Remifentanil-vista
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT REMIFENTANIL-VISTA REMIFENTANIL-VISTA
Composition:
active substance: remifentanil hydrochloride;
1 vial contains remifentanil hydrochloride 1 mg, 2 mg or 5 mg;
excipients: glycine, hydrochloric acid, water for injections*;
*present in residual amounts after sublimation drying.
Pharmaceutical form. Powder for concentrate for solution for injection or infusion. Main physicochemical characteristics: White or almost white powder.
Pharmacotherapeutic group. Agents acting on the nervous system. Anaesthetics. General anaesthetics. Agents for opioid anaesthesia. Opioid anaesthetics. ATC code N01AH06.
Pharmacological Properties.
Pharmacodynamics.
Remifentanil is a selective mu-opioid agonist with rapid onset and very short duration of action. The mu-opioid activity of remifentanil is antagonized by opioid antagonists such as naloxone. Analyses assessing histamine release in patients and healthy volunteers have not shown increased histamine levels following bolus doses of remifentanil up to 30 mcg/kg.
Newborns/Infants (up to 1 year of age).
In a randomized (2:1 remifentanil:halothane), open-label, multicenter study involving 60 neonates and infants aged ≤8 weeks (mean age 5.5 weeks) with ASA physical status I–II, the efficacy and safety of remifentanil (0.4 mcg/kg/min as an initial continuous infusion plus supplemental doses with simultaneous adjustment of infusion rate as needed) was compared to halothane during pyloromyotomy. Maintenance of anesthesia was achieved by adding 70% nitrous oxide (N2O) plus 30% oxygen. Recovery time was faster with remifentanil compared to the halothane group. Use for total intravenous anesthesia (TIVA) in children aged 6 months to 16 years.
In three randomized, open-label studies, TIVA with remifentanil in pediatric surgery was compared to inhalational anesthesia (see Table 1).
Table 1
| Surgery |
Age (years) (N) |
Study conditions (maintenance) |
Extubation (min) (mean (SD)) |
| Lower abdominal surgery / urological surgery |
0.5–16 (120) |
TIVA: propofol (5–10 mg/kg/h) + remifentanil (0.125–1.0 mcg/kg/min) |
11.8 (4.2) |
| Inhalational anesthesia: sevoflurane (1.0–1.5 MAC) and remifentanil (0.125–1.0 mcg/kg/min) |
(p<0.05) |
||
| ENT surgery |
4–11 (50) |
TIVA: propofol (3 mg/kg/h) + remifentanil (0.5 mcg/kg/min) |
11 (3.7) |
| Inhalational anesthesia: desflurane (1.3 MAC) and N2O mixture |
9.4 (2.9) Not significant |
||
| General and ENT surgery |
2–12 (153) |
TIVA: remifentanil (0.2–0.5 mcg/kg/min) + propofol (100–200 mcg/kg/min) |
Comparable extubation time (based on limited data) |
| Inhalational anesthesia: sevoflurane (1–1.5 MAC) + N2O mixture |
In a study evaluating use in abdominal/urological surgery comparing remifentanil/propofol to remifentanil/sevoflurane, hypotension was observed more frequently with remifentanil/sevoflurane, while bradycardia was observed more frequently with remifentanil/propofol. In a study in ear, nose, and throat (ENT) surgery comparing remifentanil/propofol to desflurane/nitrous oxide, significantly higher heart rates were observed in patients receiving desflurane/nitrous oxide compared to those receiving remifentanil/propofol and compared to baseline values.
Pharmacokinetics.
Following administration of recommended doses, the effective half-life of remifentanil ranged from 3 to 10 minutes. Mean remifentanil clearance in healthy young volunteers was 40 mL/min/kg, central volume of distribution was 100 mL/kg, and the steady-state volume of distribution was 350 mL/kg. In children aged 1 to 12 years, remifentanil clearance and volume of distribution decrease with increasing age; values in neonates are approximately twice those observed in healthy young adult volunteers.
Remifentanil blood concentration is proportional to the administered dose. For each 0.1 mcg/kg/min increase in infusion rate, remifentanil blood concentration increases by 2.5 ng/mL. Remifentanil is approximately 70% bound to plasma proteins.
Biotransformation.
Remifentanil is an opioid metabolized by esterases, susceptible to metabolism by nonspecific blood and tissue esterases. Metabolism of remifentanil results in the formation of an essentially inactive carboxylic acid metabolite, which in dogs has 1/4600 the activity of remifentanil. Human studies indicate that all pharmacological activity is attributable to the parent compound. Therefore, the activity of this metabolite has no clinical consequences. The elimination half-life of the metabolite in healthy adult volunteers is 2 hours. In patients with normal renal function, renal elimination of 95% of the main remifentanil metabolite takes approximately 7–10 hours. Remifentanil is not a substrate for plasma cholinesterase.
Cardiac Anesthesia.
During procedures using cardiopulmonary bypass (CPB) under hypothermic conditions (28°C), drug clearance decreases by up to 20%. A 1°C decrease in patient body temperature results in a 3% reduction in clearance.
Renal Impairment.
Renal status does not affect the rapid recovery from remifentanil-based sedation and analgesia. The pharmacokinetics of remifentanil are not significantly altered in patients with varying degrees of renal impairment, even after 3 days of administration in intensive care settings. Clearance of the carboxylic acid metabolite is reduced in patients with renal impairment. In some patients, particularly those with moderate to severe renal impairment in intensive care units, the concentration of the carboxylic acid metabolite may exceed the steady-state remifentanil concentration by up to 250-fold. Clinical data demonstrate that accumulation of the metabolite does not lead to clinically significant mu-opioid effects in such patients, even after 3 days of remifentanil administration. There is no evidence that remifentanil is removed by renal replacement therapy. The carboxylic acid metabolite is eliminated by hemodialysis by at least 30%.
Hepatic Impairment.
The pharmacokinetics of remifentanil are not altered in patients with severe hepatic dysfunction awaiting liver transplantation, or during the hepatic phase of liver transplant surgery. Patients with severe hepatic insufficiency may be somewhat more sensitive to the respiratory depressant effects of remifentanil. Such patients should be closely monitored, and remifentanil dosage should be titrated according to individual patient needs.
Pediatric Patients.
Mean clearance and steady-state volume of distribution of remifentanil are increased in younger children and decrease to values observed in healthy young adults by age 17. The elimination half-life of remifentanil in neonates does not differ significantly from that in healthy young adults. Changes in analgesic effect following changes in remifentanil infusion rate should be rapid and similar to those observed in healthy young adults. The pharmacokinetics of the carboxylic acid metabolite in pediatric patients aged 2–17 years are similar to those in adults when corrected for differences in body weight.
Elderly Patients.
Remifentanil clearance is slightly reduced in elderly patients (>65 years) compared to younger patients. The pharmacodynamic activity of remifentanil increases with age. In elderly patients, the EC50 of remifentanil for delta-wave formation on electroencephalogram (EEG) is 50% lower than in younger patients; therefore, the initial dose of remifentanil should be reduced by 50% in elderly patients, followed by careful titration according to individual patient requirements.
Placental and/or Breast Milk Excretion.
Placental transfer studies in rats and rabbits showed that offspring are exposed to remifentanil and/or its metabolites during growth and development. Remifentanil-related material passes into the milk of lactating rats. In clinical studies in humans, remifentanil concentration in fetal blood was approximately 50% of maternal blood concentration. The mean umbilical artery-to-venous concentration ratio of remifentanil was approximately 30%, indicating metabolism of remifentanil in the newborn.
Clinical characteristics.
Indications.
- The medicinal product is indicated as an analgesic agent for use during induction and/or maintenance of general anesthesia under strict medical supervision.
- The medicinal product is indicated for analgesia in patients aged 18 years and older who are on mechanical ventilation.
Contraindications.
- Hypersensitivity to remifentanil or to other fentanyl analogs, as well as to any excipient of the medicinal product.
- The medicinal product contains glycine and therefore is contraindicated for administration via epidural or spinal blockade.
- The medicinal product is contraindicated for use as the sole agent for induction of anesthesia.
Interaction with other medicinal products and other types of interactions.
Remifentanil is not metabolized by plasma cholinesterase; therefore, interactions with drugs metabolized by this enzyme are not expected.
As with other opioids, remifentanil administered by manually controlled infusion or by TCI reduces the dose of inhaled and intravenous anesthetics and benzodiazepines required for anesthesia (see section "Method of administration and dosage"). If doses of concomitantly administered CNS depressants are not reduced, the risk of adverse reactions associated with these medicinal products increases.
Sedative medicinal products, such as benzodiazepines or other similar medicinal products.
When opioids are used concomitantly with sedative medicinal products such as benzodiazepines or other similar medicinal products, the risk of sedation, respiratory depression, coma, and fatal outcome increases due to the additive CNS depressant effect. Therefore, the dose and duration of concomitant use of these medicinal products should be limited (see section "Special precautions for use"). Concomitant use of opioids and gabapentinoids (gabapentin and pregabalin) increases the risk of opioid overdose, respiratory depression, and death.
Cardiovascular effects of remifentanil (hypotension and bradycardia) may be potentiated in patients receiving concomitant cardiodepressant agents such as beta-blockers and calcium channel blockers.
Concomitant use of remifentanil with serotonergic medicinal products, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or monoamine oxidase inhibitors (MAOIs), may increase the risk of serotonin syndrome, a potentially life-threatening condition. Concomitant use with MAO inhibitors should be done with caution. Irreversible MAO inhibitors should be discontinued at least 2 weeks prior to starting remifentanil treatment.
After administration of remifentanil, consumption of alcoholic beverages should be avoided.
Special precautions for use.
The medicinal product should be administered only in fully equipped conditions for monitoring and supporting respiratory and cardiovascular function. This should be performed by appropriately trained specialists experienced in the use of anaesthetic agents, as well as in the recognition and management of expected adverse effects of potent opioids, including cardiopulmonary resuscitation. Such training should include airway management and assisted ventilation. Use of the medicinal product in patients in intensive care units receiving mechanical ventilation should not exceed 3 days.
In patients with known hypersensitivity to opioids of another class, a hypersensitivity reaction may occur after administration of remifentanil. Remifentanil should be used with caution in such patients.
Short duration of action/transition to alternative analgesia. Due to the very rapid offset of remifentanil, residual opioid activity will not be observed within 5–10 minutes after discontinuation of the drug. For patients undergoing surgical procedures where postoperative pain is anticipated, analgesics should be administered prior to discontinuation of remifentanil. When using the medicinal product in the intensive care unit, potential tolerance, hyperalgesia, and associated haemodynamic changes should be considered. Prior to discontinuation of remifentanil, alternative analgesic and sedative agents should be administered. Adequate time should be allowed for the therapeutic effect of longer-acting analgesics to be achieved. The choice of agent(s), dose, and timing of administration should be planned in advance and individually, taking into account the patient's surgical procedures and expected level of postoperative care. When other opioid agents are administered as part of a transition regimen to alternative analgesia, the benefit of adequate postoperative pain relief must always be balanced against the potential risk of respiratory depression associated with these medicinal products.
Risk of concomitant use of sedative medicinal products such as benzodiazepines or other similar medicinal products.
Concomitant use of remifentanil and sedative medicinal products such as benzodiazepines or other similar agents may result in profound sedation, respiratory depression, coma, and death. Because of these risks, concomitant prescribing of these sedative medicinal products is possible only for patients for whom alternative treatment options are not feasible. If a decision is made to prescribe remifentanil together with sedative medicinal products, the lowest effective dose should be used, and the duration of treatment should be as short as possible. Patients should be closely monitored for signs and symptoms of respiratory depression and sedation. It is recommended to inform patients and caregivers about the manifestations of these symptoms (see section "Interaction with other medicinal products and other forms of interaction").
Discontinuation of treatment and withdrawal syndrome. Repeated administration with short intervals over a prolonged period may lead to the development of a withdrawal syndrome after discontinuation of therapy. Withdrawal symptoms of remifentanil, including tachycardia, hypertension, and agitation, have occurred following abrupt discontinuation, particularly after prolonged (more than 3 days) use of the medicinal product. In cases where withdrawal symptoms occur, re-administration of remifentanil and gradual dose reduction may be beneficial. Remifentanil is not recommended for use longer than 3 days in patients receiving mechanical ventilation.
Accidental administration. The dead space of the infusion line and/or cannula may contain a sufficient amount of remifentanil to cause respiratory depression, apnoea, and/or muscle rigidity if the line is flushed with intravenous solutions or solutions of other medicinal products. This can be avoided by administering the medicinal product through a dedicated intravenous/infusion line, which should be discarded after discontinuation of the drug.
Muscle rigidity (prevention and treatment). Muscle rigidity may occur even at recommended doses. As with other opioids, the frequency of muscle rigidity depends on the dose and rate of administration. Therefore, bolus injections should be administered over no less than 30 seconds. Muscle rigidity caused by remifentanil should be managed according to the patient's clinical status using appropriate supportive measures. Excessive muscle rigidity occurring during anaesthesia induction should be treated with administration of a neuromuscular blocker and/or additional sedatives. Muscle rigidity observed during remifentanil use as an analgesic may be resolved by discontinuation or reduction of the remifentanil infusion rate. Resolution of muscle rigidity after discontinuation of remifentanil infusion occurs within a few minutes. As an alternative, an opioid antagonist may be administered; however, this may reduce the analgesic effect of remifentanil.
Respiratory depression (prevention and management). As with all potent opioids, profound analgesia is accompanied by marked respiratory depression. Therefore, remifentanil should be used in medical facilities equipped with necessary means for monitoring and supporting cardiopulmonary function. Particular caution should be exercised in patients with impaired respiratory function. At the first signs of respiratory depression, appropriate measures should be taken, including reducing the infusion rate by 50% or temporarily stopping the infusion. Unlike other fentanyl analogues, remifentanil has not been shown to cause recurrent respiratory depression even after prolonged administration. However, since many factors may influence postoperative recovery, it is important to ensure full consciousness and adequate spontaneous ventilation before patient discharge.
Tolerance and opioid use disorders (OUD) (abuse and dependence).
Tolerance, physical and psychological dependence, and OUD may develop with repeated use of opioids. Abuse or intentional misuse of opioids may lead to overdose and/or death. The risk of developing OUD is increased in patients with a personal or family history (parents or siblings) of substance use disorders (including alcohol use disorders), in current tobacco users, or in patients with other psychiatric disorders in their history (e.g. major depression, anxiety, and personality disorders).
Cardiovascular effects. The risk of cardiovascular effects such as hypotension and bradycardia (rarely potentially leading to asystole/cardiac arrest) (see section "Adverse reactions") may be reduced by decreasing the remifentanil infusion rate or doses of concomitantly administered anaesthetics, intravenous fluids, vasopressors, or anticholinergic agents, as necessary. Weakened patients, elderly patients, and patients with hypovolemia may be more sensitive to the cardiovascular effects of remifentanil.
Neonates/infants. There is limited data on the use of the medicinal product in neonates/infants under 1 year of age (see sections "Pharmacodynamics" and "Dosage and administration").
Use during pregnancy or breastfeeding.
Pregnancy.
There are no adequate and well-controlled studies in pregnant women. Remifentanil should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.
Breastfeeding period.
It is not known whether remifentanil is excreted in human breast milk. However, since data are available showing that fentanyl analogues are excreted in breast milk and metabolites of remifentanil have been detected in the milk of rats after administration of remifentanil, it is recommended to discontinue breastfeeding for 24 hours after administration of remifentanil.
Labour and delivery.
There is insufficient data to recommend remifentanil for use during labour and caesarean section. It is known that remifentanil crosses the placental barrier, and fentanyl analogues may cause respiratory depression in the newborn. If remifentanil is used, the mother and newborn should be closely monitored for signs of excessive sedation or respiratory depression (see section "Special precautions for use").
Ability to affect reaction speed when driving or operating machinery.
The medicinal product may affect the patient's ability to drive or operate vehicles or machinery, as reaction ability is reduced. Patients should be advised not to drive or operate machinery until the effects of anaesthesia have worn off.
Method of Administration and Dosage
Remifentanil should be administered only in settings equipped and designated for monitoring and supporting respiratory and cardiovascular function, and by personnel experienced in the use of anesthetics who are able to recognize and appropriately manage the expected side effects of potent opioids, including respiratory and cardiac resuscitation. Such training should include airway management and assisted ventilation.
Continuous infusions of remifentanil must be administered using a calibrated infusion device through a rapid intravenous line or a separate intravenous line. This intravenous line should be connected to the venous cannula or as close to it as possible and should be primed to minimize potential dead space.
Remifentanil is intended for intravenous use only and must not be administered via epidural or intrathecal injection.
Reconstitution and Dilution
Remifentanil may be further diluted after reconstitution (see information in section "Special precautions for disposal and other handling" and section "Incompatibilities" regarding storage conditions of the reconstituted/diluted medicinal product and recommended solvents for use).
For manually controlled infusions, remifentanil may be diluted to concentrations ranging from 20 to 250 mcg/mL (50 mcg/mL is the recommended dilution for adults; 20–25 mcg/mL for pediatric patients aged 1 year and older).
For remifentanil infusion administered via an automated infusion system, the recommended dilution of remifentanil is 20 to 50 mcg/mL.
General Anesthesia
Remifentanil administration should be individualized based on the patient's response. Specific dosage recommendations for cardiac surgical patients are provided in Table 2. Adults.
Administration by Standard Infusion (Manually Controlled)
Table 2 summarizes initial infusion rates and dosage ranges.
Table 2
RECOMMENDED DOSAGE GUIDELINES FOR ADULTS
| Indications |
BOLUS INJECTION (mcg/kg) |
CONTINUOUS INFUSION (mcg/kg/min) |
|
| Starting dose |
Range |
||
| Anesthesia induction |
1 (over not less than 30 seconds) |
0.5–1 |
- |
| Maintenance of anesthesia in patients connected to mechanical ventilation |
|||
|
0.5–1 |
0.4 |
0.1–2 |
|
0.5–1 |
0.25 |
0.05–2 |
|
0.5–1 |
0.25 |
0.05–2 |
When using a bolus injection during induction, remifentanil should be administered over at least 30 seconds.
At the doses recommended above, remifentanil substantially reduces the amount of anaesthetic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended above to avoid potentiation of haemodynamic effects such as hypotension and bradycardia.
There are no data regarding dosage recommendations for concomitant use of other anaesthetic agents except those listed in Table 2.
Induction of anaesthesia. Remifentanil should be administered with a standard dose of an anaesthetic agent such as propofol, thiopentone, or isoflurane for induction of anaesthesia. Administration of remifentanil after the anaesthetic agent will reduce the incidence of muscle rigidity. Remifentanil may be administered at an infusion rate of 0.5 to 1 mcg/kg/min with or without an initial slow bolus injection of 1 mcg/kg over at least 30 seconds. If endotracheal intubation is to occur more than 8–10 minutes after the start of remifentanil infusion, a bolus injection is not required.
Maintenance of anaesthesia in patients undergoing mechanical ventilation. After endotracheal intubation, the remifentanil infusion rate should be reduced accordingly, as indicated in Table 2. Due to the rapid onset and short duration of action of remifentanil, the administration rate during anaesthesia may be titrated by increasing the dose in increments of 25% to 100% or decreasing the dose by 25% to 50% every 2–5 minutes to achieve the desired mu-opioid response. Depending on the response to light anaesthesia, additional slow bolus injections may be administered every 2–5 minutes.
Anaesthesia in patients with inhalational anaesthesia (with spontaneous breathing) and protected airways (e.g., via laryngeal mask).
In patients with inhalational anaesthesia who are spontaneously breathing with protected airways, respiratory depression may occur. Particular caution is required to adjust the dose according to patient needs, and ventilatory support may be necessary. The recommended initial infusion rate for supplemental analgesia in patients with inhalational anaesthesia is 0.04 mcg/kg/min, titrated to effect. A range of infusion rates from 0.025 to 0.1 mcg/kg/min has been studied. Bolus injections are not recommended for patients undergoing anaesthesia with spontaneous breathing.
Remifentanil should not be used as a sedative analgesic during procedures/manipulations when patients remain conscious or do not receive respiratory support during the procedure/manipulation.
Concomitant medications. The use of remifentanil allows for reduction in both the amount and dosage of inhaled anaesthetics and benzodiazepines required for anaesthesia (see section "Interaction with other medicinal products and other forms of interaction"). When used concomitantly with remifentanil, doses of anaesthetic agents such as isoflurane, sodium thiopentone, propofol, and temazepam were reduced by up to 75%.
Recommendations for discontinuation/continuation of the medicinal product in the postoperative period. Due to the very rapid onset of action of remifentanil, residual opioid activity will be observed for 5–10 minutes after discontinuation of administration. For surgical procedures expected to result in postoperative pain, analgesics should be administered prior to discontinuation of remifentanil. Sufficient time should be allowed for the analgesic agents to reach their maximum effect. The choice of analgesic should be appropriate for the patient's surgical procedure and level of postoperative care. Accidental administration of remifentanil remaining in infusion lines and cannulae should be avoided (see section "Special precautions for use"). If longer-acting analgesia has not been provided before the end of surgery, it may be necessary to continue remifentanil analgesia during the immediate postoperative period until longer-acting analgesia reaches its maximum effect. In patients breathing spontaneously, the remifentanil infusion rate should initially be reduced to 0.1 mcg/kg/min. The infusion rate may then be increased or decreased by no more than 0.025 mcg/kg/min every 5 minutes to balance the level of analgesia and the patient's respiratory rate. Administration of remifentanil bolus injections for treatment of pain in spontaneously breathing patients in the postoperative period is not recommended.
Administration by target-controlled infusion (TCI) system.
Induction and maintenance of anaesthesia in patients undergoing mechanical ventilation. Remifentanil should be used in combination with an intravenous or inhaled anaesthetic agent during induction and maintenance of anaesthesia in adult patients undergoing mechanical ventilation. In combination with these medicinal products, adequate analgesia for induction of anaesthesia and surgical procedures is usually achieved with target blood concentrations of remifentanil ranging from 3 to 8 ng/ml. Remifentanil should be titrated according to the individual patient's response. For particularly painful surgical procedures, target blood concentrations up to 15 ng/ml may be required. At the recommended doses above, remifentanil substantially reduces the amount of anaesthetic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended above to avoid potentiation of haemodynamic effects such as hypotension and bradycardia.
Due to insufficient data, the use of remifentanil via TCI for anaesthesia in patients with spontaneous ventilation is not recommended.
Recommendations for discontinuation/continuation of the medicinal product in the postoperative period. At the end of surgery, when the infusion administered via a target-controlled infusion (TCI) system is stopped or the target concentration is reduced, spontaneous respiration will return at predicted remifentanil blood concentrations of 1 to 2 ng/ml. As with manually controlled infusion, postoperative analgesia should be established prior to the end of surgery using longer-acting analgesics.
Due to insufficient data, administration of remifentanil via a target-controlled infusion (TCI) system for treatment of postoperative pain is not recommended.
Paediatric patients (aged 1 to 12 years). The concomitant use of remifentanil and intravenous anaesthetic agents for induction of anaesthesia has not been adequately studied and is therefore not recommended.
Administration of remifentanil via a target-controlled infusion (TCI) system has not been studied in paediatric patients and is therefore not recommended for this patient group. When administering a bolus injection, remifentanil should be administered over at least 30 seconds. Surgical intervention should not begin at least 5 minutes after the start of remifentanil infusion if a concomitant bolus dose has not yet been administered.
For concomitant administration of nitrous oxide (70%) with remifentanil, the typical maintenance infusion rate should range from 0.4 to 3 mcg/kg/min, and although not specifically studied, data from adults suggest that 0.4 mcg/kg/min is an adequate initial rate.
Paediatric patients should be closely monitored and the dose titrated to the depth of analgesia according to the severity of the surgical procedure.
Induction of anaesthesia. The use of remifentanil for induction of anaesthesia in patients aged 1 to 12 years is not recommended due to lack of experience with this medicinal product in this patient group.
Maintenance of anaesthesia. The following remifentanil doses are recommended for maintenance of anaesthesia (see Table 3).
Table 3
DOSAGE RECOMMENDATIONS FOR PAEDIATRIC PATIENTS (aged 1 to 12 years).
| *Concomitant anesthetic medicinal products |
BOLUS INJECTION (mcg/kg) |
CONTINUOUS INFUSION (mcg/kg/min) |
|
| Initial dose |
Range |
||
| Halothane (initial dose 0.3MAC) |
1 |
0.25 |
0.05–1.3 |
| Sevoflurane (initial dose 0.3MAC) |
1 |
0.25 |
0.05–0.9 |
| Isoflurane (initial dose 0.5MAC) |
1 |
0.25 |
0.06–0.9 |
* concomitant administration with nitrous oxide/oxygen in a 2:1 ratio.
Concomitant medications: At the recommended doses above, remifentanil significantly reduces the amount of anaesthetic agent required to maintain anaesthesia. Therefore, to avoid potentiation of haemodynamic effects such as hypotension and bradycardia, isoflurane, halothane, and sevoflurane should be used. There are no data available to provide dosage recommendations for concomitant use of other anaesthetic agents except those listed in the table with remifentanil (see Adults).
Guidelines for postoperative patient management/alternative analgesia prior to discontinuation of remifentanil. Due to the very rapid onset of action of remifentanil, residual activity will not persist longer than 5–10 minutes after discontinuation of the drug. For patients undergoing surgical procedures expected to be associated with postoperative pain, analgesics should be initiated prior to discontinuation of remifentanil. Sufficient time should be allowed for the therapeutic effect of the analgesic agent to be achieved. The choice of analgesic (agents), dosage, and timing of administration should be planned in advance and individually tailored according to the surgical procedure severity and expected level of postoperative care (see section "Special precautions for use"). Neonates/infants (under 1 year of age). Clinical experience with remifentanil in neonates and infants (under 1 year of age) is limited.
The pharmacokinetic profile of remifentanil in neonates/infants (under 1 year of age) is comparable to that in adults after correction for differences in body weight. Because clinical data are insufficient, remifentanil is not recommended for use in this age group.
Since clinical trial/use experience with remifentanil in infants for general intravenous anaesthesia is limited, there are insufficient data to provide dosage recommendations.
Anaesthesia in cardiac surgery.
Adults
Administration by conventional infusion.
Table 4
RECOMMENDED DOSAGES FOR CARDIAC ANAESTHESIA
| Indications |
BOLUS INJECTION (mcg/kg) |
CONTINUOUS INFUSION (mcg/kg/min) |
|
| Initial dose |
Range |
||
| Anesthesia induction |
not recommended |
1 |
- |
| Maintenance of anesthesia in patients connected to a mechanical ventilator |
|||
|
0.5–1 |
1 |
0.003–4 |
|
0.5–1 |
1 |
0.01–4.3 |
| Continuation of postoperative analgesia until extubation |
not recommended |
1 |
0–1 |
Induction of anesthesia. After administration of a hypnotic agent to achieve loss of consciousness, remifentanil should be administered at an initial infusion rate of 1 mcg/kg/min. Bolus injections of remifentanil during induction are not recommended in cardiac surgical patients. Endotracheal intubation should not be performed earlier than 5 minutes after the start of infusion.
Maintenance of anesthesia. After endotracheal intubation, the remifentanil infusion rate should be titrated according to the patient's needs. Additional slow bolus doses may be administered if required. For high-risk cardiac patients, such as those with poor ventricular function, the maximum bolus dose should be 0.5 mcg/kg. These dosing recommendations also apply during hypothermic cardiopulmonary bypass (see section "Pharmacokinetics").
Concomitant therapy:
At the doses recommended above, remifentanil substantially reduces the amount of hypnotic agent required to maintain anesthesia. Therefore, isoflurane and propofol should be administered as recommended above to avoid exacerbation of hemodynamic effects such as hypotension and bradycardia. There are no data regarding dosing recommendations for the concomitant use of other hypnotic agents except those listed in Table 2 (see above General anesthesia).
Recommendations for postoperative management of patients.
Continuation of remifentanil administration after surgery for analgesia prior to extubation. It is recommended to maintain remifentanil infusion at the final intraoperative rate during patient transfer to the post-anesthesia care unit. Upon arrival, the patient's level of analgesia and sedation should be closely monitored, and the remifentanil infusion rate adjusted according to individual patient needs.
Transition to alternative analgesia prior to discontinuation of remifentanil. Due to the very rapid offset of remifentanil's effect, residual opioid activity will only be observed for 5–10 minutes after discontinuation of remifentanil. Prior to stopping remifentanil, alternative analgesic and sedative agents should be administered in advance to ensure therapeutic efficacy of these agents. Therefore, it is recommended to plan the selection, dosage, and timing of these medications before disconnecting the patient from mechanical ventilation.
Recommendations for discontinuation of remifentanil. Due to the rapid action of remifentanil, hypertension, shivering, and pain have been reported in cardiac patients immediately after discontinuation of the drug (see section "Adverse reactions"). To minimize the risk of these effects, adequate alternative analgesia should be established before stopping the remifentanil infusion (as described above). The infusion rate should be reduced by 25% at intervals of at least 10 minutes until the infusion is discontinued. During weaning from mechanical ventilation, remifentanil infusion should not be increased; only dose titration by gradual reduction is permitted, supplemented as needed with alternative analgesics. Hemodynamic changes such as arterial hypertension and tachycardia should be treated, if necessary, with alternative agents.
When opioid agents are used as part of the transition to alternative analgesia, careful patient monitoring is required. The benefits of postoperative analgesia must always be balanced against the potential risk of respiratory depression associated with these medications.
Administration by target-controlled infusion (TCI) system.
Induction and maintenance of anesthesia. Remifentanil administered via a target-controlled infusion (TCI) system should be used in combination with intravenous or inhalational anesthetic agents in adult patients undergoing mechanical ventilation (see section "Administration and dosage"). In combination with these agents, adequate analgesia in cardiac surgery is usually achieved at higher target blood concentrations of remifentanil than those used for general surgical procedures. In clinical studies, after titration of remifentanil to individual patient response, blood concentrations up to 20 ng/mL were used. At the doses recommended above, remifentanil significantly reduces the amount of anesthetic agent required to maintain anesthesia. Therefore, isoflurane and propofol should be administered as recommended above to avoid exacerbation of hemodynamic effects such as hypotension and bradycardia.
Information on remifentanil blood concentrations achieved with conventional manually controlled infusion can be found in Table 12.
Recommendations for discontinuation/continuation in the postoperative period.
At the end of surgery, when the target-controlled infusion (TCI) is stopped or the target concentration is reduced, spontaneous respiration will return at predicted remifentanil blood concentrations of 1 to 2 ng/mL. As with manually controlled infusion, postoperative analgesia should be established before the end of surgery using longer-acting analgesics. Due to insufficient data, the use of remifentanil via a target-controlled infusion (TCI) system for treatment of postoperative pain is not recommended.
Pediatric patients (aged 1 to 12 years)
There is insufficient information to provide dosing recommendations for use during cardiac surgery in this patient population.
Use in intensive care and resuscitation units.
Adults
Remifentanil may be used for analgesia in adult patients in intensive care and resuscitation units who are on mechanical ventilation. Sedative agents should be added as needed. Remifentanil has been studied in patients in intensive care units who were on mechanical ventilation in well-controlled clinical trials for up to three days. Since administration of the drug beyond three days has not been studied, there is no evidence of safety and efficacy for prolonged treatment. Therefore, remifentanil should not be used for longer than 3 days.
The use of remifentanil via a target-controlled infusion (TCI) system has not been studied in intensive care patients and is therefore not recommended for these patients. For adults, remifentanil infusion should be initiated at a rate of 0.1 mcg/kg/min (6 mcg/kg/hour) to 0.15 mcg/kg/min (9 mcg/kg/hour). The infusion rate should be titrated in increments of 0.025 mcg/kg/min (1.5 mcg/kg/hour) to achieve the desired level of sedation and analgesia. A minimum interval of 5 minutes should be allowed between dose adjustments. The level of sedation and analgesia should be carefully monitored, regularly reassessed, and the remifentanil infusion rate adjusted accordingly. If the infusion rate reaches 0.2 mcg/kg/min (12 mcg/kg/hour) and the desired level of sedation is not achieved, administration of an appropriate sedative agent should be initiated (see below). The dose of the sedative agent should be titrated to achieve the desired level of sedation. Further increases in the remifentanil infusion rate in increments of 0.025 mcg/kg/min (1.5 mcg/kg/hour) may be performed if additional analgesia is required.
Table 5 summarizes the initial infusion rates and typical dose ranges recommended for providing analgesia and sedation in individual patients.
Table 5
RECOMMENDED DOSING FOR REMIFENTANIL USE IN INTENSIVE CARE TREATMENT
| CONTINUOUS INFUSION, mcg/kg/min (mcg/kg/hr) |
|
| Initial dose |
Range |
| 0.1 (6) to 0.15 (9) |
0.006 (0.36) to 0.74 (44.4) |
Bolus doses of remifentanil are not recommended in intensive care settings. The use of remifentanil will reduce the dosage of any concomitant sedative agents. Typical initial doses for sedative agents, if required, are provided below (see Table 6).
Table 6
RECOMMENDED INITIAL DOSES OF SEDATIVE AGENTS, IF REQUIRED
| Sedative agent |
Bolus (mg/kg) |
Infusion (mg/kg/h) |
| Propofol |
up to 0.5 |
0.5 |
| Midazolam |
up to 0.03 |
0.03 |
To ensure separate titration of the respective medicinal products, sedatives should not be administered as a single mixture in one infusion bottle.
Additional analgesia for mechanically ventilated patients undergoing stimulating procedures. An increase in the existing remifentanil infusion rate may be required to provide additional analgesia for mechanically ventilated patients undergoing physiotherapeutic and/or painful procedures such as endotracheal suctioning, wound dressing, and physiotherapy. It is recommended to maintain the remifentanil infusion rate at not less than 0.1 mcg/kg/min (6 mcg/kg/h) for at least 5 minutes prior to the start of the procedure. Further dose adjustments can be made every 2–5 minutes in increments of 25–50%. The average infusion rate is 0.25 mcg/kg/min (15 mcg/kg/h), with a maximum of 0.74 mcg/kg/min (45 mcg/kg/h), administered to provide additional analgesia during appropriate procedures.
Addition of alternative analgesia prior to discontinuation of remifentanil. Due to the very rapid offset of remifentanil, residual opioid activity is observed only for 5–10 minutes after discontinuation, regardless of the duration of infusion. After administration of remifentanil, the possibility of developing tolerance and hyperalgesia, as well as associated hemodynamic changes, should be considered when used in intensive care units (see section "Special precautions"). Therefore, before discontinuing remifentanil, patients should be administered alternative analgesics and anesthetics to prevent hyperalgesia and associated hemodynamic changes. These agents should be administered in advance to allow establishment of their therapeutic effects. Available analgesic options include long-acting analgesics administered orally, intravenously, or locally under nurse or patient control. These methods should always be adapted to individual patient needs. It is recommended to plan the selection of drug(s), dosage, and timing of administration prior to discontinuation of remifentanil.
There is a possibility of developing tolerance over time with prolonged administration of mu-opioid agonists.
Recommendations for tracheal extubation and discontinuation of remifentanil.
To ensure a smooth emergence after remifentanil administration, it is recommended that the remifentanil infusion rate be titrated down stepwise to 0.1 mcg/kg/min (6 mcg/kg/h) over a period of up to 1 hour before extubation.
After extubation, the infusion rate should be reduced by 25% at 10-minute intervals until the infusion is discontinued.
During weaning from mechanical ventilation, remifentanil infusion should not be increased, but only titrated downward, supplemented, as needed, with alternative analgesics. After discontinuation of remifentanil, the intravenous cannula should be flushed or removed to avoid further unintentional administration of the drug.
When opioid agents are used as part of the transition to alternative analgesia, careful patient monitoring is required. The benefit of adequate analgesia must always be balanced against the potential risk of respiratory depression. Pediatric patients in intensive care.
The use of remifentanil in intensive care patients under 18 years of age is not recommended due to lack of data on the use of the drug in this patient group.
Intensive care patients with renal impairment.
No dose adjustments are required for patients with renal impairment, including those undergoing renal replacement therapy; however, available data indicate that the clearance of the carboxylic acid metabolite is reduced in patients with renal insufficiency. Special patient groups.
Elderly patients (aged 65 years and older).
General anesthesia: The initial dose of remifentanil administered to patients aged 65 years and older should be half the recommended adult dose, and then titrated to individual patient needs, as this group of patients exhibits increased sensitivity to the pharmacological effects of remifentanil. This dose adjustment applies to all phases of anesthesia, including induction, maintenance, and immediate postoperative analgesia.
Due to increased sensitivity of elderly patients to remifentanil, when administered via controlled (device-assisted) infusion, the initial target concentration should be 1.5–4 ng/mL, followed by titration to the required response.
Cardiac anesthesia. Initial dose reduction is not required (see Cardiac anesthesia).
Intensive care: Initial dose reduction is not required (see Use in intensive care and resuscitation units).
Obese patients.
For standard infusion, it is recommended to reduce the remifentanil dose in obese patients based on ideal body weight calculation, as the clearance and volume of distribution of remifentanil correlate better with ideal body weight than with actual body weight. When calculating lean body mass (LBM) used in the Minto model, this index is likely to be lower in female patients with a body mass index (BMI) greater than 35 kg/m² and in male patients with a BMI greater than 40 kg/m². To avoid underdosing in these patients, remifentanil administered via controlled (device-assisted) infusion should be carefully titrated to individual patient response.
Renal impairment.
Based on available data, dose adjustment in patients with renal impairment, including those in intensive care units, is not required. Hepatic impairment.
Studies conducted in a limited number of patients with hepatic impairment show that no specific dosage recommendations are necessary. However, patients with severe hepatic insufficiency may be somewhat more sensitive to remifentanil, resulting in respiratory depression. These patients should be closely monitored, and the remifentanil dose should be titrated according to individual patient needs.
Neurosurgery.
Limited clinical experience with the use of remifentanil in patients undergoing neurosurgical procedures has shown that no specific dosage recommendations are required.
ASA III/IV class patients.
General anesthesia: Since hemodynamic effects of potent opioids may be more pronounced in ASA III/IV patients, caution should be exercised in this population.
It is recommended to reduce the initial dose and subsequent titration to achieve the appropriate effect. In pediatric patients, there is insufficient data for dosage recommendations. For administration of remifentanil via target-controlled infusion (TCI), a lower initial target concentration of 1.5 to 4 ng/mL should be used in patients with ASA III or IV and subsequently titrated.
Cardiac anesthesia: Initial dose reduction is not required. (see Cardiac anesthesia).
Special precautions for disposal and handling. The medicinal product should only be dissolved and diluted with the infusion solutions recommended. Remifentanil should be prepared for intravenous administration by adding 1, 2, or 5 mL of solvent, respectively, to obtain a reconstituted solution with a concentration of 1 mg/mL of remifentanil. The reconstituted solution is clear, colorless, and practically free from visible particles. After reconstitution, the vial should be visually inspected for the presence of visible solid particles, color change, or damage. Do not use the solution if such defects are observed. The reconstituted product is intended for single use only. Unused product should be disposed of according to approved local requirements.
Reconstituted solution
Chemical and physical stability of the reconstituted solution has been demonstrated for 24 hours at 25°C. From a microbiological standpoint, the product should be used immediately. If not used immediately, the responsibility for the duration and conditions of storage of the reconstituted solution prior to use lies with the user and should generally not exceed 24 hours at 2–8°C, unless reconstitution was performed under controlled and validated aseptic conditions.
Diluted solution
Diluted remifentanil solutions should be used immediately. Any unused diluted solution should be discarded.
Remifentanil should not be administered via manually controlled infusion without dilution to concentrations between 20 and 250 mcg/mL (50 mcg/mL is the recommended dilution for adults and 20 to 25 mcg/mL for pediatric patients aged 1 year and older).
Remifentanil should not be administered via controlled (device-assisted) infusion without further dilution (20–50 mcg/mL is the recommended dilution for controlled (device-assisted) infusion).
Dilution depends on the technical capabilities of the infusion device and the anticipated patient needs.
The following intravenous fluids should be used for dilution:
- Water for injection.
- 5% glucose solution for injection.
- 5% glucose and 0.9% sodium chloride solution for injection.
- 0.9% sodium chloride solution for injection.
- 0.45% sodium chloride solution for injection.
Remifentanil is compatible with the following intravenous fluids when administered through an intravenous catheter:
- Ringer's lactate solution for injection.
- Ringer's lactate and 5% glucose solution for injection.
Remifentanil has been shown to be compatible with propofol when administered through an intravenous catheter.
The following tables provide guidance on remifentanil infusion rates for manually controlled infusions.
Table 7
Remifentanil for injection rate indicators (mL/kg/h)
| Infusion rate of the drug (mcg/kg/min) |
Infusion rate (ml/kg/h) for solution with corresponding concentration |
|||
| 20 mcg/ml 1 mg/50 ml |
25 mcg/ml 1 mg/40 ml |
50 mcg/ml 1 mg/20 ml |
250 mcg/ml 10 mg/40 ml |
|
| 0.0125 |
0.038 |
0.03 |
0.015 |
not recommended |
| 0.025 |
0.075 |
0.06 |
0.03 |
not recommended |
| 0.05 |
0.15 |
0.12 |
0.06 |
0.012 |
| 0.075 |
0.23 |
0.18 |
0.09 |
0.018 |
| 0.1 |
0.3 |
0.24 |
0.12 |
0.024 |
| 0.15 |
0.45 |
0.36 |
0.18 |
0.036 |
| 0.2 |
0.6 |
0.48 |
0.24 |
0.048 |
| 0.25 |
0.75 |
0.6 |
0.3 |
0.06 |
| 0.5 |
1.5 |
1.2 |
0.6 |
0.12 |
| 0.75 |
2.25 |
1.8 |
0.9 |
0.18 |
| 1.0 |
3.0 |
2.4 |
1.2 |
0.24 |
| 1.25 |
3.75 |
3.0 |
1.5 |
0.3 |
| 1.5 |
4.5 |
3.6 |
1.8 |
0.36 |
| 1.75 |
5.25 |
4.2 |
2.1 |
0.42 |
| 2.0 |
6.0 |
4.8 |
2.4 |
0.48 |
Table 8
Remifentanil for injection, infusion rate guidelines (mL/h) for 20 mcg/mL solution
| Infusion rate (mcg/kg/min) |
Patient weight (kg) |
||||||
| 5 |
10 |
20 |
30 |
40 |
50 |
60 |
|
| 0.0125 |
0.188 |
0.375 |
0.75 |
1.125 |
1.5 |
1.875 |
2.25 |
| 0.025 |
0.375 |
0.75 |
1.5 |
2.25 |
3.0 |
3.75 |
4.5 |
| 0.05 |
0.75 |
1.5 |
3.0 |
4.5 |
6.0 |
7.5 |
9.0 |
| 0.075 |
1.125 |
2.25 |
4.5 |
6.75 |
9.0 |
11.25 |
13.5 |
| 0.1 |
1.5 |
3.0 |
6.0 |
9.0 |
12.0 |
15.0 |
18.0 |
| 0.15 |
2.25 |
4.5 |
9.0 |
13.5 |
18.0 |
22.5 |
27.0 |
| 0.2 |
3.0 |
6.0 |
12.0 |
18.0 |
24.0 |
30.0 |
36.0 |
| 0.25 |
3.75 |
7.5 |
15.0 |
22.5 |
30.0 |
37.5 |
45.0 |
| 0.3 |
4.5 |
9.0 |
18.0 |
27.0 |
36.0 |
45.0 |
54.0 |
| 0.35 |
5.25 |
10.5 |
21.0 |
31.5 |
42.0 |
52.5 |
63.0 |
| 0.4 |
6.0 |
12.0 |
24.0 |
36.0 |
48.0 |
60.0 |
72.0 |
Table 9
Remifentanil for injection indicators of infusion rates (ml/h) for 25 mcg/ml solution
| Infusion rate (mcg/kg/min) |
Patient weight (kg) |
|||||||||
| 10 |
20 |
30 |
40 |
50 |
60 |
70 |
80 |
90 |
100 |
|
| 0.0125 |
0.3 |
0.6 |
0.9 |
1.2 |
1.5 |
1.8 |
2.1 |
2.4 |
2.7 |
3.0 |
| 0.025 |
0.6 |
1.2 |
1.8 |
2.4 |
3.0 |
3.6 |
4.2 |
4.8 |
5.4 |
6.0 |
| 0.05 |
1.2 |
2.4 |
3.6 |
4.8 |
6.0 |
7.2 |
8.4 |
9.6 |
10.8 |
12.0 |
| 0.075 |
1.8 |
3.6 |
5.4 |
7.2 |
9.0 |
10.8 |
12.6 |
14.4 |
16.2 |
18.0 |
| 0.1 |
2.4 |
4.8 |
7.2 |
9.6 |
12.0 |
14.4 |
16.8 |
19.2 |
21.6 |
24.0 |
| 0.15 |
3.6 |
7.2 |
10.8 |
14.4 |
18.0 |
21.6 |
25.2 |
28.8 |
32.4 |
36.0 |
| 0.2 |
4.8 |
9.6 |
14.4 |
19.2 |
24.0 |
28.8 |
33.6 |
38.4 |
43.2 |
48.0 |
Table 10
Remifentanil for injection infusion rates (ml/h) for a 50 mcg/ml solution
| Infusion rate (mcg/kg/min) |
Patient weight (kg) |
|||||||
| 30 |
40 |
50 |
60 |
70 |
80 |
90 |
100 |
|
| 0.025 |
0.9 |
1.2 |
1.5 |
1.8 |
2.1 |
2.4 |
2.7 |
3.0 |
| 0.05 |
1.8 |
2.4 |
3.0 |
3.6 |
4.2 |
4.8 |
5.4 |
6.0 |
| 0.075 |
2.7 |
3.6 |
4.5 |
5.4 |
6.3 |
7.2 |
8.1 |
9.0 |
| 0.1 |
3.6 |
4.8 |
6.0 |
7.2 |
8.4 |
9.6 |
10.8 |
12.0 |
| 0.15 |
5.4 |
7.2 |
9.0 |
10.8 |
12.6 |
14.4 |
16.2 |
18.0 |
| 0.2 |
7.2 |
9.6 |
12.0 |
14.4 |
16.8 |
19.2 |
21.6 |
24.0 |
| 0.25 |
9.0 |
12.0 |
15.0 |
18.0 |
21.0 |
24.0 |
27.0 |
30.0 |
| 0.5 |
18.0 |
24.0 |
30.0 |
36.0 |
42.0 |
48.0 |
54.0 |
60.0 |
| 0.75 |
27.0 |
36.0 |
45.0 |
54.0 |
63.0 |
72.0 |
81.0 |
90.0 |
| 1.0 |
36.0 |
48.0 |
60.0 |
72.0 |
84.0 |
96.0 |
108.0 |
120.0 |
| 1.25 |
45.0 |
60.0 |
75.0 |
90.0 |
105.0 |
120.0 |
135.0 |
150.0 |
| 1.5 |
54.0 |
72.0 |
90.0 |
108.0 |
126.0 |
144.0 |
162.0 |
180.0 |
| 1.75 |
63.0 |
84.0 |
105.0 |
126.0 |
147.0 |
168.0 |
189.0 |
210.0 |
| 2.0 |
72.0 |
96.0 |
120.0 |
144.0 |
168.0 |
192.0 |
216.0 |
240.0 |
Table 11
Remifentanil for injection infusion rates (ml/h) for 250 mcg/ml solution
| Infusion rate (mcg/kg/min) |
Patient weight (kg) |
|||||||
| 30 |
40 |
50 |
60 |
70 |
80 |
90 |
100 |
|
| 0.1 |
0.72 |
0.96 |
1.2 |
1.44 |
1.68 |
1.92 |
2.16 |
2.4 |
| 0.15 |
1.08 |
1.44 |
1.8 |
2.16 |
2.52 |
2.88 |
3.24 |
3.6 |
| 0.2 |
1.44 |
1.92 |
2.4 |
2.88 |
3.36 |
3.84 |
4.32 |
4.8 |
| 0.25 |
1.8 |
2.40 |
3.0 |
3.60 |
4.20 |
4.80 |
5.4 |
6.0 |
| 0.5 |
3.6 |
4.80 |
6.0 |
7.20 |
8.40 |
9.60 |
10.8 |
12.0 |
| 0.75 |
5.4 |
7.20 |
9.0 |
10.8 |
12.6 |
14.4 |
16.2 |
18.0 |
| 1.0 |
7.2 |
9.60 |
12.0 |
14.4 |
16.8 |
19.2 |
21.6 |
24.0 |
| 1.25 |
9.0 |
12.0 |
15.0 |
18.0 |
21.0 |
24.0 |
27.0 |
30.0 |
| 1.5 |
10.8 |
14.4 |
18.0 |
21.6 |
25.2 |
28.8 |
32.4 |
36.0 |
| 1.75 |
12.6 |
16.8 |
21.0 |
25.2 |
29.4 |
33.6 |
37.8 |
42.0 |
| 2.0 |
14.4 |
19.2 |
24.0 |
28.8 |
33.6 |
38.4 |
43.2 |
48.0 |
Table 12 shows the equivalent blood concentration of remifentanil using the TCI (target controlled infusion, effect-controlled infusion) approach for different manually controlled infusion rates at steady state.
Table 12
Remifentanil blood concentrations (nanograms/ml), estimated using the Minto (1997) pharmacokinetic model in a male patient weighing 70 kg, 170 cm tall, 40 years of age, for different manually controlled infusion rates (mcg/kg/min) at steady state
| Remifentanil infusion rate (mcg/kg/min) |
Remifentanil blood concentration (ng/mL) |
| 0.05 |
1.3 |
| 0.10 |
2.6 |
| 0.25 |
6.3 |
| 0.40 |
10.4 |
| 0.50 |
12.6 |
| 1.0 |
25.2 |
| 2.0 |
50.5 |
Children.
The medicinal product is used in pediatric practice according to the recommendations outlined in the section "Administration and Dosage".
Overdose.
Symptoms. As with all potent opioid analgesics, overdose is manifested by an extension of the pharmacologically predictable effects of remifentanil. Due to the very short duration of action of remifentanil, the potential for adverse effects following overdose is limited to the immediate period after administration of the drug. The response to discontinuation of the drug is rapid, with return to baseline within 10 minutes.
Treatment. In case of overdose, administration of the drug should be discontinued, airway patency maintained, and assisted or controlled ventilation with oxygen, as well as cardiovascular support, provided. If respiratory depression is associated with muscle rigidity, administration of muscle relaxants may be required to facilitate assisted or controlled ventilation. Intravenous fluids, vasopressors, and other supportive measures may be used to treat hypotension. Intravenous administration of an opioid antagonist such as naloxone may be used as a specific antidote, in addition to ventilatory support, to treat severe respiratory depression and muscle rigidity. The duration of respiratory depression following remifentanil overdose is unlikely to exceed the duration of action of the opioid antagonist.
Adverse reactions
The most common adverse reactions associated with remifentanil are a direct extension of the pharmacology of mu-opioid agonists. These adverse reactions resolve within a few minutes after discontinuation or reduction of the remifentanil infusion rate. All adverse reactions are listed by system organ class and frequency: very common (≥1/10), common (≥1/100 – <1/10), uncommon (≥1/1000 – <1/100), rare (≥1/10000 – <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from the available data).
| Organ system classes |
Frequency |
Adverse reactions |
| Immune system disorders |
rare |
allergic reactions, including anaphylaxis, in patients who received remifentanil in combination with one or more anesthetic agents |
| frequency unknown |
anaphylactic shock |
|
| Psychiatric disorders |
frequency unknown |
drug dependence on the medicinal product, withdrawal syndrome. |
| Nervous system disorders |
very common |
skeletal muscle rigidity |
| rare |
sedative effect (during recovery from general anesthesia) |
|
| frequency unknown |
seizures |
|
| Cardiovascular system disorders |
very common |
hypotension |
| common |
postoperative hypertension, bradycardia |
|
| rare |
asystole/cardiac arrest, usually preceded by bradycardia, in patients who received remifentanil in combination with other anesthetic agents |
|
| frequency unknown |
atrioventricular block, arrhythmia. |
|
| Respiratory, thoracic and mediastinal disorders |
common |
Acute respiratory depression, apnea, cough. |
| uncommon |
hypoxia |
|
| Gastrointestinal disorders |
very common |
nausea, vomiting |
| uncommon |
constipation |
|
| Skin and subcutaneous tissue disorders |
common |
itching |
| General disorders and administration site conditions |
common |
postoperative shivering |
| uncommon |
postoperative pain |
|
| frequency unknown |
tolerance to narcotic agents |
Discontinuation of treatment.
Symptoms following remifentanil discontinuation, including tachycardia, arterial hypertension, and agitation, have been rarely observed upon abrupt cessation, especially after prolonged use of the medicinal product for more than 3 days (see section "Special precautions"). Reporting of suspected adverse reactions.
Reporting of suspected adverse reactions after medicinal product authorization is an important procedure. It allows continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.
Shelf life.
For 1 mg – 18 months; 2 mg – 24 months; 5 mg – 36 months.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 ºC. Keep out of reach and sight of children.
Incompatibilities.
Only the infusion solutions specified in the section "Dosage and administration" should be used for dissolution and dilution of the medicinal product.
- Do not dissolve, dilute, or mix (infuse) with lactated Ringer's solution or lactated Ringer's injection solution and 5% dextrose solution.
- The medicinal product should not be mixed with propofol in the same infusion bag/bottle prior to administration.
- Concomitant administration of the medicinal product and blood/serum/plasma through the same intravenous system/line is not recommended. Nonspecific esterases present in blood products may lead to hydrolysis of remifentanil to its inactive metabolite.
- The medicinal product should not be mixed with other therapeutic agents prior to administration.
Packaging.
1 mg, 2 mg, or 5 mg in a glass vial; 5 vials per cardboard box.
Prescription status. Prescription only. For hospital use only.
Manufacturer.
LABORATORIOS DR. JOHNSON, S. A.
Manufacturer's address and location of operations.
C/Gran Capitán, 10, Sant Joan Despí, Barcelona, 08970, Spain.