Diprivan

Mechanism of Action

Short-acting, lipophilic sedative/hypnotic; causes global CNS depression, presumably through agonist actions on GABAa receptors

Absorption

Onset: 30-45 sec

Duration: 3-10 min (dose-dependent duration; dissipation is function of drug redistribution from CNS)

Distribution

Protein bound: 97-99%

Metabolism

Metabolized by hepatic conjugation to inactive compound

Elimination

Half-life: 40 min (initial); 24-72 hr (after 10-day infusion)

Excretion: Urine, feces

Common Side Effects of Propofol

Common side effects of propofol include:

• High triglycerides (because of the potential for hypertriglyceridemia, serum triglyceride levels should be obtained prior to initiation of therapy and every 3 to 7 days thereafter in patients who will be on propofol for more than 48 hours)
• Rash
• Itching

Serious Side Effects and Reactions

The following are serious effects that may occur when given propofol:

• Irritation of the skin and veins where the drug was injected
• Breathing suppression, or trouble breathing
• Lung dysfunction, such as a drop in pH (respiratory acidosis) or development of ventilator failure
• A severe allergic reaction, causing swelling of the tongue and uvula, throat closing up, red and swollen eyes, severe rash (hives)
• A rare and usually deadly condition known as propofol infusion syndrome, where kidneys fail, muscles breakdown, high levels of proteins in the blood, and the heart stops working properly
• Slow heartbeat, "flatlining"; of the heartbeat (asystole), or heart attack
• Low blood pressure
• Unintentional movement of the muscles or severe spasms where the spine curls backwards with the head towards the heels
• Seizures
• Inflammation of the pancreas (pancreatitis)
• Low count of granulocytes in the blood (granulocytopenia)
• Low count of clotting cells (thrombocytopenia) or more blood clotting than usual (thrombosis)
• Chills, fever, or body aches

DIPRIVAN® (Propofol) Injectable Emulsion, USP is a sterile, nonpyrogenic emulsion containing 10 mg/mL of propofol suitable for intravenous administration. Propofol is chemically described as 2,6 diisopropylphenol. The structural formula is:

C12H18O     M.W. 178.27

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); and disodium edetate (0.005%); with sodium hydroxide to adjust pH. DIPRIVAN Injectable Emulsion, USP is isotonic and has a pH of 7 to 8.5.

Since propofol is given by a healthcare professional in a controlled setting, you are not likely to miss a dose.

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 DIPRIVAN 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 DIPRIVAN 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 DIPRIVAN Injectable Emulsion 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 DIPRIVAN 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 DIPRIVAN 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.

Incidence greater than 1% - Probably Causally Related

Incidence less than 1% - Probably Causally Related

Incidence less than 1% - Causal Relationship Unknown

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.

Read the entire FDA prescribing information for Diprivan (Propofol)

Metabolized mainly by CYP2B6 and to a lesser extent by CYP2C9.179

Inhibits CYP isoenzymes 1A1, 1A2, 2B1, 2C9, 2D6, 2E1, and 3A4.72 73

Drugs Metabolized by or Affecting Hepatic Microsomal Enzymes

Possibility of interactions; however, because of the increased value for hepatic extraction (50 µM) of propofol,179 there have been relatively few clinically important interactions with drugs metabolized by or affecting CYP isoenzymes.71 192

Specific Drugs

Absorption

Onset

Following a single IV injection, onset as determined by time to unconsciousness (i.e., loss of response to voice command) usually ranges from 15–30 seconds and depends on the administration rate.6 18 20 117

Duration

Following a single rapid IV injection, duration of action usually is about 5–10 minutes.20 117

Plasma Concentrations

Following a single rapid IV injection, most patients will awaken as blood propofol concentrations decline to approximately 1 mcg/mL; improvement of psychomotor performance (as measured by patient response to verbal command) usually occurs at concentrations of 0.5–0.6 mcg/mL.9

Distribution

Extent

Highly lipophilic; rapidly distributed from plasma into body tissues, including the CNS.5 6 9 10 117 Following IV administration, widely distributed, initially to highly perfused tissues (e.g., brain), then to lean muscle tissue, and finally to fat tissue.5 6 7 9 117 Equilibration between blood and CSF occurs within about 2–3 minutes.5 6 9 10 117

Readily crosses the placenta.1 2 6 19 31 32

Distributed into milk in low concentrations.1 2 6 19

Plasma Protein Binding

Approximately 95–99% (mainly albumin and hemoglobin).5 6 9 18 Binding appears to be independent of plasma propofol concentration.6

Elimination

Metabolism

Rapidly and extensively metabolized in the liver1 2 5 6 8 9 20 179 by CYP2B6 and to a lesser extent by CYP2C9.179

Elimination Route

Excreted mainly in urine, principally as sulfate and/or glucuronide conjugates;6 9 10 20 <0.3% of a dose is eliminated unchanged in urine,5 6 9 10 and <2% of a dose is eliminated in feces.8

Half-life

Triphasic;1 2 5 6 10 45 following a single rapid injection or a continuous infusion, half-life averages 1.8–9.5 minutes in the initial distribution phase, 21–70 minutes in the second redistribution phase, and 1.5–31 hours in the terminal elimination phase.5 6 8 9 45 46

Terminal plasma half-life may not affect clinical outcome as substantially as the distribution half-life does, since rapid awakening from anesthesia occurs once blood propofol concentrations decrease below the range required for hypnosis.6 7

Special Populations

In geriatric patients, clearance may be reduced substantially,5 6 8 9 10 18 106 possibly because of decreased hepatic metabolism resulting from decreased hepatic blood flow.6

Obese patients have a substantially higher clearance than leaner individuals; mean total body clearance appears to be proportional to body weight.5 6 180 192

Chronic renal failure or chronic hepatic cirrhosis does not appear to affect pharmacokinetics of propofol;1 2 5 6 7 8 9 10 not studied in patients with acute renal or hepatic failure.1

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

• It is used to put you to sleep for surgery.
• It is used to cause sleep during care.
• It may be given to you for other reasons. Talk with the doctor.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take Diprivan or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Diprivan (propofol). This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

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

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

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 Diprivan 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 Diprivan 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 Diprivan Injectable Emulsion 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 Diprivan 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 Diprivan 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.

Incidence greater than 1% - Probably Causally Related

Events without an * or % had an icidence of 1% to 3%

*Incidence of events 3% to 10%

Incidence less than 1% - Probably Causally Related

Incidence less than 1% - Causal Relationship Unknown

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.

Shake well before use.  Do not use if there is evidence of excessive creaming or aggregation, if large droplets are visible, or if there are other forms of phase separation indicating that the stability of the product has been compromised.  Slight creaming, which should disappear after shaking, may be visible upon prolonged standing.

When administering Diprivan Injectable Emulsion by infusion, syringe or volumetric pumps are recommended to provide controlled infusion rates.  When infusing Diprivan Injectable Emulsion to patients undergoing magnetic resonance imaging, metered control devices may be utilized if mechanical pumps are impractical.

Changes in vital signs 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 Diprivan Injectable Emulsion.  

For minor surgical procedures (e.g., body surface) nitrous oxide (60% to 70%) can be combined with a variable rate Diprivan 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 Diprivan Injectable Emulsion and/or opioids should be increased in order to provide adequate anesthesia.

Infusion rates should always be titrated downward in the absence of clinical signs of light anesthesia until a mild response to surgical stimulation is obtained in order to avoid administration of Diprivan Injectable Emulsion at rates higher than are clinically necessary.  Generally, rates of 50 to 100 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 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 Diprivan Injectable Emulsion for induction when unpremedicated or when premedicated with oral benzodiazepines or intramuscular opioids.  For induction, Diprivan Injectable Emulsion should be titrated (approximately 40 mg every 10 seconds) against the response of the patient until the clinical signs show the onset of anesthesia.  As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of Diprivan Injectable Emulsion.

Elderly, Debilitated, or ASA-PS III or IV Patients

It is important to be familiar and experienced with the intravenous use of Diprivan 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 Diprivan Injectable Emulsion for induction of anesthesia according to their condition and responses.  A rapid bolus should not be used, as this will increase the likelihood of undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation (see DOSAGE AND ADMINISTRATION).

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 Diprivan 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 Diprivan 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 Diprivan Injectable Emulsion to pediatric patients.  Boluses of Diprivan 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 Diprivan Injectable Emulsion for induction of anesthesia, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 to 2 mg/kg) (see PRECAUTIONS and DOSAGE AND ADMINISTRATION

Cardiac Anesthesia

Diprivan Injectable Emulsion has been well‑studied in patients with coronary artery disease, but experience in patients with hemodynamically significant valvular or congenital heart disease is limited.  As with other anesthetic and sedative-hypnotic agents, Diprivan Injectable Emulsion in healthy patients causes a decrease in blood pressure that is secondary to decreases in preload (ventricular filling volume at the end of the diastole) and afterload (arterial resistance at the beginning of the systole).  The magnitude of these changes is proportional to the blood and effect site concentrations achieved.  These concentrations depend upon the dose and speed of the induction and maintenance infusion rates.

In addition, lower heart rates are observed during maintenance with Diprivan Injectable Emulsion, possibly due to reduction of the sympathetic activity and/or resetting of the baroreceptor reflexes.  Therefore, anticholinergic agents should be administered when increases in vagal tone are anticipated.

As with other anesthetic agents, Diprivan Injectable Emulsion reduces myocardial oxygen consumption.  Further studies are needed to confirm and delineate the extent of these effects on the myocardium and the coronary vascular system.  

Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary Diprivan Injectable Emulsion maintenance infusion rates and therapeutic blood concentrations when compared to non‑narcotic (lorazepam) premedication.  The rate of Diprivan Injectable Emulsion administration should be determined based on the patient's premedication and adjusted according to clinical responses.  

A rapid bolus induction should be avoided.  A slow rate of approximately 20 mg every 10 seconds until induction onset (0.5 to 1.5 mg/kg) should be used.  In order to assure adequate anesthesia, when Diprivan Injectable Emulsion is used as the primary agent, maintenance infusion rates should not be less than 100 mcg/kg/min and should be supplemented with analgesic levels of continuous opioid administration.  When an opioid is used as the primary agent, Diprivan Injectable Emulsion maintenance rates should not be less than 50 mcg/kg/min, and care should be taken to ensure amnesia.  Higher doses of Diprivan Injectable Emulsion will reduce the opioid requirements (see Table 4).  When Diprivan Injectable Emulsion is used as the primary anesthetic, it should not be administered with the high-dose opioid technique as this may increase the likelihood of hypotension (seePRECAUTIONS, Cardiac Anesthesia).

Table 4.  Cardiac Anesthesia Techniques

OPIOIDa is defined in terms of fentanyl equivalents, i.e.,

1mcg of fentanyl = 5 mcg of alfentanil (for bolus)

                         = 10 mcg of alfentanil (for maintenance)

                         or

                         = 0.1 mcg of sufentanil

bCare should be taken to ensure amnesia.

Maintenance of General Anesthesia

Adult Patients

In adults, anesthesia can be maintained by administering Diprivan Injectable Emulsion by infusion or intermittent IV bolus injection.  The patient's clinical response will determine the infusion rate or the amount and frequency of incremental injections.

Continuous Infusion

Diprivan Injectable Emulsion 100 to 200 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 Diprivan Injectable Emulsion should immediately follow the induction dose in order to provide satisfactory or continuous anesthesia during the induction phase.  During this initial period following the induction dose, higher rates of infusion are generally required (150 to 200 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 Diprivan Injectable Emulsion 25 mg (2.5 mL) to 50 mg (5 mL) may be administered with nitrous oxide in adult patients undergoing general surgery.  The incremental boluses should be administered when changes in vital signs indicate a response to surgical stimulation or light anesthesia.

Pediatric Patients

Diprivan 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 Diprivan 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.  Diprivan 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 Table 2 Clinical Trials.)

Diprivan Injectable Emulsion has been used with a variety of agents commonly used in anesthesia such as atropine, scopolamine, glycopyrrolate, diazepam, depolarizing and nondepolarizing muscle relaxants, and opioid analgesics, as well as with inhalational and regional anesthetic agents.

In the elderly, debilitated, or ASA-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 Diprivan Injectable Emulsion is administered for MAC sedation, rates of administration should be individualized and titrated to clinical response.  In most patients, the rates of Diprivan Injectable Emulsion administration will be in the range of 25 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 Diprivan 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 Diprivan Injectable Emulsion is administered slowly over 3 to 5 minutes, most patients will be adequately sedated, and the peak drug effect can be achieved while minimizing undesirable cardiorespiratory effects occurring at high plasma levels.

In the elderly, debilitated, or ASA-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 to 5 minutes and the dosage of Diprivan Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

Maintenance of MAC Sedation

For maintenance of sedation, a variable rate infusion method is preferable over an intermittent bolus dose method.  With the variable rate infusion method, patients will generally require maintenance rates of 25 to 75 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 Diprivan Injectable Emulsion at rates higher than are clinically necessary.

If the intermittent bolus dose method is used, increments of Diprivan Injectable Emulsion 10 mg (1 mL) or 20 mg (2 mL) can be administered and titrated to desired 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 Diprivan Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

Diprivan Injectable Emulsion can be administered as the sole agent for maintenance of MAC sedation during surgical/diagnostic procedures.  When Diprivan Injectable Emulsion sedation is supplemented with opioid and/or benzodiazepine medications, these agents increase the sedative and respiratory effects of Diprivan Injectable Emulsion and may also result in a slower recovery profile (see PRECAUTIONS, Drug Interactions).

ICU Sedation

(See WARNINGS andDOSAGE AND ADMINISTRATION, Handling Procedures)

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 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.  Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS). 

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).

Diprivan 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 be allowed 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.  Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS.  Dosages of Diprivan Injectable Emulsion should be reduced in patients who have received large dosages of narcotics.  Conversely, the Diprivan 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 GUIDLINES).  Evaluation of level of sedation and assessment of cns function should be carried out daily throughout maintenance to determine the minimum dose of Diprivan required for sedation (see Clinical Trials, Intensive Care Unit (ICU).  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 Diprivan, it is recommended that it be administered prior to Diprivan administration or that it be added to Diprivan 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 DEPENDANCE).

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 inhibit the rate of growth of microogranisms, up to 12 hours, in the even 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 limits (see DOSAGE AND ADMINISTRATION, Handling Procedures).  There have been reports in which the 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.

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 should be prepared for use just prior to initiation of each individual anesthetic/sedative procedure.  The vial syringe rubber stopper should be disinfected using 70% isopropyl alcohol.  Diprivan Injectable Emulsion should be drawn into sterile syringes immediately after vials are opened.  When withdrawing Diprivan Injectable Emulsion 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.

Diprivan Injectable Emulsion should be prepared for single‑patient use only.  Any unused portions of Diprivan Injectable Emulsion, 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 should be prepared for single-patient use only.  When Diprivan 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 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 portions of Diprivan Injectable Emulsion must be discarded after 12 hours.

If Diprivan 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.

Diprivan can cause severe drowsiness or dizziness, which may last for several hours. You will need someone to drive you home after your surgery or procedure. Do not drive yourself or do anything that requires you to be awake and alert for at least 24 hours after you have been treated with Diprivan.

Applies to propofol: intravenous emulsion

Cardiovascular

Very common (10% or more): Hypotension (up to 75%)
Common (1% to 10%): Hypertension, bradycardia
Uncommon (0.1% to 1%): Arrhythmias, tachycardia, extrasystole
Rare (0.01% to 0.1%): Pulmonary edema, asystole, syncope, perioperative arrhythmias, cardiac arrest
Very rare (less than 0.01%): Cardiac failure, pulmonary edema
Frequency not reported: Cardiac arrhythmia[Ref]

Dermatologic

Very common (10% or more): Pruritus (up to 28%)
Common (1% to 10%): Transient flush, rash[Ref]

Gastrointestinal

Common (1% to 10%): Nausea, vomiting
Very rare (less than 0.01%): Pancreatitis, abdominal cramps[Ref]

Genitourinary

Rare (Less than 0.1%): Discoloration of the urine following prolonged use[Ref]

Hepatic

Frequency not reported: Hepatomegaly[Ref]

Hypersensitivity

Rare (0.01% to 0.1%): Anaphylaxis, in some cases with angioedema, bronchospasm, erythema, and hypotension (these reactions have been reported to respond to adrenaline)[Ref]

Local

Common (1% to 10%): Pain during injection (burning, tingling/slinging)
Very rare (less than 0.01%): Tissue necrosis following accidental extravascular administration[Ref]

Metabolic

Very rare (less than 0.01%): Metabolic acidosis, hyperkalemia, hyperlipidemia[Ref]

Musculoskeletal

Very rare (less than 0.01%): Rhabdomyolysis (when administered at doses greater than 4 mg/kg/hour for ICU sedation)[Ref]

Nervous system

Very common (10% or more): Paresthesia (up to 74%), excitation phenomena such as involuntary movements, twitches, tremors, hypertonus, hiccup
Common (1% to 10%): Headache, shivering
Rare (0.01% to 0.1%): Convulsions and seizures of the epileptic type
Very rare (less than 0.01%): Postoperative unconsciousness
Frequency not reported: Involuntary movements[Ref]

Paresthesias (including burning, tingling, stinging) and/or pruritus, usually manifested in the perineal region, were the most frequently recorded adverse reactions in clinical trials. Paresthesias and pruritus generally occurred within 5 minutes after administration of the initial dose and were generally transient and mild to moderate in intensity. The pharmacologic basis of these sensory phenomena is unknown. No pretreatments, including the use of nonsteroidal anti-inflammatory drugs, opioids, or lidocaine, are known to have an effect on or to reduce the incidence of these sensations.[Ref]

Respiratory

Very common (10% or more): Hypoxemia (up to 11%)
Common (1% to 10%): Procedural pain (bronchoscopy), transient apnea, cough
Very rare (less than 0.01%): Pulmonary edema, hiccough[Ref]

Renal

Very rare (less than 0.01%): Renal failure[Ref]

Hematologic

Common (1% to 10%): Thrombosis, phlebitis[Ref]

Some side effects of Diprivan may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.