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 (eg, 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
children. 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 the 213 pediatric patients between the ages of 3 and
12 years assessable for apnea who received 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
(eg, 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) DIPRIVAN 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 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 liver
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 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 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 - 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 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: DIPRIVAN Injectable Emulsion
was compared to intravenous and inhalational anesthetic
or sedative agents in 91 trials involving a total of 5135
patients. Of these, 3354 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 compared to standard anesthetic
agents in 12 clinical trials involving 534 patients receiving
DIPRIVAN 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 DIPRIVAN Injectable Emulsion
Median and (Range) |
|
Induction Only |
Induction and 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 µg/kg/min |
| |
|
(107-418) |
| Maintenance
Duration |
-- |
78 min |
| |
|
(29-268) |
| *Body weight not recorded
for one patient. |
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
2. 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 |
146 |
285 |
|
|
(0.9-6.9) |
(68-425) |
(48-622) |
In 10 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:
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 3. ICU SEDATION
CLINICAL TRIALS AND LITERATURE
Patients receiving DIPRIVAN Injectable Emulsion Median
and (Range) |
|
Number
of
Patients |
Sedation
Dose |
Sedation
Duration |
| ICU Patient Type |
Trials |
Literature |
µg/kg/min |
mg/kg/h |
Hours |
| Post-CABG |
41 |
-- |
11 |
.66 |
10 |
|
|
|
(0.1-30) |
(0.006-1.8) |
(2-14) |
|
-- |
334 |
(5-100) |
(0.3-6) |
(4-24) |
| Postsurgical |
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) |
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 R.T.(R.) THE R.T. 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 L.M.T. (SEE DOSAGE AND ADMINISTRATION,
HANDLING PROCEDURES). THERE HAVE B.E. REPORTS IN WHICH
FAILURE TO USE ASEPTIC TECHNIQUE WHEN HANDLING DIPRIVAN
INJECTECTABEL 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 (eg, 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 (eg, 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 nonnarcotic (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)
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
nonnarcotic (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 insure amnesia with concomitant benzodiazepines.
Higher doses of DIPRIVAN Injectable Emulsion will reduce
the opioid requirements (see Table 4). 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
4. Cardiac Anesthesia Techniques |
| Primary
Agent |
Rate |
Secondary
Agent/Rate |
| |
|
(Following
Induction with Primary Agent) |
| DIPRIVAN
Injectable Emulsion |
|
OPIOIDa/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 |
100-150
µg/kg/min |
|
(Titrated to Clinical Response)
|
|
| OPIOIDb
|
|
DIPRIVAN
Injectable Emulsion / |
| |
|
50-100
µg/kg/min (no bolus) |
|
Induction |
25-50
µg/kg |
|
|
Maintenance |
0.2-0.3
µg/kg/min |
|
| aOPIOID
is defined in terms of fentanyl equivalents, ie, |
| 1
µg of fentanyl |
=
5 µg of alfentanil (for bolus) |
| |
=
10 µg of alfentanil (for maintenance) or |
| |
=
0.1 µg of sufentanil |
| bCare
should be taken to ensure amnesia with concomitant
benzodiazepine therapy |
Maintenance of General Anesthesia: 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.
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.
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.
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 DIPRIVAN 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 DIPRIVAN
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
DIPRIVAN Injectable Emulsion to pediatric patients. Rapid
boluses of DIPRIVAN Injectable Emulsion may be administered
if small veins are pretreated with lidocaine or when antecubital
or larger veins are utilized (See PRECAUTIONS - General).
DIPRIVAN 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 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,
if clinical signs of light anesthesia are not present,
the infusion rate should be decreased; during this period,
infusion rates of 125-150 µg/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 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
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 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 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 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.) 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 3)
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 3).
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 3)
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 3)
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)
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