1. Name Of The Medicinal Product
Remifentanil 5 mg powder for concentrate for solution for injection/infusion
2. Qualitative And Quantitative Composition
Remifentanil 5 mg powder for concentrate for solution for injection/infusion:
1 vial contains 5 mg remifentanil (as remifentanil hydrochloride).
After reconstitution the solution contains 1 mg/ml remifentanil (as hydrochloride), if prepared as recommended (see section 6.6)
Excipients: sodium 1.15 mg
3. Pharmaceutical Form
Powder for concentrate for solution for injection/infusion
Lyophilized white to slightly yellow cake or powdery mass.
4. Clinical Particulars
4.1 Therapeutic Indications
Remifentanil is indicated as an analgesic agent for use during induction and/or maintenance of general anaesthesia.
Remifentanil is indicated for provision of analgesia in mechanically ventilated intensive care patients of 18 years of age and older.
4.2 Posology And Method Of Administration
Remifentanil should be administered only in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function and by persons specifically trained in the use of anaesthetic drugs and the recognition and management of the expected adverse effects of potent opioids, including respiratory and cardiac resuscitation. Such training must include the establishment and maintenance of a patent airway and assisted ventilation.
Continuous infusions of remifentanil must be administered by a calibrated infusion device into a fast flowing IV line or via a dedicated IV line. This infusion line should be connected at, or close to, the venous cannula to minimise the potential dead space (see section 6.6 for additional information, including tables with examples of infusion rates by body weight to help titrate remifentanil to the patient's anaesthetic needs). Care should be taken to avoid obstruction or disconnection of infusion lines and to adequately clear the lines to remove residual remifentanil after use (see section 4.4). IV lines/infusion system should be removed after cessation of use to avoid inadvertent administration.
Remifentanil may be given by target-controlled infusion (TCI) with an approved infusion device incorporating the Minto pharmacokinetic model with covariates for age and lean body mass (LBM).
Congestion of the infusion drips or tearing off should be avoided, and the infusion drips should be sufficiently rinsed in order to remove residual Remifentanil after discontinuation of medication (see also section 4.4).
Remifentanil is for intravenous use only and must not be administered by epidural or intrathecal injection (see section 4.3).
Dilution
Remifentanil should not be administered without further dilution after reconstitution of the lyophilized powder. See section 6.3 for storage conditions and section 6.6 for recommended diluents and instructions on reconstitution / dilution of the product before administration.
For manually-controlled infusion [Invented name] can be diluted to concentrations of 20 to 250 micrograms /ml (50 micrograms /ml is the recommended dilution for adults and 20 to 25 micrograms /ml for paediatric patients aged 1 year and over).
For TCI the recommended dilution of Remifentanil is 20 to 50 micrograms /ml.
General Anaesthesia
The administration of Remifentanil must be individualised based on the patient's response.
Adults
Administration by manually-controlled infusion (MCI)
DOSING GUIDELINES FOR ADULTS
|
| ||
|
| ||
|
|
| |
| |||
|
|
|
|
|
|
|
|
|
|
|
|
When given by bolus injection at induction Remifentanil should be administered over not less than 30 seconds.
At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended above to avoid an increase of haemodynamic effects (hypotension and bradycardia) of remifentanil.
No data are available for dosage recommendations for simultaneous use of other hypnotics other than those listed in the table with remifentanil.
Induction of anaesthesia
Remifentanil should be co-administered with a hypnotic agent, such as propofol, thiopentone, or isoflurane, for the induction of anaesthesia. Administering Remifentanil after a hypnotic agent will reduce the incidence of muscle rigidity. Remifentanil can be administered at an infusion rate of 0.5 to 1 micrograms /kg/min, with or without an initial bolus injection of 1 micrograms /kg given over not less than 30 seconds. If endotracheal intubation is to occur more than 8 to 10 minutes after the start of the infusion of [Invented name], then a bolus injection is not necessary.
Maintenance of anaesthesia in ventilated patients
After endotracheal intubation, the infusion rate of Remifentanil should be decreased, according to anaesthetic technique, as indicated in the above table. Due to the fast onset and short duration of action of remifentanil, the rate of administration during anaesthesia can be titrated upward in 25% to 100% increments or downward in 25% to 50% decrements, every 2 to 5 minutes to attain the desired level of μ-opioid response. In response to light anaesthesia, supplemental bolus injections may be administered every 2 to 5 minutes.
Anaesthesia in spontaneously breathing patients
In spontaneously breathing anaesthetised patients with a secured airway respiratory depression is likely to occur. Therefore attention must be given to respiratory effects eventually combined with muscular rigidity. Special care is needed to adjust the dose to the patient requirements and ventilatory support may be required. Adequate facilities should be available for monitoring of patients administered remifentanil. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression (intubation equipment must be available) and/or muscle rigidity (for more information see section 4.4).
The recommended starting infusion rate for supplemental analgesia in spontaneously breathing anaesthetised patients is 0.04 μg/kg/min with titration to effect. A range of infusion rates from 0.025 to 0.1 μg/kg/min has been studied.
Bolus injections are not recommended in spontaneously breathing anaesthetised patients.
Remifentanil should not be used as an analgesic in procedures where patients remain conscious or do not receive any airway support during the procedure.
Concomitant medication
Remifentanil decreases the amounts or doses of inhalational anaesthetics, hypnotics and benzodiazepines required for anaesthesia (see section 4.5).
Doses of the following agents used in anaesthesia: isoflurane, thiopentone, propofol and temazepam have been reduced by up to 75 % when used concurrently with remifentanil.
Guidelines for discontinuation/continuation during immediate postoperative period
Due to the very rapid offset of action of remifentanil no residual opioid activity will be present within 5 to 10 minutes after discontinuation. For those patients undergoing surgical procedures where post-operative pain is anticipated, analgesics should be administered prior to discontinuation of remifentanil. Sufficient time must be allowed to reach the maximum effect of the longer acting analgesic. The choice of analgesic should be appropriate for the patient's surgical procedure and the level of post-operative care.
In case the longer acting analgesic has not reached the appropriate effect before the end of surgery, the administration of remifentanil can be continued to maintain analgesia during immediate postoperative period until the longer acting analgesic has reached the maximum effect.
If remifentanil is continued post-procedural, it should only be used in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function, under the close supervision of persons specifically trained in the recognition and management of the respiratory effects of potent opioids.
Furthermore it is recommended that patients should be closely monitored post-operatively for pain, hypotension and bradycardia.
Further information about the administration in mechanically ventilated intensive care patients is given in section 4.2.
In spontaneously breathing patients the initial infusion rate of remifentanil may be decreased to 0.1 µg/kg/min and thereafter can be increased or decreased every 5 min in steps of 0.025 µg/kg/min to balance the extent of analgesia against the degree of respiratory depression.
In spontaneously breathing patients bolus doses for analgesia are not recommended during postoperative period.
Administration by Target-Controlled Infusion (TCI)
Induction and maintenance of anaesthesia in ventilated patients
Remifentanil TCI should be used in association with an intravenous or inhalational hypnotic agent during the induction and maintenance of anaesthesia in ventilated adult patients (see table 1 above for manually controlled infusion). In association with these agents, adequate analgesia for induction of anaesthesia and surgery can generally be achieved with target blood remifentanil concentrations ranging from 3 to 8 ng/ml. Remifentanil should be titrated to individual patient response. For particularly stimulating surgical procedures target blood concentrations up to 15 ng/ml may be required.
At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended to avoid an increase of haemodynamic effects (hypotension and bradycardia) of remifentanil (see table 1 above for manually controlled infusion).
The following table provides the equivalent blood remifentanil concentration using a TCI approach for various manually controlled infusion rates at steady state:
Remifentanil blood concentrations (nanograms/ml) estimated using the Minto (1997) pharmacokinetic model in a 70 kg, 170 cm, 40 year old male patient for various manually controlled infusion rates (micrograms/kg/min) at steady state
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
As there are insufficient data, the administration of remifentanil by TCI for spontaneous ventilation anaesthesia is not recommended.
Guidelines for discontinuation/continuation into the immediate post-operative period
At the end of surgery when the TCI infusion is stopped or the target concentration reduced, spontaneous respiration is likely to return at calculated remifentanil concentrations in the region of 1 to 2 ng/ml. As with manually controlled infusion, post-operative analgesia should be established before the end of surgery with longer acting analgesics (see also Guidelines for discontinuation / continuation during immediate postoperative period in section above for Manually Controlled Infusion).
As there are insufficient data, the administration of [Invented name] by TCI for the management of post-operative analgesia is not recommended.
Paediatric patients (1 to12 years of age)
Co-administration of remifentanil with induction agents has not been studied. The use of remifentanil for induction of anaesthesia by TCI in patients aged 1 to12 years is not recommended as there are no data available in this patient population.
Maintenance of anaesthesia
The following doses of remifentanil (see table) are recommended for maintenance of anaesthesia:
DOSING GUIDELINES FOR PAEDIATRIC PATIENTS (1 to12 years of age)
|
|
| |
|
| ||
|
|
|
|
|
|
|
|
|
|
|
|
*co-administered with nitrous oxide/oxygen in a ratio of 2:1
When given by bolus injection, Remifentanil should be administered over not less than 30 seconds. Surgery should not commence until at least 5 minutes after the start of the Remifentanil infusion, if a simultaneous bolus dose has not been given.
For exclusive administration of nitrous oxide (70 %) and Remifentanil infusion rates for maintenance of anaesthesia should be between 0.4 und 3 micrograms/kg/min. Data gained from adults suggest that 0.4 micrograms/kg/min may be a convenient initial dose although specific studies are lacking.
Paediatric patients should be monitored and the dose titrated to the depth of analgesia appropriate for the surgical procedure.
Concomitant medication
At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane, halothane and sevoflurane should be administered as recommended above to avoid an increase of haemodynamic effects (hypotension and bradycardia) of remifentanil. No data are available for dosage recommendations for simultaneous use of other hypnotics with remifentanil (see in section above: Administration by Manually Controlled Infusion (MCI), Concomitant medication).
Guidelines for patient management in the immediate post-operative period
Establishment of alternative analgesia prior to discontinuation of Remifentanil:
Due to the very rapid offset of action of remifentanil, no residual activity will be present within 5 to 10 minutes after discontinuation. For those patients undergoing surgical procedures where post-operative pain is anticipated, analgesics should be administered prior to discontinuation of remifentanil. Sufficient time must be allowed to reach the therapeutic effect of the longer acting analgesic. The choice of agent(s), the dose and the time of administration should be planned in advance and individually tailored to be appropriate for the patient's surgical procedure and the level of post-operative care anticipated (see section 4.4).
Neonates/infants (aged less than 1 year):
The pharmacokinetic profile of remifentanil in neonates and infants (aged less than 1 year) is comparable to that seen in adults after correction for body weight differences. However, because there are insufficient clinical data, the administration of remifentanil is not recommended for this age group.
Special Patient groups
For dosage recommendations for special patient groups (elderly and obese patients, renally and hepatically impaired patients, patients undergoing neurosurgery and ASA III/IV patients; see section 4.2).
Cardiac Surgery
Administration by Manually-Controlled Infusion
For dosage recommendations in patients undergoing cardiac surgery see table below:
DOSING GUIDELINES FOR CARDIAC ANAESTHESIA
|
|
| |
|
| ||
|
|
|
|
| |||
|
|
|
|
|
|
|
|
|
|
|
|
Induction of anaesthesia
After administration of hypnotic to achieve loss of consciousness, Remifentanil should be administered at an initial infusion rate of 1 micrograms /kg/min. The use of bolus injections of Remifentanil during induction in cardiac surgical patients is not recommended. Endotracheal intubation should not occur until at least 5 minutes after the start of the infusion.
Maintenance period of anaesthesia
After endotracheal intubation the infusion rate of Remifentanil should be titrated according to the patient need. Supplemental bolus doses may also be administered as required. High risk cardiac patients, such as those undergoing valve surgery or with poor left ventricular function, should be administered a maximum bolus dose of 0.5 micrograms/kg.
These dosing recommendations also apply during hypothermic cardiopulmonary bypass (see section 5.2).
Concomitant medication
At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended above to avoid an increase of haemodynamic effects (hypotension and bradycardia) of remifentanil. No data are available for dosage recommendations for simultaneous use of other hypnotics with remifentanil (see in section above: Administration by Manually Controlled Infusion (MCI), Concomitant medication).
Guidelines for postoperative supply of patient
Continuation of Remifentanil post-operatively to provide analgesia prior to extubation
It is recommended that the infusion of Remifentanil is maintained at the final intra-operative rate during transfer of patients to the post-operative care area. The patient's level of analgesia and sedation should be closely monitored and the Remifentanil infusion rate adjusted to meet the individual patient's requirements (see Intensive care, below, for further information on management of intensive care patients.
Establishment of alternative analgesia prior to discontinuation of Remifentanil
Due to the very rapid offset of action of remifentanil, no residual opioid activity will be present within 5 to 10 minutes after discontinuation. Prior to discontinuation of Remifentanil, patients must be given alternative analgesic and sedative agents at a sufficient time in advance to allow the therapeutic effects of these agents to become established. It is therefore recommended that the choice of agent(s), the dose and the time of administration are planned, before weaning the patient from the ventilator.
Guidelines for discontinuation of Remifentanil
Due to the very rapid offset of action of Remifentanil, hypertension, shivering and aches have been reported in cardiac patients immediately following discontinuation of Remifentanil (see section 4.8 Undesirable effects). To minimise the risk of these events, adequate alternative analgesia must be established (as described above), before the Remifentanil infusion is discontinued. The infusion rate should be reduced by 25% decrements in at least 10-minute intervals until the infusion is discontinued.
During weaning from the ventilator the Remifentanil infusion should not be increased and only down titration should occur, supplemented as required with alternative analgesics. Haemodynamic changes such as hypertension and tachycardia should be treated with alternative agents as appropriate.
When other opioid agents are administered as part of the regimen for transition to alternative analgesia, the patient must be carefully monitored. The benefit of providing adequate post-operative analgesia must always be balanced against the potential risk of respiratory depression with these agents.
Administration by Target-Controlled Infusion
Induction and maintenance of anaesthesia in ventilated patients
Remifentanil TCI should be used in association with an intravenous or inhalational hypnotic agent during the induction and maintenance of anaesthesia in ventilated adult patients (see the table in section 4.2 under Cardiac surgery/Administration by Manually-Controlled Infusion/Dosing guidelines for cardiac anaesthesia). In association with these agents, adequate analgesia for cardiac surgery is generally achieved at the higher end of the range of target blood remifentanil concentrations used for general surgical procedures. Following titration of remifentanil to individual patient response, blood concentrations as high as 20 nanograms /ml have been achieved in clinical studies.
At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended above to avoid an increase of haemodynamic effects (hypotension and bradycardia) of remifentanil (see table in section 4.2 under Cardiac surgery/Administration by Manually-Controlled Infusion/Dosing guidelines for cardiac anaesthesia).
For information on blood remifentanil concentrations achieved with manually controlled infusion see Table 6
Guidelines for discontinuation/continuation into the immediate post-operative period
At the end of surgery when the TCI infusion is stopped or the target concentration reduced, spontaneous respiration is likely to return at calculated remifentanil concentrations in the range of 1 to 2 nanograms /ml. As with manually-controlled infusion, post-operative analgesia should be established before the end of surgery with longer acting analgesics (see section 4.2 under Cardiac surgery/Administration by Manually-Controlled Infusion/Guidelines for discontinuation of Remifentanil.
As there are insufficient data, the administration of Remifentanil by TCI for the management of post-operative analgesia is not recommended.
Intensive Care – Adults
Remifentanil can be used in mechanically ventilated intensive care patients. If required, additionally sedating drugs should be applied.
Remifentanil has been studied in intensive care patients in well controlled clinical trials for up to three days. As patients were not studied beyond three days, no evidence of safety and efficacy for longer treatment has been established. Therefore, a usage longer than three days is not recommended.
Due to the lack of data the administration of remifentanil by TCI is not recommended for ICU patients.
In adults, it is recommended that Remifentanil is initiated at an infusion rate of 0.1 micrograms /kg/min (6 micrograms /kg/h) to 0.15 micrograms /kg/min (9 micrograms /kg/h). The infusion rate should be titrated in increments of 0.025 micrograms /kg/min (1.5 micrograms /kg/h) to achieve the desired level of analgesia. A period of at least 5 minutes should be allowed between dose adjustments. The patient should be carefully monitored, regularly reassessed and the Remifentanil infusion rate adjusted accordingly. If an infusion rate of 0.2 micrograms /kg/min (12 micrograms /kg/h) is reached and the desired level of sedation is not achieved, it is recommended that dosing with an appropriate sedative agent is initiated (see below). The dose of the sedative agent should be titrated to obtain the desired level of sedation. Further increases to the [Invented name] infusion rate in increments of 0.025 micrograms /kg/min (1.5 micrograms /kg/h) may be made if additional analgesia is required.
The following table summarises the starting infusion rates and typical dose range for provision of analgesia in individual patients:
DOSING GUIDELINES FOR USE OF REMIFENTANIL WITHIN THE INTENSIVE CARE SETTING
| |
|
|
|
|
Bolus doses of Remifentanil are not recommended in the intensive care setting.
The use of Remifentanil will reduce the dosage requirement of any concomitant sedative agents. Typical starting doses for sedative agents, if required, are given below.
RECOMMENDED STARTING DOSE OF SEDATIVE AGENTS, IF REQUIRED
|
|
|
|
|
|
|
|
|
To allow separate titration of the respective agents, sedative agents should not be administered as an admixture.
Additional analgesia for ventilated patients undergoing painful procedures
An increase in the existing Remifentanil infusion rate may be required to provide additional analgesic cover for ventilated patients undergoing stimulating and/or painful procedures such as endotracheal suctioning, wound dressing and physiotherapy. It is recommended that a Remifentanil infusion rate of at least 0.1 micrograms /kg/min (6 micrograms /kg/h) is maintained for at least 5 minutes prior to the start of the stimulating procedure. Further dose adjustments may be made every 2 to 5 minutes in increments of 25%-50% in anticipation of, or in response to, additional requirement for analgesia. A mean infusion rate of 0.25 micrograms /kg/min (15 micrograms /kg/h), maximum 0.75 micrograms kg/min (44,4 micrograms /kg/h), has been administered for provision of additional analgesia during stimulating procedures.
Establishment of alternative analgesia prior to discontinuation of Remifentanil
Due to the very rapid offset of action of remifentanil, no residual opioid activity will be present within 5 to 10 minutes after discontinuation regardless of the duration of infusion. After administration of remifentanil the potential for the development of tolerance and hyperalgesia should be attended. Therefore, prior to discontinuation of remifentanil, patients must be given alternative analgesic and sedative agents at a sufficient time in advance to allow the therapeutic effects of these agents to become established and to prevent hyperalgesia and concomitant haemodynamic changes. It is therefore recommended that the choice of agent(s), the dose and the time of administration are planned prior to discontinuation of remifentanil. Long acting analgetics or intravenous or local analgetics, which can be controlled by the health care staff or the patient are alternative options for analgesia and should be chosen carefully according to the patients needs.
Prolonged administration of µ-opioid agonists may induce development of tolerance.
Guidelines for extubation and discontinuation of Remifentanil
In order to ensure a smooth emergence from a remifentanil-based regimen it is recommended that the infusion rate of Remifentanil is titrated gradually to 0.1 micrograms /kg/min (6 micrograms /kg/h) over a period up to 1 hour prior to extubation.
Following extubation, the infusion rate should be reduced by 25% decrements in at least 10-minute intervals until the infusion is discontinued. During weaning from the ventilator the Remifentanil infusion should not be increased and only down titration should occur, supplemented as required with alternative analgesics.
Upon discontinuation of Remifentanil, the IV cannula should be cleared or removed to prevent subsequent inadvertent administration.
When other opioid agents are administered as part of the regimen for transition to alternative analgesia, the patient must be carefully monitored. The benefit of providing adequate analgesia must always be balanced against the potential risk of respiratory depression.
The following tables 1-5 give guidelines for infusion rates of Remifentanil for manually-controlled infusion:
Table 1: Remifentanil – Infusion rates (ml/kg/h)
|
| |||
|
|
|
| |
|
|
|
|
|
Table 2: Remifentanil – Infusion rates (ml/h) for a 20 micrograms /ml solution
|
| ||||||
|
|
|
|
|
|
| |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
No comments:
Post a Comment