Diprivan Drug Information

• ADMINISTRATION: 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. 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 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. 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 until a mild response to surgical stimulation is obtained 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 (e.g., sedatives, 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 mg/kg to 2.5 mg/kg of Diprivan for induction when unpremedicated or when premedicated with oral benzodiazepines or intramuscular opioids. For induction, Diprivan 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 general anesthetics, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of Diprivan. Elderly, Debilitated, or ASA-PS III or IV Patients It is important to be familiar and experienced with the intravenous use of Diprivan 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 mg/kg to 1.5 mg/kg (approximately 20 mg every 10 seconds) of Diprivan 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 mg/kg to 3.5 mg/kg of Diprivan 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. 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 to pediatric patients. Boluses of Diprivan 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 for induction of anesthesia, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 mg/kg to 2 mg/kg) (see PRECAUTIONS and DOSAGE AND ADMINISTRATION ). Cardiac Anesthesia Diprivan 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 general anesthetics and sedation drugs, 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. The rate of Diprivan administration should be determined based on the patient's premedication and adjusted according to clinical responses. A rapid bolus induction should be avoided. In order to assure adequate anesthesia, when Diprivan 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 maintenance rates should not be less than 50 mcg/kg/min, and care should be taken to ensure amnesia. Higher doses of Diprivan will reduce the opioid requirements (see Table 4). When Diprivan 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 a OPIOID 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 b Care should be taken to ensure amnesia. Maintenance of General Anesthesia 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 cardiorespiratory effects including hypotension, apnea, airway obstruction, and oxygen desaturation. Adult Patients In adults, anesthesia can be maintained by administering Diprivan 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. Maintenance by infusion of Diprivan should immediately follow the induction dose in order to provide satisfactory or continuous anesthesia during the induction phase. Infusion rates should subsequently be decreased 30% to 50% during the first half-hour of maintenance. The incremental boluses should be administered when changes in vital signs indicate a response to surgical stimulation or light anesthesia. Pediatric Patients Diprivan 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 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. (See Table 2 Clinical Trials.) Monitored Anesthesia Care (MAC) Sedation 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 (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 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. 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 (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. 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. With the intermittent bolus method of sedation maintenance, there is increased potential for respiratory depression, transient increases in sedation depth, and prolongation of recovery. 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 (see PRECAUTIONS, Drug Interactions ). ICU Sedation ( See WARNINGS and DOSAGE AND ADMINISTRATION, Handling Procedures. ) Abrupt discontinuation of Diprivan 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 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 mcg/kg/min to 50 mcg/kg/min (0.3 mg/kg/h 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. 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 should be individualized according to the patient's condition and response, blood lipid profile, and vital signs (see PRECAUTIONS, Intensive Care Unit Sedation ). When indicated, initiation of sedation should begin at 5 mcg/kg/min (0.3 mg/kg/h). A minimum period of 5 minutes between adjustments should be allowed for onset of peak drug effect. Dosages of Diprivan should be reduced in patients who have received large dosages of narcotics. 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 (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 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 (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 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 (see WARNINGS ). When administered using a y-type infusion set, Diprivan 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 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. Do not use if there is evidence of separation of the phases of the emulsion. Rare cases of self-administration of Diprivan 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 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 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 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 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 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 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 vial has been opened. Diprivan must be prepared for single-patient use 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 IV line should be flushed every 12 hours and at the end of the anesthetic procedure to remove residual Diprivan. Strict aseptic techniques must be followed. A sterile vent spike and sterile tubing must be used for administration of Diprivan. As with other lipid emulsions, the number of IV line manipulations should be minimized. Diprivan should be discarded and administration lines changed after 12 hours.

REACTIONS: To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. General Adverse event information is derived from controlled clinical trials and worldwide marketing experience. In the description below, rates of the more common events represent US/Canadian clinical study results.

Less frequent events are also derived from publications and marketing experience in over 8 million patients; there are insufficient data to support an accurate estimate of their incidence rates. These studies were conducted using a variety of premedicants, varying lengths of surgical/diagnostic procedures, and various other anesthetic/sedative agents. Most adverse events were mild and transient.

Anesthesia and MAC Sedation in Adults The following estimates of adverse events for DIPRIVAN include data from clinical trials in general anesthesia/MAC sedation (N=2,889 adult patients). The adverse events listed below as probably causally related are those events in which the actual incidence rate in patients treated with DIPRIVAN was greater than the comparator incidence rate in these trials. Therefore, incidence rates for anesthesia and MAC sedation in adults generally represent estimates of the percentage of clinical trial patients which appeared to have probable causal relationship.

The adverse experience profile from reports of 150 patients in the MAC sedation clinical trials is similar to the profile established with DIPRIVAN during anesthesia (see below). During MAC sedation clinical trials, significant respiratory events included cough, upper airway obstruction, apnea, hypoventilation, and dyspnea. Anesthesia in Pediatric Patients Generally the adverse experience profile from reports of 506 DIPRIVAN pediatric patients from 6 days through 16 years of age in the US/Canadian anesthesia clinical trials is similar to the profile established with DIPRIVAN during anesthesia in adults (see Pediatric percentages below).

Although not reported as an adverse event in clinical trials, apnea is frequently observed in pediatric patients. ICU Sedation in Adults The following estimates of adverse events include data from clinical trials in ICU sedation (N=159 adult patients). Probably related incidence rates for ICU sedation were determined by individual case report form review.

Probable causality was based upon an apparent dose response relationship and/or positive responses to rechallenge. In many instances the presence of concomitant disease and concomitant therapy made the causal relationship unknown.

CONTRAINDICATIONS: DIPRIVAN is contraindicated in patients with a known hypersensitivity to propofol or any of DIPRIVAN components. DIPRIVAN is contraindicated in patients with allergies to eggs, egg products, soybeans or soy products.

OVERDOSAGE: If overdosage occurs, DIPRIVAN administration should be discontinued immediately. Overdosage is likely to cause cardiorespiratory depression. Respiratory depression should be treated by artificial ventilation with oxygen.

Cardiovascular depression may require repositioning of the patient by raising the patient's legs, increasing the flow rate of intravenous fluids, and administering pressor agents and/or anticholinergic agents.