Propofol Injectable Emulsion

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 [see Pediatric Use ( 8.4 )]. 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 [see Pediatric Use ( 8.4 )] . Propofol injectable emulsion is not indicated for use in Pediatric ICU sedation since the safety of this regimen has not been established [see Pediatric Use ( 8.4 )]. 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 2months. MAC sedation in the pediatric population is not recommended propofol injectable emulsion is not indicated for use in Pediatric ICU sedation.

Propofol injectable emulsion, USP is available in single-dose vials as follows: 200 mg of propofol per 20 mL of an oil-in-water emulsion (10 mg per mL), 20 mL vial 500 mg of propofol per 50 mL of an oil-in-water emulsion (10 mg per mL), 50 mL vial 1,000 mg of propofol per 100 mL of an oil-in-water emulsion (10 mg per mL), 100 mL vial Injectable emulsion: 200 mg per 20 mL (10 mg/mL), 500 mg per 50 mL (10 mg/mL), and 1,000 mg per 100 mL (10 mg/mL) single-dose vials ( 3 )

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 ( 4 )

Hypersensitivity Reactions : Serious and sometimes fatal reactions ( 5.1 ) Microbial Contamination : Strict aseptic technique must be maintained during handling. Propofol injectable emulsion vials are never to be accessed more than once or used on more than one person. Administration should commence promptly and be completed within 12 hours after the vial has been opened. Discard unused drug product. Do not use if contamination is suspected ( 5.2 ) Cardiovascular depression : Cases of bradycardia, asystole, and cardiac arrest have been reported. Pediatric patients are susceptible to this effect, particularly when fentanyl is given concomitantly ( 5.4 )

5.1 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.

5.2 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 0.15% benzyl alcohol 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.

5.3 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 [see Animal Toxicology and/or Pharmacology ( 13.2 )] . 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.

5.4 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.

5.5 Risk of Seizures When propofol injectable emulsion is administered to an epileptic patient, there is a risk of seizure during the recovery phase.

5.6 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 responsed, 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 [see Dosage and Administration ( 2.1 )].

5.7 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.

5.8 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 [see Overdosage ( 10 ) and Dosage and Administration ( 2.5 )]. 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. […]

The following serious or otherwise important adverse reactions are discussed elsewhere in the labeling:

• Hypersensitivity reaction [see Warnings and Precautions ( 5.1 )]
• Hypotension and/or bradycardia [see Warnings and Precautions ( 5.4 )]
• Propofol Infusion Syndrome [see Warnings and Precautions ( 5.9 )] In the description below, rates of the more common events represent U.S/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 include data from clinical trials in general anesthesia/MAC sedation (N=2889 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 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 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 pediatric patients from 6 days through 16 years of age in the U.S/Canadian anesthesia clinical trials is similar to the profile established with propofol 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, trunkpain, whole body weakness Cardiovascular: Premature atrial contractions Syncope, hypotension [see also Clinical Pharmacology ( 12 )], tachycardia 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, rightheart 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, somnolenceDelirium 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, kidneyfailure 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 [see Warnings and Precautions ( 5.14 )]. 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 ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories Inc., at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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 ( 7 ) Valproate : May lead to increased blood levels of propofol ( 7 )

8.1 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 [see Data, Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.4 )]). 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 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 [see Warnings and Precautions ( 5.3 ), Pediatric Use ( 8.4 ), and Animal Toxicology and/or Pharmacology ( 13.2 )] .

8.2 Lactation Risk Summary Based on data from published studies, propofol is present in human milk. Variable concentrations have been reported in human milk with administration of propofol to nursing mothers in the early post-partum period. Available data have not shown adverse reactions in breastfed infants. There are no data on the effects of propofol on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for propofol injectable emulsion and any potential adverse effects on the breastfed infant form propofol injectable emulsion or from the underlying maternal condition.

8.4 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 [see Warnings and Precautions ( 5.4 )]. 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 (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 is not indicated for ICU sedation in pediatric patients until further studies have been performed to document its safety in that population [see Clinical Pharmacology ( 12.3 ) and Dosage and Administration ( 2.1 and 2.2 )]. 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. Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. […]

The mechanism of action, like all general anesthetics, is poorly understood. However, propofol is thought to produce its sedative/anesthetic effects by the positive modulation of the inhibitory function of the neurotransmitter GABA through the ligand-gated GABA A receptors.