Medication Guide App

Remifentanil Hydrochloride

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
Brands: Ultiva

Introduction

Selective μ-receptor opiate agonist; fentanyl analog.1 2 3 4 10 11 12

Uses for Remifentanil Hydrochloride

General Anesthesia

As the analgesic component in the induction and maintenance of general anesthesia for inpatient and outpatient procedures.1 2 3 9 10 12 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.1 2 3

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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).1 25 36 37 38 39 40 41 Long-term (i.e., >16 hours) use of remifentanil in ICU patients has not been established to date.1

May be particularly useful in surgical procedures requiring a rapid onset of analgesia and rapid recovery.2 3 8

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,1 32 33 breast biopsy,31 34 35 and other superficial surgical procedures1 31 ) in adults.1 9

Remifentanil Hydrochloride 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.1

Concomitant Anesthetics

  • Selection of concomitant anesthetic agent(s) must be based on the individual needs of the patient.1

  • Synergistic activity with other anesthetics; dosage adjustment for concomitantly administered anesthetic(s) may be needed.1 3 (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.1 (See Discontinuance of Therapy under Cautions.)

  • Residual analgesic activity absent within 5–10 minutes of drug discontinuance.1 Consider administering alternative analgesics prior to remifentanil discontinuance in surgical patients who may experience postoperative pain.1 3 9 10 Choose analgesic based on surgical procedure and level of follow-up care.1

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.1

Inject remifentanil into IV tubing at or close to the venous cannula.1

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.1

Clear remifentanil from the IV tubing upon discontinuance of the drug to prevent subsequent inadvertent administration of residual drug.1 (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.1 Shake well to dissolve.1 Resultant solution contains approximately 1 mg of remifentanil per mL.1

Dilution

Reconstituted solutions must be diluted prior to administration.1

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

Table 1. Reconstitution and Dilution of Remifentanil Powder for Injection1

 

Final Volume (mL) After Reconstitution and Dilution

Final Concentration (mcg/mL)

1-mg Vial

2-mg Vial

5-mg Vial

20

50

100

250

25

40

80

200

50

20

40

100

250

...

...

20

A final concentration of 25 mcg/mL is recommended when the drug is used for monitored analgesia care.1 A final concentration of 20 or 25 mcg/mL is recommended for pediatric patients ≥1 year of age.1 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.1

Rate of Administration

Individualize rate of administration based on patient response.1 3 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.1

In nonintubated patients, administer single doses of remifentanil over 30–60 seconds.1

Induction of anesthesia: Administer remifentanil as a continuous IV infusion.1 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.1

Maintenance of anesthesia: Administer remifentanil as a continuous IV infusion.1 May administer rapid IV (bolus) doses every 2–5 minutes in response to light anesthesia or transient episodes of intense surgical stress.1

Analgesia in the immediate postoperative period: Administer as a continuous IV infusion.1 Infusion rates >0.2 mcg/kg per minute are associated with respiratory depression.1 Supplemental rapid IV (bolus) doses of remifentanil are not recommended because of risk for respiratory depression and muscle rigidity.1

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.1 Supplemental rapid IV (bolus) doses of remifentanil are not recommended because of risk for respiratory depression and muscle rigidity.1

Not recommended.1

Table 2. IV Infusion Rates Required to Administer Remifentanil at Usual Recommended Dosages as a 20-, 25-, 50-, or 250-mcg/mL Solution1

 

Infusion Rate (mL/kg per hour)

Dosage (mcg/kg per minute)

20 mcg/mL

25 mcg/mL

50 mcg/mL

250 mcg/mL

0.0125

0.038

0.03

0.015

0.025

0.075

0.06

0.03

0.05

0.15

0.12

0.06

0.012

0.075

0.23

0.18

0.09

0.018

0.1

0.3

0.24

0.12

0.024

0.15

0.45

0.36

0.18

0.036

0.2

0.6

0.48

0.24

0.048

0.25

0.75

0.6

0.3

0.06

0.5

1.5

1.2

0.6

0.12

0.75

2.25

1.8

0.9

0.18

1

3

2.4

1.2

0.24

1.25

3.75

3

1.5

0.3

1.5

4.5

3.6

1.8

0.36

1.75

5.25

4.2

2.1

0.42

2

6

4.8

2.4

0.48

Risk of muscle rigidity is related to the dose and rate of IV administration.1 11 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.1 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.1 Prior or simultaneous administration of propofol or thiopental or a neuromuscular blocking agent may attenuate the development of rigidity.1 For excessive rigidity, consider decreasing the infusion rate or discontinuing the infusion of remifentanil or administering a neuromuscular blocking agent or naloxone.1 (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.1 In spontaneously breathing patients, manage respiratory depression by reducing infusion rate of remifentanil by 50% or by temporarily discontinuing the infusion.1 (See Respiratory Depression under Cautions.)

Dosage

Available as remifentanil hydrochloride; dosage expressed in terms of remifentanil.1

Synergistic activity with other anesthetics; dosage adjustment of concomitantly administered anesthetic(s) may be needed.1 3 (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.1 41

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.1 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.1 Recommended infusion rate: 0.4–1 mcg/kg per minute.1

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.1 16 30 Individualize dosage.1 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.1

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.1 Adjust infusion rate upward by 50% or downward by 25–50% based on patient's response at intervals of 2–5 minutes.1 Recommended infusion rate: 0.05–1.3 mcg/kg per minute.1 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.1

An initial dose of 1 mcg/kg may be administered over 30–60 seconds.1 13

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

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.1

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.1

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.1 Adjust infusion rate upward by 25–100% or downward by 25–50% based on patient's response at intervals of 2–5 minutes.1 Recommended infusion rate: 0.1–2 mcg/kg per minute.1 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.1

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.1 Adjust infusion rate upward by 25–100% or downward by 25–50% based on patient's response at intervals of 2–5 minutes.1 Recommended infusion rate: 0.05–2 mcg/kg per minute.1 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.1

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

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.1 Adjust infusion rate in increments of 0.025 mcg/kg per minute at 5-minute intervals based on level of analgesia and respiratory rate.1 Recommended infusion rate: 0.025–0.2 mcg/kg per minute.1

Supplemental rapid IV (bolus) doses of remifentanil are not recommended because of risk for respiratory depression and muscle rigidity.1

Infusion rates >0.2 mcg/kg per minute associated with respiratory depression.1

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.1 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.1

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.1 Recommended infusion rate: 0.125–4 mcg/kg per minute.1 Supplemental rapid IV (bolus) doses of 0.5–1 mcg/kg may be administered.1 41

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.1 Recommended infusion rate: 0.05–1 mcg/kg per minute.1

Monitored Anesthesia Care

Supplemental oxygen strongly recommended for patients receiving remifentanil for monitored anesthesia care.1

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.1 When used in this manner in conjunction with midazolam 2 mg, reduce remifentanil dose to 0.5 mcg/kg (over 30–60 seconds).1

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.1 Because of risk of respiratory depression, reduce infusion rate to 0.05 mcg/kg per minute following nerve block placement.1 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.1 Recommended infusion rate: 0.025–0.2 mcg/kg per minute.1

When used in conjunction with midazolam 2 mg, remifentanil 0.05 mcg/kg per minute, beginning 5 minutes before the local anesthetic.1 Because of risk of respiratory depression, reduce infusion rate to 0.025 mcg/kg per minute following nerve block placement.1 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.1 Recommended infusion rate: 0.025–0.2 mcg/kg per minute.1

Infusion rates >0.2 mcg/kg per minute associated with respiratory depression.1

Administration of rapid IV (bolus) doses of remifentanil concomitantly with a continuous infusion of the drug in spontaneously breathing patients is not recommended.1 11

Special Populations

Geriatric Patients

Decrease initial and, possibly, subsequent doses of remifentanil by 50% in patients >65 years of age; titrate cautiously.1 2 9 12 (See Geriatric Use under Cautions.)

Consider extending anticipated time to clinical effect by 50–100% in geriatric patients.9 (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%.1 Base subsequent dosage reductions on an estimate of ideal body weight.2 9 12

Cautions for Remifentanil Hydrochloride

Contraindications

  • Contains glycine; contraindicated for epidural or intrathecal administration.1 2 3 9

  • Known hypersensitivity to fentanyl analogs.1

Warnings/Precautions

Warnings

Shares the toxic potentials of the opiate agonists; observe the usual precautions of opiate agonist therapy.1 2 3

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.1 Such training must include the establishment and maintenance of a patent airway and assisted ventilation.1

Do not use for diagnostic or therapeutic procedures outside a monitored anesthesia care setting.1 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.1

Monitor oxygen saturation continuously and have resuscitative and intubation equipment, oxygen, and an opiate antagonist readily available.1

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.1

Respiratory Depression

Apnea and dose-dependent respiratory depression reported with remifentanil.1 2 3 9 11 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.1 Peak respiratory depression after rapid IV (bolus) doses generally occurs within 2.5–5 minutes.2 8 11

Respiratory depression may occur up to 30 minutes after discontinuance of remifentanil infusion secondary to residual effects of concomitant anesthetics.1 Monitor patients in postoperative period to ensure adequate recovery without stimulation.1 To date, no reported cases of remifentanil-induced delayed respiratory depression occurring >30 minutes after drug discontinuance.1

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). 1

Manage respiratory depression in spontaneously breathing patients by reducing infusion rate of remifentanil by 50% or by temporarily discontinuing the infusion.1 Spontaneous respiration occurs at plasma remifentanil concentrations of 4–5 ng/mL in the absence of other anesthetic agents.1 In patients undergoing general anesthesia, rate of respiratory recovery is dependent upon concomitant anesthetics.1 (See Duration under Pharmacokinetics.)

Supplemental oxygen strongly recommended for patients receiving remifentanil for monitored anesthesia care.1

Musculoskeletal Effects

Dose-dependent muscle rigidity, particularly involving respiratory muscles.1 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.1 Peripheral rigidity may occur at lower doses.1 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.1

To manage rigidity occurring during anesthesia induction, administer a neuromuscular blocking agent prior to or simultaneously with the induction regimen.1 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.1

To treat rigidity in spontaneously breathing patients, decrease remifentanil infusion rate or discontinue the drug; resolution of rigidity evident within minutes after infusion discontinuance.1 For life-threatening rigidity, administer rapid-onset neuromuscular blocking agent or naloxone.1

General Precautions

Monitor vital signs and oxygenation continuously during remifentanil administration.1

Cardiovascular Effects

Dose-dependent bradycardia and hypotension reported in premedicated patients who received remifentanil doses of <2 mcg/kg over 1 minute.1 Additional doses of >2 mcg/kg (up to 30 mcg/kg) did not produce further decreases in heart rate or BP.1 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.1

Bradycardia responsive to ephedrine or antimuscarinic agents (e.g., atropine, glycopyrrolate).1 Hypotension responsive to decreases in rate of administration of remifentanil or concomitant anesthetics, administration of IV fluids, or catecholamines (e.g., ephedrine, epinephrine, norepinephrine).1 (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).1

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.1 3

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.1 3

Obesity

Use remifentanil with caution in morbidly obese individuals since alterations in cardiovascular and respiratory physiology may be present.1

Specific Populations

Pregnancy

Category C.1

Safety of remifentanil during labor or delivery not established to date.1 Respiratory depression and other opiate effects may occur in neonates whose mothers are given remifentanil shortly prior to delivery.1

Lactation

Not known whether remifentanil is distributed into human milk.1 However, other fentanyl analogs distribute into human milk.1 Caution if used in nursing women.1

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.1

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.1

Geriatric Use

Geriatric patients may be twice as sensitive to the pharmacodynamic effects of remifentanil compared with young adults; monitor carefully.1 3 9 Adjust dosage accordingly.1 2 9 12 (See Geriatric Patients under Dosage and Administration.)

Geriatric patients may exhibit reduced clearance of remifentanil;1 2 9 12 however, half-life is unchanged, and plasma concentrations decline as rapidly after drug discontinuance as in young adults.1 (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.1

Pharmacokinetics of remifentanil and its metabolite are unaltered in the presence of hepatic impairment.1 2 3 12

Renal Impairment

Pharmacodynamics (ventilatory response to hypercarbia) of remifentanil are unaltered in patients with end-stage renal disease.1

Pharmacokinetics of remifentanil are unaltered in the presence of renal impairment, including end-stage renal disease.1 2 12 (See Elimination: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

Respiratory depression,1 9 10 11 bradycardia,1 2 9 10 11 12 hypotension,1 2 9 10 11 12 skeletal muscle rigidity,1 2 9 10 11 12 nausea,1 2 9 11 12 vomiting,1 2 9 11 12 pruritus,1 9 headache,1 shivering,1 2 11 12 dizziness.1

Interactions for Remifentanil Hydrochloride

Specific Drugs

Drug

Interaction

Comments

Anesthetics (e.g., isoflurane, propofol, thiopental)

Synergistic effect when administered concomitantly with remifentanil1 2 3 12

Clearance of remifentanil unaltered by thiopental, isoflurane, or propofol1

Propofol or thiopental may attenuate development of remifentanil-associated muscle rigidity1

May need to reduce dosage of anesthetic by up to 75%1 3

Antimuscarinics (atropine, glycopyrrolate)

May blunt the potential for remifentanil-associated bradycardia1 3

Cholinesterase inhibitors

Remifentanil hydrolysis was not inhibited by neostigmine or physostigmine in vitro1 9

Esmolol

Remifentanil hydrolysis was not inhibited by esmolol in vitro1

Esmolol metabolism was not altered by remifentanil9

Midazolam

Synergistic effect when administered concomitantly with remifentanil1 2 3 9

Remifentanil hydrolysis was not inhibited by midazolam in vitro1

May need to reduce midazolam dosage by up to 75%1

Neuromuscular blocking agents

May attenuate development of remifentanil-associated muscle rigidity1

Remifentanil hydrolysis was not inhibited by atracurium or mivacurium in vitro1

Succinylcholine metabolism was not altered by remifentanil 9

Temazepam

Clearance of remifentanil unaltered by temazepam1

Remifentanil Hydrochloride Pharmacokinetics

Absorption

Onset

Rapid onset of action (within 1–1.5 minutes) and peak analgesic effect (within 1–3 minutes).1 2 4 8 9 10 12 Remifentanil has a faster onset of action than fentanyl or sufentanil.8 9

Duration

Short duration of action.1 2 3 4 Remifentanil has a shorter duration of action than alfentanil or fentanyl.10

Recovery is rapid (within 3–15 minutes), predictable, and independent of duration of infusion.1 2 8 10 12 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.1 8

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.1 16

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.1 2 Recovery was faster when used in conjunction with nitrous oxide and propofol than when used in conjunction with isoflurane.1 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.2 21 22 23 24 25 26 27 28 29 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.2 21 22 25 26 27 28 29

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.1 2 17 18 19

Plasma Concentrations

Exhibits a linear, dose-dependent pharmacokinetic profile.2 9 12 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.1 2 3 4 9 11 12

New steady-state concentrations evident within 5–10 minutes after change in infusion rate.1 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.1 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.1

Special Populations

In patients with end-stage renal disease, recovery times appear to be similar to those in patients with normal renal function.2

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.2 20

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.1 13 14 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.1 15

Onset of action may be delayed in geriatric patients compared with younger individuals.9

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.2

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.1 2 3 11 12

Rapidly equilibrates across blood-brain barrier.1 2 9 12

Crosses placenta;2 9 12 average maternal remifentanil concentrations are about twice those observed in fetus.1

Plasma Protein Binding

70–92% (primarily α1-acid glycoprotein).1 2 8 9 12

Special Populations

Distribution volumes generally correlate with total body weight; however, in markedly obese patients, distribution volume correlates better with ideal body weight.1 2

Distribution volume is increased in younger children and declines to young healthy adult values by 17 years of age.1

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.1 2 3 4 8 9 10 12 Remifentanil is not metabolized by plasma cholinesterase and is not appreciably metabolized in the liver or lungs.1 2 3

Elimination Route

Rapidly eliminated; ≥88% of dose eliminated in urine as carboxylic acid metabolite.1 2 3 9 11 12

Half-life

Remifentanil: Terminal elimination half-life: 8–40 minutes;1 2 8 9 11 12 effective biologic half-life: 3–10 minutes.1 2 3 9 11

Carboxylic acid metabolite: 90–120 minutes.1 9

Special Populations

Hepatic impairment: Pharmacokinetics of remifentanil1 2 3 12 and carboxylic acid metabolite unchanged.1

Renal impairment: Pharmacokinetics of remifentanil unchanged.1 2 3 12 Half-life of carboxylic acid metabolite is increased to 30 hours in anephric patients.1 Carboxylic acid metabolite is removed by hemodialysis (dialysis extraction ratio: 30%).1

Obesity: Clearance generally correlates with total body weight; however, in severely obese patients, clearance correlates better with ideal body weight.1 2 12

Pediatric patients: Clearance is generally higher in younger children and declines to young healthy adult values by 17 years of age.1 Neonatal clearance is variable and may average twice that observed in young adults.1

Geriatric patients: Remifentanil clearance is reduced by about 25% in patients >65 years of age compared with young adults;1 9 12 however, plasma concentrations decline as rapidly after drug discontinuance as in young adults.1

Hypothermic cardiopulmonary bypass: Clearance of remifentanil is reduced by about 20%.1 2 12

Stability

Storage

Parenteral

Powder for Injection

2–25°C.1

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.1

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.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

May be incompatible with blood products.1 (See IV Administration under Dosage and Administration.)

Solution Compatibility

Compatible

Dextrose 5% in water1

Dextrose 5% in sodium chloride 0.9%1

Sodium chloride 0.45 or 0.9%1

Dextrose 5% in Ringer's injection, lactated1

Ringer's injection, lactated1

Drug Compatibility
Y-Site CompatibilityHID

Compatible

Acyclovir sodium

Alfentanil HCl

Amikacin sulfate

Aminophylline

Ampicillin sodium

Ampicillin sodium–sulbactam sodium

Aztreonam

Bretylium tosylate

Bumetanide

Buprenorphine HCl

Butorphanol tartrate

Calcium gluconate

Cefazolin sodium

Cefepime HCl

Cefotaxime sodium

Cefotetan disodium

Cefoxitin sodium

Ceftazidime

Ceftizoxime sodium

Ceftriaxone sodium

Cefuroxime sodium

Cimetidine HCl

Ciprofloxacin

Cisatracurium besylate

Clindamycin phosphate

Co-trimoxazole

Dexamethasone sodium phosphate

Dexmedetomidine HCl

Digoxin

Diphenhydramine HCl

Dobutamine HCl

Dopamine HCl

Doxycycline hyclate

Droperidol

Enalaprilat

Epinephrine HCl

Esmolol HCl

Famotidine

Fenoldopam mesylate

Fentanyl citrate

Fluconazole

Furosemide

Ganciclovir sodium

Gatifloxacin

Gentamicin sulfate

Haloperidol lactate

Heparin sodium

Hydrocortisone sodium succinate

Hydromorphone HCl

Hydroxyzine HCl

Imipenem-cilastatin sodium

Inamrinone lactate

Isoproterenol HCl

Ketorolac tromethamine

Lidocaine HCl

Linezolid

Lorazepam

Magnesium sulfate

Mannitol

Meperidine HCl

Methylprednisolone sodium succinate

Metoclopramide HCl

Metronidazole

Midazolam HCl

Morphine sulfate

Nalbuphine HCl

Nitroglycerin

Norepinephrine bitartrate

Ondansetron HCl

Phenylephrine HCl

Piperacillin sodium–tazobactam sodium

Potassium chloride

Procainamide HCl

Prochlorperazine edisylate

Promethazine HCl

Ranitidine HCl

Sodium bicarbonate

Sufentanil citrate

Theophylline

Thiopental sodium

Ticarcillin disodium–clavulanate potassium

Tobramycin sulfate

Vancomycin HCl

Zidovudine

Incompatible

Amphotericin B cholesteryl sulfate complex

Variable

Amphotericin B

Chlorpromazine HCl

Diazepam

Compatible with propofol (Diprivan) when both drugs are administered into a running IV infusion solution.1

Actions

  • A selective μ-receptor agonist with similar potency to fentanyl; shares the actions of the opiate agonists.2 3 4 8 9 10 11 12

  • Precise mechanism of action has not been fully elucidated; opiate agonists act at several CNS sites, involving several neurotransmitter systems to produce analgesia.5 8

  • Remifentanil exhibits greater affinity for μ-receptor than for the δ- or κ-receptors.3 11 Does not substantially bind to other nonopioid receptors.3

  • Agonist activity at the opiate μ-receptor can result in analgesia and respiratory depression.2 8 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.5 7

  • Opiate agonists alter perception of and emotional response to pain.5

  • 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).5 6

  • Opiate agonists do not alter the threshold or responsiveness of afferent nerve endings to noxious stimuli, nor peripheral nerve impulse conduction.5 6

  • 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.5

  • Remifentanil does not substantially affect intracranial pressure,1 2 3 12 cerebral blood flow or cerebral capacity,2 12 or cerebrovascular reactivity to carbon dioxide.1 2 3 12 Remifentanil does not substantially affect cerebral cortical cells, thereby exerting minimal effect on cognitive function.9

  • Remifentanil exhibits hypnotic-sparing effects similar to those of other opiates.1 2 3 12

  • Remifentanil does not appear to cause histamine release.1 3 11

  • Does not appear to alter intraocular pressure.1 2 3 12

Advice to Patients

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • 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).1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

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

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule II (C-II) drug.1

Remifentanil Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV use only

1 mg (of remifentanil)

Ultiva (C-II; with glycine; preservative-free)

Abbott

2 mg (of remifentanil)

Ultiva (C-II; with glycine; preservative-free)

Abbott

5 mg (of remifentanil)

Ultiva (C-II; with glycine; preservative-free)

Abbott

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions March 1, 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Abbott Laboratories. Ultiva (remifentanil hydrochloride) injection prescribing information. North Chicago, IL; 2006 Aug.

2. Scott LJ, Perry CM. Remifentanil: a review of its use during the induction and maintenance of general anesthesia. Drugs. 2005; 65:1793-1823. [PubMed 16114980]

3. Bürkle H, Dunbar S, Van Aken H. Remifentanil: a novel, short-acting, μ-opioid. Anesth Analg. 1996; 83:646-51.

4. Martinelli C, Davoli M, Rutili A et al. Remifentanil for analgesia and sedation of critically ill patients in intensive care units (protocol). Cochrane Database of Syst Rev. 2006; 1:CD005577.

5. Bailey PL. Clinical Pharmacology and Applications of Opioid Agonists. In: Bowdle TA, Horita A, Kharasch ED. The pharmacologic basis of anesthesiology. New York: Churchill Livingstone; 1994:96-103.

6. Jaffe JH, Martin WR. Opioid analgesics and antagonists. In: Gilman AG, Goodman L, Gilman A, eds. Goodman and Gilman’s the pharmacological basis of therapeutics. 6th ed. New York: Macmillan Publishing Company; 1980:494-534.

7. Reisner L, Koo PJS. Pain and its management. In: Koda-Kimble MA, Young LY et al, eds. Applied Therapeutics: the clinical use of drugs. 8th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2005: 9-1-9-40.

8. Gutstein HB, Akil H. Opioid analgesics. In: Brunton LL, Lazo JS et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 11th ed. New York: McGraw-Hill; 547-90.

9. Beers R, Camporesi E. Remifentanil update: clinical science and utility. CNS Drugs. 2004; 18:1085-1104. [PubMed 15581380]

10. Mason P. Remifentanil. Intensive Crit Care Nurs. 2002; 18:355-57. [PubMed 12526873]

11. Richardson SP, Egan TD. The safety of remifentanil by bolus injection. Expert Opin. Drug Saf. 2005; 4:643-51.

12. Scott LJ, Perry CM. Spotlight on remifentanil for general anaesthesia. CNS Drugs. 2005; 19:1069-74. [PubMed 16332149]

13. Davis PJ, Lerman J, Suresh S et al. A randomized multicenter study of remifentanil compared with alfentanil, isoflurane, or propofol in anesthetized pediatric patients undergoing elective strasbismus surgery. Anesth Analg. 1997; 84:982-9. [PubMed 9141919]

14. Davis PJ, Finkel JC, Orr RJ et al. A randomized, double-blinded study of remifentanil versus fentanyl for tonsillectomy and adenoidectomy surgery in pediatric ambulatory surgical patients. Anesth Analg. 2000; 90:863-7. [PubMed 10735790]

15. Prys-Roberts C, Lerman J, Murat I et al. Comparison of remifentanil versus regional anaesthesia in children anaesthetised with isoflurane/nitrous oxide. International Remifentanil Paediatric Anaesthesia Study group. Anaesthesia. 2000;55:870-6.

16. Galinkin JL, Davis PJ, McGowan FX et al. A randomized multicenter study of remifentanil compared with halothane in neonates and infants undergoing pyloromyotomy. II. Perioperative breathing patterns in neonates and infants with pyloric stenosis. Anesth Analg. 2001; 93:1387-92. [PubMed 11726412]

17. Balakrishnan G, Raudzens P, Samra SK et al. A comparison of remifentanil and fentanyl in patients undergoing surgery for intracranial mass lesions. Anesth Analg. 2000; 91:163-9. [PubMed 10866905]

18. Gelb AW, Salevsky F, Chung F et al. Remifentanil with morphine transitional analgesia shortens neurological recovery compared to fentanyl for supratentorial craniotomy. Can J Anesth. 2003; 50:946-52. [PubMed 14617595]

19. Sneyd JR, Whaley A, Dimpel HL et al. An open, randomized comparison of alfentanil, remifentanil and alfentanil followed by remifentanil in anaesthesia for craniotomy. Br J Anaesth. 1998; 81:361-4. [PubMed 9861120]

20. Song D, Whitten CW, White PF. Remifentanil infusion facilitates early recovery for obese outpatients undergoing laparoscopic cholecystectomy. Anesth Analg. 2000; 90:1111-3. [PubMed 10781462]

21. Chung F, Mulier JP, Scholz J et al. A comparison of anaesthesia using remifentanil combined with either isoflurane, enflurane or propofol in patients undergoing gynaecological laparoscopy, varicose vein or arthroscopic surgery. Acta Anaesthesiol Scand. 2000; 44:790-8. [PubMed 10939691]

22. Hogue CW Jr, Bowdle TA, O'Leary C et al. A multicenter evaluation of total intravenous anesthesia with remifentanil and propofol for elective inpatient surgery. Anesth Analg. 1996; 83:279-85. [PubMed 8694306]

23. Rowbotham DJ, Peacock JE, Jones RM et al. Comparison of remifentanil in combination with isoflurane or propofol for short-stay surgical procedures. Br J Anaesth. 1998; 80:752-5. [PubMed 9771302]

24. Wilhelm W, Grundmann U, Van Aken H et al. A multicenter comparison of isoflurane and propofol as adjuncts to remifentanil-based anesthesia. J Clin Anesth. 2000; 12:129-35. [PubMed 10818327]

25. Schuttler J, Albrecht S, Breivik H et al. A comparison of remifentanil and alfentanil in patients undergoing major abdominal surgery. Anaesthesia. 1997; 52:307-17. [PubMed 9135180]

26. Sneyd JR, Camu R, Doenicke A et al. Remifentanil and fentanyl during anaesthesia for major abdominal and gynaecological surgery. An open, comparative study of safety and efficacy. Eur J Anaesthesiol. 2001; 18:605-14. [PubMed 11553256]

27. Twersky RS, Jamerson B, Warner DS et al. Hemodynamics and emergence profile of remifentanil versus fentanyl prospectively compared in a large population of surgical patients. J Clin Anesth. 2001; 13:407-16. [PubMed 11578883]

28. Cartwright DP, Kvalsvik O, Cassuto J et al. A randomized, blind comparison of remifentanil and alfentanil during anesthesia for outpatient surgery. Anesth Analg. 1997; 85:1014-9. [PubMed 9356093]

29. Philip BK, Scuderi PE, Chung F et al. Remifentanil compared with alfentanil for ambulatory surgery using total intravenous anesthesia. Anesth Analg. 1997; 84:515-21. [PubMed 9052293]

30. Davis P. Galinkin J, McGowan FX et al. A randomized multicenter study of remifentanil compared with halothane in neonates and infants undergoing pyloromyotomy. I. Emergence and recovery profiles. Anesth Analg. 2001; 93:1380-6 [PubMed 11726411]

31. Gold MI, Watkins WD, Sung YF et al. Remifentanil versus remifentanil/midazolam for ambulatory surgery during monitored anesthesia care. Anesthesiology. 1997; 87:51-7. [PubMed 9232133]

32. Ahmad S, Leavell ME, Fragen RJ et al. Remifentanil versus alfentanil as analgesic adjuncts during placement of ophthalmologic nerve blocks. Reg Anesth Pain Med. 1999; 24:331-6. [PubMed 10445772]

33. Leidinger W, Schwinn P, Hofmann HM et al. Remifentanil for analgesia during retrobulbar nerve block placement. Eur J Anaesthesiol. 2005; 22:40-3. [PubMed 15816572]

34. Dilger JA, Sprung J, Maurer W et al. Remifentanil provides better analgesia than alfentanil during breast biopsy surgery under monitored anesthesia care. Can J Anaesth. 2004; 51:20-4. [PubMed 14709455]

35. Avramov MN, Smith I, White PF. Interactions between midazolam and remifentanil during monitored anesthesia care. Anesthesiology. 1996; 85:1283-9. [PubMed 8968175]

36. Yarmush J, D'Angelo R, O'Leary C et al. Remifentanil versus morphine for acute postoperative analgesia (abstract). Anesth Analg. 1996; 82:S504.

37. Yarmush J, D'Angelo R, Kirkhart B et al. A comparison of remifentanil and morphine sulfate for acute postoperative analgesia after total intravenous anesthesia with remifentanil and propofil. Anesthesiol. 1997; 87:235-45.

38. Camu F, Sneyd JR, Holgersen D et al. Efficacy and safety of remifentanil to control immediate postoperative pain prior to transfer to ward analgesia (abstract). Presented at the 11th World Congress of Anaesthesiologists, 14-20 April 1996, Sydney, D311.

39. Bowdle TA, Camporesi EM, Maysick L et al. A multicenter evaluation of remifentanil for early postoperative analgesia. Anesth Analg. 1996; 83:1292-97. [PubMed 8942602]

40. Bowdle TA, Ready LB, Kharasch ED et al. Transition to post-operative epidural or patient-controlled intravenous analgesia following total intravenous anaesthesia with remifentanil and propofol for abdominal surgery. Eur J Anesth. 1997; 14:374-79.

41. Abbott, Abbott Park, IL: Personal communication.

HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:1455-61.

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