Ultiva 1 mg Powder for Concentrate for Solution for Infusion

Rapid offset of action/Transition to alternative analgesia

Due to the very rapid offset of action of Ultiva, no residual opioid activity will be present within 5 to 10 minutes after the discontinuation of Ultiva.  For those patients undergoing surgical procedures where post-operative pain is anticipated, analgesics should be administered prior to discontinuation of Ultiva.  The possibility of tolerance, hyperalgesia and associated haemodynamic changes should be considered when used in Intensive Care Unit.  Prior to discontinuation of Ultiva, patients must be given alternative analgesic and sedative agents.  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.  When other opioid agents are administered as part of the regimen for transition to alternative analgesia, the benefit of providing adequate post-operative analgesia must always be balanced against the potential risk of respiratory depression with these agents.

Discontinuation of treatment

Symptoms following withdrawal of remifentanil including tachycardia, hypertension and agitation have been reported infrequently upon abrupt cessation, particularly after prolonged administration of more than 3 days. Where reported, re-introduction and tapering of the infusion has been beneficial. The use of Ultiva in mechanically ventilated intensive care patients is not recommended for duration of treatment greater than 3 days.

Muscle rigidity - prevention and management

At the doses recommended muscle rigidity, sometimes severe, may occur.  As with other opioids, the incidence of muscle rigidity is related to the dose and rate of administration.  Therefore, slow bolus injections shall be administered over not less than 30 seconds.

Muscle rigidity induced by remifentanil must be treated in the context of the patients clinical condition with appropriate supporting measures.  Excessive muscle rigidity occurring during the induction of anaesthesia should be treated by the administration of a neuromuscular blocking agent and/or additional hypnotic agents.  Muscle rigidity seen during the use of remifentanil as an analgesic may be treated by stopping or decreasing the rate of administration of remifentanil.  Resolution of muscle rigidity after discontinuing the infusion of remifentanil occurs within minutes.  Alternatively an opioid antagonist may be administered, however this may reverse or attenuate the analgesic effect of remifentanil.

Respiratory depression - prevention and management

As with all potent opioids, profound analgesia is accompanied by marked respiratory depression.  Therefore, remifentanil shall only be used in areas where facilities for monitoring and dealing with respiratory depression are available.  Special care should be taken in patients with respiratory dysfunction.  Theoretically, the risk of late depression should be absent with remifentanil, however in the presence of confounding factors (inadvertent administration of bolus doses (see section below) and administration of concomitant longer acting opioids), respiratory depression occurring up to 50 minutes after discontinuation of infusion has been reported (see also Interaction with other medicaments and other forms of interaction-concurrent use with other opioids).  It is important to ensure that full consciousness and adequate spontaneous ventilation are achieved before the patient is discharged from the recovery area. The appearance of respiratory depression shall be managed appropriately, including decreasing the rate of infusion by 50%, or a temporary discontinuation of the infusion.  Unlike other fentanyl analogues, remifentanil has not been shown to cause recurrent respiratory depression, even after prolonged administration.  However, as many factors may affect post-operative recovery it is important to ensure that full consciousness and adequate spontaneous ventilation are achieved before the patient is discharged from the recovery area.

Cardiovascular effects

Hypotension and bradycardia may be managed by reducing the rate of infusion of Ultiva or the dose of concurrent anaesthetics or by using IV fluids, vasopressor or anticholinergic agents as appropriate.

The risk of cardiovascular effects such as hypotension and bradycardia, which may rarely lead to asystole/cardiac arrest (see section 4.5 and 4.8) may be reduced by lowering the rate of infusion of Ultiva or the dose of concurrent anaesthetics or by using IV fluids, vasopressor or anticholinergic agents as appropriate.

Debilitated, hypovolaemic, hypotensive and elderly patients may be more sensitive to the cardiovascular effects of remifentanil.

Inadvertent administration

A sufficient amount of Ultiva may be present in the dead space of the IV line and/or cannula to cause respiratory depression, apnoea and/or muscle rigidity if the line is flushed with IV fluids or other drugs.  This may be avoided by administering Ultiva into a fast flowing IV line or via a dedicated IV line which is removed when Ultiva is discontinued.

Neonates/infants

There are no data available on use in neonates/infants under 1 year of age.

Drug abuse

As with other opioids remifentanil may produce dependency.

4.5       Interaction with Other Medicaments and Other Forms of Interaction

Remifentanil is not metabolised by plasmacholinesterase, therefore, interactions with drugs metabolised by this enzyme are not anticipated.

As with other opioids, sedative premedication may enhance the effects of remifentanil and remifentanil also decreases the doses of inhaled and IV anaesthetics, and benzodiazepines required during for anaesthesia.  The concurrent administration of remifentanil may exacerbate the sympatholytic/vagotonic effects of other drugs (See section 4.2 Posology and method of administration).  If doses of concomitantly administered CNS depressant drugs, including opioids, are not reduced, patients may experience an increased incidence of adverse effects associated with these agents.

The cardiovascular effects of Ultiva (hypotension and bradycardia – see section 4.4 and 4.8) may be exacerbated in patients receiving concomitant cardiac depressant drugs, such as beta-blockers and calcium channel blocking agents.

4.6       Pregnancy and Lactation

There are no adequate and well-controlled studies in pregnant women.  Ultiva should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

It is not known whether remifentanil is excreted in human milk.  However, because fentanyl analogues are excreted in human milk and remifentanil­related material was found in rat milk after dosing with remifentanil, nursing mothers should be advised to discontinue breast-feeding for 24 hours following administration of remifentanil.

Labour and delivery

The safety profile of remifentanil during labour or delivery has not been demonstrated.  Remifentanil should not be used during labour and caesarean sections because There are insufficient data to recommend remifentanil for use during labour and caesarean section. It is known that remifentanil crosses the placental barrier and fentanyl analogues can cause respiratory depression in the child.

4.8       Undesirable effects

Clinical Trial Data
The most common adverse events undesirable effects associated with remifentanil are direct extensions of m-opioid agonist pharmacology. The overall reporting incidence, as determined from all phases of controlled anaesthesia studies at recommended doses, is presented below. These adverse events resolve within minutes of discontinuing or decreasing the rate of remifentanil administration.

Adverse events are listed below by system organ class and frequency. The frequencies below are defined as very common ( ³1/10), common ( ³1/100 and to <1/10), uncommon ( ³1/1,000 and to <1/100), rare ( ³1/10,000 and to <1/1,000) and very rare ( <1/10,000), not known (cannot be estimated from the available data).

Immune System Disorders

Rare:                           Allergic reactions including anaphylaxis have been reported in patients receiving                                                               remifentanil in conjunction with one or more anaesthetic agents.

Psychiatric disorders

Not known:                  Drug dependence

Nervous System Disorders

Very common:            Skeletal muscle rigidity

Rare:                           Sedation (during recovery from general anaesthesia)

Not known:                  Convulsions

Cardiac Disorders

Common:                    Bradycardia

Rare:                           Asystole/cardiac arrest, usually preceded by bradycardia, has been reported in patients                                                    receiving remifentanil in conjunction with other anaesthetic agents.

Not known:                  Atrioventricular block

Vascular Disorders

Very common:            Hypotension

Common:                    Post-operative hypertension

Respiratory, Thoracic and Mediastinal Disorders

Common:                    Acute respiratory depression, apnoea

Uncommon:                Hypoxia

Gastrointestinal Disorders

Very common:            Nausea, vomiting

Uncommon:                Constipation

Skin and Subcutaneous Tissue Disorders

Common:                    Pruritus

General Disorders and Administration Site Conditions

Common:                    Post-operative shivering

Uncommon:                Post-operative aches

Not known:                  Drug tolerance

Discontinuation of treatment

Symptoms following withdrawal of remifentanil including tachycardia, hypertension and agitation have been reported infrequently upon abrupt cessation, particularly after prolonged administration of more than 3 days (see section 4.4).

Post-marketing Data
The following adverse events and reporting frequencies have been determined from post-marketing reporting:

Immune System Disorders

Rare: Allergic reactions including anaphylaxis have been reported in patients receiving remifentanil

in conjunction with one or more anaesthetic agents.

Cardiac Disorders

Rare: Asystole/cardiac arrest, usually preceded by bradycardia, has been reported in patients

receiving remifentanil in conjunction with other anaesthetic agents.

6.         PHARMACEUTICAL PARTICULARS

6.1       List of Excipients

Glycine

Hydrochloric acid (for pH adjustment) 

Sodium hydroxide (for pH adjustment if needed)

6.2       Incompatibilities

It should not be admixed with Lactated Ringer’s Injection or Lactated Ringer’s and 5% Dextrose Injection.

Ultiva should not be mixed with propofol in the same intravenous admixture solution.

Administration of Ultiva into the same intravenous line with blood/serum/plasma is not recommended as non-specific esterase in blood products may lead to the hydrolysis of remifentanil to its inactive metabolite.

Ultiva should not be mixed with other therapeutic agents prior to administration.

Ultiva should only be admixed with those infusion solutions recommended (See Instructions for use/handling). (See Section 6.6 )

6.3       Shelf life

Unopened

Ultiva 1mg:  18 months; Ultiva 2mg:  2 years; Ultiva 5mg:  3 years.

Reconstituted solution:

Chemical and physical in-use stability has been demonstrated for 24 hours at room temperature (25^oC). 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^oC, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions. Any unused solution remaining after this time should be discarded.

6.4       Special precautions for storage

Do not store above 25°C.

Chemical and physical in-use stability of the reconstituted solution of Ultiva has been demonstrated for 24 hours at room temperature (25°C).  However, Ultiva does not contain an antimicrobial preservative and thus from a microbiological point of view, the prepared solution should be used immediately.  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.  Any unused solution remaining after this time, should be discarded.

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

Rapid offset of action/Transition to alternative analgesia

Due to the very rapid offset of action of Ultiva, no residual opioid activity will be present within 5 to 10 minutes after the discontinuation of Ultiva.  For those patients undergoing surgical procedures where post-operative pain is anticipated, analgesics should be administered prior to discontinuation of Ultiva.  The possibility of tolerance, hyperalgesia and associated haemodynamic changes should be considered when used in Intensive Care Unit.  Prior to discontinuation of Ultiva, patients must be given alternative analgesic and sedative agents.  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.  When other opioid agents are administered as part of the regimen for transition to alternative analgesia, the benefit of providing adequate post-operative analgesia must always be balanced against the potential risk of respiratory depression with these agents.

Discontinuation of treatment

Symptoms following withdrawal of remifentanil including tachycardia, hypertension and agitation have been reported infrequently upon abrupt cessation, particularly after prolonged administration of more than 3 days. Where reported, re-introduction and tapering of the infusion has been beneficial. The use of Ultiva in mechanically ventilated intensive care patients is not recommended for duration of treatment greater than 3 days.

Muscle rigidity - prevention and management

At the doses recommended muscle rigidity, sometimes severe, may occur.  As with other opioids, the incidence of muscle rigidity is related to the dose and rate of administration.  Therefore, slow bolus injections shall be administered over not less than 30 seconds.

Muscle rigidity induced by remifentanil must be treated in the context of the patients clinical condition with appropriate supporting measures.  Excessive muscle rigidity occurring during the induction of anaesthesia should be treated by the administration of a neuromuscular blocking agent and/or additional hypnotic agents.  Muscle rigidity seen during the use of remifentanil as an analgesic may be treated by stopping or decreasing the rate of administration of remifentanil.  Resolution of muscle rigidity after discontinuing the infusion of remifentanil occurs within minutes.  Alternatively an opioid antagonist may be administered, however this may reverse or attenuate the analgesic effect of remifentanil.

Respiratory depression - prevention and management

As with all potent opioids, profound analgesia is accompanied by marked respiratory depression.  Therefore, remifentanil shall only be used in areas where facilities for monitoring and dealing with respiratory depression are available.  Special care should be taken in patients with respiratory dysfunction.  Theoretically, the risk of late depression should be absent with remifentanil, however in the presence of confounding factors (inadvertent administration of bolus doses (see section below) and administration of concomitant longer acting opioids), respiratory depression occurring up to 50 minutes after discontinuation of infusion has been reported (see also Interaction with other medicaments and other forms of interaction-concurrent use with other opioids).  It is important to ensure that full consciousness and adequate spontaneous ventilation are achieved before the patient is discharged from the recovery area. The appearance of respiratory depression shall be managed appropriately, including decreasing the rate of infusion by 50%, or a temporary discontinuation of the infusion.  Unlike other fentanyl analogues, remifentanil has not been shown to cause recurrent respiratory depression, even after prolonged administration.  However, as many factors may affect post-operative recovery it is important to ensure that full consciousness and adequate spontaneous ventilation are achieved before the patient is discharged from the recovery area.

Cardiovascular effects

Hypotension and bradycardia may be managed by reducing the rate of infusion of Ultiva or the dose of concurrent anaesthetics or by using IV fluids, vasopressor or anticholinergic agents as appropriate.

The risk of cardiovascular effects such as hypotension and bradycardia, which may rarely lead to asystole/cardiac arrest (see section 4.5 and 4.8) may be reduced by lowering the rate of infusion of Ultiva or the dose of concurrent anaesthetics or by using IV fluids, vasopressor or anticholinergic agents as appropriate.

Debilitated, hypovolaemic, hypotensive and elderly patients may be more sensitive to the cardiovascular effects of remifentanil.

Inadvertent administration

A sufficient amount of Ultiva may be present in the dead space of the IV line and/or cannula to cause respiratory depression, apnoea and/or muscle rigidity if the line is flushed with IV fluids or other drugs.  This may be avoided by administering Ultiva into a fast flowing IV line or via a dedicated IV line which is removed when Ultiva is discontinued.

Neonates/infants

There are no data available on use in neonates/infants under 1 year of age.

Drug abuse

As with other opioids remifentanil may produce dependency.

4.5       Interaction with Other Medicaments and Other Forms of Interaction

Remifentanil is not metabolised by plasmacholinesterase, therefore, interactions with drugs metabolised by this enzyme are not anticipated.

As with other opioids, sedative premedication may enhance the effects of remifentanil and remifentanil also decreases the doses of inhaled and IV anaesthetics, and benzodiazepines required during for anaesthesia.  The concurrent administration of remifentanil may exacerbate the sympatholytic/vagotonic effects of other drugs (See section 4.2 Posology and method of administration).  If doses of concomitantly administered CNS depressant drugs, including opioids, are not reduced, patients may experience an increased incidence of adverse effects associated with these agents.

The cardiovascular effects of Ultiva (hypotension and bradycardia – see section 4.4 and 4.8) may be exacerbated in patients receiving concomitant cardiac depressant drugs, such as beta-blockers and calcium channel blocking agents.

4.6       Pregnancy and Lactation

There are no adequate and well-controlled studies in pregnant women.  Ultiva should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

It is not known whether remifentanil is excreted in human milk.  However, because fentanyl analogues are excreted in human milk and remifentanil­related material was found in rat milk after dosing with remifentanil, nursing mothers should be advised to discontinue breast-feeding for 24 hours following administration of remifentanil.

Labour and delivery

The safety profile of remifentanil during labour or delivery has not been demonstrated.  Remifentanil should not be used during labour and caesarean sections because There are insufficient data to recommend remifentanil for use during labour and caesarean section. It is known that remifentanil crosses the placental barrier and fentanyl analogues can cause respiratory depression in the child.

4.8       Undesirable effects

Clinical Trial Data
The most common adverse events undesirable effects associated with remifentanil are direct extensions of m-opioid agonist pharmacology. The overall reporting incidence, as determined from all phases of controlled anaesthesia studies at recommended doses, is presented below. These adverse events resolve within minutes of discontinuing or decreasing the rate of remifentanil administration.

Adverse events are listed below by system organ class and frequency. The frequencies below are defined as very common ( ³1/10), common ( ³1/100 and to <1/10), uncommon ( ³1/1,000 and to <1/100), rare ( ³1/10,000 and to <1/1,000) and very rare ( <1/10,000), not known (cannot be estimated from the available data).

Immune System Disorders

Rare:                           Allergic reactions including anaphylaxis have been reported in patients receiving                                                               remifentanil in conjunction with one or more anaesthetic agents.

Psychiatric disorders

Not known:                  Drug dependence

Nervous System Disorders

Very common:            Skeletal muscle rigidity

Rare:                           Sedation (during recovery from general anaesthesia)

Not known:                  Convulsions

Cardiac Disorders

Common:                    Bradycardia

Rare:                           Asystole/cardiac arrest, usually preceded by bradycardia, has been reported in patients                                                    receiving remifentanil in conjunction with other anaesthetic agents.

Not known:                  Atrioventricular block

Vascular Disorders

Very common:            Hypotension

Common:                    Post-operative hypertension

Respiratory, Thoracic and Mediastinal Disorders

Common:                    Acute respiratory depression, apnoea

Uncommon:                Hypoxia

Gastrointestinal Disorders

Very common:            Nausea, vomiting

Uncommon:                Constipation

Skin and Subcutaneous Tissue Disorders

Common:                    Pruritus

General Disorders and Administration Site Conditions

Common:                    Post-operative shivering

Uncommon:                Post-operative aches

Not known:                  Drug tolerance

Discontinuation of treatment

Symptoms following withdrawal of remifentanil including tachycardia, hypertension and agitation have been reported infrequently upon abrupt cessation, particularly after prolonged administration of more than 3 days (see section 4.4).

Post-marketing Data
The following adverse events and reporting frequencies have been determined from post-marketing reporting:

Immune System Disorders

Rare: Allergic reactions including anaphylaxis have been reported in patients receiving remifentanil

in conjunction with one or more anaesthetic agents.

Cardiac Disorders

Rare: Asystole/cardiac arrest, usually preceded by bradycardia, has been reported in patients

receiving remifentanil in conjunction with other anaesthetic agents.

6.         PHARMACEUTICAL PARTICULARS

6.1       List of Excipients

Glycine

Hydrochloric acid (for pH adjustment) 

Sodium hydroxide (for pH adjustment if needed)

6.2       Incompatibilities

It should not be admixed with Lactated Ringer’s Injection or Lactated Ringer’s and 5% Dextrose Injection.

Ultiva should not be mixed with propofol in the same intravenous admixture solution.

Administration of Ultiva into the same intravenous line with blood/serum/plasma is not recommended as non-specific esterase in blood products may lead to the hydrolysis of remifentanil to its inactive metabolite.

Ultiva should not be mixed with other therapeutic agents prior to administration.

Ultiva should only be admixed with those infusion solutions recommended (See Instructions for use/handling). (See Section 6.6 )

6.3       Shelf life

Unopened

Ultiva 1mg:  18 months; Ultiva 2mg:  2 years; Ultiva 5mg:  3 years.

Reconstituted solution:

Chemical and physical in-use stability has been demonstrated for 24 hours at room temperature (25^oC). 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^oC, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions. Any unused solution remaining after this time should be discarded.

6.4       Special precautions for storage

Do not store above 25°C.

Chemical and physical in-use stability of the reconstituted solution of Ultiva has been demonstrated for 24 hours at room temperature (25°C).  However, Ultiva does not contain an antimicrobial preservative and thus from a microbiological point of view, the prepared solution should be used immediately.  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.  Any unused solution remaining after this time, should be discarded.

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