Anesthesia S / I-40

Name: Anesthesia S / I-40

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of a pancreas problem (pancreatitis) like very bad stomach pain, very bad back pain, or very bad upset stomach or throwing up.
  • Signs of high or low blood pressure like very bad headache or dizziness, passing out, change in eyesight.
  • Trouble breathing, slow breathing, or shallow breathing.
  • Slow heartbeat.
  • Chest pain or pressure.
  • Trouble controlling body movements, twitching, change in balance, trouble swallowing or speaking.
  • Seizures.
  • Change in eyesight.
  • Muscle stiffness.
  • This medicine may rarely cause a very bad and sometimes deadly health problem called propofol infusion syndrome (PRIS). The chance of PRIS may be higher if you get high doses of this medicine or use it for a long time. The chance may also be higher if you have certain other health problems like a very bad brain injury or a very bad infection. Call your doctor right away if you have dark urine or are not able to pass urine; have fast breathing; have a fast heartbeat or a heartbeat that is not normal; are very sleepy; have a very upset stomach or are throwing up; have very bad muscle pain or weakness; or have shortness of breath, a big weight gain, or swelling in the arms or legs.
  • This medicine may cause tissue damage if the drug leaks from the vein. Tell your nurse if you have any redness, burning, pain, swelling, blisters, skin sores, or leaking of fluid where the drug is going into your body.

What are some other side effects of Anesthesia S/I-40?

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

  • Feeling sleepy.
  • Irritation where the shot is given.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Anesthesia S/I-40 - Clinical Pharmacology

General

DIPRIVAN Injectable Emulsion is an intravenous sedative-hypnotic agent for use in the induction and maintenance of anesthesia or sedation. Intravenous injection of a therapeutic dose of propofol 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. The mechanism of action, like all general anesthetics, is poorly understood. However, propofol is thought to produce its sedative/anesthetic effects by the positive modulation of the inhibitory function of the neurotransmitter GABA through the ligand-gated GABAA receptors.

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 dose adjustments in order to assess clinical effects.

The hemodynamic effects of DIPRIVAN 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 DIPRIVAN Injectable Emulsion, the stimulation of endotracheal intubation and surgery may return arterial pressure towards normal. However, cardiac output may remain depressed. Comparative clinical studies have shown that the hemodynamic effects of DIPRIVAN Injectable Emulsion during induction of anesthesia are generally more pronounced than with other intravenous (IV) induction agents.

Induction of anesthesia with DIPRIVAN Injectable Emulsion is frequently associated with apnea in both adults and pediatric patients. In adult patients who received DIPRIVAN 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 DIPRIVAN 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, DIPRIVAN 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 DIPRIVAN Injectable Emulsion. Hypotension, oxyhemoglobin desaturation, apnea, and airway obstruction can occur, especially following a rapid bolus of DIPRIVAN Injectable Emulsion. During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration. 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 DIPRIVAN Injectable Emulsion is rarely associated with elevation of plasma histamine levels.

Preliminary findings in patients with normal intraocular pressure indicate that DIPRIVAN Injectable Emulsion produces a decrease in intraocular pressure which may be associated with a concomitant decrease in systemic vascular resistance.

Clinical studies indicate that DIPRIVAN Injectable Emulsion when used in combination with hypocarbia increases cerebrovascular resistance and decreases cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure. DIPRIVAN Injectable Emulsion does not affect cerebrovascular reactivity to changes in arterial carbon dioxide tension (see Clinical Trials, Neuroanesthesia).

Clinical studies indicate that DIPRIVAN Injectable Emulsion does not suppress the adrenal response to ACTH.

Animal studies and limited experience in susceptible patients have not indicated any propensity of DIPRIVAN Injectable Emulsion to induce malignant hyperthermia.

Hemosiderin deposits have been observed in the livers of dogs receiving DIPRIVAN 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 IV bolus dose, there is rapid equilibration between the plasma and the brain, 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 DIPRIVAN Injectable Emulsion after the maintenance of anesthesia for approximately one hour, or for sedation in the ICU for one day, results in a prompt decrease in blood propofol concentrations and rapid awakening. Longer infusions (10 days of ICU sedation) result in accumulation of significant tissue stores of propofol, such that the reduction in circulating propofol is slowed and the time to awakening is increased.

By daily titration of DIPRIVAN Injectable Emulsion dosage to achieve only the minimum effective therapeutic concentration, rapid awakening within 10 to 15 minutes 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.

Fall of Plasma Propofol Levels

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 the 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 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.

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 end point (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 IV bolus dose, higher peak plasma concentrations occur, which can explain the decreased dose requirement. These higher peak plasma concentrations in the elderly can predispose patients to cardiorespiratory effects including hypotension, apnea, airway obstruction, and/or arterial oxygen desaturation. The higher plasma levels reflect an 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 DIPRIVAN 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.

Clinical Trials 

Anesthesia and Monitored Anesthesia Care (MAC) Sedation

Pediatric Anesthesia

DIPRIVAN 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.

                              TABLE 1. PEDIATRIC INDUCTION OF ANESTHESIA

Age Range

Induction Dose
Median (range)

Injection Duration
Median (range)

Birth through 16 years

2.5 mg/kg
(1 to 3.6)

20 sec.
(6 to 45)


                                 TABLE 2. PEDIATRIC MAINTENANCE OF ANESTHESIA

Age Range

Maintenance Dosage (mcg/kg/min)

Duration
(minutes)

2 months to 2 years

199 (82 to 394)

65 (12 to 282)

2 to 12 years

188 (12 to 1041)

69 (23 to 374)

>12 through 16 years

161 (84 to 359)

69 (26 to 251)


Neuroanesthesia

DIPRIVAN 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 DIPRIVAN dose of 1.4 mg/kg (range: 0.9 to 6.9 mg/kg) and maintained with a median maintenance DIPRIVAN dose of 146 mcg/kg/min (range: 68 to 425 mcg/kg/min). The median duration of the DIPRIVAN Injectable Emulsion maintenance infusion was 285 minutes (range: 48 to 622 minutes).

DIPRIVAN 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), DIPRIVAN 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

DIPRIVAN Injectable Emulsion was compared to benzodiazepines and opioids in clinical trials involving ICU patients. Of these, 302 received DIPRIVAN Injectable Emulsion and comprise the overall safety database for ICU sedation.

Across all clinical studies, the mean infusion maintenance rate for all DIPRIVAN 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 DIPRIVAN Injectable Emulsion to benzodiazepine infusion or bolus, there were no apparent differences in maintenance of adequate sedation, mean arterial pressure, or laboratory findings. Like the comparators, DIPRIVAN Injectable Emulsion reduced blood cortisol during sedation while maintaining responsivity to challenges with adrenocorticotropic hormone (ACTH). Case reports from the published literature generally reflect that DIPRIVAN Injectable Emulsion has been used safely in patients with a history of porphyria or malignant hyperthermia.

In hemodynamically stable head trauma patients ranging in age from 19 to 43 years, adequate sedation was maintained with DIPRIVAN 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, DIPRIVAN 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.

DIPRIVAN Injectable Emulsion was found to be effective in status epilepticus which was refractory to the standard anticonvulsant therapies. For these patients, as well as for ARDS/ respiratory failure and tetanus patients, sedation maintenance dosages were generally higher than those for other critically ill patient populations.

Pediatric Patients

A single, randomized, controlled, clinical trial that evaluated the safety and effectiveness of DIPRIVAN Injectable Emulsion versus standard sedative agents (SSA) was conducted on 327 pediatric ICU patients. Patients were randomized to receive either DIPRIVAN Injectable Emulsion 2%, (113 patients), DIPRIVAN Injectable Emulsion 1%, (109 patients), or an SSA (eg, lorazepam, chloral hydrate, fentanyl, ketamine, morphine, or phenobarbital). DIPRIVAN Injectable Emulsion 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 DIPRIVAN Injectable Emulsion 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 DIPRIVAN Injectable Emulsion 2% treatment group, 9 (8% were) in the DIPRIVAN Injectable Emulsion 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 with underlying disease status or a correlation to the drug or a definitive pattern to the causes of death.

Cardiac Anesthesia

DIPRIVAN 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 propofol administration was usually low (median 11 mcg/kg/min) due to the intraoperative administration of high opioid doses. Patients receiving DIPRIVAN 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.

Indications and Usage for Anesthesia S/I-40

DIPRIVAN Injectable Emulsion is an IV sedative-hypnotic agent that can be used as described in the table below.

                                 Table 3. Indications for DIPRIVAN Injectable Emulsion

Indication

Approved Patient Population

Initiation and maintenance of Monitored Anesthesia Care (MAC) sedation

Adults only

Combined sedation and regional anesthesia

Adults only (seePRECAUTIONS)

Induction of General Anesthesia

Patients ≥ 3 years of age

Maintenance of General Anesthesia

Patients ≥ 2 months of age

Intensive Care Unit (ICU) sedation of intubated, mechanically ventilated patients

Adults only


Safety, effectiveness and dosing guidelines for DIPRIVAN 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).

DIPRIVAN 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), DIPRIVAN 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.

DIPRIVAN 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).

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 (see PRECAUTIONS).

DIPRIVAN Injectable Emulsion is not recommended for use in nursing mothers because propofol 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).


Contraindications

DIPRIVAN Injectable Emulsion is contraindicated in patients with a known hypersensitivity to propofol or any of DIPRIVAN Injectable Emulsion components.

DIPRIVAN Injectable Emulsion is contraindicated in patients with allergies to eggs, egg products, soybeans or soy products.

Drug Abuse and Dependence

There are reports of the abuse of propofol for recreational and other improper purposes, which have resulted in fatalities and other injuries. Instances of self-administration of DIPRIVAN Injectable Emulsion by health care professionals have also been reported, which have resulted in fatalities and other injuries. Inventories of DIPRIVAN Injectable Emulsion should be stored and managed to prevent the risk of diversion, including restriction of access and accounting procedures as appropriate to the clinical setting.

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.

INDICATION DOSAGE AND ADMINISTRATION
Induction of General Anesthesia Healthy Adults Less Than 55 Years of Age:
40 mg every 10 seconds until induction onset (2 to 2.5 mg/kg).
Elderly, Debilitated, or ASA-PS III or IV Patients:
20 mg every 10 seconds until induction onset (1 to 1.5 mg/kg).
Cardiac Anesthesia:
20 mg every 10 seconds until induction onset (0.5 to 1.5 mg/kg).
Neurosurgical Patients:
20 mg every 10 seconds until induction onset (1 to 2 mg/kg).
Pediatric Patients - healthy, from 3 years to 16 years
of age:
2.5 to 3.5 mg/kg administered over 20 to 30 seconds.
(seePRECAUTIONS,Pediatric UseandCLINICAL
PHARMACOLOGY, Pediatrics)
Maintenance of General Anesthesia

Infusion

Healthy Adults Less Than 55 Years of Age:
100 to 200 mcg/kg/min (6 to 12 mg/kg/h).

Elderly, Debilitated, ASA-PS III or IV Patients:
50 to 100 mcg/kg/min (3 to 6 mg/kg/h).

Cardiac Anesthesia:Most patients require:
Primary DIPRIVAN Injectable Emulsion with Secondary
Opioid – 100 to 150 mcg/kg/min.

Low-Dose DIPRIVAN Injectable Emulsion with Primary
Opioid – 50 to 100 mcg/kg/min.
(seeDOSAGE AND ADMINISTRATION,Table 4)

Neurosurgical Patients:
100 to 200 mcg/kg/min (6 to 12 mg/kg/h).

Pediatric Patients - healthy, from 2 months of age
to 16 years of age:
125 to 300 mcg/kg/min (7.5 to 18 mg/kg/h).
Following the first half hour of maintenance, if clinical signs
of light anesthesia are not present, the infusion rate should
be decreased.
(seePRECAUTIONS,Pediatric UseandCLINICAL
PHARMACOLOGY, Pediatrics)

Maintenance of General Anesthesia Intermittent Bolus

Healthy Adults Less Than 55 Years of Age:
Increments of 20 to 50 mg as needed.

Initiation of MAC Sedation

Healthy Adults Less Than 55 Years of Age:
Slow infusion or slow injection techniques are recommended
to avoid apnea or hypotension. Most patients require an infusion
of 100 to 150 mcg/kg/min (6 to 9 mg/kg/h) for 3 to 5 minutes or a slow injection of 0.5 mg/kg over 3 to 5 minutes followed immediately by a maintenance infusion.


Elderly, Debilitated, Neurosurgical, or ASA-PS IIIor IV Patients:
Most patients require dosages similar to healthy adults.
Rapid boluses are to be avoided (seeWARNINGS).

Maintenance of MAC Sedation

Healthy Adults Less Than 55 Years of Age:
A variable rate infusion technique is preferable over an
intermittent bolus technique. Most patients require an
infusion of 25 to 75 mcg/kg/min (1.5 to 4.5 mg/kg/h) or
incremental bolus doses of 10 mg or 20 mg.

In Elderly, Debilitated, Neurosurgical, or ASA-PS III
or IV Patients:
Most patients require 80% of the usual adult dose. A rapid (single
or repeated) bolus dose should not be used (seeWARNINGS).

Initiation and Maintenance of ICU Sedation in Intubated, Mechanically Ventilated

Adult Patients -Because of the residual effects of previous
anesthetic or sedative agents, in most patients the initial
infusion should be 5 mcg/kg/min (0.3 mg/kg/h) for at least
5 minutes. Subsequent increments of 5 to 10 mcg/kg/min
(0.3 to 0.6 mg/kg/h) over 5 to 10 minutes may be used until
desired clinical effect is achieved. Maintenance rates of 5 to
50 mcg/kg/min (0.3 to 3 mg/kg/h) or higher may be required.
Administration should not exceed 4 mg/kg/hour unless the
benefits outweigh the risks (seeWARNINGS).

Evaluation of clinical effect and assessment of CNS
function should be carried out daily throughout
maintenance to determine the minimum dose of
DIPRIVAN Injectable Emulsion required for sedation.


The tubing and any unused DIPRIVAN Injectable
Emulsion drug product should be discarded after
12 hours because DIPRIVAN Injectable Emulsion
contains no preservatives and is capable of supporting
growth of microorganisms (see WARNINGS andDOSAGE AND ADMINISTRATION).


Administration with Lidocaine

If lidocaine is to be administered to minimize pain on injection of DIPRIVAN Injectable Emulsion, it is recommended that it 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.

Compatibility and Stability

DIPRIVAN Injectable Emulsion should not be mixed with other therapeutic agents prior to administration.

Dilution Prior to Administration

DIPRIVAN 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 DIPRIVAN Injectable Emulsion with the coadministration of blood/serum/plasma has not been established (see WARNINGS). When administered using a y-type infusion set, DIPRIVAN 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 DIPRIVAN Injectable Emulsion during anesthesia or ICU/MAC sedation is limited. DIPRIVAN 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 DIPRIVAN 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 DIPRIVAN 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. DIPRIVAN Injectable Emulsion is a single access parenteral product (single patient infusion vial) which contains 0.005% disodium edetate to inhibit the rate of growth of microorganisms, up to 12 hours, 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. Do not use if contamination is suspected. Discard unused drug product as directed within the required time limits. 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 lifethreatening illness, and/or death.

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 vials are never to be accessed more than once or used on more than one person.

Diprivan, with EDTA inhibits microbial growth for up to 12 hours, as demonstrated by test data for representative USP microorganisms.

Guidelines for Aseptic Technique for General Anesthesia/MAC Sedation

DIPRIVAN Injectable Emulsion must be prepared for use just prior to initiation of each individual anesthetic/sedative procedure. The vial rubber stopper should be disinfected using 70% isopropyl alcohol. DIPRIVAN Injectable Emulsion should be drawn into a sterile syringe immediately after a vial is opened. When withdrawing DIPRIVAN Injectable Emulsion from vials, a sterile vent spike should be used. The syringe should be labelled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened.

DIPRIVAN Injectable Emulsion must be prepared for single-patient use only. Any unused DIPRIVAN Injectable Emulsion drug product, reservoirs, dedicated administration tubing and/or solutions containing DIPRIVAN Injectable Emulsion must be discarded at the end of the anesthetic procedure or at 12 hours, whichever occurs sooner. The IV line should be flushed every 12 hours and at the end of the anesthetic procedure to remove residual DIPRIVAN Injectable Emulsion.

Guidelines for Aseptic Technique for ICU Sedation

DIPRIVAN Injectable Emulsion must be prepared for single-patient use only.  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 DIPRIVAN Injectable Emulsion.  As with other lipid emulsions, the number of IV 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 DIPRIVAN Injectable Emulsion drug product must be discarded after 12 hours.

If DIPRIVAN Injectable Emulsion is transferred to a syringe prior to administration, it should be drawn into a sterile syringe immediately after a vial is opened.  When withdrawing DIPRIVAN Injectable Emulsion from a vial, a sterile vent spike should be used.  The syringe should be labelled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened.  DIPRIVAN Injectable Emulsion should be discarded and administration lines changed after 12 hours.

Usual Adult Dose for Anesthesia

INDUCTION OF GENERAL ANESTHESIA:
-ADULTS LESS THAN 55 YEARS OF AGE AND CLASSIFIED AS ASA-PS I OR II: 40 mg IV every 10 seconds until induction onset (2 to 2.5 mg/kg)
-CARDIAC ANESTHESIA: 20 mg IV every 10 seconds until induction onset (0.5 to 1.5 mg/kg)
-NEUROSURGICAL PATIENTS: 20 mg IV every 10 seconds until induction onset (1 to 2 mg/kg)

MAINTENANCE OF GENERAL ANESTHESIA (INFUSION):
-ADULTS LESS THAN 55 YEARS OF AGE AND CLASSIFIED AS ASA-PS I OR II: 100 to 200 mcg/kg/min IV (6 to 12 mg/kg/hr)
-CARDIAC ANESTHESIA: Most patients require:
PRIMARY PROPOFOL WITH SECONDARY OPIOID: 100 to 150 mcg/kg/min IV
PRIMARY OPIOID WITH SECONDARY PROPOFOL: 50 to 100 mcg/kg/min IV
-NEUROSURGICAL PATIENTS: 100 to 200 mcg/kg/min (6 to 12 mg/kg/hr)

MAINTENANCE OF GENERAL ANESTHESIA (INTERMITTENT BOLUS):
-ADULTS LESS THAN 55 YEARS OF AGE AND CLASSIFIED AS ASA-PS I OR II: Increments of 20 to 50 mg as needed

INITIATION OF MONITORED ANESTHESIA CARE (MAC) SEDATION:
-ADULTS LESS THAN 55 YEARS OF AGE AND CLASSIFIED AS ASA-PS I OR II: A variable rate infusion technique is preferable over an intermittent bolus technique; most patients require an infusion of 25 to 75 mcg/kg/min IV (1.5 to 4.5 mg/kg/hr) or incremental bolus doses of 10 mg or 20 mg

INITIATION AND MAINTENANCE OF ICU SEDATION IN INTUBATED, MECHANICALLY VENTILATED PATIENTS:
-ADULT PATIENTS: Because of the residual effects of previous anesthetic or sedative agents, in most patients the initial infusion should be 5 mcg/kg/min IV (0.3 mg/kg/hr) for at least 5 minutes; subsequent increments of 5 to 10 mcg/kg/min (0.3 to 0.6 mg/kg/hr) over 5 to 10 minutes may be used until the desired clinical effect is achieved; maintenance rates of 5 to 50 mcg/kg/min IV (0.3 to 3 mg/kg/hr) or higher may be required; administration should not exceed 4 mg/kg/hr IV unless the benefits outweigh the risks

Uses:
-Induction of general anesthesia
-Maintenance of general anesthesia
-Initiation and maintenance of monitored anesthesia care (MAC) sedation
-Intensive care unit (ICU) sedation of intubated, mechanically ventilated patients

Precautions

-Safety and efficacy have not been established in patients younger than 3 years for induction of general anesthesia.
-Safety and efficacy have not been established in patients younger than 2 months for maintenance of general anesthesia.
-Safety and efficacy have not been established in patients younger than 16 years for initiation and maintenance of monitored anesthesia care (MAC) sedation.
-Safety and efficacy have not been established in patients younger than 16 years for intensive care unit (ICU) sedation of intubated, mechanically ventilated patients.

Consult WARNINGS section for additional precautions.

Propofol Breastfeeding Warnings

-Amounts of this drug in milk are very small and are not expected to be absorbed by the infant. -Some experts recommend that women should not breastfeed for 24 hours after administration of this drug and any milk produced during this period should be discarded; however, others say that breastfeeding can be resumed as soon as the mother has recovered sufficiently from general anesthesia to nurse and that discarding milk is unnecessary. -When a combination of anesthetic agents is used for a procedure, the recommendations for the most problematic medication used during the procedure should be followed. -General anesthesia for cesarean section using this drug as a component for induction may delay the onset of lactation.

Use is not recommended; some manufacturers consider this drug to be contraindicated in lactation. Excreted into human milk: Yes (in small amounts) Comment: -The effects in the nursing infant are unknown.

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