Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/608
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Propofol (Injection, Emulsion)
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NOTE: CONTAINS BENZYL ALCOHOL (See PRECAUTIONS section.) 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 dose adjustments to allow for and
assess the clinical effects. When administering
propofol injectable emulsion by infusion, syringe or volumetric pumps
are recommended to provide controlled infusion rates. When infusing
propofol injectable emulsion to patients undergoing magnetic resonance
imaging, metered control devices may be utilized if mechanical pumps
are impractical. Changes in vital signs indicating
a stress response to surgical stimulation or the emergence from anesthesia
may be controlled by the administration of 25 mg (2.5 mL) to 50 mg
(5 mL) incremental boluses and/or by increasing the infusion rate
of propofol injectable emulsion. For minor surgical
procedures (e.g., body surface) nitrous oxide (60% to 70%) can be
combined with a variable rate propofol 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 propofol 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 propofol injectable emulsion at rates higher
than are clinically necessary. Generally, rates of 50 to 100 mcg/kg/min
in adults should be achieved during maintenance in order to optimize
recovery time. 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 as ASA-PS
I or II require 2 to 2.5 mg/kg of propofol injectable emulsion for
induction when unpremedicated or when premedicated with oral benzodiazepines
or intramuscular opioids. For induction, propofol 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 propofol injectable
emulsion. Elderly,
Debilitated, or ASA-PS III or IV Patients: It is important
to be familiar and experienced with the intravenous use of propofol
injectable emulsion before treating elderly, debilitated, or ASA-PS
III or 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 propofol 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-PS
I or II require 2.5 to 3.5 mg/kg of propofol 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
propofol injectable emulsion. A lower dosage is recommended for pediatric
patients classified as ASA-PS III or IV. Attention should be paid
to minimize pain on injection when administering propofol injectable
emulsion to pediatric patients. Boluses of propofol 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 propofol
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: Propofol 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, propofol 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 propofol 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, propofol 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 propofol injectable emulsion maintenance infusion rates
and therapeutic blood concentrations when compared to non-narcotic
(lorazepam) premedication. The rate of propofol injectable emulsion
administrationshould 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 propofol injectable
emulsion is used as the primary agent, maintenance infusion rates
should not be less than 100 mcg/kg/min and should be supplemented
with analgesic levels of continuousopioid administration. When an
opioid is used as the primary agent, propofol injectable emulsion
maintenance rates should not be less than 50 mcg/kg/min, and care
should be taken to ensure amnesia. Higher doses of propofol injectable
emulsion will reduce the opioid requirements (see TABLE 4). When propofol 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). Maintenance of General
Anesthesia Adult Patients: In adults, anesthesia can be maintained
by administering propofol injectable emulsion by infusion or intermittent
I.V. bolus injection. The patient's clinical response will determine
the infusion rate or the amount and frequency of incremental injections. Continuous Infusion: Propofol injectable emulsion 100 to 200 mcg/kg/min administered
in a variable rate infusion with 60% to 70% nitrous oxide and oxygen
provides anesthesia for patients undergoing general surgery. Maintenance
by infusion of propofol 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 mcg/kg/min) for the first 10 to 15 minutes. Infusion
rates should subsequently be decreased 30% to 50% during the first
half-hour of maintenance. Generally, rates of 50 to 100 mcg/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 propofol
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: Propofol injectable emulsion administered as a variable rate infusion
supplemented with nitrous oxide 60% to 70% provides satisfactory anesthesia
for most children 2 months of age or older, ASA-PS I or II, undergoing
general anesthesia. In general, for the pediatric
population, maintenance by infusion of propofol injectable emulsion
at a rate of 200 to 300 mcg/kg/min should immediately follow the induction
dose. Following the first half-hour of maintenance, infusion rates
of 125 to 150 mcg/kg/min are typically needed. Propofol 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 Clinical Trials - TABLE 2.) Propofol
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-PS III or IV patients,
rapid bolus doses should not be used, as this will increase cardiorespiratory
effects including hypotension, apnea, airway obstruction, and oxygen
desaturation. Monitored
Anesthesia Care (MAC) Sedation Adult Patients: When propofol injectable
emulsion is administered for MAC sedation, rates of administration
should be individualized and titrated to clinical response. In most
patients, the rates of propofol injectable emulsion administration
will be in the range of 25 to 75 mcg/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-PS III or 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 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
propofol injectable emulsion at 100 to 150 mcg/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 propofol 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-PS III or 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 propofol 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 mcg/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 mcg/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 propofol injectable emulsion at
rates higher than are clinically necessary. If the intermittent bolus dose method is used, increments of propofol
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 increased potential for respiratory
depression, transient increases in sedation depth, and prolongation
of recovery. In the elderly, debilitated, or
ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration
should not be used for MAC sedation. (See WARNINGS.) The rate of administration
and the dosage of propofol 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.) Propofol injectable emulsion can be administered as the
sole agent for maintenance of MAC sedation during surgical/diagnostic
procedures. When propofol injectable emulsion sedation is supplemented
with opioid and/or benzodiazepine medications, these agents increase
the sedative and respiratory effects of propofol 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.) Abrupt discontinuation of propofol injectable emulsion prior to weaning
or for daily evaluation of sedation levels should be avoided. This
may result in rapid awakening with associated anxiety, agitation,
and resistance to mechanical ventilation. Infusions of propofol injectable
emulsion should be adjusted to assure a minimal level of sedation
is maintained throughout the weaning process and when assessing the
level of sedation. (See PRECAUTIONS.) 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.) Most adult ICU
patients recovering from the effects of general anesthesia or deep
sedation will require maintenance rates of 5 to 50 mcg/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 mcg/kg/min or higher may be required to achieve adequate sedation.
These higher rates of administration may increase the likelihood of
patients developing hypotension. Dosage and
rate of administration should be individualized and titrated to the
desired effect, according to clinically relevant factors including
the patient's underlying medical problems, preinduction and
concomitant medications, age, ASA-PS classification, and level of
debilitation of the patient. The elderly, debilitated, and ASA-PS
III or IV patients may have exaggerated hemodynamic and respiratory
responses to rapid bolus doses. (See WARNINGS.) Propofol injectable emulsion
should be individualized according to the patient's condition and
response, blood lipid profile, and vital signs. (See PRECAUTIONS - Intensive Care Unit Sedation.) For intubated, mechanically
ventilated adult patients, Intensive Care Unit (ICU) sedation should
be initiated slowly with a continuous infusion in order to titrate
to desired clinical effect and minimize hypotension. When indicated,
initiation of sedation should begin at 5 mcg/kg/min (0.3 mg/kg/h).
The infusion rate should be increased by increments of 5 to 10 mcg/kg/min
(0.3 to 0.6 mg/kg/h) until the desired level of sedation is achieved.
A minimum period of 5 minutes between adjustments should beallowed
for onset of peak drug effect. Most adult patients require maintenance
rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) or higher. Dosages
of propofol injectable emulsion should be reduced in patients who
have received large dosages of narcotics. Conversely, the propofol
injectable emulsion dosage requirement may be reduced by adequate
management of pain with analgesic agents. As with other sedative medications,
there is interpatient variability in dosage requirements, and these
requirements may change with time. (See SUMMARY OF DOSAGE GUIDELINES.) Evaluation of level of sedation
and assessment of CNS function should be carried out daily throughout
maintenance to determine the minimum dose of propofol required for
sedation (see Clinical Trials - Intensive
Care Unit (ICU) Sedation). Bolus administration of 10 or
20 mg should only be used to rapidly increase depth of sedation in
patients where hypotension is not likely to occur. Patients with compromised
myocardial function, intravascular volume depletion, or abnormally
low vascular tone (e.g., sepsis) may be more susceptible to hypotension.
(See PRECAUTIONS.) SUMMARY OF DOSAGE GUIDELINES Dosages and rates of administration in the
following table should be individualized and titrated to clinical
response. Safety and dosing requirements for induction of anesthesia
in pediatric patients have only been established for children 3 years
of age or older. Safety and dosing requirements for the maintenance
of anesthesia have only been established for children 2 months of
age and older. For complete dosage information,
see DOSAGE AND ADMINISTRATION. Administration with Lidocaine:
If lidocaine is to be administered to minimize pain on
injection of propofol, it is recommended that it be administered prior
to propofol administration or that it be added to propofol immediately
before administration and in quantities not exceeding 20 mg lidocaine/200
mg propofol. Compatibility
and Stability: Propofol injectable emulsion should not be
mixed with other therapeutic agents prior to administration. Dilution Prior to Administration: Propofol injectable emulsion is provided as a ready-to-use formulation.
However, should dilution be necessary, it should only be diluted with
5% Dextrose Injection, USP, and it should not be diluted to a concentration
less than 2 mg/mL because it is an emulsion. In diluted form it has
been shown to be more stable when in contact with glass than with
plastic (95% potency after 2 hours of running infusion in plastic). Administration with Other Fluids: Compatibility of propofol injectable emulsion with the coadministration
of blood/serum/plasma has not been established. (See WARNINGS.) When administered using
a y-type infusion set, propofol injectable emulsion has been shown
to be compatible with the following intravenous fluids. ���5% Dextrose Injection, USP ���Lactated Ringers Injection, USP ���Lactated Ringers and 5% Dextrose Injection ���5% Dextrose and 0.45% Sodium Chloride Injection, USP ���5% Dextrose and 0.2% Sodium Chloride Injection, USP Handling Procedures General Parenteral drug products should be inspected
visually for particulate matter and discoloration prior to administration
whenever solution and container permit. Clinical
experience with the use of in-line filters and propofol injectable
emulsion during anesthesia or ICU/MAC sedation is limited. Propofol
injectable emulsion should only be administered through a filter with
a pore size of 5 micron or greater unless it has been demonstrated
that the filter does not restrict the flow of propofol injectable
emulsion and/or cause the breakdown of the emulsion. Filters should
be used with caution and where clinically appropriate. Continuous
monitoring is necessary due to the potential for restricted flow and/or
breakdown of the emulsion. Do not use if there
is evidence of separation of the phases of the emulsion. Rare cases of self-administration of propofol injectable
emulsion, by health care professionals have been reported, including
some fatalities. (See DRUG ABUSE
AND DEPENDENCE.) Strict aseptic technique must always be maintained
during handling. Propofol injectable emulsion is a single-use parenteral
product which contains benzyl alcohol 1.5 mg/mL and sodium benzoate
0.7 mg/mL to inhibit the rate of growth of microorganisms, up to 12
hours, in the event of accidental extrinsic contamination. However,
propofol injectable emulsion can still support the growth of microorganisms
as it is not an antimicrobially preserved product under USP standards.
Accordingly, strict aseptic technique must still be adhered to. Do
not use if contamination is suspected. Discard unused portions asdirected within the required time limits (see DOSAGE AND ADMINISTRATION���Handling Procedures). There have been reports
in which failure to use aseptic technique when handling propofol injectable
emulsion was associated with microbial contamination of the product
and with fever, infection/sepsis, other life-threatening illness,
and/or death. Guidelines for Aseptic Technique for General Anesthesia/MAC Sedation Propofol should be prepared for use just prior
to initiation of each individual anesthetic/sedative procedure. Thevial rubber stopper should be disinfected using 70% isopropyl alcohol.
Propofol should be drawn into sterile syringes immediately after vials
are opened. When withdrawing propofol from vials, a sterile vent spike
should be used. The syringe(s) should be labeled with appropriate
information including the date and time the vial was opened. Administration
should commence promptly and be completed within 12 hours after the
vials have been opened. Propofol injectable
emulsion should be prepared for single-patient use only. Any unused
portions of propofol injectable emulsion, reservoirs, dedicated administration
tubing and/or solutions containing propofol injectable emulsion must
be discarded at the end of the anesthetic procedure or at 12 hours,
whichever occurs sooner. The I.V. line should be flushed every 12
hours and at the end of the anesthetic procedure to remove residual
propofol injectable emulsion. Guidelines for Aseptic Technique for ICU Sedation Propofol injectable emulsion should be prepared
for single-patient use only. When propofol injectable emulsion is
administered directly from the vial, strict aseptic techniques must
be followed. The vial rubber stopper should be disinfected using 70%
isopropyl alcohol. A sterile vent spike and sterile tubing must be
used for administration of propofol injectable emulsion. As with other
lipid emulsions, the number of I.V. line manipulations should be minimized.
Administration should commence promptly and must be completed within
12 hours after the vial has been spiked.The tubing and any unused
portions of propofol injectable emulsion must be discarded after 12
hours. If propofol injectable emulsion is transferred
to a syringe or other container prior to administration, the handling
procedures for General Anesthesia/MAC Sedation should be followed
and the product should be discarded and administration lines changed
after 12 hours.
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| dailymed-instance:descripti... |
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 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 to 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), benzyl
alcohol (1.5 mg/mL) and sodium benzoate (0.7 mg/mL) added. The pH
is adjusted with sodium hydroxide. The propofol injectable emulsion
is isotonic and has a pH of 7 to 8.5.
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General Propofol is an intravenous sedative-hypnotic agent for
use in the induction and maintenance of anesthesia or sedation. Intravenous
injection of a therapeutic dose of propofol induces hypnosis with
minimal excitation, usually within 40 seconds from the start of injection
(the time for one arm-brain circulation). As with other rapidly acting
intravenous anesthetic agents, the half-time of the blood-brain equilibration
is approximately 1 to 3 minutes, accounting for the rate of induction
of anesthesia. Pharmacodynamics Pharmacodynamic properties of propofol are
dependent upon the therapeutic blood propofol concentrations. Steady-state
propofol blood concentrations are generally proportional to infusion
rates. Undesirable side effects such as cardiorespiratory depression
are likely to occur at higher blood concentrations which result from
bolus dosing or rapid increases in infusion rates. An adequate interval
(3 to 5 minutes) must be allowed between dosage adjustments in order
to assess clinical effects. The hemodynamic
effects of propofol injectable emulsion during induction of anesthesia
vary. If spontaneous ventilation is maintained, the major cardiovascular
effect is arterial hypotension (sometimes greater than a 30% decrease)
with little or no change in heart rate and no appreciable decrease
in cardiac output. If ventilation is assisted or controlled (positive
pressure ventilation), there is an increase in the incidence and the
degree of depression of cardiac output. Addition of an opioid, used
as a premedicant, further decreases cardiac output and respiratory
drive. If anesthesia is continued by infusion
of propofol injectable emulsion, the stimulation of endotracheal intubation
and surgery may return arterial pressure towards normal. However,
cardiac output may remain depressed. Comparative clinical studies
have shown that the hemodynamic effects of propofol injectable emulsion
during induction of anesthesia are generally more pronounced than
with other intravenous (I.V.) induction agents. Induction of anesthesia with propofol injectable emulsion is frequently
associated with apnea in both adults and pediatric patients. In adult
patients who received propofol injectable emulsion (2 to 2.5 mg/kg),
apnea lasted less than 30 seconds in 7% of patients, 30 to 60 seconds
in 24% of patients, and more than 60 seconds in 12% of patients. In
pediatric patients from birth through 16 years of age assessable
for apnea who received bolus doses of propofol injectable emulsion
(1 to 3.6 mg/kg), apnea lasted less than 30 seconds in 12% of patients,
30 to 60 seconds in 10% of patients, and more than 60 seconds in 5%
of patients. During maintenance of general anesthesia,
propofol injectable emulsion causes a decrease in spontaneous minute
ventilation usually associated with an increase in carbon dioxide
tension which may be marked depending upon the rate of administration
and concurrent use of other medications (e.g., opioids, sedatives,
etc.). During monitored anesthesia care (MAC)
sedation, attention must be given to the cardiorespiratory effects
of propofol injectable emulsion. Hypotension, oxyhemoglobin desaturation,
apnea, and airway obstruction can occur, especially following a rapid
bolus of propofol injectable emulsion. During initiation of MAC sedation,
slow infusion or slow injection techniques are preferable over rapid
bolus administration. During maintenance of MAC sedation, a variable
rate infusion is preferable over intermittent bolus administration
in order to minimize undesirable cardiorespiratory effects. In the
elderly, debilitated, or ASA-PS III or IV patients, rapid (single
or repeated) bolus dose administration should not be used for MAC
sedation (see WARNINGS). Clinical and preclinical studies suggest
that propofol injectable emulsion is rarely associated with elevation
of plasma histamine levels. Preliminary findings
in patients with normal intraocular pressure indicate that propofol
injectable emulsion produces a decrease in intraocular pressure which
may be associated with a concomitant decrease in systemic vascular
resistance. Clinical studies indicate that propofol
injectable emulsion when used in combination with hypocarbia increases
cerebrovascular resistance and decreases cerebral blood flow, cerebral
metabolic oxygen consumption, and intracranial pressure. Propofol
injectable emulsion does not affect cerebrovascular reactivity to
changes in arterial carbon dioxide tension (see Clinical Trials - Neuroanesthesia). Clinical studies indicate that propofol
injectable emulsion does not suppress the adrenal response to ACTH. Animal studies and limited experience in susceptible patients
have not indicated any propensity of propofol injectable emulsion
to induce malignant hyperthermia. Hemosiderin
deposits have been observed in the livers of dogs receiving propofol
injectable emulsion containing 0.005% disodium edetate over a four-week
period; the clinical significance of this is unknown. Pharmacokinetics The pharmacokinetics of propofol are well described by a three compartment
linear model with compartments representing the plasma, rapidly equilibrating
tissues, and slowly equilibrating tissues. Following
an I.V. bolus dose, there is rapid equilibration between the plasma
and the brain, thus accounting for the rapid onset of anesthesia.
Plasma levels initially decline rapidly as a result of both distribution
and metabolic clearance. Distribution accounts for about half of this
decline following a bolus of propofol. However,
distribution is not constant over time, but decreases as body tissues
equilibrate with plasma and become saturated. The rate at which equilibration
occurs is a function of the rate and duration of the infusion. When
equilibration occurs there is no longer a net transfer of propofol
between tissues and plasma. Discontinuation
of the recommended doses of propofol injectable emulsion after the
maintenance of anesthesia for approximately one hour, or for sedation
in the ICU for one day, results in a prompt decrease in blood propofol
concentrations and rapid awakening. Longer infusions (10 days of ICU
sedation) result in accumulation of significant tissue stores of propofol,
such that the reduction in circulating propofol is slowed and the
time to awakening is increased. By daily titration
of propofol injectable emulsion dosage to achieve only the minimum
effective therapeutic concentration, rapid awakening within 10 to
15 minutes can occur even after long-term administration. If, however,
higher than necessary infusion levels have been maintained for a long
time, propofol redistribution from fat and muscle to the plasma, can
be significant and slow recovery. The figure
below illustrates the fall of plasma propofol levels following infusions
of various durations to provide ICU sedation. The large contribution of distribution (about
50%) to the fall of propofol plasma levels following brief infusions
means that after very long infusions a reduction in infusion rate
is appropriate by as much as half the initial infusion rate in order
to maintain a constant plasma level. Therefore, failure to reduce
the infusion rate in patients receiving propofol injectable emulsion
for extended periods may result in excessively high blood concentrations
of the drug. Thus, titration to clinical response and daily evaluation
of sedation levels are important during use of propofol injectable
emulsion infusion for ICU sedation. Adults: Propofol clearance ranges from
23 to 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 in pharmacodynamics
or brain sensitivity, as measured by EEG burst suppression. With increasing
patient age, pharmacokinetic changes are such that for a given I.V.
bolus dose, higher peak plasma concentrations occur, which can explain
the decreased dose requirement. These higher peak plasma concentrations
in the elderly can predispose patients to cardiorespiratory effects
including hypotension, apnea, airway obstruction, and/or arterial
oxygen desaturation. The higher plasma levels reflect age-related
decrease in volume of distribution and intercompartmental clearance.
Lower doses are therefore recommended for initiation and maintenance
of sedation and anesthesia in elderly patients. (See DOSAGE AND ADMINISTRATION.) Pediatrics: The pharmacokinetics
of propofol were studied in children between 3 and 12 years of age
who received propofol injectable emulsion for periods of approximately
1 to 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.<br/>Clinical Trials: Anesthesia and Monitored
Anesthesia Care (MAC) Sedation Pediatric Anesthesia Propofol injectable emulsion was studied in clinical trials which
included cardiac surgical patients. Most patients were 3 years of
age or older. The majority of the patients were healthy ASA-PS I or
II patients. The range of doses in these studies are described in
Tables 1 and 2. Neuroanesthesia Propofol injectable emulsion was studied in
patients undergoing craniotomy for supratentorial tumors in two clinical
trials. The mean lesion size (anterior/posterior x lateral) was 31
mm x 32 mm in one trial and 55 mm x 42 mm in the other trial respectively.
Anesthesia was induced with a median propofol dose of 1.4 mg/kg (range:
0.9 to 6.9 mg/kg) and maintained with a median maintenance propofol
dose of 146 mcg/kg/min (range: 68 to 425 mcg/kg/min). The median duration
of the propofol maintenance infusion was 285 minutes (range: 48 to622 minutes). Propofol injectable emulsion was
administered by infusion in a controlled clinical trial to evaluate
its effect on cerebrospinal fluid pressure (CSFP). The mean arterial
pressure was maintained relatively constant over 25 minutes with a
change from baseline of -4%��17% (mean��SD). The change
in CSFP was -46%��14%. As CSFP is an indirect measure of intracranial
pressure (ICP), propofol injectable emulsion, when given by infusion
or slow bolus in combination with hypocarbia, is capable of decreasing
ICP independent of changes in arterial pressure. Intensive Care Unit (ICU) Sedation Adult Patients: Propofol injectable emulsion was compared
to benzodiazepines and opioids in clinical trials involving ICU patients.
Of these, 302 received propofol injectable emulsion and comprise the
overall safety database for ICU sedation. Across
all clinical studies, the mean infusion maintenance rate for all propofol
injectable emulsion patients was 27��21 mcg/kg/min. The maintenance
infusion rates required to maintain adequate sedation ranged from
2.8 mcg/kg/min to 130 mcg/kg/min. The infusion rate was lower in patients
over 55 years of age (approximately 20 mcg/kg/min) compared to patients
under 55 years of age (approximately 38 mcg/kg/min). Although there
are reports of reduced analgesic requirements, most patients received
opioids for analgesia during maintenance of ICU sedation.In these
studies, morphine or fentanyl was used as needed for analgesia. Some
patients also received benzodiazepines and/or neuromuscular blocking
agents. During long-term maintenance of sedation, some ICU patients
were awakened once or twice every 24 hours for assessment of neurologic
or respiratory function. In Medical and Postsurgical
ICU studies comparing propofol injectable emulsion to benzodiazepine
infusion or bolus, there were no apparent differences in maintenance
of adequate sedation, mean arterial pressure, or laboratory findings.
Like the comparators, propofol injectable emulsion reduced blood cortisol
during sedation while maintaining responsivity to challenges with
adrenocorticotropic hormone (ACTH). Case reports from the published
literature generally reflect that propofol injectable emulsion has
been used safely in patients with a history of porphyria or malignant
hyperthermia. In hemodynamically stable head
trauma patients ranging in age from 19 to 43 years, adequate sedation
was maintained with propofol injectable emulsion or morphine. There
were no apparent differences in adequacy of sedation, intracranial
pressure, cerebral perfusion pressure, or neurologic recovery between
the treatment groups. In literature reports of severely head-injured
patients in Neurosurgical ICUs, propofol injectable emulsion infusion
and hyperventilation, both with and without diuretics, controlled
intracranial pressure while maintaining cerebral perfusion pressure.
In some patients, bolus doses resulted in decreased blood pressure
and compromised cerebral perfusion pressure. Propofol injectable emulsion was found to be effective in status
epilepticus which was refractory to the standard anticonvulsant therapies.
For these patients, as well as for ARDS/respiratory failure and tetanus
patients, sedation maintenance dosages were generally higher than
those for other critically ill patient populations. Pediatric Patients: A single, randomized, controlled, clinical trial that
evaluated the safety and effectiveness of propofol versus standard
sedative agents (SSA) was conducted on 327 pediatric ICU patients.
Patients were randomized to receive either propofol 2% (113 patients),
propofol 1% (109 patients), or an SSA (e.g., lorazepam, chloral hydrate,
fentanyl, ketamine, morphine, or phenobarbital). Propofol therapy
was initiated at an infusion rate of 5.5 mg/kg/hr and titrated as
needed to maintain sedation at a standardized level. The results of
the study showed an increase in the number of deaths in patients treated
with propofol as compared to SSAs. Of the 25 patients who died during
the trial or within the 28-day follow-up period: 12 (11% were) in
the propofol 2% treatment group, 9 (8% were) in the propofol 1% treatment
group, and 4% were (4%) in the SSA treatment group. The differences
in mortality rate between the groups were not statistically significant.
Review of the deaths failed to reveal a correlation withunderlying
disease status or a correlation to the drug or a definitive pattern
to the causes of death. Cardiac Anesthesia Propofol injectable
emulsion was evaluated in clinical trials involving patients undergoing
coronary artery bypass graft (CABG). In post-CABG
(coronary artery bypass graft) patients, the maintenance rate of propofoladministration was usually low (median 11 mcg/kg/min) due to the intraoperative
administration of high opioid doses. Patients receiving propofol injectable
emulsion required 35% less nitroprusside than midazolam patients.
During initiation of sedation in post-CABG patients, a 15% to 20%
decrease in blood pressure was seen in the first 60 minutes. It was
not possible to determine cardiovascular effects in patients with
severely compromised ventricular function.
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| dailymed-instance:contraind... |
Propofol injectable emulsion is contraindicated in
patients with a known hypersensitivity to propofol injectable emulsion
or any of its components. Propofol injectable
emulsion is contraindicated in patients with allergies to eggs, egg
products, soybeans or soy products.
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| dailymed-instance:supply |
Propofol injectable emulsion is supplied in ready-to-use
vials containing 10 mg/mL of propofol as follows: Propofol undergoes oxidative degradation in the
presence of oxygen and is therefore packaged under nitrogen to eliminate
this degradation path. Store at 20 to 25��C
(68 to 77��F). [See USP Controlled Room Temperature.] Do not
freeze. Shake well before use. Revised: June,
2008
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| dailymed-instance:precautio... |
General: Adult and Pediatric Patients:
A lower induction dose and a slower maintenance rate of
administration should be used in elderly, debilitated, or ASA-PS III
or IV patients. (See DOSAGE AND
ADMINISTRATION.) Patients should be continuously monitored
for early signs of hypotension and/or bradycardia. Apnea requiring
ventilatory support often occurs during induction and may persist
for more than 60 seconds. Propofol injectable emulsion use requires
caution when administered to patientswith disorders of lipid metabolism
such as primary hyperlipoproteinemia, diabetic hyperlipemia, and pancreatitis. Very rarely the use of propofol injectable emulsion may
be associated with the development of a period of postoperative unconsciousness
which may be accompanied by an increase in muscle tone. This may or
may not be preceded by a brief period of wakefulness. Recovery is
spontaneous. When propofol injectable emulsion
is administered to an epileptic patient, there is a risk of seizure
during the recovery phase. Attention should
be paid to minimize pain on administration of propofol injectable
emulsion. Transient local pain can be minimized if the larger veins
of the forearm or antecubital fossa are used. Pain during intravenous
injection may also be reduced by prior injection of I.V. 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
withoutlidocaine pretreatment. With lidocaine pretreatment or when
antecubital veins were utilized, pain was minimal (incidence less
than 10%) and well-tolerated. There have been reports in the literature
indicating that the addition of lidocaine to propofol in quantities
greater than 20 mg lidocaine/200 mg propofol results in instability
of the emulsion which is associated with increases in globule sizes
over time and (in rat studies) a reduction in anesthetic potency.
Therefore, it is recommended that lidocainebe administered prior
to propofol administration or that it be added to propofol immediately
before administration and in quantities not exceeding 20 mg lidocaine/200
mg propofol. Venous sequelae, i.e., phlebitis
or thrombosis, have been reported rarely (<1%). In two clinical
studies using dedicated intravenous catheters, no instances of venous
sequelae were observed up to 14 days following induction. Intra-arterial injection in animals did not induce local
tissue effects. Accidental intra-arterial injection has been reported
in patients, and other than pain, there were no major sequelae. Intentional injection into subcutaneous or perivascular
tissues of animals caused minimal tissue reaction. During the post-marketing
period, there have been rare reports of local pain, swelling, blisters
and/or tissue necrosis following accidental extravasation of propofol
injectable emulsion. Perioperative myoclonia,
rarely including convulsions and opisthotonos, has occurred in association
with propofol injectable emulsion administration. Clinical features of anaphylaxis, including angioedema, bronchospasm,
erythema and hypotension, occur rarely following propofol injectable
emulsion administration. There have been rare
reports of pulmonary edema in temporal relationship to the administration
of propofol injectable emulsion, although a causal relationship is
unknown. Rarely, cases of unexplained postoperative
pancreatitis (requiring hospital admission) have been reported after
anesthesia in which propofol injectable emulsion was one of the induction
agents used. Due to a variety of confounding factors in these cases,
including concomitant medications, a causal relationship to propofol
injectable emulsion is unclear. Propofol injectable
emulsion has no vagolytic activity. Reports of bradycardia, asystole,
and rarely, cardiac arrest have been associated with propofol injectable
emulsion. Pediatric patients are susceptible to this effect, particularly
when fentanyl is given concomitantly. The intravenous administration
of anticholinergic agents (e.g., atropine or glycopyrrolate) should
be considered to modify potential increases in vagal tone due to concomitant
agents (e.g., succinylcholine) or surgical stimuli. Intensive Care Unit Sedation: Adult Patients: (See WARNINGS and DOSAGE AND ADMINISTRATION - Handling
Procedures.) The administration of propofol injectable
emulsion should be initiated as a continuous infusion and changes
in the rate of administration made slowly (>5 min) in order to minimize
hypotension and avoid acute overdosage. (See DOSAGE AND ADMINISTRATION.) Patients should be monitored for early signs of significant
hypotension and/or cardiovascular depression, which may be profound.
These effects are responsive to discontinuation of propofol injectable
emulsion, I.V. fluid administration, and/or vasopressor therapy. In
the elderly, debilitated, or ASA-PS III or IV patients, rapid (single
or repeated) bolus administration should not be used during sedation
in order to minimize undesirable cardiorespiratory depression, including
hypotension, apnea, airway obstruction, and oxygen desaturation. As with other sedative medications, there is wide interpatient
variability in propofol injectable emulsion dosage requirements, and
these requirements may change with time. Failure
to reduce the infusion rate in patients receiving propofol injectable
emulsion for extended periods may result in excessively high blood
concentrations of the drug. Thus, titration to clinical response and
daily evaluation of sedation levels are important during use of propofol
injectable emulsion infusion for ICU sedation, especially when it
is used for long durations. Opioids and paralytic
agents should be discontinued and respiratory function optimized prior
to weaning patients from mechanical ventilation. Infusions of propofol
injectable emulsion should be adjusted to maintain a light level of
sedation prior to weaning patients from mechanical ventilatory support.
Throughout the weaning process, this level of sedation may be maintained
in the absence of respiratory depression. Because of the rapid clearance
of propofol injectable emulsion, abrupt discontinuation of a patient's
infusion may result in rapid awakening with associated anxiety, agitation,
and resistance to mechanical ventilation, making weaning from mechanical
ventilation difficult. It is therefore recommended that administration
of propofol injectable emulsion be continued in order to maintain
a light level of sedation throughout the weaning process until 10
to 15 minutes prior to extubation at which time the infusion can be
discontinued. Since propofol injectable emulsion
is formulated in an oil-in-water emulsion, elevations in serum triglycerides
may occur when propofol injectable emulsion is administered for extended
periods of time. Patients at risk of hyperlipidemia should be monitored
for increases in serum triglycerides or serum turbidity. Administration
of propofol injectable emulsion should be adjusted if fat is being
inadequately cleared from the body. A reduction in the quantity of
concurrently administered lipids is indicated to compensate for the
amount of lipid infused as part of the propofol injectable emulsion
formulation; 1 mL of propofol injectable emulsion contains approximately
0.1 g of fat (1.1 kcal). The long-term administration
of propofol injectable emulsion to patients with renal failure and/or
hepatic insufficiency has not been evaluated. Neurosurgical Anesthesia: When
propofol injectable emulsion is used in patients with increased intracranial
pressure or impaired cerebral circulation, significant decreases in
mean arterial pressure should be avoided because of the resultant
decreases in cerebral perfusion pressure. To avoid significant hypotension
and decreases in cerebral perfusion pressure, an infusion or slow
bolus of approximately 20 mg every 10 seconds should be utilized instead
of rapid, more frequent, and/or larger boluses of propofol injectable
emulsion. Slower induction, titrated to clinical responses, will generally
result in reduced induction dosage requirements (1 to 2 mg/kg). When
increased ICP is suspected, hyperventilation and hypocarbia should
accompany the administration of propofol injectable emulsion. (See DOSAGE AND ADMINISTRATION.) Cardiac Anesthesia: Slower rates of administration should be utilized in premedicated
patients, geriatric patients, patients with recent fluid shifts, and
patients who are hemodynamically unstable. Fluid deficits should be
corrected prior to administration of propofol injectable emulsion.
In those patients where additional fluid therapy may be contraindicated,
other measures, e.g., elevation of lower extremities, or use of pressor
agents, may be useful to offset the hypotension which is associated
with the induction of anesthesia with propofol injectable emulsion.<br/>Information for Patients:: Patients should be advised that performance of activities
requiring mental alertness, such as operating a motor vehicle, or
hazardous machinery or signing legal documents, may be impaired forsome time after general anesthesia or sedation.<br/>Drug Interactions:: The induction dose requirements of propofol injectable
emulsion may be reduced in patients with intramuscular or intravenous
premedication, particularly with narcotics (e.g., morphine, meperidine,
and fentanyl, etc.) and combinations of opioids and sedatives (e.g.,
benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.).
These agents may increase the anesthetic or sedative effects of propofol
injectable emulsion and may also result in more pronounced decreases
in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate
of propofol injectable emulsion administration should be adjusted
according to the desired level of anesthesia or sedation and may be
reduced in the presence of supplemental analgesic agents (e.g., nitrous
oxide or opioids). The concurrent administration of potent inhalational
agents (e.g., isoflurane, enflurane, and halothane) during maintenance
with propofol injectable emulsion has not been extensively evaluated.
These inhalational agents can also be expected to increase the anesthetic
or sedative and cardiorespiratory effects of propofol injectable emulsion. Propofol injectable emulsion does not cause a clinically
significant change in onset, intensity or duration of action of the
commonly used neuromuscular blocking agents (e.g., succinylcholine
and nondepolarizing muscle relaxants). No significant
adverse interactions with commonly used premedications or drugs used
during anesthesia or sedation (including a range of muscle relaxants,
inhalational agents, analgesic agents, and local anesthetic agents)
have been observed in adults. In pediatric patients, administration
of fentanyl concomitantly with propofol injectable emulsion may result
in serious bradycardia.<br/>Carcinogenesis, mutagenesis, impairment of fertility:: Carcinogenesis: Long-term studies in animals have not been performed to evaluate
the carcinogenic potential of propofol. Mutagenesis: Propofol was not mutagenic
in the in vitro bacterial reverse
mutation assay (Ames test) using Salmonella
typhimurium strains TA98, TA100, TA1535, TA1537, and TA
1538. Propofol was not mutagenic in either the gene mutation/gene
conversion test using Saccharomyces cerevisiae, or in vitro cytogenetic
studies in Chinese hamsters. In the in
vivo mouse micronucleus assay with Chinese Hamsters propofol
administration did not produce chromosome aberrations. Impairment of fertility: Female Wistar rats were administered either 0, 10, or 15 mg/kg/day
propofol intravenously from 2 weeks before pregnancy to day 7 of gestation
did not show impaired fertility. Male fertility in rats was not affected
in a dominant lethal study at intravenous doses up to 15 mg/kg/day
for 5 days.<br/>Pregnancy: Teratogenic Effects Pregnancy Category
B: Reproduction studies have been
performed in rats and rabbits at intravenous doses of 15 mg/kg/day
(approximately equivalent to the recommended human induction dose
on a mg/mbasis) and have revealed no evidence of impaired
fertility or harm to the fetus due to propofol. Propofol, however,
has been shown to cause maternal deaths in rats and rabbits and decreased
pup survival during the lactating period in dams treated with 15 mg/kg/day
(approximately equivalent to the recommended human induction dose
on a mg/mbasis). The pharmacological activity (anesthesia)
of the drug on the mother is probably responsible for the adverse
effects seen in the offspring. There are, however, no adequate and
well-controlled studies in pregnant women. Because animal reproduction
studies are not always predictive of human responses, this drug should
be used during pregnancy only if clearly needed.<br/>Labor and Delivery:: Propofol injectable emulsion is not recommended for
obstetrics, including cesarean section deliveries. Propofol injectable
emulsion crosses the placenta, and as with other general anesthetic
agents, the administration of propofol injectable emulsion may be
associated with neonatal depression.<br/>Nursing Mothers:: Propofol injectable emulsion is not recommended for
use in nursing mothers because propofol injectable emulsion has been
reported to be excreted in human milk and the effects of oral absorption
of small amounts of propofol are not known.<br/>Pediatric Use:: The safety and effectiveness of propofol injectable
emulsion have been established for induction of anesthesia in pediatric
patients aged 3 years and older and for the maintenance of anesthesia
aged 2 months and older. Propofol injectable
emulsion is not recommended for the induction of anesthesia in patients
younger than 3 years of age and for the maintenance of anesthesia
in patients younger than 2 months of age as safety and effectiveness
have not been established. In pediatric patients,
administration of fentanyl concomitantly with propofol injectable
emulsion may result in serious bradycardia. (See PRECAUTIONS���General.) Propofol injectable
emulsion is not indicated for use in pediatric patients for ICU sedation
or for MAC sedation for surgical, nonsurgical or diagnostic procedures
as safety and effectiveness have not been established. There have been anecdotal reports of serious adverse events
and death in pediatric patients with upper respiratory tract infections
receiving propofol injectable emulsion for ICU sedation. In one multicenter clinical trial of ICU sedation in critically
ill pediatric patients that excluded patients with upper respiratory
tract infections, the incidence of mortality observed in patients
who received propofol injectable emulsion (n=222) was 9%, while that
for patients who received standard sedative agents (n=105) was 4%.
While causality has not been established, propofol injectable emulsion
is not indicated for sedation in pediatric patients until further
studies have been performed to document its safety in that population.
(See CLINICAL PHARMACOLOGY, Pharmacokinetics���Pediatric Patients and DOSAGE AND ADMINISTRATION.) In pediatric patients, abrupt discontinuation
following prolonged infusion may result in flushing of the hands and
feet, agitation, tremulousness and hyperirritability. Increased incidences
of bradycardia (5%), agitation (4%), and jitteriness (9%) have also
been observed. Benzyl alcohol, a component of
this product, has been associated with serious adverse events and
death, particularly in pediatric patients. The "gasping syndrome,"
(characterized by central nervous system depression, metabolic acidosis,
gasping respirations, and high levels of benzyl alcohol and its metabolites
found in the blood and urine) has been associated with benzyl alcohol
dosages>99 mg/kg/day in neonates and low-birth weight neonates. Additional
symptoms may include gradual neurological deterioration, seizures,
intracranial hemorrhage, hematologic abnormalities, skin breakdown,
hepatic and renal failure, hypotension, bradycardia, and cardiovascular
collapse. Although normal therapeutic doses
of this product deliver amounts of benzyl alcohol that are substantially
lower than those reported in association with the "gasping syndrome,"
the minimum amount of benzyl alcohol at which toxicity may occur is
not known. Premature and low-birth weight infants, as well as patients
receiving high dosages, may be more likely to develop toxicity. Practitioners
administering this and other medications containing benzyl alcohol
should consider the combined daily metabolic load of benzyl alcohol
from all sources.<br/>Geriatric Use:: The effect of age on induction dose requirements
for propofol was assessed in an open-label study involving 211 unpremedicated
patients with approximately 30 patients in each decade between the
ages of 16 and 80. The average dose to induce anesthesia was calculated
for patients up to 54 years of age and for patients 55 years of age
or older. The average dose to induce anesthesia in patients up to
54 years of age was 1.99 mg/kg and in patients above 54 it was 1.66
mg/kg. Subsequent clinical studies have demonstrated lower dosing
requirements for subjects greater than 60 years of age. A lower induction dose and a slower maintenance rate of
administration of propofol injectable emulsion should be used in elderly
patients. In this group of patients, rapid (single or repeated) bolus
administration should not be used in order to minimize undesirable
cardiorespiratory depression including hypotension, apnea, airway
obstruction, and/or oxygen desaturation. All dosing should be titrated
according to patient condition and response. (See DOSAGE AND ADMINISTRATION���Elderly, debilitated or ASA-PS III or IV
patients and CLINICAL
PHARMACOLOGY���Geriatrics.)
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| dailymed-instance:overdosag... |
If overdosage occurs, propofol injectable emulsion
administration should be discontinued immediately. Overdosage is likely
to cause cardiorespiratory depression. Respiratory depression should
be treated by artificial ventilation with oxygen. Cardiovascular depression
may require repositioning of the patient by raising the patient's
legs, increasing the flow rate of intravenous fluids, and administering
pressor agents and/or anticholinergic agents.
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Propofol
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Propofol (Injection, Emulsion)
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| dailymed-instance:adverseRe... |
General Adverse event information is derived from controlled clinical
trials and worldwide marketing experience. In the description below,
rates of the more common events represent US/Canadian clinical study
results. Less frequent events are also derived from publications and
marketing experience in over 8 million patients; there are insufficient
data to support an accurate estimate of their incidence rates. These
studies were conducted using a variety of premedicants, varying lengths
of surgical/diagnostic procedures, and various other anesthetic/sedative
agents. Most adverse events were mild and transient. Anesthesia and MAC Sedation in Adults The following estimates of adverse events
for propofol injectable emulsion include data from clinical trials
in general anesthesia/MAC sedation (N=2889 adult patients). The adverse
events listed below as probably causally related are those events
in which the actual incidence rate in patients treated with propofol
injectable emulsion was greater than the comparator incidence rate
in these trials. Therefore, incidence rates for anesthesia and MAC
sedation in adults generally represent estimates of the percentage
of clinical trial patients which appeared to have probable causal
relationship. The adverse experience profile
from reports of 150 patients in the MAC sedation clinical trials is
similar to the profile established with propofol during anesthesia
(see below). During MAC sedation clinical trials, significant respiratory
events included cough, upper airway obstruction, apnea, hypoventilation,
and dyspnea. Anesthesia
in Pediatric Patients Generally the
adverse experience profile from reports of 506 propofol injectable
emulsion pediatric patients from 6 days through 16 years of age in
the US/Canadian anesthesia clinical trials is similar to the profile
established with propofol injectable emulsion during anesthesia in
adults (see Pediatric percentages [Peds %] below). Although not reported
as an adverse event in clinical trials, apnea is frequently observed
in pediatric patients. ICU Sedation in Adults The following
estimates of adverse events include data from clinical trials in ICU
sedation (N=159 adult patients). Probably related incidence rates
for ICU sedation were determined by individual case report form review.
Probable causality was based upon an apparent dose response relationship
and/or positive responses to rechallenge. In many instances the presence
of concomitant disease and concomitant therapy made the causal relationship
unknown. Therefore, incidence rates for ICU sedation generally represent
estimates of the percentage of clinical trial patients which appeared
to have a probable causal relationship.
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| dailymed-instance:warning |
Use of propofol injectable emulsion has been associated
with both fatal and life-threatening anaphylactic and anaphylactoid
reactions. For general anesthesia or monitored
anesthesia care (MAC) sedation, propofol injectable emulsion should
be administered only by persons trained in the administration of general
anesthesia and not involved in the conduct of the surgical/diagnostic
procedure. Sedated patients should be continuously monitored, and
facilities for maintenance of a patent airway, providing artificial
ventilation, administering supplemental oxygen, and instituting cardiovascular
resuscitation must be immediately available. Patients should be continuously
monitored for early signs of hypotension, apnea, airway obstruction,
and/or oxygen desaturation. These cardiorespiratory effects are more
likely to occur following rapid bolus administration, especially in
the elderly, debilitated, or ASA-PS III or IV patients. For sedation of intubated, mechanically ventilated patients
in the Intensive Care Unit (ICU), propofol injectable emulsion should
be administered only by persons skilled in the management of critically
ill patients and trained in cardiovascular resuscitation and airway
management. Use of
propofol injectable emulsion for both adult and pediatric ICU sedation
has been associated with a constellation of metabolic derangements
and organ system failures, referred to as Propofol Infusion Syndrome,
that have resulted in death. The syndrome is characterized by severe
metabolic acidosis, hyperkalemia, lipemia, rhabdomyolysis, hepatomegaly,
cardiac and renal failure. The syndrome is most often associated with
prolonged, high-dose infusions (>5 mg/kg/h for>48h) but has also
been reported following large-dose, short-term infusions during surgical
anesthesia. In the setting of prolonged need for sedation, increasing
propofol dose requirements to maintain a constant level of sedation,
or onset of metabolic acidosis during administration of a propofol
infusion, consideration should be given to using alternative means
of sedation. Abrupt discontinuation
of propofol injectable emulsion prior to weaning or for daily evaluation
of sedation levels should be avoided. This may result in rapid awakening
with associated anxiety, agitation, and resistance to mechanical ventilation.
Infusions of propofol injectable emulsion should be adjusted to maintain
a light level of sedation through the weaning process or evaluation
of sedation level. (See PRECAUTIONS.) Propofol injectable emulsion should not
be coadministered through the same I.V. catheter with blood or plasma
because compatibility has not been established. In vitro tests have shown that aggregates
of the globular component of the emulsion vehicle have occurred with
blood/plasma/serum from humans and animals. The clinical significance
of these findings is not known. There have been reports in which failure to use aseptic
technique when handling propofol injectable emulsion was associated
with microbial contamination of the product and with fever, infection,
sepsis, other life-threatening illness, and death. Do not use if contamination
is suspected. Discard unused portions as directed within the required
time limits (see DOSAGE
AND ADMINISTRATION - Handling
Procedures).
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| dailymed-instance:indicatio... |
Propofol injectable emulsion is an I.V. sedative-hypnotic
agent that can be used as described in the table below. Safety, effectiveness and dosing guidelines for
propofol injectable emulsion have not been established for MAC Sedation
in the pediatric population; therefore, it is not recommended for
this use. (See PRECAUTIONS - Pediatric Use.) Propofol injectable emulsion is not recommended for induction
of anesthesia below the age of 3 years or for maintenance of anesthesia
below the age of 2 months because its safety and effectiveness have
not been established in those populations. In
the Intensive Care Unit (ICU), propofol injectable emulsion can be
administered to intubated, mechanically ventilated adult patients
to provide continuous sedation and control of stress responses, only
by persons skilled in the medical management of critically ill patients
and trained in cardiovascular resuscitation and airway management. Propofol injectable emulsion is not indicated for use
in Pediatric ICU sedation since the safety of this regimen has not
been established. (See PRECAUTIONS���Pediatric Use.) Propofol injectable
emulsion is not recommended for obstetrics, including Cesarean section
deliveries. Propofol injectable emulsion crosses the placenta, and
as with other general anesthetic agents, the administration of propofol
injectable emulsion may be associated with neonatal depression. (See PRECAUTIONS.) Propofol is not recommended for use in nursing mothers because propofol
injectable emulsion has been reported to be excreted in human milk
and the effects of oral absorption of small amounts of propofol are
not known. (See PRECAUTIONS.)
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Propofol
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