Propofol Drug Information
Generic name: PROPOFOL
General Anesthetic [EPC]
Uses of Propofol
Propofol injectable emulsion is an intravenous general anesthetic and sedation drug indicated for: Induction of General Anesthesia for Patients Greater than or Equal to 3 Years of Age Maintenance of General Anesthesia for Patients Greater than or Equal to 2 Months of Age Initiation and Maintenance of Monitored Anesthesia Care (MAC) Sedation in Adult Patients Sedation for Adult Patients in Combination with Regional Anesthesia Intensive Care Unit (ICU) Sedation of Intubated, Mechanically Ventilated Adult Patients Limitations of Use Propofol injectable emulsion is not recommended for induction of anesthesia below the age of 3 years or for maintenance of anesthesia below the age of 2 months because its safety and effectiveness have not been established in those populations . Safety, effectiveness and dosing guidelines for propofol injectable emulsion have not been established for MAC sedation in the pediatric population; therefore, it is not recommended for this use. Propofol injectable emulsion is not indicated for use in Pediatric ICU sedation since the safety of this regimen has not been established. Propofol injectable emulsion is an intravenous general anesthetic and sedation drug indicated for: Induction of General Anesthesia for Patients Greater than or Equal to 3 Years of Age Maintenance of General Anesthesia for Patients Greater than or Equal to 2 Months of Age Initiation and Maintenance of Monitored Anesthesia Care (MAC) Sedation in Adult Patients Sedation for Adult Patients in Combination with Regional Anesthesia Intensive Care Unit (ICU) Sedation of Intubated, Mechanically Ventilated Adult Patients Limitations of Use : Propofol injectable emulsion is not recommended for induction of anesthesia below the age of 3 years or for maintenance of anesthesia below the age of 2 months MAC sedation in the pediatric population is not recommended Propofol injectable emulsion is not indicated for use in Pediatric ICU sedation
Dosage & Administration of Propofol
| 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 [ | |
| 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 | |
| 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 | |
| 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 | |
Side Effects of Propofol
The following serious or otherwise important adverse reactions are discussed elsewhere in the labeling: Hypersensitivity reaction Hypotension and/or bradycardia Propofol Infusion Syndrome 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. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Anesthesia and MAC Sedation in Adults The following estimates of adverse events for propofol injectable emulsion 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 propofol injectable emulsion 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 propofol injectable emulsion during anesthesia (see Table 3 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 propofol injectable emulsion pediatric patients from 6 days through 16 years of age in the US/Canadian anesthesia clinical trials is similar to the profile established with propofol injectable emulsion during anesthesia in adults.
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. Therefore, incidence rates for ICU sedation generally represent estimates of the percentage of clinical trial patients which appeared to have a probable causal relationship. Table 2. Treatment Emergent Adverse Events Observed from Clinical Trials Anesthesia/MAC Sedation ICU Sedation Body as a Whole: Anaphylaxis/Anaphylactoid reaction perinatal disorder, tachycardia, bigeminy, bradycardia, premature ventricular contractions, hemorrhage, ECG abnormal arrhythmia atrial, fever, extremities pain, anticholinergic syndrome, asthenia, awareness, chest pain, extremities pain, fever, increased drug effect, neck rigidity/stiffness, trunk pain Fever, sepsis, trunk pain, whole body weakness Cardiovascular: Premature atrial contractions Syncope, hypotension, t achycardia Nodal, arrhythmia Bradycardia, arrhythmia, atrial fibrillation, atrioventricular heart block, bigeminy, bleeding, bundle branch block, cardiac arrest, ECG abnormal, edema, extrasystole, heart block, hypertension, myocardial infarction, myocardial ischemia, premature ventricular contractions, ST segment depression, supraventricular tachycardia, tachycardia, ventricular fibrillation Bradycardia, decreased cardiac output, arrhythmia, atrial fibrillation, bigeminy, cardiac arrest, extrasystole, right heart failure, ventricular tachycardia Central Nervous System: Hypertonia/Dystonia, paresthesia, movement, abnormal dreams, agitation, amorous behavior, anxiety, bucking/jerking/thrashing, chills/shivering/clonic/myoclonic movement, combativeness, confusion, delirium, depression, dizziness, emotional lability, euphoria, fatigue, hallucinations, headache, hypotonia, hysteria, insomnia, moaning, neuropathy, opisthotonos, rigidity, seizures, somnolence, tremor, twitching Agitation, hypotension, hills/shivering, intracranial hypertension, seizures, somnolence, thinking abnormal Digestive: Hypersalivation, nausea, cramping, diarrhea, dry mouth, enlarged parotid, nausea, swallowing, vomiting Ileus, liver function abnormal Hemic/Lymphatic: Leukocytosis, coagulation disorder, leukocytosis Injection Site: Phlebitis, pruritus, burning/Stinging or pain, hives/itching, phlebitis, redness/discoloration Metabolic/Nutritional: hypomagnesemia, hyperkalemia, hyperlipemia BUN increased, creatinine increased, dehydration, hyperglycemia, metabolic acidosis, osmolality increased, hyperlipemia Musculoskeletal: Myalgia Nervous: Dizziness, agitation, chills, somnolence Delirium Respiratory: Wheezing, cough, laryngospasm, hypoxia, apnea, bronchospasm, burning in throat, dyspnea, hiccough, hyperventilation, hypoventilation, pharyngitis, sneezing, tachypnea, upper airway obstruction Decreased lung function, respiratory acidosis during weaning, hypoxia Skin and Appendages: Flushing, Pruritus, rash, conjunctival hyperemia, diaphoresis, urticaria Rash Special Senses: Amblyopia, vision abnormal, diplopia, ear pain, eye pain, nystagmus, taste perversion, tinnitus Urogenital: Cloudy urine, oliguria, urine retention Green urine, kidney failure Postmarketing Experience During the post-marketing period, there have been rare reports of local pain, swelling, blisters, and/or tissue necrosis following accidental extravasation of propofol injectable emulsion.
Venous sequelae, i.e., phlebitis or thrombosis, have been reported rarely (<1 %). the most common adverse reactions>1% were bradycardia, arrhythmia, tachycardia, hypotension, hypertension, decreased cardiac output, movement, apnea, respiratory acidosis during weaning, rash, pruritus, burning/stinging or pain at injection site, and hyperlipemia To report SUSPECTED ADVERSE REACTIONS, contact Avet Pharmaceuticals Inc. at 1-866-901-DRUG or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
Warnings & Cautions for Propofol
Anaphylactic and Anaphylactoid Reactions Use of propofol injectable emulsion has been associated
with both fatal and life threatening anaphylactic and anaphylactoid reactions. Clinical features of anaphylaxis, including angioedema, bronchospasm, erythema, and hypotension, occur rarely following propofol injectable emulsion administration.
Risks of Microbial Contamination Strict aseptic technique must always be maintained during
handling. Propofol injectable emulsion is a single-dose parenteral product (single patient infusion vial) which contains 0.005% disodium edetate (EDTA) to inhibit the rate of growth of microorganisms, for 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.
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 propofol injectable emulsion was associated with microbial contamination of the product and with fever, infection/sepsis, other life-threatening illness, and/or death.
Propofol injectable emulsion vials are never to be accessed more than once or used on more than one person. 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 of the use of propofol vials intended for single use on multiple persons.
Risks of Pediatric Neurotoxicity Published animal studies demonstrate that the administration of
anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance of these findings is not clear. However, based on the available data, 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 three years of age in humans.
Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects. These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness. Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other.
Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.
Risks of Bradycardia, Asystole, and Cardiac Arrest Propofol injectable emulsion has no
vagolytic activity. Reports of bradycardia, asystole, and rarely, cardiac arrest have been associated with propofol injectable emulsion. Pediatric patients are susceptible to this effect, particularly when fentanyl is given concomitantly.
The intravenous administration of anticholinergic agents (e.g., atropine or glycopyrrolate) should be considered to modify potential increases in vagal tone due to concomitant agents (e.g., succinylcholine) or surgical stimuli.
Risk of Seizures
When propofol injectable emulsion is administered to an epileptic patient, there is a risk of seizure during the recovery phase.
Neurosurgical Anesthesia
When propofol injectable emulsion is used in patients with increased intracranial pressure or impaired cerebral circulation, significant decreases in mean arterial pressure should be avoided because of the resultant decreases in cerebral perfusion pressure. To avoid significant hypotension and decreases in cerebral perfusion pressure, an infusion or slow bolus should be utilized instead of rapid, more frequent, and/or larger boluses of propofol injectable emulsion. Slower induction, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 mg/kg to 2 mg/kg). When increased ICP is suspected, hyperventilation and hypocarbia should accompany the administration of propofol injectable emulsion .
Cardiac Anesthesia Slower rates of administration should be utilized in premedicated patients
geriatric patients, patients with recent fluid shifts, and patients who are hemodynamically unstable. Fluid deficits should be corrected prior to administration of propofol injectable emulsion. In those patients where additional fluid therapy may be contraindicated, other measures, e.g., elevation of lower extremities, or use of pressor agents, may be useful to offset the hypotension which is associated with the induction of anesthesia with propofol injectable emulsion.
Use for Intensive Care Unit Sedation of Intubated, Mechanically Ventilated Adult Patients
The administration of propofol injectable emulsion should be initiated as a continuous infusion and changes in the rate of administration made slowly (>5 min) in order to minimize hypotension and avoid acute overdosage . Patients should be monitored for early signs of significant hypotension and/or cardiovascular depression, which may be profound. These effects are responsive to discontinuation of propofol injectable emulsion, intravenous fluid administration, and/or vasopressor therapy. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus administration should not be used during sedation in order to minimize undesirable cardiorespiratory depression.
As with other sedative medications, there is wide interpatient variability in propofol injectable emulsion dosage requirements, and these requirements may change with time. Failure to reduce the infusion rate in patients receiving propofol injectable emulsion for extended periods may result in excessively high blood concentrations of the drug. Thus, titration to clinical response and daily evaluation of sedation levels are important during use of propofol injectable emulsion infusion for ICU sedation, especially when it is used for long durations.
Opioids and paralytic agents should be discontinued and respiratory function optimized prior to weaning patients from mechanical ventilation. Infusions of propofol injectable emulsion should be adjusted to maintain a light level of sedation prior to weaning patients from mechanical ventilatory support. Throughout the weaning process, this level of sedation may be maintained in the absence of respiratory depression.
Abrupt discontinuation of propofol 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. It is therefore recommended that administration of propofol injectable emulsion be continued in order to maintain a light level of sedation throughout the weaning process until 10 to 15 minutes prior to extubation, at which time the infusion can be discontinued.
Risks of Propofol Infusion Syndrome in Patients with
ICU Sedation Use of propofol injectable emulsion infusions for both adult and pediatric ICU sedation has been associated with a constellation of metabolic derangements and organ system failures, referred to as Propofol Infusion Syndrome, that have resulted in death. The syndrome is characterized by severe metabolic acidosis, hyperkalemia, lipemia, rhabdomyolysis, hepatomegaly, renal failure, ECG changes (Coved ST segment elevation -similar to ECG changes of the Brugada syndrome) and/or cardiac failure. The following appear to be major risk factors for the development of these events: decreased oxygen delivery to tissues; serious neurological injury and/or sepsis; high dosages of one or more of the following pharmacological agents: vasoconstrictors, steroids, inotropes and/or prolonged, high-dose infusions of propofol (> 5 mg/kg/hour for > 48 hours). The syndrome has also been reported following large-dose, short-term infusions during surgical anesthesia.
In the setting of prolonged need for sedation, increasing propofol dose requirements to maintain a constant level of sedation, or onset of metabolic acidosis during administration of a propofol infusion, consideration should be given to using alternative means of sedation. Prescribers should be alert to these events in patients with the above risk factors and immediately discontinue propofol when the above signs develop. 5.10 Risk of Elevations in Serum Triglycerides Propofol injectable emulsion use requires caution when administered to patients with disorders of lipid metabolism such as primary hyperlipoproteinemia, diabetic hyperlipemia, and pancreatitis. Since propofol injectable emulsion is formulated in an oil-in-water emulsion, elevations in serum triglycerides may occur when propofol injectable emulsion is administered for extended periods of time.
Patients at risk of hyperlipidemia should be monitored for increases in serum triglycerides or serum turbidity. Administration of propofol injectable emulsion should be adjusted if fat is being inadequately cleared from the body. A reduction in the quantity of concurrently administered lipids is indicated to compensate for the amount of lipid infused as part of the propofol injectable emulsion formulation; 1 mL of propofol injectable emulsion contains approximately 0.1 g of fat (1.1 kcal). 5.11 Risks of Zinc Losses EDTA is a strong chelator of trace metals – including zinc.
Although with propofol injectable emulsion there are no reports of decreased zinc levels or zinc deficiency-related adverse events, propofol 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. In clinical trials mean urinary zinc loss was approximately 2.5 mg/day to 3 mg/day in adult patients and 1.5 mg/day to 2 mg/day in pediatric patients. In patients who are predisposed to zinc deficiency, such as those with burns, diarrhea, and/or major sepsis, the need for supplemental zinc should be considered during prolonged therapy with propofol injectable emulsion. 5.12 Use in the Elderly, Debilitated, or ASA-PS III or IV Patients A lower induction dose and a slower maintenance rate of administration should be used in elderly, debilitated, or ASA-PS III or IV patients.
Patients should be continuously monitored for early signs of hypotension and/or bradycardia. Apnea requiring ventilatory support often occurs during induction and may persist for more than 60 seconds. 5.13 Risk of Transient Local Pain Attention should be paid to minimize pain on administration of propofol injectable emulsion. Transient local pain can be minimized if the larger veins of the forearm or antecubital fossa are used.
Pain during intravenous injection may also be reduced by prior injection of intravenous lidocaine (1 mL of a 1% solution). Pain on injection occurred frequently in pediatric patients (45%) when a small vein of the hand was utilized without lidocaine pretreatment. With lidocaine pretreatment or when antecubital veins were utilized, pain was minimal (incidence less than 10%) and well-tolerated. There have been reports in the literature indicating that the addition of lidocaine to propofol injectable emulsion in quantities greater than 20 mg lidocaine/200 mg propofol injectable emulsion results in instability of the emulsion which is associated with increases in globule sizes over time and (in rat studies) a reduction in anesthetic potency.
Therefore, it is recommended that lidocaine 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. 5.14 Risk of Local Reactions Phlebitis or venous thrombosis has been reported. In two clinical studies using dedicated intravenous catheters, no instances of venous sequelae were observed up to 14 days following induction. Accidental intra-arterial injection has been reported in patients, and, other than pain, there were no major sequelae. 5.15 Risk of Aggregation if Administered through the Same Intravenous Catheter with Blood or Plasma Propofol injectable emulsion should not be coadministered through the same intravenous catheter with blood or plasma because compatibility has not been established.
In vitro tests have shown that aggregates of the globular component of the emulsion vehicle have occurred with blood/plasma/serum from humans and animals. The clinical significance of these findings is not known. 5.16 Risk of Postoperative Unconsciousness Very rarely the use of propofol injectable emulsion may be associated with the development of a period of postoperative unconsciousness which may be accompanied by an increase in muscle tone. This may or may not be preceded by a brief period of wakefulness.
Recovery is spontaneous. 5.17 Risks of Perioperative Myoclonia Perioperative myoclonia, rarely including convulsions and opisthotonos, has occurred in association with propofol injectable emulsion administration. 5.18 Risks of Pulmonary Edema There have been rare reports of pulmonary edema in temporal relationship to the administration of propofol injectable emulsion, although a causal relationship is unknown. 5.19 Risks of Unexplained Postoperative Pancreatitis Rarely, cases of unexplained postoperative pancreatitis (requiring hospital admission) have been reported after anesthesia in which propofol injectable emulsion was one of the induction agents used. Due to a variety of confounding factors in these cases, including concomitant medications, a causal relationship to propofol injectable emulsion is unclear.
Drug Interactions with Propofol
Opioids and Sedatives The induction dose requirements of propofol injectable emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with opioids (e.g., morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (e.g., benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of propofol injectable emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. In pediatric patients, administration of fentanyl concomitantly with propofol injectable emulsion may result in serious bradycardia. Analgesic Agents During maintenance of anesthesia or sedation, the rate of propofol injectable emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (e.g., nitrous oxide or opioids). The concurrent administration of potent inhalational agents (e.g., isoflurane, sevoflurane, desflurane, enflurane, and halothane) during maintenance with propofol injectable emulsion are routinely used.
These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of propofol injectable emulsion. Valproate The concomitant use of valproate and propofol may lead to increased blood levels of propofol. Reduce the dose of propofol when co-administering with valproate.
Monitor patients closely for signs of increased sedation or cardiorespiratory depression. Common Neuromuscular Blocking Agents Propofol injectable emulsion does not cause a clinically significant change in onset, intensity or duration of action of the commonly used neuromuscular blocking agents (e.g., succinylcholine and nondepolarizing muscle relaxants). Common Drugs Used as Premedication or Drugs Used During Anesthesia or Sedation No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed in adults. Opioids, Sedatives or Other Analgesic Agents : May increase the anesthetic/sedative and cardiorespiratory effects Valproate : May lead to increased blood levels of propofol
Pregnancy Safety for Propofol
Pregnancy Risk Summary 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 (see Clinical Considerations). 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 2 to 4% and 15 to 20%, respectively. Clinical Considerations 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.
Data Animal Data 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 6 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 6 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 16 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 15 and 22 of lactation at maternally toxic doses of 10 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 .
Pediatric Use of Propofol
Pediatric Use 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 .
Contraindications for Propofol
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
Overdosage Information for Propofol
Symptoms Overdosage is likely to cause cardiorespiratory depression. 10.2 Treatment
If overdosage occurs, propofol injectable emulsion administration should be discontinued immediately. 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.
Clinical Studies of Propofol
Pediatric Anesthesia Propofol injectable emulsion was studied in clinical trials which included
cardiac surgical patients. Most patients were 3 years of age or older. The majority of the patients were healthy ASA-PS I or II patients.
The range of doses in these studies are described in Tables 3 and 4. Table 3. Pediatric Induction of Anesthesia Age Range Induction Dose Median (range) Injection Duration Median (range) ≥3 years to 16 years 2.5 mg/kg (1 mg/kg to 3.6 mg/kg) 20 sec (6 sec to 45 sec) Table 4. Pediatric Maintenance of Anesthesia Age Range Maintenance Dosage (mcg/kg/min) Duration (minutes) 2 months to 2 years 199 (82 to 394) 65 (12 to 282) 2 to 12 years 188 (12 to 1,041) 69 (23 to 374) >12 through 16 years 161 (84 to 359) 69 (26 to 251)
Neuroanesthesia Propofol injectable emulsion was studied in patients undergoing craniotomy for supratentorial
tumors in two clinical trials. The mean lesion size (anterior/posterior × lateral) was 31 mm × 32 mm in one trial and 55 mm × 42 mm in the other trial respectively. Anesthesia was induced with a median propofol injectable emulsion dose of 1.4 mg/kg (range: 0.9 mg/kg to 6.9 mg/kg) and maintained with a median maintenance propofol injectable emulsion dose of 146 mcg/kg/min (range: 68 mcg/kg/min to 425 mcg/kg/min). The median duration of the propofol injectable emulsion maintenance infusion was 285 minutes (range: 48 minutes to 622 minutes). Propofol injectable emulsion was administered by infusion in a controlled clinical trial to evaluate its effect on cerebrospinal fluid pressure (CSFP). The mean arterial pressure was maintained relatively constant over 25 minutes with a change from baseline of -4% ± 17% (mean ± SD). The change in CSFP was -46% ± 14%. As CSFP is an indirect measure of intracranial pressure (ICP), propofol injectable emulsion, when given by infusion or slow bolus in combination with hypocarbia, is capable of decreasing ICP independent of changes in arterial pressure.
Cardiac Anesthesia Propofol injectable emulsion was evaluated in clinical trials involving patients
undergoing coronary artery bypass graft (CABG). In post-CABG (coronary artery bypass graft) patients, the maintenance rate of propofol administration was usually low (median 11 mcg/kg/min) due to the intraoperative administration of high opioid doses. Patients receiving propofol injectable emulsion required 35% less nitroprusside than midazolam patients. During initiation of sedation in post-CABG patients, a 15% to 20% decrease in blood pressure was seen in the first 60 minutes.
It was not possible to determine cardiovascular effects in patients with severely compromised ventricular function.
Intensive Care Unit (ICU) Sedation in Adult Patients Propofol injectable emulsion was
compared to benzodiazepines and opioids in clinical trials involving ICU patients. Of these, 302 received propofol injectable emulsion and comprise the overall safety database for ICU sedation. Across all clinical studies, the mean infusion maintenance rate for all propofol injectable emulsion patients was 27 ± 21 mcg/kg/min.
The maintenance infusion rates required to maintain adequate sedation ranged from 2.8 mcg/kg/min to 130 mcg/kg/min. The infusion rate was lower in patients over 55 years of age (approximately 20 mcg/kg/min) compared to patients under 55 years of age (approximately 38 mcg/kg/min). Although there are reports of reduced analgesic requirements, most patients received opioids for analgesia during maintenance of ICU sedation. In these studies, morphine or fentanyl was used as needed for analgesia.
Some patients also received benzodiazepines and/or neuromuscular blocking agents. During long-term maintenance of sedation, some ICU patients were awakened once or twice every 24 hours for assessment of neurologic or respiratory function. In Medical and Postsurgical ICU studies comparing propofol injectable emulsion to benzodiazepine infusion or bolus, there were no apparent differences in maintenance of adequate sedation, mean arterial pressure, or laboratory findings.
Like the comparators, propofol injectable emulsion reduced blood cortisol during sedation while maintaining responsivity to challenges with adrenocorticotropic hormone (ACTH). Case reports from the published literature generally reflect that propofol injectable emulsion has been used safely in patients with a history of porphyria or malignant hyperthermia. In hemodynamically stable head trauma patients ranging in age from 19 to 43 years, adequate sedation was maintained with propofol injectable emulsion or morphine. There were no apparent differences in adequacy of sedation, intracranial pressure, cerebral perfusion pressure, or neurologic recovery between the treatment groups.
In literature reports of severely head injured patients in Neurosurgical ICUs, propofol injectable emulsion infusion and hyperventilation, both with and without diuretics, controlled intracranial pressure while maintaining cerebral perfusion pressure. In some patients, bolus doses resulted in decreased blood pressure and compromised cerebral perfusion pressure. Propofol injectable emulsion was found to be effective in status epilepticus which was refractory to the standard anticonvulsant therapies.
For these patients, as well as for ARDS/respiratory failure and tetanus patients, sedation maintenance dosages were generally higher than those for other critically ill patient populations.
Intensive Care Unit (ICU) Sedation in Pediatric Patients
A single, randomized, controlled, clinical trial that evaluated the safety and effectiveness of propofol injectable emulsion versus standard sedative agents (SSA) was conducted on 327 pediatric ICU patients. Patients were randomized to receive either propofol injectable emulsion 2%, (113 patients), propofol injectable emulsion 1%, (109 patients), or an SSA (e.g, lorazepam, chloral hydrate, fentanyl, ketamine, morphine, or phenobarbital). Propofol injectable emulsion therapy was initiated at an infusion rate of 5.5 mg/kg/hr and titrated as needed to maintain sedation at a standardized level. The results of the study showed an increase in the number of deaths in patients treated with propofol injectable emulsion as compared to SSAs.
Of the 25 patients who died during the trial or within the 28-day follow up period: 12 (11% were) in the propofol injectable emulsion 2% treatment group, 9 (8% were) in the propofol injectable emulsion 1% treatment group, and 4% were (4%) in the SSA treatment group. The differences in mortality rate between the groups were not statistically significant. Review of the deaths failed to reveal a correlation with underlying disease status or a correlation to the drug or a definitive pattern to the causes of death.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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