WARNINGS
For general anesthesia or monitored anesthesia
care (MAC) sedation, DIPRIVAN Injectable Emulsion should
be administered only by persons trained in the administration
of general anesthesia and not involved in the conduct
of the surgical/ diagnostic procedure. Patients should
be continuously monitored, and facilities for maintenance
of a patent airway, artificial ventilation, and oxygen
enrichment and circulatory resuscitation must be immediately
available.
For sedation of intubated, mechanically ventilated
adult patients in the Intensive Care Unit (ICU), DIPRIVAN
Injectable Emulsion should be administered only by persons
skilled in the management of critically ill patients and
trained in cardiovascular resuscitation and airway management.
In the elderly, debilitated or ASA III/IV patients, rapid
(single or repeated) bolus administration should not be
used during general anesthesia or MAC sedation in order
to minimize undesirable cardiorespiratory depression including
hypotension, apnea, airway obstruction, and/or oxygen
desaturation.
MAC sedation patients should be continuously monitored
by persons not involved in the conduct of the surgical
or diagnostic procedure; oxygen supplementation should
be immediately available and provided where clinically
indicated; and oxygen saturation should be monitored in
all patients. Patients should be continuously monitored
for early signs of hypotension, apnea, airway obstruction,
and/or oxygen desaturation. These cardiorespiratory effects
are more likely to occur following rapid initiation (loading)
boluses or during supplemental maintenance boluses, especially
in the elderly, debilitated, or ASA III/IV patients.
DIPRIVAN Injectable Emulsion should not be coadministered
through the same IV catheter with blood or plasma because
compatibility has not been established. In vitro tests
have shown that aggregates of the globular component of
the emulsion vehicle have occurred with blood/plasma/serum
from humans and animals. The clinical significance is
not known.
STRICT ASEPTIC TECHNIQUE MUST ALWAYS BE MAINTAINED
DURING HANDLING. DIPRIVAN INJECTABLE EMULSION IS A SINGLE-USE
PARENTERAL PRODUCT WHICH CONTAINS 0.005% DISODIUM EDETATE
TO 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
INJECTABLE EMULSION WAS ASSOCIATED WITH MICROBIAL CONTAMINATION
OF THE PRODUCT AND WITH FEVER, INFECTION/SEPSIS, OTHER
LIFE-THREATENING ILLNESS, AND/OR DEATH.
PRECAUTIONS
General
A lower induction dose and a slower maintenance rate
of administration should be used in elderly, debilitated,
or ASA III/IV patients. (See CLINICAL PHARMACOLOGY - Individualization
of Dosage) Patients should be continuously monitored for
early signs of significant hypotension and/or bradycardia.
Treatment may include increasing the rate of intravenous
fluid, elevation of lower extremities, use of pressor
agents, or administration of atropine. Apnea often occurs
during induction and may persist for more than 60 seconds.
Ventilatory support may be required. Because DIPRIVAN
Injectable Emulsion is an emulsion, caution should be
exercised in patients with disorders of lipid metabolism
such as primary hyperlipoproteinemia, diabetic hyperlipemia,
and pancreatitis.
The clinical criteria for discharge from the recovery/day
surgery area established for each institution should be
satisfied before discharge of the patient from the care
of the anesthesiologist.
When DIPRIVAN Injectable Emulsion is administered to
an epileptic patient, there may be a risk of seizure during
the recovery phase.
In adults and children, attention should be paid to minimize
pain on administration of DIPRIVAN Injectable Emulsion.
Transient local pain can be minimized if the larger veins
of the forearm or antecubital fossa are used. Pain during
intravenous injection may also be reduced by prior injection
of IV lidocaine (1 mL of a 1% solution). Pain on injection
occurred frequently in pediatric patients (45%) when a
small vein of the hand was utilized without lidocaine
pretreatment. With lidocaine pretreatment or when antecubital
veins were utilized, pain was minimal (incidence less
than 10%) and well tolerated.
Venous sequelae (phlebitis or thrombosis) have been reported
rarely (<1%). In two well-controlled clinical studies
using dedicated intravenous catheters, no instances of
venous sequelae were observed up to 14 days following
induction.
Intra-arterial injection in animals did not induce local
tissue effects. Accidental intra-arterial injection has
been reported in patients, and other than pain, there
were no major sequelae.
Intentional injection into subcutaneous or perivascular
tissues of animals caused minimal tissue reaction. During
the postmarketing period there have been rare reports
of local pain, swelling, blisters, and/or tissue necrosis
following accidental extravasation of DIPRIVAN Injectable
Emulsion.
Perioperative myoclonia, rarely including convulsions
and opisthotonos, has occurred in temporal relationship
in cases in which DIPRIVAN Injectable Emulsion has been
administered.
Clinical features of anaphylaxis, which may include angioedema,
bronchospasm, erythema, and hypotension, occur rarely
following DIPRIVAN Injectable Emulsion administration,
although use of other drugs in most instances makes the
relationship to DIPRIVAN Injectable Emulsion unclear.
There have been rare reports of pulmonary edema in temporal
relationship to the administration of DIPRIVAN Injectable
Emulsion, although a causal relationship is unknown.
Very rarely, cases of unexplained postoperative pancreatitis
(requiring hospital admission) have been reported after
anesthesia in which DIPRIVAN Injectable Emulsion was one
of the induction agents used. Due to a variety of confounding
factors in these cases, including concomitant medications,
a causal relationship to DIPRIVAN Injectable Emulsion
is unclear.
DIPRIVAN Injectable Emulsion has no vagolytic activity.
Reports of bradycardia, asystole, and rarely, cardiac
arrest have been associated with DIPRIVAN Injectable Emulsion.
The intravenous administration of anticholinergic agents
(eg, atropine or glycopyrrolate) should be considered
to modify potential increases in vagal tone due to concomitant
agents (eg, succinylcholine) or surgical stimuli.
Intensive Care Unit Sedation
(See
WARNINGS
and DOSAGE AND ADMINISTRATION) The administration of DIPRIVAN
Injectable Emulsion should be initiated as a continuous
infusion and changes in the rate of administration made
slowly (>5 min) in order to minimize hypotension and
avoid acute overdosage. (See CLINICAL PHARMACOLOGY- Individualization
of Dosage)
Patients should be monitored for early signs of significant
hypotension and/or cardiovascular depression, which may
be profound. These effects are responsive to discontinuation
of DIPRIVAN Injectable Emulsion, IV fluid administration,
and/or vasopressor therapy.
As with other sedative medications, there is wide interpatient
variability in DIPRIVAN Injectable Emulsion dosage requirements,
and these requirements may change with time.
Failure to reduce the infusion rate in patients receiving
DIPRIVAN Injectable Emulsion for extended periods may
result in excessively high blood concentrations of the
drug. Thus, titration to clinical response and daily evaluation
of sedation levels are important during use of DIPRIVAN
Injectable Emulsion infusion for ICU sedation, especially
of long duration.
Opioids and paralytic agents should be discontinued and
respiratory function optimized prior to weaning patients
from mechanical ventilation. Infusions of DIPRIVAN Injectable
Emulsion should be adjusted to maintain a light level
of sedation prior to weaning patients from mechanical
ventilatory support. Throughout the weaning process this
level of sedation may be maintained in the absence of
respiratory depression. Because of the rapid clearance
of DIPRIVAN Injectable Emulsion, abrupt discontinuation
of a patient's infusion may result in rapid awakening
of the patient with associated anxiety, agitation, and
resistance to mechanical ventilation, making weaning from
mechanical ventilation difficult. It is therefore recommended
that administration of DIPRIVAN Injectable Emulsion be
continued in order to maintain a light level of sedation
throughout the weaning process until 10-15 minutes prior
to extubation at which time the infusion can be discontinued.
Since DIPRIVAN Injectable Emulsion is formulated in an
oil-in-water emulsion, elevations in serum triglycerides
may occur when DIPRIVAN Injectable Emulsion is administered
for extended periods of time. Patients at risk of hyperlipidemia
should be monitored for increases in serum triglycerides
or serum turbidity. Administration of DIPRIVAN Injectable
Emulsion should be adjusted if fat is being inadequately
cleared from the body. A reduction in the quantity of
concurrently administered lipids is indicated to compensate
for the amount of lipid infused as part of the DIPRIVAN
Injectable Emulsion formulation; 1 mL of DIPRIVAN Injectable
Emulsion contains approximately 0.1 g of fat (1.1 kcal).
In patients who are predisposed to zinc deficiency, such
as those with burns, diarrhea, and/or major sepsis, the
need for supplemental zinc should be considered during
prolonged therapy with DIPRIVAN Injectable Emulsion.
EDTA is a strong chelator of trace metals – including
zinc. Calcium disodium edetate has been used in gram quantities
to treat heavy metal toxicity. When used in this manner
it is possible that as much as 10 mg of elemental zinc
can be lost per day via this mechanism. Although with
DIPRIVAN Injectable Emulsion there are no reports of decreased
zinc levels or zinc deficiency-related adverse events,
DIPRIVAN Injectable Emulsion should not be infused for
longer than 5 days without providing a drug holiday to
safely replace estimated or measured urine zinc losses.
At high doses (2-3 grams per day), EDTA has been reported,
on rare occasions, to be toxic to the renal tubules. Studies
to-date, in patients with normal or impaired renal function
have not shown any alteration in renal function with DIPRIVAN
Injectable Emulsion containing 0.005% disodium edetate.
In patients at risk for renal impairment, urinalysis and
urine sediment should be checked before initiation of
sedation and then be monitored on alternate days during
sedation.
The long-term administration of DIPRIVAN Injectable Emulsion
to patients with renal failure and/or hepatic insufficiency
has not been evaluated.
Neurosurgical Anesthesia
When DIPRIVAN Injectable Emulsion is used in patients
with increased intracranial pressure or impaired cerebral
circulation, significant decreases in mean arterial pressure
should be avoided because of the resultant decreases in
cerebral perfusion pressure. To avoid significant hypotension
and decreases in cerebral perfusion pressure, an infusion
or slow bolus of approximately 20 mg every 10 seconds
should be utilized instead of rapid, more frequent, and/or
larger boluses of DIPRIVAN Injectable Emulsion. Slower
induction titrated to clinical responses will generally
result in reduced induction dosage requirements (1 to
2 mg/kg). When increased ICP is suspected, hyperventilation
and hypocarbia should accompany the administration of
DIPRIVAN Injectable Emulsion. (See DOSAGE AND ADMINISTRATION)
Cardiac Anesthesia
Slower rates of administration should be utilized in
premedicated patients, geriatric patients, patients with
recent fluid shifts, or patients who are hemodynamically
unstable. Any fluid deficits should be corrected prior
to administration of DIPRIVAN Injectable Emulsion. In
those patients where additional fluid therapy may be contraindicated,
other measures, eg, elevation of lower extremities or
use of pressor agents, may be useful to offset the hypotension
which is associated with the induction of anesthesia with
DIPRIVAN Injectable Emulsion.
Information for Patients
Patients should be advised that performance of activities
requiring mental alertness, such as operating a motor
vehicle or hazardous machinery or signing legal documents
may be impaired for some time after general anesthesia
or sedation.
Drug Interactions
The induction dose requirements of DIPRIVAN Injectable
Emulsion may be reduced in patients with intramuscular
or intravenous premedication, particularly with narcotics
(eg, morphine, meperidine, and fentanyl, etc.) and combinations
of opioids and sedatives (eg, benzodiazepines, barbiturates,
chloral hydrate, droperidol, etc.). These agents may increase
the anesthetic or sedative effects of DIPRIVAN 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 DIPRIVAN 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 (eg, nitrous oxide or opioids). The concurrent
administration of potent inhalational agents (eg, isoflurane,
enflurane, and halothane) during maintenance with DIPRIVAN
Injectable Emulsion has not been extensively evaluated.
These inhalational agents can also be expected to increase
the anesthetic or sedative and cardiorespiratory effects
of DIPRIVAN Injectable Emulsion.
DIPRIVAN Injectable Emulsion does not cause a clinically
significant change in onset, intensity, or duration of
action of the commonly used neuromuscular blocking agents
(eg, 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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Animal carcinogenicity studies have not been performed
with propofol.
In vitro and in vivo animal tests failed to show any
potential for mutagenicity by propofol. Tests for mutagenicity
included the Ames (using Salmonella sp) mutation test,
gene mutation/gene conversion using Saccharomyces cerevisiae,
in vitro cytogenetic studies in Chinese hamsters, and
a mouse micronucleus test.
Studies in female rats at intravenous doses up to 15
mg/kg/day (6 times the maximum recommended human induction
dose) for 2 weeks before pregnancy to day 7 of gestation
did not show impaired fertility. Male fertility in rats
was not affected in a dominant lethal study at intravenous
doses up to 15 mg/kg/day for 5 days.
Pregnancy Category B
Reproduction studies have been performed in rats and
rabbits at intravenous doses of 15 mg/kg/day (6 times
the recommended human induction dose) 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 (or 6 times the recommended human induction
dose). The pharmacological activity (anesthesia) of the
drug on the mother is probably responsible for the adverse
effects seen in the offspring. There are, however, no
adequate and well-controlled studies in pregnant women.
Because animal reproduction studies are not always predictive
of human responses, this drug should be used during pregnancy
only if clearly needed.
Labor and Delivery
DIPRIVAN Injectable Emulsion is not recommended for obstetrics,
including cesarean section deliveries. DIPRIVAN Injectable
Emulsion crosses the placenta and, as with other general
anesthetic agents, the administration of DIPRIVAN Injectable
Emulsion may be associated with neonatal depression.
Nursing Mothers
DIPRIVAN Injectable Emulsion is not recommended for use
in nursing mothers because DIPRIVAN Injectable Emulsion
has been reported to be excreted in human milk, and the
effects of oral absorption of small amounts of propofol
are not known.
Pediatrics
DIPRIVAN Injectable Emulsion is not recommended for use
in pediatric patients for ICU or MAC sedation. In addition,
DIPRIVAN Injectable Emulsion is not recommended for general
anesthesia for children below the age of 3 years because
safety and effectiveness have not been established.
Although no causal relationship has been established,
serious adverse events (including fatalities) have been
reported in children given DIPRIVAN Injectable Emulsion
for ICU sedation. These events were seen most often in
children with respiratory tract infections given doses
in excess of those recommended for adults.
Geriatric Use
A lower induction dose and a slower maintenance rate
of administration of DIPRIVAN® 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 and CLINICAL PHARMACOLOGY - Geriatrics).
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