Diprivan

Generic Name: propofol
Dosage Form: Injectable emulsion

Diprivan Description

Diprivan® (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 lecithin (12 mg/mL), and disodium edetate (0.005%); with sodium hydroxide to adjust pH. The Diprivan Injectable Emulsion is isotonic and has a pH of 7-8.5.

STRICT ASEPTIC TECHNIQUE MUST ALWAYS BE MAINTAINED DURING HANDLING. Diprivan INJECTABLE EMULSION IS A SINGLE-USE PARENTERAL PRODUCT WHICH CONTAINS 0.005% DISODIUM EDETATE TO RETARD THE RATE OF GROWTH OF MICROORGANISMS IN THE EVENT OF ACCIDENTAL EXTRINSIC CONTAMINATION. HOWEVER, Diprivan 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 Diprivan INJECTABLE EMULSION WAS ASSOCIATED WITH MICROBIAL CONTAMINATION OF THE PRODUCT AND WITH FEVER, INFECTION/SEPSIS, OTHER LIFE-THREATENING ILLNESS, AND/OR DEATH.

Diprivan - Clinical Pharmacology

General

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 produces hypnosis rapidly with minimal excitation, usually within 40 seconds from the start of an injection (the time for one arm-brain circulation). As with other rapidly acting intravenous anesthetic agents, the half-time of the blood-brain equilibration is approximately 1 to 3 minutes, and this accounts for the rapid 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, especially within an individual patient. Undesirable side effects such as cardiorespiratory depression are likely to occur at higher blood concentrations which result from bolus dosing or rapid increase in infusion rate. An adequate interval (3 to 5 minutes) must be allowed between clinical dosage adjustments in order to assess drug effects.

The hemodynamic effects of Diprivan Injectable Emulsion during induction of anesthesia 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. Addition of a potent opioid (e.g., fentanyl) when 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 IV induction agents traditionally used for this purpose.

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

Induction of anesthesia with Diprivan Injectable Emulsion is frequently associated with apnea in both adults and pediatric patients. In 1573 adult patients who received Diprivan 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 218 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, 30-60 seconds in 10% of patients, and more than 60 seconds in 5% of patients.

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

During monitored anesthesia care (MAC) sedation, attention must be given to the cardiorespiratory effects of Diprivan Injectable Emulsion. Hypotension, oxyhemoglobin desaturation, apnea, airway obstruction, and/or oxygen desaturation 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, and 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 III/IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation. (See WARNINGS.)

Clinical studies in humans and studies in animals show that Diprivan Injectable Emulsion does not suppress the adrenal response to ACTH.

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

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

Studies to date 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).

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 is unknown.

Pharmacokinetics

The proper use of Diprivan Injectable Emulsion requires an understanding of the disposition and elimination characteristics of propofol.

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 highly perfused tissue of the brain, thus accounting for the rapid onset of anesthesia. Plasma levels initially decline rapidly as a result of both rapid distribution and high 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 will occur even after long-term administration. If, however, higher than necessary infusion levels have been maintained for a long time, propofol will be redistributed from fat and muscle to the plasma, and this return of propofol from peripheral tissues will slow recovery.

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

The large contribution of distribution (about 50%) to the fall of propofol plasma levels following brief infusions means that after very long infusions (at steady state), about half the initial rate will maintain the same plasma levels. 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, especially of long duration.

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 of 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 oxygen desaturation. The higher plasma levels reflect an age-related decrease in volume of distribution and reduced intercompartmental clearance. Lower doses are thus recommended for initiation and maintenance of sedation/anesthesia in elderly patients. (See CLINICAL PHARMACOLOGY- Individualization of Dosage.)

Pediatrics: The pharmacokinetics of propofol were studied in 53 children between the ages of 3 and 12 years who received Diprivan 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

Diprivan Injectable Emulsion was compared to intravenous and inhalational anesthetic or sedative agents in 91 trials involving a total of 5,135 patients. Of these, 3,354 received Diprivan Injectable Emulsion and comprised the overall safety database for anesthesia and MAC sedation. Fifty-five of these trials, 20 for anesthesia induction and 35 for induction and maintenance of anesthesia or MAC sedation, were carried out in the US or Canada and provided the basis for dosage recommendations and the adverse event profile during anesthesia or MAC sedation.

Pediatric Anesthesia

Diprivan Injectable Emulsion was studied in 14 clinical trials involving 691 pediatric patients, including 42 cardiac surgical patients. Of the total 691 patients, 90 were less than 3 years of age and 601 were 3 years of age or older. Of these, 506 were from US/Canadian clinical trials and comprised the overall safety and efficacy database for Pediatric Anesthesia. The majority of the remaining patients were healthy ASA I/II patients. (See Table 1)

Table 1: PEDIATRIC INDUCTION OF ANESTHESIA Patients Receiving Diprivan Injectable Emulsion Median and (Range)

Age Range	No. of Patients	Induction Dose	Injection Duration
Birth through 16 years	353	2.5 mg/kg (1-3.6)	20 sec. (6-45)

Table 2: PEDIATRIC MAINTENANCE OF ANESTHESIA Patients Receiving Diprivan Injectable Emulsion Median and (Range)

Age Range	No. of Patients	Maintenance Dosage µg/kg/min	Duration Minutes*
* Also includes all time following induction dose.
2 months to 2 years	68	199 (82 − 394)	65 (12 - 282)
2 to 12 years	165	188 (12 − 1041)	69 (23 − 374)
>12 through 16 years	27	161 (84 − 359)	69 (26 − 251)

Neuroanesthesia:

Diprivan Injectable Emulsion was studied in 50 patients undergoing craniotomy for supratentorial tumors in two clinical trials. The mean lesion size (anterior/posterior and lateral) was 31 mm and 32 mm in one trial and 55 mm and 42 mm in the other trial respectively.

Table 3: NEUROANESTHESIA CLINICAL TRIALS Patients Receiving Diprivan Injectable Emulsion Median and (Range)

Patient Type	No. of Patients	Induction Bolus Dosages (mg/kg)	Maintenance Dosage (µg/kg/min)	Maintenance Duration (min)
Craniotomy patients	50	1.36 (0.9-6.9)	146 (68-425)	285 (48-622)

In ten of these patients, Diprivan Injectable Emulsion was administered by infusion in a controlled clinical trial to evaluate the effect of Diprivan Injectable Emulsion 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), whereas the percent change in cerebrospinal fluid pressure (CSFP) was -46% ± 14%. As CSFP is an indirect measure of intracranial pressure (ICP), when given by infusion or slow bolus, Diprivan Injectable Emulsion, in combination with hypocarbia, is capable of decreasing ICP independent of changes in arterial pressure.

Intensive Care Unit (ICU) Sedation

Adult Patients:

Diprivan Injectable Emulsion was compared to benzodiazepines and/or opioids in 14 clinical trials involving a total of 550 ICU patients. Of these, 302 received Diprivan Injectable Emulsion and comprise the overall safety database for ICU sedation. Six of these studies were carried out in the US or Canada and provide the basis for dosage recommendations and the adverse event profile.

Information from 193 literature reports of Diprivan Injectable Emulsion used for ICU sedation in over 950 patients and information from the clinical trials are summarized below:

Table 4: ADULT ICU SEDATION CLINICAL TRIALS AND LITERATURE Patients receiving Diprivan Injectable Emulsion Median and (Range)

ICU	Number of Patients		Sedation Dose		Sedation Duration
Patient Type	Trials*	Literature†	(µg/kg/min)	mg/kg/h	Hours
* Trials (Individual patients from clinical studies) † Literature (Individual patients from published reports) ‡ CABG (Coronary Artery Bypass Graft) § ARDS (Adult Respiratory Distress Syndrome)
Post-CABG‡	41	-	11 (0.1-30)	0.66 (0.006-1.8)	10 (2-14)
	-	334	(5-100)	(0.3-6)	(4-24)
Post-Surgical	60	-	20	1.2	18
			(6-53)	(0.4-3.2)	(0.3-187)
	-	142	(23-82)	(1.4-4.9)	(6-96)
Neuro/Head Trauma	7	-	25 (13-37)	1.5 (0.8-2.2)	168 (112-282)
	-	184	(8.3-87)	(0.5-5.2)	(8 hr-5days)
Medical	49	-	41 (9-131)	2.5 (0.5-7.9)	72 (0.4-337)
	-	76	(3.3-62)	(0.2-3.7)	(4-96)
Special Patients
ARDS§/Resp. Failure	-	56	(10-142)	(0.6-8.5)	(1 hr-8 days)
COPD/Asthma	-	49	(17-75)	(1-4.5)	(1-8 days)
Status Epilepticus	-	15	(25-167)	(1.5-10)	(1-21 days)
Tetanus	-	11	(5–100)	(0.3–6)	(1–25 days)

Cardiac Anesthesia

Diprivan Injectable Emulsion was evaluated in 5 clinical trials conducted in the US and Canada, involving a total of 569 patients undergoing coronary artery bypass graft (CABG). Of these, 301 patients received Diprivan Injectable Emulsion. They comprise the safety database for cardiac anesthesia and provide the basis for dosage recommendations in this patient population, in conjunction with reports in the published literature.

Individualization of Dosage

General: STRICT ASEPTIC TECHNIQUE MUST ALWAYS BE MAINTAINED DURING HANDLING. Diprivan INJECTABLE EMULSION IS A SINGLE-USE PARENTERAL PRODUCT WHICH CONTAINS 0.005% DISODIUM EDETATE TO RETARD THE RATE OF GROWTH OF MICROORGANISMS IN THE EVENT OF ACCIDENTAL EXTRINSIC CONTAMINATION. HOWEVER, Diprivan 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 Diprivan INJECTABLE EMULSION WAS ASSOCIATED WITH MICROBIAL CONTAMINATION OF THE PRODUCT AND WITH FEVER, INFECTION/SEPSIS, OTHER LIFE-THREATENING ILLNESS, AND/OR DEATH.

Propofol blood concentrations at steady state are generally proportional to infusion rates, especially in individual patients. Undesirable effects such as cardiorespiratory depression are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in the infusion rate. An adequate interval (3 to 5 minutes) must be allowed between clinical dosage adjustments in order to assess drug effects.

When administering Diprivan Injectable Emulsion by infusion, syringe pumps or volumetric pumps are recommended to provide controlled infusion rates. When infusing Diprivan Injectable Emulsion to patients undergoing magnetic resonance imaging, metered control devices may be utilized if mechanical pumps are impractical.

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 Diprivan Injectable Emulsion 25 mg (2.5 mL) to 50 mg (5 mL) incremental boluses and/or by increasing the infusion rate.

For minor surgical procedures (e.g., body surface) nitrous oxide (60%-70%) can be combined with a variable rate Diprivan Injectable Emulsion infusion to provide satisfactory anesthesia. With more stimulating surgical procedures (e.g., intra-abdominal), or if supplementation with nitrous oxide is not provided, administration rate(s) of Diprivan Injectable Emulsion 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 Diprivan Injectable Emulsion at rates higher than are clinically necessary. Generally, rates of 50 to 100 µg/kg/min in adults should be achieved during maintenance in order to optimize recovery times.

Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase CNS depression induced by propofol. Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary propofol injection maintenance infusion rate and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication.

Induction of General Anesthesia

Adult Patients: Most adult patients under 55 years of age and classified ASA I/II require 2 to 2.5 mg/kg of Diprivan Injectable Emulsion for induction when unpremedicated or when premedicated with oral benzodiazepines or intramuscular opioids. For induction, Diprivan Injectable Emulsion should be titrated (approximately 40 mg every 10 seconds) against the response of the patient until the clinical signs show the onset of anesthesia. As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of Diprivan Injectable Emulsion.

Elderly, Debilitated, or ASA III/IV Patients: It is important to be familiar and experienced with the intravenous use of Diprivan Injectable Emulsion before treating elderly, debilitated, or ASA III/IV patients. Due to the reduced clearance and higher blood concentrations, most of these patients require approximately 1 to 1.5 mg/kg (approximately 20 mg every 10 seconds) of Diprivan Injectable Emulsion for induction of anesthesia according to their condition and responses. 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 DOSAGE AND ADMINISTRATION.)

Pediatric Patients: Most patients aged 3 years through 16 years and classified ASA I or II require 2.5 to 3.5 mg/kg of Diprivan Injectable Emulsion for induction when unpremedicated or when lightly premedicated with oral benzodiazepines or intramuscular opioids. Within this dosage range, younger pediatric patients may require higher induction doses than older pediatric patients. As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of Diprivan Injectable Emulsion. A lower dosage is recommended for pediatric patients classified as ASA III or IV. Attention should be paid to minimize pain on injection when administering Diprivan Injectable Emulsion to pediatric patients. Boluses of Diprivan Injectable Emulsion may be administered via small veins if pretreated with lidocaine or via antecubital or larger veins (See PRECAUTIONS- General).

Neurosurgical Patients: Slower induction is recommended using boluses of 20 mg every 10 seconds. Slower boluses or infusions of Diprivan Injectable Emulsion for induction of anesthesia, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 to 2 mg/kg). (See PRECAUTIONS and DOSAGE AND ADMINISTRATION.)

Cardiac Anesthesia: Diprivan Injectable Emulsion has been well-studied in patients with coronary artery disease, but experience in patients with hemodynamically significant valvular or congenital heart disease is limited. As with other anesthetic and sedative-hypnotic agents, Diprivan Injectable Emulsion in healthy patients causes a decrease in blood pressure that is secondary to decreases in preload (ventricular filling volume at the end of the diastole) and afterload (arterial resistance at the beginning of the systole). The magnitude of these changes is proportional to the blood and effect site concentrations achieved. These concentrations depend upon the dose and speed of the induction and maintenance infusion rates.

In addition, lower heart rates are observed during maintenance with Diprivan Injectable Emulsion, possibly due to reduction of the sympathetic activity and/or resetting of the baroreceptor reflexes. Therefore, anticholinergic agents should be administered when increases in vagal tone are anticipated.

As with other anesthetic agents, Diprivan Injectable Emulsion reduces myocardial oxygen consumption. Further studies are needed to confirm and delineate the extent of these effects on the myocardium and the coronary vascular system.

Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary Diprivan Injectable Emulsion maintenance infusion rates and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication. The rate of Diprivan Injectable Emulsion administration should be determined based on the patient"s premedication and adjusted according to clinical responses.

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. In order to assure adequate anesthesia, when Diprivan Injectable Emulsion is used as the primary agent, maintenance infusion rates should not be less than 100 µg/kg/min and should be supplemented with analgesic levels of continuous opioid administration. When an opioid is used as the primary agent, Diprivan Injectable Emulsion maintenance rates should not be less than 50 µg/kg/min, and care should be taken to ensure amnesia with concomitant benzodiazepines. Higher doses of Diprivan Injectable Emulsion will reduce the opioid requirements (see Table 5). When Diprivan Injectable Emulsion is used as the primary anesthetic, it should not be administered with the high-dose opioid technique as this may increase the likelihood of hypotension (see PRECAUTIONS - Cardiac Anesthesia).

Table 5: Cardiac Anesthesia Techniques

Primary Agent	Rate	Secondary Agent/Rate(Following Induction with Primary Agent)
* OPIOID is defined in terms of fentanyl equivalents, i.e., 1 µg of fentanyl = 5 µg of alfentanil (for bolus); = 10 µg of alfentanil (for maintenance) or = 0.1 µg of sufentanil † Care should be taken to ensure amnesia with concomitant benzodiazepine therapy
Diprivan Injectable Emulsion		OPIOID*/0.05-0.075 μg/kg/min (no bolus)
Preinduction Anxiolysis	25 μg/kg/min
Induction	0.5-1.5 mg/kg over 60 sec
Maintenance (Titrated to Clinical Response)	100-150 μg/kg/min
OPIOID†		Diprivan Injectable Emulsion/50-100 μg/kg/min (no bolus)
Induction	25-50 μg/kg
Maintenance	0.2-0.3 μg/kg/min

Maintenance of General Anesthesia

Adult Patients: In adults, anesthesia can be maintained by administering Diprivan Injectable Emulsion by infusion or intermittent IV bolus injection. The patient"s clinical response will determine the infusion rate or the amount and frequency of incremental injections.

Continuous Infusion: Diprivan Injectable Emulsion 100 to 200 µg/kg/min administered in a variable rate infusion with 60%-70% nitrous oxide and oxygen provides anesthesia for patients undergoing general surgery. Maintenance by infusion of Diprivan Injectable Emulsion 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 dose, higher rates of infusion are generally required (150 to 200 µg/kg/min) for the first 10 to 15 minutes. Infusion rates should subsequently be decreased 30%-50% during the first half-hour of maintenance. Generally, rates of 50 - 100 μg/kg/min in adults should be achieved during maintenance in order to optimize recovery times.

Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase the CNS depression induced by propofol.

Intermittent Bolus: Increments of Diprivan Injectable Emulsion 25 mg (2.5 mL) to 50 mg (5 mL) may be administered with nitrous oxide in adult patients undergoing general surgery. The incremental boluses should be administered when changes in vital signs indicate a response to surgical stimulation or light anesthesia.

Pediatric Patients: Diprivan Injectable Emulsion administered as a variable rate infusion supplemented with nitrous oxide 60% - 70% provides satisfactory anesthesia for most children 2 months of age or older, ASA class I or II, undergoing general anesthesia.

In general, for the pediatric population, maintenance by infusion of Diprivan Injectable Emulsion at a rate of 200 − 300 μg/kg/min should immediately follow the induction dose. Following the first half-hour of maintenance, infusion rates of 125-150 μg/kg/min are typically needed. Diprivan Injectable Emulsion SHOULD BE TITRATED TO ACHIEVE THE DESIRED CLINICAL EFFECT. Younger pediatric patients may require higher maintenance infusion rates than older pediatric patients. (See Table 2 Clinical Trials.)

Diprivan Injectable Emulsion has been used with a variety of agents commonly used in anesthesia such as atropine, scopolamine, glycopyrrolate, diazepam, depolarizing and nondepolarizing muscle relaxants, and opioid analgesics, as well as with inhalational and regional anesthetic agents.

In the elderly, debilitated, or ASA III/IV patients, rapid bolus doses should not be used as this will increase cardiorespiratory effects including hypotension, apnea, airway obstruction, and/or oxygen desaturation.

Monitored Anesthesia Care (MAC) Sedation

Adult Patients: When Diprivan Injectable Emulsion is administered for MAC sedation, rates of administration should be individualized and titrated to clinical response. In most patients, the rates of Diprivan Injectable Emulsion administration will be in the range of 25-75 µg/kg/min.

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 dose administration. In the elderly, debilitated, or ASA III/IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation. (See WARNINGS.) A rapid bolus injection can result in undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation.

Initiation of MAC Sedation: For initiation of MAC sedation, either an infusion or a slow injection method may be utilized while closely monitoring cardiorespiratory function. With the infusion method, sedation may be initiated by infusing Diprivan Injectable Emulsion at 100 to 150 µg/kg/min (6 to 9 mg/kg/h) for a period of 3 to 5 minutes and titrating to the desired clinical effect while closely monitoring respiratory function. With the slow injection method for initiation, patients will require approximately 0.5 mg/kg administered over 3 to 5 minutes and titrated to clinical responses. When Diprivan Injectable Emulsion is administered slowly over 3 to 5 minutes, most patients will be adequately sedated, and the peak drug effect can be achieved while minimizing undesirable cardiorespiratory effects occurring at high plasma levels.

In the elderly, debilitated, or ASA III/IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation. (See WARNINGS.) The rate of administration should be over 3-5 minutes and the dosage of Diprivan Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs. (See DOSAGE AND ADMINISTRATION.)

Maintenance of MAC Sedation: For maintenance of sedation, a variable rate infusion method is preferable over an intermittent bolus dose method. With the variable rate infusion method, patients will generally require maintenance rates of 25 to 75 µg/kg/min (1.5 to 4.5 mg/kg/h) during the first 10 to 15 minutes of sedation maintenance. Infusion rates should subsequently be decreased over time to 25 to 50 µg/kg/min and adjusted to clinical responses. In titrating to clinical effect, allow approximately 2 minutes for onset of peak drug effect.

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 Diprivan Injectable Emulsion at rates higher than are clinically necessary.

If the intermittent bolus dose method is used, increments of Diprivan Injectable Emulsion 10 mg (1 mL) or 20 mg (2 mL) can be administered and titrated to desired clinical effect. With the intermittent bolus method of sedation maintenance, there is the potential for respiratory depression, transient increases in sedation depth, and/or prolongation of recovery.

In the elderly, debilitated, or ASA III/IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation. (See WARNINGS.) The rate of administration and the dosage of Diprivan Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs. (See DOSAGE AND ADMINISTRATION.)

Diprivan Injectable Emulsion can be administered as the sole agent for maintenance of MAC sedation during surgical/diagnostic procedures. When Diprivan Injectable Emulsion sedation is supplemented with opioid and/or benzodiazepine medications, these agents increase the sedative and respiratory effects of Diprivan Injectable Emulsion and may also result in a slower recovery profile. (See PRECAUTIONS, Drug Interactions.)

ICU Sedation: (See WARNINGS and DOSAGE AND ADMINISTRATION, Handling Procedures.)

Adult Patients: 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. (See DOSAGE AND ADMINISTRATION.)

Across all 6 US/Canadian clinical studies, the mean infusion maintenance rate for all Diprivan Injectable Emulsion patients was 27 ± 21 µg/kg/min. The maintenance infusion rates required to maintain adequate sedation ranged from 2.8 µg/kg/min to 130 µg/kg/min. The infusion rate was lower in patients over 55 years of age (approximately 20 µg/kg/min) compared to patients under 55 years of age (approximately 38 µg/kg/min). In these studies, morphine or fentanyl was used as needed for analgesia.

Most adult ICU patients recovering from the effects of general anesthesia or deep sedation will require maintenance rates of 5 to 50 µg/kg/min (0.3 to 3 mg/kg/h) individualized and titrated to clinical response. (See DOSAGE AND ADMINISTRATION.) With medical ICU patients or patients who have recovered from the effects of general anesthesia or deep sedation, the rate of administration of 50 µg/kg/min or higher may be required to achieve adequate sedation. These higher rates of administration may increase the likelihood of patients developing hypotension.

Although there are reports of reduced analgesic requirements, most patients received opioids for analgesia during maintenance of ICU sedation. 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. (See Clinical Trials, Table 4.)

In post-CABG (coronary artery bypass graft) patients, the maintenance rate of propofol administration was usually low (median 11 μg/kg/min) due to the intraoperative administration of high opioid doses. Patients receiving Diprivan Injectable Emulsion required 35% less nitroprusside than midazolam patients; this difference was statistically significant (P<0.05). 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. (See Clinical Trials, Table 4.)

In Medical or 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 19-43 years, adequate sedation was maintained with Diprivan Injectable Emulsion or morphine (N=7 in each group). There were no apparent differences in adequacy of sedation, intracranial pressure, cerebral perfusion pressure, or neurologic recovery between the treatment groups. In literature reports from Neurosurgical ICU and severely head-injured patients Diprivan Injectable Emulsion infusion with or without diuretics and hyperventilation controlled intracranial pressure while maintaining cerebral perfusion pressure. In some patients, bolus doses resulted in decreased blood pressure and compromised cerebral perfusion pressure. (See Clinical Trials, Table 4.)

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. (See Clinical Trials, Table 4.)

Abrupt discontinuation of Diprivan 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 Diprivan Injectable Emulsion should be adjusted to maintain a light level of sedation through the weaning process or evaluation of sedation level. (See PRECAUTIONS.)

Indications and Usage for Diprivan

Diprivan Injectable Emulsion is an IV sedative-hypnotic agent that can be used for both induction and/or maintenance of anesthesia as part of a balanced anesthetic technique for inpatient and outpatient surgery in adult patients and pediatric patients greater than 3 years of age. Diprivan Injectable Emulsion can also be used for maintenance of anesthesia as part of a balanced anesthetic technique for inpatient and outpatient surgery in adult patients and in pediatric patients greater than 2 months of age. Diprivan 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 adult patients, Diprivan Injectable Emulsion, when administered intravenously as directed, can be used to initiate and maintain monitored anesthesia care (MAC) sedation during diagnostic procedures. Diprivan Injectable Emulsion may also be used for MAC sedation in conjunction with local/regional anesthesia in patients undergoing surgical procedures. (See PRECAUTIONS.)

Safety, effectiveness and dosing guidelines for Diprivan Injectable Emulsion have not been established for MAC Sedation/light general anesthesia in the pediatric population undergoing diagnostic or nonsurgical procedures and therefore it is not recommended for this use. (See PRECAUTIONS, Pediatric Use).

Diprivan Injectable Emulsion 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, Diprivan Injectable Emulsion should be administered only by persons skilled in the medical management of critically ill patients and trained in cardiovascular resuscitation and airway management.

Diprivan 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).

Diprivan Injectable Emulsion is not recommended for obstetrics, including cesarean section deliveries. Diprivan Injectable Emulsion crosses the placenta, and as with other general anesthetic agents, the administration of Diprivan Injectable Emulsion may be associated with neonatal depression. (See PRECAUTIONS.)

Diprivan Injectable Emulsion is not recommended for use in nursing mothers because Diprivan 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

Diprivan Injectable Emulsion is contraindicated in patients with a known hypersensitivity to Diprivan Injectable Emulsion or its components, or when general anesthesia or sedation are contraindicated.

Warnings

For general anesthesia or monitored anesthesia care (MAC) sedation, Diprivan 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. 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), Diprivan Injectable Emulsion should be administered only by persons skilled in the management of critically ill patients and trained in cardiovascular resuscitation and airway management.

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

MAC sedation patients should be continuously monitored by persons not involved in the conduct of the surgical or 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, or ASA III/IV patients.

Diprivan 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 is not known.

STRICT ASEPTIC TECHNIQUE MUST ALWAYS BE MAINTAINED DURING HANDLING. Diprivan INJECTABLE EMULSION IS A SINGLE-USE PARENTERAL PRODUCT WHICH CONTAINS 0.005% DISODIUM EDETATE TO RETARD THE RATE OF GROWTH OF MICROORGANISMS IN THE EVENT OF ACCIDENTAL EXTRINSIC CONTAMINATION. HOWEVER, Diprivan 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 Diprivan INJECTABLE EMULSION WAS ASSOCIATED WITH MICROBIAL CONTAMINATION OF THE PRODUCT AND WITH FEVER, INFECTION/SEPSIS, OTHER LIFE-THREATENING ILLNESS, AND/OR DEATH.

Precautions

General:

Adult and Pediatric Patients: A lower induction dose and a slower maintenance rate of administration should be used in elderly, debilitated, or ASA III/IV patients. (See CLINICAL PHARMACOLOGY- Individualization of Dosage.) Patients should be continuously monitored for early signs of significant hypotension and/or bradycardia. Treatment may include increasing the rate of intravenous fluid, elevation of lower extremities, use of pressor agents, or administration of atropine. Apnea often occurs during induction and may persist for more than 60 seconds. Ventilatory support may be required. Because Diprivan Injectable Emulsion is an emulsion, caution should be exercised in patients with disorders of lipid metabolism such as primary hyperlipoproteinemia, diabetic hyperlipemia, and pancreatitis.

Very rarely the use of Diprivan 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. The clinical criteria for discharge from the recovery/day surgery area established for each institution should be satisfied before discharge of the patient from the care of the anesthesiologist.

When Diprivan Injectable Emulsion is administered to an epileptic patient, there may be a risk of seizure during the recovery phase.

Attention should be paid to minimize pain on administration of Diprivan 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.

Venous sequelae (phlebitis or thrombosis) have been reported rarely (<1%). In two well-controlled 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 Diprivan Injectable Emulsion.

Perioperative myoclonia, rarely including convulsions and opisthotonos, has occurred in temporal relationship in cases in which Diprivan Injectable Emulsion has been administered.

Clinical features of anaphylaxis, which may include angioedema, bronchospasm, erythema, and hypotension, occur rarely following Diprivan Injectable Emulsion administration.

There have been rare reports of pulmonary edema in temporal relationship to the administration of Diprivan Injectable Emulsion, although a causal relationship is unknown.

Very rarely, cases of unexplained postoperative pancreatitis (requiring hospital admission) have been reported after anesthesia in which Diprivan 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 Diprivan Injectable Emulsion is unclear.

Diprivan Injectable Emulsion has no vagolytic activity. Reports of bradycardia, asystole, and rarely, cardiac arrest have been associated with Diprivan 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 Diprivan 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 CLINICAL PHARMACOLOGY- Individualization of Dosage.)

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 Diprivan Injectable Emulsion, IV fluid administration, and/or vasopressor therapy.

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

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, especially of long duration.

Opioids and paralytic agents should be discontinued and respiratory function optimized prior to weaning patients from mechanical ventilation. Infusions of Diprivan 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 Diprivan Injectable Emulsion, abrupt discontinuation of a patient"s infusion may result in rapid awakening of the patient with associated anxiety, agitation, and resistance to mechanical ventilation, making weaning from mechanical ventilation difficult. It is therefore recommended that administration of Diprivan 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.

Very rare reports of metabolic acidosis, rhabdomyolysis, hyperkalemia, and/or cardiac failure, in some cases with a fatal outcome, have been received concerning seriously ill patients receiving Diprivan for ICU sedation. These reports demonstrated that a failure of oxygen delivery to the tissues was likely to have occurred. A causal relationship between these reported events and Diprivan has not been established. All sedative and therapeutic agents used in the ICU (including Diprivan) should be titrated to maintain optimal oxygen delivery and hemodynamic parameters.

Since Diprivan Injectable Emulsion is formulated in an oil-in-water emulsion, elevations in serum triglycerides may occur when Diprivan 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 Diprivan 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 Diprivan Injectable Emulsion formulation; 1 mL of Diprivan Injectable Emulsion contains approximately 0.1 g of fat (1.1 kcal).

EDTA is a strong chelator of trace metals -- including zinc. Although with Diprivan Injectable Emulsion there are no reports of decreased zinc levels or zinc deficiency-related adverse events, Diprivan Injectable Emulsion should not be infused for longer than 5 days without providing a drug holiday to safely replace estimated or measured urine zinc losses.

In clinical trials mean urinary zinc loss was approximately 2.5 to 3.0 mg/day in adult patients and 1.5 to 2.0 mg/day in pediatric patients.

In patients who are predisposed to zinc deficiency, such as those with burns, diarrhea, and/or major sepsis, the need for supplemental zinc should be considered during prolonged therapy with Diprivan Injectable Emulsion.

At high doses (2-3 grams per day), EDTA has been reported, on rare occasions, to be toxic to the renal tubules. Studies to-date, in patients with normal or impaired renal function have not shown any alteration in renal function with Diprivan Injectable Emulsion containing 0.005% disodium edetate. In patients at risk for renal impairment, urinalysis and urine sediment should be checked before initiation of sedation and then be monitored on alternate days during sedation.

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

Neurosurgical Anesthesia: When Diprivan 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 Diprivan 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 Diprivan 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, or patients who are hemodynamically unstable. Any fluid deficits should be corrected prior to administration of Diprivan 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 Diprivan Injectable Emulsion.

Information for Patients:

Patients should be advised that performance of activities requiring mental alertness, such as operating a motor ve



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