Diprivan

Diprivan Manufacturers

• Astrazeneca Pharmaceuticals Lp
  

  ×

  Diprivan | Astrazeneca Pharmaceuticals Lp

  

  ---

  Dosage and rate of administration should be individualized and titrated to the desired effect, according to clinically relevant factors, including preinduction and concomitant medications, age, ASA physical classification, and level of debilitation of the patient.

  The following is abbreviated dosage and administration information which is only intended as a general guide in the use of DIPRIVAN Injectable Emulsion. Prior to administering DIPRIVAN Injectable Emulsion, it is imperative that the physician review and be completely familiar with the specific dosage and administration information detailed in the CLINICAL PHARMACOLOGY - Individualization of Dosage section.

  In the elderly, debilitated, or ASA III/IV patients, rapid bolus doses should not be the method of administration. (See WARNINGS.)

  Intensive Care Unit Sedation:

  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 RETARD THE RATE OF GROWTH OF MICROORGANISMS IN THE EVENT OF ACCIDENTAL EXTRINSIC CONTAMINATION. HOWEVER, DIPRIVAN INJECTABLE EMULSION CAN STILL SUPPORT THE GROWTH OF MICROORGANISMS AS IT IS NOT AN ANTIMICROBIALLY PRESERVED PRODUCT UNDER USP STANDARDS. ACCORDINGLY, STRICT ASEPTIC TECHNIQUE MUST STILL BE ADHERED TO. DO NOT USE IF CONTAMINATION IS SUSPECTED. (See DOSAGE AND ADMINISTRATION, Handling Procedures.)

  DIPRIVAN Injectable Emulsion should be individualized according to the patient's condition and response, blood lipid profile, and vital signs. (See PRECAUTIONS- ICU 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 µg/kg/min (0.3 mg/kg/h). The infusion rate should be increased by increments of 5 to 10 µg/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 µg/kg/min (0.3 to 3 mg/kg/h) or higher. 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 dosage guide.) EVALUATION OF LEVEL OF SEDATION AND ASSESSMENT OF CNS FUNCTION SHOULD BE CARRIED OUT DAILY THROUGHOUT MAINTENANCE TO DETERMINE THE MINIMUM DOSE OF DIPRIVAN INJECTABLE EMULSION REQUIRED FOR SEDATION (SEE CLINICAL TRIALS, ICU SEDATION). Bolus administration of 10 or 20 mg should only be used to rapidly increase depth of sedation in patients where hypotension is not likely to occur. Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension. (See PRECAUTIONS.).

  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.

  At high doses (2-3 grams per day), EDTA has been reported, on rare occasions, to be toxic to the renal tubules. Studies to-date, in patients with normal or impaired renal function have not shown any alteration in renal function with DIPRIVAN Injectable Emulsion containing 0.005% disodium edetate. In patients at risk for renal impairment, urinalysis and urine sediment should be checked before initiation of sedation and then be monitored on alternate days during sedation.

  Close
  No Recall

  More Info
• General Injectables & Vaccines, Inc
  

  ×

  Diprivan | General Injectables & Vaccines, Inc

  

  ---

  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

  Primary Agent Rate Secondary Agent/Rate
  (Following Induction with Primary Agent) DIPRIVAN Injectable Emulsion
  
  OPIOIDa /0.05 to 0.075 mcg/kg/min (no bolus)
  Preindunction
  Anxiolysis
  25 mcg/kg/min
  
  Induction
  0.5 to 1.5 mg/kg
  over 60 sec
  
  Maintenance
  (Titrated to Clinical
  Response)
  100 to 150 mcg/kg/min
  
  OPIOIDb
  DIPRIVAN Injectable Emulsion/50 to 100 mcg/kg/min
  (no bolus)
  Induction
  25 to 50 mcg/kg
  
  Maintenance
  0.2 to 0.3 mcg/kg/min
  
  

  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

  
  INDICATION DOSAGE AND ADMINISTRATION Induction of General Anethesia
  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 of 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.
  (see PRECAUTIONS, Pediatric Use and CLINICAL
  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:
  50-100 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
  (see DOSAGE 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.
  (see PRECAUTIONS, Pediatric Use and CLINICAL
  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, Debilitate, Neurosurgical, or ASA-PS III or IV Patients:
  Most patients require dosages similar to healthy adults.
  Rapid boluses are to be avoided (see WARNINGS)
  Maintenance of MAC Sedation
  Healthy Adults Less Than 55 Years of Age:
  A variable rate infusin technique is preferable over an intermittent bolus
  technique.  Most patients require and 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 (see WARNINGS)
  Initiations 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 mdg/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 (see
  WARNINGS).
  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 portions of DIPRIVAN Injectable Emulsion
  should be discarded after 12 hours because DIPRIVAN Injectable
  Emulsion contains no preservatives and is capable of supporting growth
  of microorganisms (see WARNINGS and 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.

  
  

  
  

  Close
  No Recall

  More Info
• Fresenius Kabi Usa, Llc
  

  ×

  Diprivan | Fresenius Kabi Usa, Llc

  

  ---

  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 (see PRECAUTIONS, Cardiac Anesthesia).

   

                                            Table 4.  Cardiac Anesthesia Techniques

              Primary Agent

              Rate

                       Secondary Agent/Rate

         (Following Induction with Primary Agent)

  
  

  DIPRIVAN Injectable Emulsion

  
  

  OPIOIDa/0.05 to 0.075 mcg/kg/min (no bolus)

              Preinduction

              Anxiolysis

  
  

  25 mcg/kg/min

  
  

              Induction

  0.5 to 1.5 mg/kg

  over 60 sec

  
  

              Maintenance

              (Titrated to Clinical

                Response)

  100 to 150 mcg/kg/min

  
  

  OPIOIDb

  
  

  DIPRIVAN Injectable Emulsion/50 to 100 mcg/kg/min

  (no bolus)

              Induction

  25 to 50 mcg/kg

  
  

              Maintenance

  0.2 to 0.3 mcg/kg/min

  
  

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

  1 mcg 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
  

  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.

  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.)

  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 and DOSAGE 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.  The DIPRIVAN Injectable Emulsion dosage requirement may also be reduced by adequate management of pain with analgesic agents.  As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time (see SUMMARY OF DOSAGE GUIDELINES).  Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN required for sedation (see Clinical Trials, Intensive Care Unit (ICU) Sedation).  Bolus administration of 10 or 20 mg should only be used to rapidly increase depth of sedation in patients where hypotension is not likely to occur.  Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension (see PRECAUTIONS).

  SUMMARY OF DOSAGE GUIDELINES:

  Dosages and rates of administration in the following table should be individualized and titrated to clinical response.  Safety and dosing requirements for induction of anesthesia in pediatric patients have only been established for children 3 years of age or older.  Safety and dosing requirements for the maintenance of anesthesia have only been established for children 2 months of age and older. 

  For complete dosage information, see DOSAGE AND ADMINISTRATION.

  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.

  (see PRECAUTIONS, Pediatric Use and CLINICAL

  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.

  (see DOSAGE 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.

  (see PRECAUTIONS, Pediatric Use and CLINICAL

  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 III or IV Patients:

  Most patients require dosages similar to healthy adults.

  Rapid boluses are to be avoided (see WARNINGS).

  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 (see WARNINGS).

  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 (see

  WARNINGS).

  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 and DOSAGE 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 life-threatening 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.

  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 (see PRECAUTIONS, Cardiac Anesthesia).

   

                                            Table 4.  Cardiac Anesthesia Techniques

              Primary Agent

              Rate

                       Secondary Agent/Rate

         (Following Induction with Primary Agent)

  
  

  DIPRIVAN Injectable Emulsion

  
  

  OPIOIDa/0.05 to 0.075 mcg/kg/min (no bolus)

              Preinduction

              Anxiolysis

  
  

  25 mcg/kg/min

  
  

              Induction

  0.5 to 1.5 mg/kg

  over 60 sec

  
  

              Maintenance

              (Titrated to Clinical

                Response)

  100 to 150 mcg/kg/min

  
  

  OPIOIDb

  
  

  DIPRIVAN Injectable Emulsion/50 to 100 mcg/kg/min

  (no bolus)

              Induction

  25 to 50 mcg/kg

  
  

              Maintenance

  0.2 to 0.3 mcg/kg/min

  
  

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

  1 mcg 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
  

  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.

  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.)

  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 and DOSAGE 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.  The DIPRIVAN Injectable Emulsion dosage requirement may also be reduced by adequate management of pain with analgesic agents.  As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time (see SUMMARY OF DOSAGE GUIDELINES).  Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN required for sedation (see Clinical Trials, Intensive Care Unit (ICU) Sedation).  Bolus administration of 10 or 20 mg should only be used to rapidly increase depth of sedation in patients where hypotension is not likely to occur.  Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension (see PRECAUTIONS).

  SUMMARY OF DOSAGE GUIDELINES:

  Dosages and rates of administration in the following table should be individualized and titrated to clinical response.  Safety and dosing requirements for induction of anesthesia in pediatric patients have only been established for children 3 years of age or older.  Safety and dosing requirements for the maintenance of anesthesia have only been established for children 2 months of age and older. 

  For complete dosage information, see DOSAGE AND ADMINISTRATION.

  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.

  (see PRECAUTIONS, Pediatric Use and CLINICAL

  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.

  (see DOSAGE 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.

  (see PRECAUTIONS, Pediatric Use and CLINICAL

  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 III or IV Patients:

  Most patients require dosages similar to healthy adults.

  Rapid boluses are to be avoided (see WARNINGS).

  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 (see WARNINGS).

  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 (see

  WARNINGS).

  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 and DOSAGE 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 life-threatening 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.

  Close
  No Recall

  More Info
• Fresenius Kabi Usa, Llc
  

  ×

  Diprivan | Fresenius Kabi Usa, Llc

  

  ---

  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 (see PRECAUTIONS, Cardiac Anesthesia).

                                                   Table 4.  Cardiac Anesthesia Techniques

              Primary Agent

              Rate

                       Secondary Agent/Rate

         (Following Induction with Primary Agent)

  
  

  DIPRIVAN Injectable Emulsion

  
  

  OPIOIDa/0.05 to 0.075 mcg/kg/min (no bolus)

              Preinduction

              Anxiolysis

  
  

  25 mcg/kg/min

  
  

              Induction

  0.5 to 1.5 mg/kg

  over 60 sec

  
  

              Maintenance

              (Titrated to Clinical

                Response)

  100 to 150 mcg/kg/min

  
  

  OPIOIDb

  
  

  DIPRIVAN Injectable Emulsion/50 to 100 mcg/kg/min

  (no bolus)

              Induction

  25 to 50 mcg/kg

  
  

              Maintenance

  0.2 to 0.3 mcg/kg/min

  
  

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

  1 mcg 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
  

  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.

  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.)

  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 and DOSAGE 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.  The DIPRIVAN Injectable Emulsion dosage requirement may also be reduced by adequate management of pain with analgesic agents.  As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time (see SUMMARY OF DOSAGE GUIDELINES).  Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN required for sedation (see Clinical Trials, Intensive Care Unit (ICU) Sedation).  Bolus administration of 10 or 20 mg should only be used to rapidly increase depth of sedation in patients where hypotension is not likely to occur.  Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension (see PRECAUTIONS).

  SUMMARY OF DOSAGE GUIDELINES:

  Dosages and rates of administration in the following table should be individualized and titrated to clinical response.  Safety and dosing requirements for induction of anesthesia in pediatric patients have only been established for children 3 years of age or older.  Safety and dosing requirements for the maintenance of anesthesia have only been established for children 2 months of age and older. 

  For complete dosage information, see DOSAGE AND ADMINISTRATION.

  
  

  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.

  (see PRECAUTIONS, Pediatric Use and CLINICAL

  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.

  (see DOSAGE 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.

  (see PRECAUTIONS, Pediatric Use and CLINICAL

  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 III or IV Patients:

  Most patients require dosages similar to healthy adults.

  Rapid boluses are to be avoided (see WARNINGS).

  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 (see WARNINGS).

  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 (see

  WARNINGS).

  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 and DOSAGE 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 life-threatening 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 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.

  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 (see PRECAUTIONS, Cardiac Anesthesia).

                                                   Table 4.  Cardiac Anesthesia Techniques

              Primary Agent

              Rate

                       Secondary Agent/Rate

         (Following Induction with Primary Agent)

  
  

  DIPRIVAN Injectable Emulsion

  
  

  OPIOIDa/0.05 to 0.075 mcg/kg/min (no bolus)

              Preinduction

              Anxiolysis

  
  

  25 mcg/kg/min

  
  

              Induction

  0.5 to 1.5 mg/kg

  over 60 sec

  
  

              Maintenance

              (Titrated to Clinical

                Response)

  100 to 150 mcg/kg/min

  
  

  OPIOIDb

  
  

  DIPRIVAN Injectable Emulsion/50 to 100 mcg/kg/min

  (no bolus)

              Induction

  25 to 50 mcg/kg

  
  

              Maintenance

  0.2 to 0.3 mcg/kg/min

  
  

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

  1 mcg 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
  

  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.

  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.)

  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 and DOSAGE 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.  The DIPRIVAN Injectable Emulsion dosage requirement may also be reduced by adequate management of pain with analgesic agents.  As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time (see SUMMARY OF DOSAGE GUIDELINES).  Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN required for sedation (see Clinical Trials, Intensive Care Unit (ICU) Sedation).  Bolus administration of 10 or 20 mg should only be used to rapidly increase depth of sedation in patients where hypotension is not likely to occur.  Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension (see PRECAUTIONS).

  SUMMARY OF DOSAGE GUIDELINES:

  Dosages and rates of administration in the following table should be individualized and titrated to clinical response.  Safety and dosing requirements for induction of anesthesia in pediatric patients have only been established for children 3 years of age or older.  Safety and dosing requirements for the maintenance of anesthesia have only been established for children 2 months of age and older. 

  For complete dosage information, see DOSAGE AND ADMINISTRATION.

  
  

  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.

  (see PRECAUTIONS, Pediatric Use and CLINICAL

  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.

  (see DOSAGE 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.

  (see PRECAUTIONS, Pediatric Use and CLINICAL

  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 III or IV Patients:

  Most patients require dosages similar to healthy adults.

  Rapid boluses are to be avoided (see WARNINGS).

  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 (see WARNINGS).

  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 (see

  WARNINGS).

  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 and DOSAGE 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 life-threatening 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 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.

  Close
  No Recall

  More Info
• Fresenius Kabi Usa, Llc
  

  ×

  Diprivan | Fresenius Kabi Usa, Llc

  

  ---

  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 (see PRECAUTIONS, Cardiac Anesthesia).

   

                                                                Table 4.  Cardiac Anesthesia Techniques

              Primary Agent

              Rate

                       Secondary Agent/Rate

         (Following Induction with Primary Agent)

  
  

  DIPRIVAN Injectable Emulsion

  
  

  OPIOIDa/0.05 to 0.075 mcg/kg/min (no bolus)

              Preinduction

              Anxiolysis

  
  

  25 mcg/kg/min

  
  

              Induction

  0.5 to 1.5 mg/kg

  over 60 sec

  
  

              Maintenance

              (Titrated to Clinical

                Response)

  100 to 150 mcg/kg/min

  
  

  OPIOIDb

  
  

  DIPRIVAN Injectable Emulsion/50 to 100 mcg/kg/min

  (no bolus)

              Induction

  25 to 50 mcg/kg

  
  

              Maintenance

  0.2 to 0.3 mcg/kg/min

  
  

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

  1 mcg 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
  

  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.

  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.)

  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 and DOSAGE 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.  The DIPRIVAN Injectable Emulsion dosage requirement may also be reduced by adequate management of pain with analgesic agents.  As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time (see SUMMARY OF DOSAGE GUIDELINES).  Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN required for sedation (see Clinical Trials, Intensive Care Unit (ICU) Sedation).  Bolus administration of 10 or 20 mg should only be used to rapidly increase depth of sedation in patients where hypotension is not likely to occur.  Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension (see PRECAUTIONS).

  SUMMARY OF DOSAGE GUIDELINES:

  Dosages and rates of administration in the following table should be individualized and titrated to clinical response.  Safety and dosing requirements for induction of anesthesia in pediatric patients have only been established for children 3 years of age or older.  Safety and dosing requirements for the maintenance of anesthesia have only been established for children 2 months of age and older. 

  For complete dosage information, see DOSAGE AND ADMINISTRATION.

  
  

  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.

  (see PRECAUTIONS, Pediatric Use and CLINICAL 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.

  (see DOSAGE 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.

  (see PRECAUTIONS, Pediatric Use and CLINICAL 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 III or IV Patients:

  Most patients require dosages similar to healthy adults.

  Rapid boluses are to be avoided (see WARNINGS).

  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 (see WARNINGS).

  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 (see WARNINGS).

   

  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 and DOSAGE 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 life-threatening 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 portions of 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 informaiton 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.

  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 (see PRECAUTIONS, Cardiac Anesthesia).

   

                                                                Table 4.  Cardiac Anesthesia Techniques

              Primary Agent

              Rate

                       Secondary Agent/Rate

         (Following Induction with Primary Agent)

  
  

  DIPRIVAN Injectable Emulsion

  
  

  OPIOIDa/0.05 to 0.075 mcg/kg/min (no bolus)

              Preinduction

              Anxiolysis

  
  

  25 mcg/kg/min

  
  

              Induction

  0.5 to 1.5 mg/kg

  over 60 sec

  
  

              Maintenance

              (Titrated to Clinical

                Response)

  100 to 150 mcg/kg/min

  
  

  OPIOIDb

  
  

  DIPRIVAN Injectable Emulsion/50 to 100 mcg/kg/min

  (no bolus)

              Induction

  25 to 50 mcg/kg

  
  

              Maintenance

  0.2 to 0.3 mcg/kg/min

  
  

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

  1 mcg 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
  

  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.

  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.)

  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 and DOSAGE 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.  The DIPRIVAN Injectable Emulsion dosage requirement may also be reduced by adequate management of pain with analgesic agents.  As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time (see SUMMARY OF DOSAGE GUIDELINES).  Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN required for sedation (see Clinical Trials, Intensive Care Unit (ICU) Sedation).  Bolus administration of 10 or 20 mg should only be used to rapidly increase depth of sedation in patients where hypotension is not likely to occur.  Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension (see PRECAUTIONS).

  SUMMARY OF DOSAGE GUIDELINES:

  Dosages and rates of administration in the following table should be individualized and titrated to clinical response.  Safety and dosing requirements for induction of anesthesia in pediatric patients have only been established for children 3 years of age or older.  Safety and dosing requirements for the maintenance of anesthesia have only been established for children 2 months of age and older. 

  For complete dosage information, see DOSAGE AND ADMINISTRATION.

  
  

  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.

  (see PRECAUTIONS, Pediatric Use and CLINICAL 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.

  (see DOSAGE 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.

  (see PRECAUTIONS, Pediatric Use and CLINICAL 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 III or IV Patients:

  Most patients require dosages similar to healthy adults.

  Rapid boluses are to be avoided (see WARNINGS).

  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 (see WARNINGS).

  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 (see WARNINGS).

   

  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 and DOSAGE 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 life-threatening 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 portions of 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 informaiton 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.

  Close
  No Recall

  More Info
• Fresenius Kabi Usa, Llc
  

  ×

  Diprivan | Fresenius Kabi Usa, Llc

  

  ---

  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 (see PRECAUTIONS, Cardiac Anesthesia).

                                                   Table 4.  Cardiac Anesthesia Techniques

              Primary Agent

              Rate

                       Secondary Agent/Rate

         (Following Induction with Primary Agent)

  
  

  DIPRIVAN Injectable Emulsion

  
  

  OPIOIDa/0.05 to 0.075 mcg/kg/min (no bolus)

              Preinduction

              Anxiolysis

  
  

  25 mcg/kg/min

  
  

              Induction

  0.5 to 1.5 mg/kg

  over 60 sec

  
  

              Maintenance

              (Titrated to Clinical

                Response)

  100 to 150 mcg/kg/min

  
  

  OPIOIDb

  
  

  DIPRIVAN Injectable Emulsion/50 to 100 mcg/kg/min

  (no bolus)

              Induction

  25 to 50 mcg/kg

  
  

              Maintenance

  0.2 to 0.3 mcg/kg/min

  
  

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

  1 mcg 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
  

  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.

  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.)

  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 and DOSAGE 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.  The DIPRIVAN Injectable Emulsion dosage requirement may also be reduced by adequate management of pain with analgesic agents.  As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time (see SUMMARY OF DOSAGE GUIDELINES).  Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN required for sedation (see Clinical Trials, Intensive Care Unit (ICU) Sedation).  Bolus administration of 10 or 20 mg should only be used to rapidly increase depth of sedation in patients where hypotension is not likely to occur.  Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension (see PRECAUTIONS).

  SUMMARY OF DOSAGE GUIDELINES:

  Dosages and rates of administration in the following table should be individualized and titrated to clinical response.  Safety and dosing requirements for induction of anesthesia in pediatric patients have only been established for children 3 years of age or older.  Safety and dosing requirements for the maintenance of anesthesia have only been established for children 2 months of age and older. 

  For complete dosage information, see DOSAGE AND ADMINISTRATION.

  
  

  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.

  (see PRECAUTIONS, Pediatric Use and CLINICAL

  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.

  (see DOSAGE 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.

  (see PRECAUTIONS, Pediatric Use and CLINICAL

  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 III or IV Patients:

  Most patients require dosages similar to healthy adults.

  Rapid boluses are to be avoided (see WARNINGS).

  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 (see WARNINGS).

  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 (see

  WARNINGS).

  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 and DOSAGE 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 life-threatening 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 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.

  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 (see PRECAUTIONS, Cardiac Anesthesia).

                                                   Table 4.  Cardiac Anesthesia Techniques

              Primary Agent

              Rate

                       Secondary Agent/Rate

         (Following Induction with Primary Agent)

  
  

  DIPRIVAN Injectable Emulsion

  
  

  OPIOIDa/0.05 to 0.075 mcg/kg/min (no bolus)

              Preinduction

              Anxiolysis

  
  

  25 mcg/kg/min

  
  

              Induction

  0.5 to 1.5 mg/kg

  over 60 sec

  
  

              Maintenance

              (Titrated to Clinical

                Response)

  100 to 150 mcg/kg/min

  
  

  OPIOIDb

  
  

  DIPRIVAN Injectable Emulsion/50 to 100 mcg/kg/min

  (no bolus)

              Induction

  25 to 50 mcg/kg

  
  

              Maintenance

  0.2 to 0.3 mcg/kg/min

  
  

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

  1 mcg 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
  

  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.

  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.)

  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 and DOSAGE 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.  The DIPRIVAN Injectable Emulsion dosage requirement may also be reduced by adequate management of pain with analgesic agents.  As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time (see SUMMARY OF DOSAGE GUIDELINES).  Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN required for sedation (see Clinical Trials, Intensive Care Unit (ICU) Sedation).  Bolus administration of 10 or 20 mg should only be used to rapidly increase depth of sedation in patients where hypotension is not likely to occur.  Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension (see PRECAUTIONS).

  SUMMARY OF DOSAGE GUIDELINES:

  Dosages and rates of administration in the following table should be individualized and titrated to clinical response.  Safety and dosing requirements for induction of anesthesia in pediatric patients have only been established for children 3 years of age or older.  Safety and dosing requirements for the maintenance of anesthesia have only been established for children 2 months of age and older. 

  For complete dosage information, see DOSAGE AND ADMINISTRATION.

  
  

  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.

  (see PRECAUTIONS, Pediatric Use and CLINICAL

  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.

  (see DOSAGE 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.

  (see PRECAUTIONS, Pediatric Use and CLINICAL

  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 III or IV Patients:

  Most patients require dosages similar to healthy adults.

  Rapid boluses are to be avoided (see WARNINGS).

  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 (see WARNINGS).

  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 (see

  WARNINGS).

  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 and DOSAGE 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 life-threatening 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 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.

  Close
  No Recall

  More Info