PROPOFOL
DESCRIPTION:
PROPOVAN Injectable Emulsion is a sterile, nonpyrogenic emulsion containing
10mg/mL of propofol suitable for intravenous administration. Propofol is
chemically described as 2,6-diisopropylphenol and has a molecular weight of
178.27.
Propofol is very slightly soluble in water and, thus, is formulated in a white,
oil-in-water emulsion. The pKa is 11. The octanol/water partition coefficient
for propofol 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 PROPOVAN Injectable emulsion is isotonic and has a
pH of 7-8.5.
STRICT ASEPTIC TECHNIQUE MUST ALWAYS BE MAINTAINED DURING HANDLING. PROPOVAN
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, PROPOVAN 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 PROPOVAN INJECTABLE EMULSION WAS
ASSOCIATED WITH MICROBIAL CONTAMINATION OF THE PRODUCT AND WITH FEVER,
INFECTION/SEPSIS, OTHER LIFE-THREATENING ILLNESS, AND/OR DEATH.
ACTIONS/CLINICAL PHARMACOLOGY:
GENERAL
PROPOVAN 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 PROPOVAN 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 PROPOVAN 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 PROPOVAN 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 PROPOVAN Injectable Emulsion is
rarely associated with elevation of plasma histamine levels.
Induction of anesthesia with PROPOVAN Injectable Emulsion is frequently
associated with apnea in both adults and children. In 1573 adult patients who
received PROPOVAN 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 the 213 pediatric patients between the ages of 3
and 12 years assessable for apnea who received PROPOVAN 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, PROPOVAN 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 PROPOVAN Injectable Emulsion. Hypotension,
oxyhemoglobin desaturation, apnea, airway obstruction, and/or oxygen
desaturation can occur, especially following a rapid bolus of PROPOVAN
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.) PROPOVAN Injectable Emulsion is not recommended for
MAC Sedation in children because safety and effectiveness have not been
established.
Clinical studies in humans and studies in animals show that PROPOVAN Injectable
Emulsion does not suppress the adrenal response to ACTH. Preliminary findings in
patients with normal intraocular pressure indicate that PROPOVAN 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 PROPOVAN Injectable Emulsion to induce malignant hyperthermia.
Studies to date indicate that PROPOVAN Injectable Emulsion when used in
combination with hypocarbia increases cerebrovascular resistance and decreases
cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial
pressure. PROPOVAN 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 liver of dogs receiving PROPOVAN
Injectable Emulsion containing 0.005% disodium edetate over a four week period;
the clinical significance is unknown.
PHARMACOKINETICS
The Proper Use Of PROPOVAN 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 PROPOVAN 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 PROPOVAN 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.
Click here for illustration(s).
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 PROPOVAN 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 PROPOVAN Injectable
Emulsion infusion for ICU sedation, especially of long duration.
ADULTS:
Propofol clearance ranges from 23-50mL/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 endpoint (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 ACTIONS/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 PROPOVAN Injectable Emulsion for periods of
approximately 1-2 hours. The observed distribution and clearance of propofol in
these children was 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
PROPOVAN 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 PROPOVAN 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
PROPOVAN Injectable Emulsion was compared to standard anesthetic agents in 12
clinical trials involving 534 patients receiving PROPOVAN Injectable Emulsion.
Of these, 349 were from US/Canadian clinical trials and comprised the overall
safety database for Pediatric Anesthesia.
TABLE 1. PEDIATRIC ANESTHESIA CLINICAL TRIALS
Patients Receiving PROPOVAN Injectable Emulsion Median and (Range)
-----------------------------------------------------------------------------
Induction
Induction and
ONLY MAINTENANCE
--------- ----------------
Number of Patients* 243 105
Induction Bolus Dosages 2.5 mg/kg 3 mg/kg
(1-3.5) (2-3.6)
Injection Duration 20 sec
(6-45)
Maintenance Dosage -- 181 mcgm/kg/min
(107-418)
Maintenance Duration -- 78 min
(29-268)
* Body weight not recorded for one patient.
NEUROANESTHESIA
PROPOVAN 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 2. NEUROANESTHESIA CLINICAL TRIALS
Patients Receiving PROPOVAN Injectable Emulsion Median and (Range)
------------------------------------------------------------------
Maintenance Maintenance
No. of Induction Bolus Dosage Duration
PATIENT TYPE PATIENTS DOSAGES (MG/KG) (MCGM/KG/MIN) (MIN)
-------------------- -------- -------------- ----------- -----------
Craniotomy patients 50 136 146 285
(0.9-6.9) (68-425) (48-622)
In ten of these patients, PROPOVAN Injectable Emulsion was administered by
infusion in a controlled clinical trial to evaluate the effect of PROPOVAN
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,
PROPOVAN Injectable Emulsion, in combination with hypocarbia, is capable of
decreasing ICP independent of changes in arterial pressure.
INTENSIVE CARE UNIT (ICU) SEDATION
PROPOVAN Injectable Emulsion was compared to benzodiazepines and/or opioids in
14 clinical trials involving a total of 550 ICU patients. Of these, 302 received
PROPOVAN 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 PROPOVAN Injectable Emulsion used for
ICU sedation in over 950 patients and information from the clinical trials are
summarized below:
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TABLE 3. ICU SEDATION CLINICAL TRIALS AND LITERATURE
Patients receiving PROPOVAN Injectable Emulsion Median and (Range)
-----------------------------------------------------------------------------
ICU Number Patients Sedation Dose Sedation Duration
PATIENT TYPE OF TRIALS LITERATURE MCGM/KG/MIN MG/KG/H HOURS
-----------------------------------------------------------------------
Post-CABG 41 -- 11 0.66 10
(0.1-30) (0.006-1.8) (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 1.5 168
(13-37) (0.8-2.2) (112-282)
-- 184 (8.3-87) (0.5-5.2) (8 hr-5 days)
Medical 49 -- 41 2.5 72
(9-131) (0.5-7.9) (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)
Trials (Individual Patients From Clinical Studies)
Literature (Individual Patients From Published Reports)
CABG (Coronary Artery Bypass Graft)
ARDS (Adult Respiratory Distress Syndrome)
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CARDIAC ANESTHESIA
PROPOVAN 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 PROPOVAN 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. PROPOVAN
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, PROPOVAN 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 PROPOVAN 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 PROPOVAN Injectable Emulsion by infusion, syringe pumps or
volumetric pumps are recommended to provide controlled infusion rates. When
infusing PROPOVAN 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 PROPOVAN Injectable
Emulsion 25mg (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 PROPOVAN 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 PROPOVAN 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 PROPOVAN Injectable Emulsion at
rates higher than are clinically necessary. Generally, rates of 50 to 100
mcgm/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 PROPOVAN Injectable Emulsion for induction when unpremedicated or
when premedicated with oral benzodiazepines or intramuscular opioids. For
induction, PROPOVAN 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 PROPOVAN Injectable Emulsion.
ELDERLY, DEBILITATED, OR ASA III/IV PATIENTS:
It is important to be familiar and experienced with the intravenous use of
PROPOVAN 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 PROPOVAN 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.)
NEUROSURGICAL PATIENTS:
Slower induction is recommended using boluses of 20 mg every 10 seconds. Slower
boluses or infusions of PROPOVAN 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:
PROPOVAN 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, PROPOVAN 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 PROPOVAN
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, PROPOVAN 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 PROPOVAN Injectable Emulsion maintenance
infusion rates and therapeutic blood concentrations when compared to non
narcotic (lorazepam) premedication. The rate of PROPOVAN 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 PROPOVAN Injectable Emulsion is used
as the primary agent, maintenance infusion rates should not be less than 100
mcgm/kg/min and should be supplemented with analgesic levels of continuous
opioid administration. When an opioid is used as the primary agent, PROPOVAN
Injectable Emulsion maintenance rates should not be less than 50 mcgm/kg/min and
care should be taken to insure amnesia with concomitant benzodiazepines. Higher
doses of PROPOVAN Injectable Emulsion will reduce the opioid requirements (see
Table 4). When PROPOVAN 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 4. CARDIAC ANESTHESIA TECHNIQUES
PRIMARY AGENT RATE SECONDARY AGENT/RATE
------------------------------------------------------------------------------
(Following Induction with Primary Agent)
PROPOVAN Injectable Emulsion
Preinduction anxiolysis OPIOID(a)/0.05-0.075 mcgm/kg/min (no bolus)
Induction 25 mcgm/kg/min
Induction 0.5-1.5 mg/kg
over 60 sec
Maintenance 100-150 mcgm/
(Titrated to Clinical Response) kg/min
OPIOID(b) PROPOVAN Injectable Emulsion/50-100 mcgm/kg/min (no bolus)
Induction 25-50 mcgm/kg
Maintenance 0.2-0.3 mcgm/kg/min
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(a) OPIOID is defined in terms of fentanyl equivalents, i.e.
1 mcgm of fentanyl = 5 mcgm of alfentanil (for bolus)
= 10 mcgm of alfentanil (for maintenance)
or
= 0.1 mcgm of sufentanil
(b) Care should be taken to ensure amnesia with concomitant benzodiazepine
therapy
----------------------------------------------------------------------------
MAINTENANCE OF GENERAL ANESTHESIA
In adults, anesthesia can be maintained by administering PROPOVAN 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:
PROPOVAN Injectable Emulsion 100 to 200 mcgm/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 PROPOVAN
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 mcgm/kg/min) for the first 10 to 15 minutes.
Infusion rates should subsequently be decreased 30%-50% during the first half-
hour of maintenance.
Other drugs that cause CNS depression (hypnotics/sedatives, inhalational
anesthetics and opioids) can increase the CNS depression induced by propofol.
INTERMITTENT BOLUS:
Increments of PROPOVAN Injectable Emulsion 25 mg (2.5 mL) to 50mg (5mL) 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.
PROPOVAN 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.
PEDIATRIC ANESTHESIA
INDUCTION OF GENERAL ANESTHESIA:
Most pediatric patients 3 years of age or older and classified ASA I or II
require 2.5 to 3.5 mg/kg of PROPOVAN Injectable Emulsion for induction when
unpremedicated or when lightly premedicated with oral benzodiazepines or
intramuscular opioids. Within this dosage range, younger children may require
larger induction doses than older children. 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 PROPOVAN
Injectable Emulsion. In addition, a lower dosage is recommended for children
classified ASA III or IV. Attention should be paid to minimize pain on injection
when administering PROPOVAN Injectable Emulsion to pediatric patients. Rapid
boluses of PROPOVAN Injectable Emulsion may be administered if small veins are
pretreated with lidocaine or when antecubital or larger veins are utilized (See
PRECAUTIONS - General).
PROPOVAN Injectable Emulsion administered in a variable rate infusion with
nitrous oxide 60-70% provides satisfactory anesthesia for most pediatric
patients 3 years of age or older, ASA I or II, undergoing general anesthesia.
MAINTENANCE OF GENERAL ANESTHESIA:
Maintenance by infusion of PROPOVAN Injectable Emulsion at a rate of 200-300
mcgm/kg/min should immediately follow the induction dose. Following the first
half hour of maintenance, if clinical signs of light anesthesia are not present,
the infusion rate should be decreased; during this period, infusion rates of
125-150 mcgm/kg/min are typically needed. However, younger children (5 years of
age or less) may require larger maintenance infusion rates than older children.
MONITORED ANESTHESIA CARE (MAC) SEDATION IN ADULTS
When PROPOVAN Injectable Emulsion is administered for MAC sedation, rates of
administration should be individualized and titrated to clinical response. In
most patients the rates of PROPOVAN Injectable Emulsion administration will be
in the range of 25-75 mcgm/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 PROPOVAN Injectable
Emulsion at 100 to 150 mcgm/kg/min (6 to 9 mg/kg/h) for a period of 3 to 5
minutes and titrating to the desired level of sedation 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 PROPOVAN 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 PROPOVAN
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 mcgm/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
mcgm/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 PROPOVAN Injectable Emulsion at rates
higher than are clinically necessary.
If the intermittent bolus dose method is used, increments of PROPOVAN Injectable
Emulsion 10 mg (1 mL) or 20 mg (2 mL) can be administered and titrated to
desired level of sedation. 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 PROPOVAN 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.)
PROPOVAN Injectable Emulsion can be administered as the sole agent for
maintenance of MAC sedation during surgical/diagnostic procedures. When PROPOVAN
Injectable Emulsion sedation is supplemented with opioid and/or benzodiazepine
medications, these agents increase the sedative and respiratory effects of
PROPOVAN 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.) 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 PROPOVAN Injectable Emulsion patients was 27 +/- 21 mcgm/kg/min. The
maintenance infusion rates required to maintain adequate sedation ranged from
2.8 mcgm/kg/min to 130 mcgm/kg/min. The infusion rate was lower in patients over
55 years of age (approximately 20 mcgm/kg/min) compared to patients under 55
years of age (approximately 38 mcgm/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 mcgm/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 mcgm/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 3.)
In post-CABG (coronary artery bypass graft) patients, the maintenance rate of
propofol administration was usually low (median 11 mcgm/kg/min) due to the
intraoperative administration of high opioid doses. Patients receiving PROPOVAN
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 3).
In Medical or Postsurgical ICU studies comparing PROPOVAN 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, PROPOVAN 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 PROPOVAN 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 PROPOVAN 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 PROPOVAN 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 3.)
PROPOVAN 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 3.)
Abrupt discontinuation of PROPOVAN 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 PROPOVAN 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:
PROPOVAN 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 adults and in
children 3 years of age or older.
PROPOVAN Injectable Emulsion, when administered intravenously as directed, can
be used to initiate and maintain monitored anesthesia care (MAC) sedation during
diagnostic procedures in adults. PROPOVAN Injectable Emulsion may also be used
for MAC sedation in conjunction with local/regional anesthesia in patients
undergoing surgical procedures. (See PRECAUTIONS.)
PROPOVAN 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,
PROPOVAN 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.
PROPOVAN Injectable Emulsion is not recommended for obstetrics, including
cesarean section deliveries. PROPOVAN Injectable Emulsion crosses the placenta,
and as with other general anesthetic agents, the administration of PROPOVAN
Injectable Emulsion may be associated with neonatal depression. (See
PRECAUTIONS.)
PROPOVAN Injectable Emulsion is not recommended for use in nursing mothers
because PROPOVAN 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.)
PROPOVAN Injectable Emulsion is not recommended for anesthesia in children below
the age of 3 years because safety and effectiveness have not been established.
PROPOVAN Injectable Emulsion is not recommended for MAC sedation in children
because safety and effectiveness have not been established. PROPOVAN Injectable
Emulsion is not recommended for pediatric ICU sedation because safety and
effectiveness have not been established.
CONTRAINDICATIONS:
PROPOVAN Injectable Emulsion is contraindicated in patients with a known
hypersensitivity to PROPOVAN Injectable Emulsion or its components, or when
general anesthesia or sedation are contraindicated.
WARNINGS:
FOR GENERAL ANESTHESIA OR MONITORED ANESTHESIA CARE (MAC) SEDATION, PROPOVAN
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), PROPOVAN 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.
PROPOVAN 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. PROPOVAN
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, PROPOVAN 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 PROPOVAN INJECTABLE EMULSION WAS
ASSOCIATED WITH MICROBIAL CONTAMINATION OF THE PRODUCT AND WITH FEVER,
INFECTION/SEPSIS, OTHER LIFE-THREATENING ILLNESS, AND/OR DEATH.