Ultiva 1 mg Powder for Concentrate for Solution for Infusion

  • Name:

    Ultiva 1 mg Powder for Concentrate for Solution for Infusion

  • Company:
    info
  • Active Ingredients:

    Remifentanil Hydrochloride

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

Summary of Product Characteristics last updated on medicines.ie: 26/3/2019

Click on this link to Download PDF directly

Aspen

Aspen

Company Products

Medicine NameActive Ingredients
Medicine Name Aldomet Tablets 250 mg Active Ingredients Methyldopa
Medicine Name Aldomet tablets 500 mg Active Ingredients Methyldopa
Medicine Name Alkeran 2 mg Film-coated Tablets Active Ingredients Melphalan
Medicine Name Alkeran 50 mg, Powder and Solvent for Solution for Infusion Active Ingredients Melphalan
Medicine Name Anectine 50 mg/ml Solution for Injection or Infusion Active Ingredients Suxamethonium Chloride
Medicine Name Arixtra Fondaparinux sodium solution for injection 1,5 mg/ 0,3 ml Active Ingredients Fondaparinux sodium
Medicine Name Arixtra Fondaparinux sodium solution for injection 10 mg/ 0,8 ml Active Ingredients Fondaparinux sodium
Medicine Name Arixtra Fondaparinux sodium solution for injection 2,5 mg/ 0,5 ml Active Ingredients Fondaparinux sodium
Medicine Name Arixtra Fondaparinux sodium solution for injection 5 mg/ 0,4 ml Active Ingredients Fondaparinux sodium
Medicine Name Arixtra Fondaparinux sodium solution for injection 7,5 mg/ 0,6 ml Active Ingredients Fondaparinux sodium
Medicine Name Dexamethasone 2mg Tablets Active Ingredients Dexamethasone
Medicine Name Diprivan 1% w/v Emulsion for Injection or Infusion, Pre-filled Syringe (50ml) Active Ingredients Propofol
Medicine Name Emla Cream 5% Active Ingredients Lidocaine, Prilocaine
Medicine Name Fludrocortisone acetate 0.1mg Tablets Active Ingredients Fludrocortisone Acetate
Medicine Name Imuran Powder for Solution for Injection or Infusion 50mg Active Ingredients azathioprine sodium
Medicine Name Imuran Tablets 25mg Active Ingredients Azathioprine
Medicine Name Imuran Tablets 50mg Active Ingredients Azathioprine
Medicine Name Kemadrin Tablets Active Ingredients Procyclidine Hydrochloride
Medicine Name Lanoxin 250 microgram tablets Active Ingredients Digoxin
Medicine Name Lanoxin Injection Active Ingredients Digoxin
Medicine Name Lanoxin PG 50 micrograms/ml Elixir Active Ingredients Digoxin
Medicine Name Lanoxin PG Tablets Active Ingredients Digoxin
Medicine Name Lanvis 40 mg tablets Active Ingredients Tioguanine
Medicine Name Leukeran 2mg Film-coated Tablets Active Ingredients Chlorambucil
Medicine Name Marcain 0.25% with Adrenaline (5 micrograms per ml) 1:200,000 Active Ingredients Adrenaline tartrate, Bupivacaine Hydrochloride
1 - 0 of 63 items.Total: Infinity pages

When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 26 March 2019 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.3 - Shelf life
  • Change to section 6.5 - Nature and contents of container
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 15 October 2018 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.3 - Shelf life
  • Change to section 6.5 - Nature and contents of container
  • Change to section 10 - Date of revision of the text
  • Improved presentation of SmPC

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 24 August 2017 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 24 August 2017 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 8 - Marketing authorisation number(s)
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Text in red = new text
Text strikethrough = deleted text

 

7.         MARKETING AUTHORISATION HOLDER

           

GlaxoSmithKline (Ireland) Limited

12 Riverwalk,

Citywest Business Campus,

Dublin 24

Aspen Pharma Trading Limited,

3016 Lake Drive,

Citywest Business Campus,

Dublin 24,

Ireland

 

 

8.         MARKETING AUTHORISATION NUMBER

 

PA 1077/100/1 PA 1691/032/001

 

10.       DATE OF (PARTIAL) REVISION OF THE TEXT

 

            01 Jul 2015       04 Aug2017

 

Updated on 24 August 2017 PIL

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 8 - Marketing authorisation number(s)
  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company

Text in red = new text
Text strikethrough = deleted text

 

7.         MARKETING AUTHORISATION HOLDER

           

GlaxoSmithKline (Ireland) Limited

12 Riverwalk,

Citywest Business Campus,

Dublin 24

Aspen Pharma Trading Limited,

3016 Lake Drive,

Citywest Business Campus,

Dublin 24,

Ireland

 

 

8.         MARKETING AUTHORISATION NUMBER

 

PA 1077/100/1 PA 1691/032/001

 

10.       DATE OF (PARTIAL) REVISION OF THE TEXT

 

            01 Jul 2015       04 Aug2017

 

Updated on 17 July 2015 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Update to section 7 - MA holder address change

Updated on 17 July 2015 PIL

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company

Update to section 7 - MA holder address change

Updated on 12 June 2015 PIL

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 6.2 - Incompatibilities
  • Change to section 10 - Date of revision of the text
  • Correction of spelling/typing errors
  • Change to improve clarity and readability

Free text change information supplied by the pharmaceutical company

Brief description of changes(s):

·         add information on hypersensitivity and cross reactivity between opioids of different classes to Section 4.4 Special Warnings and Precautions for Use of the SmPC and the corresponding sections in the Package Leaflet

 

·         amend the statements regarding the preparation of infusion solutions in Section 4.2 & 6.2 of SmPC.  It was noted that the statements in section 6.2 & 6.6 are interpreted as being in conflict with each other

 

·         update the SPCs & shared PIL in line with QRD version 9. The company has also taken the opportunity to make some administrative and formatting amendments throughout the SPCs (Sections 1, 4.1, 4.2, 4.3, 4.4 4.5, 4.6, 4.7, 4.8, 4.9, 5.1, 5.2, 5.3, 6.3, 6.5, 6.6, 8 & 9) and to add the ATC code to section 5.1.  Section 4.2.2 Dosing in Cardiac Anaesthesia has been updated to clearly reflect the dosing in Adult and paediatric headings.

 

·         additional changes made to PIL and labelling components.  Changes made include GSK logo update, formatting updates, change in layout of the information on pack and inclusion of trademark and copyright statement.  On the PIL, the description of common side effect “dizziness, tiredness or fainting” has been deleted as it is not in line with the adverse drug reactions listed in the current SPC.  The warning in relation to method & use of administration of Ultiva in Section 2 of the PIL has been relocated to Section 3 “How Ultiva is given”.

 

Updated on 12 June 2015 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 6.2 - Incompatibilities
  • Change to section 10 - Date of revision of the text
  • Correction of spelling/typing errors
  • Change to improve clarity and readability

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Brief description of changes(s):

·         add information on hypersensitivity and cross reactivity between opioids of different classes to Section 4.4 Special Warnings and Precautions for Use of the SmPC and the corresponding sections in the Package Leaflet

 

·         amend the statements regarding the preparation of infusion solutions in Section 4.2 & 6.2 of SmPC.  It was noted that the statements in section 6.2 & 6.6 are interpreted as being in conflict with each other

 

·         update the SPCs & shared PIL in line with QRD version 9. The company has also taken the opportunity to make some administrative and formatting amendments throughout the SPCs (Sections 1, 4.1, 4.2, 4.3, 4.4 4.5, 4.6, 4.7, 4.8, 4.9, 5.1, 5.2, 5.3, 6.3, 6.5, 6.6, 8 & 9) and to add the ATC code to section 5.1.  Section 4.2.2 Dosing in Cardiac Anaesthesia has been updated to clearly reflect the dosing in Adult and paediatric headings.

 

·         additional changes made to PIL and labelling components.  Changes made include GSK logo update, formatting updates, change in layout of the information on pack and inclusion of trademark and copyright statement.  On the PIL, the description of common side effect “dizziness, tiredness or fainting” has been deleted as it is not in line with the adverse drug reactions listed in the current SPC.  The warning in relation to method & use of administration of Ultiva in Section 2 of the PIL has been relocated to Section 3 “How Ultiva is given”.

 

Updated on 30 January 2015 PIL

Reasons for updating

  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company

Update section 6.6 to correct error in recommended dilution for paediatric patients.

Update to corresponding section (Instructions on use and handling) of technical leaflet.

Updated on 30 January 2015 SmPC

Reasons for updating

  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Update section 6.6 to correct error in recommended dilution for paediatric patients.

Update to corresponding section (Instructions on use and handling) of technical leaflet.

Updated on 15 July 2011 PIL

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 6.3 - Shelf life
  • Change to section 6.6 - Special precautions for disposal and other handling

Free text change information supplied by the pharmaceutical company

1.         TRADE NAME OF THE MEDICINAL PRODUCT

 

Ultiva 1mg, 2mg or 5 mg Powder for Concentrate for Solution for Infusion

 

 

4.2.3.   Use in Intensive Care

……………………………….

 

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 miocrograms/kg/min (45 micrograms/kg/h), has been administered for provision of additional anaesthesia during stimulating procedures.

 

…………………….etc

 

 

4.5       Interaction with Other Medicaments Medicinal Products and Other Forms of Interaction

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

 

…………………..etc

 

6.3       Shelf life

………………..

 

Following reconstituted reconstitution/dilution:

 

…………………….etc

 

 

 

 

 

 

 

 

 

 

 

 

 

 

6.6       Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product

………………….

 

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

 

Drug Delivery Rate

(micrograms/kg/min)

Infusion Delivery Rate (ml/kg/h) for Solution Concentrations of

 

20micrograms/ml

1mg/50ml

25micrograms/ml

1mg/40ml

50micrograms/ml

1mg/20ml

250micrograms/ml

10mg/40ml

0.025

0.075

0.6 0.06

0.03

Not recommended

0.05

0.15

0.12

0.06

0.012

0.075

0.23

0.18

0.09

0.018

0.1

0.3

0.24

0.12

0.024

0.15

0.45

0.36

0.18

0.036

0.2

0.6

0.48

0.24

0.048

0.25

0.75

0.6

0.3

0.06

0.5

1.5

1.2

0.6

0.12

0.75

2.25

1.8

0.9

0.18

1.0

3.0

2.4

1.2

0.24

1.25

3.75

3.0

1.5

0.3

1.5

4.5

3.6

1.8

0.36

1.75

5.25

4.2

2.1

0.42

2.0

6.0

4.8

2.4

0.48

 

………………………etc

Updated on 15 July 2011 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 6.3 - Shelf life
  • Change to section 6.6 - Special precautions for disposal and other handling

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

1.         TRADE NAME OF THE MEDICINAL PRODUCT

 

Ultiva 1mg, 2mg or 5 mg Powder for Concentrate for Solution for Infusion

 

 

4.2.3.   Use in Intensive Care

……………………………….

 

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 miocrograms/kg/min (45 micrograms/kg/h), has been administered for provision of additional anaesthesia during stimulating procedures.

 

…………………….etc

 

 

4.5       Interaction with Other Medicaments Medicinal Products and Other Forms of Interaction

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

 

…………………..etc

 

6.3       Shelf life

………………..

 

Following reconstituted reconstitution/dilution:

 

…………………….etc

 

 

 

 

 

 

 

 

 

 

 

 

 

 

6.6       Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product

………………….

 

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

 

Drug Delivery Rate

(micrograms/kg/min)

Infusion Delivery Rate (ml/kg/h) for Solution Concentrations of

 

20micrograms/ml

1mg/50ml

25micrograms/ml

1mg/40ml

50micrograms/ml

1mg/20ml

250micrograms/ml

10mg/40ml

0.025

0.075

0.6 0.06

0.03

Not recommended

0.05

0.15

0.12

0.06

0.012

0.075

0.23

0.18

0.09

0.018

0.1

0.3

0.24

0.12

0.024

0.15

0.45

0.36

0.18

0.036

0.2

0.6

0.48

0.24

0.048

0.25

0.75

0.6

0.3

0.06

0.5

1.5

1.2

0.6

0.12

0.75

2.25

1.8

0.9

0.18

1.0

3.0

2.4

1.2

0.24

1.25

3.75

3.0

1.5

0.3

1.5

4.5

3.6

1.8

0.36

1.75

5.25

4.2

2.1

0.42

2.0

6.0

4.8

2.4

0.48

 

………………………etc

Updated on 27 January 2011 PIL

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties

Free text change information supplied by the pharmaceutical company

 
Summary of SPC CHANGES (marked IN RED)

 

1.         TRADE NAME OF THE MEDICINAL PRODUCT

 

Ultiva 1mg, 2mg or 5 mg Powder for Concentrate for Solution for Infusion

 

4.1       Therapeutic Indications

 

Ultiva is indicated as an opioid analgesic adjunct for use with other agents during induction and/or maintenance of general anaesthesia in conjunction with controlled ventilation.

 

Ultiva is indicated for provision of analgesia in mechanically ventilated intensive care patients of 18 years of age and over for up to 72 hours.

 

Ultiva is not indicated for use for post-operative analgesia or for use during spontaneous ventilation anaesthesia until further information becomes available.

 

4.2       Posology and Method of Administration

…………………..etc.

 

4.2.1.2 Paediatric patients (1-12 years of age)

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

 

…………………..etc

 

4.2.1.3 Neonates/infants (aged less than 1 year):

There is limited clinical trial experience of remifentanil in neonates and infants (aged under 1 year old; see section 5.1). The pharmacokinetic profile of remifentanil 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 anaesthaesia (TIVA): There is limited clinical trial experience of remifentanil for TIVA in infants (see section 5.1). However, there are insufficient clinical data to make dosage recommendations.

 

…………………etc

 

4.4       Special Warnings and Precautions for Use

 

……………...etc

 

Neonates/infants

There are no is limited data available on use in neonates/infants under 1 year of age (see sections 4.2.1.3 and 5.1).

 

………………etc

 

 

 

 

5.1       Pharmacodynamic Properties

Remifentanil is a selective m-opioid agonist with a rapid onset and very short duration of action.  The m-opioid activity of remifentanil is antagonized by narcotic antagonists, such as naloxone.

 

Assays of histamine in patients and normal volunteers have shown no elevation in histamine levels after administration of remifentanil in bolus doses up to 30 micrograms/kg.

 

Neonates/infants (aged less than 1 year):

 

In a randomised (ratio of 2:1, remifentanil:halothane), open label, parallel group, multicentre study in 60 young infants and neonates ≤8 weeks of age (mean 5.5 weeks) with an ASA physical status of I-II who were undergoing pyloromyotomy, the efficacy and safety of remifentanil (given as a 0.4 μg/kg/min initial continuous infusion plus supplemental doses or infusion rate changes as needed) was compared with halothane (given at 0.4% with supplemental increases as needed). Maintenance of anaesthesia was achieved by the additional administration of 70% nitrous oxide (N20) plus 30% oxygen. Recovery times were superior in the remifentanil relative to the halothane groups (not significant).

 

Use for Total Intravenous anaesthesia (TIVA) - children aged 6 months to 16 years

 

TIVA with remifenanil in paediatric surgery was compared to inhalation anaesthesia in three randomised, open-label studies. The results are summarised in the table below.

 

Surgical intervention

Age (y), (N)

Study condition (maintenance)

Extubation (min)

(mean (SD))

Lower abdominal/urological surgery

0.5-16 (120)

TIVA: propofol (5 - 10 mg/kg/h) + remifentanil (0.125 - 1.0 μg/kg/min)

11.8 (4.2)

Inhalation anaesthesia: sevoflurane (1.0 - 1.5 MAC) and remifentanil (0.125 - 1.0 μg/kg/min)

15.0 (5.6)

(p<0.05)

ENT-surgery

4-11

(50)

TIVA: propofol (3 mg/kg/h) + remifentanil (0.5 μg/kg/min)

11 (3.7)

Inhalation anaesthesia: desflurane (1.3 MAC) and N2O mixture

9.4 (2.9)

Not significant

General or ENT surgery

2-12 (153)

TIVA: remifentanil (0.2 - 0.5 μg/kg/min) + propofol (100 - 200 μg/kg/min)

Comparable extubation times (based on limited data)

 

 

Inhalation anaesthesia: sevoflurane (1 - 1.5 MAC) + N2O mixture

 

In the study in lower abdominal/urological surgery comparing remifentanil/propofol with remifentanil/sevoflurane, hypotension occurred significantly more often under remifentanil/sevoflurane, and bradycardia occurred significantly more often under remifentanil/propofol. In the study in ENT surgery comparing remifentanil/propofol with desflurane/nitrous oxide, a significantly higher heart rate was seen in subjects receiving desflurane/nitrous oxide compared with remifentanil/propofol and with baseline values.

 

 

5.2       Pharmacokinetic Properties

…………….etc

 

Renal impairment

In the clinical studies conducted to date, the rapid recovery from remifentanil-based analgesia appears unaffected by renal status.

 

The pharmacokinetics of remifentanil are not significantly changed in patients with varying degrees of renal impairment even after administration for up to 3 days in the intensive care setting.

 

The clearance of the carboxylic acid metabolite is reduced in patients with renal impairment.  In intensive care patients with moderate/severe renal impairment, the concentration of the carboxylic acid metabolite is expected to may exceed  reach approximately 100 250-fold the level of remifentanil at steady-state in some patients.  Clinical data demonstrates that accumulation of the metabolite does not result in clinically relevant µ-opioid effects even after administration of remifentanil infusions for up to 3 days in these patients.

 

There is no evidence that remifentanil is extracted during renal replacement therapy.

 

The carboxylic acid metabolite is extracted during haemodialysis by at least 30%.

 

……………………etc

 

Updated on 27 January 2011 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

 
Summary of SPC CHANGES (marked IN RED)

 

1.         TRADE NAME OF THE MEDICINAL PRODUCT

 

Ultiva 1mg, 2mg or 5 mg Powder for Concentrate for Solution for Infusion

 

4.1       Therapeutic Indications

 

Ultiva is indicated as an opioid analgesic adjunct for use with other agents during induction and/or maintenance of general anaesthesia in conjunction with controlled ventilation.

 

Ultiva is indicated for provision of analgesia in mechanically ventilated intensive care patients of 18 years of age and over for up to 72 hours.

 

Ultiva is not indicated for use for post-operative analgesia or for use during spontaneous ventilation anaesthesia until further information becomes available.

 

4.2       Posology and Method of Administration

…………………..etc.

 

4.2.1.2 Paediatric patients (1-12 years of age)

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

 

…………………..etc

 

4.2.1.3 Neonates/infants (aged less than 1 year):

There is limited clinical trial experience of remifentanil in neonates and infants (aged under 1 year old; see section 5.1). The pharmacokinetic profile of remifentanil 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 anaesthaesia (TIVA): There is limited clinical trial experience of remifentanil for TIVA in infants (see section 5.1). However, there are insufficient clinical data to make dosage recommendations.

 

…………………etc

 

4.4       Special Warnings and Precautions for Use

 

……………...etc

 

Neonates/infants

There are no is limited data available on use in neonates/infants under 1 year of age (see sections 4.2.1.3 and 5.1).

 

………………etc

 

 

 

 

5.1       Pharmacodynamic Properties

Remifentanil is a selective m-opioid agonist with a rapid onset and very short duration of action.  The m-opioid activity of remifentanil is antagonized by narcotic antagonists, such as naloxone.

 

Assays of histamine in patients and normal volunteers have shown no elevation in histamine levels after administration of remifentanil in bolus doses up to 30 micrograms/kg.

 

Neonates/infants (aged less than 1 year):

 

In a randomised (ratio of 2:1, remifentanil:halothane), open label, parallel group, multicentre study in 60 young infants and neonates ≤8 weeks of age (mean 5.5 weeks) with an ASA physical status of I-II who were undergoing pyloromyotomy, the efficacy and safety of remifentanil (given as a 0.4 μg/kg/min initial continuous infusion plus supplemental doses or infusion rate changes as needed) was compared with halothane (given at 0.4% with supplemental increases as needed). Maintenance of anaesthesia was achieved by the additional administration of 70% nitrous oxide (N20) plus 30% oxygen. Recovery times were superior in the remifentanil relative to the halothane groups (not significant).

 

Use for Total Intravenous anaesthesia (TIVA) - children aged 6 months to 16 years

 

TIVA with remifenanil in paediatric surgery was compared to inhalation anaesthesia in three randomised, open-label studies. The results are summarised in the table below.

 

Surgical intervention

Age (y), (N)

Study condition (maintenance)

Extubation (min)

(mean (SD))

Lower abdominal/urological surgery

0.5-16 (120)

TIVA: propofol (5 - 10 mg/kg/h) + remifentanil (0.125 - 1.0 μg/kg/min)

11.8 (4.2)

Inhalation anaesthesia: sevoflurane (1.0 - 1.5 MAC) and remifentanil (0.125 - 1.0 μg/kg/min)

15.0 (5.6)

(p<0.05)

ENT-surgery

4-11

(50)

TIVA: propofol (3 mg/kg/h) + remifentanil (0.5 μg/kg/min)

11 (3.7)

Inhalation anaesthesia: desflurane (1.3 MAC) and N2O mixture

9.4 (2.9)

Not significant

General or ENT surgery

2-12 (153)

TIVA: remifentanil (0.2 - 0.5 μg/kg/min) + propofol (100 - 200 μg/kg/min)

Comparable extubation times (based on limited data)

 

 

Inhalation anaesthesia: sevoflurane (1 - 1.5 MAC) + N2O mixture

 

In the study in lower abdominal/urological surgery comparing remifentanil/propofol with remifentanil/sevoflurane, hypotension occurred significantly more often under remifentanil/sevoflurane, and bradycardia occurred significantly more often under remifentanil/propofol. In the study in ENT surgery comparing remifentanil/propofol with desflurane/nitrous oxide, a significantly higher heart rate was seen in subjects receiving desflurane/nitrous oxide compared with remifentanil/propofol and with baseline values.

 

 

5.2       Pharmacokinetic Properties

…………….etc

 

Renal impairment

In the clinical studies conducted to date, the rapid recovery from remifentanil-based analgesia appears unaffected by renal status.

 

The pharmacokinetics of remifentanil are not significantly changed in patients with varying degrees of renal impairment even after administration for up to 3 days in the intensive care setting.

 

The clearance of the carboxylic acid metabolite is reduced in patients with renal impairment.  In intensive care patients with moderate/severe renal impairment, the concentration of the carboxylic acid metabolite is expected to may exceed  reach approximately 100 250-fold the level of remifentanil at steady-state in some patients.  Clinical data demonstrates that accumulation of the metabolite does not result in clinically relevant µ-opioid effects even after administration of remifentanil infusions for up to 3 days in these patients.

 

There is no evidence that remifentanil is extracted during renal replacement therapy.

 

The carboxylic acid metabolite is extracted during haemodialysis by at least 30%.

 

……………………etc

 

Updated on 10 September 2010 PIL

Reasons for updating

  • Change to section 1 - Name of medicinal product
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 6.1 - List of excipients
  • Change to section 6.3 - Shelf life
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.5 - Nature and contents of container
  • Change to section 6.6 - Special precautions for disposal and other handling

Free text change information supplied by the pharmaceutical company



1.         TRADE NAME OF THE MEDICINAL PRODUCT

 

Ultiva 1mg, 2mg or 5 mg Powder for Concentrate for Solution for Infusion 1mg, 2mg or 5 mg

 

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Ultiva 1 mg

1 vial contains 1 mg remifentanil (as remifentanil hydrochloride).

 

Ultiva 2 mg

1 vial contains 2 mg remifentanil (as remifentanil hydrochloride).

 

Ultiva 5 mg

1 vial contains 5 mg remifentanil (as remifentanil hydrochloride).

 

For a full list of excipients, see section 6.1.

 

3.         PHARMACEUTICAL FORM

 

Powder for concentrate for solution for infusion

A white to off-white powder.

 

4.         CLINICAL PARTICULARS

4.2       Posology and Method of Administration

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 Instructions for use/handling  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 Special Warnings and precautions for use section 4.4).  IV lines/infusion system should be removed after cessation of use to avoid inadvertent administration.

 

Ultiva is for intravenous use only and must not be administered by epidural or intrathecal injection (see Contra-indications section 4.3).

 

Ultiva is stable for 24 hours at room temperature after reconstitution and should not be administered without further dilution to concentrations of 20 to 250 micrograms/ml (50 micrograms/ml /ml is the recommended dilution for adults and 20-50 micrograms/ml for paediatric patients aged 1 year and over) with one of the following IV fluids listed below:

 

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

 

However, as Ultiva does not contain a preservative it is recommended that Ultiva is used immediately after dilution and any remaining solution should be discarded.  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 2-8°C.

 

(See Section 6.6 Instructions for Use/Handling for additional information, including tables to help titrate Ultiva to the patient’s anaesthetic needs.)

 

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).

 

4.2.1 General Anaesthesia

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

 

4.2.1.1 Adults

 

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

 

Dosing guidelines for adults

INDICATION

BOLUS INJECTION

 (micrograms/kg)

CONTINUOUS INFUSION

(micrograms/kg/min)

Starting Rate

Range

Induction of anaesthesia

1
(give over not less than 30 seconds)

0.5 to 1

_

Maintenance of anaesthesia in ventilated patients

 

 

 

§ Nitrous oxide (66%)

0.5 to 1

0.4

0.1 to 2

§ Isoflurane (starting dose 0.5MAC)

0.5 to 1

0.25

0.05 to 2

§ Propofol (Starting dose 100 micrograms/kg/min)

0.5 to 1

0.25

0.05 to 2

 

When given by slow bolus injection at induction Ultiva shall 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 and below to avoid excessive depth of anaesthesia 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 remifentanil.  There is very limited experience of concurrent use with other opioids (see Concomitant medication).

 

Premedication:  Premedication with an anticholinergic agent may be considered to offset any exacerbation of sympatholytic/vagotonic effects of drugs administered concurrently with remifentanil.

Administration of sedative premedication may enhance the effects of remifentanil.

 

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 m-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: Remifentanil decreases the amounts or doses of inhaled anaesthetics, hypnotics and benzodiazepines required for anaesthesia (see Interaction with other medicaments and other forms of interaction 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:  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.  Patients should be closely monitored post-operatively for pain, respiratory depression, hypotension and bradycardia.  The choice of analgesic should be appropriate for the patient’s surgical procedure and the level of post-operative care. , for example clinical trial data has shown that intra-operative administration of either fentanyl (0.15mg), buprenorphine (0.3mg) or morphine (15mg or 0.2mg/kg) given IV 20-30 minutes before the end of major surgery provides adequate analgesia in the immediate post-operative period without delay in recovery.  Additional smaller doses of these agents may then be administered according to individual patient requirements prior to transfer to routine analgesia e.g. patient controlled analgesia (PCA).  For procedures involving a lower degree of post-operative pain such as day-case surgery, administration of non-steroidal anti-inflammatory drugs (NSAIDs), simple analgesics and wound infiltration with local anaesthetics provides effective analgesia.

 

Guidance on use in mechanically ventilated intensive care patients is provided in section 4.2.3.7.

 

4.2.1.2 General Anaesthesia - Paediatric patients (1-12 years of age)

Co-administration of Ultiva with induction agents has not been studied.  The following doses of Ultiva are recommended for maintenance of anaesthesia:

 

Dosing guidelines for paediatric patients (1-12 years of age)

 

 

INDICATION

Maintenance Anaesthesia

*CONCOMITANT ANAESTHETIC AGENT

BOLUS

INFUSION

INJECTION

(micrograms/kg)

CONTINUOUS

INFUSION

(micrograms /kg/min)

 

 

Starting Rate

Range

Typical Maintenance Rates

§ Nitrous oxide (70%)

1

0.4

0.4 to 3

§ Halothane (starting dose 0.3 MAC)

1

0.25

0.05 to 1.3

§ Sevoflurane (starting dose 0.3 MAC)

1

0.25

0.05 to 0.9

§ Isoflurane (starting dose 0.5 MAC)

1

0.25

0.06 to 0.9

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

 

Maintenance of anaesthesia

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, 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 excessive depth of anaesthesia 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 remifentanil (see section 4.2.1.1. Adults - Concomitant medication).

 

Guidelines for discontinuation

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. Special warnings and precautions for use).

 

4.2.1.3 Neonates/infants (aged less than 1 year):

The pharmacokinetic profile of remifentanil in neonates/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, to make dosage recommendations for this age group. the administration of Ultiva is not recommended for this age group.

 

4.2.2 Cardiac Surgery anaesthesia

 

Dosing guidelines for cardiac Anaesthesia

 

 

INDICATION

BOLUS

INFUSION

INJECTION

(micrograms/kg)

CONTINUOUS

INFUSION

(micrograms/kg/min)

 

 

Starting Rate

Range

Typical Infusion Rates

Induction of anaesthesia

Not recommended

1

-

Maintenance of Anaesthesia

 

 

 

§  Isoflurane (starting dose 0.4 MAC)

0.5-1

1

0.003-4

§  Propofol (starting dose 50 micrograms/kg/min)

0.5-1

1

0.01 to 4.3

Continuation of post-operative analgesia, prior to extubation

Not recommended

1

0 to 1

 

Induction period of anaesthesia:

After administration of hypnotic to achieve loss of consciousness, Ultiva should be administered at an initial infusion rate of 1 micrograms/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 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, 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 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 remifentanil (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:

Prior to discontinuation of Ultiva, patient must be given alternative analgesic and sedative agents at a sufficient time in advance. The choice and dose of agent(s) should be appropriate to the patient’s level of post-operative care (See General Anaesthesia – Adults)

 

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.

 

It is recommended that the Ultiva infusion is discontinued by reducing the infusion rate in three or four steps of 50% at 10 minute intervals.  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.

 

4.2.3.7 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.

 

Ultiva has been studied in intensive care patients in well controlled clinical trials for up to three days.

 

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

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 Agents

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 administered as an admixture.

 

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 miocrograms/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 therefore 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.

 

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.

 

4.2.3.8 1.         Paediatric intensive care patients

There are no data available on use in paediatric patients.

 

4.2.3.9. 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 Pharmacokinetic Properties).

 

4.2.3 4 Special patient populations

 

4.2.3 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, especially the hypotensive effects, 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 4.2.3.7 Use in Intensive Care)

 

4.2.3.3 4.2.      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 in this population.

 

4.2.3.4 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.

 

4.2.3.5 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 Special warnings and precautions for use).  These patients shall be closely monitored and the dose of remifentanil shall be titrated to individual patient need.

 

4.2.3.6 4.5.      Neurosurgery

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

 

4.2.3.2 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.  The haemodynamic effects of remifentanil can be expected to be more pronounced and frequent in ASA III/IV patients, than with other opioids. 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).

 

4.3       Contra-indications

As glycine is present in the formulation, Ultiva is contra-indicated for epidural and intrathecal use (see Preclinical safety data).

 

Ultiva is contra-indicated in patients with known hypersensitivity to the active substance or any component of the preparation and other fentanyl analogues or to any of the excipients.

 

Ultiva is contra-indicated for use as the sole agent for induction of anaesthesia.

 

4.4       Special Warnings and Precautions for Use

 

Ultiva shall 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. The use of Ultiva in mechanically ventilated intensive care patients is not recommended for a duration of treatment greater than 3 days.

 

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 (25oC). 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 8oC, 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

 

6.5       Nature and Contents of Container

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

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

2mg Remifentanil lyophilised powder in 5ml vials in cartons of 5.

5mg Remifentanil lyophilised powder in 10ml vials in cartons of 5.

 

Not all pack sizes may be marketed.

 

6.6       Instructions for Use/Handling Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product

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 1mg/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 micrograms/ml (50 micrograms/ml is the recommended dilution for adults and 25-50 micrograms/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………………etc

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Updated on 10 September 2010 SmPC

Reasons for updating

  • Change to section 1 - Name of medicinal product
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 6.1 - List of excipients
  • Change to section 6.3 - Shelf life
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.5 - Nature and contents of container
  • Change to section 6.6 - Special precautions for disposal and other handling

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company



1.         TRADE NAME OF THE MEDICINAL PRODUCT

 

Ultiva 1mg, 2mg or 5 mg Powder for Concentrate for Solution for Infusion 1mg, 2mg or 5 mg

 

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Ultiva 1 mg

1 vial contains 1 mg remifentanil (as remifentanil hydrochloride).

 

Ultiva 2 mg

1 vial contains 2 mg remifentanil (as remifentanil hydrochloride).

 

Ultiva 5 mg

1 vial contains 5 mg remifentanil (as remifentanil hydrochloride).

 

For a full list of excipients, see section 6.1.

 

3.         PHARMACEUTICAL FORM

 

Powder for concentrate for solution for infusion

A white to off-white powder.

 

4.         CLINICAL PARTICULARS

4.2       Posology and Method of Administration

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 Instructions for use/handling  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 Special Warnings and precautions for use section 4.4).  IV lines/infusion system should be removed after cessation of use to avoid inadvertent administration.

 

Ultiva is for intravenous use only and must not be administered by epidural or intrathecal injection (see Contra-indications section 4.3).

 

Ultiva is stable for 24 hours at room temperature after reconstitution and should not be administered without further dilution to concentrations of 20 to 250 micrograms/ml (50 micrograms/ml /ml is the recommended dilution for adults and 20-50 micrograms/ml for paediatric patients aged 1 year and over) with one of the following IV fluids listed below:

 

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

 

However, as Ultiva does not contain a preservative it is recommended that Ultiva is used immediately after dilution and any remaining solution should be discarded.  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 2-8°C.

 

(See Section 6.6 Instructions for Use/Handling for additional information, including tables to help titrate Ultiva to the patient’s anaesthetic needs.)

 

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).

 

4.2.1 General Anaesthesia

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

 

4.2.1.1 Adults

 

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

 

Dosing guidelines for adults

INDICATION

BOLUS INJECTION

 (micrograms/kg)

CONTINUOUS INFUSION

(micrograms/kg/min)

Starting Rate

Range

Induction of anaesthesia

1
(give over not less than 30 seconds)

0.5 to 1

_

Maintenance of anaesthesia in ventilated patients

 

 

 

§ Nitrous oxide (66%)

0.5 to 1

0.4

0.1 to 2

§ Isoflurane (starting dose 0.5MAC)

0.5 to 1

0.25

0.05 to 2

§ Propofol (Starting dose 100 micrograms/kg/min)

0.5 to 1

0.25

0.05 to 2

 

When given by slow bolus injection at induction Ultiva shall 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 and below to avoid excessive depth of anaesthesia 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 remifentanil.  There is very limited experience of concurrent use with other opioids (see Concomitant medication).

 

Premedication:  Premedication with an anticholinergic agent may be considered to offset any exacerbation of sympatholytic/vagotonic effects of drugs administered concurrently with remifentanil.

Administration of sedative premedication may enhance the effects of remifentanil.

 

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 m-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: Remifentanil decreases the amounts or doses of inhaled anaesthetics, hypnotics and benzodiazepines required for anaesthesia (see Interaction with other medicaments and other forms of interaction 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:  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.  Patients should be closely monitored post-operatively for pain, respiratory depression, hypotension and bradycardia.  The choice of analgesic should be appropriate for the patient’s surgical procedure and the level of post-operative care. , for example clinical trial data has shown that intra-operative administration of either fentanyl (0.15mg), buprenorphine (0.3mg) or morphine (15mg or 0.2mg/kg) given IV 20-30 minutes before the end of major surgery provides adequate analgesia in the immediate post-operative period without delay in recovery.  Additional smaller doses of these agents may then be administered according to individual patient requirements prior to transfer to routine analgesia e.g. patient controlled analgesia (PCA).  For procedures involving a lower degree of post-operative pain such as day-case surgery, administration of non-steroidal anti-inflammatory drugs (NSAIDs), simple analgesics and wound infiltration with local anaesthetics provides effective analgesia.

 

Guidance on use in mechanically ventilated intensive care patients is provided in section 4.2.3.7.

 

4.2.1.2 General Anaesthesia - Paediatric patients (1-12 years of age)

Co-administration of Ultiva with induction agents has not been studied.  The following doses of Ultiva are recommended for maintenance of anaesthesia:

 

Dosing guidelines for paediatric patients (1-12 years of age)

 

 

INDICATION

Maintenance Anaesthesia

*CONCOMITANT ANAESTHETIC AGENT

BOLUS

INFUSION

INJECTION

(micrograms/kg)

CONTINUOUS

INFUSION

(micrograms /kg/min)

 

 

Starting Rate

Range

Typical Maintenance Rates

§ Nitrous oxide (70%)

1

0.4

0.4 to 3

§ Halothane (starting dose 0.3 MAC)

1

0.25

0.05 to 1.3

§ Sevoflurane (starting dose 0.3 MAC)

1

0.25

0.05 to 0.9

§ Isoflurane (starting dose 0.5 MAC)

1

0.25

0.06 to 0.9

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

 

Maintenance of anaesthesia

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, 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 excessive depth of anaesthesia 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 remifentanil (see section 4.2.1.1. Adults - Concomitant medication).

 

Guidelines for discontinuation

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. Special warnings and precautions for use).

 

4.2.1.3 Neonates/infants (aged less than 1 year):

The pharmacokinetic profile of remifentanil in neonates/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, to make dosage recommendations for this age group. the administration of Ultiva is not recommended for this age group.

 

4.2.2 Cardiac Surgery anaesthesia

 

Dosing guidelines for cardiac Anaesthesia

 

 

INDICATION

BOLUS

INFUSION

INJECTION

(micrograms/kg)

CONTINUOUS

INFUSION

(micrograms/kg/min)

 

 

Starting Rate

Range

Typical Infusion Rates

Induction of anaesthesia

Not recommended

1

-

Maintenance of Anaesthesia

 

 

 

§  Isoflurane (starting dose 0.4 MAC)

0.5-1

1

0.003-4

§  Propofol (starting dose 50 micrograms/kg/min)

0.5-1

1

0.01 to 4.3

Continuation of post-operative analgesia, prior to extubation

Not recommended

1

0 to 1

 

Induction period of anaesthesia:

After administration of hypnotic to achieve loss of consciousness, Ultiva should be administered at an initial infusion rate of 1 micrograms/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 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, 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 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 remifentanil (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:

Prior to discontinuation of Ultiva, patient must be given alternative analgesic and sedative agents at a sufficient time in advance. The choice and dose of agent(s) should be appropriate to the patient’s level of post-operative care (See General Anaesthesia – Adults)

 

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.

 

It is recommended that the Ultiva infusion is discontinued by reducing the infusion rate in three or four steps of 50% at 10 minute intervals.  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.

 

4.2.3.7 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.

 

Ultiva has been studied in intensive care patients in well controlled clinical trials for up to three days.

 

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

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 Agents

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 administered as an admixture.

 

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 miocrograms/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 therefore 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.

 

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.

 

4.2.3.8 1.         Paediatric intensive care patients

There are no data available on use in paediatric patients.

 

4.2.3.9. 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 Pharmacokinetic Properties).

 

4.2.3 4 Special patient populations

 

4.2.3 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, especially the hypotensive effects, 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 4.2.3.7 Use in Intensive Care)

 

4.2.3.3 4.2.      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 in this population.

 

4.2.3.4 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.

 

4.2.3.5 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 Special warnings and precautions for use).  These patients shall be closely monitored and the dose of remifentanil shall be titrated to individual patient need.

 

4.2.3.6 4.5.      Neurosurgery

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

 

4.2.3.2 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.  The haemodynamic effects of remifentanil can be expected to be more pronounced and frequent in ASA III/IV patients, than with other opioids. 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).

 

4.3       Contra-indications

As glycine is present in the formulation, Ultiva is contra-indicated for epidural and intrathecal use (see Preclinical safety data).

 

Ultiva is contra-indicated in patients with known hypersensitivity to the active substance or any component of the preparation and other fentanyl analogues or to any of the excipients.

 

Ultiva is contra-indicated for use as the sole agent for induction of anaesthesia.

 

4.4       Special Warnings and Precautions for Use

 

Ultiva shall 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. The use of Ultiva in mechanically ventilated intensive care patients is not recommended for a duration of treatment greater than 3 days.

 

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 (25oC). 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 8oC, 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

 

6.5       Nature and Contents of Container

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

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

2mg Remifentanil lyophilised powder in 5ml vials in cartons of 5.

5mg Remifentanil lyophilised powder in 10ml vials in cartons of 5.

 

Not all pack sizes may be marketed.

 

6.6       Instructions for Use/Handling Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product

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 1mg/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 micrograms/ml (50 micrograms/ml is the recommended dilution for adults and 25-50 micrograms/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………………etc

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Updated on 12 September 2008 SmPC

Reasons for updating

  • Correction of spelling/typing errors

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 12 September 2008 PIL

Reasons for updating

  • Correction of spelling/typing errors

Updated on 11 September 2008 PIL

Reasons for updating

  • Correction of spelling/typing errors

Updated on 11 September 2008 SmPC

Reasons for updating

  • Correction of spelling/typing errors

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 26 August 2008 SmPC

Reasons for updating

  • Improved electronic presentation

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 26 August 2008 PIL

Reasons for updating

  • Improved electronic presentation

Updated on 8 August 2005 SmPC

Reasons for updating

  • New SPC for medicines.ie

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 8 August 2005 PIL

Reasons for updating

  • New SPC for medicines.ie