Dilution Propofol - Diprivan ®

Propofol (Diprivan ®)

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Usual Diluents

N/A - Commercial prep

Standard Dilutions [Amount of drug] [Infusion volume] [Infusion rate]

DIPRIVAN Injectable Emulsion is provided as a ready to use preparation:

[1000 mg] [100 ml] [Titrate]
[500 mg] [50 ml] [Titrate]
[200 mg] [20 ml] [Titrate]

[Concentration: 10 mg/ml]

Stability / Miscellaneous

Label: Do not Refrigerate / Shake well before use/ Replace IV tubing q12h - STRICT ASEPTIC TECHNIQUE MUST ALWAYS BE MAINTAINED DURING HANDLING..

Stability data:

Drug

Stability
Refrigerated

Stability
Room Temp.

Reconstituted
Vial/Powder

Notes

Diprivan - Propofol

Store between 4° to 25°C (40° to 77°F).

Should be discarded and administration lines changed after 12 hours.

Solution

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).

Propofol undergoes oxidative degradation, in the presence of oxygen, and is therefore packaged under nitrogen to eliminate this degradation path.

Do not freeze. Shake well before use.

Dosing:
-Induction: Healthy adults <55 yrs: I.V.: 2-2.5 mg/kg (~40 mg q10 sec).
[Elderly, debilitated: 1-1.5 mg/kg (~20 mg q10 sec).
-ICU sedation: 5 mcg/kg/min ( 0.3 mg/kg/hour); increase by 5-10 mcg/kg/min (or 0.3-0.6 mg/kg/hour) q5-10 min desired sedation. Usual maintenance range: 5-50 mcg/kg/min (or 0.3-3 mg/kg/hr).

Calculation of rate (ml/hr) = (mg/kg/hr) x 0.1 (Note: changes in the rate of administration should be made slowly (>5 minutes) in order to minimize hypotension and avoid acute overdosage.

Monitoring: Patients should be monitored for early signs of significant hypotension and/or cardiovascular depression, which may be profound.

DOSAGE AND ADMINISTRATION
Dosage and rate of administration should be individualized and titrated to the desired effect, according to clinically relevant factors, including reinduction 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 package insert section 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.

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. 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.

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.

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.

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 III/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 20-30 seconds.

Maintenance of General Anesthesia:	Infusion Healthy Adults Less Than 55 Years of Age: 100 to 200 µg/kg/min (6 to 12 mg/kg/h). Elderly, Debilitated, ASA III/IV Patients: 50 to 100 µg/kg/min (3 to 6 mg/kg/h). Cardiac Anesthesia: Most patients require: Primary DIPRIVAN Injectable Emulsion with Secondary Opioid - 100 - 150 µg/kg/min Low-Dose DIPRIVAN Injectable Emulsion with Primary Opioid - 50 - 100 µg/kg/min (See package insert section: CLINICAL PHARMACOLOGY) Neurosurgical Patients: 100 to 200 µg/kg/min (6 to 12 mg/kg/h). Pediatric Patients - healthy, from 2 months of age to 16 years of age: 125 to 300 µg/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.
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 µg/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 III/IV Patients: Most patients require dosages similar to healthy adults. Rapid boluses are to be avoided.
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 µg/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 III/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 - 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 Propofol Injectable Emulsion required for sedation. The tubing and any unused portions of Propofol Injectable Emulsion should be discarded after 12 hours because Propofol Injectable Emulsion contains no preservatives and is capable of supporting growth of microorganisms.

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 Propofol Injectable Emulsion during anesthesia or ICU/MAC sedation is limited. Propofol 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 Propofol 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 Propofol 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. Propofol Injectable Emulsion is a single-use parenteral product 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, Propofol 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 failure to use aseptic technique when handling Propofol Injectable Emulsion was associated with microbial contamination of the product and with fever, infection/sepsis, other life-threatening illness, and/or death.

Propofol, 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
Propofol 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. Propofol Injectable Emulsion should be drawn into sterile syringes immediately after vials are opened. When withdrawing Propofol 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.

Propofol Injectable Emulsion should be prepared for single-patient use only. Any unused portions of Propofol Injectable Emulsion, reservoirs, dedicated administration tubing and/or solutions containing Propofol 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 Propofol Injectable Emulsion.

Guidelines for Aseptic Technique for ICU Sedation
Propofol Injectable Emulsion should be prepared for single-patient use only. When Propofol 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 Propofol 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 Propofol Injectable Emulsion must be discarded after 12 hours.

If Propofol 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.

HOW SUPPLIED
DIPRIVAN Injectable Emulsion is available in ready to use 20 mL infusion vials, 50 mL infusion vials, and 100 mL infusion vials containing 10mg/mL of propofol.

20 mL infusion vials (NDC 0310-0300-22)
50 mL infusion vials (NDC 0310-0300-50)
100 mL infusion vials (NDC 0310-0300-11)

Propofol undergoes oxidative degradation, in the presence of oxygen, and is therefore packaged under nitrogen to eliminate this degradation path.

Store between 4-22°C (40-72°F). Do not freeze. Shake well before use.

Source: [package insert]