Consumer medicine information

Ultiva for Injection

Remifentanil

BRAND INFORMATION

Brand name

Ultiva

Active ingredient

Remifentanil

Schedule

S8

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Ultiva for Injection.

What is in this leaflet?

This leaflet answers some common questions about Ultiva. It does not contain all of the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you being given Ultiva against the benefits this medicine is expected to have for you.

If you have any concerns about being given this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Ultiva is used for

Ultiva is an anaesthetic used with other anaesthetic medicines, to produce and/or maintain heavy sleep during your operation. If you are a cardiac patient, it may also be used to help relieve any pain immediately following your operation.

Ultiva may also be used for patients in the Intensive Care Unit to maintain sedation and relieve pain.

Ultiva belongs to a group of medicines called opioids. It differs from other medicines in this group by its very quick onset and very short duration of action.

Your doctor may have prescribed Ultiva for another reason.

Ask your doctor if you have any questions about why Ultiva has been prescribed for you.

As with other opioids, Ultiva can be addictive. This is unlikely to happen when Ultiva is only used during your operation.

Before you are given Ultiva

When you must not receive Ultiva

You must not receive Ultiva if you have ever had an allergic reaction to remifentanil hydrochloride or any of the ingredients listed at the end of this leaflet.

You should not receive Ultiva if you are allergic (hypersensitive) to other pain-relieving medicines which are similar to fentanyl and which are related to the class of medicines known as opioids.

Symptoms of an allergic reaction may be mild or severe. They usually include some or all of the following:

wheezing, swelling of the lips/mouth, difficulty in breathing, hayfever, lumpy rash ("hives") or fainting.

Before you receive Ultiva

You must tell your doctor if:

  • you have had any adverse reactions during an operation.
  • you have had any type of allergic reaction (hypersensitivity) to any other opioid medicines (e.g., morphine, fentanyl, pethidine, codeine), or to any medicines used during an operation.
    You probably have an increased chance of being allergic to Ultiva if you are allergic to other opioids.
  • you are allergic to any other medicines or any other substance, such as foods, dyes or preservatives.
  • you have or have ever had any of the following medical conditions:
    - slow heart beat
    - low blood pressure
    - chest or breathing problems.
  • you are pregnant, intend to become pregnant, are breast feeding or plan to breast feed.
    Like most medicines, Ultiva is not recommended in pregnancy and breast-feeding. However, your doctor will discuss the possible risks and benefits of being given Ultiva if you are pregnant or breast-feeding.

If you have not told your doctor about any of the above, tell them before you are given Ultiva.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines you buy without a prescription from a pharmacy, supermarket or health food shop.

Tell your doctor if you have recently been taking medicines for blood pressure or heart problems (known as beta-blockers or calcium channel blockers).

Some medicines, such as benzodiazepines, may interfere with Ultiva. Your doctor or pharmacist will be able to tell you what to do when being given Ultiva with other medicines.

How Ultiva is given

Ultiva can be given into a vein in two ways:

  • as a slow injection, or
  • as a slow infusion.

Ultiva will be administered by an anaesthetist or other highly trained doctor. You will never be expected to give yourself this medication. The dosage will vary according to many factors such as your body weight and the type of operation you have.

While you are using Ultiva

Things to be careful of

If you are discharged early, following treatment with Ultiva or any other anaesthetic agents, do not drive or operate machinery.

Side-Effects

Check with your doctor as soon as possible if you have any problems after receiving Ultiva, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

Like other medicines, Ultiva can cause some side-effects.

The most commonly reported side-effects are:

  • slow breathing
  • breathlessness
  • slow heart beat
  • drop in blood pressure
  • increased blood pressure which may cause a headache or sensation of warmth/flushing.
  • muscle stiffness
  • shivering
  • nausea
  • vomiting
  • aches

Ask your doctor or pharmacist to answer any questions you may have.

This is not a complete list of all possible side-effects. Others may occur in some people and there may be some side-effects not yet known.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

Ask your doctor or pharmacist if you don't understand anything in this list.

Do not be alarmed by this list of possible side-effects. You may not experience any of them.

Product description

What Ultiva looks like

Ultiva is supplied as 1mg, 2mg or 5mg of white to off-white powder in a clear, glass vial.

Ingredients

Ultiva contains the active ingredient remifentanil (as hydrochloride) 1mg, 2mg or 5mg per vial. Other ingredients are glycine and hydrochloric acid. The powder is dissolved in a suitable sterile liquid before use.

Ultiva does not contain gluten or lactose.

Manufacturer

Your Ultiva is supplied by:

Aspen Pharmacare Pty Ltd
34-36 Chandos St, St Leonards, NSW 2065
Australia.

Further Information

Pharmaceutical companies are not in a position to give people an individual diagnosis or medical advice. Your doctor or pharmacist is the best person to give you advice on the treatment of your condition. You may also be able to find general information about your disease and its treatment from books, for example in public libraries.

Do not throw this leaflet away. You may need to read it again.

This leaflet was prepared on 13 November 2018

The information provided applies only to: Ultiva® for Injection.

Trademarks are owned by or licensed to the Aspen group of companies. © 2018 Aspen group of companies or its licensor. All rights reserved.

Ultiva 1 mg: AUST R 58688

Ultiva 2 mg: AUST R 58689

Ultiva 5 mg: AUST R 58690

Version 4.0

Published by MIMS January 2019

BRAND INFORMATION

Brand name

Ultiva

Active ingredient

Remifentanil

Schedule

S8

 

1 Name of Medicine

Remifentanil hydrochloride.

2 Qualitative and Quantitative Composition

Active substance.

Remifentanil hydrochloride - 1 mg, 2 mg and 5 mg as remifentanil base.

List of excipients.

Glycine, hydrochloric acid, sodium hydroxide and water for injection. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Ultiva (remifentanil hydrochloride) for injection is supplied as sterile, non-pyrogenic, preservative-free lyophilised powder for intravenous administration. The product is formulated in glycine and requires reconstitution and dilution before use.
When reconstituted as directed, solutions of Ultiva are clear and colourless and contain 1 mg/mL of remifentanil base as remifentanil hydrochloride.
Ultiva for injection is available as glass vials containing 1 mg, 2 mg or 5 mg of remifentanil base (as the hydrochloride salt) packed in clear glass vials with siliconised stoppers and overseals.

4 Clinical Particulars

4.1 Therapeutic Indications

Ultiva for injection is indicated:
as an opioid adjunct for use during induction and/or maintenance of general anaesthesia during surgical procedures including cardiac surgery in adults;
as an opioid adjunct for use during induction and/or maintenance of general anaesthesia during surgical but not cardiac procedures in children aged 1 to 12 years;
for continuation as an analgesic into the immediate postoperative period under the close supervision of medically qualified persons trained in the use of anaesthetic drugs, during transition to longer acting analgesia following adult cardiac surgery when endotracheal intubation and controlled ventilation are anticipated;
for provision of analgesia and sedation in mechanically ventilated intensive care patients.

4.2 Dose and Method of Administration

Ultiva should be administered only in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function and by medically qualified 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 intubation and assisted ventilation.
Continuous infusions of Ultiva must be administered by a calibrated infusion device, where possible via a dedicated intravenous line, otherwise into a fast flowing IV line. The Ultiva infusion line should be connected at, or close to, the intravenous cannula and primed, to minimise the potential dead space. (See Section 4.2 Dose and Method of Administration, Instructions for use for additional information, including tables with examples of infusion rates by bodyweight to help titrate Ultiva to the patient's anaesthetic needs).
Care should be taken to avoid obstruction or disconnection of infusion lines and to adequately clear the lines to remove residual Ultiva after use (see Section 4.4 Special Warnings and Precautions for Use). Failure to clear the intravenous tubing to remove residual Ultiva has been associated with the appearance of respiratory depression, apnoea and muscle rigidity upon later administration of fluids or medications through the same IV tubing.
Ultiva is for intravenous use only and must not be administered by epidural or intrathecal injection (see Section 4.3 Contraindications).

Administration by manually controlled infusion.

For manually controlled infusion Ultiva can be diluted to concentrations of 20 to 250 microgram/mL (50 microgram/mL is the recommended dilution for adults and 20 to 25 microgram/mL for paediatric patients aged 1 year and over).

Administration by target controlled infusion.

Ultiva may also be given by target controlled infusion (TCI) with an approved infusion device incorporating a validated pharmacokinetic model (the Minto pharmacokinetic model with covariates for age and lean body mass (LBM) is an example of a model available with current devices).
TCI can be used for induction and maintenance of ASA I and II adult patients in general and cardiac anaesthesia. There are insufficient data to make recommendations for delivery of Ultiva by TCI for ASA III and IV patients, spontaneous ventilation anaesthesia, use in ICU sedation, monitored conscious sedation or in children.
For TCI in adults the recommended dilution of Ultiva is 20 to 50 microgram/mL.

Instructions for use.

Reconstitution and dilution.

To reconstitute the powder, add 1 mL of diluent (see Compatibilities for recommended diluents) per mg of remifentanil. Shake well to dissolve. When reconstituted as directed, the solution contains approximately 1 mg of remifentanil activity per 1 mL. Ultiva should be diluted to a final concentration of 20, 25, 50, or 250 microgram/mL prior to administration (see Table 1).
50 microgram/mL is the recommended dilution for adults and 20-25 microgram/mL for paediatric patients aged 1 year and over. The dilution is dependent upon the technical capability of the infusion device and the expected requirements of the patient. Ultiva should not be administered without dilution.

Compatibilities.

Ultiva is chemically and physically stable and should be used within 24 hours of preparation and storage at 2-8°C, after reconstitution and further dilution to concentrations of 20 to 250 microgram/mL with one of the following recommended intravenous fluids: sterile water for injection, 5% glucose injection, 5% glucose and 0.9% sodium chloride injection, 0.9% sodium chloride injection, 0.45% sodium chloride injection.
Ultiva contains no antimicrobial preservatives and care must be taken to assure the sterility of prepared solutions. Reconstituted product should be used promptly and any unused material discarded. If storage is necessary, hold at 2-8°C for not more than 24 hours to reduce microbiological hazard (see Section 6.2 Incompatibilities).
Ultiva has been shown to be compatible with the following intravenous fluids when administered into a running intravenous line of: lactated Ringer's injection, lactated Ringer's and 5% glucose injection.
Ultiva has been shown to be compatible with propofol when administered into a running intravenous line.
Administration by manually controlled infusion. For manually controlled infusion Ultiva can be diluted to concentrations of 20 to 250 microgram/mL (50 microgram/mL is the recommended dilution for adults and 20 to 25 microgram/mL for paediatric patients aged 1 year and over). Tables 2 to 6 give guidelines for infusion rates of Ultiva for manually controlled infusion.
Administration by target controlled infusion. For TCI the recommended dilution of Ultiva is 20 to 50 microgram/mL.
Table 7 gives guidelines for blood concentrations achieved at steady steady state with MCI in a 70 kg, 170 cm, 40 year old, male patient (using Minto PK model).

Discontinuation.

Upon discontinuation of Ultiva sufficient drug may remain in intravenous lines or in the dead space of cannulae to cause opioid related effects (e.g. respiratory depression) if the line is flushed. Therefore, appropriate measures should be taken to avoid such inadvertent administration of Ultiva (see Section 4.4 Special Warnings and Precautions for Use).

4.2.1 General anaesthesia.

The administration of Ultiva must be individualised based on the patient's response. It is not recommended for use as the sole agent in general anaesthesia.
Dosage in adults. Administration by manually controlled infusion. Table 8 summarises the starting infusion rates and dose range for various anaesthetic situations.
(See Instructions for use for additional information, including tables to help titrate Ultiva to the patient's anaesthetic needs.)
At the doses recommended in Table 8, Ultiva significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended in Table 8 to avoid excessive depth of anaesthesia (see Concomitant medication).
No data are available for dosage recommendations for simultaneous use of other hypnotics with Ultiva.

Induction of anaesthesia.

Ultiva should be administered with a hypnotic agent such as propofol, thiopentone or isoflurane for the induction of anaesthesia (see Section 4.4 Special Warnings and Precautions for Use, Muscle rigidity, prevention and management). Ultiva can be administered at an infusion rate of 0.5 to 1 microgram/kg/minute with or without an initial bolus infusion of 1 microgram/kg over 60 seconds. If endotracheal intubation is to occur more than eight to ten minutes after the start of the infusion of Ultiva, then a bolus infusion 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 Table 8. 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 two to five minutes to attain the desired level of mu-opioid response. In response to light anaesthesia, supplemental bolus infusions may be administered every two to five minutes.

Analgesia.

On cessation of infusion, Ultiva has a short lasting analgesic effect. Postoperative pain management should be considered and, where appropriate, begun prior to the termination of Ultiva infusion.

Guidelines for discontinuation.

Upon discontinuation of Ultiva the intravenous tubing should be cleared to prevent the inadvertent administration of Ultiva at a later point in time (see Section 4.4 Special Warnings and Precautions for Use). Due to the rapid offset of action of Ultiva, no residual opioid activity will be present within five to ten minutes after discontinuation. For those patients undergoing surgical procedures where postoperative pain is generally anticipated, alternative analgesics should be administered prior to discontinuation of Ultiva. Sufficient time must be allowed to reach the maximum effect of the longer acting analgesic. The choice of analgesic should be appropriate for the patient's surgical procedure and the level of follow-up care.

Concomitant medication.

Ultiva decreases the dose of inhaled anaesthetics, hypnotics and benzodiazepines required for anaesthesia (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Doses of the following agents used in anaesthesia, isoflurane, thiopentone, propofol and temazepam have been reduced by up to 75% when used concurrently with Ultiva.
Administration by target controlled infusion. Induction and maintenance of anaesthesia in ventilated patients. Ultiva TCI should be used in association with an intravenous or inhalational hypnotic agent during the induction and maintenance of anaesthesia in ventilated adult patients (see Table 8). In association with these agents, adequate analgesia for induction of anaesthesia and surgery can generally be achieved with target blood remifentanil concentrations ranging from 3 to 8 nanogram/mL. Ultiva should be titrated to individual patient response. For particularly stimulating surgical procedures target blood concentrations up to 15 nanogram/mL may be required.
As with manually controlled infusion, at the doses recommended above, Ultiva significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended to avoid excessive depth of anaesthesia (see Table 8).
There are insufficient data to make recommendations on the use of TCI for spontaneous ventilation anaesthesia.

Guidelines for discontinuation/ continuation into the immediate postoperative period.

At the end of surgery when the TCI infusion is stopped or the target concentration reduced, spontaneous respiration is likely to return at calculated remifentanil concentrations in the region of 1 to 2 nanogram/mL. As with manually controlled infusion, postoperative analgesia should be established before the end of surgery with longer acting analgesics (see Section 4.2 Dose and Method of Administration, General anaesthesia, Dosage in adults, Administration by manually controlled infusion, Guidelines for discontinuation).
There are insufficient data to make recommendations on the use of TCI for the management of postoperative analgesia.
Dosage in paediatric patients (1 to 12 years of age). Administration by manually controlled infusion.

Induction of anaesthesia.

There are insufficient data to make a dosage recommendation.

Maintenance of anaesthesia.

See Table 9.
When given by bolus injection Ultiva should be administered over not less than 30 seconds. Surgery should not commence until at least five minutes after the start of the Ultiva infusion, if a simultaneous bolus dose has not been given. 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 in Table 9, Ultiva significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore isoflurane, halothane and sevoflurane should be administered as recommended in Table 9 to avoid excessive depth of anaesthesia. No data are available for dosage recommendations for simultaneous use of other hypnotics with Ultiva (see General anaesthesia, Dosage in adults, Concomitant medication).

Guidelines for discontinuation.

Following discontinuation of the infusion, the offset of analgesic effect of Ultiva is rapid and similar to that seen in adult patients. Appropriate postoperative analgesic requirements should be anticipated and implemented (see General anaesthesia, Dosage in adults, Guidelines for discontinuation).
Administration by target controlled infusion. Ultiva TCI has not been studied in paediatric patients.

Paediatric patients aged less than 1 year.

The pharmacokinetic profile of remifentanil in paediatric patients aged more than 2 months is comparable to that seen in adults after correction for bodyweight differences. However, there are insufficient pharmacokinetic and clinical data to make dosage recommendations for patients aged less than 1 year.

4.2.2 Cardiac anaesthesia.

Dosage in adults. Administration by manually controlled infusion. See Table 10.

Induction period of anaesthesia.

After administration of hypnotic to achieve loss of consciousness, Ultiva should be administered at an initial infusion rate of 1 microgram/kg/minute. The use of bolus injections of Ultiva during induction in cardiac surgical patients is not recommended. Endotracheal intubation should not occur until at least six minutes after the start of infusion in order to minimise the response to intubation.

Maintenance period of anaesthesia.

After endotracheal intubation the infusion rate of Ultiva should be titrated according to patient need. Supplemental 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 microgram/kg. These dosing recommendations also apply during hypothermic cardiopulmonary bypass (see Section 5.2 Pharmacokinetic Properties, Cardiac anaesthesia).

Concomitant medication.

At the doses recommended in Table 10, Ultiva significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended in Table 10 to avoid excessive depth of anaesthesia. No data are available for dosage recommendations for simultaneous use of other hypnotics with Ultiva (see General anaesthesia, Dosage in adults, Concomitant medication).

Continuation of postoperative analgesia prior to extubation.

It is recommended that the infusion of Ultiva should be maintained at the final intraoperative rate during transfer of patients to the postoperative care area. Upon arrival into this area, the patient's level of analgesia and sedation should be closely monitored and the Ultiva rate adjusted to meet the individual patient's requirements.

Guidelines for discontinuation.

Ultiva should only be continued as an analgesic in the immediate postoperative period, and subsequently discontinued during transition to longer acting analgesia, in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function and by medically qualified 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 intubation, and assisted ventilation.
Prior to discontinuation of Ultiva, patients must be given alternative analgesic and sedative agents at a sufficient time in advance. The choice and dose of agent(s) should be appropriate for the patient's level of postoperative care (see General anaesthesia, Dosage in adults, Guidelines for discontinuation).
It is recommended that the Ultiva infusion is discontinued by reducing the infusion rate by 25% decrements in at least ten 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.
It is recommended that haemodynamic changes such as hypertension and tachycardia should be treated with alternative agents as appropriate.
Administration by target controlled infusion. There are insufficient data to make recommendations for delivery of Ultiva by TCI for ASA III and IV patients undergoing cardiac surgery.
There are insufficient data to make recommendations on the use of TCI for the management of postoperative analgesia.

Induction and maintenance of anaesthesia.

Ultiva TCI should be used in association with an intravenous or inhalational hypnotic agent during the induction and maintenance of anaesthesia in ventilated adult patients (see Table 10). In association with these agents, adequate analgesia for cardiac surgery is generally achieved at the higher end of the range of target blood remifentanil concentrations used for general surgical procedures. Following titration of remifentanil to individual patient response, blood concentrations as high as 20 nanogram/mL have been used in clinical studies. At the doses recommended in Table 10, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended to avoid excessive depth of anaesthesia (see Table 10).

Guidelines for discontinuation/ continuation into the immediate postoperative period.

At the end of surgery when the TCI infusion is stopped or the target concentration reduced, spontaneous respiration is likely to return at calculated remifentanil concentrations in the region of 1 to 2 nanogram/mL. As with manually controlled infusion, postoperative analgesia should be established before the end of surgery with longer acting analgesics (see Cardiac anaesthesia, Dosage in adults, Administration by manually controlled infusion, Guidelines for discontinuation).
Dosage in paediatric patients. There are insufficient data to make a dosage recommendation for use during cardiac surgery.

4.2.3 Special patient populations.

3.1 Dosage in elderly patients (over 65 years of age).

(a) General anaesthesia.

The initial starting dose of Ultiva administered to patients over 65 should be half the recommended adult dose and then titrated to individual patient need, as an increased sensitivity to the pharmacological effects of Ultiva has been seen in this patient population. This dose adjustment applies to use in all phases of anaesthesia including induction, maintenance and immediate postoperative analgesia.

(b) Cardiac anaesthesia.

No initial dose reduction is required (see Table 10).
Administration by manually controlled infusion. Intensive care. No initial dose reduction is required (see Section 4.2 Dose and Method of Administration, Use in intensive care).
Administration by target controlled infusion. General anaesthesia. Because of the increased sensitivity of elderly patients to remifentanil, when administering Ultiva by TCI in this population the initial target concentration should be 1.5 to 4 nanogram/mL with subsequent titration to response.
Dosage in obese patients. Administration by manually controlled infusion. For manually controlled infusion, it is recommended that for obese patients the dosage of Ultiva should be reduced and based upon ideal bodyweight as the clearance and volume of distribution of remifentanil are better correlated with ideal bodyweight than actual bodyweight in this population.
Administration by target controlled infusion. With the calculation of lean body mass (LBM) used in the Minto model, LBM is likely to be underestimated in female patients with a body mass index (BMI) greater than 35 kg/m2 and in male patients with BMI greater than 40 kg/m2. To avoid underdosing in these patients, Ultiva TCI should be titrated carefully to individual response.
Dosage in patients with renal impairment. No dosage adjustment, relative to that used in healthy adults, is necessary as the pharmacokinetic profile of Ultiva is unchanged in this patient population.
Dosage in patients with hepatic impairment. No adjustment of the initial dose, relative to that used in healthy adults, is necessary as the pharmacokinetic profile of Ultiva is unchanged in this patient population. However, patients with severe hepatic impairment may be slightly more sensitive to the respiratory depressant effects of Ultiva. These patients should be closely monitored and the dose of Ultiva titrated to individual patient needs.
Neurosurgery. There is limited clinical experience with patients undergoing neurosurgery.
ASA III/IV patients.

(a) 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.
Manually controlled infusion. Initial dosage reduction and subsequent titration to effect is therefore recommended.
Target controlled infusion. TCI is not recommended for ASA III or IV patients.

(b) Cardiac anaesthesia.

No initial dose reduction is required (see Table 10).

(c) Intensive care.

No initial dose reduction is required (see Use in intensive care).
Use in intensive care. Administration by manually controlled infusion.

Adults.

Ultiva can be initially used alone for the provision of analgesia and sedation in mechanically ventilated intensive care patients.
It is recommended that Ultiva is initiated at an infusion rate of 0.1 microgram/kg/min to 0.15 microgram/kg/min. The infusion rate should be titrated in increments of 0.025 microgram/kg/min to achieve the desired level of analgesia and sedation. A period of at least 5 minutes should be allowed between dose adjustments. The level of analgesia and sedation should be carefully monitored, regularly reassessed and the Ultiva infusion rate adjusted accordingly. If an infusion rate of 0.2 microgram/kg/min is reached and the desired level of sedation is not achieved, it is recommended that dosing with an appropriate sedative agent is initiated. 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 microgram/kg/min may be made if additional analgesia is required.
Ultiva has been studied in intensive care patients in well controlled clinical trials for up to 3 days (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Intensive care unit).
Table 11 summarises the starting infusion rates and typical dose range for provision of analgesia and sedation in individual patients.
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 in Table 12.
To allow separate titration of the respective agents sedative agents should not be prepared as one mixture in the same infusion bag.
Additional analgesia for ventilated patients undergoing stimulating procedures. An increase in the existing Ultiva infusion rate may be required to provide additional analgesic cover for ventilated patients undergoing stimulating and/or painful procedures such as endotracheal suctioning, wound dressing and physiotherapy. It is recommended that an Ultiva infusion rate of at least 0.1 microgram/kg/min should be maintained for at least 5 minutes prior to the start of the stimulating procedure. Further dose adjustments may be made every 2 to 5 minutes in increments of 25%-50% in anticipation of, or in response to, additional requirement for analgesia. A mean infusion rate of 0.25 microgram/kg/min, maximum 0.75 microgram/kg/min, 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. 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. The range of options for analgesia includes long acting oral, intravenous, or regional analgesics controlled by the nurse of the patient. These techniques should always be titrated to individual patient need as the infusion of Ultiva is reduced (see below). It is recommended that the choice of agent(s), the dose, and the time of administration are planned prior to 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 down in stages to 0.1 microgram/kg/min 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.

Paediatric intensive care patients.

There are no data available on use in paediatric patients.

Renally impaired intensive care patients.

No adjustments to the doses recommended above are necessary in renally impaired patients including those undergoing renal replacement therapy.
Recovery following discontinuation of a remifentanil infusion may be slightly prolonged in moderate to severe renal impairment (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in patients with renal impairment).
Administration by target controlled infusion. Ultiva TCI has not been studied in intensive care patients.

4.3 Contraindications

Ultiva is not suitable as the sole agent for induction of general anaesthesia.
Ultiva is not recommended for use in spontaneous ventilation anaesthesia or as an analgesic in the immediate postoperative period due to inadequate safety data in such uses, except in ventilated cardiac surgery patients (see Section 4.1 Therapeutic Indications; Section 4.2 Dose and Method of Administration, Cardiac anaesthesia).
As glycine is present in the formulation, Ultiva is contraindicated for epidural and intrathecal use.
Ultiva is contraindicated for use in patients with severe respiratory disease, acute respiratory disease and respiratory depression.
Ultiva is contraindicated for use in chronic non-cancer pain.
Ultiva for injection is contraindicated in patients with known hypersensitivity to any component of the preparation and to other fentanyl analogues.

4.4 Special Warnings and Precautions for Use

As with all opioids, Ultiva is not recommended for use as the sole agent in general anaesthesia.

Hypersensitivity.

Patients with a known hypersensitivity to opioids of a different class may exhibit a hypersensitivity reaction following administration of Ultiva. Caution should be exercised before using Ultiva in these patients (see Section 4.3 Contraindications).

Hazardous and harmful use.

Ultiva contains the opioid remifentanil hydrochloride and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Ultiva at recommended doses.
The risk of addiction is increased in patients with a personal or family history of substance abuse (including alcohol and prescription and illicit drugs) or mental illness. The risk also increases the longer the drug is used and with higher doses. Patients should be assessed for their risks for opioid abuse or addiction prior to being prescribed Ultiva.
All patients receiving opioids should be routinely monitored for signs of misuse and abuse. Opioids are sought by people with addiction and may be subject to diversion. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the safe storage and proper disposal of any unused drug (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal). Caution patients that abuse of oral or transdermal forms of opioids by parenteral administration can result in serious adverse events, which may be fatal.
Patients should be advised not to share Ultiva with anyone else.

Respiratory depression.

Serious, life-threatening or fatal respiratory depression can occur with the use of opioids even when used as recommended. It can occur at any time during the use of Ultiva but the risk is greatest during initiation of therapy or following an increase in dose. Patients should be monitored closely for respiratory depression at these times.
The risk of life-threatening respiratory depression is also higher in elderly, frail, or debilitated patients, in patients with severe hepatic impairment and in patients with existing impairment of respiratory function (e.g. chronic obstructive pulmonary disease; asthma). Opioids should be used with caution and with close monitoring in these patients (see Section 4.2 Dose and Method of Administration). The use of opioids is contraindicated in patients with severe respiratory disease, acute respiratory disease and respiratory depression (see Section 4.3 Contraindications).
The risk of respiratory depression is greater with the use of high doses of opioids, especially high potency and modified release formulations, and in opioid naïve patients. Initiation of opioid treatment should be at the lower end of the dosage recommendations with careful titration of doses to achieve effective pain relief. Careful calculation of equianalgesic doses is required when changing opioids or switching from immediate release to modified release formulations, (see Section 4.2 Dose and Method of Administration), together with consideration of pharmacological differences between opioids. Consider starting the new opioid at a reduced dose to account for individual variation in response.
The use of Ultiva may be associated with apnoea and respiratory depression. Ultiva should be administered only in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function and by medically qualified 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 intubation and assisted ventilation.

Respiratory depression - management.

The use of Ultiva may be associated with apnoea and respiratory depression. Therefore, Ultiva should only be used where facilities for monitoring and treating respiratory depression are available. The occurrence of respiratory depression should be managed appropriately, including decreasing the rate of infusion by 50% or a temporary discontinuation of the infusion. Ultiva has not been shown to cause recurrent respiratory depression even after prolonged administration. However, respiratory depression may occur in some patients up to 30 minutes after cessation of the Ultiva infusion due to residual effects of concomitant anaesthetics, and therefore it is important to ensure that full consciousness and adequate spontaneous ventilation are achieved before the patient is discharged from the recovery area (see also Inadvertent administration).

Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol.

Concomitant use of opioids and benzodiazepines or other CNS depressants, including alcohol, may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of Ultiva with CNS depressant medicines, such as other opioid
analgesics, benzodiazepines, gabapentinoids, cannabis, sedatives, hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, centrally-active anti-emetics and other CNS depressants, should be reserved for patients for whom other treatment options are not possible. If a decision is made to prescribe Ultiva concomitantly with any of the medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible. Patients should be followed closely for signs and symptoms of respiratory depression and sedation. Patients and their caregivers should be made aware of these symptoms. Patients and their caregivers should also be informed of the potential harms of consuming alcohol while taking Ultiva.

Tolerance, dependence and withdrawal.

Neuroadaptation of the opioid receptors to repeated administration of opioids can produce tolerance and physical dependence. Tolerance is the need for increasing doses to maintain analgesia. Tolerance may occur to both the desired and undesired effects of the opioid.
Physical dependence, which can occur after several days to weeks of continued opioid usage, results in withdrawal symptoms if the opioid is ceased abruptly or the dose is significantly reduced. Withdrawal symptoms can also occur following the administration of an opioid antagonist (e.g. naloxone) or partial agonist (e.g. buprenorphine). Withdrawal can result in some or all of the following symptoms: dysphoria, restlessness/agitation, lacrimation, rhinorrhoea, yawning, sweating, chills, myalgia, mydriasis, irritability, anxiety, increasing pain, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea, increased blood pressure, increased respiratory rate and increased heart rate.
When discontinuing Ultiva in a person who may be physically-dependent, the drug should not be ceased abruptly but withdrawn by tapering the dose gradually (see Ceasing opioids; see Section 4.2 Dose and Method of Administration).

Accidental ingestion/exposure.

Accidental ingestion or exposure of Ultiva, especially by children, can result in a fatal overdose of remifentanil hydrochloride. Patients and their caregivers should be given information on safe storage and disposal of unused Ultiva (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal).

Hyperalgesia.

Hyperalgesia may occur with the use of opioids, particularly at high doses. Hyperalgesia may manifest as an unexplained increase in pain, increased levels of pain with increasing opioid dosages or diffuse sensitivity not associated with the original pain. Hyperalgesia should not be confused with tolerance (see Tolerance, dependence and withdrawal). If opioid induced hyperalgesia is suspected, the dose should be reduced and tapered off if possible. A change to a different opioid may be required.

Ceasing opioids.

Abrupt discontinuation or rapid decreasing of the dose in a person physically dependent on an opioid may result in serious withdrawal symptoms and uncontrolled pain (see Tolerance, dependence and withdrawal). Such symptoms may lead the patient to seek other sources of licit or illicit opioids. Opioids should not be ceased abruptly in a patient who is physically dependent but withdrawn by tapering the dose slowly. Factors to take into account when deciding how to discontinue or decrease therapy include the dose and duration of the opioid the patient has been taking, the type of pain being treated and the physical and psychological attributes of the patient. A multimodal approach to pain management should be in place before initiating an opioid analgesic taper. During tapering, patients require regular review and support to manage any increase in pain, psychological distress and withdrawal symptoms.
There are no standard tapering schedules suitable for all patients and an individualised plan is necessary. In general, tapering should involve a dose reduction of no more than 10 percent to 25 percent every 2 to 4 weeks (see Section 4.2 Dose and Method of Administration). If the patient is experiencing increased pain or serious withdrawal symptoms, it may be necessary to go back to the previous dose until stable before proceeding with a more gradual taper.
When ceasing opioids in a patient who has a suspected opioid use disorder, the need for medication assisted treatment and/or referral to a specialist should be considered.

Rapid offset of action.

Within five to ten minutes after the discontinuation of Ultiva no residual opioid activity will be present. For those patients undergoing surgical procedures where postoperative pain is generally anticipated alternative analgesics should be administered prior to the discontinuation of Ultiva. Sufficient time must be allowed to reach the maximum effect of the longer acting analgesic. The choice of analgesic should be appropriate for the patient's surgical procedure and the level of follow-up care.

Discontinuation of treatment.

Symptoms including tachycardia, hypertension and agitation have been reported infrequently upon abrupt cessation, particularly after prolonged administration of remifentanil. Where reported, reintroduction and tapering of the infusion has been beneficial.

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. Ultiva should be administered, where possible, via a dedicated IV line which is removed when Ultiva is discontinued, otherwise into a fast flowing IV line at or close to the venous cannula and primed, in order to avoid administration of drug into the single dead space.

Muscle rigidity - prevention and management.

At the recommended doses, Ultiva can cause muscle rigidity. Profound chest wall rigidity and inability to ventilate the patient has occurred during induction, and following inadvertent boluses after intravenous line flushing. The incidence of muscle rigidity is related to the dose and rate of administration. Therefore, boluses should be administered slowly, over 60 seconds.
Muscle rigidity induced by Ultiva must be treated in the context of the patient's 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 and may require intubation for ventilation. Muscle rigidity seen during the use of Ultiva as an analgesic may be treated by stopping or decreasing the rate of administration of Ultiva. Resolution of muscle rigidity after discontinuing the infusion of Ultiva occurs within minutes. Alternatively, an opioid antagonist may be administered, however this may reverse or attenuate the analgesic effect of Ultiva. In the case of life-threatening muscle rigidity, a rapid onset neuromuscular blocker or an opioid antagonist may be administered.

Cardiovascular effects.

Ultiva causes dose-dependent hypotension and bradycardia. These effects may be attenuated by the pre-administration of an appropriate anticholinergic agent such as glycopyrrolate or atropine. Hypotension and bradycardia may be managed by reducing the rate of infusion of Ultiva or the dose of concurrent anaesthetics, and by using intravenous fluids, vasopressor or anticholinergic agents as appropriate.
Debilitated, hypovolaemic, and elderly patients may be more sensitive to the cardiovascular effects of Ultiva.

Awareness.

Intraoperative awareness has been reported when remifentanil has been administered with propofol infusion rates less than 75 microgram/kg/min for Ultiva.

Use in the elderly.

See Section 4.2 Dose and Method of Administration, Dosage in elderly patients (over 65 years of age).

Paediatric use.

There are insufficient data available on use in paediatric patients under 1 year of age.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Ultiva is not metabolised by plasma cholinesterase, therefore, interactions with drugs metabolised by this enzyme are not anticipated.
As with other opioids, Ultiva decreases the dose of inhaled and intravenous anaesthetics and benzodiazepines required for anaesthesia (see Section 4.2 Dose and Method of Administration). If doses of concomitantly administered CNS depressant drugs are not reduced, patients may experience an increased incidence of adverse effects associated with these agents. Also see Section 4.4 Special Warnings and Precautions for Use, Risks from concomitant use of benzodiazepines or other CNS depressants including alcohol.
The cardiovascular effects of Ultiva (hypotension and bradycardia) may be exacerbated in patients receiving concomitant cardiac depressant drugs such as beta-blockers and calcium channel blocking agents.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Daily administration of remifentanil to male rats was associated with pathological changes in the epididymides at exposures to remifentanil and its major metabolite GR90291 of < 1 and > 200-fold, respectively, the anticipated clinical exposure, and pathological changes in the testes and reduced fertility and pregnancies at exposures to remifentanil and GR90291 of 1 to 2 and > 600-fold, respectively, the anticipated clinical exposure.
(Category C)
Although placental transfer of remifentanil and its major metabolite GR90291 was found in rats, rabbits and monkeys, there was no evidence of teratogenicity in rats at exposures to remifentanil and its major metabolite of 6 and > 200-fold, respectively, the anticipated clinical exposure. In rabbits, teratogenicity was observed only at remifentanil doses greater than those producing maternotoxicity and fetotoxicity, with remifentanil exposures of about 200-fold anticipated human remifentanil exposure. However, there are no adequate and well controlled studies in pregnant women. The use of Ultiva in pregnant women is not recommended.
 It is not known whether Ultiva is excreted in human milk. However, because fentanyl analogues are excreted in human milk and remifentanil related material was found in rat milk after dosing with Ultiva, caution should be exercised when Ultiva is administered to mothers who are breastfeeding.

Use in obstetrics.

The safety profile of Ultiva during labour or delivery has not been demonstrated. Ultiva should not be used during labour and Caesarean sections because it is known that remifentanil crosses the placental barrier and fentanyl analogues can cause respiratory depression in the infant.

4.7 Effects on Ability to Drive and Use Machines

Following treatment using anaesthetic agents, patients should be advised not to drive or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

The most common adverse events associated with remifentanil are direct extensions of mu-opioid agonist pharmacology, such as respiratory depression, bradycardia, hypotension and skeletal muscle rigidity. These are dose dependent events and hence dissipate within minutes of discontinuing or decreasing the infusion rate of Ultiva. Hypotension may be relatively more common in the elderly (> 65 years).
Approximately 3,800 patients have been exposed to Ultiva in controlled clinical trials.
The frequencies of adverse events during general anaesthesia with the recommended doses of Ultiva are given in Table 13. Each patient was counted once for each type of adverse event.

Cardiac anaesthesia.

The side effect profile of Ultiva was consistent with the known pharmacology of mu-opioid agonists. Hypotension observed in maintenance regimens (4% versus 1%); and hypertension (2% versus 0%), shivering (4% versus 2%) and aches (2% versus 0%) observed postoperatively; occurred at a greater frequency with remifentanil compared to fast track comparator opioid (fentanyl and sufentanil) regimens. Although there was a higher frequency of the above adverse events, the incidence of adverse cardiac outcomes in each of the randomised, double blind trials was similar for remifentanil and comparator opioid.

Paediatric anaesthesia.

Ultiva was well tolerated and the incidence of adverse events at the recommended doses was similar to that reported for adults.

Intensive care unit.

The overall incidence of drug related adverse events across treatment groups was: remifentanil 22% versus fentanyl 17% versus morphine 16%. The incidence of hypotension was comparable between groups (remifentanil 9% versus fentanyl 9% versus morphine 7%); the majority of hypotensive reports being drug related (remifentanil 6% versus fentanyl 6% versus morphine 6%). Episodes of hypotension (defined as a mean arterial pressure 50 mmHg) were more frequent with remifentanil (11% to 17% compared with morphine 2% and fentanyl 10%), however this was not associated with an increase in adverse event reporting. (See Section 4.4 Special Warnings and Precautions for Use). In the remifentanil group the majority of drug related episodes of hypotension were mild or moderate in severity and in the majority of cases, the average duration was less than 20 minutes.
Pruritus was one of the most commonly reported drug related adverse events in the remifentanil group (2% incidence).

Other adverse events.

Less commonly reported adverse clinical events (incidence < 1%) from all controlled studies are presented below:

Digestive.

Constipation, abdominal discomfort, xerostomia, gastroesophageal reflux, dysphagia, diarrhoea, heartburn, ileus.

Cardiovascular.

Various atrial and ventricular arrhythmias, heart block, ECG change consistent with myocardial ischaemia, elevated CPK-MB level, syncope.

Musculoskeletal.

Muscle stiffness, musculoskeletal chest pain, postoperative aches.

Respiratory.

Cough, dyspnoea, bronchospasm, laryngospasm, rhonchi, stridor, nasal congestion, pharyngitis, pleural effusion, hiccups, pulmonary oedema, rales, bronchitis, rhinorrhoea.

Nervous.

Anxiety, involuntary movement, prolonged emergence from anaesthesia, confusion, awareness under anaesthesia without pain, rapid awakening from anaesthesia, tremors, disorientation, dysphoria, nightmares, hallucinations, paraesthesia, nystagmus, twitch, sleep disorder, seizure, amnesia.

Body as a whole.

Decreased body temperature, anaphylactic reaction, delayed recovery from neuromuscular block.

Skin.

Rash, urticaria.

Urogenital.

Urine retention, oliguria, dysuria, urine incontinence.

Infusion site reactions.

Erythema, pruritus, rash.

Metabolic and nutrition.

Abnormal liver function, hyperglycaemia, electrolyte disorders, increased CPK level.

Haematologic and lymphatic.

Anaemia, lymphopenia, leucocytosis, thrombocytopenia.

Observed during clinical practice.

In addition to adverse events reported from clinical trials, the following events have been identified during postapproval use of remifentanil in conjunction with one or more anaesthetic agents in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting or potential causal connection to remifentanil.

Non-site specific.

Very rarely, allergic reactions including anaphylaxis have been reported in patients receiving Ultiva in conjunction with one or more anaesthetic agents.

Cardiovascular.

Rare cases of asystole/ cardiac arrest, usually preceded by bradycardia, have been reported in patients receiving remifentanil in conjunction with other anaesthetic agents.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Overdosage is manifested by an extension of the pharmacologically predictable actions of Ultiva.
In the event of overdosage or suspected overdosage, take the following actions: discontinue administration of Ultiva, maintain a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function. If depressed respiration is associated with muscle rigidity, a neuromuscular blocking agent may be required to facilitate assisted or controlled respiration. Intravenous fluids and vasopressor agents for the treatment of hypotension and other supportive measures may be employed.
Intravenous administration of naloxone may be given as a specific antidote to manage severe respiratory depression and muscle rigidity.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Remifentanil is a potent, selective, 4-anilidopiperidine mu-opioid agonist with pharmacological action typical of this class of compound. It is distinguished from other 4-anilidopiperidines (fentanyl analogues) by its rapid onset and very short duration of action. The mu-opioid activity of remifentanil is antagonised by naloxone. Remifentanil in humans has a rapid blood-brain equilibration half-time of 1 ± 1 minutes (mean ± SD) and a rapid onset of action. The pharmacodynamic effects of remifentanil closely follow the measured blood concentrations, allowing direct correlation between dose, blood levels, and response. Blood concentration decreases 50% in three to six minutes after a one minute infusion or after prolonged continuous infusion due to rapid distribution and elimination processes and is independent of duration of drug administration. Recovery from the effects of remifentanil occurs rapidly (within five to ten minutes). New steady-state concentrations occur within five to ten minutes after changes in infusion rate.
When used as a component of an anaesthetic technique, remifentanil can be rapidly titrated to the desired depth of anaesthesia/ analgesia (e.g. as required by varying levels of intraoperative stress) by changing the continuous infusion rate or by administering an IV bolus injection.
Remifentanil is a potent opioid, therefore, careful adherence to Section 4.2 and Section 4.4 of this document is essential to avoid unacceptable adverse events (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Haemodynamics.

In premedicated patients undergoing anaesthesia, one minute infusions of < 2 microgram/kg of remifentanil caused dose dependent hypotension and bradycardia. While additional doses > 2 microgram/kg (up to 30 microgram/kg) do not produce any further decreases in heart rate or blood pressure, the duration of the haemodynamic change is increased in proportion to the blood concentrations achieved. Peak haemodynamic effects occur within three to five minutes of a single dose of remifentanil or an infusion rate increase. Glycopyrrolate, atropine, and vagolytic neuromuscular blocking agents attenuate the haemodynamic effects associated with remifentanil. When appropriate, bradycardia and hypotension can be reversed by reduction of the rate of infusion of remifentanil, or the dose of concurrent anaesthetics, or by the administration of fluids or vasopressors.

Respiration.

Remifentanil depresses respiration in a dose related fashion. Unlike other fentanyl analogues, the duration of action of remifentanil at a given dose does not increase with increasing duration of administration, due to lack of drug accumulation. When remifentanil and alfentanil were dosed to equal levels of respiratory depression, recovery of respiratory drive after three hour infusions was more rapid and less variable with remifentanil (see Figure 1).
Spontaneous respiration occurs at blood concentrations of 4 to 5 nanogram/mL in the absence of other anaesthetic agents; for example, after discontinuation of a 0.25 microgram/kg/minute infusion of remifentanil, these blood concentrations would be reached in two to four minutes. In patients undergoing general anaesthesia, the rate of respiratory recovery depends upon the concurrent anaesthetic; it is fastest after N2O, slower with propofol, and slowest after isoflurane.

Muscle rigidity.

Skeletal muscle rigidity can be caused by remifentanil and is related to the dose and speed of administration. Remifentanil may cause chest wall rigidity (inability to ventilate) after single doses of > 1 microgram/kg administered over 30 to 60 seconds or infusion rates > 0.1 microgram/kg/minute. Administration of doses < 1 microgram/kg may cause chest wall rigidity when given concurrently with a continuous infusion of remifentanil.

Histamine release.

Assays of histamine in patients and normal volunteers have shown no elevation in histamine levels after administration of remifentanil in doses up to 30 microgram/kg over 60 seconds.

Clinical trials.

Clinical trials have demonstrated that remifentanil is unsuitable as a sole agent for induction. For induction, remifentanil should only be used as an opioid adjunct where intubation and mechanical ventilation are intended. Remifentanil is not recommended for use in postoperative analgesia, except for ventilated cardiac surgery patients in an environment where the patient is under the close supervision of medically qualified persons trained in the use of anaesthetic drugs (see Section 4.1 Therapeutic Indications; Section 4.3 Contraindications).
Ultiva was evaluated in 3,562 patients undergoing general anaesthesia (n = 2,923) and monitored anaesthesia care (n = 639). These patients were evaluated in the following settings: inpatient (n = 2,213) which included cardiovascular (n = 675) and neurosurgical (n = 61) and outpatient (n = 1,349). Three hundred and seventy-seven (377) elderly patients (age range 66 to 90 years) and 440 paediatric patients received Ultiva. Of the general anaesthesia patients, 1,132 also received Ultiva as an IV analgesic agent during the immediate postoperative period.

Induction and maintenance of general anaesthesia, inpatient/ outpatient.

The efficacy of Ultiva was investigated in 1,562 patients in 15 randomised, controlled trials as the analgesic component for the induction and maintenance of general anaesthesia. Eight of these studies compared Ultiva to alfentanil and two studies compared Ultiva to fentanyl. In these studies, doses of Ultiva up to the ED90 were compared to recommended doses (approximately ED50) of alfentanil or fentanyl.

Induction of anaesthesia.

Ultiva was administered with isoflurane, propofol, or thiopentone for the induction of anaesthesia (n = 1,562). The majority of patients (80%) received propofol as the concurrent agent. Ultiva reduced the propofol and thiopentone requirements for loss of consciousness. Compared to alfentanil and fentanyl, a higher relative dose of Ultiva resulted in fewer responses to intubation (see Table 14). Overall, hypotension occurred in 5% of patients receiving Ultiva compared to 2% of patients receiving the other opioids.
Ultiva has been used as a primary agent for the induction of anaesthesia; however, it should not be used as a sole agent because loss of consciousness cannot be assured and because of a high incidence of apnoea, muscle rigidity and tachycardia. The administration of an induction dose of propofol or thiopentone or a paralysing dose of a muscle relaxant prior to or concurrently with Ultiva during the induction of anaesthesia markedly decreased the incidence of muscle rigidity from 20% to < 1%.

Use during maintenance of anaesthesia.

Ultiva was investigated in 929 patients in seven well controlled general surgery studies in conjunction with nitrous oxide, isoflurane, or propofol in both inpatient and outpatient settings. These studies demonstrated that Ultiva could be dosed to high levels of opioid effect and rapidly titrated to optimise analgesia intraoperatively without delaying or prolonging recovery. Remifentanil was inadequate as a sole agent for maintenance of anaesthesia.
Compared to alfentanil and fentanyl, these higher relative doses (ED90) of Ultiva resulted in fewer responses to intraoperative stimuli (see Table 15) and a higher frequency of hypotension (16% compared to 5% for the other opioids). Ultiva was infused to the end of surgery, while alfentanil was discontinued 5 to 30 minutes before the end of surgery as recommended. The mean final infusion rates of Ultiva were between 0.25 and 0.48 microgram/kg/minute.
In three randomised, controlled studies (n = 407) during general anaesthesia, Ultiva attenuated the signs of light anaesthesia within a median time of three to six minutes after bolus doses of 1 microgram/kg with or without infusion rate increases of 50% to 100% (up to a maximum rate of 2 microgram/kg/minute).
In an additional double blind, randomised study (n = 103), a constant rate (0.25 microgram/kg/minute) of Ultiva was compared to doubling the rate to 0.5 microgram/kg/minute approximately five minutes before the start of the major surgical stress event. Doubling the rate decreased the incidence of signs of light anaesthesia from 67% to 8% in patients undergoing abdominal hysterectomy, and from 19% to 10% in patients undergoing radical prostatectomy. In patients undergoing laminectomy the lower dose was adequate.

Recovery.

In 2,169 patients receiving Ultiva for periods up to 16 hours, recovery from anaesthesia was rapid, predictable, and independent of the duration of the infusion of Ultiva. In the seven controlled general surgery studies, extubation occurred in a median of five minutes (range: -3 to 17 minutes in 95% of patients) in outpatient anaesthesia and ten minutes (range: 0 to 32 minutes in 95% of patients) in inpatient anaesthesia. Recovery in studies using nitrous oxide or propofol was faster than in those using isoflurane as the concurrent anaesthetic. There was no case of remifentanil induced delayed respiratory depression (occurring more than 30 minutes after discontinuation of remifentanil).
In a double blind, randomised study, administration of morphine sulfate (0.15 mg/kg) intravenously 20 minutes before the anticipated end of surgery to 98 patients did not delay recovery of respiratory drive in patients undergoing major surgery with remifentanil/ propofol total IV anaesthesia.

Paediatric anaesthesia.

The safety, efficacy and pharmacokinetics of Ultiva have been established in five studies which included 687 paediatric patients (aged 5 days to 17 years). Of these, 437 patients received Ultiva: 65 patients were enrolled in pharmacokinetic studies and 372 paediatric patients were studied undergoing general anaesthesia for routine surgical procedures in the inpatient (n = 190) and outpatient (n = 182) settings. Two hundred and fifty patients were administered comparator anaesthetic regimens. Four of these studies were open labelled.
One randomised, double blind, parallel comparator controlled study consisted of 206 patients, of which 103 received Ultiva. This study found the median time to extubation was nine minutes versus ten minutes for fentanyl. The overall incidences of adverse events were 38% for Ultiva and 39% for fentanyl, drug related adverse events were 19% and 22% respectively.
The studies confirmed the effectiveness of the initial adult dosing in paediatric patients > 1 year of age with subsequent titration to clinical effect according to individual patient requirements. Ultiva based anaesthesia was shown to be as effective as conventional anaesthetic regimens in attenuation of responses to stimulating procedures and the provision of intraoperative haemodynamic stability. Ultiva could be continued until the end of surgery and recovery from anaesthesia was rapid, predictable and similar to conventional anaesthetic regimens. Generally higher postoperative pain scores were observed when using Ultiva, consistent with the rapid offset of action of Ultiva. This highlights that longer acting analgesia must be established at an appropriate time in advance of the discontinuation of Ultiva to minimise postoperative pain (see Guidelines for discontinuation).
No relationship was found between age and the final infusion rate of Ultiva, indicating that the starting dose was appropriate across the range of ages studied. There were no clinically significant differences in time to extubation or other recovery parameters between Ultiva based anaesthesia and conventional anaesthetic regimens. Ultiva was well tolerated and the incidence of adverse events at the recommended maintenance doses in combination with inhalational anaesthetics was similar to that reported in adults.

Cardiac surgery.

In preliminary investigations of cardiac anaesthesia, two studies evaluated the pharmacokinetics of Ultiva in patients (n = 25) undergoing hypothermic CABG surgery; and two dose ranging studies were conducted which included a total of 217 ASA II to IV patients undergoing CABG surgery. The data indicated that high dose Ultiva (starting doses 1-3 microgram/kg/minute) effectively attenuated responses to major surgical stress and was associated with a rapid recovery profile. However, none of these studies included comparator opioids.
Subsequently Ultiva was evaluated in four randomised, double blind studies including a total of 830 patients (450 Ultiva, 380 comparator opioid) undergoing coronary artery bypass graft (CABG) or valve replacement/ repair surgery. This was initiated to develop dosing guidelines for use of Ultiva in cardiac patients, establish the safety and efficacy of Ultiva compared with the use of fentanyl and sufentanil in fast track cardiac anaesthesia; and especially in higher risk cardiac patients, those with impaired left ventricular function (ejection fraction < 0.35) or undergoing valve surgery.
A high dose Ultiva based regimen was generally more effective in attenuating major surgical stress responses compared to conventional opioid regimens (low/ medium intermittent dose) used for fast track cardiac surgery (e.g. attenuation of response to maximal sternal spread was 11-21% with Ultiva versus 44-52% fentanyl and 39% sufentanil). Comparable haemodynamic stability was observed during surgery with Ultiva and comparator opioid regimens. After induction and during maintenance, remifentanil was associated with a higher incidence of hypotension or requirement for treatment of excessive anaesthesia than comparator opioid regimens.
Continuation of an Ultiva regimen at a fixed rate of 1 microgram/kg/minute into the immediate postoperative period (ICU) was effective in managing patient comfort. The protocol regimen for transition to alternative analgesia in advance of down titration and discontinuation from Ultiva during weaning for extubation, was effective. Although sedation was increased it did not result in significant delay in postoperative recovery. Times to discharge from an intensive care setting were comparable to fast track opioid regimens.
For the side effect profile in cardiac surgery, see Section 4.8 Adverse Effects (Undesirable Effects).

Neurosurgery.

Ultiva was administered to 61 patients undergoing craniotomy for removal of a supratentorial mass lesion. In these studies, ventilation was controlled to maintain a predicted PaCO2 of approximately 28 mmHg. In one study (n = 30) with Ultiva and 66% nitrous oxide, the median time to extubation and to patient response to verbal commands was five minutes (range 1 to 19 minutes). Intracranial pressure and cerebrovascular responsiveness to carbon dioxide were normal.
A randomised, controlled study compared Ultiva (n = 31) to fentanyl (n = 32). Ultiva (1 microgram/kg/minute) and fentanyl (2 microgram/kg/minute) were administered after induction with thiopentone and pancuronium. A similar number of patients (6%) receiving Ultiva and fentanyl had hypotension during induction. Anaesthesia was maintained with nitrous oxide and Ultiva at a mean infusion rate of 0.23 microgram/kg/minute (range 0.1 to 0.4) compared with a fentanyl mean infusion rate of 0.04 microgram/kg/minute (range 0.02 to 0.07). Supplemental isoflurane was administered as needed. The patients receiving Ultiva required a lower mean isoflurane dose (0.07 MAC hours) compared with 0.64 MAC hours for the fentanyl patients (p = 0.04). Ultiva was discontinued at the end of anaesthesia, whereas fentanyl was discontinued at the time of bone flap replacement (a median time of 44 minutes before the end of surgery). Median time to extubation was similar (5 and 3.5 minutes, respectively, with Ultiva and fentanyl). None of the patients receiving Ultiva required naloxone compared to seven of the fentanyl patients (p = 0.01). Eighty-one percent (81%) of patients receiving Ultiva recovered (awake, alert, and oriented) within 30 minutes after surgery compared with 59% of fentanyl patients (p = 0.06). At 45 minutes, recovery rates were similar (81% and 69%, respectively, for Ultiva and fentanyl, p = 0.27). Patients receiving Ultiva required an analgesic for headache sooner than fentanyl patients (median of 35 minutes compared with 136 minutes, respectively, p = 0.04). No adverse cerebrovascular effects were seen in this study.

Intensive care unit.

Three clinical studies were conducted to determine the safety and efficacy of remifentanil in a clinically relevant intensive care population requiring mechanical ventilation for up to three days. Two of these studies (USA03206 and USA 30207) were randomised, double blind, controlled, parallel group studies, the third of these (USA30212) was an open labelled, non-comparator study. A total of 261 patients received remifentanil, 81 received fentanyl and 83 received morphine. Of those receiving remifentanil, 32 were treated for ≥ 48 hours, 12 of whom had moderate/ severe renal impairment.
The randomised, double blind studies compared a remifentanil based analgesia/ sedation regimen with fentanyl or morphine based regimens. The opioid was initially titrated to achieve adequate levels for sedation (a patient who was calm, easily rousable and followed commands) and analgesia (no or mild pain). Frequent monitoring of the depth of sedation and analgesia was undertaken. Administration of sedative agent was initiated only if the target level of sedation could not be achieved with opioid alone.
A remifentanil based regimen was effective in providing optimal sedation for the majority (82% to 90%) of the maintenance phase. Fentanyl and morphine comparator regimens provided similar efficacy in terms of duration of optimal sedation. Remifentanil infusion alone provided optimal sedation in the majority (65% in USA30206, 78% in USA30207 and 43% in USA30212) of patients without the need for a supplementary sedative agent.
The primary end point, between patient variability in the percentage of hours of optimal sedation, was not statistically significantly different for remifentanil compared with fentanyl (study USA30206) or morphine (study USA30207).
Remifentanil was effective in providing adequate analgesia (no pain/ mild pain) for the majority (> 94%) of the maintenance phase. Fentanyl and morphine provided similar efficacy in terms of duration of adequate analgesia. Moderate/ severe pain was reported in a higher percentage of patients administered remifentanil compared to those administered morphine and fentanyl subsequent to down titration and discontinuation of the opioid. This was consistent with the rapid offset of the analgesic effects of remifentanil.
The time to extubation was rapid and comparable between remifentanil and the comparator regimens (median values ≤ 1.3 hours in studies USA30206 and USA30207).
Remifentanil was associated with acceptable haemodynamic stability during the maintenance phase, which was similar to that observed in patients administered morphine or fentanyl. A greater incidence of haemodynamic changes were reported in the extubation, post-extubation and post-treatment phases in the remifentanil group, which were related to a greater incidence of pain.
The data indicate that a remifentanil based regimen (starting infusion rate 0.1-0.15 microgram/kg/minute), was very effective for establishing and maintaining optimal analgesia and sedation in a wide range of IC patients, including those with severe renal impairment. In the majority of patients (≥ 60%) in the comparator studies there was no requirement for infusion of supplementary sedative agents (midazolam or propofol) to maintain optimal sedation (SAS 4). In study USA30212, where patients could be more deeply sedated (SAS 2-4), there was a greater requirement for supplementary use of sedative, i.e. 58% of patients required propofol infusion. Use of a remifentanil based regimen resulted in rapid extubation of the patients, similar to the comparator opioid regimens.

5.2 Pharmacokinetic Properties

Absorption.

Blood concentrations of remifentanil are proportional to the dose administered throughout the recommended dose range. For every 0.1 microgram/kg/min increase in infusion rate, the blood concentration of remifentanil will rise 2.5 nanogram/mL. Unlike other fentanyl analogues, the duration of action does not increase with prolonged administration.

Distribution.

The central volume of distribution is 100 mL/kg, and the steady-state volume of distribution is 350 mL/kg.
Remifentanil is approximately 70% bound to plasma proteins.

Metabolism.

Remifentanil is an esterase metabolised opioid. It is rapidly and extensively metabolised by nonspecific esterases in blood and tissues to the carboxylic acid derivative, GR90291. This metabolite is 4,600 times less active than the parent compound in quantitative EEG analysis of opioid activity.
It is unlikely that there is any clinically significant activity of the metabolite. The half-life of the metabolite in healthy adults is 2 hours. Approximately 95% of remifentanil is recovered in the urine as the carboxylic acid metabolite. Remifentanil is not a substrate for plasma cholinesterase.

Excretion.

Following administration of the recommended doses of remifentanil, the effective biological half-life is three to ten minutes due to redistribution. The terminal half-life of the unchanged drug is 10 to 20 minutes. The average clearance of remifentanil in young healthy adults is 40 mL/minute/kg. Clearance generally correlates with total bodyweight (with the exception of severely obese patients in whom it correlates with ideal bodyweight).

Placental and milk transfer.

Placental transfer studies in rats and rabbits showed that pups are exposed to remifentanil and/or its metabolites during growth and development. Remifentanil related material is transferred to the milk of lactating rats. In a human clinical trial, the concentration of remifentanil in foetal blood was approximately 50% of that in maternal blood. The foetal arteriovenous ratio of remifentanil concentrations was approximately 30% suggesting metabolism of remifentanil in the neonate.

Cardiac anaesthesia.

The clearance of remifentanil is reduced by approximately 20% during hypothermic (28°C) cardiopulmonary bypass. A decrease in body temperature lowers elimination clearance by 3% per degree Celsius.

Pharmacokinetics in patients with renal impairment.

After 72 hours of infusion, the rapid recovery from remifentanil based sedation and analgesia is unaffected by mild renal impairment and may be slightly prolonged in patients with moderate/ severe renal impairment (median time to offset of effects of remifentanil was 30 minutes in patients with moderate/ severe renal impairment compared with 13.5 minutes in mild renal impairment).
The pharmacokinetics of remifentanil are not significantly changed in patients with varying degrees of renal impairment even after administration for up to three 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 may exceed 250-fold the level of remifentanil at steady-state in some patients. There is no evidence that the metabolite produces clinically relevant mu-opioid effects even after administration of remifentanil infusions for up to three days in these patients. However, due to the limited data available, it is not known whether the accumulated metabolite has any other clinically relevant effects. (See Section 5.1 Pharmacodynamic Properties, Clinical trials, Intensive care unit.)
There is no evidence that remifentanil is extracted during renal replacement therapy.
The carboxylic acid metabolite is extracted during haemodialysis by at least 30%.

Pharmacokinetics in patients with hepatic impairment.

The pharmacokinetics of remifentanil are not changed in patients with severe hepatic impairment awaiting liver transplant, or during the anhepatic phase of liver transplant surgery. Individuals with severe hepatic impairment demonstrated statistically significant, reduced sensitivity to carbon dioxide stimulation of minute ventilation, which may indicate an increased sensitivity to the respiratory depressant effects of remifentanil. These patients should be closely monitored, and the dose of remifentanil should be titrated to the individual patient's need.

Pharmacokinetics in paediatric patients.

In paediatric patients 5 days to 17 years of age, the average clearance and steady-state volume of distribution of remifentanil are increased in younger children and decline to young healthy adult values by age 17. The half-life of remifentanil is not significantly different in neonates suggesting that changes in analgesic effect after changes in infusion rate of remifentanil should be rapid and similar to that seen in young healthy adults. The pharmacokinetics of the carboxylic acid metabolite in paediatric patients 2 to 17 years of age are similar to those seen in adults after correcting for differences in bodyweight.

Pharmacokinetics in elderly patients.

The clearance of remifentanil is reduced (approximately 25%) in elderly patients (> 65 years) compared to young patients. The pharmacodynamic activity of remifentanil increases with increasing age. The EC50 for formation of delta waves on the electroencephalogram (EEG) in elderly patients receiving remifentanil is 50% lower than in young patients; therefore, the initial dose of remifentanil should be reduced by 50% in elderly patients and then carefully titrated to meet the individual patient's need.

5.3 Preclinical Safety Data

Genotoxicity.

Remifentanil was not mutagenic in bacterial assays for gene mutations (Salmonella typhimurium histidine reversion assay), chromosomal aberrations (mouse micronucleus and Chinese hamster ovary chromosome) and a DNA repair assay (rat hepatocytes). However, a positive result was obtained in the mouse lymphoma L5178Y/tk+/- assay in the presence of metabolic activation.

Carcinogenicity.

There is no information currently available on the carcinogenic potential of remifentanil.

6 Pharmaceutical Particulars

6.1 List of Excipients

Glycine, hydrochloric acid, sodium hydroxide and water for injection.

6.2 Incompatibilities

Continuous infusions of Ultiva must be administered by a calibrated infusion device, where possible via a dedicated intravenous line, otherwise into a fast flowing IV line.
Ultiva should only be reconstituted and diluted with those infusion solutions recommended (see Section 4.2 Dose and Method of Administration, Instructions for use, Compatibilities).
Ultiva should not be reconstituted, diluted, or mixed with lactated Ringer's injection or lactated Ringer's and 5% glucose injection.
Ultiva should not be mixed with propofol in the same infusion bag prior to administration.
Administration of Ultiva into the same intravenous line with blood/serum/plasma is not recommended. Non-specific esterase in blood products may lead to the hydrolysis of Ultiva to its inactive metabolite.
Ultiva should not be mixed with other therapeutic agents prior to administration.

6.3 Shelf Life

1 mg - 18 months; 2 mg - 2 years; 5 mg - 3 years.
The reconstituted solution is chemically and physically stable for 48 hours at room temperature but since the product includes no preservative, reconstituted product should be used promptly and any unused material discarded.

6.4 Special Precautions for Storage

Store below 25°C.
For the reconstituted solution, if storage is necessary, hold at 2-8°C for not more than 24 hours to reduce microbiological hazard.

6.5 Nature and Contents of Container

Ultiva Injection is a sterile, non-pyrogenic, preservative-free, white to off-white lyophilised powder for intravenous use and is available as:
1 mg remifentanil base (as the hydrochloride salt) in 3 mL vials in cartons of 5.
2 mg remifentanil base (as the hydrochloride salt) in 5 mL vials in cartons of 5.
5 mg remifentanil base (as the hydrochloride salt) in 10 mL vials in cartons of 5.
Container labelled "Single dose".

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

The chemical name of remifentanil hydrochloride is 1-(2-methoxycarbonyl-ethyl)- 4-(phenyl-propionyl-amino)-piperidine-4-carboxylic acid methyl ester hydrochloride. The structural formula is given below:
Molecular formula: C20H28N2O5.HCl.
Molecular weight: 412.9.
The log Pn-octanol/water is 17.9. Remifentanil HCl possesses no chiral centres.

CAS number.

13539-07-2.

7 Medicine Schedule (Poisons Standard)

Schedule 8 - Controlled Drug.

Summary Table of Changes