ULTIVA Powder for concentrate for solution for infusion Ref.[8163] Active ingredients: Remifentanil

Ultiva shall be administered in hospitals 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 (IV) 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 section 6.3 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 and 20 to 25 micrograms/ml for paediatric patients aged 1 year and over).

General Anaesthesia

The administration of Ultiva must be individualised based on the patient’s response.

Adults

The following table summarises the starting injection/infusion rates and dose range:

Dosing guidelines for adults:

When given by slow bolus injection at induction Ultiva shall be administered over not less than 30 seconds.

At the doses recommended above, Ultiva significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended above and below to avoid an increase of haemodynamic effects such as hypotension and bradycardia (see Concomitant medication).

No data are available for dosage recommendations for simultaneous use of other hypnotics other than those listed in the table with Ultiva.

Induction of anaesthesia

Ultiva should be administered with a reduced dose of hypnotic agent, such as propofol, thiopentone, or isoflurane, for the induction of anaesthesia. 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 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 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, over not less than 30 seconds may be administered every 2 to 5 minutes.

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 Ultiva.

Guidelines for discontinuation

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.

Guidance on use in mechanically ventilated intensive care patients is provided in section 4.2.3.

Paediatric patients (1 to 12 years of age)

Co-administration of Ultiva and an intravenous anaesthetic agent for induction of anaesthesia has not been studied in detail and is therefore not recommended.

The following doses of Ultiva are recommended for maintenance of anaesthesia:

Dosing guidelines for maintenance of anaesthesia in paediatric patients (1 to 12 years of age):

^* co-administered with nitrous oxide/oxygen in a ratio of 2:1

When given by bolus injection Ultiva should be administered over not less than 30 seconds. Surgery should not commence until at least 5 minutes after the start of the Ultiva infusion, if a simultaneous bolus dose has not been given. For sole administration of nitrous oxide (70%) with Ultiva, typical maintenance infusion rates should be between 0.4 and 3 micrograms/kg/min, and although not specifically studied, adult data suggest that 0.4 micrograms/kg/min is an appropriate starting rate. 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, Ultiva 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 such as hypotension and bradycardia. No data are available for dosage recommendations for simultaneous use of other hypnotics other than those listed in the table with Ultiva (see section 4.2.1.1. General Anaesthesia – Adults – Concomitant medication).

Guidelines for patient management in the immediate post-operative period/Establishment of alternative analgesia prior to discontinuation of Ultiva

Due to the very rapid offset of action of Ultiva, 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 Ultiva.

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)

There is limited clinical trial experience of Ultiva in neonates and infants (aged under 1 year old; see section 5.1). The pharmacokinetic profile of Ultiva in neonates/infants (aged less than 1 year) is comparable to that seen in adults after correction for body weight differences (see section 5.2). However, because there are insufficient clinical data, the administration of Ultiva is not recommended for this age group.

Use for Total Intravenous anaesthesia (TIVA)

There is limited clinical trial experience of Ultiva for TIVA in infants (see section 5.1). However, there are insufficient clinical data to make dosage recommendations.

Cardiac anaesthesia

Adults

Dosing guidelines for cardiac anaesthesia:

Maintenance period of anaesthesia

After endotracheal intubation the infusion rate of Ultiva should be titrated according to patient need. Supplemental slow bolus doses may also be given as required. High risk cardiac patients, such as those with poor 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 Pharmacokinetic properties – Cardiac anaesthesia).

Concomitant medication

At the doses recommended above, Ultiva 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. No data are available for dosage recommendations for simultaneous use of other hypnotics other than those listed in the table with Ultiva (see section 4.2.1.1 General Anaesthesia – Adults – Concomitant medication).

Continuation of Ultiva post-operatively to provide analgesia prior to 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 4.2.3.7 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.

Use in Intensive Care

Ultiva can be used for the provision of analgesia in mechanically ventilated intensive care patients of 18 years of age and over. Sedative agents should be used as appropriate.

The safety and efficacy from well-controlled clinical trials of Ultiva in mechanically ventilated intensive care patients has been established for durations up to 3 days (see section 4.2.3.2. and section 5.2). 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 microgram/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 regularly assessed and the Ultiva infusion rate adjusted accordingly. If an infusion rate of 0.2 micrograms/kg/min (12 micrograms/kg/h) is reached and sedation is required, 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 in individual patients:-

Dosing Guidelines for use of Ultiva within the Intensive Care Setting:

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:

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% to 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 0.74 micrograms/kg/min (45 micrograms/kg/h), has been administered for provision of additional anaesthesia 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 µ-opioid agonists.

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 microgram/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 with these agents.

Paediatric intensive care patients

There are no data available on use in paediatric patients.

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.).

Special patient populations

Elderly (over 65 years of age)

General Anaesthesia

The initial starting dose of Ultiva 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 Ultiva has been seen in this patient population. This dose adjustment applies to use in all phases of anaesthesia.

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.)

Obese patients

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.

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.

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 Ultiva shall be titrated to individual patient need.

Neurosurgery

There is only limited clinical experience in patients undergoing neurosurgery and insufficient information to recommend a dose.

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).

Symptoms

As with all potent opioid analgesics, overdose would be manifested by an extension of the pharmacologically predictable actions of remifentanil. Due to the very short duration of action of Ultiva, the potential for deleterious effects due to overdose are limited to the immediate time period following drug administration. Response to discontinuation of the drug is rapid, with return to baseline within 10 minutes.

Management

In the event of overdose or suspected overdose, take the following actions: discontinue administration of Ultiva, maintain a patent airway, initiate assisted or controlled ventilation with oxygen and maintain adequate cardiovascular function. If depressed respiration is associated with muscle rigidity, a neuromuscular blocking agent may be required to facilitate assisted or controlled respiration. Intravenous fluids and vasopressor for the treatment of hypotension and other supportive measures may be employed.

Intravenous administration of an opioid antagonist such as naloxone may be given as a specific antidote to manage severe respiratory depression and muscle rigidity. The duration of respiratory depression following overdose with Ultiva is unlikely to exceed the duration of action of the opioid antagonist.

Unopened: 18 months.

Following reconstitution/dilution:

Chemical and physical in-use stability of the reconstituted solution of Ultiva has been demonstrated for 24 hours at room temperature (25°C). Ultiva should not be administered without further dilution (see section 6.6).

From a microbiological point of view, both the reconstituted product and the diluted product should be used immediately, following preparation. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution/dilution had taken place in controlled and validated aseptic conditions. Any unused solution should be discarded.

Do not store above 25°C.

For storage instructions of the reconstituted medicinal product, see section 6.3.

Ultiva injection for intravenous use is available as a glass vial with rubber stopper and aluminium overseal:

1 mg Remifentanil lyophilised powder in 3 ml vials in cartons of 5.

Not all pack sizes may be marketed.

Ultiva should be prepared for intravenous use by adding, as appropriate 1, 2 or 5ml of diluent to give a reconstituted solution with a concentration of approximately 1 mg/ml remifentanil. The reconstituted solution is clear, colourless and practically free from particulate material.

After reconstitution, Ultiva should not be administered without further dilution to concentrations of 20 to 250 µg/ml (50 µg/ml is the recommended dilution for adults and 20-25 µg/ml for paediatric patients aged 1 year and over) with one of the following IV fluids listed below:

The dilution is dependent upon the technical capability of the infusion device and the anticipated requirements of the patient.

Sterilised Water for Injections
5% Dextrose Injection
5% Dextrose and 0.9% Sodium Chloride Injection
0.9% Sodium Chloride Injection
0.45% Sodium Chloride Injection

Ultiva has been shown to be compatible with the following intravenous fluids when administered into a running IV catheter:

Lactated Ringer’s Injection
Lactated Ringer’s and 5% Dextrose Injection

Ultiva has been shown to be compatible with propofol when administered into a running IV catheter.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

The following tables give guidelines for infusion rates of Ultiva:usion rates of Ultiva for manually-controlled infusion:

Table 1. Ultiva for Injection Infusion Rates (ml/kg/h):

Table 2. Ultiva for Injection Infusion Rates (ml/h) for a 20µg/ml Solution:

Table 3. Ultiva for Injection Infusion Rates (ml/h) for a 25µg/ml Solution:

Table 4. Ultiva for Injection Infusion Rates (ml/h) for a 50µg/ml Solution:

Table 5. Ultiva for Injection Infusion Rates (ml/h) for a 250µg/ml Solution: