Opioid Component to Anesthesia
Action And Clinical Pharmacology: Remifentanil is an opioid agonist with rapid onset and peak effect and ultra-short duration of action. The opioid activity of remifentanil is antagonized by opioid antagonists such as naloxone.
The analgesic effects of remifentanil are rapid in onset and offset. Its effects and side effects are dose dependent and similar to other opioids. Remifentanil in humans has a rapid blood-brain equilibration half-time of 1±1 minutes (mean±SD) and a rapid onset of action. The pharmacodynamic effects of remifentanil 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 remifentanil 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, remifentanil 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 i.v. bolus injection.
Hemodynamics: In premedicated patients undergoing anesthesia, 1-minute infusions of 2 g/kg (up to 30 g/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 remifentanil or an infusion rate increase. Glycopyrrolate, atropine and vagolytic neuromuscular blocking agents attenuate the hemodynamic effects associated with remifentanil. When appropriate, bradycardia and hypotension can be reversed by reduction of the rate of infusion of remifentanil, or the dose of concurrent anesthetics, or by the administration of fluids or vasopressors.
Respiration: Remifentanil depresses respiration in a dose-related fashion. Unlike other fentanyl analogs, the duration of action of remifentanil at a given dose does not increase with increasing duration of administration, due to lack of drug accumulation. When remifentanil 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 remifentanil.
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-g/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; N20
Muscle Rigidity: Skeletal muscle rigidity can be caused by remifentanil and is related to the dose and speed of administration. Remifentanil may cause chest wall rigidity (inability to ventilate) after single doses of >1 g/kg administered over 30 to 60 seconds or infusion rates >0.1 g/kg/min; peripheral muscle rigidity may occur at lower doses. Administration of doses
Histamine Release: Assays of histamine in patients and normal volunteers have shown no elevation in plasma histamine levels after administration of remifentanil in doses up to 30 g/kg over 60 seconds.
Anesthesia: Remifentanil is synergistic with the activity of hypnotics (propofol and thiopental), inhaled anesthetics and benzodiazepines (see Precautions and Dosage).
Gender: No differences have been shown in the pharmacodynamic activity (as measured by the EEG) of remifentanil between men and women.
Pharmacokinetics: After i.v. doses administered over 60 seconds, the pharmacokinetics of remifentanil fit a 3-compartment model with a rapid distribution half-life of 1 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 remifentanil 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) 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.
Distribution: 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.
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 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 (1/4 600 as potent as remifentanil in dogs) and is excreted by the kidneys with an elimination half-life of approximately 90 minutes. Remifentanil is not metabolized by plasma cholinesterase (pseudocholinesterase) and is not appreciably metabolized by the liver or lung.
Elimination: 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 ideal body weight). 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. 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.
Titration to Effect: The rapid elimination of remifentanil permits the titration of infusion rate without concern for prolonged duration. In general, every 0.1-g/kg/min change in the i.v. 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-g/kg bolus dose in conjunction with an infusion rate increase.
Clinical Experience: Remifentanil was evaluated in 2 169 patients undergoing general anesthesia. Currently investigation of remifentanil is ongoing in the following areas: in spontaneous ventilation anesthesia, in monitored anesthesia care, for continuation as an analgesic in the immediate postoperative period, in neurosurgery, in cardiac surgery and in pediatric anesthesia. Currently there are insufficient safety and/or efficacy data to make dosage recommendations in these areas.
Indications And Clinical Uses: For i.v. administration as an analgesic agent for use during the induction and maintenance of general anesthesia for inpatient and outpatient procedures.
Due to insufficient safety and efficacy data, remifentanil is not recommended for use in spontaneous ventilation anesthesia, in monitored anesthesia care, for continuation as an analgesic in the immediate postoperative period, in neurosurgery, in cardiac surgery or in pediatric anesthesia.
Contra-Indications: Due to the presence of glycine in the formulation, remifentanil is contraindicated for epidural or intrathecal administration.
Remifentanil is also contraindicated in patients with known hypersensitivity to the drug or any component of its formulation/preparation or to other fentanyl analogs.
Manufacturers’ Warnings In Clinical States: Remifentanil is not recommended for use as the sole agent in general anesthesia because loss of consciousness cannot be assured and because of a high incidence of apnea, muscle rigidity and tachycardia.
Continuous infusions of remifentanil should be administered only by an infusion device. I.V. bolus administration should only be used in intubated patients during the maintenance of general anesthesia. For induction of anesthesia in nonintubated patients, a single dose of remifentanil, not exceeding 1 g/kg, may be administered over 30 to 60 seconds.
Interruption of an infusion of remifentanil will result in rapid offset of effect. Rapid clearance and lack of drug accumulation result in rapid dissipation of respiratory depressant and analgesic effects upon discontinuation of remifentanil at recommended doses. However, delayed respiratory depression may occur in some patients up to 30 minutes after termination of remifentanil infusions due to residual effects of concomitant anesthetics. Discontinuation of an infusion of remifentanil should be preceded by the establishment of adequate postoperative analgesia (see Precautions and Dosage).
Injections of remifentanil should be made into i.v. tubing at or close to the venous cannula. Upon discontinuation of remifentanil, the i.v. tubing should be removed or cleared to prevent the inadvertent administration of remifentanil at a later point in time. Failure to adequately clear the i.v. tubing to remove residual remifentanil has been associated with the appearance of respiratory depression, apnea and muscle rigidity upon the administration of additional fluids or medications through the same i.v. tubing.
Use of remifentanil is associated with apnea and respiratory depression. Remifentanil should be administered only in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function. Resuscitative and intubation equipment, oxygen and an opioid antagonist must be readily available.
Remifentanil should be administered only by persons specifically trained in the use of anesthetic drugs and the recognition and management of the expected adverse effects of potent opioids, including respiratory and cardiac resuscitation of patients in the age-group being treated. Such training must include the establishment and maintenance of a patent airway and assisted ventilation.
Skeletal muscle rigidity can be caused by remifentanil and is related to the dose and speed of administration. Remifentanil may cause chest wall rigidity (inability to ventilate) after single doses >1 g/kg administered over 30 to 60 seconds, or after infusion rates >0.1 g/kg/min.
Muscle rigidity induced by remifentanil should be managed in the context of the patient’s clinical condition. Muscle rigidity occurring during the induction of anesthesia should be treated by the administration of a neuromuscular blocking agent and the concurrent induction medications.
Remifentanil should not be administered into the same i.v. tubing with blood/serum/plasma due to potential inactivation by nonspecific esterases in blood products.
Precautions: Rapid Offset of Action: Within 5 to 10 minutes after the discontinuation of remifentanil, no residual analgesic activity will be present. However, respiratory depression may occur in some patients up to 30 minutes after termination of infusion due to residual effects of concomitant anesthetics. Standard monitoring should be maintained in the postoperative period to ensure adequate recovery without stimulation. For patients undergoing surgical procedures where postoperative pain is generally anticipated, other analgesics should be administered prior to the discontinuation of remifentanil.
General: Vital Signs and oxygenation must be continually monitored during the administration of remifentanil.
Bradycardia has been reported with remifentanil and is responsive to ephedrine or anticholinergic drugs, such as atropine and glycopyrrolate.
Hypotension has been reported with remifentanil and is responsive to decreases in the administration of remifentanil or to i.v. fluids or catecholamine (ephedrine, epinephrine, norepinephrine, etc.) administration.
Intraoperative awareness has been reported in patients under 55 years of age when remifentanil has been administered with propofol infusion rates of £75 g/kg/min. Therefore, propofol rates
Renal Impairment: The pharmacodynamic/pharmacokinetic profile of remifentanil is not changed in patients with end stage renal disease (creatinine clearance
In anephric patients, the half-life of the carboxylic acid metabolite increases from 90 minutes to approximately 30 hours. The metabolite is removed by hemodialysis with a dialysis extraction ratio of approximately 30%.
Hepatic Impairment: Remifentanil pharmacokinetic/pharmacodynamic profile is not changed in patients with severe hepatic impairment. However, these patients may be slightly more sensitive to respiratory depressant effects of remifentanil. Therefore, these patients should be closely monitored and the dose of remifentanil titrated to individual patient need.
Geriatrics: (>65 years): 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. The pharmacodynamic activity of remifentanil (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); therefore, the recommended starting dose of remifentanil should be decreased by 50% in elderly patients and then titrated to individual patient need (see Dosage).
Morbidly Obese Patients: As for all potent opioids, caution is required when used in morbidly obese patients because of alterations in cardiovascular and respiratory physiology (see Dosage).
Cardiovascular Surgery: Clinical experience with remifentanil in patients undergoing cardiac surgery is limited to coronary artery bypass graft procedures (CABG). There are insufficient data to make a dosage recommendation.
Neurosurgery: Due to the limited number of patients studied, there are insufficient data to make dosage recommendations.
Pregnancy , Labor and Delivery and Lactation: There are insufficient clinical data to support safety, and therefore, remifentanil is not recommended for use in these populations.
ASA III/IV Patients: Limited data are available from 65 ASA III and 1 ASA IV patients. As the hemodynamic effects of potent opioids can be expected to be more pronounced in ASA III/IV patients, caution should be exercised in the administration of remifentanil in this population. Initial dosage reduction and subsequent titration to effect is therefore recommended.
Dependence Liability: As with other opioids, remifentanil can produce drug dependence of the morphine type and therefore has the potential of being abused.
Drug Interactions: 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. In animals the duration of muscle paralysis from succinylcholine is not prolonged by remifentanil.
Remifentanil is synergistic with other anesthetics and doses of thiopental, propofol, isoflurane and midazolam have been reduced by up to 75% with the coadministration of remifentanil. If doses of concomitantly administered CNS depressant drugs are not reduced, patients may experience an increased incidence of adverse effects associated with these agents.
Adverse Reactions: Remifentanil produces adverse events that are characteristic of opioids, such as respiratory depression, bradycardia, hypotension and skeletal muscle rigidity. These adverse events dissipate within minutes of discontinuing or decreasing the infusion rate of remifentanil. See Pharmacology, Warnings and Precautions on the management of these events.
Adverse event information is derived from controlled clinical trials that were conducted in a variety of surgical procedures of varying duration, using a variety of premedications and other anesthetics, and in patient populations with diverse characteristics including underlying disease.
In the elderly population (>65 years), the incidence of hypotension is higher, whereas the incidence of nausea and vomiting is lower (see Precautions).
Data from cardiac risk analysis in noncardiac general anesthesia studies indicate the incidence of hypotension in patients with cardiac risk factors (i.e., >65 years of age, concomitant use of cardiac medication) is higher with remifentanil than comparator drugs (27% vs 12%, respectively).
Symptoms And Treatment Of Overdose: Symptoms and Treatment: As with all potent opioid analgesics, overdosage would be manifested by an extension of the pharmacological actions of remifentanil. Expected signs and symptoms of overdosage include: apnea, chest-wall rigidity, seizures, hypoxemia, hypotension and bradycardia.
In case of overdosage or suspected overdosage, discontinue administration of remifentanil, maintain a patent airway, initiate assisted or controlled ventilation with oxygen and maintain adequate cardiovascular function. If depressed respiration is associated with muscle rigidity, a neuromuscular blocking agent or an opioid antagonist may be required to facilitate assisted or controlled respiration. I.V. fluids and vasopressors for the treatment of hypotension and other supportive measures may be employed. Glycopyrrolate or atropine may be useful for the treatment of bradycardia and/or hypotension.
I.V. administration of an opioid antagonist such as naloxone may be employed as a specific antidote to manage severe respiratory depression or muscle rigidity. Respiratory depression following overdosage with remifentanil is not expected to last longer than the opioid antagonist, naloxone. Reversal of the opioid effects may lead to acute pain and sympathetic hyperactivity.
Dosage And Administration: Due to insufficient safety and efficacy data, remifentanil is not recommended for use in spontaneous ventilation anesthesia, in monitored anesthesia care, for continuation as an analgesic in the immediate postoperative period, in neurosurgery, in cardiac surgery, or in pediatric anesthesia.
Remifentanil is not recommended as the sole agent in general anesthesia because loss of consciousness cannot be assured and because of a high incidence of apnea, muscle rigidity and tachycardia.
Remifentanil should be administered only in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function. Resuscitative and intubation equipment, oxygen and an opioid antagonist must be readily available.
Remifentanil should only be administered by persons specifically trained in the use of anesthetic drugs and the recognition and management of the expected adverse effects of potent opioids, including respiratory and cardiac resuscitation of patients in the age-group being treated. Such training must include the establishment and maintenance of a patent airway and assisted ventilation.
Remifentanil is for i.v. use only and must not be administered by epidural or intrathecal injection. Continuous infusions of remifentanil should be administered only by an infusion device. The injection site should be close to the venous cannula and all i.v. tubing should be cleared at the time of discontinuation of infusion.
Remifentanil is synergistic with other anesthetics and doses of thiopental, propofol, isoflurane and midazolam have been reduced by up to 75% with the coadministration of remifentanil.
Intraoperative awareness has been reported in patients under 55 years of age when remifentanil has been administered with propofol infusion rates of £75 g/kg/min. Therefore, propofol rates
I.V. bolus administration should only be used in intubated patients during the maintenance of general anesthesia. For induction of anesthesia in nonintubated patients, a single dose of remifentanil, not exceeding 1 g/kg, may be administered over 30 to 60 seconds.
Reconstituted solutions of remifentanil should be diluted prior to administration (see Reconstituted Solutions).
The administration of remifentanil must be individualized based on the patient’s response.
During Induction of Anesthesia: Remifentanil should be administered at an infusion rate of 0.5 to 1 g/kg/min with a hypnotic or volatile agent for the induction of anesthesia. If endotracheal intubation is to occur less than 8 minutes after the start of the infusion of remifentanil, then an initial dose of 1 g/kg may be administered over 30 to 60 seconds.
Due to the fast onset and short duration of action of remifentanil, the rate of administration during anesthesia can be titrated upward in 25 to 100% increments or downward in 25 to 50% decrements every 2 to 5 minutes to attain the desired level of opioid effect. In response to light anesthesia or transient episodes of intense surgical stress, supplemental bolus doses of 0.5 to 1 g/kg may be administered every 2 to 5 minutes. At infusion rates >1 g/kg/min, increases in the concomitant anesthetic agents should be considered to increase the depth of anesthesia.
Guidelines for Discontinuation: Upon discontinuation of remifentanil, the i.v. tubing should be cleared to prevent the inadvertent administration of remifentanil at a later time. Due to the rapid offset of action of remifentanil, no residual analgesic activity will be present within 5 to 10 minutes after discontinuation. However respiratory depression may occur in some patients up to 30 minutes after termination of infusion due to residual effects of concomitant anesthetics. Standard monitoring should be maintained in the postoperative period to ensure adequate recovery without stimulation. For those patients undergoing surgical procedures where postoperative pain is generally anticipated, alternative analgesics should be administered prior to discontinuation of remifentanil. Sufficient time must be allowed to reach the maximum effect of the longer acting analgesic. The choice of analgesic should be appropriate for the patient’s surgical procedure and the level of follow-up care.
Geriatrics: Due to the increased sensitivity to the pharmacological effects of remifentanil in this population (>65 years), the starting doses of remifentanil should be decreased by 50% and then be titrated to individual patient need.
Obese Patients: The starting doses of remifentanil should be based on ideal body weight in obese patients as the clearance and volume of distribution of remifentanil are better correlated with ideal body weight than actual body weight in this population.
Preanesthetic Medication: The need for premedication and the choice of anesthetic agents must be individualized. In clinical studies, patients who received remifentanil frequently received a benzodiazepine premedication.
Reconstituted Solutions: Preparation for Administration: To reconstitute solution, add 1 mL of diluent per mg of remifentanil. Shake well to dissolve. When reconstituted as directed, the solution contains approximately 1 mg of remifentanil activity per 1 mL. Ultiva should be reconstituted and diluted to a recommended final concentration of 25, 50, or 250 g/mL prior to administration. Remifentanil should not be administered without dilution. The product does not contain any antimicrobial preservatives and thus care must be taken to assure the sterility of prepared solutions.
Remifentanil can be reconstituted and diluted to concentrations of 20 to 250 g/mL in any of the following i.v. fluids: Sterile Water for Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium Chloride Injection, USP; 0.9% Sodium Chloride Injection, USP; 0.45% Sodium Chloride Injection, USP; Lactated Ringer’s and 5% Dextrose Injection, USP; Lactated Ringer’s Injection, USP.
Remifentanil has been shown to be compatible with these i.v. fluids when coadministered into a running i.v. administration set.
Compatibility With Other Therapeutic Agents: Remifentanil has been shown to be compatible with propofol injection when coadministered into a running i.v. administration set. The compatibility of remifentanil with other therapeutic agents has not been evaluated.
Incompatibilities: Nonspecific esterases in blood products may lead to the hydrolysis of remifentanil to its carboxylic acid metabolite. Therefore, administration of remifentanil into the same i.v. tubing with blood/serum/plasma is not recommended.
Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Product should be a clear, colorless liquid after reconstitution and free of visible particulate matter.
Availability And Storage: 1 mg: Each vial of lyophilized powder contains: remifentanil base (as the HCl salt) 1 mg. Nonmedicinal ingredients: glycine and hydrochloric acid (adjust pH). Vials of 3 mL, cartons of 5.
2 mg: Each vial of lyophilized powder contains: remifentanil base (as the HCl salt) 2 mg. Nonmedicinal ingredients: glycine and hydrochloric acid (adjust pH). Vials of 5 mL, cartons of 5.
5 mg: Each vial of lyophilized powder contains: remifentanil base (as the HCl salt) 5 mg. Nonmedicinal ingredients: glycine and hydrochloric acid (adjust pH). Vials of 10 mL, cartons of 5.
Store between 2 and 25°C. Reconstituted and diluted solutions (20 to 250 g/mL) are stable for 24 hours at room temperature for all recommended i.v. fluids except those containing Lactated Ringer’s Solution (stable for 4 hours).
ULTIVA® Glaxo Wellcome Remifentanil HCl Opioid Component to Anesthesia
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