction agents used. Due to a variety of confounding factors in these cases, including concomitant medications, a causal relationship to Propofol Injectable Emulsion is unclear.
Propofol Injectable Emulsion has no vagolytic activity. Reports of bradycardia, asystole, and rarely, cardiac arrest have been associated with Propofol Injectable Emulsion. Pediatric patients are susceptible to this effect, particularly when fentanyl is given concomitantly. The intravenous administration of anticholinergic agents (e.g., atropine or glycopyrrolate) should be considered to modify potential increases in vagal tone due to concomitant agents (e.g., succinylcholine) or surgical stimuli.
Intensive Care Unit Sedation
Adult Patients
(See WARNINGS and DOSAGE AND ADMINISTRATION, Handling Procedures.)
The administration of Propofol Injectable Emulsion 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. (See DOSAGE AND ADMINISTRATION.)
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 Injectable Emulsion, IV fluid administration, and/or vasopressor therapy. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus administration should not be used during sedation in order to minimize undesirable cardiorespiratory depression, including hypotension, apnea, airway obstruction, and oxygen desaturation.
As with other sedative medications, there is wide interpatient variability in Propofol Injectable Emulsion dosage requirements, and these requirements may change with time.
Failure to reduce the infusion rate in patients receiving Propofol 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 Injectable Emulsion infusion for ICU sedation, especially when it is used for long durations.
Opioids and paralytic agents should be discontinued and respiratory function optimized prior to weaning patients from mechanical ventilation. Infusions of Propofol Injectable Emulsion should be adjusted to maintain a light level of sedation prior to weaning patients from mechanical ventilatory support. Throughout the weaning process, this level of sedation may be maintained in the absence of respiratory depression. Because of the rapid clearance of Propofol Injectable Emulsion, abrupt discontinuation of a patient's infusion may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation, making weaning from mechanical ventilation difficult. It is therefore recommended that administration of Propofol Injectable Emulsion be continued in order to maintain a light level of sedation throughout the weaning process until 10-15 minutes prior to extubation, at which time the infusion can be discontinued.
Since Propofol Injectable Emulsion is formulated in an oil-in-water emulsion, elevations in serum triglycerides may occur when Propofol Injectable Emulsion is administered for extended periods of time. Patients at risk of hyperlipidemia should be monitored for increases in serum triglycerides or serum turbidity. Administration of Propofol Injectable Emulsion 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 Injectable Emulsion formulation; 1 mL of Propofol Injectable Emulsion contains approximately 0.1 g of fat (1.1 kcal).
The long-term administration of Propofol Injectable Emulsion to patients with renal failure and/or hepatic insufficiency has not been evaluated.
Neurosurgical Anesthesia
When Propofol Injectable Emulsion is used in patients with increased intracranial pressure or impaired cerebral circulation, significant decreases in mean arterial pressure should be avoided because of the resultant decreases in cerebral perfusion pressure. To avoid significant hypotension and decreases in cerebral perfusion pressure, an infusion or slow bolus of approximately 20 mg every 10 seconds should be utilized instead of rapid, more frequent, and/or larger boluses of Propofol Injectable Emulsion. Slower induction, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 to 2 mg/kg). When increased ICP is suspected, hyperventilation and hypocarbia should accompany the administration of Propofol Injectable Emulsion. (See DOSAGE AND ADMINISTRATION.)
Cardiac Anesthesia
Slower rates of administration should be utilized in premedicated patients, geriatric patients, patients with recent fluid shifts, and patients who are hemodynamically unstable. Fluid deficits should be corrected prior to administration of Propofol Injectable Emulsion. 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 Injectable Emulsion.
Information for Patients
Patients should be advised that performance of activities requiring mental alertness, such as operating a motor vehicle, or hazardous machinery or signing legal documents may be impaired for some time after general anesthesia or sedation.
Drug Interactions
The induction dose requirements of Propofol Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (e.g., morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (e.g., benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of Propofol Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output.
During maintenance of anesthesia or sedation, the rate of Propofol Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (e.g., nitrous oxide or opioids). The concurrent administration of potent inhalational agents (e.g., isoflurane, enflurane, and halothane) during maintenance with Propofol Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of Propofol Injectable Emulsion.
Propofol Injectable Emulsion does not cause a clinically significant change in onset, intensity or duration of action of the commonly used neuromuscular blocking agents (e.g., succinylcholine and nondepolarizing muscle relaxants).
No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed in adults. In pediatric patients, administration of fentanyl concomitantly with Propofol Injectable Emulsion may result in serious bradycardia.
Carcinogenesis, mutagenesis, impairment of fertility
Carcinogenesis
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Propofol.
Mutagenesis
Propofol was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) using Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538. Propofol was not mutagenic in either the gene mutation/gene conversion test using Saccharomyces cerevisiae, or in vitro cytogenetic studies in Chinese hamsters. In the in vivo mouse micronucleus assay with Chinese Hamsters Propofol administration did not produce chromosome aberrations.
Impairment of fertility
Female Wistar rats were administered either 0, 10, or 15 mg/kg/day Propofol intravenously from 2 weeks before pregnancy to day 7 of gestation did not show impaired fertility. Male fertility in rats was not affected in a dominant lethal study at intravenous doses up to 15 mg/kg/day for 5 days.
Pregnancy
Teratogenic effects
Pregnancy Category B
Reproduction studies have been performed in rats and rabbits at intravenous doses of 15 mg/kg/day (approximately equivalent to the recommended human induction dose on a mg/m2 basis) and have revealed no evidence of impaired fertility or harm to the fetus due to Propofol. Propofol, however, has been shown to cause maternal deaths in rats and rabbits and decreased pup survival during the lactating period in dams treated with 15 mg/kg/day (approximately equivalent to the recommended human induction dose on a mg/m2 basis). The pharmacological activity (anesthesia) of the drug on the mother is probably responsible for the adverse effects seen in the offspring. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human responses, this drug should be used during pregnancy only if clearly needed.
Labor and Delivery
Propofol Injectable Emulsion is not recommended for obstetrics, including cesarean section deliveries. Propofol Injectable Emulsion crosses the placenta, and as with other general anesthetic agents, the administration of Propofol Injectable Emulsion may be associated with neonatal depression.
Nursing Mothers
Propofol Injectable Emulsion is not recommended for use in nursing mothers because Propofol Injectable Emulsion has been reported to be excreted in human milk and the effects of oral absorption of small amounts of Propofol are not known.
Pediatric Use
The safety and effectiveness of Propofol Injectable Emulsion have been established for induction of anesthesia in pediatric patients aged 3 years and older and for the maintenance of anesthesia aged 2 months and older.
Propofol Injectable Emulsion is not recommended for the induction of anesthesia in patients younger than 3 years of age and for the maintenance of anesthesia in patients younger than 2 months of age as safety and effectiveness have not been established.
In pediatric patients, administration of fentanyl concomitantly with Propofol Injectable Emulsion may result in serious bradycardia (see PRECAUTIONS – General).
Propofol Injectable Emulsion is not indicated for use in pediatric patients for ICU sedation or for MAC sedation for surgical, nonsurgical or diagnostic procedures as safety and effectiveness have not been established.
There have been anecdotal reports of serious adverse events and death in pediatric patients with upper respiratory tract infections receiving Propofol Injectable Emulsion for ICU sedation.
In one multicenter clinical trial of ICU sedation in critically ill pediatric patients that excluded patients with upper respiratory tract infections, the incidence of mortality observed in patients who received Propofol Injectable Emulsion (n=222) was 9%, while that for patients who received standard sedative agents (n=105) was 4%. While causality has not been established, Propofol Injectable Emulsion is not indicated for sedation in pediatric patients until further studies have been performed to document its safety in that population. (See CLINICAL PHARMACOLOGY, Pharmacokinetics – Pediatric Patients: and DOSAGE AND ADMINISTRATION).
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.
Geriatric Use
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 Propofol
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.)
Adverse Reactions
General
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.
Anesthesia and MAC Sedation in Adults
The following estimates of adverse events for Propofol 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 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 Injectable Emulsion during anesthesia (see below). During MAC sedation clinical trials, significant respiratory events included cough, upper airway obstruction, apnea, hypoventilation, and dyspnea.
Anesthesia in Pediatric Patients
Generally the adverse experience profile from reports of 506 Propofol 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 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.
ICU Sedation in Adults
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.
| Anesthesia/MAC Sedation | ICU Sedation | |
|---|---|---|
| Events without an * or % had an incidence of 1%-3% | ||
| ||
| Cardiovascular: | Bradycardia Arrhythmia [Peds: 1.2%] | Bradycardia |
| Tachycardia Nodal [Peds. 1.6%] | ||
| Hypotension | ||
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