Posology : מינונים

4.2      Posology and method of administration

Ultiva 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 Ultiva 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 and primed, 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 Ultiva 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 Ultiva after use (see section 4.4).
Ultiva is for intravenous use only and must not be administered by epidural or intrathecal injection (see section 4.3).

Dilution

Ultiva may be further diluted after reconstitution (see sections 6.4 and 6.6 for storage conditions of the reconstituted/diluted product and the recommended diluents).
For manually-controlled infusion Ultiva can be diluted to concentrations of 20 to 250 micrograms/ml (50 micrograms/ml is the recommended dilution for adults).

(See section 6.6 for additional information, including tables to help titrate Ultiva to the patient's anaesthetic needs).

4.2.1      General Anaesthesia

The administration of Ultiva must be individualised based on the patient's response. Specific dosing guidelines for patients undergoing cardiac surgery are provided in section 4.2.2 below.

4.2.1.1.         Adults

Administration by Manually-Controlled Infusion
The following table summarises the starting infusion rates and dose range: 
DOSING GUIDELINES FOR ADULTS

CONTINUOUS INFUSION
BOLUS INJECTION
INDICATION                                                   (micrograms/kg/min) (micrograms/kg)
Starting Rate   Range
1(give over not less than
Induction of anaesthesia                                     0.5 to 1           _ 30 seconds)
Maintenance of anaesthesia in ventilated patients
• Nitrous oxide (66%)       0.5 to 1                         0.4                0.1 to 2
• Isoflurane (starting dose 0.5 to 1                         0.25               0.05 to 2
0.5 MAC)
• Propofol (starting dose
0.5 to 1                         0.25               0.05 to 2
100 micrograms/kg/min)

When given by bolus injection at induction Ultiva 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 such as hypotension and bradycardia (see Concomitant medication below).

Induction of anaesthesia: Ultiva should be administered with a standard dose of an hypnotic agent, such as propofol, thiopentone, or isoflurane, for the induction of anaesthesia. Administering Ultiva after an hypnotic agent will reduce the incidence of muscle rigidity. Ultiva can be administered at an infusion rate of 0.5 to 1 micrograms/kg/min, with or without an initial slow bolus injection of 1 microgram/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 Ultiva, then a bolus injection is not necessary.

Maintenance of anaesthesia in ventilated patients: After endotracheal intubation, the infusion rate of Ultiva should be decreased, according to anaesthetic technique, as indicated in the above table. Due to the fast onset and short duration of action of Ultiva, 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 mu-opioid response.
In response to light anaesthesia, supplemental slow bolus injections may be administered every 2 to 5 minutes.

Anaesthesia in spontaneously breathing anaesthetised patients with a secured airway (e.g. laryngeal mask anaesthesia): In spontaneously breathing anaesthetised patients with a secured airway respiratory depression is likely to occur. Special care is needed to adjust the dose to the patient requirements and ventilatory support may be required. The recommended starting infusion rate for supplemental analgesia in spontaneously breathing anaesthetised patients is 0.04 micrograms/kg/min with titration to effect. A range of infusion rates from 0.025 to 0.1 micrograms/kg/min has been studied. Bolus injections are not recommended in spontaneously breathing anaesthetised patients.

Ultiva 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: Ultiva decreases the amounts or doses of inhaled 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 into the immediate post- operative period: Due to the very rapid offset of action of Ultiva 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 Ultiva.
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.

Care should be taken to avoid inadvertent administration of Ultiva remaining in IV lines and cannulae (see section 4.4).

In the event that longer acting analgesia has not been established prior to the end of surgery, Ultiva may need to be continued to maintain analgesia during the immediate post-operative period until longer acting analgesia has reached its maximum effect.

In ventilated patients, the infusion rate should continue to be titrated to effect.

Guidance on provision of analgesia and sedation in mechanically ventilated intensive care patients is provided in section 4.2.3 below.

In patients who are breathing spontaneously, the infusion rate of Ultiva should initially be decreased to a rate of 0.1 micrograms/kg/min. The infusion rate may then be increased or decreased by not greater than 0.025 micrograms/kg/min every five minutes, to balance the patient’s level of analgesia and respiratory rate.
Ultiva 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.

The use of bolus injections of Ultiva to treat pain during the post-operative period is not recommended in patients who are breathing spontaneously.

4.2.1.2 Paediatric patients (2 to12 years of age)

Induction of anaesthesia: There are insufficient data to make a dosage recommendation.

4.2.2   Cardiac anaesthesia

Administration by Manually-Controlled Infusion
DOSING GUIDELINES FOR CARDIAC ANAESTHESIA

CONTINUOUS INFUSION
BOLUS INJECTION
INDICATION                                                       (micrograms/kg/min) (micrograms/kg)
Starting Rate   Range
Induction of anaesthesia              Not recommended            1               _ Maintenance of anaesthesia in ventilated patients:
• Isoflurane
0.5 to 1                   1                     0.003 to 4
(starting dose 0.4 MAC)
• Propofol
(Starting dose 50                     0.5 to 1                   1                     0.01 to 4.3 micrograms/kg/min)
Continuation of post-operative        Not recommended            1                     0 to 1 
analgesia, prior to extubation

Induction period of anaesthesia: After administration of hypnotic to achieve loss of consciousness, Ultiva should be administered at an initial infusion rate of 1 microgram/kg/min. The use of bolus injections of Ultiva 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 Ultiva can be titrated upward in 25% to 100% increments, or downward in 25% to 50% decrements, every 2 to 5 minutes according to patient need.
Supplemental slow bolus doses, administered over not less than 30 seconds, may also be given every 2 to 5 minutes as required. High risk cardiac patients, such as those with poor ventricular function or undergoing valve surgery, 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 excessive depth of anaesthesia. No data are available for dosage recommendations for simultaneous use of other hypnotics other than those listed in the table with remifentanil (see section 4.2.1.1 Adults - Concomitant medication).


Guidelines for post-operative patient management
Continuation of Ultiva post-operatively to provide analgesia prior to weaning for extubation: It is recommended that the infusion of Ultiva should be maintained at the final intra-operative rate during transfer of patients to the post- operative care area. Upon arrival into this area, the patient's level of analgesia and sedation should be closely monitored and the Ultiva infusion rate adjusted to meet the individual patient's requirements (see section 4.2.3 for further information on management of intensive care patients).

Establishment of alternative analgesia prior to discontinuation of Ultiva: Due to the very rapid offset of action of Ultiva, no residual opioid activity will be present within 5 to 10 minutes after discontinuation. Prior to discontinuation of Ultiva, 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 Ultiva: Due to the very rapid offset of action of Ultiva, hypertension, shivering and aches have been reported in cardiac patients immediately following discontinuation of Ultiva (see section 4.8). To minimise the risk of these occurring, adequate alternative analgesia must be established (as described above), before the Ultiva 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 Ultiva 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.

Paediatric patients

There are insufficient data to make a dosage recommendation for use during cardiac surgery.

4.2.3   Use in Intensive Care

Ultiva can be used for the provision of analgesia in mechanically ventilated intensive care patients. Sedative agents should be added as appropriate.
Ultiva has been studied in mechanically ventilated 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, the use of Ultiva is not recommended for a duration of treatment greater than 3 days.

In adults, it is recommended that Ultiva 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 sedation and analgesia. A period of at least 5 minutes should be allowed between dose adjustments. The level of sedation and analgesia should be carefully monitored, regularly reassessed and the Ultiva 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 sedative agent should be titrated to obtain the desired level of sedation. Further increases to the Ultiva 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 and sedation in individual patients:

DOSING GUIDELINES FOR USE OF ULTIVA WITHIN THE INTENSIVE
CARE SETTING

CONTINUOUS INFUSION micrograms/kg/min (micrograms/kg/h)
Starting Rate                    Range
0.1 (6) to 0.15 (9)              0.006 (0.36) to 0.74 (44.4)
Bolus doses of Ultiva are not recommended in the intensive care setting.

The use of Ultiva 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

Sedative Agent           Bolus (mg/kg)                    Infusion (mg/kg/h) Propofol                 Up to 0.5                        0.5
Midazolam                Up to 0.03                       0.03

To allow separate titration of the respective agents, sedative agents should not be prepared as one mixture in the same infusion bag.

Additional analgesia for ventilated patients undergoing stimulating procedures: An increase in the existing Ultiva 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 an Ultiva infusion rate of at least 0.1 micrograms/kg/min (6 micrograms/kg/h) should be 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 (45 micrograms/kg/h), has been administered for provision of additional analgesia during stimulating procedures.

Establishment of alternative analgesia prior to discontinuation of Ultiva: Due to the very rapid offset of action of Ultiva, no residual opioid activity will be present within 5 to 10 minutes after discontinuation regardless of the duration of infusion. Following administration of Ultiva, the possibility of tolerance and hyperalgesia should be considered. Therefore, prior to discontinuation of Ultiva, patients must be given alternative analgesic and sedative agents to prevent hyperalgesia and associated haemodynamic changes. These agents must be given at a sufficient time in advance to allow the therapeutic effects of these agents to become established. The range of options for analgesia includes long acting oral, intravenous, or regional analgesics controlled by the nurse or the patient. These techniques should always be titrated to individual patient needs as the infusion of Ultiva is reduced. It is recommended that the choice of agent(s), the dose, and the time of administration are planned prior to discontinuation of Ultiva.

There is a potential for the development of tolerance with time during prolonged administration of mu-opioid agonists.

Guidelines for extubation and discontinuation of Ultiva: In order to ensure a smooth emergence from an Ultiva-based regimen it is recommended that the infusion rate of Ultiva is titrated in stages 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 Ultiva infusion should not be increased and only down titration should occur, supplemented as required with alternative analgesics.
Upon discontinuation of Ultiva, 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.

4.2.3.1 Paediatric intensive care patients

The use of remifentanil in intensive care patients under the age of 18 years is not recommended as there are no data available in this patient population.

4.2.3.2        Renally-impaired intensive care patients

No adjustments to the doses recommended above are necessary in renally- impaired patients, including those undergoing renal replacement therapy; however the clearance of the carboxylic acid metabolite is reduced in patients with renal impairment (see section 5.2).

4.2.4          Special patient populations

4.2.4.1        Elderly (over 65 years of age)
General anaesthesia: The initial starting dose of remifentanil administered to patients over 65 should be half the recommended adult dose and then shall be titrated to individual patient need as an increased sensitivity to the pharmacological effects of remifentanil has been seen in this patient population.
This dose adjustment applies to use in all phases of anaesthesia including induction, maintenance, and immediate post-operative analgesia.

Cardiac anaesthesia: No initial dose reduction is required (see section 4.2.2.).

Intensive Care: No initial dose reduction is required (see section 4.2.3.).
4.2.4.2        Obese patients

For manually-controlled infusion it is recommended that for obese patients the dosage of Ultiva should be reduced and based upon ideal body weight as the clearance and volume of distribution of remifentanil are better correlated with ideal body weight than actual body weight.


4.2.4.3        Renal impairment
On the basis of investigations carried out to date, a dose adjustment in patients with impaired renal function, including intensive care patients, is not necessary.


      4.2.4.4         Hepatic impairment
Studies carried out with a limited number of patients with impaired liver function, do not justify any special dosage recommendations. However, patients with severe hepatic impairment may be slightly more sensitive to the respiratory depressant effects of remifentanil (see section 4.4). These patients shall be closely monitored and the dose of remifentanil shall be titrated to individual patient need.

4.2.4.5        Neurosurgery

Limited clinical experience in patients undergoing neurosurgery has shown that no special dosage recommendations are required.

4.2.4.6        ASA III/IV patients

General anaesthesia: As the haemodynamic effects of potent opioids can be expected to be more pronounced in ASA III/IV patients, caution should be exercised in the administration of Ultiva in this population. Initial dosage reduction and subsequent titration to effect is therefore recommended. In paediatric patients, there are insufficient data to make a dosage recommendation.

Cardiac anaesthesia: No initial dose reduction is required (see section 4.2.2).