Diprivan PROPOFOL 10 mg/mL Injection, Emulsion — NDC 63323-269-94 (Billing 63323-0269-94)

12 CLINICAL PHARMACOLOGY DIPRIVAN is an intravenous general anesthetic and sedation drug for use in the induction and maintenance of anesthesia or sedation. Intravenous injection of a therapeutic dose of propofol induces anesthesia, with minimal excitation, usually within 40 seconds from the start of injection (the time for one arm-brain circulation). As with other rapidly acting intravenous anesthetic agents, the half-time of the blood-brain equilibration is approximately 1 to 3 minutes, accounting for the rate of induction of anesthesia.

12.1Mechanism of Action 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.

12.2Pharmacodynamics Pharmacodynamic properties of propofol are dependent upon the therapeutic blood propofol concentrations. Steady-state propofol blood concentrations are generally proportional to infusion rates. Undesirable side effects, such as cardiorespiratory depression, are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in infusion rates.

An adequate interval (3 to 5 minutes) must be allowed between dose adjustments in order to assess clinical effects. The hemodynamic effects of DIPRIVAN during induction of anesthesia vary. If spontaneous ventilation is maintained, the major cardiovascular effect is arterial hypotension (sometimes greater than a 30% decrease) with little or no change in heart rate and no appreciable decrease in cardiac output.

If ventilation is assisted or controlled (positive pressure ventilation), there is an increase in the incidence and the degree of depression of cardiac output. Addition of an opioid, used as a premedicant, further decreases cardiac output and respiratory drive. If anesthesia is continued by infusion of DIPRIVAN, the stimulation of endotracheal intubation and surgery may return arterial pressure towards normal.

However, cardiac output may remain depressed. Comparative clinical studies have shown that the hemodynamic effects of DIPRIVAN during induction of anesthesia are generally more pronounced than with other intravenous induction agents. Induction of anesthesia with DIPRIVAN is frequently associated with apnea in both adults and pediatric patients.

In adult patients who received DIPRIVAN (2 mg/kg to 2.5 mg/kg), apnea lasted less than 30 seconds in 7% of patients, 30 seconds to 60 seconds in 24% of patients, and more than 60 seconds in 12% of patients. In pediatric patients from birth through 16 years of age assessable for apnea who received bolus doses of DIPRIVAN (1 mg/kg to 3.6 mg/kg), apnea lasted less than 30 seconds in 12% of patients, 30 seconds to 60 seconds in 10% of patients, and more than 60 seconds in 5% of patients. During maintenance of general anesthesia, DIPRIVAN causes a decrease in spontaneous minute ventilation usually associated with an increase in carbon dioxide tension which may be marked depending upon the rate of administration and concurrent use of other medications (e.g., opioids, sedatives, etc.).

During monitored anesthesia care (MAC) sedation, attention must be given to the cardiorespiratory effects of DIPRIVAN. Hypotension, oxyhemoglobin desaturation, apnea, and airway obstruction can occur, especially following a rapid bolus of DIPRIVAN. During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration.

During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus administration in order to minimize undesirable cardiorespiratory effects. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation [see Warnings and Precautions ( 5.12 )] . Clinical and preclinical studies suggest that DIPRI… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action 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.

12.3Pharmacokinetics The pharmacokinetics of propofol are well described by a three- compartment linear model with compartments representing the plasma, rapidly equilibrating tissues, and slowly equilibrating tissues. Following an intravenous bolus dose, there is rapid equilibration between the plasma and the brain, accounting for the rapid onset of anesthesia. Plasma levels initially decline rapidly as a result of both distribution and metabolic clearance.

Distribution accounts for about half of this decline following a bolus of propofol. However, distribution is not constant over time, but decreases as body tissues equilibrate with plasma and become saturated. The rate at which equilibration occurs is a function of the rate and duration of the infusion.

When equilibration occurs there is no longer a net transfer of propofol between tissues and plasma. Discontinuation of the recommended doses of DIPRIVAN after the maintenance of anesthesia for approximately one hour, or for sedation in the ICU for one day, results in a prompt decrease in blood propofol concentrations and rapid awakening. Longer infusions (10 days of ICU sedation) result in accumulation of significant tissue stores of propofol, such that the reduction in circulating propofol is slowed and the time to awakening is increased.

By daily titration of DIPRIVAN dosage to achieve only the minimum effective therapeutic concentration, rapid awakening within 10 to 15 minutes can occur even after long-term administration. If, however, higher than necessary infusion levels have been maintained for a long time, propofol redistribution from fat and muscle to the plasma can be significant and slow recovery. The figure below illustrates the fall of plasma propofol levels following infusions of various durations to provide ICU sedation.

The large contribution of distribution (about 50%) to the fall of propofol plasma levels following brief infusions means that after very long infusions a reduction in the infusion rate is appropriate by as much as half the initial infusion rate in order to maintain a constant plasma level. Therefore, failure to reduce the infusion rate in patients receiving DIPRIVAN 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 DIPRIVAN infusion for ICU sedation.

Adults Propofol clearance ranges from 23 mL/kg/min to 50 mL/kg/min (1.6 L/min to

3.4L/min in 70 kg adults). It is chiefly eliminated by hepatic conjugation to inactive metabolites which are excreted by the kidney. A glucuronide conjugate accounts for about 50% of the administered dose.

Propofol has a steady-state volume of distribution (10-day infusion) approaching 60 L/kg in healthy adults. A difference in pharmacokinetics due to gender has not been observed. The terminal half-life of propofol after a 10-day infusion is 1 day to 3 days.

Geriatrics With increasing patient age, the dose of propofol needed to achieve a defined anesthetic end point (dose-requirement) decreases. This does not appear to be an age-related change in pharmacodynamics or brain sensitivity, as measured by EEG burst suppression. With increasing patient age, pharmacokinetic changes are such that, for a given intravenous bolus dose, higher peak plasma concentrations occur, which can explain the decreased dose requirement.

These higher peak plasma concentrations in the elderly can predispose patients to cardiorespiratory effects including hypotension, apnea, airway obstruction, and/or arterial oxygen desaturation. The higher plasma levels reflect an age-related decrease in volume of distribution and intercompartmental clearance. Lower doses are therefore recommended for initiation and maintenance of sedation and anesthesia in elderly patients [see Dosage and Administration ( 2 )] .

Pediatrics The pharmacokinetics of propofol were studied in children between 3 years and 12 years of age who… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Pharmacodynamic properties of propofol are dependent upon the therapeutic blood propofol concentrations. Steady-state propofol blood concentrations are generally proportional to infusion rates. Undesirable side effects, such as cardiorespiratory depression, are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in infusion rates.

An adequate interval (3 to 5 minutes) must be allowed between dose adjustments in order to assess clinical effects. The hemodynamic effects of DIPRIVAN during induction of anesthesia vary. If spontaneous ventilation is maintained, the major cardiovascular effect is arterial hypotension (sometimes greater than a 30% decrease) with little or no change in heart rate and no appreciable decrease in cardiac output.

If ventilation is assisted or controlled (positive pressure ventilation), there is an increase in the incidence and the degree of depression of cardiac output. Addition of an opioid, used as a premedicant, further decreases cardiac output and respiratory drive. If anesthesia is continued by infusion of DIPRIVAN, the stimulation of endotracheal intubation and surgery may return arterial pressure towards normal.

However, cardiac output may remain depressed. Comparative clinical studies have shown that the hemodynamic effects of DIPRIVAN during induction of anesthesia are generally more pronounced than with other intravenous induction agents. Induction of anesthesia with DIPRIVAN is frequently associated with apnea in both adults and pediatric patients.

In adult patients who received DIPRIVAN (2 mg/kg to 2.5 mg/kg), apnea lasted less than 30 seconds in 7% of patients, 30 seconds to 60 seconds in 24% of patients, and more than 60 seconds in 12% of patients. In pediatric patients from birth through 16 years of age assessable for apnea who received bolus doses of DIPRIVAN (1 mg/kg to 3.6 mg/kg), apnea lasted less than 30 seconds in 12% of patients, 30 seconds to 60 seconds in 10% of patients, and more than 60 seconds in 5% of patients. During maintenance of general anesthesia, DIPRIVAN causes a decrease in spontaneous minute ventilation usually associated with an increase in carbon dioxide tension which may be marked depending upon the rate of administration and concurrent use of other medications (e.g., opioids, sedatives, etc.).

During monitored anesthesia care (MAC) sedation, attention must be given to the cardiorespiratory effects of DIPRIVAN. Hypotension, oxyhemoglobin desaturation, apnea, and airway obstruction can occur, especially following a rapid bolus of DIPRIVAN. During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration.

During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus administration in order to minimize undesirable cardiorespiratory effects. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation [see Warnings and Precautions ( 5.12 )] . Clinical and preclinical studies suggest that DIPRIVAN is rarely associated with elevation of plasma histamine levels.

Preliminary findings in patients with normal intraocular pressure indicate that DIPRIVAN produces a decrease in intraocular pressure which may be associated with a concomitant decrease in systemic vascular resistance. Clinical studies indicate that DIPRIVAN when used in combination with hypocarbia increases cerebrovascular resistance and decreases cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure. DIPRIVAN does not affect cerebrovascular reactivity to changes in arterial carbon dioxide tension [see Clinical Studies ( 14.2 )].

Clinical studies indicate that DIPRIVAN does not suppress the adrenal response to ACTH. Animal studies and limited experience in susceptible patients have not indicated any propensity of DIPRIVAN to induce mali… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES

14.1Pediatric Anesthesia DIPRIVAN 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)

14.2Neuroanesthesia DIPRIVAN 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 DIPRIVAN dose of 1.4 mg/kg (range: 0.9 mg/kg to 6.9 mg/kg) and maintained with a median maintenance DIPRIVAN dose of 146 mcg/kg/min (range: 68 mcg/kg/min to 425 mcg/kg/min).

The median duration of the DIPRIVAN maintenance infusion was 285 minutes (range: 48 minutes to 622 minutes). DIPRIVAN 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), DIPRIVAN, when given by infusion or slow bolus in combination with hypocarbia, is capable of decreasing ICP independent of changes in arterial pressure.

14.3Cardiac Anesthesia DIPRIVAN 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 DIPRIVAN 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.

14.4Intensive Care Unit (ICU) Sedation in Adult Patients DIPRIVAN was compared to benzodiazepines and opioids in clinical trials involving ICU patients. Of these, 302 received DIPRIVAN and comprise the overall safety database for ICU sedation. Across all clinical studies, the mean infusion maintenance rate for all DIPRIVAN 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 DIPRIVAN to benzodiazepine infusion or bolus, there were no apparent differences in maintenance of adequate sedation, mean arterial pressure, or laboratory findings. Like the comparators, DIPRIVAN reduced blood cortisol during sedation while maintaining responsivity to challenges with adrenocorticotropic hormone (ACTH). Case reports… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals have not been performed to evaluate the carcinogenic potential of propofol. Mutagenesis Propofol was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) using Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538. Propofol was not mutagenic in either the gene mutation/gene conversion test using Saccharomyces cerevisiae , or in vitro cytogenetic studies in Chinese hamsters.

In the in vivo mouse micronucleus assay with Chinese Hamsters propofol administration did not produce chromosome aberrations. Impairment of Fertility Female Wistar rats were administered either 0, 10, or 15 mg/kg/day propofol intravenously from 2 weeks before pregnancy to day 7 of gestation did not show impaired fertility (0.65 and 1 times the human induction dose of 2.5 mg/kg based on body surface area). Male fertility in rats was not affected in a dominant lethal study at intravenous doses up to 15 mg/kg/day for 5 days.

13.2Animal Toxicology and/or Pharmacology Intra-arterial injection in animals did not induce local tissue effects. Intentional injection into subcutaneous or perivascular tissues of animals caused minimal tissue reaction. Published studies in animals demonstrate that the use of anesthetic agents 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 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 an anesthetic regimen that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer increased neuronal cell loss. Data in rodents and in primates suggest that the neuronal and oligodendrocyte cell losses are associated with subtle but 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 neonates and young children who require procedures against the potential risks suggested by the nonclinical data [see Warnings and Precautions ( 5.3 ); Pregnancy ( 8.1 ), and Pediatric Use ( 8.4 )] .