Remifentanil (Monograph)

Brand name: Ultiva
Drug class: Opiate Agonists
VA class: CN101
Chemical name: 3-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]propanoic acid methyl ester, hydrochloride salt
Molecular formula: C₂₀H₂₈N₂O₅ HCl
CAS number: CAS-132539-07-2; CAS-132875-61-7

Medically reviewed by Drugs.com on Feb 22, 2024. Written by ASHP.

Introduction

Selective μ-receptor opiate agonist; fentanyl analog.

Uses for Remifentanil

General Anesthesia

As the analgesic component in the induction and maintenance of general anesthesia for inpatient and outpatient procedures. Although remifentanil has been used as the primary agent for induction of anesthesia, its use as the sole agent in general anesthesia is not recommended because loss of consciousness cannot be ensured and a high incidence of apnea, muscle rigidity, or tachycardia is possible.

May be continued in the immediate postoperative period in adults for whom later transition to longer-acting analgesics is desired; must be used under direct supervision of an anesthesia clinician in a postoperative anesthesia care unit or intensive care unit (ICU). Long-term (i.e., >16 hours) use of remifentanil in ICU patients has not been established to date.

May be particularly useful in surgical procedures requiring a rapid onset of analgesia and rapid recovery.

Monitored Anesthesia Care

As the analgesic component of monitored anesthesia care (e.g., in conjunction with local or regional anesthesia for surgical procedures, including ophthalmic surgery, breast biopsy, and other superficial surgical procedures ) in adults.

Related/similar drugs

lidocaine, fentanyl, ketamine, hyoscyamine, propofol, glycopyrrolate

Remifentanil Dosage and Administration

General

Premedication

• Selection of preanesthetic medication(s) must be based on the individual needs of the patient; in clinical studies, remifentanil recipients frequently received a benzodiazepine.

Concomitant Anesthetics

• Selection of concomitant anesthetic agent(s) must be based on the individual needs of the patient.

• Synergistic activity with other anesthetics; dosage adjustment for concomitantly administered anesthetic(s) may be needed. (See Specific Drugs under Interactions.)

Discontinuance of Therapy

• Clear remifentanil from the IV tubing upon discontinuance of the drug to prevent subsequent inadvertent administration of residual drug. (See Discontinuance of Therapy under Cautions.)

• Residual analgesic activity absent within 5–10 minutes of drug discontinuance. Consider administering alternative analgesics prior to remifentanil discontinuance in surgical patients who may experience postoperative pain. Choose analgesic based on surgical procedure and level of follow-up care.

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Use a controlled-infusion device to ensure precise control of flow rate during continuous IV infusion of the drug.

Inject remifentanil into IV tubing at or close to the venous cannula.

Administration of remifentanil into the same IV tubing with blood products is not recommended, since premature metabolism of the drug by nonspecific esterases may occur.

Clear remifentanil from the IV tubing upon discontinuance of the drug to prevent subsequent inadvertent administration of residual drug. (See Discontinuance of Therapy under Cautions.)

Reconstitution

Reconstitute vials containing 1, 2, or 5 mg of remifentanil by adding 1 mL of diluent (sterile water for injection or other compatible IV fluid [see Compatibility under Stability]) per mg of drug. Shake well to dissolve. Resultant solution contains approximately 1 mg of remifentanil per mL.

Dilution

Reconstituted solutions must be diluted prior to administration.

Dilute reconstituted solution to desired concentration (20, 25, 50, or 250 mcg/mL; see Table 1) in a compatible IV solution. (See Storage and also see Compatibility, under Stability.)

A final concentration of 25 mcg/mL is recommended when the drug is used for monitored analgesia care. A final concentration of 20 or 25 mcg/mL is recommended for pediatric patients ≥1 year of age. Use of 250-mcg/mL solutions of the drug for infusion of dosages of 0.0125–0.025 mcg/kg per minute is not recommended.

Rate of Administration

Individualize rate of administration based on patient response. For recommended dosage ranges and continuous infusion rates, see Dosage under Dosage and Administration.

Administer rapid IV (bolus) doses of remifentanil only during the maintenance phase of general anesthesia.

In nonintubated patients, administer single doses of remifentanil over 30–60 seconds.

Induction of anesthesia: Administer remifentanil as a continuous IV infusion. If intubation is to occur within 8 minutes after initiation of the infusion, an initial dose of the drug may be given over 30–60 seconds.

Maintenance of anesthesia: Administer remifentanil as a continuous IV infusion. May administer rapid IV (bolus) doses every 2–5 minutes in response to light anesthesia or transient episodes of intense surgical stress.

Analgesia in the immediate postoperative period: Administer as a continuous IV infusion. Infusion rates >0.2 mcg/kg per minute are associated with respiratory depression. Supplemental rapid IV (bolus) doses of remifentanil are not recommended because of risk for respiratory depression and muscle rigidity.

Monitored anesthesia care: Administer prior to local or regional (nerve block) anesthesia as a single IV dose given over 30–60 seconds; alternatively, administer as a continuous IV infusion. Supplemental rapid IV (bolus) doses of remifentanil are not recommended because of risk for respiratory depression and muscle rigidity.

Not recommended.

Risk of muscle rigidity is related to the dose and rate of IV administration. Chest wall rigidity reported after single doses of >1 mcg/kg administered over 30–60 seconds, with infusion rates >0.1 mcg/kg per minute, or following single doses of <1 mcg/kg administered in conjunction with a continuous infusion of the drug. Supplemental doses of 0.5–1 mcg/kg and incremental increases in infusion rate of >0.05 mcg/kg per minute associated with transient and reversible muscle rigidity. Prior or simultaneous administration of propofol or thiopental or a neuromuscular blocking agent may attenuate the development of rigidity. For excessive rigidity, consider decreasing the infusion rate or discontinuing the infusion of remifentanil or administering a neuromuscular blocking agent or naloxone. (See Musculoskeletal Effects under Cautions.)

Doses of 0.5–1 mcg/kg administered in conjunction with a continuous infusion of the drug and incremental increases in infusion rate of >0.05 mcg/kg per minute are associated with transient and reversible respiratory depression and apnea. In spontaneously breathing patients, manage respiratory depression by reducing infusion rate of remifentanil by 50% or by temporarily discontinuing the infusion. (See Respiratory Depression under Cautions.)

Dosage

Available as remifentanil hydrochloride; dosage expressed in terms of remifentanil.

Synergistic activity with other anesthetics; dosage adjustment of concomitantly administered anesthetic(s) may be needed. (See Specific Drugs under Interactions.)

Pediatric Patients

General Anesthesia (General Dosage)

Manufacturer makes no specific recommendations regarding use or dosage of remifentanil in adolescents ≥13 years of age.

Maintenance of General Anesthesia in Neonates and Infants Up to 2 Months of Age

IV Infusion

In conjunction with 70% nitrous oxide: Initial remifentanil infusion rate of 0.4 mcg/kg per minute. Because neonatal clearance of remifentanil is variable and may average twice that observed in young adults, some neonates may require increased infusion rate to maintain adequate anesthesia; titrate dosage carefully according to individual requirements. Recommended infusion rate: 0.4–1 mcg/kg per minute.

Rapid IV (bolus) doses of 1 mcg/kg could be administered every 2–5 minutes in response to signs of inadequate anesthesia in clinical trials in full-term neonates and infants up to 2 months of age with American Society of Anesthesiologists (ASA) physical status of I or II. Individualize dosage. Some neonates, including those receiving potent inhalation anesthetics or neuraxial anesthesia, those with substantial comorbidities or fluid shifts, and those who have not received atropine premedication, may require smaller bolus doses of remifentanil to avoid hypotension and/or bradycardia.

Maintenance of General Anesthesia in Children 1–12 Years of Age

IV Infusion

In conjunction with nitrous oxide plus halothane (0.3–1.5 minimum alveolar concentration [MAC]), sevoflurane (0.3–1.5 MAC), or isoflurane (0.4–1.5 MAC): Remifentanil 0.25 mcg/kg per minute in patients with ASA physical status of I, II, or III. Adjust infusion rate upward by 50% or downward by 25–50% based on patient's response at intervals of 2–5 minutes. Recommended infusion rate: 0.05–1.3 mcg/kg per minute. May administer rapid IV (bolus) doses of 1 mcg/kg every 2–5 minutes in response to light anesthesia or transient episodes of intense surgical stress.

An initial dose of 1 mcg/kg may be administered over 30–60 seconds.

At remifentanil infusion rates >1 mcg/kg per minute, consider increases in dosage of concomitant anesthetic agent(s) to increase depth of anesthesia.

Adults

General Anesthesia (General Dosage)

Induction of General Anesthesia

IV Infusion

Remifentanil 0.5–1 mcg/kg per minute given in conjunction with a volatile anesthetic or hypnotic agent in patients with ASA physical status of I, II, or III.

If intubation is to occur within 8 minutes after initiation of the remifentanil infusion, an initial dose of 1 mcg/kg may be given over 30–60 seconds.

Maintenance of General Anesthesia

IV Infusion

In conjunction with 66% nitrous oxide: Remifentanil 0.4 mcg/kg per minute in patients with ASA physical status of I, II, or III. Adjust infusion rate upward by 25–100% or downward by 25–50% based on patient's response at intervals of 2–5 minutes. Recommended infusion rate: 0.1–2 mcg/kg per minute. May administer rapid IV (bolus) doses of 1 mcg/kg every 2–5 minutes in response to light anesthesia or transient episodes of intense surgical stress.

In conjunction with isoflurane (0.4–1.5 MAC) or propofol (100–200 mcg/kg per minute): Remifentanil 0.25 mcg/kg per minute in patients with ASA physical status of I, II, or III. Adjust infusion rate upward by 25–100% or downward by 25–50% based on patient's response at intervals of 2–5 minutes. Recommended infusion rate: 0.05–2 mcg/kg per minute. May administer rapid IV (bolus) doses of 1 mcg/kg every 2–5 minutes in response to light anesthesia or transient episodes of intense surgical stress.

At remifentanil infusion rates >1 mcg/kg per minute, consider increases in dosage of concomitant anesthetic agent(s) to increase depth of anesthesia.

Analgesia in the Immediate Postoperative Period

IV Infusion

Initial postoperative infusion rate of 0.1 mcg/kg per minute in patients with ASA physical status of I, II, or III. Adjust infusion rate in increments of 0.025 mcg/kg per minute at 5-minute intervals based on level of analgesia and respiratory rate. Recommended infusion rate: 0.025–0.2 mcg/kg per minute.

Supplemental rapid IV (bolus) doses of remifentanil are not recommended because of risk for respiratory depression and muscle rigidity.

Infusion rates >0.2 mcg/kg per minute associated with respiratory depression.

General Anesthesia for Coronary Artery Bypass Surgery

Induction of Anesthesia for Coronary Artery Bypass Surgery

IV Infusion

Remifentanil 1 mcg/kg per minute in patients with ASA physical status of III or IV. Excessive hypotension reported in clinical studies when dosage of concomitantly administered propofol exceeded 0.5 mg/kg over 1 minute followed by 10 mg every 10 seconds until loss of consciousness.

Maintenance of Anesthesia for Coronary Artery Bypass Surgery

IV Infusion

As the analgesic component of a high-dose-opiate, balanced or IV anesthetic regimen, remifentanil 1 mcg/kg per minute in patients with ASA physical status of III or IV. Recommended infusion rate: 0.125–4 mcg/kg per minute. Supplemental rapid IV (bolus) doses of 0.5–1 mcg/kg may be administered.

Analgesia in the Immediate Period After Coronary Artery Bypass Surgery

IV Infusion

Remifentanil 1 mcg/kg per minute in patients with ASA physical status of III or IV. Recommended infusion rate: 0.05–1 mcg/kg per minute.

Monitored Anesthesia Care

Supplemental oxygen strongly recommended for patients receiving remifentanil for monitored anesthesia care.

As Analgesic Component of Local or Regional (Nerve Block) Anesthesia

IV (Single Dose)

When used alone prior to local or regional anesthesia in patients with ASA physical status of I, II, or III, single remifentanil dose of 1 mcg/kg (over 30–60 seconds) administered 90 seconds before the local anesthetic. When used in this manner in conjunction with midazolam 2 mg, reduce remifentanil dose to 0.5 mcg/kg (over 30–60 seconds).

IV Infusion

When used alone in patients with ASA physical status of I, II, or III, remifentanil 0.1 mcg/kg per minute, beginning 5 minutes before the local anesthetic. Because of risk of respiratory depression, reduce infusion rate to 0.05 mcg/kg per minute following nerve block placement. Adjust subsequent infusion rate in increments of 0.025 mcg/kg per minute at 5-minute intervals based on level of analgesia and respiratory rate. Recommended infusion rate: 0.025–0.2 mcg/kg per minute.

When used in conjunction with midazolam 2 mg, remifentanil 0.05 mcg/kg per minute, beginning 5 minutes before the local anesthetic. Because of risk of respiratory depression, reduce infusion rate to 0.025 mcg/kg per minute following nerve block placement. Adjust subsequent infusion rate in increments of 0.025 mcg/kg per minute at 5-minute intervals based on level of analgesia and respiratory rate. Recommended infusion rate: 0.025–0.2 mcg/kg per minute.

Infusion rates >0.2 mcg/kg per minute associated with respiratory depression.

Administration of rapid IV (bolus) doses of remifentanil concomitantly with a continuous infusion of the drug in spontaneously breathing patients is not recommended.

Special Populations

Geriatric Patients

Decrease initial and, possibly, subsequent doses of remifentanil by 50% in patients >65 years of age; titrate cautiously. (See Geriatric Use under Cautions.)

Consider extending anticipated time to clinical effect by 50–100% in geriatric patients. (See Absorption: Special Populations under Pharmacokinetics.)

Obese Patients

Base initial dosage on an estimate of ideal (lean) body weight if body weight exceeds ideal weight by >30%. Base subsequent dosage reductions on an estimate of ideal body weight.

Cautions for Remifentanil

Contraindications

• Contains glycine; contraindicated for epidural or intrathecal administration.

• Known hypersensitivity to fentanyl analogs.

Warnings/Precautions

Warnings

Shares the toxic potentials of the opiate agonists; observe the usual precautions of opiate agonist therapy.

Supervised Administration

Remifentanil should only be administered by persons trained in the use of anesthetic drugs and the management of respiratory effects of opiates, including respiratory and cardiac resuscitation. Such training must include the establishment and maintenance of a patent airway and assisted ventilation.

Do not use for diagnostic or therapeutic procedures outside a monitored anesthesia care setting. Patients receiving the drug for monitored anesthesia care should be continuously monitored by persons not involved in the conduct of the surgical or diagnostic procedure.

Monitor oxygen saturation continuously and have resuscitative and intubation equipment, oxygen, and an opiate antagonist readily available.

Discontinuance of Therapy

Clear remifentanil from the IV tubing upon drug discontinuance; failure to remove residual remifentanil associated with respiratory depression, apnea, and muscle rigidity upon administration of fluids or drugs through the same tubing.

Respiratory Depression

Apnea and dose-dependent respiratory depression reported with remifentanil. Remifentanil infusion rates of 0.05–0.1 mcg/kg per minute are associated with minimal decreases in respiratory rate; doses of 0.5–1 mcg/kg administered in conjunction with a continuous IV infusion of the drug, incremental increases in infusion rate of >0.05 mcg/kg per minute, and plasma concentrations >5 ng/mL are associated with transient and reversible respiratory depression and apnea. Peak respiratory depression after rapid IV (bolus) doses generally occurs within 2.5–5 minutes.

Respiratory depression may occur up to 30 minutes after discontinuance of remifentanil infusion secondary to residual effects of concomitant anesthetics. Monitor patients in postoperative period to ensure adequate recovery without stimulation. To date, no reported cases of remifentanil-induced delayed respiratory depression occurring >30 minutes after drug discontinuance.

Recovery of respiratory drive after a 3-hour infusion was faster and less variable with remifentanil than with alfentanil (when dosed to produce equal levels of respiratory depression).

Manage respiratory depression in spontaneously breathing patients by reducing infusion rate of remifentanil by 50% or by temporarily discontinuing the infusion. Spontaneous respiration occurs at plasma remifentanil concentrations of 4–5 ng/mL in the absence of other anesthetic agents. In patients undergoing general anesthesia, rate of respiratory recovery is dependent upon concomitant anesthetics. (See Duration under Pharmacokinetics.)

Supplemental oxygen strongly recommended for patients receiving remifentanil for monitored anesthesia care.

Use for Postoperative Analgesia in Conjunction with Benzodiazepines or Other CNS Depressants

Concomitant use of remifentanil and benzodiazepines or other CNS depressants (e.g., anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opiate agonists, alcohol) may result in hypotension, profound sedation, respiratory depression, coma, and death. (See Specific Drugs under Interactions.)

Musculoskeletal Effects

Dose-dependent muscle rigidity, particularly involving respiratory muscles. Chest wall rigidity may occur following single remifentanil doses of >1 mcg/kg given over 30–60 seconds, with infusion rates of >0.1 mcg/kg per minute, or following single doses of <1 mcg/kg administered in conjunction with a continuous infusion of the drug. Peripheral rigidity may occur at lower doses. Supplemental doses of 0.5–1 mcg/kg, incremental increases in infusion rate of >0.05 mcg/kg per minute, and plasma concentrations >5 ng/mL are associated with transient and reversible muscle rigidity.

To manage rigidity occurring during anesthesia induction, administer a neuromuscular blocking agent prior to or simultaneously with the induction regimen. Administration of an induction dose of propofol or thiopental or a paralyzing dose of a muscle relaxant prior to or simultaneously with remifentanil during anesthesia induction decreased incidence of muscle rigidity from 20% to <1% in clinical studies.

To treat rigidity in spontaneously breathing patients, decrease remifentanil infusion rate or discontinue the drug; resolution of rigidity evident within minutes after infusion discontinuance. For life-threatening rigidity, administer rapid-onset neuromuscular blocking agent or naloxone.

Adrenal Insufficiency

Adrenal insufficiency reported in patients receiving opiate agonists or opiate partial agonists. Manifestations are nonspecific and may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension.

If adrenal insufficiency is suspected, perform appropriate laboratory testing promptly and provide physiologic (replacement) dosages of corticosteroids; taper and discontinue the opiate agonist or partial agonist to allow recovery of adrenal function. If the opiate agonist or partial agonist can be discontinued, perform follow-up assessment of adrenal function to determine if corticosteroid replacement therapy can be discontinued. In some patients, switching to a different opiate improved symptoms.

General Precautions

Monitor vital signs and oxygenation continuously during remifentanil administration.

Cardiovascular Effects

Dose-dependent bradycardia and hypotension reported in premedicated patients who received remifentanil doses of <2 mcg/kg over 1 minute. Additional doses of >2 mcg/kg (up to 30 mcg/kg) did not produce further decreases in heart rate or BP. Duration of hemodynamic change directly proportional to plasma concentrations of the drug, with peak hemodynamic effects occurring within 3–5 minutes after a single remifentanil dose or infusion rate increase.

Bradycardia responsive to ephedrine or antimuscarinic agents (e.g., atropine, glycopyrrolate). Hypotension responsive to decreases in rate of administration of remifentanil or concomitant anesthetics, administration of IV fluids, or catecholamines (e.g., ephedrine, epinephrine, norepinephrine). (See Elimination: Special Populations, under Pharmacokinetics.)

Intraoperative Awareness

Intraoperative awareness reported in patients <55 years of age when remifentanil administered with propofol (≤75 mcg/kg per minute).

Postoperative Analgesia

Because of rapid offset of action (within 5–10 minutes) after drug discontinuance, patients undergoing surgical procedures should receive other analgesics prior to remifentanil discontinuance.

Induction of Anesthesia

Do not use remifentanil as the sole agent for induction of anesthesia since loss of consciousness cannot be ensured and a high incidence of apnea, muscle rigidity, or tachycardia is possible.

Obesity

Use remifentanil with caution in morbidly obese individuals since alterations in cardiovascular and respiratory physiology may be present.

Hypogonadism

Hypogonadism or androgen deficiency reported in patients receiving long-term opiate agonist or opiate partial agonist therapy; causality not established. Manifestations may include decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility. Perform appropriate laboratory testing in patients with manifestations of hypogonadism.

Specific Populations

Pregnancy

Category C.

Safety of remifentanil during labor or delivery not established to date. Respiratory depression and other opiate effects may occur in neonates whose mothers are given remifentanil shortly prior to delivery.

Lactation

Not known whether remifentanil is distributed into human milk. However, other fentanyl analogs distribute into human milk. Caution if used in nursing women.

Pediatric Use

Safety and efficacy of remifentanil for use in the maintenance phase of general anesthesia in outpatient and inpatient surgery have been established in pediatric patients from birth to 12 years of age.

Safety and efficacy of remifentanil as an analgesic in the immediate postoperative period or as an analgesic component of monitored anesthesia care have not been established in pediatric patients.

Geriatric Use

Geriatric patients may be twice as sensitive to the pharmacodynamic effects of remifentanil compared with young adults; monitor carefully. Adjust dosage accordingly. (See Geriatric Patients under Dosage and Administration.)

Geriatric patients may exhibit reduced clearance of remifentanil; however, half-life is unchanged, and plasma concentrations decline as rapidly after drug discontinuance as in young adults. (See Elimination: Special Populations, under Pharmacokinetics.)

Hepatic Impairment

Pharmacodynamics (ventilatory response to hypercarbia) of remifentanil are unaltered in patients with severe hepatic impairment awaiting liver transplantation.

Pharmacokinetics of remifentanil and its metabolite are unaltered in the presence of hepatic impairment.

Renal Impairment

Pharmacodynamics (ventilatory response to hypercarbia) of remifentanil are unaltered in patients with end-stage renal disease.

Pharmacokinetics of remifentanil are unaltered in the presence of renal impairment, including end-stage renal disease. (See Elimination: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

Respiratory depression, bradycardia, hypotension, skeletal muscle rigidity, nausea, vomiting, pruritus, headache, shivering, dizziness.

Drug Interactions

Drugs Associated with Serotonin Syndrome

Risk of serotonin syndrome when used with other serotonergic drugs. May occur at usual dosages. Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases. (See Advice to Patients.)

If concomitant use of other serotonergic drugs is warranted, monitor patients for serotonin syndrome, particularly during initiation of therapy and dosage increases.

If serotonin syndrome is suspected, discontinue remifentanil, other opiate therapy, and/or any concurrently administered serotonergic agents.

Specific Drugs

Remifentanil Pharmacokinetics

Absorption

Onset

Rapid onset of action (within 1–1.5 minutes) and peak analgesic effect (within 1–3 minutes). Remifentanil has a faster onset of action than fentanyl or sufentanil.

Duration

Short duration of action. Remifentanil has a shorter duration of action than alfentanil or fentanyl.

Recovery is rapid (within 3–15 minutes), predictable, and independent of duration of infusion. Remifentanil does not accumulate during prolonged administration; therefore, its duration of action (unlike that of other fentanyl analogs) does not increase proportionally with duration of administration.

In full-term neonates and infants <8 weeks of age receiving maintenance anesthesia with remifentanil (0.4–1 mcg/kg per minute) and nitrous oxide, median times to spontaneous purposeful movement and extubation were 6.5 (range: 1–13) and 8.5 (range: 1–14) minutes, respectively.

In patients undergoing general surgery and receiving remifentanil as a component of anesthesia, extubation occurred in a median time of 5 (range: -3–17) and 10 (range: 0–32) minutes in outpatients and inpatients, respectively. Recovery was faster when used in conjunction with nitrous oxide and propofol than when used in conjunction with isoflurane. In those receiving maintenance anesthesia with remifentanil (0.2–0.5 mcg/kg per minute) in conjunction with isoflurane, enflurane, or propofol, with or without nitrous oxide, median or mean times to spontaneous ventilation were 2–11 or 6–8 minutes, respectively. In patients receiving maintenance anesthesia with remifentanil (0.2–0.4 mcg/kg per minute) in conjunction with isoflurane or propofol, with or without nitrous oxide, median time to respond to verbal commands was 5–15 minutes.

In patients undergoing neurosurgery and receiving maintenance anesthesia with remifentanil (0.2–0.25 mcg/kg per minute) in conjunction with IV (propofol) and/or inhalation anesthetics (isoflurane, nitrous oxide), median time to respond to verbal commands and median time to extubation were 5–13 and 5–11 minutes, respectively.

Plasma Concentrations

Exhibits a linear, dose-dependent pharmacokinetic profile. Plasma concentration of drug directly correlates with patient response and decreases 50% in 3–6 minutes after a 1-minute infusion or after prolonged continuous infusion (due to rapid distribution and elimination) and is independent of duration of drug administration.

New steady-state concentrations evident within 5–10 minutes after change in infusion rate. Increasing or decreasing the infusion rate by 0.1 mcg/kg per minute generally produces a 2- to 2.5-ng/mL change in plasma remifentanil concentrations within 5–10 minutes. A new, higher steady-state concentration may be achieved more rapidly (within 3–5 minutes) in intubated patients if 1 mcg/kg of remifentanil is given by rapid IV (bolus) injection in conjunction with an infusion rate increase.

Special Populations

In patients with end-stage renal disease, recovery times appear to be similar to those in patients with normal renal function.

In obese patients undergoing outpatient surgery, mean recovery and extubation times after maintenance anesthesia with remifentanil (0.05–2 mcg/kg per minute) in conjunction with sevoflurane and nitrous oxide were 6 and 7 minutes, respectively.

In children 2–12 years of age receiving maintenance anesthesia with remifentanil (0.2–1.95 mcg/kg per minute) in conjunction with nitrous oxide or with nitrous oxide and either halothane or sevoflurane, times to spontaneous purposeful movement and extubation were 1–24 minutes. In children 1–12 years of age receiving maintenance anesthesia with remifentanil (up to 0.75 mcg/kg per minute) in conjunction with nitrous oxide and isoflurane, median times to spontaneous purposeful movement and extubation were 15 (range: 2–75) and 13 (range: 4–31) minutes, respectively.

Onset of action may be delayed in geriatric patients compared with younger individuals.

Faster recovery times reported for patients <60 years of age compared with those >60 years of age receiving remifentanil in conjunction with propofol; mean time to spontaneous respiration was 0.8 versus 3.2 minutes, respectively, and mean time to extubation was 5 versus 9 minutes, respectively.

Distribution

Extent

Rapidly distributed throughout blood and highly perfused tissues; subsequently distributed into peripheral tissues; unlike other opiate agonists, remifentanil does not accumulate at high doses or with prolonged administration.

Rapidly equilibrates across blood-brain barrier.

Crosses placenta; average maternal remifentanil concentrations are about twice those observed in fetus.

Plasma Protein Binding

70–92% (primarily α₁-acid glycoprotein).

Special Populations

Distribution volumes generally correlate with total body weight; however, in markedly obese patients, distribution volume correlates better with ideal body weight.

Distribution volume is increased in younger children and declines to young healthy adult values by 17 years of age.

Elimination

Metabolism

Rapidly and extensively (>95%) hydrolyzed at the propanoic acid-methyl ester linkage by nonspecific esterases in blood and tissues, resulting in formation of an inactive carboxylic acid metabolite; undergoes N-dealkylation to a lesser extent. Remifentanil is not metabolized by plasma cholinesterase and is not appreciably metabolized in the liver or lungs.

Elimination Route

Rapidly eliminated; ≥88% of dose eliminated in urine as carboxylic acid metabolite.

Half-life

Remifentanil: Terminal elimination half-life: 8–40 minutes; effective biologic half-life: 3–10 minutes.

Carboxylic acid metabolite: 90–120 minutes.

Special Populations

Hepatic impairment: Pharmacokinetics of remifentanil and carboxylic acid metabolite unchanged.

Renal impairment: Pharmacokinetics of remifentanil unchanged. Half-life of carboxylic acid metabolite is increased to 30 hours in anephric patients. Carboxylic acid metabolite is removed by hemodialysis (dialysis extraction ratio: 30%).

Obesity: Clearance generally correlates with total body weight; however, in severely obese patients, clearance correlates better with ideal body weight.

Pediatric patients: Clearance is generally higher in younger children and declines to young healthy adult values by 17 years of age. Neonatal clearance is variable and may average twice that observed in young adults.

Geriatric patients: Remifentanil clearance is reduced by about 25% in patients >65 years of age compared with young adults; however, plasma concentrations decline as rapidly after drug discontinuance as in young adults.

Hypothermic cardiopulmonary bypass: Clearance of remifentanil is reduced by about 20%.

Stability

Storage

Parenteral

Powder for Injection

2–25°C.

Following reconstitution and dilution to final concentration of 20–250 mcg/mL in sterile water for injection, 5% dextrose, 5% dextrose and 0.9% sodium chloride, 0.45 or 0.9% sodium chloride, or 5% dextrose and lactated Ringer's injection, store at room temperature; use within 24 hours.

Following reconstitution and dilution to final concentration of 20–250 mcg/mL in lactated Ringer's injection, store at room temperature; use within 4 hours.

Compatibility

Parenteral

May be incompatible with blood products. (See IV Administration under Dosage and Administration.)

Solution Compatibility

Drug Compatibility

Compatible with propofol (Diprivan) when both drugs are administered into a running IV infusion solution.

Actions

• A selective μ-receptor agonist with similar potency to fentanyl; shares the actions of the opiate agonists.

• Precise mechanism of action has not been fully elucidated; opiate agonists act at several CNS sites, involving several neurotransmitter systems to produce analgesia.

• Remifentanil exhibits greater affinity for μ-receptor than for the δ- or κ-receptors. Does not substantially bind to other nonopioid receptors.

• Agonist activity at the opiate μ-receptor can result in analgesia and respiratory depression. Respiratory depression may be mediated by μ-receptors, possibly μ₂-receptors (which may be distinct from μ₁-receptors involved in analgesia); κ- and δ-receptors may also be involved in respiratory depression.

• Opiate agonists alter perception of and emotional response to pain.

• Pain perception is altered in the spinal cord and higher CNS levels (e.g., substantia gelatinosa, spinal trigeminal nucleus, periaqueductal gray, periventricular gray, medullary raphe nuclei, hypothalamus).

• Opiate agonists do not alter the threshold or responsiveness of afferent nerve endings to noxious stimuli, nor peripheral nerve impulse conduction.

• Opiate agonists act at specific receptor binding sites in the CNS and other tissues; opiate receptors are concentrated in the limbic system, thalamus, striatum, hypothalamus, midbrain, and spinal cord.

• Remifentanil does not substantially affect intracranial pressure, cerebral blood flow or cerebral capacity, or cerebrovascular reactivity to carbon dioxide. Remifentanil does not substantially affect cerebral cortical cells, thereby exerting minimal effect on cognitive function.

• Remifentanil exhibits hypnotic-sparing effects similar to those of other opiates.

• Remifentanil does not appear to cause histamine release.

• Does not appear to alter intraocular pressure.

Advice to Patients

• Risk of potentially fatal additive effects (e.g., profound sedation, respiratory depression, coma) if used concomitantly with benzodiazepines or other CNS depressants, including alcohol and other opiates, either therapeutically or illicitly. Importance of advising patients to avoid alcohol for 24 hours after surgery.

• Potential risk of serotonin syndrome with concurrent use of remifentanil and other serotonergic agents. Importance of immediately contacting clinician if manifestations of serotonin syndrome (e.g., agitation, hallucinations, tachycardia, labile BP, fever, excessive sweating, shivering, shaking, muscle stiffness, twitching, loss of coordination, nausea, vomiting, diarrhea) develop.

• Potential risk of adrenal insufficiency. Importance of contacting clinician if manifestations of adrenal insufficiency (e.g., nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, hypotension) develop.

• Possible risk (although causality not established) of hypogonadism or androgen deficiency with long-term opiate agonist or partial agonist use. Importance of informing clinician if decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility occurs following therapy.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., cardiovascular disease).

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule II (C-II) drug.

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