Brand Name: Anectine Generic Name: succinylcholine chloride ANECTINE (succinylcholine chloride) is an ultra shortacting depolarizing-type, skeletal muscle

relaxant for intravenous (IV) administration. Succinylcholine chloride is a white, odorless, slightly bitter powder and very soluble in water. The drug is unstable in alkaline solutions but relatively stable in acid solutions, depending upon the concentration of the solution and the storage temperature. Solutions of succinylcholine chloride should be stored under refrigeration to preserve potency. ANECTINE (succinylcholine chloride) Injection is a sterile nonpyrogenic solution for IV injection, containing 20 mg succinylcholine chloride in each mL and made isotonic with sodium chloride. The pH is adjusted to 3.5 with hydrochloric acid. Methylparaben (0.1%) is added as a preservative. The chemical name for succinylcholine chloride is 2,2'[(1,4-dioxo-1,4butanediyl)bis(oxy)]bis[N,N,Ntrimethylethanaminium] dichloride, and the structural formula is:

INDICATIONS Succinylcholine chloride is indicated as an adjunct to general anesthesia, to facilitate tracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation. DOSAGE AND ADMINISTRATION The dosage of succinylcholine should be individualized and should always be determined by the clinician after careful assessment of the patient (seeWARNINGS). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Solutions which are not clear and colorless should not be used. Adults For Short Surgical Procedures The average dose required to produce neuromuscular blockade and to facilitate tracheal intubation is 0.6 mg/kg ANECTINE (succinylcholine chloride) Injection given intravenously. The optimum dose will vary among individuals and may be from 0.3 to 1.1 mg/kg for adults. Following administration of doses in this range, neuromuscular blockade develops in about 1 minute; maximum blockade may persist for about 2 minutes, after which recovery takes place within 4 to 6 minutes. However, very large doses may result in more prolonged blockade. A 5- to 10-mg test dose may be used to determine the sensitivity of the patient and the individual recovery time (see PRECAUTIONS). For Long Surgical Procedures The dose of succinylcholine administered by infusion depends upon the duration of the surgical procedure and the need for muscle relaxation. The average rate for an adult ranges between 2.5 and 4.3 mg per minute.

Solutions containing from 1 to 2 mg per mL succinylcholine have commonly been used for continuous infusion. The more dilute solution (1 mg per mL) is probably preferable from the standpoint of ease of control of the rate of administration of the drug and, hence, of relaxation. This IV solution containing 1 mg per mL may be administered at a rate of 0.5 mg (0.5 mL) to 10 mg (10 mL) per minute to obtain the required amount of relaxation. The amount required per minute will depend upon the individual response as well as the degree of relaxation required. Avoid overburdening the circulation with a large volume of fluid. It is recommended that neuromuscular function be carefully monitored with a peripheral nerve stimulator when using succinylcholine by infusion in order to avoid overdose, detect development of Phase II block, follow its rate of recovery, and assess the effects of reversing agents (see PRECAUTIONS). Intermittent IV injections of succinylcholine may also be used to provide muscle relaxation for long procedures. An IV injection of 0.3 to 1.1 mg/kg may be given initially, followed, at appropriate intervals, by further injections of 0.04 to 0.07 mg/kg to maintain the degree of relaxation required. Pediatrics For emergency tracheal intubation or in instances where immediate securing of the airway is necessary, the IV dose of succinylcholine is 2 mg/kg for infants and small children; for older children and adolescents the dose is 1 mg/kg (seeBOX WARNING and PRECAUTIONS: Pediatric Use). Rarely, IV bolus administration of succinylcholine in infants and children may result in malignant ventricular arrhythmias and cardiac arrest secondary to acute rhabdomyolysis with hyperkalemia. In such situations, an underlying myopathyshould be suspected. Intravenous bolus administration of succinylcholine in infants or children may result in profound bradycardia or, rarely, asystole. As in adults, the incidence of bradycardia in children is higher following a second dose of succinylcholine. The occurrence of bradyarrhythmias may be reduced by pretreatment with atropine (see PRECAUTIONS: Pediatric Use). Intramuscular Use If necessary, succinylcholine may be given intramuscularly to infants, older children, or adults when a suitable vein is inaccessible. A dose of up to 3 to 4 mg/kg may be given, but not more than 150 mg total dose should be administered by this route. The onset of effect of succinylcholine given intramuscularly is usually observed in about 2 to 3 minutes. Compatibility and Admixtures Succinylcholine is acidic (pH 3.5) and should not be mixed with alkaline solutions having a pH greater than 8.5 (e.g., barbiturate solutions). ANECTINE (succinylcholine chloride) Injection is stable for 24 hours after dilution to a final concentration of 1 to 2 mg/mL in 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP. Aseptic techniques should be used to prepare the diluted product. Admixtures of ANECTINE (succinylcholine chloride) should be prepared for single patient use only. The unused portion of diluted ANECTINE (succinylcholine chloride) should be discarded. SIDE EFFECTS Adverse reactions to succinylcholine consist primarily of an extension of its pharmacological actions.

Succinylcholine causes profound muscle relaxation resulting in respiratory depression to the point of apnea; this effect may be prolonged. Hypersensitivity reactions, including anaphylaxis, may occur in rare instances. The following additional adverse reactions have been reported: cardiac arrest, malignant hyperthermia, arrhythmias, bradycardia, tachycardia,hypertension, hy potension, hyperkalemia, prolonged respiratory depression or apnea, increased intraocular pressure, muscle fasciculation, jaw rigidity, postoperative muscle pain, rhabdomyolysis with possible myoglobinuric acute renal failure, excessive salivation, and rash. There have been post-marketing reports of severe allergic reactions (anaphylactic and anaphylactoid reactions) associated with use of neuromuscular blocking agents, including ANECTINE (succinylcholine chloride) . These reactions, in some cases, have been life-threatening and fatal. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency (see WARNINGS AND PRECAUTIONS). DRUG INTERACTIONS Drugs which may enhance the neuromuscular blocking action of succinylcholine include: promazine, oxytocin, aprotinin, certain non-penicillin antibiotics, quinidine, -adrenergic blockers, procainamide, lidocaine, trimethaphan, lithium carbonate, magnesium salts, quinine, chloroquine, diethylether, isoflurane, desflurane, metoclopramide, and terbutaline. The neuromuscular blocking effect of succinylcholine may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase (see PRECAUTIONS). If other neuromuscular blocking agents are to be used during the same procedure, the possibility of a synergistic or antagonistic effect should be considered. WARNINGS SUCCINYLCHOLINE SHOULD BE USED ONLY BY THOSE SKILLED IN THE MANAGEMENT OF ARTIFICIAL RESPIRATION AND ONLY WHEN FACILITIES ARE INSTANTLY AVAILABLE FOR TRACHEAL INTUBATION AND FOR PROVIDING ADEQUATE VENTILATION OF THE PATIENT, INCLUDING THE ADMINISTRATION OF OXYGEN UNDER POSITIVE PRESSURE AND THE ELIMINATION OF CARBON DIOXIDE. THE CLINICIAN MUST BE PREPARED TO ASSIST OR CONTROL RESPIRATION. TO AVOID DISTRESS TO THE PATIENT, SUCCINYLCHOLINE SHOULD NOT BE ADMINISTERED BEFORE UNCONSCIOUSNESS HAS BEEN INDUCED. IN EMERGENCY SITUATIONS, HOWEVER, IT MAY BE NECESSARY TO ADMINISTER SUCCINYLCHOLINE BEFORE UNCONSCIOUSNESS IS INDUCED. SUCCINYLCHOLINE IS METABOLIZED BY PLASMA CHOLINESTERASE AND SHOULD BE USED WITH CAUTION, IF AT ALL, IN PATIENTS KNOWN TO BE OR SUSPECTED OF BEING HOMOZYGOUS FOR THE ATYPICAL PLASMA CHOLINESTERASE GENE. Anaphylaxis Severe anaphylactic reactions to neuromuscular blocking agents, including ANECTINE (succinylcholine chloride) , have been reported. These reactions have in

some cases been life-threatening and fatal. Due to the potential severity of these reactions, the necessary precautions, such as the immediate availability of appropriate emergency treatment, should be taken. Precautions should also be taken in those individuals who have had previous anaphylactic reactions to other neuromuscular blocking agents since cross-reactivity between neuromuscular blocking agents, both depolarizing and non-depolarizing, has been reported in this class of drugs. Hyperkalemia (SEE BOX WARNING.) Succinylcholine should be administered with GREAT CAUTION to patients suffering from electrolyte abnormalities and those who may have massive digitalis toxicity, because in these circumstances succinylcholine may induce serious cardiac arrhythmias or cardiac arrest due to hyperkalemia. GREAT CAUTION should be observed if succinylcholine is administered to patients during the acute phase of injury following major burns, multiple trauma, extensive denervation of skeletal muscle, or upper motor neuron injury (seeCONTRAINDICATIONS). The risk of hyperkalemia in these patients increases over time and usually peaks at 7 to 10 days after the injury. The risk is dependent on the extent and location of the injury. The precise time of onset and the duration of the risk period are undetermined. Patients with chronic abdominal infection, subarachnoid hemorrhage, or conditions causing degeneration of central and peripheral nervous systems should receive succinylcholine withGREAT CAUTION because of the potential for developing severe hyperkalemia. Malignant Hyperthermia Succinylcholine administration has been associated with acute onset of malignant hyperthermia, a potentially fatal hypermetabolic state of skeletal muscle. The risk of developing malignant hyperthermia following succinylcholine administration increases with the concomitant administration of volatile anesthetics. Malignant hyperthermia frequently presents as intractable spasm of the jaw muscles (masseter spasm) which may progress to generalized rigidity, increased oxygen demand, tachycardia, tachypnea, and profound hyperpyrexia. Successful outcome depends on recognition of early signs, such as jaw muscle spasm, acidosis, or generalized rigidity to initial administration of succinylcholine for tracheal intubation, or failure of tachycardia to respond to deepening anesthesia. Skin mottling, rising temperature, and coagulopathies may occur later in the course of the hypermetabolic process. Recognition of the syndrome is a signal for discontinuance of anesthesia, attention to increased oxygen consumption, correction of acidosis, support of circulation, assurance of adequate urinary output, and institution of measures to control rising temperature. Intravenous dantrolene sodium is recommended as an adjunct to supportive measures in the management of this problem. Consult literature references and the dantrolene prescribing information for additional information about the management of malignant hyperthermic crisis. Continuous monitoring of temperature and expired CO2 is recommended as an aid to early recognition of malignant hyperthermia.

Other In both adults and children, the incidence of bradycardia, which may progress toasystole, is higher following a second dose of succinylcholine. The incidence and severity of bradycardia is higher in children than in adults. Pretreatment withanticholinergic agents (e.g., atropine) may reduce the occurrence of bradyarrhythmias. Succinylcholine causes an increase in intraocular pressure. It should not be used in instances in which an increase in intraocular pressure is undesirable (e.g., narrow angle glaucoma, penetrating eye injury) unless the potential benefit of its use outweighs the potential risk. Succinylcholine is acidic (pH = 3.5) and should not be mixed with alkaline solutions having a pH greater than 8.5 (e.g., barbiturate solutions). PRECAUTIONS (SEE BOX WARNING.) General When succinylcholine is given over a prolonged period of time, the characteristic depolarization block of the myoneural junction (Phase I block) may change to a block with characteristics superficially resembling a nondepolarizing block (Phase II block). Prolonged respiratory muscle paralysis or weakness may be observed in patients manifesting this transition to Phase II block. The transition from Phase I to Phase II block has been reported in seven of seven patients studied under halothane anesthesia after an accumulated dose of 2 to 4 mg/kg succinylcholine (administered in repeated, divided doses). The onset of Phase II block coincided with the onset of tachyphylaxis and prolongation of spontaneous recovery. In another study, using balanced anesthesia (N2O/O2/narcoticthiopental) and succinylcholine infusion, the transition was less abrupt, with great individual variability in the dose of succinylcholine required to produce Phase II block. Of 32 patients studied, 24 developed Phase II block. Tachyphylaxis was not associated with the transition to Phase II block, and 50% of the patients who developed Phase II block experienced prolonged recovery. When Phase II block is suspected in cases of prolonged neuromuscular blockade, positive diagnosis should be made by peripheral nerve stimulation prior to administration of any anticholinesterase drug. Reversal of Phase II block is a medical decision which must be made upon the basis of the individual, clinical pharmacology, and the experience and judgment of the physician. The presence of Phase II block is indicated by fade of responses to successive stimuli (preferably train-of-four). The use of an anticholinesterase drug to reverse Phase II block should be accompanied by appropriate doses of an anticholinergic drug to prevent disturbances of cardiac rhythm. After adequate reversal of Phase II block with an anticholinesterase agent, the patient should be continually observed for at least 1 hour for signs of return of muscle relaxation. Reversal should not be attempted unless: (1) a peripheral nerve stimulator is used to determine the presence of Phase II block (since anticholinesterase agents will potentiate succinylcholine-induced Phase I block), and (2) spontaneous recovery of muscle twitch has been observed for at least 20 minutes and has reached a plateau with further recovery proceeding slowly; this delay is to ensure complete hydrolysis of

succinylcholine by plasma cholinesterase prior to administration of the anticholinesterase agent. Should the type of block be misdiagnosed, depolarization of the type initially induced by succinylcholine (i.e., Phase I block) will be prolonged by an anticholinesterase agent. Succinylcholine should be employed with caution in patients with fractures or muscle spasm because the initial muscle fasciculations may cause additional trauma. Succinylcholine may cause a transient increase in intracranial pressure; however, adequate anesthetic induction prior to administration of succinylcholine will minimize this effect. Succinylcholine may increase intragastric pressure, which could result in regurgitation and possible aspiration of stomach contents. Neuromuscular blockade may be prolonged in patients with hypokalemia orhypocalcemia. Since allergic cross-reactivity has been reported in this class, request information from your patients about previous anaphylactic reactions to other neuromuscular blocking agents. In addition, inform your patients that severe anaphylactic reactions to neuromuscular blocking agents, including ANECTINE (succinylcholine chloride) have been reported. Reduced Plasma Cholinesterase Activity Succinylcholine should be used carefully in patients with reduced plasma cholinesterase (pseudocholinesterase) activity. The likelihood of prolonged neuromuscular block following administration of succinylcholine must be considered in such patients (see DOSAGE AND ADMINISTRATION). Plasma cholinesterase activity may be diminished in the presence of genetic abnormalities of plasma cholinesterase (e.g., patients heterozygous or homozygous for atypical plasma cholinesterase gene), pregnancy, severe liver orkidney disease, malignant tumors, infections, burns, anemia, decompensatedheart disease, peptic ulcer, or myxedema. Plasma cholinesterase activity may also be diminished by chronic administration of oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors, and by irreversible inhibitors of plasma cholinesterase (e.g., organophosphate insecticides, echothiophate, and certain antineoplastic drugs). Patients homozygous for atypical plasma cholinesterase gene (1 in 2500 patients) are extremely sensitive to the neuromuscular blocking effect of succinylcholine. In these patients, a 5- to 10-mg test dose of succinylcholine may be administered to evaluate sensitivity to succinylcholine, or neuromuscular blockade may be produced by the cautious administration of a 1-mg/mL solution of succinylcholine by slow IV infusion. Apnea or prolonged muscle paralysis should be treated with controlled respiration. Carcinogenesis, Mutagenesis, Impairment of Fertility There have been no long-term studies performed in animals to evaluate carcinogenic potential. Pregnancy Teratogenic Effects - Pregnancy Category C Animal reproduction studies have not been conducted with succinylcholine chloride. It is also not known whether succinylcholine can cause fetal harm when administered to a pregnant woman or can affect

reproduction capacity. Succinylcholine should be given to a pregnant woman only if clearly needed. Nonteratogenic Effects Plasma cholinesterase levels are decreased by approximately 24% during pregnancy and for several days postpartum. Therefore, a higher proportion of patients may be expected to show increased sensitivity (prolonged apnea) to succinylcholine when pregnant than when nonpregnant. Labor and Delivery Succinylcholine is commonly used to provide muscle relaxation during delivery by cesarean section. While small amounts of succinylcholine are known to cross the placental barrier, under normal conditions the quantity of drug that enters fetal circulation after a single dose of 1 mg/kg to the mother should not endanger the fetus. However, since the amount of drug that crosses the placental barrier is dependent on the concentration gradient between the maternal and fetal circulations, residual neuromuscular blockade (apnea and flaccidity) may occur in the neonate after repeated high doses to, or in the presence of atypical plasma cholinesterase in, the mother. Nursing Mothers It is not known whether succinylcholine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised following succinylcholine administration to a nursing woman. Pediatric Use There are rare reports of ventricular dysrhythmias and cardiac arrest secondary to acute rhabdomyolysis with hyperkalemia in apparently healthy children who receive succinylcholine (see BOX WARNING). Many of these children were subsequently found to have a skeletal muscle myopathy such as Duchenne's muscular dystrophy whose clinical signs were not obvious. The syndrome often presents as sudden cardiac arrest within minutes after the administration of succinylcholine. These children are usually, but not exclusively, males, and most frequently 8 years of age or younger. There have also been reports in adolescents. There may be no signs or symptoms to alert the practitioner to which patients are at risk. A careful history and physical may identify developmental delays suggestive of a myopathy. A preoperative creatine kinase could identify some but not all patients at risk. Due to the abrupt onset of this syndrome, routine resuscitative measures are likely to be unsuccessful. Careful monitoring of the electrocardiogram may alert the practitioner to peaked T-waves (an early sign). Administration of IV calcium, bicarbonate, and glucose with insulin, with hyperventilation have resulted in successful resuscitation in some of the reported cases. Extraordinary and prolonged resuscitative efforts have been effective in some cases. In addition, in the presence of signs of malignant hyperthermia, appropriate treatment should be initiated concurrently (seeWARNINGS). Since it is difficult to identify which patients are at risk, it is recommended that the use of succinylcholine in children should be reserved for emergency intubation or instances where immediate securing of the airway is necessary, e.g., laryngospasm, difficult airway, full stomach, or for intramuscular use when a suitable vein is inaccessible. As in adults, the incidence of bradycardia in children is higher following the second dose of succinylcholine. The incidence and severity of bradycardia is higher in

children than in adults. Pretreatment with anticholinergic agents, e.g., atropine, may reduce the occurrence of bradyarrhythmias. OVERDOSE Overdosage with succinylcholine may result in neuromuscular block beyond the time needed for surgery and anesthesia. This may be manifested by skeletal muscle weakness, decreased respiratory reserve, low tidal volume, or apnea. The primary treatment is maintenance of a patent airway and respiratory support until recovery of normal respiration is assured. Depending on the dose and duration of succinylcholine administration, the characteristic depolarizing neuromuscular block (Phase I) may change to a block with characteristics superficially resembling a nondepolarizing block (Phase II) (seePRECAUTIONS). CONTRAINDICATIONS Succinylcholine is contraindicated in persons with personal or familial history of malignant hyperthermia, skeletal muscle myopathies, and known hypersensitivity to the drug. It is also contraindicated in patients after the acute phase of injury following major burns, multiple trauma, extensive denervation of skeletal muscle, or upper motor neuron injury, because succinylcholine administered to such individuals may result in severe hyperkalemia which may result in cardiac arrest (see WARNINGS). The risk of hyperkalemia in these patients increases over time and usually peaks at 7 to 10 days after the injury. The risk is dependent on the extent and location of the injury. The precise time of onset and the duration of the risk period are not known. CLINICAL PHARMACOLOGY Succinylcholine is a depolarizing skeletal muscle relaxant. As does acetylcholine, it combines with the cholinergic receptors of the motor end plate to produce depolarization. This depolarization may be observed as fasciculations. Subsequent neuromuscular transmission is inhibited so long as adequate concentration of succinylcholine remains at the receptor site. Onset of flaccid paralysis is rapid (less than 1 minute after IV administration), and with single administration lasts approximately 4 to 6 minutes. Succinylcholine is rapidly hydrolyzed by plasma cholinesterase to succinylmonocholine (which possesses clinically insignificant depolarizing muscle relaxant properties) and then more slowly to succinic acid and choline (see PRECAUTIONS). About 10% of the drug is excreted unchanged in theurine. The paralysis following administration of succinylcholine is progressive, with differing sensitivities of different muscles. This initially involves consecutively the levator muscles of the face, muscles of the glottis, and finally, the intercostals and the diaphragm and all other skeletal muscles. Succinylcholine has no direct action on the uterus or other smooth muscle structures. Because it is highly ionized and has low fat solubility, it does not readily cross the placenta. Tachyphylaxis occurs with repeated administration (see PRECAUTIONS). Depending on the dose and duration of succinylcholine administration, the characteristic depolarizing neuromuscular block (Phase I block) may change to a block with characteristics superficially resembling a nondepolarizing block (Phase II block). This may be associated with prolonged respiratory muscle paralysis

or weakness in patients who manifest the transition to Phase II block. When this diagnosis is confirmed by peripheral nerve stimulation, it may sometimes be reversed with anticholinesterase drugs such as neostigmine (seePRECAUTIONS). Anticholinesterase drugs may not always be effective. If given before succinylcholine is metabolized by cholinesterase, anticholinesterase drugs may prolong rather than shorten paralysis. Succinylcholine has no direct effect on the myocardium. Succinylcholine stimulates both autonomic ganglia and muscarinic receptors which may cause changes in cardiac rhythm, including cardiac arrest. Changes in rhythm, including cardiac arrest, may also result from vagal stimulation, which may occur during surgical procedures, or from hyperkalemia, particularly in children (seePRECAUTIONS: Pediatric Use). These effects are enhanced by halogenated anesthetics. Succinylcholine causes an increase in intraocular pressure immediately after its injection and during the fasciculation phase, and slight increases which may persist after onset of complete paralysis (see WARNINGS). Succinylcholine may cause slight increases in intracranial pressure immediately after its injection and during the fasciculation phase (see PRECAUTIONS). As with other neuromuscular blocking agents, the potential for releasing histamine is present following succinylcholine administration. Signs and symptoms of histamine-mediated release such as flushing, hypotension, and bronchoconstriction are, however, uncommon in normal clinical usage. Succinylcholine has no effect on consciousness, pain threshold, or cerebration. It should be used only with adequate anesthesia (see WARNINGS). Propofol Dosage Form: injection, emulsionPropofol Description Propofol Injectable Emulsion, USP is a sterile, nonpyrogenic emulsion containing 10 mg/mL of Propofol suitable for intravenous administration. Propofol is chemically described as 2,6diisopropylphenol. The structural formula is:

C12H18O M.W. 1Propofol Clinical Pharmacology General Propofol Injectable Emulsion is an intravenous sedative-hypnotic agent for use in the induction and maintenance of anesthesia or sedation. Intravenous injection of a therapeutic dose of Propofol induces hypnosis, 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. The mechanism of action, like all general anesthetics, is poorly understood. However, Propofol is

thought to produce its sedative/anesthetic effects by the positive mondulation of the inhibitory function of the neurotransmitter GABA through the ligand-gated GABAA receptors. Pharmacodynamics 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 Propofol Injectable Emulsion 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 Propofol Injectable Emulsion, 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 Propofol Injectable Emulsion during induction of anesthesia are generally more pronounced than with other intravenous (IV) induction agents. Induction of anesthesia with Propofol Injectable Emulsion is frequently associated with apnea in both adults and pediatric patients. In adult patients who received Propofol Injectable Emulsion (2 to 2.5 mg/kg), apnea lasted less than 30 seconds in 7% of patients, 30 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 Propofol Injectable Emulsion (1 to 3.6 mg/kg), apnea lasted less than 30 seconds in 12% of patients, 30 to 60 seconds in 10% of patients, and more than 60 seconds in 5% of patients. During maintenance of general anesthesia, Propofol Injectable Emulsion 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 Propofol Injectable Emulsion. Hypotension, oxyhemoglobin desaturation, apnea, and airway obstruction can occur, especially following a rapid bolus of Propofol Injectable Emulsion. 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 (seeWARNINGS). Clinical and preclinical studies suggest that Propofol Injectable Emulsion is rarely associated with elevation of plasma histamine levels. Preliminary findings in patients with normal intraocular pressure indicate that Propofol Injectable Emulsion produces a decrease in intraocular pressure which may be associated with a concomitant decrease in systemic vascular resistance. Clinical studies indicate that Propofol Injectable Emulsion when used in combination with hypocarbia increases cerebrovascular resistance and decreases cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure. Propofol Injectable Emulsion does not affect cerebrovascular reactivity to changes in arterial carbon dioxide tension (see Clinical Trials , Neuroanesthesia). Clinical studies indicate that Propofol Injectable Emulsion does not suppress the adrenal response to ACTH. Animal studies and limited experience in susceptible patients have not indicated any propensity of Propofol Injectable Emulsion to induce malignant hyperthermia. Hemosiderin deposits have been observed in the livers of dogs receiving Propofol Injectable Emulsion containing 0.005% disodium edetate over a four-week period; the clinical significance of this is unknown. Pharmacokinetics 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 IV 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 Propofol Injectable Emulsion 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 Propofol Injectable Emulsion 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 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. Adults Propofol clearance ranges from 23 to 50 mL/kg/min (1.6 to 3.4 L/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 halflife of Propofol after a 10-day infusion is 1 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 IV 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). Pediatrics The pharmacokinetics of Propofol were studied in children between 3 and 12 years of age who received Propofol Injectable Emulsion for periods of approximately 1 to 2 hours. The observed distribution and clearance of Propofol in these children were similar to adults. Organ Failure The pharmacokinetics of Propofol do not appear to be different in people with chronic hepatic cirrhosis or chronic renal impairment compared to adults with normal hepatic and renal function. The effects of acute hepatic or renal failure on the pharmacokinetics of Propofol have not been studied. 78.27 Propofol is slightly soluble in water and, thus, is formulated in a white, oil-in-water emulsion. The pKa is 11. The octanol/water partition coefficient for Propofol is 6761:1 at a pH of 6 to 8.5. In addition to the active component, Propofol, the formulation also contains soybean oil (100 mg/mL), glycerol (22.5 mg/mL), egg lecithin (12 mg/mL); and disodium edetate (0.005%); with sodium hydroxide to adjust pH. The Propofol Injectable Emulsion, USP is isotonic and has a pH of 7 to 8.5.

What may interact with this medicine? Do not take this medicine with any of the following medications: MAOIs like Carbex, Eldepryl, Marplan, Nardil, and Parnate St. John's Wort This medicine may also interact with the following medications: alcohol barbiturates for sleep or seizures levodopa medicines for depression, anxiety, or psychotic disturbances medicines for sleep narcotic medicines for pain other medicines for sleep during surgery Read more: http://www.healthline.com/goldcontent/p ropofol#ixzz1R3BN6u9X Healthline.com - Connect to Better Health What side effects may I notice from receiving this medicine? Side effects that you should report to your doctor or health care professional as soon as possible: allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue breathing problems changes in vision dark urine fast, irregular heartbeat feeling faint or lightheaded, falls fever low blood pressure muscle pain or weakness numbness or tingling in the hands or feet seizures stomach pain trouble passing urine or change in the amount of urine uncontrollable muscle spasm unusual weakness Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome): dizziness nausea pain at site where injected Read more: http://www.healthline.com/goldcontent/p ropofol#ixzz1R3BQS8al Healthline.com - Connect to Better Health Mechanism of action/Effect: Propofol is a short-acting hypnotic {01} {04} {09} {12} {15}. Its mechanism of action has not been well-defined {11}. Other actions/effects: Hemodynamic effects: Propofol's hemodynamic effects are generally more pronounced than those of other intravenous anesthetic agents {01} {06} {08}. Arterial hypotension, with readings decreased by as much as 30% or more {01} {04} {06} {08} {15}, has been reported, possibly due to inhibition of

sympathetic vasoconstrictor nerve activity {42}. Hypotensive effects are generally proportional to dose and rate of administration of propofol {04} {08} {09}, and may be potentiated by opioid analgesics {01}{04} {08}. Endotracheal intubation and surgical stimulation may increase arterial pressure {01} {06}{10} {11}; increases in heart rate and/or blood pressure to greater than baseline values, which occur frequently with other agents, are not as significant with propofol, possibly due to central sympatholytic and/or vagotonic effects {04}. Propofol may also decrease systemic vascular resistance {04} {06} {08} {10} {11} {24}, myocardial blood flow, and oxygen consumption {04}. The mechanism of these effects may involve direct vasodilation {04} {06} {10} and negative inotropy{04} {10}. Effects such as decreased stroke volume and cardiac output have been demonstrated in some studies {01} {04} {06} {10}. Respiratory effects: Propofol is a respiratory depressant, frequently producing apnea that may persist for longer than 60 seconds {01} {06} {08} {10} {11} {15}, depending on factors such as premedication {04} {08} {10}, rate of administration {10}, dose administered {04} {10}, and presence of hyperventilation or hyperoxia {10}. In addition, propofol may produce significant decreases in respiratory rate {10}, minute volume {06} {10}, tidal volume {06} {10}, mean inspiratory flow rate {06}, and functional residual capacity {06}. These respiratory depressant effects may be the result of depression of the central inspiratory drive as opposed to a change in central timing {06}. The ventilatory depressant effects of propofol may be counteracted by painful surgical stimulation {06}. Cerebral effects: Propofol decreases cerebral blood flow {01} {06} {10} {36}, cerebral metabolic oxygen consumption{01} {10} {36}, and intracranial pressure {01} {10}, and increases cerebrovascular resistance {01}{06} {10}. It does not appear to affect cerebrovascular reactivity to changes in arterial carbon dioxide tension {01} {06} {10} {39}. Other effects: Preliminary findings suggest that in patients with normal intraocular pressure, propofol decreases intraocular pressure {01} {10} {11} by as much as 30 to 50% {04} {06}. This decrease may be associated with a concomitant decrease in systemic vascular resistance {01}. Clinical studies have shown that propofol does not cause significant signs of histamine release{01} {04} {06} {08} {16} or significant increases in plasma immunoglobulin or complement C 3 levels{06}. Respiratory resistance after tracheal intubation is lower when propofol is used for induction of anesthesia than when thiopental or high-dose etomidate is used for induction of anesthesia{48}. Although propofol has the potential for affecting adrenal steroidogenesis {06}, it does

not appear to block cortisol and aldosterone secretion in response to surgical stress or adrenocorticotropic hormone (ACTH) in clinical practice {01} {06} {08} {10} {11} {13} {16} {24}. Although transient decreases in plasma cortisol concentrations have occurred, these reductions have not been sustained {08} {10}. Propofol appears to have no analgesic activity {06}. In addition, animal studies have demonstrated no significant effect on coagulation profiles {06} {08} {24}. Limited experience with propofol in susceptible patients and animal studies has not demonstrated a propensity to induce malignant hyperthermia {01}. Propofol has antiemetic properties {10} {43} {47}. Anesthesia with propofol results in less nausea and vomiting than anesthesia with desflurane, enflurane, isoflurane, methohexital, nitrous oxide, or thiopental {10} {16} {44} {45} {46}.Distribution: Propofol is rapidly {08} {10} {12} {14} and extensively {04} {10} {12} {14} distributed in the body. It crosses the blood-brain barrier quickly {09}, and its short duration of action is due to rapid redistribution from the CNS to other tissues {01} {09} {12}, high metabolic clearance {01} {04}, and high lipophilicity {04} {10} {11} {12} {14}. Volumes of distribution: Initial apparent (Vol D): 13 to 76 liters (L) {04} {10} {11} {12}. Steady-state (Vol DSS): 171 to 349 L {10} {12}. Elimination (Vol D): 209 to 1008 L {10} {11}. Steady-state (Vol DSS) in pediatric patients: 9.5 3.71 liters per kg of body weight (L/kg) {54}. Protein binding: Very high (95 to 99%) {04} {12}. Biotransformation: Hepatic {01} {04} {08} {11} {12} {22}; rapidly undergoes glucuronide conjugation to inactive metabolites {01} {04} {08} {10}. An unidentified route of extrahepatic metabolism may also exist, suggested by the fact that propofol clearance exceeds estimated hepatic blood flow {01} {04} {06}{10} {11} {12} {14}. Half-life: Distribution: Two distribution phases Rapid2 to 4 minutes {04} {10}. Slower30 to 64 minutes {01} {04} {12}. Elimination: Terminal elimination half-life is 3 to 12 hours {01} {09} {10} {11} {12}; prolonged administration of propofol may result in a longer duration {01} {09}. Note: The long terminal elimination half-life of propofol does not reflect elimination, as more than 70% is eliminated during the first 2 phases {12}. Some investigators believe that the second exponential phase half-life (30 to 64 minutes) best explains the properties of propofol in clinical practice {12}. Other: Blood-brain equilibration half-life: 2.9

minutes {04} {10} {12}. Onset of action: Loss of consciousness occurs rapidly and smoothly, usually within 40 seconds (one armbrain circulation time) from the start of intravenous injection of propofol {01} {04} {06} {08} {09} {10} {12}. Loss of consciousness is dependent on the dose administered, the rate of administration, and the extent of premedication {04} {10}. Plasma concentrations Propofol concentrations of 1.5 to 6 mcg per mL (8.42 to 33.66 micromoles per liter [micromoles/L]) will maintain hypnosis, although needs vary with type of surgery and use of other anesthetic agents {04}. Duration of action: Mean duration following a single bolus dose of 2 to 2.5 mg per kg of body weight is 3 to 5 minutes{04} {09}. Time to recovery Recovery from anesthesia with propofol is rapid {01} {06} {08} {09} {10} {11} {12} {15}, with minimal psychomotor impairment {10}. Emergence following induction (with 2 to 2.5 mg of propofol per kg) and maintenance (with 0.1 to 0.2 mg of propofol per kg per minute) for up to 2 hours occurs in most patients within 8 minutes {01} {04} {11}. If an opioid has been used, recovery may take up to 19 minutes {06}. Recovery occurs faster than recovery following the use of etomidate {20}, methohexital {04}, midazolam {21}, or thiopental {04} {20}. When anesthesia has included use of an opioid with propofol, recovery has occurred more quickly than with similar use of etomidate {06}, midazolam{08}, or thiopental {09}. Many investigators have noted clearheadedness in patients emerging from propofol anesthesia{04} {06} {08} {09} {15}, and less residual impairment of performance than in patients who received methohexital has been reported {10}. Elimination: Renal {01} {22}; approximately 70% of a dose is excreted in the urine within 24 hours after administration, and 90% is excreted within 5 days {01}. Clearance of propofol ranges from 1.6 to 3.4 liters per minute in healthy 70 kg patients {01}. As the age of the patient increases, total body clearance of propofol may decrease {01} {04} {06} {10} {11} {12}. Clearance rates ranging from 1.4 to 2.2 liters per minute in patients 18 to 35 years of age have been reported, in contrast to clearance rates of 1 to 1.8 liters per minute in patients 65 to 80 years of age {01}. Note: Pharmacokinetic parameters of propofol appear to be unaffected by gender {01} {10} {12}, obesity {12}, chronic hepatic cirrhosis {01} {25}, and chronic renal failure {01} {12} {22}. Precautions to Consider Carcinogenicity Studies have not been done {01}. Mutagenicity The Ames mutation test using Salmonella species, gene mutation/gene

conversion usingSaccharomyces cerevisiae , cytogenetic studies in Chinese hamsters, and a mouse micronucleus test have failed to demonstrate mutagenic potential by propofol {01}. Pregnancy/Reproduction Fertility Studies in rats given doses up to 6 times the human dose for varying lengths of time have shown no evidence of impaired fertility {01}. Pregnancy Propofol crosses the placenta. Adequate and well-controlled studies in humans have not been done. Studies in animals have shown propofol to cause increased maternal deaths in rats and rabbits and decreased pup survival during the lactating period when the dams received 6 times the recommended human dose {01}. FDA Pregnancy Category B {01}. Labor and delivery A study was conducted in 74 patients comparing the use of propofol with that of thiamylal-isoflurane for induction and maintenance of anesthesia during cesarean section. The study did not show any problems in the mothers or in the neonates with the use of propofol {55}. There was no difference between the neonates in the two groups in Apgar scores or the neurological and adaptive capacity scores (NACS) {55}. However, the manufacturer states that use of propofol is not recommended since data are insufficient to support its use in obstetrics, including cesarean section deliveries {01}. Breast-feeding Propofol is distributed into breast milk {01} {06}. However, the effects of oral administration of small amounts of propofol are not known {01}. Pediatrics Appropriate studies with propofol for sedation have not been performed in the pediatric population. There are case reports in the medical literature of pediatric patients developing metabolic acidosis after receiving propofol for sedation in the intensive care unit (ICU) {01} {30}{56}. Rarely, deaths have occurred {01} {30} {56}. The role of propofol in these deaths is controversial {01}. Other causes of metabolic acidosis could not be ruled out, and a causal relationship could not be established {01}. Note: Propofol is approved by the FDA for use in pediatric patients 3 years of age and older for induction of anesthesia and as a component of balanced anesthesia {01}, and in pediatric patients 2 months of age and older for maintenance of anesthesia and as a component of balanced anesthesia{57}. Geriatrics Dosage requirements are lower in geriatric patients than in younger adult patients, probably due to pharmacokinetic differences rather than pharmacodynamic differences in geriatric patients {01}{12}. Lower induction doses

and a slower maintenance infusion rate should be used in geriatric patients {01} {12}, due to reduced total body clearance {04} {06} {10} {11} and volume of distribution{04} {10} {23} in these patients. Drug interactions and/or related problems The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate) not necessarily inclusive ( = major clinical significance): Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication. Alcohol or CNS depressionproducing medications, other, including those commonly used for preanesthetic medication or induction or supplementation of anesthesia (see Appendix II) (concurrent administration may increase the CNS-depressant, respiratory-depressant, or hypotensive effects of propofol, as well as decreasing anesthetic requirements and prolonging recovery from anesthesia; dosage adjustments may be required {01} {06} {10} {12} {13} {33} {34}{40}; propofol may also decrease the emetic effects of some opioid drugs {33}) Droperidol (droperidol may compete with propofol for binding sites in the chemoreceptor trigger zone; concurrent use of propofol and droperidol to control nausea and vomiting is less effective than using propofol alone{17}) Fentanyl (concomitant administration of fentanyl in pediatric patients may result in serious bradycardia{57}) Medical considerations/Contraindications The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate) not necessarily inclusive ( = major clinical significance). Risk-benefit should be considered when the following medical problems exist Circulatory disorders {01} or Compromised cardiovascular function {04} {06} {10} {11} (may be aggravated by cardiovascular-depressant and hypotensive effects ) Disorders of lipid metabolism, such as primary hyperlipoproteinemia, diabetic hyperlipemia, or pancreatitis {01} (may be aggravated by emulsion vehicle of propofol) Increased intracranial pressure {01} {06} or Impaired cerebral circulation {01} (substantial decreases in mean arterial pressure and cerebral perfusion may occur) Sensitivity to propofol or its emulsion vehicle {01} Caution is also recommended in geriatric, debilitated, and/or hypovolemic patients, because they may require lower induction and maintenance doses {01} {04} {06} {10} . Side/Adverse Effects Note: Postoperative infections and subsequent deaths

have been reported following the use of propofol that was not administered using strict aseptic technique {19} {26}. Rarely, a clinical syndrome including bronchospasm, erythema, and hypotension has occurred shortly after administration of propofol {01}, and sequelae including anoxic brain damage and death have been reported {31}; concurrent use of other agents makes a causal relationship unclear {01}. The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)not necessarily inclusive: Those indicating need for medical attention Incidence more frequent Apnea bradycardia hypotension Incidence less frequent or rare Hypertension perioperative myoclonia, rarely including opisthotonus pancreatitis (abdominal pain)symptoms may not occur until after discharge from medical care following use of propofol Those indicating need for medical attention only if they continue or are bothersome Incidence more frequent Involuntary muscle movements, temporary nausea and/or vomiting pain, burning, or stinging at injection site Note: Excitatory movements reportedly occur more often than with thiopental but less often than with etomidate or methohexital Pain is usually mild and short-lived and may be decreased by using the larger veins of the forearm or the antecubital fossa or a dedicated intravenous catheter Pain may be decreased by prior intravenous injection of 10 to 20 mg of lidocainePost-injection thrombosis or phlebitis is rare Incidence less frequent or rare Abdominal cramping{01} cough{01}{15}{16} dizziness{01} fever{01} flushing{01}{16} headache{01}{06}{15}{16} hiccups{01}{06} tingling, numbness, or coldness at injection site{01}{15} Overdose For specific information on the management of a propofol overdose, see: Atropine inAnticholinergics/Antispasmodics monogr aph; and/or Sympathomimetic AgentsCardiovascular Use (Parenteral-Systemic) monograph. For more information on the management of overdose, contact a Poison Control Center (seePoison Control Center Listing ). Clinical effects of overdose The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)not necessarily inclusive: Acute Cardiovascular depression

respiratory depression Treatment of overdose Specific treatment: Discontinuation of propofol

{01}

For respiratory depression: artificial ventilation with oxygen {01}. For cardiovascular depression: elevation of legs, increasing flow rate of intravenous fluids, and administration of pressor agents and/or anticholinergic agents {01}. Monitoring: Patients should be continuously monitored for signs of significant hypotension and/or bradycardia. Patient Consultation As an aid to patient consultation, refer to Advice for the Patient, Anesthetics, General (Systemic) . In providing consultation, consider emphasizing the following selected information ( = major clinical significance): Before using this medication Conditions affecting use, especially: Sensitivity to propofol or its emulsion vehicle PregnancyPropofol crosses the placenta Use of propofol is not recommended in labor and delivery because data are insufficient to support its use in obstetrics Use in childrenPropofol should not be used for sedation in pediatric intensive care unit patients or for monitored anesthesia care (MAC) sedation in pediatric patients because safety and efficacy have not been established Use in the elderlyLower induction and maintenance doses are recommended Other medications, especially other CNS depressants Proper use of this medication Proper dosing Precautions after receiving this medication Possibility of psychomotor impairment following use of anesthetics; for about 24 hours following anesthesia, using added caution in driving or performing other tasks requiring alertness and coordination Avoiding use of alcohol or other CNS depressants within 24 hours following anesthesia except as directed by physician or dentist Side/adverse effects Signs of potential side effects, especially pancreatitis General Dosing Information Propofol should be administered only by individuals qualified in the use of general anesthetics. Appropriate resuscitative and endotracheal intubation equipment, oxygen, and medications for prevention and treatment of anesthetic emergencies must be immediately available. Airway patency must be maintained at

all times. Propofol emulsion is for intravenous administration only. Although clinical experience and animal studies have shown that inadvertent intra-arterial injection of propofol usually produces minimal tissue reaction, intra-arterial injection of propofol is not recommended {01}. To minimize the pain, burning, or stinging patients may experience at the site of injection of propofol, a larger vein of the forearm or the antecubital fossa may be used as the infusion site{01}. Pretreatment of the injection site with one mL of 1% lidocaine may also decrease the incidence of this side effect {01}. Dosage of propofol must be individualized for each patient {01}, with the dose titrated to achieve the desired clinical effect {01} {04} {09} {10}. Lower doses are usually required for elderly, debilitated, or higher risk surgical patients, or those with circulatory disorders {01} {10}. The dosage of intravenously administered propofol should be adjusted according to the type and amount of premedication used {01}. Rapid intravenous injection of propofol should not be used in elderly, debilitated, hypovolemic, or higher risk surgical patients. Rapid intravenous injection of propofol in these patients may result in cardiopulmonary depression including hypotension, apnea, airway obstruction and/or oxygen desaturation {01}. When propofol is administered by infusion, it is recommended that drop counters, syringe pumps, or volumetric pumps be utilized to control infusion rates {01}. When nitrous oxide, oxygen, and propofol are used for maintenance of general anesthesia, supplemental analgesic agents are generally required; neuromuscular blocking agents may also be required {01}. Concurrent use of propofol with neuromuscular blocking agents does not significantly alter the onset, intensity, or duration of action of these agents {01}. Propofol injection contains 0.005% disodium edetate, but it is not an antimicrobially preserved product under USP standards. The vehicle is capable of supporting the rapid growth of microorganisms {01} {19}, and particulate or bacterial contamination may be difficult to detect because propofol injection is opaque {27}. Rarely, failure to use strict aseptic technique has resulted in sepsis in patients to whom contaminated solution was administered. Therefore, strict aseptic technique must be maintained {01} {19}, and propofol injection should be administered promptly after opening {01}. Unused portions of the injection, as well as reservoirs, intravenous lines, or solutions containing propofol injection, must be discarded at the end of the procedure or within 12 hours (6 hours if propofol was transferred from the original container) {01}. Propofol should not be infused through filters with pore size smaller than 5 microns because infusion through a smaller filter may cause breakdown of the emulsion {01}. PROPOFOL INJECTABLE EMULSION Usual adult and adolescent dose Dosage must be individualized and titrated to the desired clinical effect {01}; however, as a general guideline Anesthesia, general (induction): Adults up to 55 years of age and/or American Society of Anesthesiologists (ASA) I or II patients Intravenous, 2 to 2.5 mg per kg of body weight (approximately 40 mg every ten seconds until onset of induction) {01}. Cardiac patients Intravenous, 0.5 to 1.5 mg per kg of body weight (approximately 20 mg every ten seconds until onset of induction) {01}. Elderly, debilitated, hypovolemic, and/or ASA III or IV patients Intravenous, 1 to 1.5 mg per kg of body weight (approximately 20 mg every ten seconds until onset of induction) {01}.

Neurosurgical patients Intravenous, 1 to 2 mg per kg of body weight (approximately 20 mg every ten seconds until onset of induction) {01}. Note: Slow injection of the induction dose of propofol may result in longer induction times and a lower percentage of successful inductions, probably due to rapid redistribution from the CNS {12}; however, slow injection of doses is preferable, in order to diminish some of the cardiovascular effects {01} {12} {23}. Rapid intravenous injection of propofol should not be used in elderly, debilitated, hypovolemic, or higher-risk surgical patients. Rapid intravenous injection of propofol in these patients may result in cardiopulmonary depression including hypotension, apnea, airway obstruction and/or oxygen desaturation {01}. Anesthesia, general, adjunct (maintenance) Adults up to 55 years of age and/or ASA I or II patients Intravenous infusion, 100 to 200 mcg (0.1 to 0.2 mg) per kg of body weight per minute (6 to 12 mg per kg of body weight per hour), with 60 to 70% nitrous oxide and oxygen {01}. Note: During the initial ten to fifteen minutes following induction, higher infusion rates of 150 to 200 mcg (0.15 to 0.2 mg) per kg of body weight per minute are generally required {01}. Infusion rates should subsequently be decreased by 30 to 50% during the first half-hour of maintenance{01}. Infusion rates should always be titrated downward in the absence of light anesthesia to avoid administration of propofol at rates higher than clinically necessary {01}. In general, rates of 50 to 100 mcg (0.05 to 0.1 mg) per kg of body weight per minute should be achieved during maintenance to optimize recovery times {01}. Intravenous intermittent injection, 20 to 50 mg increments, administered as needed {01}. Alternatively, some clinicians recommend increments of 500 mcg (0.5 mg) per kg of body weight{04}.

Adults receiving propofol for maintenance of general anesthesia for cardiac surgery Intravenous infusion, 50 to 150 mcg (0.05 to 0.15 mg) per kg of body weight per minute (3 to 9 mg per kg of body weight per hour) {01}. The use of an opioid as the primary anesthetic will result in a need for dosing of propofol at the lower end of this range, and the use of low-dose opioid as a secondary agent will result in a need for dosing of propofol at the higher end of this range {01}. Adults receiving propofol for maintenance of general anesthesia for neurosurgery Intravenous infusion, 100 to 200 mcg (0.1 to 0.2 mg) per kg of body weight per minute (6 to 12 mg per kg of body weight per hour) {01}. Elderly, debilitated, hypovolemic, and/or ASA III or IV patients Intravenous infusion, 50 to 100 mcg (0.05 to 0.1 mg) per kg of body weight per minute (3 to 6 mg per kg of body weight per hour) {01}. Sedation: Intensive care Individualize dose by titrating to unconsciousness with minimal hypotension: Initiation: Intravenous infusion, 5 mcg (0.005 mg) per kg of body weight per minute (0.3 mg per kg of body weight per hour) for at least 5 minutes.{57}{59} Titrate: Intravenous infusion, increments of 5 to 10 mcg (0.005 to 0.010 mg) per kg of body weight per minute (0.3 to 0.6 mg per kg of body weight per hour) over 5 to 10 minutes.{57}{59} Maintenance: Intravenous infusion, 5 to 50 mcg (0.005 to 0.050 mg) per kg of body weight per minute (0.3 to 3 mg per kg of body weight per hour). or higher may be required.{57}{59} Daily reassessment of level of sedation and CNS function should be carried out during maintenance dosing of propofol to determine the minimum dose of propofol injectable emulsion required for sedation.{57}
{59}

Note: During the initial ten to fifteen minutes following induction, higher infusion rates of 25 to 75 mcg (0.025 to 0.075 mg) per kg of body weight per minute (1.5 to 4.5 mg per kg of body weight per hour) may be needed {01}. In titrating to clinical effect, two minutes should be allowed to observe effects after an adjustment in dose. When propofol is used to provide MAC for elderly, debilitated, or ASA III or IV patients, the rate of administration and dose should be reduced to eighty percent of the usual adult dose{01}.

. Note: The mean requirement for sedation in the intensive care unit is 27 mcg per kg of body weight per minute, but the requirements vary widely, from 2.8 to 130 mcg per kg of body weight per minute. Lower rates of administration may be sufficient for patients receiving benzodiazepines or opioid analgesics. Older patients (i.e., those 55 years of age and older) require less propofol for sedation than younger patients (i.e., those up to 55 years of age) (20 and 38 mcg per kg of body weight per minute, respectively). In all cases, the infusion should be initiated slowly and titrated to effect. {01} Monitored Anesthesia Care (MAC) Initiation: Intravenous infusion, 100 to 150 mcg (0.1 to 0.15 mg) per kg of body weight per minute (6 to 9 mg per kg of body weight per hour) for three to five minutes; or slow intravenous injection over three to five minutes, 0.5 mg per kg of body weight {01}. Maintenance: Intravenous infusion, 25 to 50 mcg (0.025 to 0.05 mg) per kg of body weight per minute (1.5 to 3 mg per kg of body weight per hour) {01}.