"Potential drug treatments are tested on paper, in laboratories and eventually in thousands of people. But every drug that goes through this cycle â€“ every drug that FDA approves â€“ carries some risk. One of the first lines of defense against "...
Use of DIPRIVAN Injectable Emulsion has been associated with both fatal and lifethreatening anaphylactic and anaphylactoid reactions.
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. 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), 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.
Use of DIPRIVAN Injectable Emulsion infusions 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, renal failure, ECG changes* and/or cardiac failure. The following appear to be major risk factors for the development of these events: decreased oxygen delivery to tissues; serious neurological injury and/or sepsis; high dosages of one or more of the following pharmacological agents: vasoconstrictors, steroids, inotropes and/or prolonged, high-dose infusions of propofol ( > 5 mg/kg/h for > 48h). The syndrome 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.
*Coved ST segment elevation (similar to ECG changes of the Brugada syndrome).
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).
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 of these findings is not known.
There have been reports in which failure to use aseptic technique when handling Diprivan Injectable Emulsion was associated with microbial contamination of the product and with fever, infection, sepsis, other life-threatening illness, and death. Do not use if contamination is suspected. Discard unused drug product as directed within the required time limits (see DOSAGE AND ADMINISTRATION, Handling Procedures).
There have been reports, in the literature and other public sources, of the transmission of bloodborne pathogens (such as Hepatitis B, Hepatitis C, and HIV) from unsafe injection practices, and use of propofol vials intended for single use on multiple persons. DIPRIVAN Injectable Emulsion vial is never to be accessed more than once or used on more than one person.
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. DIPRIVAN Injectable Emulsion use requires caution when administered to patients with disorders of lipid metabolism such as primary hyperlipoproteinemia, diabetic hyperlipemia, and pancreatitis.
Very rarely the use of DIPRIVAN 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 DIPRIVAN 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 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. There have been reports in the literature indicating that the addition of lidocaine to DIPRIVAN Injectable Emulsion in quantities greater than 20 mg lidocaine/200 mg DIPRIVAN Injectable Emulsion 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 lidocaine be administered prior to DIPRIVAN Injectable Emulsion administration or that it be added to DIPRIVAN Injectable Emulsion immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg DIPRIVAN.
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 intraarterial injection has been reported in patients, and, other than pain, there were no major sequelae.
Intentional injection into subcutaneous or perivascular tissues of animals caused minimal tissue reaction. During the post-marketing period, there have been rare reports of local pain, swelling, blisters, and/or tissue necrosis following accidental extravasation of DIPRIVAN Injectable Emulsion.
Rarely, cases of unexplained postoperative pancreatitis (requiring hospital admission) have been reported after anesthesia in which DIPRIVAN Injectable Emulsion was one of the induction agents used. Due to a variety of confounding factors in these cases, including concomitant medications, a causal relationship to DIPRIVAN Injectable Emulsion is unclear.
DIPRIVAN Injectable Emulsion has no vagolytic activity. Reports of bradycardia, asystole, and rarely, cardiac arrest have been associated with DIPRIVAN Injectable Emulsion. Pediatric patients are susceptible to this effect, particularly when fentanyl is given concomitantly. The intravenous administration of anticholinergic agents (e.g., atropine or glycopyrrolate) should be considered to modify potential increases in vagal tone due to concomitant agents (e.g., succinylcholine) or surgical stimuli.
Intensive Care Unit Sedation
(See WARNINGS and DOSAGE AND ADMINISTRATION, Handling Procedures.) The administration of DIPRIVAN Injectable Emulsion should be initiated as a continuous infusion and changes in the rate of administration made slowly ( > 5 min) in order to minimize hypotension and avoid acute overdosage (see 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 DIPRIVAN Injectable Emulsion, IV 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 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 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 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 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 to 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).
EDTA is a strong chelator of trace metals - including zinc. Although with DIPRIVAN Injectable Emulsion there are no reports of decreased zinc levels or zinc deficiency-related adverse events, DIPRIVAN Injectable Emulsion should not be infused for longer than 5 days without providing a drug holiday to safely replace estimated or measured urine zinc losses.
In clinical trials mean urinary zinc loss was approximately 2.5 to 3 mg/day in adult patients and 1.5 to 2 mg/day in pediatric patients.
In patients who are predisposed to zinc deficiency, such as those with burns, diarrhea, and/or major sepsis, the need for supplemental zinc should be considered during prolonged therapy with DIPRIVAN Injectable Emulsion.
At high doses (2 to 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.
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).
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 DIPRIVAN Injectable Emulsion. In those patients where additional fluid therapy may be contraindicated, other measures, e.g., elevation of lower extremities, or use of pressor agents, may be useful to offset the hypotension which is associated with the induction of anesthesia with DIPRIVAN Injectable Emulsion.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Propofol was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) using Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538. 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.
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/m² basis) 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/m² basis). 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, DIPRIVAN Injectable Emulsion 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.
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.
The safety and effectiveness of DIPRIVAN 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.
DIPRIVAN 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 DIPRIVAN Injectable Emulsion may result in serious bradycardia (see PRECAUTIONS, General).
DIPRIVAN 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 DIPRIVAN 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 DIPRIVAN 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, DIPRIVAN 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 of DIPRIVAN Injectable Emulsion 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.
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 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, Elderly, Debilitated or ASA-PS III or IV Patients and CLINICAL PHARMACOLOGY, Geriatrics).
Last reviewed on RxList: 6/23/2014
This monograph has been modified to include the generic and brand name in many instances.
Additional Diprivan Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find out what women really need.