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Addiction, Abuse, And Misuse: REMIKAF contains remifentanil, a Schedule II controlled substance. As an opioid, REMIKAF exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence under Interactions].
Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when handling REMIKAF. 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.
Respiratory 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.
REMIKAF 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 REMIKAF by 50% or by temporarily discontinuing the infusion [see OVERDOSAGE].
Carbon dioxide (CO2) 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 REMIKAF, 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 REMIKAF.
REMIKAF 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 REMIKAF. 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 REMIKAF and when REMIKAF is given concomitantly with other drugs that depress respiration. To reduce the risk of respiratory depression, proper dosing and titration of REMIKAF are essential [see DOSAGE & ADMINISTRATION].
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 REMIKAF 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 INTERACTIONS].
Serotonin Syndrome With Concomitant Use Of Serotonergic Drugs: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of REMIKAF 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), 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 INTERACTIONS]. 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 REMIKAF if serotonin syndrome is suspected.
Administration: Continuous infusions of REMIKAF should be administered only by an infusion device. IV bolus administration of REMIKAF should be used only during the maintenance of general anesthesia. In nonintubated patients, single doses of REMIKAF should be administered over 30 to 60 seconds.
Interruption of an infusion of REMIKAF 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 REMIKAF at recommended doses. Discontinuation of an infusion of REMIKAF should be preceded by the establishment of adequate postoperative analgesia.
Injections of REMIKAF should be made into IV tubing at or close to the venous cannula. Upon discontinuation of REMIKAF, the IV tubing should be cleared to prevent the inadvertent administration of REMIKAF at a later point in time. Failure to adequately clear the IV tubing to remove residual REMIKAF 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.
Skeletal Muscle Rigidity: Skeletal muscle rigidity can be caused by REMIKAF and is related to the dose and speed of administration. REMIKAF 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 REMIKAF.
Muscle rigidity induced by REMIKAF 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 REMIKAF 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 REMIKAF in spontaneously breathing patients may be treated by stopping or decreasing the rate of administration of REMIKAF. Resolution of muscle rigidity after discontinuing the infusion of REMIKAF occurs within minutes. In the case of life-threatening muscle rigidity, a rapid onset neuromuscular blocker or naloxone may be administered.
Potential Inactivation By Nonspecific Esterases In Blood Products: REMIKAF should not be administered into the same IV tubing with blood due to potential inactivation by nonspecific esterases in blood products.
Bradycardia: Bradycardia has been reported with REMIKAF and is responsive to ephedrine or anticholinergic drugs, such as atropine and glycopyrrolate.
Hypotension: Hypotension has been reported with REMIKAF and is responsive to decreases in the administration of REMIKAF or to IV fluids or catecholamine (ephedrine, epinephrine, norepinephrine, etc.) administration.
Intraoperative Awareness: Intraoperative awareness has been reported in patients under 55 years of age when REMIKAF has been administered with propofol infusion rates of ≤ 75 mcg/kg/min.
Risks Of Use In Spontaneously Breathing Patients With Increased Intracranial Pressure, Brain Tumors, Head Injury, Or Impaired Consciousness: In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), REMIKAF may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure in spontaneously breathing patients. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with REMIKAF.
Opioids may also obscure the clinical course in a patient with a head injury.
Risks Of Use In Patients With Biliary Tract Disease: The remifentanil in REMIKAF may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.
Increased Risk Of Seizures in Patients with Seizure Disorders: The remifentanil in REMIKAF may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during REMIKAF therapy.
Rapid Offset Of Action: Analgesic activity will subside within 5 to 10 minutes after discontinuation of administration of REMIKAF. However, respiratory depression may continue in some patients for up to 30 minutes after termination of infusion due to residual effects of concomitant anesthetics. Standard monitoring should be maintained in the postoperative period to ensure adequate recovery without stimulation. For patients undergoing surgical procedures where postoperative pain is generally anticipated, other analgesics should be administered prior to the discontinuation of REMIKAF.
Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment Of Fertility: Carcinogenesis: Long-term studies in animals to evaluate the carcinogenic potential of remifentanil have not been conducted.
Mutagenesis: Mutagenicity was observed with remifentanil in the in vitro mouse lymphoma assay in the presence but not absence of metabolic activation. Remifentanil did not induce gene mutation in the in vitro bacterial reverse mutation assay (Ames test) and was not genotoxic in the in vivo rat hepatocyte unscheduled DNA synthesis assay. No clastogenic effect was seen in cultured Chinese hamster ovary cells or in the in vivo mouse micronucleus test.
Impairment Of Fertility: Remifentanil has been shown to reduce fertility in male rats when tested after 70+ days of daily IV administration of 0.5 mg/kg, which is approximately 0.2 times a human intravenous infusion of an induction dose of 1 mcg/kg with a maintenance dose of 2 mcg/kg/min in terms of mg/m2 of body surface area for a surgical procedure lasting 3 hours or 40 times a single bolus human dose of 2 mcg/kg, in terms of mg/m2 of body surface area.
The fertility of female rats was not affected at IV doses as high as 1 mg/kg which is 0.4 times a human intravenous infusion of an induction dose of 1 mcg/kg with a maintenance dose of 2 mcg/kg/min in terms of mg/m2 of body surface area for a surgical procedure lasting 3 hours or approximately 80 times a single bolus human dose of 2 mcg/kg, in terms of mg/m2 of body surface area, when administered for at least 15 days before mating.
Use In Specific Populations: Use In Morbidly Obese Patients: As for all potent opioids, caution is required with use in morbidly obese patients because of alterations in cardiovascular and respiratory physiology [see DOSAGE & ADMINISTRATION].
Long-Term Use In The ICU: No data are available on the long-term (longer than 16 hours) use of REMIKAF as an analgesic in ICU patients.
Use in Children: The efficacy and safety of REMIKAF as an analgesic agent for use in the maintenance of general anesthesia in outpatient and inpatient pediatric surgery have been established in controlled clinical studies in pediatric patients from birth to 12 years [see PHARMACOLOGY: Pharmacokinetics: Clinical Studies under Actions].
The initial maintenance infusion regimen of REMIKAF evaluated in pediatric patients from birth to 2 months of age was 0.4 mcg/kg/min, the approved adult regimen for use with N O. The clearance rate observed in neonates was highly variable and on average was 2 times higher than in the young healthy adult population. Therefore, while a starting infusion rate of 0.4 mcg/kg/min may be appropriate for some neonates, an increased infusion rate may be necessary to maintain adequate surgical anesthesia, and additional bolus doses may be required. The individual dose for each patient should be carefully titrated. [See PHARMACOLOGY: Pharmacokinetics: Specific Populations: Pediatric Population under Actions and Table 4 and Maintenance of Anesthesia under DOSAGE & ADMINISTRATION].
REMIKAF has not been studied in pediatric patients for use as a postoperative analgesic or as an analgesic component of monitored anesthesia care.
Use in Elderly: Of the total number of subjects in clinical studies of REMIKAF, 486 were 65 and over (age range 66 to 90 years). While the effective biological half-life of remifentanil is unchanged, elderly patients have been shown to be twice as sensitive as the younger population to the pharmacodynamic effects of remifentanil. The recommended starting dose of REMIKAF should be decreased by 50% in patients over 65 years of age [see PHARMACOLOGY under Actions and DOSAGE & ADMINISTRATION]. Titrate the dosage of REMIKAF slowly in geriatric patients. [See PRECAUTIONS].
The clearance of remifentanil is reduced (approximately 25%) in the elderly ( > 65 years of age) compared to young adults (average 25 years of age). However, remifentanil blood concentrations fall as rapidly after termination of administration in the elderly as in young adults.
