Remifentanil

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous [preservative free]:

Ultiva: 1 mg (1 ea); 2 mg (1 ea); 5 mg (1 ea)

Generic: 1 mg (1 ea); 2 mg (1 ea); 5 mg (1 ea)

Pharmacology

Mechanism of Action

Binds with stereospecific mu-opioid receptors at many sites within the CNS, increases pain threshold, alters pain reception, inhibits ascending pain pathways

Pharmacokinetics/Pharmacodynamics

Distribution

Pediatric patients (Ross 2001): V_dss:

Neonates ≤2 months: 453 ± 145 mL/kg

Infants and Children >2 months to <2 years: 308 ± 89 mL/kg

Children 2 to 6 years: 240 mL/kg ± 131 mL/kg

Children 7 to 12 years: 249 mL/kg ± 91 mL/kg

Adolescents 13 to <16 years: 223 ± 31 mL/kg

Adolescents 16 to 18 years: 243 ± 109 mL/kg

Adults: V_d: Initial: 100 mL/kg; V_dss: 350 mL/kg

Metabolism

Rapid via blood and tissue esterases; not metabolized by plasma cholinesterase (pseudocholinesterase) and is not appreciably metabolized by the liver

Excretion

Urine

Clearance:

Pediatric patients (Ross 2001):

Neonates ≤2 months of age: 90.5 ± 36.8 mL/minute/kg

Infants and Children >2 months to <2 years: 92.1 ± 25.8 mL/minute/kg

Children 2 to 6 years: 76.0 ± 22.4 mL/minute/kg

Children 7 to 12 years: 59.7 ± 22.5 mL/minute/kg

Adolescents 13 to <16 years: 57.2 ± 21.2 mL/minute/kg

Adolescents 16 to 18 years: 46.5 ± 2.1 mL/minute/kg

Adults: ~40 mL/minute/kg

Onset of Action

IV: 1 to 3 minutes; Peak effect: 3 to 5 minutes

Time to Peak

Intranasal: Children ≤7 years: ~3.5 minutes (Verghese 2008)

Duration of Action

3 to 10 minutes (Scott 2005)

Half-Life Elimination

Dose dependent:

Pediatric patients (Ross 2001): Effective:

Neonates ≤2 months: 5.4 minutes (range: 3 to 8 minutes)

Infants and Children >2 months to <2 years: 3.4 minutes (range: 2 to 6 minutes)

Children 2 to 6 years: 3.6 minutes (range: 1 to 6 minutes)

Children 7 to 12 years: 5.3 minutes (range: 3 to 7 minutes)

Adolescents: 13 to <16 years: 3.7 minutes (range: 2 to 5 minutes)

Adolescents 16 to 18 years: 5.7 minutes (range: 5 to 6 minutes)

Adults: Terminal: 10 to 20 minutes; Effective: 3 to 10 minutes

Protein Binding

~70% (primarily alpha₁ acid glycoprotein)

Use in Specific Populations

Special Populations: Elderly

Clearance is reduced ~25%.

Use: Labeled Indications

Anesthesia: Analgesic for use during the induction and maintenance of general anesthesia; continued analgesia into the immediate postoperative period in adults; analgesic component of monitored anesthesia in adults

Use: Off Label

Pain in mechanically ventilated patients (management)yes

Based on the Society of Critical Care Medicine guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the intensive care unit, remifentanil is an effective and recommended agent for management of pain in critically ill patients.

Contraindications

Hypersensitivity (eg, anaphylaxis) to remifentanil or any component of the formulation; intrathecal or epidural administration.

Canadian labeling: Additional contraindications (not in US labeling): Known or suspected mechanical GI obstruction (eg, bowel obstruction or strictures) or any diseases/conditions that affect bowel transit (eg, ileus of any type); suspected surgical abdomen (eg, acute appendicitis or pancreatitis); mild pain that can be managed with other pain medications; acute or severe bronchial asthma, chronic obstructive airway, status asthmaticus; acute respiratory depression; hypercapnia; cor pulmonale; acute alcoholism, delirium tremens, and convulsive disorders; severe CNS depression, increased cerebrospinal or intracranial pressure and head injury; concurrent use or use within 14 days of an MAO inhibitor

Documentation of allergenic cross-reactivity for opioids is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosage and Administration

Dosing: Adult

Anesthesia: IV continuous infusion:

Induction of anesthesia: 0.5 to 1 mcg/kg/minute; if endotracheal intubation is to occur in <8 minutes, an initial dose of 1 mcg/kg may be administered over 30 to 60 seconds

Coronary bypass surgery: 1 mcg/kg/minute

Maintenance of anesthesia: Supplemental bolus dose of 1 mcg/kg may be administered every 2 to 5 minutes. Consider increasing concomitant anesthetics with infusion rate >1 mcg/kg/minute. Infusion rate can be titrated upward in increments of 25% to 100% or downward in decrements of 25% to 50% every 2 to 5 minutes.

With nitrous oxide (66%): 0.4 mcg/kg/minute (range: 0.1 to 2 mcg/kg/minute)

With isoflurane: 0.25 mcg/kg/minute (range: 0.05 to 2 mcg/kg/minute)

With propofol: 0.25 mcg/kg/minute (range: 0.05 to 2 mcg/kg/minute)

Coronary bypass surgery: 1 mcg/kg/minute (range: 0.125 to 4 mcg/kg/minute); supplemental dose: 0.5 to 1 mcg/kg

Continuation as an analgesic in immediate postoperative period: 0.1 mcg/kg/minute (range: 0.025 to 0.2 mcg/kg/minute). Infusion rate may be adjusted every 5 minutes in increments of 0.025 mcg/kg/minute. Bolus doses are not recommended. Infusion rates >0.2 mcg/kg/minute are associated with respiratory depression.

Coronary bypass surgery, continuation as an analgesic into the ICU: 1 mcg/kg/minute (range: 0.05 to 1 mcg/kg/minute)

Analgesic component of monitored anesthesia care:

Note: Supplemental oxygen is recommended:

Single IV dose administered 90 seconds prior to local anesthetic:

Remifentanil alone: 1 mcg/kg over 30 to 60 seconds

With midazolam: 0.5 mcg/kg over 30 to 60 seconds

Continuous infusion beginning 5 minutes prior to local anesthetic:

Remifentanil alone: 0.1 mcg/kg minute

With midazolam: 0.05 mcg/kg/minute

Continuous infusion administered after local anesthetic:

Remifentanil alone: 0.05 mcg/kg/minute (range: 0.025 to 0.2 mcg/kg/minute)

With midazolam: 0.025 mcg/kg/minute (range: 0.025 to 0.2 mcg/kg/minute)

Note: Following local or anesthetic block, infusion rate should be decreased to 0.05 mcg/kg/minute; rate adjustments of 0.025 mcg/kg/minute may be done at 5-minute intervals. Infusion rates >0.2 mcg/kg/minute are associated with respiratory depression.

Pain in mechanically ventilated patients (management) (off-label dose): Loading dose: 1.5 mcg/kg; maintenance dose: 0.008 to 0.25 mcg/kg/minute (or 0.5 to 15 mcg/kg/hour) (SCCM [Barr 2013]; SCCM [Devlin 2018]).

Dosing: Geriatric

Decrease initial dose by 50% and cautiously titrate to effect. Refer to adult dosing.

Dosing: Pediatric

Note: For use of continuous IV infusion in obese patients, dose should be based on ideal body weight (IBW) in obese patients (>30% over IBW).

Analgesia (postoperative); mechanically ventilated patient: Limited data available: Children and Adolescents 3-16 years: Continuous IV infusion: 0.1 mcg/kg/minute with or without adjunctive medication, titrate to effect; dosing based on a randomized, double-blind comparative trial of remifentanil versus fentanyl in 22 postoperative orthopedic spinal surgery patients requiring mechanical ventilation (remifentanil group, n=11; age: Mean:13 years, range: 3-16 years); similar efficacy and adverse effect profile were reported with both treatment groups (Akinci, 2005)

Analgesia/sedation in mechanically ventilated patients: Limited data available: Infants ≤2 months: Continuous IV infusion: Initial: 0.15 mcg/kg/minute, titrate to effect; dosing based on a randomized, double-blind, comparative study of neonates and young infants (n=23; GA: ≥36 weeks; PNA: <60 days) requiring mechanical ventilation who were given a combination of either midazolam/remifentanil (n=11) or midazolam/fentanyl (n=12); mean remifentanil effective dose: 0.23 mcg/kg/minute; maximum reported dose: 0.5 mcg/kg/minute; efficacy data and adverse effect profile were similar to fentanyl (Welzing, 2012)

Anesthesia, maintenance of anesthesia: Continuous IV infusion:

Infants 1-2 months: Maintenance of anesthesia with nitrous oxide (70%): 0.4 mcg/kg/minute (range: 0.4-1 mcg/kg/minute); supplemental bolus dose of 1 mcg/kg may be administered, smaller bolus dose may be required with potent inhalation agents, potent neuraxial anesthesia, significant comorbidities, significant fluid shifts, or without atropine pretreatment

Infants ≥3 months, Children, and Adolescents: Limited data available: Maintenance of anesthesia with halothane, sevoflurane, or isoflurane: 0.25 mcg/kg/minute (range: 0.05-1.3 mcg/kg/minute); supplemental bolus dose of 1 mcg/kg may be administered every 2-5 minutes. Consider increasing concomitant anesthetics with infusion rate >1 mcg/kg/minute. Infusion rate can be titrated upward in increments up to 50% or titrated downward in decrements of 25% to 50%. May titrate every 2-5 minutes.

Anesthesia, total intravenous (TIVA); with or without propofol induction: Limited data available: Infants, Children, and Adolescents: IV: Loading dose (may omit if propofol induction used): 0.5 mcg/kg/minute for 3 minutes (total dose: 1.5 mcg/kg) or 1 mcg/kg over 1 minute; followed by an initial maintenance dose: 0.05-0.1 mcg/kg/minute; titrate in 0.05 mcg/kg/minute increments every 3 minutes to effect; usual effective range: 0.2-0.5 mcg/kg/minute; has been used in combination with propofol (bolus and/or infusion) (Malherbe, 2010a; Malherbe, 2010b; Mani, 2010; Shen, 2012)

Endotracheal intubation for elective procedures: Limited data available:

IV: Infants, Children, and Adolescents: Usual range: 1-3 mcg/kg/dose, doses as high as 4 mcg/kg have been used. Dosing based on multiple trials in patients undergoing elective procedures requiring intubation who were not receiving neuromuscular blockers and remifentanil administered in combination with other induction agents such as propofol, ketamine, or sevoflurane. (Begec, 2009; Blair, 2004; Hume-Smith, 2010; Klemola, 2000; Morgan, 2007; Park, 2009)

Intranasal (using parenteral 100 mcg/mL formulation): Children ≤7 years: 4 mcg/kg/dose; administer half of the total dose in each nostril; wait 2-3 minutes before attempting intubation. Dosing based on a double-blind, randomized, controlled trial (n=188), remifentanil was administered after sevoflurane induction and overall, was found more effective than saline placebo at both endpoints of 2 minutes and 3 minutes postdose. Results also showed that within the remifentanil treatment groups, good or excellent intubation conditions were reported more often at 3 minutes postdose than at 2 minutes (91.7% vs 68.2%) (Verghese, 2008).

Procedural sedation: Limited data available, dosage not established: Infants, Children, and Adolescents: IV: 0.5 mcg/kg with propofol has been used to induce analgesia and adjunct sedation prior to esophagogastroduodenoscopy (n=22; age range: 2-12 years) and short hemato-oncologic invasive procedures (n=30, age range: 2-18 years) (Hirsh, 2010; Ince, 2013). A higher dose of 3 mcg/kg was used in already sedated (sevoflurane) infants and young children who required apnea for CT or MRI imaging (n=12, age range: 6-16 months) (Joshi, 2009). In a dose-finding trial, continuous IV infusion of remifentanil at 0.2 mcg/kg/minute has been shown more effective than a lower 0.1 mcg/kg/minute in 60 children 2-12 years undergoing diagnostic cardiac catheterization; pretreatment with oral midazolam and local groin anesthetic also utilized (Kaynar, 2011).

Dosing: Obesity

Initial dose should be based on ideal body weight (IBW) in obese patients (>30% over IBW).

Reconstitution

Add 1 mL of D5LR, D5NS, D5W, ¹/₂NS, NS, or SWFI per 1 mg of remifentanil (resulting solution: 1 mg/mL). Shake well. Further dilute to a final concentration of 20, 25, 50, or 250 mcg/mL.

Administration

IV: For IV use only. An infusion device should be used to administer continuous infusions. During the maintenance of general anesthesia, IV boluses may be administered over 30 to 60 seconds. Injections should be given into IV tubing close to the venous cannula; tubing should be cleared after treatment to prevent residual effects when other fluids are administered through the same IV line.

Storage

Store intact vials at 2°C to 25°C (36°F to 77°F). Stable for 24 hours at room temperature after reconstitution and further dilution in SWFI, D5LR, D5NS, D5W, ¹/₂NS, or NS to concentrations of 20 to 250 mcg/mL (4 hours if diluted with LR).

Drug Interactions

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Alvimopan: Opioid Agonists may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Consider therapy modification

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Amphetamines: May enhance the analgesic effect of Opioid Agonists. Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Beta-Blockers: Opioids (Anilidopiperidine) may enhance the bradycardic effect of Beta-Blockers. Opioids (Anilidopiperidine) may enhance the hypotensive effect of Beta-Blockers. Monitor therapy

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromperidol: Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents. Avoid combination

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Calcium Channel Blockers (Nondihydropyridine): Opioids (Anilidopiperidine) may enhance the bradycardic effect of Calcium Channel Blockers (Nondihydropyridine). Opioids (Anilidopiperidine) may enhance the hypotensive effect of Calcium Channel Blockers (Nondihydropyridine). Monitor therapy

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

CNS Depressants: May enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Desmopressin: Opioid Agonists may enhance the adverse/toxic effect of Desmopressin. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Diuretics: Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Consider therapy modification

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Eluxadoline: Opioid Agonists may enhance the constipating effect of Eluxadoline. Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

Gastrointestinal Agents (Prokinetic): Opioid Agonists may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Consider therapy modification

Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Monoamine Oxidase Inhibitors: May enhance the adverse/toxic effect of Remifentanil. Specifically, the risk for opioid toxicity (eg, respiratory depression) may be increased. Remifentanil may enhance the serotonergic effect of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Management: The use of remifentanil is not recommended for patients taking monoamine oxidase inhibitors (MAOIs) or within 14 days of MAOI discontinuation. Consider therapy modification

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nalmefene: May diminish the therapeutic effect of Opioid Agonists. Management: Avoid the concomitant use of nalmefene and opioid agonists. Discontinue nalmefene 1 week prior to any anticipated use of opioid agonistss. If combined, larger doses of opioid agonists will likely be required. Consider therapy modification

Naltrexone: May diminish the therapeutic effect of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Consider therapy modification

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Opioids (Mixed Agonist / Antagonist): May diminish the analgesic effect of Opioid Agonists. Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Avoid combination

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Pegvisomant: Opioid Agonists may diminish the therapeutic effect of Pegvisomant. Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Ramosetron: Opioid Agonists may enhance the constipating effect of Ramosetron. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Serotonergic Agents (High Risk): Opioid Agonists may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Consider therapy modification

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Succinylcholine: May enhance the bradycardic effect of Opioid Agonists. Monitor therapy

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Adverse Reactions

Frequency of adverse events may vary based on surgical procedures and rate of infusion.

>10%:

Cardiovascular: Hypotension (2% to 19%)

Central nervous system: Headache (<2% to 18%)

Dermatologic: Pruritus (<2% to 18%)

Gastrointestinal: Nausea (<36% to 44%), vomiting (<16% to 22%)

Neuromuscular & skeletal: Muscle rigidity (≤11%; includes chest wall rigidity)

1% to 10%:

Cardiovascular: Bradycardia (1% to 7%; dose-dependent), shivering (<5%), hypertension (1% to 2%; dose-dependent), flushing (1%), flushing sensation (1%), tachycardia (≤1%; dose-dependent)

Central nervous system: Dizziness (<5%), chills (1%), agitation (≤1%)

Dermatologic: Diaphoresis (6%)

Local: Pain at injection site (1%)

Respiratory: Respiratory depression (<7%), apnea (<3%), hypoxia (≤1%)

Miscellaneous: Fever (<5%), postoperative pain (<2%)

<1%, postmarketing, and/or case reports: Abdominal distress, amnesia, anaphylaxis, anxiety, awareness under anesthesia without pain, bronchitis, bronchospasm, cardiac arrhythmia, chest pain, confusion, constipation, cough, diarrhea, disorientation, disruption of body temperature regulation, dysphagia, dysphoria, dyspnea, dysuria, ECG changes, electrolyte disturbance, erythema, gastroesophageal reflux disease, hallucination, heart block, heartburn, hepatic insufficiency, hiccups, hyperglycemia, increased creatine phosphokinase, intestinal obstruction, involuntary body movements, laryngospasm, leukocytosis, lymphocytopenia, nasal congestion, nightmares, nystagmus, oliguria, paresthesia, pharyngitis, pleural effusion, prolonged emergence from anesthesia, pulmonary edema, rales, rapid awakening from anesthesia, rhinorrhea, rhonchi, seizure, skin rash, sleep disorder, stridor, syncope, thrombocytopenia, tremor, twitching, urinary incontinence, urinary retention, urticaria, xerostomia

Warnings/Precautions

Concerns related to adverse effects:

• Hypotension: May cause hypotension; use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs which may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration.
• Intraoperative awareness: Intraoperative awareness has been reported when used with propofol infusion rates of ≤75 mcg/kg/minute in patients <55 years.
• Respiratory depression: Serious, life-threatening, or fatal respiratory depression, even when used as recommended may occur. Monitor closely for respiratory depression, especially during initiation or dose escalation. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
• Serotonin syndrome: Potentially life-threatening serotonin syndrome (SS) has occurred with concomitant use of remifentanil and serotonergic agents (eg, SSRIs, SNRIs, triptans, TCAs, 5-HT₃ receptor antagonists, mirtazapine, trazodone, tramadol) and agents that impair metabolism of serotonin (eg, MAO inhibitors). Monitor patients closely for signs of SS such as mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile blood pressure, diaphoresis); neuromuscular changes (eg, tremor, rigidity, myoclonus); GI symptoms (eg, nausea, vomiting, diarrhea); and/or seizures. Discontinue remifentanil if serotonin syndrome is suspected.

Disease-related concerns:

• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.
• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction, including acute pancreatitis; opioids may cause constriction of sphincter of Oddi.
• Bradycardia: Use with caution when administering to patients with bradycardia.
• Delirium tremens: Use with caution in patients with delirium tremens.
• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur.
• Obesity: Use with caution in patients who are morbidly obese.
• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.
• Psychosis: Use with caution in patients with toxic psychosis.
• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression, particularly when initiating and titrating therapy; critical respiratory depression may occur, even at therapeutic dosages.
• Seizures: Use with caution in patients with a history of seizure disorders; may increase risk or exacerbate preexisting seizure disorders.
• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.

Concurrent drug therapy issues:

• Benzodiazepines or other CNS depressants: Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in hypotension, profound sedation, respiratory depression, coma, and death. Alcohol should be avoided for 24 hours after surgery.
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Cachectic or debilitated patients: Use with caution in cachectic or debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages.
• Elderly: Use with caution in the elderly; may be more sensitive to adverse effects. Decrease initial dose.

Other warnings/precautions:

• Abuse/misuse/diversion: [US Boxed Warning]: Remifentanil exposes users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing remifentanil.
• Appropriate use: Inadequate clearing of IV tubing following administration has been associated with muscle rigidity, respiratory depression, and apnea when another fluid is administered through the same line. Do not administer into the same IV tubing with blood due to potential inactivation by nonspecific esterases in blood products.
• Discontinuation of therapy: Interruption of an infusion will result in offset of effect within 5 to 10 minutes; the discontinuation of an infusion should be preceded by the establishment of adequate postoperative analgesia.
• General anesthesia use: Not recommended as the sole agent for induction of anesthesia, because the loss of consciousness cannot be assured.
• Rapid infusion: Rapid IV infusion (single dose >1 mcg/kg over 30 to 60 seconds and infusion rates >0.1 mcg/kg/minute) should only be used during maintenance of general anesthesia; rapid infusion may result in skeletal muscle and chest wall rigidity. Chest wall rigidity may resolve by decreasing the infusion rate, discontinuing the infusion, or by administering a neuromuscular blocking agent.
• Trained individuals: Remifentanil should only be administered by health care providers specifically trained in the use of anesthetic agents. Should not be used in diagnostic or therapeutic procedures outside the monitored anesthesia setting; resuscitative and intubation equipment should be readily available.

Monitoring Parameters

Respiratory and cardiovascular status, blood pressure, heart rate

Critically ill: The Numeric Rating Scale should be used in patients who are able to self-report pain. In patients who are unable to self-report pain, the Behavioral Pain Scale and the Critical-Care Pain Observational Tool can be used in intubated or nonintubated patients (SCCM [Devlin 2018]).

Pregnancy

Pregnancy Considerations

Remifentanil crosses the placenta; fetal and maternal concentrations may be similar.

Prolonged use of opioids during pregnancy can cause neonatal withdrawal syndrome, which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. Opioids used as part of obstetric analgesia/anesthesia during labor and delivery may temporarily affect the fetal heart rate (ACOG 209 2019). Opioids may cause respiratory depression and psychophysiologic effects in the neonate; newborns of mothers receiving remifentanil during labor should be closely monitored (Devroe 2015; Noskova 2015).

Pharmacokinetic properties of remifentanil are not significantly altered by pregnancy; dosing adjustment is not required for maternal indications (Smith 2017). Remifentanil is used to treat maternal pain during labor and immediately postpartum (ACOG 209 2019; Devroe 2015; Weibel 2017).

The ACOG recommends that pregnant women should not be denied medically necessary surgery, regardless of trimester. If the procedure is elective, it should be delayed until after delivery (ACOG 775 2019).

Patient Education

What is this drug used for?

• It is used to ease pain.
• It is used to put you to sleep for surgery.

Frequently reported side effects of this drug

• Itching
• Nausea
• Vomiting
• Shivering
• Sweating a lot
• Constipation

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Serotonin syndrome like dizziness, severe headache, agitation, sensing things that seem real but are not, fast heartbeat, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea
• Slow breathing
• Shallow breathing
• Trouble breathing
• Seizures
• Stiff muscles
• Severe headache
• Severe dizziness
• Passing out
• Vision changes
• Slow heartbeat
• Abnormal heartbeat
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.