REMIFENTANIL Drug Interactions: What You Need to Know
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Drug Interactions (FDA Label)
INTERACTIONS Table 18 includes clinically significant drug interactions with remifentanil Hydrochloride for injection.
Table
18: Clinically Significant Drug Interactions with Remifentanil Hydrochloride for Injection 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 (5.5) ] . Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment.
Discontinue Remifentanil
Hydrochloride for injection 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 (5.5) ] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2) ]. If urgent use of Remifentanil Hydrochloride for injection 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 Hydrochloride for injection 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 Hydrochloride for injection 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 Hydrochloride for injection 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 )
Drug
Interactions In animals the duration of muscle paralysis from succinylcholine is not prolonged by remifentanil.
Contraindications
Remifentanil Hydrochloride for injection 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 )
Related Warnings
AND PRECAUTIONS Life-Threatening Respiratory Depression : 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 ) Opioid-Induced Hyperalgesia and Allodynia: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation. ( 5.4 )
Serotonin
Syndrome : Potentially life-threatening condition could result from concomitant serotonergic drug administration.
Discontinue Remifentanil
Hydrochloride for injection if serotonin syndrome is suspected. ( 5.5 ) Administration : Continuous infusions of Remifentanil Hydrochloride for injection should be administered only by an infusion device. ( 5.6 )
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. ( 5.7 )
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. ( 5.8 ) Bradycardia : Monitor heart rate during dosage initiation and titration. It is responsive to ephedrine or anticholinergic drugs ( 5.9 ) 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 ( 5.10 )
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 ( 5.11 ) Risks of Use in Spontaneously Breathing Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Monitor for sedation and respiratory depression. ( 5.12 ) Risks of Use in Patients with Biliary Tract Disease : Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. ( 5.13 )
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. ( 5.14 )
Rapid
Offset of Action : Standard monitoring should be maintained in the postoperative period to ensure adequate recovery without stimulation. ( 5.15 )
5.1 Addiction, Abuse, and Misuse Remifentanil Hydrochloride for injection contains remifentanil, a Schedule II controlled substance. As an opioid, Remifentanil Hydrochloride for injection exposes users to the risks of addiction, abuse, and misuse <span class="opacity-50 text-xs">[see Drug Abuse and Dependence (9) ]</span>. Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when handling Remifentanil Hydrochloride for injection. 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.
5.2 Life-Threatening Respiratory Depression 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
Hydrochloride for injection 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 Hydrochloride for injection 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 Hydrochloride for injection, 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 Hydrochloride for injection.
Remifentanil
Hydrochloride for injection 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 Hydrochloride for injection. 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 Hydrochloride for injection and when Remifentanil Hydrochloride for injection is given concomitantly with other drugs that depress respiration. To reduce the risk of respiratory depression, proper dosing and titration of Remifentanil Hydrochloride for injection are essential [see Dosage and Administration (2.11) ].
5.3 Risks from Use as Postoperative Analgesia with Concomitant Benzodiazepines or Other CNS Depressants When benzodiazepines or other CNS depressants are used with Remifentanil Hydrochloride for injection, pulmonary arterial pressure may be decreased. This fact should be considered by those who conduct diagnostic and surgical procedures where interpretation of pulmonary arterial pressure measurements might determine final management of the patient. When high dose or anesthetic dosages of Remifentanil Hydrochloride for injection are employed, even relatively small dosages of diazepam may cause cardiovascular depression.
When Remifentanil
Hydrochloride for injection is used with CNS depressants, hypotension can occur. If it occurs, consider the possibility of hypovolemia and manage with appropriate parenteral fluid therapy. When operative conditions permit, consider repositioning the patient to improve venous return to the heart. Exercise care in moving and repositioning of patients because of the possibility of orthostatic hypotension. If volume expansion with fluids plus other countermeasures do not correct hypotension, consider administration of pressor agents other than epinephrine. Epinephrine may paradoxically decrease blood pressure in patients treated with a neuroleptic that blocks alpha adrenergic activity. Hypotension, profound sedation, respiratory depression, coma, and death may result from the concomitant use of Remifentanil Hydrochloride for injection with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Patients should be advised to avoid alcohol for 24 hours after surgery [see Drug Interactions (7) ] . Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7) ] . If the decision is made to manage postoperative pain with Remifentanil Hydrochloride for injection concomitantly with a benzodiazepine or other CNS depressant, start dosing with the lowest effective dosage and titrate based on clinical response. Monitor patients closely for signs and symptoms of respiratory depression, sedation, and hypotension. Fluids or other measures to counter hypotension should be available [see Drug Interactions (7) ] .
5.4 Opioid-Induced Hyperalgesia and Allodynia Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect <span class="opacity-50 text-xs">[see Dependence (9.3) ]</span> . Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) <span class="opacity-50 text-xs">[see Dosage and Administration (2) , Warnings and Precautions (5.2) ]</span> .
5.5 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of Remifentanil Hydrochloride for injection 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
Hydrochloride for injection if serotonin syndrome is suspected.
5.6 Administration Continuous infusions of Remifentanil Hydrochloride for injection should be administered only by an infusion device. IV bolus administration of Remifentanil Hydrochloride for injection should be used only during the maintenance of general anesthesia. In nonintubated patients, single doses of Remifentanil Hydrochloride for injection should be administered over 30 to 60 seconds. Interruption of an infusion of Remifentanil Hydrochloride for injection will result in rapid offset of effect. Rapid clearance and lack of drug accumulation result in rapid dissipation of respiratory depressant and analgesic effects upon discontinuation of Remifentanil Hydrochloride for injection at recommended doses. Discontinuation of an infusion of Remifentanil Hydrochloride for injection should be preceded by the establishment of adequate postoperative analgesia. Injections of Remifentanil Hydrochloride for injection should be made into IV tubing at or close to the venous cannula. Upon discontinuation of Remifentanil Hydrochloride for injection, the IV tubing should be cleared to prevent the inadvertent administration of Remifentanil Hydrochloride for injection at a later point in time. Failure to adequately clear the IV tubing to remove residual Remifentanil Hydrochloride for injection has been associated with the appearance of respiratory depression, apnea, and muscle rigidity upon the administration of additional fluids or medications through the same IV tubing.
5.7 Skeletal Muscle Rigidity Skeletal muscle rigidity can be caused by Remifentanil Hydrochloride for injection and is related to the dose and speed of administration.
Remifentanil
Hydrochloride for injection may cause chest wall rigidity (inability to ventilate) after single doses of > 1 mcg/kg administered over 30 to 60 seconds, or after infusion rates > 0.1 mcg/kg/min. Single doses < 1 mcg/kg may cause chest wall rigidity when given concurrently with a continuous infusion of Remifentanil Hydrochloride for injection. Muscle rigidity induced by Remifentanil Hydrochloride for injection should be managed in the context of the patient's clinical condition. Muscle rigidity occurring during the induction of anesthesia should be treated by the administration of a neuromuscular blocking agent and the concurrent induction medications and can be treated by decreasing the rate or discontinuing the infusion of Remifentanil Hydrochloride for injection or by administering a neuromuscular blocking agent. The neuromuscular blocking agents used should be compatible with the patient's cardiovascular status. Muscle rigidity seen during the use of Remifentanil Hydrochloride for injection in spontaneously breathing patients may be treated by stopping or decreasing the rate of administration of Remifentanil Hydrochloride for injection. Resolution of muscle rigidity after discontinuing the infusion of Remifentanil Hydrochloride for injection occurs within minutes. In the case of life-threatening muscle rigidity, a rapid onset neuromuscular blocker or naloxone may be administered.