PROPOFOL FRESENIUS

Propofol is an intravenous anaesthetic agent used for induction and maintenance of general anaesthesia.

Intravenous administration of propfol is used to induce unconsciousness after which anaesthesia may be maintained using a combination of medications.

Recovery from propofol-induced anaesthesia is generally rapid and associated with less frequent side effects (e.g. drowsiness, nausea, vomiting) than with thiopental, methohexital, and etomidate.

Propofol may be used prior to diagnostic procedures requiring anaesthesia, in the management of refractory status epilepticus, and for induction and/or maintenance of anaesthesia prior to and during surgeries.

Used for induction and/or maintenance of anaesthesia and for management of refractory status epilepticus.

Propofol is a sedative-hypnotic agent for use in the induction and maintenance of anesthesia or sedation.

Intravenous injection of a therapeutic dose of propofol produces hypnosis rapidly with minimal excitation, usually within 40 seconds from the start of an injection (the time for one arm-brain circulation).

Gamma-aminobutyric acid receptor subunit beta-2 Potentiator Gamma-aminobutyric acid receptor subunit beta-3 Potentiator GABA(A) Receptor Positive allosteric modulator.

• time to onset of unconsciousness is 15-30 seconds, due to rapid distribution from plasma to the CNS.

Distribution is so rapid that peak plasma concentrations cannot be readily measured.

Duration of action is 5-10 minutes.

Hepatically metabolized mainly by glucuronidation at the C1-hydroxyl.

Hydroxylation of the benzene ring to 4-hydroxypropofol may also occur via CYP2B6 and 2C9 with subsequent conjugation to sulfuric and/or glucuronic acid.

Hydroxypropofol has approximately 1/3 of hypnotic activity of propofol.

Hover over products below to view reaction partners Propofol 4-Hydroxypropofol 4-Quinol sulfate 1-Quinol glucuronide Propofol glucuronide 1-Quinol glucuronide 4-OH-propofol.

It is chiefly eliminated by hepatic conjugation to inactive metabolites which are excreted by the kidney.

Initial distribution phase t 1/2α =1.8-9.5 minutes.

Second redistirubtion phase t 1/2β =21-70 minutes.

Terminal elimination phase t 1/2γ =1.5-31 hours.

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Overdosage may increase pharmacologic and adverse effects or cause death.

LD 50 =53 mg/kg (mice), 42 mg/kg (rats).

LD 50 (as a solution in soybean oil)=1230 mg/kg (mice), 600 mg/kg (rats).

Propofol injectable emulsion is contraindicated in patients with a known hypersensitivity to propofol or any of propofol injectable emulsion components.

Propofol injectable emulsion is contraindicated in patients with a history of anaphylaxis to eggs, egg products, soybeans or soy products.

Known hypersensitivity to propofol, egg or soybean.

Information for detailed dosing instructions. 2.1 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.

Propofol injectable emulsion 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, propofol injectable emulsion 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, propofol injectable emulsion should be administered only by persons skilled in the management of critically ill patients and trained in cardiovascular resuscitation and airway management.

Anesthesia/MAC Sedation Propofol 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.

Propofol injectable emulsion should be drawn into a sterile syringe immediately after a vial is opened.

When withdrawing propofol 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.

Propofol injectable emulsion must be prepared for single dose only.

Any unused propofol injectable emulsion drug product, 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 intravenous 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 must be prepared for single dose only.

Strict aseptic techniques must be followed.

A sterile vent spike and sterile tubing must be used for administration of propofol injectable emulsion.

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 propofol injectable emulsion drug product must be discarded after 12 hours.

If propofol 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 propofol injectable emulsion from a vial, a sterile vent spike should be used.

Propofol injectable emulsion should be discarded and administration lines changed after 12 hours.

If lidocaine is to be administered to minimize pain on injection of propofol injectable emulsion, it is recommended that it be administered prior to propofol injectable emulsion administration or that it be added to propofol injectable emulsion immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg propofol injectable emulsion.

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

Propofol 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).

Compatibility of propofol injectable emulsion with the coadministration of blood/serum/plasma has not been established.

When administered using a y-type infusion set, propofol 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.

When administering propofol injectable emulsion by infusion, syringe or volumetric pumps are recommended to provide controlled infusion rates.

When infusing propofol injectable emulsion to patients undergoing magnetic resonance imaging, metered control devices may be utilized if mechanical pumps are impractical.

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. 2.2 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 propofol injectable emulsion.

For induction, whether administered by infusion or intravenous injection the dose of propofol injectable emulsion 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 propofol injectable emulsion 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 propofol injectable emulsion for induction of anesthesia.

For induction, whether administered by infusion or intravenous injection the dose administration of propofol injectable emulsion 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.

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 propofol injectable emulsion for induction.

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.

Boluses of propofol injectable emulsion may be administered via small veins if pretreated with lidocaine or via antecubital or larger veins.

Most adult neurosurgical patients require 1 mg/kg to 2 mg/kg of propofol injectable emulsion.

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 propofol injectable emulsion to the patient should be titrated against the response of the patient and until there are clinical signs consistent with the onset of anesthesia.

Most adult cardiac patients require 0.5 mg/kg to 1.5 mg/kg of propofol injectable emulsion.

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 propofol injectable emulsion 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 propofol injectable emulsion for induction and maintenance of anesthesia may require propofol injectable emulsion doses to be titrated to ensure adequate sedation level.

Propofol injectable emulsion 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, propofol 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 propofol 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, propofol 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 propofol injectable emulsion maintenance infusion rates and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication.

The rate of propofol injectable emulsion administration should be determined based.

Propofol injectable emulsion, USP is available as follows: Strength Package Sizes and NDC No. 200 mg per 20 mL (10 mg/mL) 20 mL ready-to-use single-dose infusion vial in packages of 10 (NDC 23155-345-41) and in packages of 20 (NDC 23155-345-44) 500 mg per 50 mL (10 mg/mL) 50 mL ready-to-use single-dose infusion vial in packages of 20 (NDC 23155-345-42) 1,000 mg per 100 mL (10 mg/mL) 100 mL ready-to-use single-dose infusion vial in packages of 10 (NDC 23155-345-43) Store between 4° to 25°C (40° to 77°F).

Do not freeze.

Shake well before use.

Data from randomized controlled trials, cohort studies and case series over several decades with propofol use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Most of the reported exposures to propofol describe propofol exposure at the time of cesarean delivery.

There are reports of neonatal depression in infants exposed to propofol during delivery.

In animal reproduction studies, decreased pup survival concurrent with increased maternal mortality was observed with intravenous administration of propofol to pregnant rats either prior to mating and during early gestation or during late gestation and early lactation at exposures less than the human induction dose of 2.5 mg/kg. In pregnant rats administered 15 mg/kg/day intravenous propofol (equivalent to the human induction dose) from two weeks prior to mating to early in gestation (Gestation Day 7), offspring that were allowed to mate had increased postimplantation losses.

The pharmacological activity (anesthesia) of the drug on the mother is probably responsible for the adverse effects seen in the offspring.

Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours.

There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans ).

The clinical significance of these nonclinical findings is not known, and the benefits of appropriate anesthesia in pregnant women who require procedures should be balanced with the potential risks suggested by the nonclinical data.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

Fetal/neonatal Adverse Reactions propofol injectable emulsion crosses the placenta and may be associated with neonatal depression.

Monitor neonates for hypotonia and sedation following maternal exposure to propofol.

Pregnant rats were administered propofol intravenously at 0, 5, 10, and 15 mg/kg/day (0.3, 0.65, and 1 times the human induction dose of 2.5 mg/kg based on body surface area) during organogenesis (Gestational Days to 15).

Propofol did not cause adverse effects to the fetus at exposures up to 1 times the human induction dose despite evidence of maternal toxicity (decreased weight gain in all groups).

Pregnant rabbits were administered propofol intravenously at 0, 5, 10, and 15 mg/kg/day (0.65, 1.3, 2 times the human induction dose of 2.5 mg/kg based on body surface area comparison) during organogenesis (Gestation Days to 18).

Propofol treatment decreased total numbers of corpora lutea in all treatment groups but did not cause fetal malformations at any dose despite maternal toxicity (one maternal death from anesthesia-related respiratory depression in the high dose group).

Pregnant rats were administered propofol intravenously at 0, 10, and 15 mg/kg/day (0.65 and 1 times the human induction dose of 2.5 mg/kg based on body surface area) from late gestation through lactation (Gestation Day to Lactation Day 22).

Decreased pup survival was noted at all doses in the presence of maternal toxicity (deaths from anesthesia-induced respiratory depression).

This study did not evaluate neurobehavioral function including learning and memory in the pups.

Pregnant rats were administered propofol intravenously at 0, 10, or 15 mg/kg/day (0.3 and 1 times the human induction dose of 2.5 mg/kg based on body surface area) from 2 weeks prior to mating to Gestational Day 7.

Pup (F1) survival was decreased on Day and 22 of lactation at maternally toxic doses of and 15 mg/kg/day. When F1 offspring were allowed to mate, postimplantation losses were increased in the 15 mg/kg/day treatment group.

In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus.

In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring.

With respect to brain development, this time period corresponds to the third trimester of gestation in the human.

The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits.

The safety and effectiveness of propofol injectable emulsion have been established for induction of anesthesia in pediatric patients aged 3 years and older and for the maintenance of anesthesia aged 2 months and older.

In pediatric patients, administration of fentanyl concomitantly with propofol injectable emulsion may result in serious bradycardia.

Propofol injectable emulsion is not indicated for use in pediatric patients for ICU sedation or for MAC sedation for surgical, nonsurgical or diagnostic procedures as safety and effectiveness have not been established.

There have been anecdotal reports of serious adverse events and death in pediatric patients with upper respiratory tract infections receiving propofol injectable emulsion for ICU sedation.

In one multicenter clinical trial of

ICU sedation in critically ill pediatric patients that excluded patients with upper respiratory tract infections, the incidence of mortality observed in patients who received propofol injectable emulsion (n=222) was 9%, while that for patients who received standard sedative agents (n=105) was 4%.

While causality was not established in this study, propofol injectable emulsion is not indicated for ICU sedation in pediatric patients until further studies have been performed to document its safety in that population.

However, propofol infusions are routinely used to provide safe sedation to critically ill pediatric patients in ICUs.

In pediatric patients, abrupt discontinuation of propofol injectable emulsion following prolonged infusion may result in flushing of the hands and feet, agitation, tremulousness and hyperirritability.

Increased incidences of bradycardia (5%), agitation (4%), and jitteriness (9%) have also been observed.

Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as propofol injectable emulsion, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis.

Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss.

Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory.

The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data.

The effect of age on induction dose requirements for propofol was assessed in an open-label study involving 211 unpremedicated patients with approximately 30 patients in each decade between the ages of and 80.

The average dose to induce anesthesia was calculated for patients up to 54 years of age and for patients 55 years of age or older.

The average dose to induce anesthesia in patients up to 54 years of age was 1.99 mg/kg and in patients above 54 it was 1.66 mg/kg. Subsequent clinical studies have demonstrated lower dosing requirements for subjects greater than 60 years of age.

A lower induction dose and a slower maintenance rate of administration of propofol injectable emulsion should be used in elderly patients.

In this group of patients, rapid (single or repeated) bolus administration should not be used in order to minimize undesirable cardiorespiratory depression.

All dosing should be titrated according to patient condition and response.