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Remifentanil Hydrochloride

FDA Drug Information • Also known as: Remifentanil Hydrochloride, Ultiva

Brand Names
Remifentanil Hydrochloride, Ultiva
Route
INTRAVENOUS
Dosage Form
INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION
Product Type
HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: ADDICTION, ABUSE, AND MISUSE Addiction, Abuse, and Misuse Remifentanil hydrochloride for injection exposes patients and other 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 hydrochloride for injection [see Warnings and Precautions ( 5.1 )] . WARNING: ADDICTION, ABUSE, AND MISUSE See full prescribing information for complete boxed warning . Remifentanil hydrochloride for injection exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. ( 5.1 )

Description

11 DESCRIPTION Remifentanil hydrochloride for injection is an opioid agonist. The chemical name is 3-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]propanoic acid methyl ester, hydrochloride salt. The molecular weight is 412.91. Its molecular formula is C 20 H 28 N 2 O 5

  • HCl, and it has the following chemical structure. Remifentanil hydrochloride for injection is a sterile, nonpyrogenic, preservative-free, white to off-white lyophilized powder for intravenous (IV) administration after reconstitution and dilution. Each vial contains 1 mg, 2 mg, or 5 mg of remifentanil base; 15 mg glycine; and hydrochloric acid to buffer the solutions to a nominal pH of 3 after reconstitution. When reconstituted as directed, solutions of remifentanil HCl are clear and colorless and contain remifentanil hydrochloride (HCl) equivalent to 1 mg/mL of remifentanil base. The pH of reconstituted solutions of remifentanil HCl ranges from 2.5 to 3.5. Remifentanil HCl has a pKa of 7.07. Remifentanil HCl has an n-octanol:water partition coefficient of 17.9 at pH 7.3. Chemical Structure

    • What Is Remifentanil Hydrochloride Used For?

    1 INDICATIONS AND USAGE Remifentanil hydrochloride (HCl) for injection is indicated for intravenous (IV) administration:

  • As an analgesic agent for use during the induction and maintenance of general anesthesia for inpatient and outpatient procedures.
  • For continuation as an analgesic into the immediate postoperative period in adult patients under the direct supervision of an anesthesia practitioner in a postoperative anesthesia care unit or intensive care setting.
  • As an analgesic component of monitored anesthesia care in adult patients. Remifentanil hydrochloride for injection is an opioid agonist indicated for intravenous administration:
  • As an analgesic agent for use during the induction and maintenance of general anesthesia for inpatient and outpatient procedures. ( 1 )
  • For continuation as an analgesic into the immediate postoperative period in adult patients under the direct supervision of an anesthesia practitioner in a postoperative anesthesia care unit or intensive care setting. ( 1 )
  • As an analgesic component of monitored anesthesia care in adult patients. ( 1 )

    • Dosage and Administration

    2 DOSAGE AND ADMINISTRATION

  • Monitor patients closely for respiratory depression when initiating therapy and following dosage increases and adjust the dosage accordingly. ( 2.1 )
  • Initial Dosage in Adults : See full prescribing information for recommended doses in adult patients. ( 2.2 , 2.3 )
  • Initial Dosage in Pediatric Patients : See full prescribing information for recommended doses in pediatric patients. ( 2.2 )
  • Geriatric Patients : The starting doses should be decreased by 50% in elderly patients (> 65 years). ( 2.6 ) 2.1 Important Dosage and Administration Instructions Monitor patients closely for respiratory depression when initiating therapy and following dosage increases with remifentanil HCl and adjust the dosage accordingly [see Warnings and Precautions ( 5.2 )]. Remifentanil HCl is for intravenous use only. Continuous infusions of remifentanil HCl should be administered only by an infusion device. The injection site should be close to the venous cannula and all IV tubing should be cleared at the time of discontinuation of infusion. Remifentanil HCl should not be administered without dilution. Consider an alternative to remifentanil HCl for patients taking mixed agonist/antagonist and partial agonist opioid analgesics due to reduced analgesic effect or potential withdrawal symptoms. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue remifentanil HCl if patient is not responding appropriately to treatment. Discard unused portion. 2.2 General Anesthesia Remifentanil HCl is not recommended as the sole agent in general anesthesia because loss of consciousness cannot be assured and because of a high incidence of apnea, muscle rigidity, and tachycardia. Remifentanil HCl is synergistic with other anesthetics; therefore, clinicians may need to reduce doses of thiopental, propofol, isoflurane, and midazolam by up to 75% with the coadministration of remifentanil HCl. The administration of remifentanil HCl must be individualized based on the patient's response. Induction of Anesthesia Remifentanil HCl should be administered at an infusion rate of 0.5 to 1 mcg/kg/min with a hypnotic or volatile agent for the induction of anesthesia. If endotracheal intubation is to occur less than 8 minutes after the start of the infusion of remifentanil HCl, then an initial dose of 1 mcg/kg may be administered over 30 to 60 seconds. Remifentanil HCl should not be used as a sole agent for induction of anesthesia because loss of consciousness cannot be assured and because of a high incidence of apnea, muscle rigidity, and tachycardia. Maintenance of Anesthesia After endotracheal intubation, the infusion rate of remifentanil HCl should be decreased in accordance with the dosing guidelines in Tables 1 (adults, predominately ASA physical status I, II, or III) and 2 (pediatric patients).
  • Due to the fast onset and short duration of action of remifentanil HCl, the rate of...

    • Side Effects (Adverse Reactions)

    6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections:

  • Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )]
  • Respiratory Depression in Spontaneously Breathing Patients [see Warnings and Precautions ( 5.2 )]
  • Interactions with Benzodiazepines or other CNS Depressants [see Warnings and Precautions ( 5.3 )]
  • Serotonin Syndrome [see Warnings and Precautions ( 5.4 )]
  • Skeletal Muscle Rigidity [see Warnings and Precautions ( 5.6 )]
  • Bradycardia [see Warnings and Precautions ( 5.8 )]
  • Hypotension [see Warnings and Precautions ( 5.9 )]
  • Biliary Tract Disease [see Warnings and Precautions ( 5.12 )]
  • Seizures [see Warnings and Precautions ( 5.13 )] Most common adverse reactions (incidence ≥ 1%) were respiratory depression, bradycardia, hypotension, and skeletal muscle rigidity. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse event information is derived from controlled clinical studies that were conducted in a variety of surgical procedures of varying duration, using a variety of premedications and other anesthetics, and in patient populations with diverse characteristics including underlying disease. Adults Approximately 2,770 adult patients were exposed to remifentanil HCl in controlled clinical studies. The frequencies of adverse events during general anesthesia with the recommended doses of remifentanil HCl are given in Table 11. Each patient was counted once for each type of adverse event. Table 11: Adverse Events Reported in ≥ 1% of Adult Patients in General Anesthesia Studies a at the Recommended Doses b of Remifentanil HCl Adverse Event Induction/Maintenance Postoperative Analgesia After Discontinuation Remifentanil HCl (n = 921) Alfentanil/ Fentanyl (n = 466) Remifentanil HCl (n = 281) Morphine (n = 98) Remifentanil HCl (n = 929) Alfentanil/ Fentanyl (n = 466) Nausea 8 (< 1%) 0 61 (22%) 15 (15%) 339 (36%) 202 (43%) Hypotension 178 (19%) 30 (6%) 0 0 16 (2%) 9 (2%) Vomiting 4 (< 1%) 1 (< 1%) 22 (8%) 5 (5%) 150 (16%) 91 (20%) Muscle rigidity 98 (11%) c 37 (8%) 7 (2%) 0 2 (< 1%) 1 (< 1%) Bradycardia 62 (7%) 24 (5%) 3 (1%) 3 (3%) 11 (1%) 6 (1%) Shivering 3 (< 1%) 0 15 (5%) 9 (9%) 49 (5%) 10 (2%) Fever 1 (< 1%) 0 2 (< 1%) 0 44 (5%) 9 (2%) Dizziness 0 0 1 (< 1%) 0 27 (3%) 9 (2%) Visual disturbance 0 0 0 0 24 (3%) 14 (3%) Headache 0 0 1 (< 1%) 1 (1%) 21 (2%) 8 (2%) Respiratory depression 1 (< 1%) 0 19 (7%) 4 (4%) 17 (2%) 20 (4%) Apnea 0 1 (< 1%) 9 (3%) 2 (2%) 2 (< 1%) 1 (< 1%) Pruritus 2 (< 1%) 0 7 (2%) 1 (1%) 22 (2%) 7 (2%) Tachycardia 6 (< 1%) 7 (2%) 0 0 10 (1%) 8 (2%) Postoperative pain 0 0 7 (2%) 0 4 (< 1%) 5 (1%) Hypertension 10 (1%) 7 (2%) 5 (2%) 3 (3%) 12 (1%) 8 (2%) Agitation 2 (< 1%) 0 3 (1%) 1 (1%) 6 (< 1%) 1 (< 1%) Hypoxia 0 0 1 (< 1%) 0 10 (1%) 7 (2%) a Does not include adverse events from cardiac studies or the neonatal study. See Tables 14, 15, and 16 for cardiac information. b See Table 1 for recommended doses. Not all doses of remifentanil HCl were equipotent to the comparator opioid. Administration of remifentanil HCl in excess of the recommended dose (i.e., doses > 1 and up to 20 mcg/kg) resulted in a higher incidence of some adverse events: muscle rigidity (37%), bradycardia (12%), hypertension (4%), and tachycardia (4%). c Included in the muscle rigidity incidence is chest wall rigidity (5%). The overall muscle rigidity incidence is < 1% when remifentanil is administered concurrently or after a hypnotic induction agent. In the elderly population (> 65 years), the incidence of hypotension is higher, whereas the incidence of...

    • Drug Interactions

    7 DRUG INTERACTIONS Table 18 includes clinically significant drug interactions with remifentanil HCl. Table 18: Clinically Significant Drug Interactions with Remifentanil HCl Benzodiazepines and other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation. Patients should be advised to avoid alcohol for 24 hours after surgery [see Warnings and Precautions ( 5.3 )] . Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions ( 5.4 )]. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue remifentanil HCl if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions ( 5.4 )] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions ( 5.2 )]. If urgent use of remifentanil HCl is necessary, use test doses and frequent titration of small doses while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. Intervention: The use of remifentanil HCl is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of remifentanil HCl and/or precipitate withdrawal symptoms. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Consider discontinuing remifentanil HCl if patient is not responding appropriately to treatment and institute alternative analgesic treatment. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine

  • Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics : May reduce the...

    • Contraindications

    4 CONTRAINDICATIONS Remifentanil HCl is contraindicated:

  • For epidural or intrathecal administration due to the presence of glycine in the formulation [see Nonclinical Toxicology ( 13 )] .
  • In patients with hypersensitivity to remifentanil (e.g., anaphylaxis) [see Adverse Reactions ( 6.2 )] . Remifentanil hydrochloride for injection is contraindicated:
  • For epidural or intrathecal administration due to the presence of glycine in the formulation. ( 4 )
  • In patients with hypersensitivity to remifentanil (e.g., anaphylaxis). ( 4 )

    • Pregnancy and Breastfeeding

    8.1 Pregnancy Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with remifentanil hydrochloride in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, reduced fetal rat body weight and pup weights were reported at 2.2 times a human intravenous infusion of an induction dose of 1 mcg/kg with a maintenance dose of 2 mcg/kg/min for a surgical procedure lasting 3 hours. There were no malformations noted when remifentanil was administered via bolus injection to pregnant rats or rabbits during organogenesis at doses approximately 5 times and approximately equal, respectively, to a human intravenous infusion of an induction dose of 1 mcg/kg with a maintenance dose of 2 mcg/kg/min for a surgical procedure lasting 3 hours [ see Data ].The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Remifentanil HCl is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including remifentanil HCl, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten...

    Overdosage

    10 OVERDOSAGE Clinical Presentation Acute overdose with remifentanil HCl can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology ( 12.2 )] . Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques. The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to remifentanil overdose, stop the infusion or administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to remifentanil overdose. In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING Remifentanil HCl for injection should be stored at 2° to 25°C (36° to 77°F). Remifentanil HCl for IV use is supplied as follows: Product Code Unit of Sale Strength Each 723103 NDC 63323-723-03 Unit of 10 1 mg per vial NDC 63323-723-01 3 mL Single Dose Vial 724105 NDC 63323-724-05 Unit of 10 2 mg per vial NDC 63323-724-01 5 mL Single Dose Vial 725110 NDC 63323-725-10 Unit of 10 5 mg per vial NDC 63323-725-01 10 mL Single Dose Vial Discard unused portion. The container closure is not made with natural rubber latex. The brand names mentioned in this document are the trademarks of their respective owners.

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.