Index of drugs

As an analgesic for use during the introduction and / or maintenance of general anesthesia. The drug is indicated for providing anesthesia in patients 18 years of age, mechanically ventilated, staying in intensive care units.

1 vial contains 1 mg, 2 mg or 5 mg of remifentanil as hydrochloride.

A selective μ-opioid receptor agonist characterized by rapid onset and very short duration of action. Within the range of the recommended dosage, the concentration of the drug in the blood is proportional to the dose; increasing the infusion rate by 0.1 μg / kg / min increases the plasma concentration by 2.5 ng / ml. It does not release histamine. It binds plasma proteins to an average of 70%. Metabolized by non-specific blood and tissue esterases for the virtually inactive carboxylic acid. T_0,5 remifentanil is 3-10 min, the metabolite is 2 h. Approximately 95% of the remifentanil is excreted in the urine as a metabolite. The clearance and volume of distribution of remifentanil at steady state is increased in young children, then decreases with age, reaching approximately 17 years of age as in adults. The pharmacokinetics of the carboxyl metabolite in children (2-17 years) is not different from adults; T_0,5 the elimination phase of remifentanil in newborns is not significantly different from young healthy adults. In patients> 65 years, clearance is reduced by 25% and EC₅₀ it is 50% smaller. The pharmacokinetics of remifentanil are not significantly altered in patients with varying degrees of renal function, even after administration for 3 days under intensive care. The clearance of the carboxylic acid is reduced in patients with renal insufficiency, the accumulation does not cause significant μ-opioid effects even after 3 days of infusion. The pharmacokinetics of remifentanil are unchanged in patients with severe hepatic impairment, awaiting liver transplantation and during the "liver" phase of liver transplant surgery. Patients with severe hepatic impairment may be slightly more sensitive to the inhibitory effect of remifentanil on the respiratory center. Clearance of remifentanil decreases by approximately 20% in patients during extracorporeal circulation with hypothermia (body temperature 28st.C). Reduction in body temperature by 1st.C reduces excretion of remifentanil by 3%. There is no evidence of remifentanil removal during dialysis; the carboxylic metabolite is removed at approx. 30% during hemodialysis. In patients with T anemia_0,5 carboxylic acid, extends to 30 hours.

Hypersensitivity to remifentanil, other fentanyl derivatives or other ingredients of the preparation. The use of remifentanil as the only agent for anesthesia is contraindicated. Due to the content of Glycine, the drug is contraindicated for epidural and intrathecal use.

Remifentanil can only be used in departments fully equipped with equipment to monitor and support breathing and circulation in patients and administered only by people specially trained in the use of anesthetics, in the recognition and treatment of adverse reactions of strong opioids, including respiratory and cardiopulmonary resuscitation. The experience of these people should include providing airway patency and assisted ventilation. The use of the preparation in mechanically ventilated patients staying in the ICU for more than 3 days is not recommended. Due to the very fast termination of remifentanil, after 5-10 minutes after the end of the infusion, the anesthetic effect may end and there will be no residual effect. To prevent the occurrence of hyperalgesia and associated haemodynamic disturbances, the patient must receive alternative analgesics and sedatives early enough before completing the remifentanil infusion. In patients undergoing surgical procedures, after which postoperative pain is expected, analgesics should be administered prior to discontinuation of remifentanil. If other opioid medicines are administered as part of a changeover procedure for alternative painkillers, the benefits of providing adequate post-operative analgesia must always take into account the potential risk of respiratory depression. If discontinuation symptoms occur after sudden discontinuation of remifentanil, re-administration and gradual dose reduction are preferred. Muscle stiffness may occur during use, therefore a single injection should not last for less than 30 seconds.In the case of muscle stiffness, appropriate supportive treatment, including breathing assistance, should be applied depending on the clinical condition of the patient. Excessive muscle stiffness, occurring during the introduction of anesthesia, should be treated using neuromuscular blocking agents and / or an additional dose of anesthetics. Muscle stiffness observed with remifentanil as a painkiller can be treated by interrupting or decreasing the rate of infusion. After stopping the infusion, muscle stiffness subsides within a few minutes. Alternatively, a μ-opioid receptor antagonist may be administered. Special care should be taken in patients with impaired lung function and severe hepatic impairment - these patients may be slightly more sensitive to the effects of remifentanil on the respiratory center; these patients should be carefully monitored and the dose should be adjusted individually. In the case of respiratory depression, among others slow the remifentanil infusion by 50% or temporarily discontinue it. Remifentanil has not been shown to cause recurrent inhibition of the respiratory center even after prolonged administration. However, in the case of additional factors (eg unintentional single-dose administration or co-administration of opioids with a longer duration of action) respiratory depression occurring up to 50 min after discontinuation of remifentanil infusion was observed. Before moving the patient from the post-operative room, make sure that he regained full awareness and the ability to breathe effectively. If there is a decrease in pressure and bradycardia that may cause asystole and cardiac arrest, reduce the infusion rate of remifentanil or reduce the dose of concomitantly administered anesthetics, or use intravenous fluids, decongestants or anticholinergics, respectively. Patients who are debilitated, with a reduced volume of circulating blood and elderly patients may be more sensitive to the effects of remifentanil on the cardiovascular system. Chronic use of μ-opioid receptor agonists may result in the development of tolerance. Remifentanil may cause addiction.

The preparation should not be used in pregnant women, unless it is absolutely necessary. There is insufficient data to recommend the use of remifentanil during labor or Caesarean section. Remifentanil crosses the placenta. Fentanyl derivatives may cause respiratory depression in the child. There are no data on the excretion of remifentanil in human milk, however, fentanyl analogues are excreted in human milk. Therefore, caution should be exercised and breastfeeding mothers should be advised to discontinue breast-feeding 24 hours after administration of remifentanil.

Very common: skeletal muscle rigidity, hypotension, nausea, vomiting. Common: bradycardia, post-operative hypertension, acute respiratory depression, apnea, pruritus, postoperative shivering. Uncommon: hypoxia, constipation, postoperative pain. Rarely: sedation (when awakening from general anesthesia), patients receiving one or more anesthetics at the same time have reported hypersensitivity reactions (including anaphylaxis), asystole / cardiac arrest with prior bradycardia. Frequency unknown: addiction. After discontinuation of remifentanil, discontinuation symptoms such as tachycardia, hypertension and agitation were rare, especially after administration for more than 3 days.

General anesthesia. The administration of remifentanil must be individualized depending on the patient's response. Adults.Administration in manual infusion (MCI). Introduction to general anesthesia: 1 μg / kg in a single injection, the administration time should not be less than 30 s; continuous infusion: initial speed 0.5-1 μg / kg bw / min. Maintenance of general anesthesia in ventilated patients: with nitric oxide (66%) 0.5-1 μg remifentanil / kg body weight. in a single injection, continuous infusion is 0.4 μg / kg / min, range 0.1-2 μg / kg / min; with isoflurane (initial dose of 0.5 MAC) or propofol (initial dose 100 μg / kg / min) 0.5-1 μg / kg in a single injection, continuous infusion rate is 0.25 μg / kg / min, range 0.05-2 μg / kg / min.Introduction to anesthesia (induction). When entering anesthesia, remifentanil should be given with an anesthetic such as propofol, thiopental or isoflurane.Administration of remifentanil after the anesthetic reduces the incidence of muscle stiffness. Remifentanil can be infused at a rate of 0.5-1 μg / kg / min, preceded or not, by a single 1 μg / kg initial injection lasting not less than 30 s. A single injection is not necessary if endotracheal intubation performed later than 8-10 minutes after starting the remifentanil infusion.Maintenance of anesthesia in mechanically ventilated patients. After endotracheal intubation, the remifentanil infusion rate should be reduced according to the instructions given above, according to the method of anesthesia. Because the onset of remifentanil activity is rapid and its duration is short, the rate of administration during anesthesia can be adjusted by increasing the dose by 25-100% or by 25-50% reducing it every 2-5 min to achieve the desired μ-receptor response. opioid. In case of too shallow anesthesia, additional remifentanil injections may be administered every 2-5 min.Anesthesia of patients with their own breathing activity and with protected airway patency (e.g., larynx mask for inhalation anesthesia). For additional analgesia, the recommended initial infusion rate is 0.04 μg / kg / min, with adaptation depending on the desired effect. The infusion rate in the range of 0.025-0.1 μg / kg / min was investigated. Single injections of remifentanil are not recommended. Remifentanil should not be used as an analgesic during treatments during which the patient remains conscious or does not receive any respiratory support.Simultaneous use of other medicines. Remifentanil allows the use of fewer inhaled anesthetics or reduced doses of intravenous anesthetics and benzodiazepines. The doses of isoflurane, thiopental, propofol and temazepam were reduced by up to 75%.Recommendations for termination of drug administration in the immediate postoperative period. Within 5-10 minutes after the administration of remifentanil, no opioid activity can be detected. Patients in whom post-operative pain is expected, analgesics should be administered prior to completion of remifentanil infusion. It is necessary to ensure the time necessary to achieve the maximum therapeutic effect of a longer-acting analgesic. If the administration of a longer-acting analgesic does not reach the desired effect before the end of the operation, remifentanil should be continued in the immediate post-operative period to maintain analgesic effect until the maximum effect of a longer-acting analgesic is obtained. In patients with their own breathing activity, the initial infusion rate of remifentanil can be reduced to 0.1 μg / kg / min, and then it can be increased or decreased every 5 min by 0.025 μg / kg / min each time, to balance the analgesic effect and the severity of respiratory depression. In patients who have their own breathing activity, in the post-operative period, administration of remifentanil in single injections is not recommended in order to relieve pain.Administration of target controlled infusion (TCI) in the system. Introduction and maintenance of anesthesia in ventilated patients. Remifentanil should be used in conjunction with an intravenous or inhaled anesthetic. In combination with these agents, adequate analgesia can be achieved with a target concentration of remifenatanyl in the blood range of 3-8 ng / ml. In the case of surgical procedures associated with extremely strong pain stimulation, it may be necessary to apply a target blood concentration of 15 ng / ml. Remifentanil at the recommended doses significantly reduces the amount of anesthetic needed to maintain anesthesia. Therefore, isoflurane and propofol should be administered as recommended to avoid an increase in the effects of remifentanil on hypotension and bradycardia (see information above for administration in a manually controlled infusion). Remifentanil concentrations in the blood estimated using the Minto pharmacokinetic model for a male (40 years, 70 kg, 170 cm) and the corresponding infusion rates in a manually controlled infusion at steady state: infusion rate 0.05 μg / kg / min - remifentanil concentration in blood 1.3 ng / ml; 0.1 μg / kg / min - 2.6 ng / ml; 0.25 μg / kg / min - 6.3 ng / ml; 0.4 μg / kg / min - 10.4 ng / ml; 0.5 μg / kg / min - 12.6 ng / ml; 1.0 μg / kg / min - 25.2 ng / ml; 2.0 μg / kg / min - 50.5 ng / ml. There is insufficient data on the TCI system under anesthesia in spontaneously ventilated patients.Information on interruption or continuation of treatment in the immediate postoperative period. At the end of the surgical procedure, after the infusion has been completed in the target controlled infusion system or reduction of the target concentration, the patient's own respiratory function should return at a remifentanil concentration of 1-2 ng / ml. The analgesic effect obtained with long-acting analgesics should be obtained before the end of the surgical procedure. The use of remifentanil in the target controlled infusion system for the treatment of post-operative pain is not recommended. Children from 1 to 12 years. Co-administration of remifentanil with intravenous anesthetics used in the introduction of anesthesia is not recommended. The use of remifentanil in order to induce TCI anesthesia in patients aged 1-12 years is not recommended due to the lack of data for this patient population.Maintenance of anesthesia. Single injection: 1 μg / kg body weight, simultaneous anesthetic: halotan (initial dose 0.3 MAC), sevoflurane (initial dose 0.3 MAC) or isoflurane (initial dose 0.5 MAC). Continuous infusion: with halothane (initial dose 0.3 MAC), initial dose 0.25 μg remifentanil / kg / min, range 0.05-1.3 μg remifentanil / kg / min, with sevoflurane (initial dose 0.3 MAC), initial dose 0.25 μg / kg / min, range 0.05-0.9 μg / kg / min, with isoflurane (initial dose 0.5 MAC), initial dose 0, 25 μg / kg bw / min, range 0.06-0.9 μg / kg bw / min. If remifentanil is given as a single injection, it should last not less than 30 seconds. The treatment can be started no earlier than 5 minutes after the start of remifentanil, if it was not accompanied by a single injection. If you administer nitrous oxide alone (70%) with remifentanil, the infusion rate for maintaining anesthesia should be 0.4-3 μg / kg / min. Data from observations in adult patients indicate that the rate of 0.4 μg / kg / min may be the appropriate starting dose. The child's condition should be monitored and the dose adjusted to the depth of anesthesia required for surgery.Recommendations for dealing with patients in the immediate postoperative period. / Establishing alternative analgesia prior to completing remifentanil. Due to the rapid disappearance of action, no opioid activity can be detected within 5-10 minutes after the administration of remifentanil. For patients undergoing surgical procedures, after which postoperative pain is expected, analgesics should be administered before the end of the remifentanil infusion. Sufficient time should be allowed for the maximal therapeutic effect of a longer-acting analgesic. Newborns / infants (<1 year). There is limited experience from clinical studies regarding the use of remifentanil in this age group. The pharmacokinetics of remifentanil in children aged <1 year, taking into account the difference in body weight, are comparable to that seen in adults, but in the absence of sufficient clinical data, remifentanil is not recommended in this age group. There is limited clinical experience in the use of remifentanil under fully intravenous anesthesia in infants (TIVA), insufficient clinical data to make dose recommendations.Cardio. Administration in a manually adjustable infusion. Introduction to anesthesia: it is not recommended to administer remifentanil in a single injection, continuous infusion of 1 μg / kg / min. Maintenance of anesthesia in ventilated patients: with isoflurane (initial dose 0.4 MAC), 0.5-1 μg remifentanil / kg body weight. in a single injection, continuous infusion is 1 μg / kg / min, typical infusion rates 0.003-4 μg / kg / min; with propofol (initial dose 50 μg / kg / min), 0.5-1 μg remifentanil / kg body weight in a single injection, continuous infusion is 1 μg / kg / min, typical infusion rates 0.01-4.3 μg / kg / min. Continuation of analgesia after surgery, before extubation: remifentanil is not recommended for single injection, continuous infusion of 1 μg / kg / min, typical infusion rates of 0-1 μg / kg / min. Endotracheal intubation should be performed at least 5 minutes after commencement of remifentanil infusion. After intubation, if necessary, individual single remifentanil injections may be used.In high-risk cardiac patients, such as patients undergoing valvular surgery or patients with impaired left ventricular function, a single 0.5 μg / kg intravenous injection is not recommended. These recommendations also apply to patients under hypothermic conditions using extracorporeal circulation.Continuation of anesthesia with remifentanil in the post-operative period before the patient is extubated. During the transport of the patient to the surgical ward, it is recommended to continue administration of remifentanil in the last dose from the period of surgery. The level of analgesia and sedation should be closely monitored and the rate of remifentanil infusion should be adjusted to the patient's needs as soon as the patient arrives at the surgical ward.Introduction of alternative analgesia before remifentanil administration. Due to the very fast termination of remifentanil, there will be no residual opioid action 5-10 minutes after the end of the infusion. Approximately before the end of remifentanil administration, patients should be given alternative analgesics and sedatives, taking into account the time necessary for the therapeutic effect to occur. For this reason, it is recommended that the choice of painkiller drug (s), dose level and time of drug administration are pre-planned before disconnecting the patient from the ventilator.Tips on how to stop remifentanil. Due to the very rapid disappearance of remifentanil, after cardiac infusion a rise in blood pressure, chills and pain were observed in cardiac patients. Appropriate alternative analgesic therapy should be used prior to completion of remifentanil infusion. It is recommended that the remifentanil infusion be stopped by reducing the infusion rate by 25% at intervals of at least 10 minutes until the end of the infusion. Do not increase the infusion rate of remifentanil when disconnecting the patient from the ventilator, but only reduce the infusion rate by supplementing it with other painkillers. If hypertension and tachycardia occur, appropriate medication is recommended. When administering other opioid medicines that are part of alternative analgesia, the patient's condition should be closely monitored. The benefits of providing adequate analgesia must always take into account the potential risk of respiratory depression caused by these medications.Infusion in the target controlled infusion (TCI) system. Introduction and maintenance of anesthesia in a ventilated patient. In adult, ventilated patients, the targeted controlled infusion of remifentanil should be used in combination with an intravenous or inhaled anesthetic. In combination with these drugs, an appropriate analgesic effect during the introduction of anesthesia and cardiac surgery can generally be obtained when using target concentrations of remifentanil in the blood from the upper end of the range used in general surgical procedures. In clinical trials, blood levels of up to 20 ng / ml were used after adjusting the dose of remifentanil depending on the clinical response of the patient. Information on the concentrations of remifentanil in the blood obtained during manual infusion adjustment can be found in the section: "General anesthesia. Adults. "Recommendations for termination / continuation of administration in the immediate postoperative period. At the end of the surgical procedure, after the end of the targeted controlled infusion or reduction of the target concentration, the patient's own respiratory function should return at the concentrations of remifentanil in the range of 1-2 ng / ml. As with a manually controlled infusion, the analgesic effect obtained with long-acting analgesics should be obtained before the end of the surgical procedure. Due to the lack of sufficient data, remifentanil is not recommended for targeted infusion in the treatment of post-operative pain.Intensive care. Adults. Remifentanil can be used as a painkiller in mechanically ventilated patients who are in the ICU. If necessary, you should additionally use sedatives. It is not recommended to use it for more than 3 days. Due to the lack of data, the use of remifentanil in the TCI system in ICU patients is not recommended. The initial rate is 0.1 μg / kg / min (6 μg / kg / h) to 0.15 μg / kg / min (9 μg / kg / h), range 0.006 μg / kg mc./min (0.38 μg / kg / h) to 0.74 μg / kg / min (44.4 μg / kg / h). The infusion should be increased by 0.025 μg / kg / min (1.5 μg / kg / h) to achieve the desired level of analgesia and sedation. There should be at least a 5-minute interval between consecutive dose changes. The level of analgesia and sedation should be carefully monitored to properly adjust the remifentanil infusion rate.If the desired level of sedation is not achieved despite the remifentanil infusion at the rate of 0.2 μg / kg / min (12 μg / kg / h), it is recommended to start the infusion of a suitable sedative. The remifentanil infusion rate may be increased again by 0.025 μg / kg / min (1.5 μg / kg / h) if additional pain relief is required. Single doses of remifentanil are not recommended in ICU patients. Remifentanil reduces the amount of needed doses of concomitant sedatives. Recommended, if necessary, initial doses of sedatives: propofol - up to 0.5 mg / kg. in a single injection, infusion rate of 0.5 mg / kg / h; midazolam - up to 0.03 mg / kg in a single injection, the infusion rate is 0.03 mg / kg / h. In order to ensure an independent dosage of individual sedatives, they should not be administered to a solution containing remifentanil.Additional anesthesia of mechanically ventilated patients undergoing pain-relieving procedures such as tracheal suction, dressing changes or physiotherapy. It may be necessary to increase the speed of an already-run remifentanil infusion. It is recommended that remifentanil should be kept at a rate of at least 0.1 μg / kg / min (6 μg / kg / h) for at least 5 minutes before the beginning of the painful procedure. The dose can then be adjusted every 2-5 min, increasing it by 25-50%, expecting or responding to an increased demand for analgesia. During pain treatments remifentanil was administered with an average infusion rate of 0.25 μg / kg / min (15 μg / kg / h), and the maximum infusion rate was 0.74 μg / kg / min ( 44.4 μg / kg / h).Establishing an alternative analgesic treatment before completing the remifentanil infusion. Within 5-10 minutes after completing the infusion, regardless of its duration, there is no residual opioid effect. After the administration of remifentanil, consideration should be given to the development of tolerance and hyperalgesia. Therefore, before completing the remifentanil infusion, the patient must receive alternative analgesics and sedatives early enough, taking into account the time necessary for the therapeutic effect of these drugs to prevent the occurrence of hyperalgesia and associated haemodynamic disorders. It is recommended to choose the drug (s), dose and time of administration before completing the remifentanil infusion. Alternative pain treatment options are long-acting analgesics or painkillers administered intravenously or topically, the administration of which can be controlled by a medical professional or the patient himself.Recommendations for the remixing and completion of remifentanil infusion. It is recommended to gradually reduce the infusion rate of remifentanil for 1 hour until the patient is extensively diluted to achieve a dose of 0.1 μg / kg / min (6 μg / kg / h). After extubation, the infusion rate should be reduced by 25% at intervals of at least 10 minutes until the infusion is completed. When removing the patient from the ventilator, the infusion rate of remifentanil should not be increased, it should only be reduced and, if necessary, supplemented with other analgesics. When administering other opioid medicines that are part of alternative analgesia, the patient's condition should be closely monitored. The benefits of providing adequate analgesia must always take into account the potential risk of respiratory depression caused by these medications. Children. The use of remifentanil in children in the ICU is not recommended because there is no data available for this group of patients.Special groups of patients. Patients> 65 years. General anesthesia - the initial dose is half of the recommended dose in adults, then the dosage should be adjusted individually; dose adjustment refers to all stages of anesthesia, both the induction phase, the maintenance of anesthesia and the treatment of pain in the immediate postoperative period; when administering remifentanil in TCI, the initial target concentration should be 1.5-4 ng / ml, and then it should be adjusted individually. Anesthesia in cardiac surgery, intensive therapy - no reduction of the initial dose is required.Patients with obesity. In the case of a controlled infusion, it is recommended to reduce the dose of remifentanil and adjust to their proper body weight. When calculating lean body mass (LBM) used in the Minto model, the LBM value is often undervalued in women with BMI> 35 kg / m² and in men with BMI> 40 kg / m². To avoid underdosing in these patients, the dose of remifentanil administered in TCI should be adjusted individually.Patients with impaired renal function. There is no need to adjust the dose, also in patients who are in the ICU, but in these patients the clearance of the carboxylic acid is reduced.Patients with impaired liver function. It is not necessary to change the initial dose. Patients with severe hepatic insufficiency should be carefully monitored and the dose of remifentanil should be adjusted individually.Patients undergoing neurosurgical procedures. There is no need for special recommendations.Patients from group III / IV ASA. General anesthesia - caution should be exercised when administering, reducing the starting dose and then adjusting the infusion rate to the patient's individual response; due to insufficient data, there are no recommendations for use in children; in TCI, the initial target concentration should be 1.5-4 ng / ml, and then it should be adjusted individually.Anesthesia in cardiac surgery. A reduction of the initial dose is not required. Detailed dosing rules are included in the Summary of Product Characteristics.