Pharmacology: Mechanism Of Action:
REMIKAF is a μ-opioid agonist with rapid onset and peak effect, and short duration of action. The μ- opioid activity of REMIKAF is antagonized by opioid antagonists such as naloxone.
Unlike other opioids, REMIKAF is rapidly metabolized by hydrolysis of the propanoic acid-methyl ester linkage by nonspecific blood and tissue esterases. REMIKAF is not a substrate for plasma cholinesterase (pseudocholinesterase) and, therefore, patients with atypical cholinesterase are expected to have a normal duration of action.
The analgesic effects of REMIKAF are rapid in onset and offset. Its effects and side effects are dose dependent and similar to other μ-opioids. REMIKAF in humans has a rapid blood-brain equilibration halftime of 1 ± 1 minutes (mean ± SD) and a rapid onset of action. The pharmacodynamic effects of REMIKAF closely follow the measured blood concentrations, allowing direct correlation between dose, blood levels, and response. Blood concentration decreases 50% in 3 to 6 minutes after a 1-minute infusion or after prolonged continuous infusion due to rapid distribution and elimination processes and is independent of duration of drug administration. Recovery from the effects of REMIKAF occurs rapidly (within 5 to 10 minutes). New steady-state concentrations occur within 5 to 10 minutes after changes in infusion rate. When used as a component of an anesthetic technique, REMIKAF can be rapidly titrated to the desired depth of anesthesia/analgesia (e.g., as required by varying levels of intraoperative stress) by changing the continuous infusion rate or by administering an IV bolus injection.
Effects On The Central Nervous System:
Remifentanil produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves both a reduction in the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension and to electrical stimulation.
Remifentanil causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.
Effects On The Gastrointestinal Tract And Other Smooth Muscle:
Remifentanil causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.
Effects On The Cardiovascular System:
Remifentanil produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension. Caution must be used in hypovolemic patients, such as those suffering acute myocardial infarction, because remifentanil may cause or further aggravate their hypotension. Caution must also be used in patients with cor pulmonale who have received therapeutic doses of opioids.
Effects On The Endocrine System:
Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.
Effects On The Immune System:
Opioids have been shown to have a variety of effects on components of the immune system in in vitro
and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.
The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids [see DOSAGE & ADMINISTRATION]. The minimum effective analgesic concentration of remifentanil for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance.
Concentration-Adverse Reaction Relationships:
There is a relationship between increasing remifentanil plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see DOSAGE & ADMINISTRATION].
In premedicated patients undergoing anesthesia, 1-minute infusions of < 2 mcg/kg of REMIKAF cause dose-dependent hypotension and bradycardia. While additional doses > 2 mcg/kg (up to 30 mcg/kg) do not produce any further decreases in heart rate or blood pressure, the duration of the hemodynamic change is increased in proportion to the blood concentrations achieved. Peak hemodynamic effects occur within 3 to 5 minutes of a single dose of REMIKAF or an infusion rate increase. Glycopyrrolate, atropine, and vagolytic neuromuscular blocking agents attenuate the hemodynamic effects associated with REMIKAF. When appropriate, bradycardia and hypotension can be reversed by reduction of the rate of infusion of REMIKAF, or the dose of concurrent anesthetics, or by the administration of fluids or vasopressors.
REMIKAF depresses respiration in a dose-related fashion. Unlike other fentanyl analogs, the duration of action of REMIKAF at a given dose does not increase with increasing duration of administration, due to lack of drug accumulation. When REMIKAF and alfentanil were dosed to equal levels of respiratory depression, recovery of respiratory drive after 3-hour infusions was more rapid and less variable with REMIKAF (see Figure 1).
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Spontaneous respiration occurs at blood concentrations of 4 to 5 ng/mL in the absence of other anesthetic agents; for example, after discontinuation of a 0.25 mcg/kg/min infusion of remifentanil, these blood concentrations would be reached in 2 to 4 minutes. In patients undergoing general anesthesia, the rate of respiratory recovery depends upon the concurrent anesthetic; N2O < propofol < isoflurane [see Pharmacology: Pharmacokinetics: Clinical Studies: Recovery under Actions].
Skeletal muscle rigidity can be caused by REMIKAF and is related to the dose and speed of administration. REMIKAF may cause chest wall rigidity (inability to ventilate) after single doses of > 1 mcg/kg administered over 30 to 60 seconds or infusion rates > 0.1 mcg/kg/min; peripheral muscle rigidity may occur at lower doses. Administration of doses < 1 mcg/kg may cause chest wall rigidity when given concurrently with a continuous infusion of REMIKAF.
Assays of histamine in patients and normal volunteers have shown no elevation in plasma histamine levels after administration of REMIKAF in doses up to 30 mcg/kg over 60 seconds.
Infusions of 0.05 to 0.1 mcg/kg/min, producing blood concentrations of 1 to 3 ng/mL, are typically associated with analgesia with minimal decrease in respiratory rate. Supplemental doses of 0.5 to 1 mcg/kg, incremental increases in infusion rate > 0.05 mcg/kg/min, and blood concentrations exceeding 5 ng/mL (typically produced by infusions of 0.2 mcg/kg/min) have been associated with transient and reversible respiratory depression, apnea, and muscle rigidity.
REMIKAF is synergistic with the activity of hypnotics (propofol and thiopental), inhaled anesthetics, and benzodiazepines [see Pharmacology: Pharmacokinetics: Clinical Studies under Actions, PRECAUTIONS, and DOSAGE & ADMINISTRATION].
The pharmacodynamic activity of REMIKAF (as measured by the EC50 for development of delta waves on the EEG) increases with increasing age. The EC50 of remifentanil for this measure was 50% less in patients over 65 years of age when compared to healthy volunteers (25 years of age) [see DOSAGE & ADMINISTRATION].
No differences have been shown in the pharmacodynamic activity (as measured by the EEG) of REMIKAF between men and women.
In animals the duration of muscle paralysis from succinylcholine is not prolonged by remifentanil.
There was no change in intraocular pressure after the administration of REMIKAF prior to ophthalmic surgery under monitored anesthesia care.
Under isoflurane-nitrous oxide anesthesia (PaCO2 < 30 mmHg), a 1-minute infusion of REMIKAF (0.5 or 1.0 mcg/kg) produced no change in intracranial pressure. Mean arterial pressure and cerebral perfusion decreased as expected with opioids. In patients receiving REMIKAF and nitrous oxide anesthesia, cerebrovascular reactivity to carbon dioxide remained intact. In humans, no epileptiform activity was seen on the EEG (n = 44) at remifentanil doses up to 8 mcg/kg/min.
The pharmacodynamics of REMIKAF (ventilatory response to hypercarbia) are unaltered in patients with end stage renal disease (creatinine clearance < 10 mL/min).
The pharmacodynamics of REMIKAF (ventilatory response to hypercarbia) are unaltered in patients with severe hepatic dysfunction awaiting liver transplant.
After IV doses administered over 60 seconds, the pharmacokinetics of remifentanil fit a three compartment model with a rapid distribution half-life of one minute, a slower distribution half-life of 6 minutes, and a terminal elimination half-life of 10 to 20 minutes. Since the terminal elimination component contributes less than 10% of the overall area under the concentration versus time curve (AUC), the effective biological half-life of REMIKAF is 3 to 10 minutes. This is similar to the 3- to 10- minute half-life measured after termination of prolonged infusions (up to 4 hours; see Figure 2) and correlates with recovery times observed in the clinical setting after infusions up to 12 hours. Concentrations of remifentanil are proportional to the dose administered throughout the recommended dose range. The pharmacokinetics of remifentanil are unaffected by the presence of renal or hepatic impairment.
The initial volume of distribution (Vd) of remifentanil is approximately 100 mL/kg and represents distribution throughout the blood and rapidly perfused tissues. Remifentanil subsequently distributes into peripheral tissues with a steady-state volume of distribution of approximately 350 mL/kg. These two distribution volumes generally correlate with total body weight (except in severely obese patients when they correlate better with ideal body weight [IBW]). Remifentanil is approximately 70% bound to plasma proteins of which two-thirds is binding to alpha-1-acid-glycoprotein.
The clearance of remifentanil in young, healthy adults is approximately 40 mL/min/kg. Clearance generally correlates with total body weight (except in severely obese patients when it correlates better with IBW). The high clearance of remifentanil combined with a relatively small volume of distribution produces a short elimination half-life of approximately 3 to 10 minutes (see Figure 2). This value is consistent with the time taken for blood or effect site concentrations to fall by 50% (context-sensitive half-times) which is approximately 3 to 6 minutes. Unlike other fentanyl analogs, the duration of action does not increase with prolonged administration. (See Figure 2.)
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Titration to Effect: The rapid elimination of remifentanil permits the titration of infusion rate without concern for prolonged duration. In general, every 0.1 mcg/kg/min change in the IV infusion rate will lead to a corresponding 2.5 ng/mL change in blood remifentanil concentration within 5 to 10 minutes. In intubated patients only, a more rapid increase (within 3 to 5 minutes) to a new steady state can be achieved with a 1.0 mcg/kg bolus dose in conjunction with an infusion rate increase.
Metabolism: Remifentanil is an esterase-metabolized opioid. A labile ester linkage renders this compound susceptible to hydrolysis by nonspecific esterases in blood and tissues. This hydrolysis results in the production of the carboxylic acid metabolite (3-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1- piperidine]propanoic acid), and represents the principal metabolic pathway for remifentanil ( > 95%). The carboxylic acid metabolite is essentially inactive (1/4600 as potent as remifentanil in dogs). Remifentanil is not metabolized by plasma cholinesterase (pseudocholinesterase) and is not appreciably metabolized by the liver or lung.
Excretion: The carboxylic acid metabolite is excreted by the kidneys with an elimination half-life of approximately 90 minutes.
Age: Geriatric Population: The clearance of remifentanil is reduced (approximately 25%) in the elderly ( > 65 years of age) compared to young adults (average 25 years of age). However, remifentanil blood concentrations fall as rapidly after termination of administration in the elderly as in young adults.
Age: Pediatric Population: In pediatric patients, 5 days to 17 years of age (n = 47), the clearance and volume of distribution of remifentanil were increased in younger children and declined to young healthy adult values by age 17. The average clearance of remifentanil in neonates (less than 2 months of age) was approximately 90.5 ± 36.8 mL/min/kg (mean ± SD) while in adolescents (13 to 16 years) this value was 57.2 ± 21.1 mL/min/kg. The total (steady-state) volume of distribution in neonates was 452 ± 144 mL/kg versus 223 ± 30.6 mL/kg in adolescents. The half-life of remifentanil was the same in neonates and adolescents. Clearance of remifentanil was maintained at or above normal adult values in patients 5 days to 17 years of age.
Sex: There is no significant difference in the pharmacokinetics of remifentanil in male and female patients after correcting for differences in weight.
Hepatic Impairment: The pharmacokinetics of remifentanil and its carboxylic acid metabolite are unchanged in patients with severe hepatic impairment.
Renal Impairment: The pharmacokinetic profile of REMIKAF is not changed in patients with end stage renal disease (creatinine clearance < 10 mL/min). In anephric patients, the half-life of the carboxylic acid metabolite increases from 90 minutes to 30 hours. The metabolite is removed by hemodialysis with a dialysis extraction ratio of approximately 30%.
Obesity: There is no difference in the pharmacokinetics of remifentanil in non-obese versus obese (greater than 30% over IBW) patients when normalized to IBW.
Cardiopulmonary Bypass (CPB): Remifentanil clearance is reduced by approximately 20% during hypothermic CPB.
Drug Interaction Studies:
Remifentanil clearance is not altered by concomitant administration of thiopental, isoflurane, propofol, or temazepam during anesthesia. In vitro
studies with atracurium, mivacurium, esmolol, echothiophate, neostigmine, physostigmine, and midazolam revealed no inhibition of remifentanil hydrolysis in whole human blood by these drugs.
REMIKAF was evaluated in 3,341 patients undergoing general anesthesia (n = 2,706) and monitored anesthesia care (n = 639). These patients were evaluated in the following settings: inpatient (n = 2,079) which included cardiovascular (n = 426), and neurosurgical (n = 61), and outpatient (n = 1,349). Four hundred and eighty-six (486) elderly patients (age range 66 to 90 years) and 410 pediatric patients (age range birth to 12 years) received REMIKAF. Of the general anesthesia patients, 682 also received REMIKAF as an IV analgesic agent during the immediate postoperative period.
Induction And Maintenance Of General Anesthesia - Inpatient/Outpatient:
The efficacy of REMIKAF was investigated in 1,562 patients in 15 randomized, controlled trials as the analgesic component for the induction and maintenance of general anesthesia. Eight of these studies compared REMIKAF to alfentanil and two studies compared REMIKAF to fentanyl. In these studies, doses of REMIKAF up to the ED were compared to recommended doses (approximately ED ) of alfentanil or fentanyl.
Induction Of Anesthesia: REMIKAF was administered with isoflurane, propofol, or thiopental for the induction of anesthesia (n = 1,562). The majority of patients (80%) received propofol as the concurrent agent. REMIKAF reduced the propofol and thiopental requirements for loss of consciousness. Compared to alfentanil and fentanyl, a higher relative dose of REMIKAF resulted in fewer responses to intubation (see Table 1). Overall, hypotension occurred in 5% of patients receiving REMIKAF compared to 2% of patients receiving the other opioids.
REMIKAF has been used as a primary agent for the induction of anesthesia; however, it should not be used as a sole agent because loss of consciousness cannot be assured and because of a high incidence of apnea, muscle rigidity, and tachycardia. The administration of an induction dose of propofol or thiopental or a paralyzing dose of a muscle relaxant prior to or concurrently with REMIKAF during the induction of anesthesia markedly decreased the incidence of muscle rigidity from 20% to < 1%. (See Table 1.)
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Use During Maintenance Of Anesthesia: REMIKAF was investigated in 929 patients in seven well controlled general surgery studies in conjunction with nitrous oxide, isoflurane, or propofol in both inpatient and outpatient settings. These studies demonstrated that REMIKAF could be dosed to high levels of opioid effect and rapidly titrated to optimize analgesia intraoperatively without delaying or prolonging recovery.
Compared to alfentanil and fentanyl, these higher relative doses (ED ) of REMIKAF resulted in fewer responses to intraoperative stimuli (see Table 2) and a higher frequency of hypotension (16% compared to 5% for the other opioids). REMIKAF was infused to the end of surgery, while alfentanil was discontinued 5 to 30 minutes before the end of surgery as recommended. The mean final infusion rates of REMIKAF were between 0.25 and 0.48 mcg/kg/min. (See Table 2.)
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In three randomized, controlled studies (n = 407) during general anesthesia, REMIKAF attenuated the signs of light anesthesia within a median time of 3 to 6 minutes after bolus doses of 1 mcg/kg with or without infusion rate increases of 50% to 100% (up to a maximum rate of 2 mcg/kg/min).
In an additional double-blind, randomized study (n = 103), a constant rate (0.25 mcg/kg/min) of REMIKAF was compared to doubling the rate to 0.5 mcg/kg/min approximately 5 minutes before the start of the major surgical stress event. Doubling the rate decreased the incidence of signs of light anesthesia from 67% to 8% in patients undergoing abdominal hysterectomy, and from 19% to 10% in patients undergoing radical prostatectomy. In patients undergoing laminectomy the lower dose was adequate.
In 2,169 patients receiving REMIKAF for periods up to 16 hours, recovery from anesthesia was rapid, predictable, and independent of the duration of the infusion of REMIKAF. In the seven controlled, general surgery studies, extubation occurred in a median of 5 minutes (range: -3 to 17 minutes in 95% of patients) in outpatient anesthesia and 10 minutes (range: 0 to 32 minutes in 95% of patients) in inpatient anesthesia. Recovery in studies using nitrous oxide or propofol was faster than in those using isoflurane as the concurrent anesthetic. There was no case of remifentanil-induced delayed respiratory depression occurring more than 30 minutes after discontinuation of remifentanil [see PRECAUTIONS].
In a double-blind, randomized study, administration of morphine sulfate (0.15 mg/kg) intravenously 20 minutes before the anticipated end of surgery to 98 patients did not delay recovery of respiratory drive in patients undergoing major surgery with remifentanil-propofol total IV anesthesia.
Spontaneous Ventilation Anesthesia:
Two randomized, dose-ranging studies (n = 127) examined the administration of REMIKAF to outpatients undergoing general anesthesia with a laryngeal mask. Starting infusion rates of REMIKAF of ≤ 0.05 mcg/kg/min provided supplemental analgesia while allowing spontaneous ventilation with propofol or isoflurane. Bolus doses of REMIKAF during spontaneous ventilation lead to transient periods of apnea, respiratory depression, and muscle rigidity.
REMIKAF has been evaluated for maintenance of general anesthesia in 410 pediatric patients from birth to 12 years undergoing inpatient and outpatient procedures. Four clinical studies have been performed.
Study 1, an open-label, randomized, controlled clinical trial (n = 129), compared REMIKAF (n = 68) with alfentanil (n = 19), isoflurane (n = 22), or propofol (n = 20) in children 2 to 12 years of age undergoing strabismus surgery. After induction of anesthesia which included the administration of atropine, REMIKAF was administered as an initial infusion of 1 mcg/kg/min with 70% nitrous oxide. The infusion rate required during maintenance of anesthesia was 0.73 to 1.95 mcg/kg/min. Time to extubation and to purposeful movement was a median of 10 minutes (range 1 to 24 minutes).
Study 2, a double-blind, randomized, controlled trial (n = 222), compared REMIKAF (n = 119) to fentanyl (n = 103) in children 2 to 12 years of age undergoing tonsillectomy with or without adenoidectomy. After induction of anesthesia, patients received a 0.25 mcg/kg/min infusion of REMIKAF or fentanyl by IV bolus with nitrous oxide/oxygen (2:1) and either halothane or sevoflurane for maintenance of anesthesia. The mean infusion rate required during maintenance of anesthesia was 0.3 mcg/kg/min (range 0.2 to 1.3 mcg/kg/min). The continuous infusion rate was decreased to 0.05 mcg/kg/min approximately 10 minutes prior to the end of surgery. Time to spontaneous purposeful movement was a median of 8 minutes (range 1 to 19 minutes). Time to extubation was a median of 9 minutes (range 2 to 19 minutes).
Study 3, an open-label, randomized, controlled trial (n = 271), compared REMIKAF (n = 185) with a regional anesthetic technique (n = 86) in children 1 to 12 years of age undergoing major abdominal, urological, or orthopedic surgery. Patients received a 0.25 mcg/kg/min infusion of REMIKAF following a 1.0 mcg/kg bolus or bupivacaine by epidural infusion, along with isoflurane and nitrous oxide after the induction of anesthesia. The mean infusion rate required during maintenance of anesthesia was 0.25 mcg/kg/min (range 0 to 0.75 mcg/kg/min). Both treatments were effective in attenuating responses to skin incision during surgery. The hemodynamic profile of the REMIKAF group was consistent with an opioid-based general anesthetic technique. Time to spontaneous purposeful movement was a median of 15 minutes (range, 2 to 75 minutes) in the remifentanil group. Time to extubation was a median of 13 minutes (range, 4 to 31 minutes) in the remifentanil group.
Study 4, an open-label, randomized, controlled trial (n = 60), compared REMIKAF (n = 38) with halothane (n = 22) in ASA 1 or 2, full term neonates and infants ≤ 8 weeks of age weighing at least 2500 grams who were undergoing pyloromyotomy. After induction of anesthesia, which included the administration of atropine, patients received 0.4 mcg/kg/min of REMIKAF or 0.4% halothane with 70% nitrous oxide for initial maintenance of anesthesia and then both agents were adjusted according to clinical response. Bolus doses of 1 mcg/kg administered over 30 to 60 seconds were used to treat brief episodes of hypertension and tachycardia, and infusion rates were increased by 50% to treat sustained hypertension and tachycardia. The range of infusion rates of REMIKAF required during maintenance of anesthesia was 0.4 to 1 mcg/kg/min.
Seventy-one percent (71%) of REMIKAF patients required supplementary boluses or rate increases from the starting dose of 0.4 mcg/kg/min to treat hypertension, tachycardia, movement or somatic signs of light anesthesia. Twenty-four percent of the patients required an increase from the initial rate of 0.4 mcg/kg/min prior to incision and 26% of patients required an infusion rate between 0.8 and 1.0 mcg/kg/min, most often during gastric manipulation. The continuous infusion rate was decreased to 0.05 mcg/kg/min approximately 10 minutes before the end of surgery.
In the REMIKAF group, median time from discontinuation of anesthesia to spontaneous purposeful movement was 6.5 minutes (range, 1 to 13 minutes) and median time to extubation was 8.5 minutes (range, 1 to 14 minutes).
The initial maintenance infusion regimen of REMIKAF evaluated in pediatric patients from birth to 2 months of age was 0.4 mcg/kg/min, the approved adult regimen for use with N2O. The clearance rate observed in the neonatal population was highly variable and on average was two times higher than in the young healthy adult population. [See PHARMACOLOGY: Pharmacokinetics: Specific Populations: Pediatric Population under Actions and Table 4 under DOSAGE & ADMINISTRATION].
No pediatric patients receiving REMIKAF required naloxone during the immediate postoperative recovery period.
Coronary Artery Bypass Surgery:
REMIKAF was originally administered to 225 subjects undergoing elective CABG surgery in two dose ranging studies without active comparators. Subsequently, two double-blind, double-dummy clinical studies (N = 426) evaluated REMIKAF (n = 236) at recommended doses versus active comparators (n = 190).
The first comparator study, a multi-center, randomized, double-blind, double-dummy, parallel-group study (N = 369), compared REMIKAF (n = 201) with fentanyl (n = 168) in adult patients undergoing elective CABG surgery. Subjects received 1 to 3 mg midazolam and 0.05 mg/kg morphine IV as premedication. Anesthesia was induced with propofol 0.5 mg/kg (higher doses administered with REMIKAF were associated with excessive hypotension) over one minute plus 10-mg boluses every 10 seconds until loss of consciousness followed by either cisatracurium 0.2 mg/kg or vecuronium 0.15 mg/kg. Patients randomized to REMIKAF received a 1 mcg/kg/min infusion of REMIKAF followed by placebo bolus administered over 3 minutes. In the active control group, a placebo IV infusion was started and a fentanyl bolus 10 mcg/kg was administered over 3 minutes. All subjects received isoflurane titrated initially to end tidal concentration of 0.5%. During maintenance, the group randomized to REMIKAF received as needed 0.5-1 mcg/kg/min IV rate increases (to a maximum of 4 mcg/kg/min) of REMIKAF and 1 mcg/kg IV boluses of REMIKAF. The active control group received 2 mcg/kg IV boluses of fentanyl and increases in placebo IV infusion rate.
The second comparator study, a multi-center, double-blind, randomized, parallel group study (N = 57), compared REMIKAF (n = 35) to fentanyl (n = 22) in adult patients undergoing elective CABG surgery with poor left ventricular function (ejection fraction < 0.35). Subjects received oral lorazepam 40 mcg/kg as premedication. Anesthesia was induced using etomidate until loss of consciousness, followed by a low-dose propofol infusion (3 mg/kg/hr) and pancuronium 0.15 mg/kg. Subjects in the group administered REMIKAF received a placebo bolus dose and a continuous infusion of REMIKAF 1 mcg/kg/min and subjects in the fentanyl group received a bolus loading dose of 15 mcg/kg and placebo continuous infusion. During maintenance, supplemental bolus doses of REMIKAF (0.5 mcg/kg) and infusion rate increases of 0.5 to 1 mcg/kg/min (maximum rate allowed was 4 mcg/kg/min) of REMIKAF were administered to one group; while the fentanyl group was given intermittent maintenance bolus doses of 2 mcg/kg and increases in the placebo infusion rate.
In these two studies, using a high dose opioid technique with REMIKAF as a component of a balanced or total intravenous anesthetic regimen, the remifentanil regimen effectively attenuated response to maximal sternal spread generally better than the dose and regimen studied for the active control (fentanyl). While this provides evidence for the efficacy of remifentanil as an analgesic in this setting, caution must be exercised in interpreting these results as evidence of superiority of remifentanil over the active control, since these studies did not make any attempt to evaluate and compare the optimal analgesic doses of either drug in this setting.
REMIKAF was administered to 61 patients undergoing craniotomy for removal of a supratentorial mass lesion. In these studies, ventilation was controlled to maintain a predicted PaCO of approximately 28 mmHg. In one study (n = 30) with REMIKAF and 66% nitrous oxide, the median time to extubation and to patient response to verbal commands was 5 minutes (range -1 to 19 minutes). Intracranial pressure and cerebrovascular responsiveness to carbon dioxide were normal [see PHARMACOLOGY under Actions].
A randomized, controlled study compared REMIKAF (n = 31) to fentanyl (n = 32). REMIKAF (1 mcg/kg/min) and fentanyl (2 mcg/kg/min) were administered after induction with thiopental and pancuronium. A similar number of patients (6%) receiving REMIKAF and fentanyl had hypotension during induction. Anesthesia was maintained with nitrous oxide and REMIKAF at a mean infusion rate of 0.23 mcg/kg/min (range 0.1 to 0.4) compared with a fentanyl mean infusion rate of 0.04 mcg/kg/min (range 0.02 to 0.07). Supplemental isoflurane was administered as needed. The patients receiving REMIKAF required a lower mean isoflurane dose (0.07 MAC-hours) compared with 0.64 MAC-hours for the fentanyl patients (P = 0.04). REMIKAF was discontinued at the end of anesthesia, whereas fentanyl was discontinued at the time of bone flap replacement (a median time of 44 minutes before the end of surgery). Median time to extubation was similar (5 and 3.5 minutes, respectively, with REMIKAF and fentanyl). None of the patients receiving REMIKAF required naloxone compared to seven of the fentanyl patients (P = 0.01). Eighty-one percent (81%) of patients receiving REMIKAF recovered (awake, alert, and oriented) within 30 minutes after surgery compared with 59% of fentanyl patients (P = 0.06). At 45 minutes, recovery rates were similar (81% and 69% respectively for REMIKAF and fentanyl, P = 0.27). Patients receiving REMIKAF required an analgesic for headache sooner than fentanyl patients (median of 35 minutes compared with 136 minutes, respectively [P = 0.04]). No adverse cerebrovascular effects were seen in this study [see PHARMACOLOGY under Actions].
Continuation Of Analgesic Use Into The Immediate Postoperative Period:
Analgesia with REMIKAF in the immediate postoperative period (until approximately 30 minutes after extubation) was studied in 401 patients in four dose-finding studies and in 281 patients in two efficacy studies. In the dose-finding studies, the use of bolus doses of REMIKAF and incremental infusion rate increases ≥ 0.05 mcg/kg/min led to respiratory depression and muscle rigidity.
In two efficacy studies, REMIKAF 0.1 mcg/kg/min was started immediately after discontinuing anesthesia. Incremental infusion rate increases of 0.025 mcg/kg/min every 5 minutes were given to treat moderate to severe postoperative pain. In Study 1, 50% decreases in infusion rate were made if respiratory rate decreased below 12 breaths/min and in Study 2, the same decreases were made if respiratory rate was below 8 breaths/min. With this difference in criteria for infusion rate decrease, the incidence of respiratory depression was lower in Study 1 (4%) than in Study 2 (12%). In both studies, REMIKAF provided effective analgesia (no or mild pain with respiratory rate ≥ 8 breaths/min) in approximately 60% of patients at mean final infusion rates of 0.1 to 0.125 mcg/kg/min.
Study 2 was a double-blind, randomized, controlled study in which patients received either morphine sulfate (0.15 mg/kg administered 20 minutes before the anticipated end of surgery plus 2 mg bolus doses for supplemental analgesia) or REMIKAF (as described previously). Emergence from anesthesia was similar between groups; median time to extubation was 5 to 6 minutes for both. REMIKAF provided effective analgesia in 58% of patients compared to 33% of patients who received morphine. Respiratory depression occurred in 12% of patients receiving REMIKAF compared to 4% of morphine patients. For patients who received REMIKAF, morphine sulfate (0.15 mg/kg) was administered in divided doses 5 and 10 minutes before discontinuing REMIKAF. Within 30 minutes after discontinuation of REMIKAF, the percentage of patients with effective analgesia decreased to 34%.
Monitored Anesthesia Care:
REMIKAF has been studied in the monitored anesthesia care setting in 609 patients in eight clinical studies. Nearly all patients received supplemental oxygen in these studies. Two early dose-finding studies demonstrated that use of sedation as an endpoint for titration of REMIKAF led to a high incidence of muscle rigidity (69%) and respiratory depression. Subsequent trials titrated REMIKAF to specific clinical endpoints of patient comfort, analgesia, and adequate respiration (respiratory rate > 8 breaths/min) with a corresponding lower incidence of muscle rigidity (3%) and respiratory depression. With doses of midazolam > 2 mg (4 to 8 mg), the dose of REMIKAF could be decreased by 50%, but the incidence of respiratory depression rose to 32%.
The efficacy of a single dose of REMIKAF (1.0 mcg/kg over 30 seconds) was compared to alfentanil (7 mcg/kg over 30 seconds) in patients undergoing ophthalmic surgery. More patients receiving REMIKAF were pain free at the time of the nerve block (77% versus 44%, P = 0.02) and more experienced nausea (12% versus 4%) than those receiving alfentanil.
In a randomized, controlled study (n = 118), REMIKAF 0.5 mcg/kg over 30 to 60 seconds followed by a continuous infusion of 0.1 mcg/kg/min, was compared to a propofol bolus (500 mcg/kg) followed by a continuous infusion (50 mcg/kg/min) in patients who received a local or regional anesthetic nerve block 5 minutes later. The incidence of moderate or severe pain during placement of the block was similar between groups (2% with REMIKAF and 8% with propofol, P = 0.2) and more patients receiving REMIKAF experienced nausea (26% versus 2%, P < 0.001). The final mean infusion rate of REMIKAF was 0.08 mcg/kg/min.
In a randomized, double-blind study, REMIKAF with or without midazolam was evaluated in 159 patients undergoing superficial surgical procedures under local anesthesia. REMIKAF was administered without midazolam as a 1 mcg/kg dose over 30 seconds followed by a continuous infusion of 0.1 mcg/kg/min. In the group of patients that received midazolam, REMIKAF was administered as a 0.5 mcg/kg dose over 30 seconds followed by a continuous infusion of 0.05 mcg/kg/min and midazolam 2 mg was administered 5 minutes later. The occurrence of moderate or severe pain during the local anesthetic injection was similar between groups (16% and 20%). Other effects for REMIKAF alone and REMIKAF/midazolam were: respiratory depression with oxygen desaturation (SPO2 < 90%), 5% and 2%; nausea, 8% and 2%; and pruritus, 23% and 12%. Titration of REMIKAF resulted in prompt resolution of respiratory depression (median 3 minutes, range 0 to 6 minutes). The final mean infusion rate of REMIKAF was 0.12 mcg/kg/min (range 0.03 to 0.3) for the group receiving REMIKAF alone and 0.07 mcg/kg/min (range 0.02 to 0.2) for the group receiving REMIKAF/midazolam.