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 )
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 )
Warnings and precautions
Respiratory Depression in Spontaneously Breathing Patients : Monitor closely, particularly during initiation and titration. ( 5.2 )
Risks from Use as Postoperative Analgesia with Concomitant Benzodiazepines or other CNS Depressants : Hypotension, profound sedation, respiratory depression, coma, and death may result from the concomitant use of Remifentanil hydrochloride for injection with benzodiazepines or other CNS depressants. ( 5.3 )
Serotonin Syndrome : Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue Remifentanil hydrochloride for injection if serotonin syndrome is suspected. ( 5.4 )
Administration : Continuous infusions of Remifentanil hydrochloride for injection should be administered only by an infusion device. ( 5.5 )
Skeletal Muscle Rigidity : is related to the dose and speed of administration. Muscle rigidity induced by Remifentanil hydrochloride for injection should be managed in the context of the patient's clinical condition. ( 5.6 )
Potential Inactivation by Nonspecific Esterases in Blood Products : Remifentanil hydrochloride for injection should not be administered into the same IV tubing with blood due to potential inactivation by nonspecific esterases in blood products. ( 5.7 )
Bradycardia : Monitor heart rate during dosage initiation and titration. It is responsive to ephedrine or anticholinergic drugs. ( 5.8 )
Hypotension : Monitor blood pressure during dosage initiation and titration. It is responsive to decreases in the administration of Remifentanil hydrochloride for injection or to IV fluids or catecholamine administration. ( 5.9 )
Intraoperative Awareness : Inoperative awareness has been reported in patients under 55 years of age when Remifentanil hydrochloride for injection has been administered with propofol infusion rates of ≤ 75 mcg/kg/min. ( 5.10 )
Risks of Use in Spontaneously Breathing Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Monitor for sedation and respiratory depression. ( 5.11 )
Risks of Use in Patients with Biliary Tract Disease : Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. ( 5.12 )
Increased Risk of Seizures in Patients with Seizure Disorders : Monitor patients with a history of seizure disorders for worsened seizure control during Remifentanil hydrochloride for injection therapy. ( 5.13 )
Rapid Offset of Action : Standard monitoring should be maintained in the postoperative period to ensure adequate recovery without stimulation. ( 5.14 )
5.1Addiction, Abuse, and Misuse Remifentanil
HCl contains remifentanil, a Schedule II controlled substance. As an opioid, remifentanil HCl exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence ( 9 )]. Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when handling remifentanil HCl. Strategies to reduce these risks include proper product storage and control practices for a C-II drug.
Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
5.2Respiratory Depression in Spontaneously Breathing Patients
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Remifentanil HCl should be administered only by persons specifically trained in the use of anesthetic drugs and the management of the respiratory effects of potent opioids, including respiration and cardiac resuscitation of patients in the age group being treated.
Such training must include the establishment and maintenance of a patent airway and assisted ventilation. Resuscitative and intubation equipment, oxygen, and opioid antagonists must be readily available. Respiratory depression in spontaneously breathing patients is generally managed by decreasing the rate of the infusion of remifentanil HCl by 50% or by temporarily discontinuing the infusion [see Overdosage ( 10 )] .
Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of remifentanil HCl, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially when initiating therapy with and following dosage increases of remifentanil HCl.
Remifentanil HCl should not be used in diagnostic or therapeutic procedures outside the monitored anesthesia care setting. Patients receiving monitored anesthesia care should be continuously monitored by persons not involved in the conduct of the surgical or diagnostic procedure. Oxygen saturation should be monitored on a continuous basis. Patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of remifentanil HCl.
Elderly, cachectic, or debilitated patients may have altered pharmacokinetics or altered clearance compared to younger, healthier patients resulting in greater risk for respiratory depression. Monitor such patients closely including vital signs, particularly when initiating and titrating remifentanil HCl and when remifentanil HCl is given concomitantly with other drugs that depress respiration. To reduce the risk of respiratory depression, proper dosing and titration of remifentanil HCl are essential [see Dosage and Administration ( 2.11 )] .
5.3Risks from Use as Postoperative Analgesia with Concomitant Benzodiazepines or Other CNS Depressants
Hypotension, profound sedation, respiratory depression, coma, and death may result from the concomitant use of remifentanil HCl with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, or alcohol). Patients should be advised to avoid alcohol for 24 hours after surgery [see Drug Interactions ( 7 )] .
5.4Serotonin Syndrome with Concomitant Use of Serotonergic Drugs Cases
of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of remifentanil HCl with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions ( 7 )] .
This may occur within the recommended dosage range. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that.
Discontinue remifentanil HCl if serotonin syndrome is suspected.
5.5Administration
Continuous infusions of remifentanil HCl sho
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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 analgesic effect of Remifentanil hydrochloride for injection and/or precipitate withdrawal symptoms. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. ( 7 )
Pregnancy and breastfeeding
8.1Pregnancy 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 labor.
Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Human Data In a human clinical trial, the average maternal remifentanil concentrations were approximately twice those seen in the fetus. In some cases, however, fetal concentrations were similar to those in the mother. The umbilical arteriovenous ratio of remifentanil concentrations was approximately 30% suggesting metabolism of remifentanil in the neonate.
Animal Data Pregnant rats were treated from Gestation Day 6 to 15 with intravenous remifentanil doses of 0.5, 1.6, or 5 mg/kg/day (0.2, 0.7, or 2.2 times a human intravenous infusion of an induction dose of 1 mcg/kg with a maintenance dose of 2 mcg/kg/min based on body surface area for a surgical procedure lasting 3 hours based on body surface area, respectively). Reduced fetal weights were reported in the high dose group; however, no malformations were reported in surviving fetuses despite a non-dose dependent increase in maternal mortality.
Pregnant rabbits were treated from Gestation Day 6 to 18 with intravenous remifentanil doses of 0.1, 0.5, or 0.8 mg/kg/day (0.09, 0.4, or 0.7 times a human intravenous infusion of an induction dose of 1 mcg/kg with a maintenance dose of 2 mcg/kg/min based on body surface area for a surgical procedure lasting 3 hours based on body surface area, respectively). No malformations were reported in surviving fetuses despite clear maternal toxicity (decreased food consumption and body weights and increased mortality in all treatment groups).
Pregnant rats were treated from Gestation Day 6 to Lactation Day 21 with intravenous boluses of remifentanil 0.5, 1.6, or 5 mg/kg/day (0.2, 0.7, or 2.2 times a human intravenous infusion of an induction dose of 1 mcg/kg with a maintenance dose of 2 mcg/kg/min based on body surface area for a surgical procedure lasting 3 hours based on body surface area, respectively). Reduced birth weights were noted in the high-dose groups in the presence of maternal toxicity (increased mortality in all groups).
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.
6.1Clinical 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 nausea and vomiting is lower. Table 12: Incidence (%) of Most Common Adverse Events by Gender in General Anesthesia Studies a at the Recommended Doses b of Remifentanil HCl Adverse Event n Induction/Maintenance Postoperative Analgesia After Discontinuation Remifentanil HCl Alfentanil/Fentanyl Remifentanil HCl Morphine Remifentanil HCl Alfentanil/Fentanyl Male 326 Female 595 Male 183 Female 283 Male 85 Female 196 Male 36 Female 62 Male 332 Female 597 Male 183 Female 283 Nausea 2% < 1% 0 0 12% 26% 8% 19% 22% 45% 30% 52% Hypotension 29% 14% 7% 6% 0 0 0 0 2% 2% 2% 2% Vomiting < 1% < 1% 0 < 1% 4% 10% 0 8% 5% 22% 8% 27% Muscle rigidity 17% 7% 14% 4% 6% 1% 0 0 < 1% < 1% 0 < 1% a Does not include adverse events from cardiac studies or the neonatal study. b See Table 1 for recommended doses.
Not all doses of remifentanil HCl were equipotent to the comparator opioid. The frequencies of adverse events from the clinical studies at the recommended doses of remifentanil HCl in monitored anesthesia care are given in Table 13. Table 13: Adverse Events Reported in ≥ 1% of Adult Patients in Monitored Anesthesia Care Studies at the Recommended Doses a of Remifentanil HCl Adverse Event Remifentanil HCl (n = 159) Remifentanil HCl + 2 mg Midazolam b (n = 103) Propofol (0.5 mg/kg then 50 mcg/kg/min) (n = 63) Nausea 70 (44%) 19 (18%) 20 (32%) Vomiting 35 (22%) 5 (5%) 13 (21%) Pruritus 28 (18%) 16 (16%) 0 Headache 28 (18%) 12 (12%) 6 (10%) Sweating 10 (6%) 0 1 (2%) Shivering 8 (5%) 1 (< 1%) 1 (2%) Dizziness 8 (5%) 5 (5%) 1 (2%) Hypotension 7 (4%) 0 6 (10%) Bradycardia 6 (4%) 0 7 (11%) Respiratory depression 4 (3%) 1 (< 1%) a 0 Muscle rigidity 4 (3%) 0 1 (2%) Chills 2 (1%) 0 2 (3%) Flushing 2 (1%) 0 0 Warm sensation 2 (1%) 0 0 Pain at study IV site 2 (1%) 0 11 (17%) a See Table 3 for recommended doses.
Administration of remifentanil HCl in excess of the recommended infusion rate (i.e., starting doses > 0.1 mcg/kg/min) resulted in a higher incidence of some adverse events: nausea (60%), apnea (8%), and muscle rigidity (5%). b With higher midazolam doses, higher incidences of respiratory depression and apnea were observed. Other Adverse Events in Adult Patients The frequencies of less commonly reported adverse clinical events from all controlled general anesthesia and monitored anesthesia care studies are presented below.
Event frequencies are calculated as the number of patients who were administered remifentanil HCl and reported an event divided by the total number of patients exposed to remifentanil HCl in all controlled studies including cardiac dose-ranging and neurosurgery studies (n = 1,883 general anesthesia, n = 609 monitored anesthesia care). Incidence Less than 1% Digestive: constipation, abdominal discomfort, xerostomia, gastro-esophageal reflux, dysphagia, diarrhea, ileus.
Cardiovascular: various atrial and ventricular arrhythmias, heart block, ECG change consistent with myocardial ischemia, elevated CPK-MB level, syncope. Musculoskeletal: muscle stiffness, musculoskeletal chest pain. Respiratory: cough, dyspnea, bronchospasm, laryngospasm, rhonchi, stridor, nasal congestion, pharyngitis, pleural effusion, hiccup(s), pulmonary edema, rales, bronchitis, rhinorrhea. Nervous: anxiety, involuntary movement, prolonged emergence from anesthesia, confusion, awareness under anesthesia without pain, rapid awakening from anesthesia, tremors, disorientation, dysphoria, nightmare(s), hallucinations, paresthesia, nystagmus, twitch, seizure, amnesia.
Body as a Whole: decreased body temperature, anaphylactic reaction, delayed recovery from neuromuscular block. Skin: rash, urticaria. Urogenital: urine retention, oliguria, dysuria, urine incontinence. Infusion Site Reaction: erythema, pruritus, rash. Metabolic and Nutrition: abnormal liver function, hyperglycemia, electrolyte disorders, increased CPK level. Hematologic and Lymphatic: anemia, lymphopenia, leukocytosis, thrombocytopenia.
The frequencies of adverse events from the clinical studies at the recommended
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Composition
Active ingredients
REMIFENTANIL HYDROCHLORIDE EQ 5MG BASE/VIAL
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
