Professional Information

Remifentanil (Systemic)

VA CLASSIFICATION
Primary: CN206
Secondary: CN101

Note: Controlled substance classification—

Note: Controlled substance classification

U.S.—Schedule II ^{01}

Canada— N ^{48}
Commonly used brand name(s): Ultiva.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Category:

Anesthesia adjunct (opioid analgesic)^{01}—

Indications

Accepted

Anesthesia adjunct—Remifentanil is indicated as an opioid analgesic adjunct for the induction ^{01} ^{02} ^{48} and maintenance ^{01} ^{02} ^{03} ^{04} ^{05} ^{06} ^{48} of general anesthesia for inpatient and outpatient procedures, and as the analgesic component of anesthetic care in the immediate postoperative period¹ ^{01} ^{04} ^{06} ^{07}. Remifentanil also is indicated as an analgesic supplement to local or regional anesthesia¹ in a monitored anesthesia setting ^{01} ^{08} ^{49} ^{50} ^{51}.

Unaccepted
Remifentanil is not a general anesthetic and should not be used alone for induction of general anesthesia; the use of remifentanil as the sole agent to induce general anesthesia may not provide adequate anesthesia ^{03} ^{06}, is associated with a high incidence of apnea, muscle rigidity, and bradycardia/tachycardia ^{01} ^{46} ^{47}, and may be associated with an unacceptable incidence of recall ^{39}.

Remifentanil should not be used for epidural or intrathecal administration, because glycine in the formulation may cause neurotoxicity ^{01}.

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Piperidine propanoic acid methyl ester, hydrochloride salt ^{01} ^{04} ^{06}.
Molecular weight—
    412.92 ^{09}

pH
    2.5 to 3.5 ^{01}.

pKa—
    7.07 ^{01}

Mechanism of action/Effect:

Remifentanil exerts its analgesic effect via agonist actions at mu-opioid receptors ^{01} ^{04} ^{06}.

Other actions/effects:

Remifentanil depresses respiration and cardiac function in a dose-dependent manner ^{01} ^{02} ^{10} ^{11}.

Remifentanil can cause skeletal muscle rigidity, especially if it is administered in moderate to high doses over a short period of time ^{01} ^{02} ^{13}. Doses greater than 1 mcg per kg of body weight (mcg/kg) administered over 30 to 60 seconds may cause chest wall rigidity ^{01} and glottic closure ^{40}. Peripheral muscle rigidity can occur with lower doses ^{01} ^{02}.

Distribution:

Remifentanil has biphasic distribution ^{01}. The initial volume of distribution of remifentanil is about 100 mL per kg of body weight (mL/kg) ^{01} ^{12} ^{13}. Remifentanil is then distributed to peripheral tissues with a steady-state volume of distribution of 350 mL/kg ^{01}.

Protein binding:

High (70%), of which two-thirds is to alpha ₁-acid glycoprotein ^{01}.

Biotransformation:

Hydrolyzed to a carboxylic acid metabolite by nonspecific esterases in the blood and tissues ^{01} ^{04} ^{06}. This metabolite has minimal activity ^{01}.

Half-life:

Distribution:

Rapid distribution—1 minute ^{01} ^{12} ^{13} ^{14}.

Slower distribution—6 minutes ^{01} ^{12} ^{13} ^{14}.

Elimination:

3 to 10 minutes ^{01} ^{13} ^{14} ^{16}.

Note: Remifentanil clearance is not dependent on dose^{16}. Elimination of remifentanil occurs rapidly, even after prolonged continuous infusion ^{01} ^{04} ^{12} ^{13} ^{14} ^{17} ^{18} ^{19} ^{25}. Context-sensitive half-time (CSHT), the time to a 50% decrease of an effective site concentration after a continuous infusion is stopped, is a more useful parameter than elimination half-life to describe the activity of remifentanil. The CSHT for remifentanil is 3 to 4 minutes, regardless of the duration of the infusion ^{04} ^{12} ^{14} ^{16} ^{18} ^{19} ^{25} ^{29}.

Onset of action:

Within 1 minute ^{01} ^{12} ^{13} ^{14} ^{21}.

Peak serum concentration:

Dependent on dose ^{01}.

Time to peak effect:

1 to 2 minutes after a single intravenous injection ^{01} ^{21}.

Duration of action:

5 to 10 minutes following discontinuation of an infusion of remifentanil ^{01} ^{02} ^{03} ^{05} ^{12} ^{13} ^{14} ^{17} ^{21} ^{29}; the duration of action is shorter following a single intravenous injection of a low or moderate dose of remifentanil ^{14} ^{47}.

Elimination:
    After hydrolysis of remifentanil by nonspecific esterases, the carboxylic acid metabolite is excreted by the kidneys ^{01}; remifentanil is not metabolized by pseudocholinesterase ^{01}.

In dialysis—
        The carboxylic acid metabolite is removed by hemodialysis, with an extraction ratio of about 30% ^{01}.

Precautions to Consider

Cross-sensitivity and/or related problems

Patients allergic to alfentanil, fentanyl, or sufentanil may be allergic to remifentanil also ^{01}.

Carcinogenicity/Tumorigenicity

Studies have not been done to determine the carcinogenic and tumorigenic potential of remifentanil.

Mutagenicity

Mutagenicity was not observed in in vitro testing in prokaryotic cells ^{01}. No clastogenic effect was observed in the cultured Chinese hamster ovary cell test, in the in vivo test of unscheduled DNA synthesis in rat hepatocytes, or in the mouse micronucleus assay ^{01}. Mutagenicity was seen with metabolic activation in the in vitro mouse lymphoma assay ^{01}.

Pregnancy/Reproduction
Fertility—
Adequate and well-controlled studies have not been done in humans ^{01}.

Remifentanil reduced the fertility of male rats when administered at doses 40 times greater than the maximum recommended human dose (MRHD) for 70 days ^{01}. Fertility was not affected in female rats given IV doses as high as 1 mg per kg, 80 times greater than the MRHD for 15 days prior to mating ^{01}.

Pregnancy—
Remifentanil crosses the placenta ^{01}. Adequate and well-controlled studies have not been done in humans ^{01}.

Teratogenic effects were not observed in studies in rats and rabbits given 400 and 125 times the MRHD, respectively ^{01}.

FDA Pregnancy Category C ^{01}.

Labor and delivery—

Respiratory depression may occur in newborns whose mothers are given remifentanil shortly before delivery ^{01}. In preapproval clinical studies of labor and delivery, fetal blood concentrations of remifentanil were 50 to nearly 100% of maternal concentrations ^{01}. In a study in 19 neonates whose mothers had received remifentanil intravenously as part of the analgesic regimen for nonemergent cesarean section, the mean umbilical venous (UV) to maternal arterial (MA) remifentanil concentration ratio was 0.88 ± 0.78 ^{55}. The mean umbilical arterial (UA) to UV concentration ratio was 0.29 ± 0.07, suggesting rapid redistribution and metabolism of remifentanil ^{55}. The Apgar scores and Neurobehavioral and Adaptive Capacity Scores (NACS) for the neonates were within normal limits ^{55}.

Breast-feeding

It is not known whether remifentanil is distributed into breast milk ^{01}. However, since related drugs are distributed into breast milk, it is expected that remifentanil may be distributed into breast milk. Since remifentanil is eliminated rapidly ^{01}, problems are not expected when remifentanil is administered to a nursing mother.

Pediatrics

Remifentanil is not approved by drug regulatory agencies in the United States (i.e., the Food and Drug Administration) or Canada (i.e., the Health Protection Branch) for use in pediatric patients younger than 2 years of age ^{01}. Appropriate studies on the relationship of age to the effects of remifentanil have not been performed in children up to 2 years of age ^{01}. Distribution, clearance, and half-life of remifentanil in children 2 to 13 years of age are similar to those in adult patients ^{01} ^{30}.

In a study in 129 pediatric patients 2 to 12 years of age undergoing strabismus surgery, remifentanil–nitrous oxide–oxygen anesthesia was compared with alfentanil–nitrous oxide–oxygen anesthesia, isoflurane–nitrous oxide–oxygen anesthesia, and propofol–nitrous oxide–oxygen anesthesia ^{56}. There was no difference in early recovery variables, or in discharge from the postanesthesia care unit (PACU) or the hospital, among the anesthesia regimens ^{56}. The patients receiving remifentanil had higher objective pain-discomfort scores in the PACU ^{56}. It is possible that the failure to achieve faster discharge times from the PACU and the higher objective pain-discomfort scores in the PACU for the patients receiving remifentanil may have been due to inadequate planning for postoperative analgesia in these patients ^{56}.

Geriatrics

The clearance of remifentanil is reduced in geriatric patients as compared with that in younger adult patients ^{01}. In addition, geriatric patients are more sensitive to the effects of remifentanil ^{01} ^{37}. Geriatric patients have greater interpatient variability as compared with younger adult patients ^{37}. It is recommended that the initial dose of remifentanil be reduced by 50% in geriatric patients ^{01} ^{37}.

Surgical

Remifentanil is eliminated rapidly. Within 5 to 10 minutes after the discontinuation of a remifentanil infusion, no opioid analgesia is present ^{01} ^{02} ^{03} ^{05} ^{12} ^{13} ^{14} ^{17} ^{21}. Surgical patients may experience a sudden onset of postoperative pain unless other analgesics are administered ^{01} ^{21}. Initiation of postoperative pain management should be considered prior to emergence from anesthesia.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Anesthetics, barbiturate^{01} or
» Anesthetics, inhalation^{01}^{03}^{21}^{27} or
» Benzodiazepines^{01}^{11}^{21}^{50} or
» Propofol^{01}^{02}^{21}    (the effects of remifentanil are synergistic with barbiturate or inhalation anesthetics, benzodiazepines, and propofol, increasing the risk of hypotension and respiratory depression ^{01} ^{02} ^{03}; the dose of remifentanil or the dose of anesthetic, benzodiazepine, or propofol should be decreased ^{01} ^{02} ^{03} ^{27})

Atropine^{01} or
Glycopyrrolate^{01}    (may reverse bradycardia caused by remifentanil ^{01})

Ephedrine^{01} or
Epinephrine^{01} or
Norepinephrine^{01}    (may reverse hypotension caused by remifentanil ^{01})

Neuromuscular blocking agents^{01}    (attenuates the skeletal muscle rigidity induced by remifentanil ^{01})

Opioid antagonists^{01} , such as:
» Nalmefene
» Naloxone
» Naltrexone    (opioid antagonists may reverse the hypotension, muscle rigidity, and respiratory depression induced by remifentanil; the analgesic effects of remifentanil may also be reversed, leading to pain and sympathetic hyperactivity ^{01} ^{31} ^{32})

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Except under special circumstances, this medication should not be used when the following medical problem exists:
» Allergic reaction to alfentanil, fentanyl, remifentanil, or sufentanil, history of^{01}
Risk-benefit should be considered when the following medical problems exist
Cardiac bradyarrhythmias^{01}^{10}    (may be exacerbated ^{01})

Hepatic function impairment^{22}^{23}    (patients with hepatic function impairment may be more sensitive to the respiratory depressant effects of remifentanil ^{22} ^{23}; clearance of remifentanil is unchanged in patients with hepatic function impairment as compared with patients with normal hepatic function ^{22} ^{23})

Obesity^{01}    (bradycardia or reduced respiratory drive may occur; it is recommended that dosing for obese patients [patients weighing more than 130% of ideal body weight] be initiated based on ideal body weight [IBW], and then titrated to achieve the desired effect ^{01})

Respiratory impairment, pre-existing^{01}    (respiratory drive may be further decreased; respiratory support may be required with doses that usually permit spontaneous breathing ^{01})

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Blood oxygenation^{01}^{33} and
» Blood pressure^{01}^{33} and
» Respiratory status^{01}^{33} and
» Vital signs, other^{01}^{33}    (it is recommended that patients be monitored continuously; when remifentanil is used for surgical or diagnostic procedures, it is recommended that the patient be monitored continuously by someone not involved in conducting the surgical or diagnostic procedure and who is expert in the management of the airway and providing artificial respiration, because rapid changes in patient status may occur ^{01})

Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent

Hypotension^{01}^{02}^{05}^{07}^{10}^{11}^{20}

muscle rigidity, including chest wall rigidity ^{01}^{02}^{13}^{29} (difficulty breathing)

Incidence less frequent

Bradycardia^{01}^{02}^{05}^{10}^{20}

Incidence rare

Agitation^{01}

apnea^{01}^{07} (bluish lips or skin)

hypertension^{01}

postoperative pain^{01}

pruritus^{01} (itching)

respiratory depression^{01}^{03}^{28}^{32} (slow breathing)

Note: Although postoperative pain occurred rarely in preapproval clinical trials, it may not be a rare event in clinical practice. The rapid elimination of remifentanil and the subsequent loss of opioid analgesia may result in postoperative pain unless pain management is initiated prior to emergence from anesthesia ^{06} ^{19} ^{29}.

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent

Nausea^{01}^{07}^{13}^{14}

Incidence less frequent

Headache^{01}

shivering^{01}

vomiting^{01}^{07}^{13}^{14}

Overdose
For specific information on the agents used in the management of remifentanil overdose, see:    • Atropine in Anticholinergics/Antispasmodics (Systemic) monograph;
   • Epinephrine in Sympathomimetic Agents—Cardiovascular Use (Parenteral-Systemic) monograph;
   • Glycopyrrolate in Anticholinergics/Antispasmodics (Systemic) monograph;
   • Isoproterenol in Sympathomimetic Agents—Cardiovascular Use (Parenteral-Systemic) monograph;
   • Naloxone (Systemic) monograph; and/or
   • Succinylcholine in Neuromuscular Blocking Agents (Systemic) monograph.

For more information on the management of overdose, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose

Note: The clinical effects of overdose are an extension of the pharmacologic effects of remifentanil ^{01}.

The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute

Apnea^{01}^{07}^{32} (bluish lips or skin)

bradycardia^{01}^{02}^{10}^{20}

glottic closure

hypotension^{01}^{02}^{07}^{10}^{20}

hypoxemia^{01} (bluish lips or skin)

muscle rigidity, including chest wall rigidity^{01}^{29}

Treatment of overdose

Specific treatment:
Discontinue administration of remifentanil; administer oxygen and support ventilation ^{01} ^{31} ^{32}. Since the context-sensitive half-time (CSHT) of remifentanil is very short, discontinuing the infusion and supporting ventilation may be the only measures required in many cases of overdose ^{45}.

For bradycardia: Atropine or glycopyrrolate may be needed to treat bradycardia ^{01}. Epinephrine or isoproterenol may be needed to treat bradycardia in patients receiving beta-adrenergic blocking agents ^{47}.

For chest wall rigidity and glottic closure: Administration of a rapidly acting neuromuscular blocking agent (e.g., rocuronium or succinylcholine) may reverse chest wall rigidity ^{01} and glottic closure ^{40}. It may be necessary to treat chest wall rigidity and glottic closure ^{40} to allow artificial ventilation ^{01}. An opioid antagonist (e.g., naloxone) may be used to reverse chest wall rigidity ^{01} and glottic closure ^{40}. However, loss of analgesia may result ^{01}.
Note: Use of naloxone is not the preferred method for treating chest wall rigidity and glottic closure. The preferred method for treating chest wall rigidity and glottic closure is administration of a neuromuscular blocking agent to allow artificial ventilation. This approach avoids the danger of sudden loss of analgesia and sympathetic overactivity. The use of naloxone should be reserved for situations in which treatment of chest wall rigidity and glottic closure with a neuromuscular blocking agent and artificial ventilation is not possible or desirable ^{45}.

For respiratory depression: Maintain a patent airway. Initiate assisted or controlled ventilation ^{01}. Treatment of chest wall rigidity may be required to facilitate assisted ventilation ^{01}.

If adequate spontaneous ventilation does not return within several minutes of discontinuing remifentanil, other causes of ventilatory depression should be considered. The need for opioid antagonists also should be reconsidered in these circumstances ^{52}.

Monitoring:
Vital signs and oxygenation should be monitored continuously ^{01}.

Supportive care:
Support cardiovascular function with fluids and vasopressors as needed ^{01} ^{10}.

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Narcotic Analgesics—For Surgery and Obstetrics (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before receiving this medication
»   Conditions affecting use, especially:
Allergy to alfentanil, fentanyl, remifentanil, or sufentanil

Pregnancy—Remifentanil crosses the placenta; respiratory depression may occur in newborns whose mothers are given remifentanil shortly before delivery

Breast-feeding—Related drugs are distributed into breast milk; since remifentanil is eliminated rapidly, problems are not expected when remifentanil is given to a nursing mother

Use in the elderly—Increased sensitivity and greater interpatient variability to the effects of remifentanil; reduced clearance of remifentanil
Other medications, especially barbiturate anesthetics, benzodiazepines, inhalation anesthetics, nalmefene, naloxone, naltrexone, or propofol

Side/adverse effects
Signs of potential side effects, especially hypotension, muscle rigidity, bradycardia, agitation, apnea, hypertension, postoperative pain, pruritus, and respiratory depression

General Dosing Information
Remifentanil should be used only in closely monitored situations by persons trained in the use of anesthetic drugs, airway management, and cardiac and respiratory resuscitation. Equipment for emergency endotracheal intubation and resuscitation, oxygen, and an opioid antagonist must be immediately available while remifentanil is administered. Blood oxygenation and vital signs must be monitored continuously while remifentanil is administered ^{01}.

Remifentanil should be injected into intravenous tubing close to the site of entry into the patient ^{01} ^{07}. When remifentanil is discontinued, remifentanil remaining in the intravenous tubing should be cleared to prevent accidental administration of remifentanil when another medication or fluid is infused through the intravenous line ^{01} ^{07}. Accidental administration of remifentanil can result in respiratory depression and chest wall rigidity ^{01} ^{07}.

Skeletal muscle rigidity may result from rapid injection of remifentanil or from overdoses of remifentanil ^{01} ^{02} ^{13} ^{29}. Injection of more than 1 mcg per kg of body weight over 30 to 60 seconds, or infusion of greater than 0.1 mcg per kg of body weight per minute, may result in chest wall rigidity ^{01} and glottic closure ^{40} ^{42}.

The dose of remifentanil for obese patients ( > 30% over ideal body weight) should be based on ideal body weight ^{01} ^{37} ^{38}, not actual body weight.

Remifentanil should not be infused through the same intravenous line at the same time as blood, because esterases in the blood may inactivate the drug ^{01}.

Remifentanil should not be used for epidural or intrathecal administration, because glycine in the formulation may cause neurotoxicity ^{01}.

Infusions of remifentanil should be administered only with an infusion device ^{01}.

Spontaneously breathing patients receiving infusions of remifentanil should not receive additional intermittent injections of remifentanil, due to the potential for overdose ^{01} ^{07}.

When remifentanil is administered to a patient as an analgesic supplement to local or regional anesthesia, it is recommended that the patient also receive supplemental oxygen ^{01}.

Because of its extremely short context-sensitive half-time (CSHT), intermittent intravenous injections for analgesia in postoperative patients are not recommended. However, closely monitored continuous infusions may be used in selected patients ^{01} ^{43}. Since rapid changes in the status of the patient are possible while receiving remifentanil, it may be advisable to switch the patient to another opioid analgesic while the patient is still in the intraoperative period ^{44}.

Discontinuation of remifentanil will result in rapid discontinuation of opioid effects ^{26}, including analgesia ^{01} ^{26}. The analgesic needs of the patient should be considered before remifentanil is discontinued ^{36}. The transition from remifentanil to another analgesic may be accomplished by administering another analgesic intravenously during the intraoperative period ^{40} or by reducing the dose of remifentanil administered to the patient from anesthetic doses to analgesic doses when surgery has been completed ^{07}, then gradually switching to another analgesic ^{07}.

For treatment of adverse effects
Recommended treatment consists of the following:
   • Muscle rigidity occurring during administration of remifentanil can be treated with discontinuation of the drug, reduction of the rate of administration of the drug, or administration of a rapidly acting neuromuscular blocking agent ^{01}. Simultaneous endotracheal intubation and ventilation may be necessary ^{01}. Hypnotic induction agents, including inhalational agents, may be used to prevent muscle rigidity ^{41} ^{42}.

Parenteral Dosage Forms

Note: The dosing and strengths of the dosage form available are expressed in terms of remifentanil base (not the hydrochloride salt).

REMIFENTANIL HYDROCHLORIDE FOR INJECTION

Usual adult dose
Induction of general anesthesia, adjunct
Intravenous infusion, 0.5 to 1 mcg (0.0005 to 0.001 mg) (base) per kg of body weight, administered with an inhalation or intravenous anesthetic ^{01} ^{02} ^{15}.

Note: The FDA-approved dosage of remifentanil as an adjunct in the induction of general anesthesia is 0.5 to 1 mcg (0.0005 to 0.001 mg) (base) per kg of body weight per minute, administered with an inhalation or intravenous anesthetic. However, most USP medical experts believe the approved dosage is unnecessarily high ^{53}.

Maintenance of nitrous oxide anesthesia (general), adjunct
Intravenous infusion, 0.05 to 0.2 mcg (0.00005 to 0.0002 mg) (base) per kg of body weight per minute ^{01} ^{24}; supplemental doses of 0.5 to 1 mcg (0.0005 to 0.001 mg) per kg of body weight may be administered every two to five minutes if needed because of inadequate anesthesia or transiently increased surgical stress ^{01}.

Note: The FDA-approved dosage of remifentanil for the maintenance of nitrous oxide anesthesia is 0.4 (range, 0.1 to 2) mcg per kg of body weight per minute. However, most USP medical experts believe the approved dosage is unnecessarily high ^{53}. Additionally, many USP medical experts believe that any adjustments needed in the dose of remifentanil should be accomplished by adjustments in the rate of the infusion, not by giving additional intermittent injections of remifentanil ^{53}. Administration of intermittent supplemental doses increases the risks of bradycardia, hypotension, respiratory depression, and chest wall rigidity ^{53}.
It should be noted that both the FDA-approved and USP-recommended dosages for the maintenance of nitrous oxide anesthesia are incompatible with spontaneous ventilation; patients receiving these dosages require ventilatory support ^{54}.

Maintenance of isoflurane or propofol anesthesia (general), adjunct
Intravenous infusion, 0.05 to 0.2 mcg (0.00005 to 0.0002 mg) (base) per kg of body weight per minute ^{01} ^{02} ^{15} ^{27}; supplemental doses of 0.5 to 1 mcg (0.0005 to 0.001 mg) per kg of body weight may be administered every two to five minutes if needed because of inadequate anesthesia or transiently increased surgical stress ^{01}.

Note: The FDA-approved dosage of remifentanil for the maintenance of isoflurane or propofol anesthesia is 0.25 (range, 0.05 to 2) mcg per kg of body weight per minute. However, most USP medical experts believe this dosage is unnecessarily high ^{53}. Additionally, many USP medical experts believe that any adjustments needed in the dose of remifentanil should be accomplished by adjustments in the rate of the infusion, not by giving additional intermittent injections of remifentanil ^{53}. Administration of intermittent supplemental doses increases the risks of bradycardia, hypotension, respiratory depression, and chest wall rigidity ^{53}.
It should be noted that both the FDA-approved and USP-recommended dosages for the maintenance of isoflurane or propofol anesthesia are incompatible with spontaneous ventilation; patients receiving these dosages require ventilatory support ^{54}.

Continuation into the immediate postoperative period¹
Intravenous infusion, 0.1 mcg (0.0001 mg) (base) per kg of body weight per minute initially ^{01} ^{07}; the infusion may be adjusted every five minutes in increments of 0.025 mcg (0.000025 mg) per kg of body weight per minute to reach the desired balance of analgesia and adequate respiratory rate ^{01} ^{32}.

Note: Remifentanil is intended for use only into the immediate postoperative period; the use of remifentanil for periods longer than sixteen hours postoperatively has not been studied ^{01}. Continuation of remifentanil into the postoperative period should be reserved for selected patients in whom conversion to another opioid analgesic in the intraoperative period is not advisable, and only when the patient will be closely monitored by personnel trained in use of anesthetic drugs, airway management, and cardiac and respiratory resuscitation ^{43}. Equipment for emergency endotracheal intubation and resuscitation, oxygen, and an opioid antagonist must be immediately available. Blood oxygenation and vital signs must be monitored continuously while remifentanil is administered ^{01}.

Analgesic supplement to local or regional anesthesia in a monitored anesthesia setting¹

Intravenous:
When used with benzodiazepine sedation (i.e., midazolam 2 mg)—0.5 mcg (0.0005 mg) (base) per kg of body weight, administered over thirty to sixty seconds as a single dose sixty to ninety seconds before the local anesthetic is administered ^{01} ^{47}.

When used without benzodiazepine sedation—1 mcg (0.001 mg) per kg of body weight administered over thirty to sixty seconds as a single dose sixty to ninety seconds before the local anesthetic is administered ^{01}.

Intravenous infusion:
When used with benzodiazepine sedation (i.e., midazolam 2 mg)—0.05 mcg (0.00005 mg) (base) per kg of body weight per minute, beginning five minutes before placement of local or regional block; after placement of the block, the infusion rate should be decreased to 0.025 mcg (0.000025 mg) per kg of body weight per minute. Thereafter, the infusion can be adjusted in increments of 0.025 mcg (0.000025 mg) per kg of body weight per minute at five-minute intervals ^{01} ^{57}.

When used without benzodiazepine sedation—0.1 mcg (0.0001 mg) per kg of body weight per minute beginning five minutes before placement of local or regional block; after placement of the block, the infusion rate should be decreased to 0.05 mcg (0.00005 mg) per kg of body weight per minute. Thereafter, the infusion can be adjusted in increments of 0.025 mcg (0.000025 mg) per kg of body weight per minute at five-minute intervals ^{01}.

Note: Administration of more than 0.2 mcg per kg of body weight per minute is associated with respiratory depression ^{01}. This effect should be considered if remifentanil is administered to a patient whose ventilation is not assisted or controlled ^{01}.
Bolus doses of remifentanil to treat postoperative pain are NOT recommended^{01} .
In obese patients, the initial dose of remifentanil should be based on ideal body weight (IBW), then titrated to achieve the desired effect ^{01} ^{34}.

Usual pediatric dose
Anesthesia adjunct
Infants and children up to 2 years of age: Dosage has not been established ^{01}.
Children 2 years of age or older¹: See Usual adult dose ^{01} ^{30}.

Usual geriatric dose
Anesthesia adjunct
The initial dose for geriatric patients should be 50% of the usual adult dose ^{01} ^{37}. The dose should be titrated to achieve the desired effect ^{01}.

Size(s) usually available:
U.S.—

1 mg (base) (Rx) [Ultiva (lyophilized powder) (glycine 15 mg) ( hydrochloric acid)]^{01}

2 mg (base) (Rx) [Ultiva (lyophilized powder) (glycine 15 mg) ( hydrochloric acid)]^{01}

5 mg (base) (Rx) [Ultiva (lyophilized powder) (glycine 15 mg) ( hydrochloric acid)]^{01}

Canada—

1 mg (base) (Rx) [Ultiva (lyophilized powder) (glycine 15 mg) ( hydrochloric acid)]^{48}

2 mg (base) (Rx) [Ultiva (lyophilized powder) (glycine 15 mg) ( hydrochloric acid)]^{48}

5 mg (base) (Rx) [Ultiva (lyophilized powder) (glycine 15 mg) ( hydrochloric acid)]^{48}

Packaging and storage:
Store between 2 and 25 ºC (36 and 77 ºF) ^{01}.

Preparation of dosage form:
One mL of diluent per mg of remifentanil (base) should be added to the vial, resulting in a solution containing 1 mg of remifentanil per mL ^{01}. Remifentanil should be further diluted as follows before administration to the patient: the 1-mg vial of remifentanil can be diluted with 40 or 20 mL for a final concentration of 25 or 50 mcg (0.025 or 0.05 mg) per mL, respectively ^{01}; the 2-mg vial of remifentanil can be diluted with 80 or 40 mL for a final concentration of 25 or 50 mcg (0.025 or 0.05 mg) per mL, respectively ^{01}; and the 5-mg vial of remifentanil can be diluted with 200, 100, or 20 mL for a final concentration of 25, 50, or 250 mcg (0.025, 0.05, or 0.25 mg) per mL, respectively ^{01}.

Remifentanil may be diluted with sterile water for injection, 5% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, lactated Ringer"s injection, lactated Ringer"s and 5% dextrose injection, 0.9% sodium chloride injection, or 0.45% sodium chloride injection ^{01}.

Remifentanil does not contain an antimicrobial preservative ^{01}. Aseptic technique should be used when diluting remifentanil.

Stability:
After preparation with sterile water for injection, 5% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, lactated Ringer"s and 5% dextrose injection, 0.9% sodium chloride injection, or 0.45% sodium chloride injection, the solution should be used within 24 hours and may remain at room temperature ^{01}. After preparation with lactated Ringer"s injection, the solution should be used within 4 hours ^{01}. The prepared solution should be inspected for particulate matter and clarity before administration to the patient, and should be discarded if particulate matter is present ^{01}.

Incompatibilities:
Remifentanil should not be infused through the same intravenous line at the same time as blood, because esterases in the blood may inactivate the drug ^{01}.

Revised: 10/29/1999

References

Product Information: Ultiva ®, remifentanil hydrochloride. Glaxo Wellcome, Kalamazoo, MI, USA, 1999.

Hogue C, Bowdle T, 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.

Lang E, Kaplia A, Shlugman D, et al. Reduction of isoflurane minimal alveolar concentration by remifentanil. Anesthesiology 1996; 85: 721-8.

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Panel comment, 4/97.

Panel comment, 4/97.

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