propofol injectable emulsion (contains edetate disodium) Use in Specific Populations

(propofol injectable emulsion (contains edetate disodium))

8 USE IN SPECIFIC POPULATIONS

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 post implantation 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), and 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 2–4% and 15–20%, 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 6–15). 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 6–18). 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 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 [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.

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 [see Warnings and Precaution (5.3), Pregnancy (8.1), and Animal Toxicology and/or Pharmacology (13.2)].

8.5 Geriatric Use

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 16 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 [see Dosage and Administration (2) and Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

The long-term administration of propofol injectable emulsion to patients with hepatic insufficiency has not been evaluated.

The pharmacokinetics of propofol do not appear to be different in people with chronic hepatic cirrhosis compared to adults with normal hepatic function. The effects of acute hepatic failure on the pharmacokinetics of propofol have not been studied.

8.7 Renal Impairment

Studies to date in patients with normal or impaired renal function have not shown any alteration in renal function with propofol injectable emulsion containing 0.005% disodium edetate. In patients at risk for renal impairment, urinalysis and urine sediment should be checked before initiation of sedation and then be monitored on alternate days during sedation.

Propofol injectable emulsion contains 0.005% disodium edetate. At high doses (2 to 3 grams per day), EDTA has been reported, on rare occasions, to be toxic to the renal tubules.

The long-term administration of propofol injectable emulsion to patients with renal failure has not been evaluated.

The pharmacokinetics of propofol do not appear to be different in people with chronic renal impairment compared to adults with normal renal function. The effects of acute renal failure on the pharmacokinetics of propofol have not been studied.

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Use in Specific Populations

8 USE IN SPECIFIC POPULATIONS

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 post implantation 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), and 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 2–4% and 15–20%, 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 6–15). 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 6–18). 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 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 [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.

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 [see Warnings and Precaution (5.3), Pregnancy (8.1), and Animal Toxicology and/or Pharmacology (13.2)].

8.5 Geriatric Use

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 16 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 [see Dosage and Administration (2) and Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

The long-term administration of propofol injectable emulsion to patients with hepatic insufficiency has not been evaluated.

The pharmacokinetics of propofol do not appear to be different in people with chronic hepatic cirrhosis compared to adults with normal hepatic function. The effects of acute hepatic failure on the pharmacokinetics of propofol have not been studied.

8.7 Renal Impairment

Studies to date in patients with normal or impaired renal function have not shown any alteration in renal function with propofol injectable emulsion containing 0.005% disodium edetate. In patients at risk for renal impairment, urinalysis and urine sediment should be checked before initiation of sedation and then be monitored on alternate days during sedation.

Propofol injectable emulsion contains 0.005% disodium edetate. At high doses (2 to 3 grams per day), EDTA has been reported, on rare occasions, to be toxic to the renal tubules.

The long-term administration of propofol injectable emulsion to patients with renal failure has not been evaluated.

The pharmacokinetics of propofol do not appear to be different in people with chronic renal impairment compared to adults with normal renal function. The effects of acute renal failure on the pharmacokinetics of propofol have not been studied.

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