propofol injectable emulsion (contains benzyl alcohol) Clinical Studies

(propofol injectable emulsion (contains benzyl alcohol))

14 CLINICAL STUDIES

     

14.1 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 1041)

69 (23 to 374)

>12 through 16 years

161 (84 to 359)

69 (26 to 251)

14.2 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.

14.3 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.

14.4 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.

14.5 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.

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Clinical Studies

14 CLINICAL STUDIES

     

14.1 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 1041)

69 (23 to 374)

>12 through 16 years

161 (84 to 359)

69 (26 to 251)

14.2 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.

14.3 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.

14.4 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.

14.5 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.

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