Diprivan Dosage

Important Dosage and Administration Information

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

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. Do not use if there is evidence of separation of the phases of the emulsion.

DIPRIVAN with EDTA inhibits microbial growth for up to 12 hours, as demonstrated by test data for representative USP microorganisms. Product is packaged under nitrogen.

For general anesthesia or monitored anesthesia care (MAC) sedation, DIPRIVAN should be administered only by persons trained in the administration of general anesthesia and not involved in the conduct of the surgical/diagnostic procedure. Sedated patients should be continuously monitored, and equipment for maintaining a patent airway, providing artificial ventilation, administering supplemental oxygen, and instituting cardiovascular resuscitation must be immediately available. Patients should be continuously monitored for early signs of hypotension, apnea, airway obstruction, and/or oxygen desaturation. These cardiorespiratory effects are more likely to occur following rapid bolus administration, especially in the elderly, debilitated, or ASA-PS III or IV patients.

For sedation of intubated, mechanically ventilated adult patients in the Intensive Care Unit, DIPRIVAN should be administered only by persons skilled in the management of critically ill patients and trained in cardiovascular resuscitation and airway management.

Guidelines for Aseptic Technique for General Anesthesia/MAC Sedation

DIPRIVAN 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 should be drawn into a sterile syringe immediately after a vial is opened. When withdrawing DIPRIVAN 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 must be prepared for single dose only. Any unused DIPRIVAN drug product, reservoirs, dedicated administration tubing and/or solutions containing DIPRIVAN must be discarded at the end of the anesthetic procedure or at 12 hours, whichever occurs sooner. The intravenous line should be flushed every 12 hours and at the end of the anesthetic procedure to remove residual DIPRIVAN..

Guidelines for Aseptic Technique for ICU Sedation

DIPRIVAN must be prepared for single dose 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. As with other lipid emulsions, the number of intravenous 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 drug product must be discarded after 12 hours.

If DIPRIVAN 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 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 should be discarded and administration lines changed after 12 hours.

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

Dilution Prior to Administration

DIPRIVAN 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 with the coadministration of blood/serum/plasma has not been established.

When administered using a y-type infusion set, DIPRIVAN has been shown to be compatible with the following intravenous fluids:

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5% Dextrose Injection, USP

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Lactated Ringers Injection, USP

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Lactated Ringers and 5% Dextrose Injection

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5% Dextrose and 0.45% Sodium Chloride Injection, USP

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5% Dextrose and 0.2% Sodium Chloride Injection, USP.

Administration with Pumps

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

Administration with Filters

Clinical experience with the use of in-line filters and DIPRIVAN during anesthesia or ICU/MAC sedation is limited. DIPRIVAN 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 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.

Induction of General Anesthesia for Patients Greater than or Equal to 3 Years of Age

Adult Patients

Most adult patients under 65 years of age and classified as ASA-PS I or II require 2 mg/kg to 2.5 mg/kg of DIPRIVAN. For induction, whether administered by infusion or intravenous injection the dose of DIPRIVAN to the patient should be titrated against the response of the patient and until there are clinical signs consistent with the onset of anesthesia. As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication may impact the dose of DIPRIVAN required for induction of general anesthesia.

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

Due to the reduced clearance and higher blood concentrations, most elderly, debilitated, or ASA-PS III or IV patients require approximately 1 mg/kg to 1.5 mg/kg of DIPRIVAN for induction of anesthesia. For induction, whether administered by infusion or intravenous injection the dose administration of DIPRIVAN to the patient should be titrated against the response of the patient and until there are clinical signs consistent with the onset of anesthesia. A rapid bolus may increase the likelihood of undesirable cardiorespiratory depression.

Pediatric Patients

Most patients aged 3 years through 16 years and classified ASA-PS I or II require 2.5 mg/kg to 3.5 mg/kg of DIPRIVAN for induction. 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 may impact the dose of DIPRIVAN required for induction of general anesthesia. A lower dosage is recommended for pediatric patients classified as ASA-PS III or IV. Boluses of DIPRIVAN may be administered via small veins if pretreated with lidocaine or via antecubital or larger veins.

Neurosurgical Patients

Most adult neurosurgical patients require 1 mg/kg to 2 mg/kg of DIPRIVAN. Slower induction is recommended to allow for titration to achieve an adequate clinical response. Whether administered by infusion or an intravenous injection, the dose of DIPRIVAN to the patient should be titrated against the response of the patient and until there are clinical signs consistent with the onset of anesthesia.

Cardiac Anesthesia

Most adult cardiac patients require 0.5 mg/kg to 1.5 mg/kg of DIPRIVAN. Slower induction is recommended to allow for titration to clinical response and to prevent hemodynamic instability. Whether administered by infusion or intravenous injection, the dose of DIPRIVAN to the patient should be titrated against the response of the patient until the clinical signs show the onset of anesthesia. Other agents used in addition to DIPRIVAN for induction and maintenance of anesthesia may require DIPRIVAN doses to be titrated to ensure adequate sedation level.

DIPRIVAN has been well-studied in patients with coronary artery disease and in patients with hemodynamically significant valvular or congenital heart disease. No significant safety issues or changes to the induction of anesthesia is generally required for these patient groups. Dosing should be titrated based on depth of anesthesia.

As with other anesthetic and sedative-hypnotic agents, DIPRIVAN 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, 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 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 maintenance infusion rates and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication. The rate of DIPRIVAN administration should be determined based on the patient's premedication and adjusted according to clinical responses.

Maintenance of General Anesthesia for Patients Greater than or Equal to 2 Months of Age

DIPRIVAN 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 the likelihood of undesirable cardiorespiratory depression.

Adult Patients

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

Continuous Infusion

DIPRIVAN 100 mcg/kg/min 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 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 mcg/kg/min to 200 mcg/kg/min) for the first 10 minutes to 15 minutes. Infusion rates should subsequently be decreased 30% to 50% during the first half-hour of maintenance. Generally, rates of 50 mcg/kg/min 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 25 mg (2.5 mL) to 50 mg (5 mL) may be administered 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.

Cardiac Anesthesia

The maintenance dose of propofol in adult cardiac patients should be administered as 25 to 100 mcg/kg/min, and should be adjusted according to the patient’s sedation level and clinical response.

Pediatric Patients

In children greater than or equal to 2 months of age, anesthesia can be maintained by administering DIPRIVAN by infusion or intermittent intravenous bolus injection. An initial bolus of between 1-4 mg/kg, followed by subsequent administration of smaller aliquots based on patients’ response (0.5 – 2 mg/kg). The patient's clinical response will determine the infusion rate or the amount and frequency of incremental injections.

Continuous Infusion

DIPRIVAN administered as a variable rate infusion 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 at a rate of 200 mcg/kg/min to 300 mcg/kg/min should immediately follow the induction dose. Following the first half-hour of maintenance, infusion rates of 125 mcg/kg/min to 150 mcg/kg/min are typically needed. DIPRIVAN should be titrated to achieve the desired clinical effect. Younger pediatric patients may require higher maintenance infusion rates than older pediatric patients.

Intermittent Bolus

An initial bolus of 1-4 mg/kg should be administered, with additional 0.5 to2 mg/kg doses as needed. The incremental boluses should be administered when changes in vital signs indicate a response to surgical stimulation or light anesthesia.

Initiation and Maintenance of Monitored Anesthesia Care (MAC) Sedation in Adult Patients

When DIPRIVAN is administered for MAC sedation, rates of administration should be individualized and titrated to clinical response. In most patients, the rates of DIPRIVAN administration will be in the range of 25 mcg/kg/min 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. A rapid bolus injection may result in undesirable cardiorespiratory depression.

Initiation of MAC Sedation in Adult Patients

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 at 100 mcg/kg/min to 150 mcg/kg/min (6 mg/kg/hour to 9 mg/kg/hour) for a period of 3 minutes 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 minutes to 5 minutes and titrated to clinical responses. When DIPRIVAN is administered slowly over 3 minutes 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. The rate of administration should be over 3 minutes to 5 minutes and the dosage of DIPRIVAN should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs.

Maintenance of MAC Sedation in Adult Patients

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 mcg/kg/min to 75 mcg/kg/min (1.5 mg/kg/hour to 4.5 mg/kg/hour) during the first 10 minutes to 15 minutes of sedation maintenance. Infusion rates should subsequently be decreased over time to 25 mcg/kg/min 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 at rates higher than are clinically necessary.

If the intermittent bolus dose method is used, increments of DIPRIVAN 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. The rate of administration and the dosage of DIPRIVAN should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs.

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

Clinical Responses and Dose Titrations

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.

For minor surgical procedures (e.g., body surface) nitrous oxide (60% to 70%) can be combined with a variable rate DIPRIVAN 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 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 in order to avoid administration of DIPRIVAN at rates higher than are clinically necessary. Generally, rates of 50 mcg/kg/min 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.

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 minutes to 5 minutes) must be allowed between dose adjustments to allow for and assess the clinical effects.

Intensive Care Unit (ICU) Sedation of Intubated, Mechanically Ventilated Adult Patients

In the Intensive Care Unit (ICU), DIPRIVAN can be administered to intubated, mechanically ventilated adult patients to provide continuous sedation and control of stress responses only by persons skilled in the medical management of critically ill patients and trained in cardiovascular resuscitation and airway management.

DIPRIVAN should be individualized according to the patient's condition and response, blood lipid profile, and vital signs. 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/hour). The infusion rate should be increased by increments of 5 mcg/kg/min to 10 mcg/kg/min (0.3 mg/kg/hour to 0.6 mg/kg/hour) 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 ICU patients recovering from the effects of general anesthesia or deep sedation will require maintenance rates of 5 mcg/kg/min to 50 mcg/kg/min (0.3 mg/kg/hour to 3 mg/kg/hour) titrated to desired level of clinical response. 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.

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.

Dosages of DIPRIVAN should be reduced in patients who have received large dosages of opioids. The DIPRIVAN 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.

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. Bolus administration of 10 mg 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.

Abrupt discontinuation of DIPRIVAN prior to weaning or for daily evaluation of sedation levels should be avoided.

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.

Table 1. Summary of Dosage Guidelines for Different Indications

INDICATION	DOSAGE AND ADMINISTRATION
Induction of General Anesthesia:	Healthy Adults Less Than 65 Years of Age: 2 mg/kg to 2.5 mg/kg until induction onset, as determined by clinical response of the patient. Elderly, Debilitated, or ASA-PS III or IV Patients: 1 mg/kg to 1.5 mg/kg until induction onset, as determined by clinical response to the onset of anesthesia. Cardiac Anesthesia: 0.5 mg/kg to 1.5 mg/kg until induction onset, as determined by clinical response of the patient. Neurosurgical Patients: 1 mg/kg to 2 mg/kg until induction onset, as determined by clinical response of the patient. Pediatric Patients – healthy, from 3 years to 16 years of age: 2.5 mg/kg to 3.5 mg/kg administered until induction onset, as determined by clinical response of the patient.
Maintenance of General Anesthesia:	Infusion Healthy Adults Less Than 65 Years of Age: Infusion of 100 mcg/kg/min to 200 mcg/kg/min (6 mg/kg/hour to 12 mg/kg/hour). Elderly, Debilitated, ASA-PS III or IV Patients: Infusion of 50 mcg/kg/min to 100 mcg/kg/min (3 mg/kg/hour to 6 mg/kg/hour). Cardiac Anesthesia: Infusion of 25 mcg/kg/min to 100 mcg/kg/min Neurosurgical Patients: Infusion of 100 mcg/kg/min to 200 mcg/kg/min (6 mg/kg/hour to 12 mg/kg/hour). Pediatric Patients - healthy, from 2 months of age to 16 years of age: Infusion of 125 mcg/kg/min to 300 mcg/kg/min (7.5 mg/kg/hour to 18 mg/kg/hour). Following the first half hour of maintenance, if clinical signs of light anesthesia are not present, the infusion rate should be decreased
	Intermittent Bolus Healthy Adults Less Than 65 Years of Age: Increments of 20 mg to 50 mg as needed.
Initiation of MAC Sedation:	Healthy Adults Less Than 65 Years of Age: Slow infusion or slow injection techniques are recommended to avoid apnea or hypotension. Most patients require an infusion of 100 mcg/kg/min to 150 mcg/kg/min (6 mg/kg/hour to 9 mg/kg/hour) for 3 minutes to 5 minutes or a slow injection of 0.5 mg/kg over 3 minutes 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.
Maintenance of MAC Sedation:	Healthy Adults Less Than 65 Years of Age: A variable rate infusion technique is preferable over an intermittent bolus technique. Most patients require an infusion of 25 mcg/kg/min to 75 mcg/kg/min (1.5 mg/kg/hour to 4.5 mg/kg/hour) 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.
Initiation and Maintenance of ICU Sedation in Intubated, Mechanically Ventilated Adult Patients:	Adult Patients - Because of the residual effects of previous anesthetic or sedative agents, in most patients the initial infusion should be 5 mcg/kg/min (0.3 mg/kg/hour) for at least 5 minutes. Subsequent increments of 5 mcg/kg/min to 10 mcg/kg/min (0.3 mg/kg/hour to 0.6 mg/kg/hour) over 5 minutes to 10 minutes may be used until desired clinical effect is achieved. Maintenance rates of 5 mcg/kg/min to 50 mcg/kg/min (0.3 mg/kg/hour to 3 mg/kg/hour) or higher may be required. Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks. Evaluation of clinical effect and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN required for sedation. The tubing and any unused DIPRIVAN drug product should be discarded after 12 hours because DIPRIVAN contains no preservatives and is capable of supporting growth of microorganisms.