Ultiva (remifentanil hydrochloride) for Injection 1 mg

Ultiva (remifentanil hydrochloride) for Injection 2 mg

Ultiva (remifentanil hydrochloride) for Injection 5 mg

Ultiva is a sterile, endotoxin-free, preservative-free, white to off white, lyophilized powder, to be reconstituted before use.

When reconstituted as directed, solutions of Ultiva are clear and colourless and contain 1mg/ml of remifentanil base as remifentanil hydrochloride.

Ultiva for injection is available in glass vials containing 1 mg, 2 mg or 5 mg of remifentanil base.

Lyophilized powder for reconstitution for intravenous administration.

Ultiva is indicated as an analgesic agent for use during induction and/or maintenance of general anaesthesia under close supervision.

Ultiva is indicated for provision of analgesia and sedation in mechanically ventilated intensive care patients 18 years of age and over.

Ultiva should be administered only in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function and by persons specifically trained in the use of anaesthetic drugs and the recognition and management of the expected adverse effects of potent opioids, including respiratory and cardiac resuscitation. Such training must include the establishment and maintenance of a patent airway and assisted ventilation.

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

There is a potential for the development of tolerance during administration of μ-opioid agonists.

Ultiva may be given by target controlled infusion (TCI) with an approved infusion device incorporating the Minto pharmacokinetic model with covariates for age and lean body mass (LBM) (Anesthesiology 1997;86;10-23)

Ultiva is stable for 24 hours at room temperature after reconstitution and further dilution 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 Injection0.45% Sodium Chloride Injection

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).

For TCI the recommended dilution of Ultiva is 20 to 50 micrograms/ml.

(See Section 6.6 Instructions for use/handling for additional information, including tables to help titrate Ultiva to the patient's anaesthetic needs).

General Anaesthesia - Adults

Administration by Manually-Controlled Infusion

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

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

DOSING GUIDELINES FOR ADULTS

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

At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended above to avoid excessive depth of anaesthesia (see Concomitant medication below).

Induction of anaesthesia: Ultiva should be administered with an hypnotic agent, such as propofol, thiopentone, or isoflurane, for the induction of anaesthesia. Administering Ultiva after an hypnotic agent will reduce the incidence of muscle rigidity. Ultiva can be administered at an infusion rate of 0.5 to 1 microgram/kg/min, with or without an initial bolus injection of 1 microgram/kg given over not less than 30 seconds. If endotracheal intubation is to occur more than 8 to 10 minutes after the start of the infusion of Ultiva, then a bolus injection is not necessary.

Maintenance of anaesthesia in ventilated patients: After endotracheal intubation, the infusion rate of Ultiva should be decreased, according to anaesthetic technique, as indicated in the above table. Due to the fast onset and short duration of action of Ultiva, the rate of administration during anaesthesia can be titrated upward in 25% to 100% increments or downward in 25% to 50% decrements, every 2 to 5 minutes to attain the desired level of μ-opioid response. In response to light anaesthesia, supplemental bolus injections may be administered every 2 to 5 minutes.

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

Concomitant medication: Ultiva decreases the amounts or doses of inhaled anaesthetics, hypnotics and benzodiazepines required for anaesthesia (see Section 4.5 Interaction with other medicaments and other forms of interaction).

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. The choice of analgesic should be appropriate for the patient's surgical procedure and the level of post-operative care.

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

Guidance on provision of analgesia and sedation in mechanically ventilated intensive care patients is provided below (see Intensive Care).

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 the table in Dosing Guidelines For Adults under 4.2 Posology and method of administration – General Anaesthesia – Adults - Administration by Manually-Controlled Infusion). 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 nanograms/ml. Ultiva should be titrated to individual patient response. For particularly stimulating surgical procedures target blood concentrations up to 15 nanograms/ml may be required.

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 (see Dosing Guidelines for Adults and Concomitant Medication under 4.2 Posology and method of administration – General Anaesthesia – Adults - Administration by Manually-Controlled Infusion).

For information on blood remifentanil concentrations achieved with manually-controlled infusion see Table 5.

There are insufficient data to make recommendations on the use of TCI for spontaneous ventilation anaesthesia.

Guidelines for discontinuation/continuation into the immediate post-operative 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 nanograms/ml. As with manually-controlled infusion, post-operative analgesia should be established before the end of surgery with longer acting analgesics (see Guidelines for discontinuation under 4.2 Posology and method of administration – General Anaesthesia – Adults - Administration by Manually-Controlled Infusion)

As there are insufficient data, the administration of Ultiva by TCI for the management of post-operative analgesia is not recommended.

General Anaesthesia - Paediatric patients (1 to12 years of age)

Co-administration of Ultiva with induction agents has not been studied. Ultiva TCI has not been studied in paediatric patients.

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. Paediatric patients should be monitored and the dose titrated to the depth of analgesia appropriate for the surgical procedure.

Induction of anaesthesia: The use of remifentanil for induction of anaesthesia in patients aged 1 to12 years is not recommended as there are no data available in this patient population.

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

DOSING GUIDELINES FOR PAEDIATRIC PATIENTS (1 to12 years of age)

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

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. No data are available for dosage recommendations for simultaneous use of other hypnotics with remifentanil (see section 4.2. Posology and method of administration, General Anaesthesia – Adults, Concomitant medication).

Guidelines for patient management in the immediate post-operative period/ Establishment of alternative analgesia prior to discontinuation of Ultiva: Due to the very rapid offset of action of Ultiva, no residual activity will be present within 5 to 10 minutes after discontinuation. For those patients undergoing surgical procedures where post-operative pain is anticipated, analgesics should be administered prior to discontinuation of Ultiva. Sufficient time must be allowed to reach the therapeutic effect of the longer acting analgesic. The choice of agent(s), the dose and the time of administration should be planned in advance and individually tailored to be appropriate for the patient's surgical procedure and the level of post-operative care anticipated (see section 4.4. Special warnings and precautions for use).

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, there are insufficient clinical data to make dosage recommendations for this age group.

Elderly (over 65 years of age):

General anaesthesia: Caution should be exercised in the administration of Ultiva in this population. 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 pharmacodynamic effects of remifentanil has been seen in this patient population.

Because of the increased sensitivity of elderly patients to Ultiva, when administering Ultiva by TCI in this population the initial target concentration should be 1.5 to 4 nanograms/ml with subsequent titration to response.

Cardiac anaesthesia: No initial dose reduction is required (See Cardiac Surgery below).

Intensive Care: No initial dose reduction is required (see Intensive Care).

Cardiac Surgery

Administration by Manually-Controlled Infusion

DOSING GUIDELINES FOR CARDIAC ANAESTHESIA

Ultiva is not recommended for use in patients with poor left ventricular function (left ventricular ejection fraction less than 0.35), since the safe use of the product in this patient group has not been established. There are no data available on use in patients under 18 years of age undergoing cardiac surgery.

Induction period of anaesthesia: After administration of hypnotic to achieve loss of consciousness, Ultiva should be administered at an initial infusion rate of 1 microgram/kg/min. The use of bolus injections of Ultiva during induction in cardiac surgical patients is not recommended. Endotracheal intubation should not occur until at least 5 minutes after the start of the infusion.

Maintenance period of anaesthesia: After endotracheal intubation the infusion rate of Ultiva can be titrated upward in 25% to 100% increments, or downward in 25% to 50% decrements, every 2 to 5 minutes according to patient need. Supplemental bolus doses, administered over not less than 30 seconds, may also be given every 2 to 5 minutes as required. High risk cardiac patients, such as those undergoing valve surgery, 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 above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended above to avoid excessive depth of anaesthesia. No data are available for dosage recommendations for simultaneous use of other hypnotics with remifentanil (see above under General Anaesthesia - Adults - Concomitant medication).

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

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 Undesirable effects). To minimise the risk of these occurring, adequate alternative analgesia must be established (as described above), before the Ultiva infusion is discontinued. The infusion rate should be reduced by 25% decrements in at least 10-minute intervals until the infusion is discontinued. During weaning from the ventilator the Ultiva infusion should not be increased and only down titration should occur, supplemented as required with alternative analgesics. Haemodynamic changes such as hypertension and tachycardia should be treated with alternative agents as appropriate.

Administration by Target-Controlled Infusion

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 the table in Dosing Guidelines for Cardiac Anaesthesia under 4.2 Posology and method of administration – Cardiac Surgery - Administration by Manually-Controlled Infusion). 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 nanograms/ml have been used in clinical studies. 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 (see table in Dosing Guidelines for Cardiac Anaesthesia and Concomitant medication paragraph under 4.2 Posology and method of administration - Cardiac Surgery -Administration by Manually-Controlled Infusion).

For information on blood remifentanil concentrations achieved with manually-controlled infusion see Table 5.

Guidelines for discontinuation/continuation into the immediate post-operative 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 nanograms/ml. As with manually-controlled infusion, post-operative analgesia should be established before the end of surgery with longer acting analgesics (see Guidelines for discontinuation under 4.2 Posology and method of administration – Cardiac Surgery - Administration by Manually-Controlled Infusion)

As there are insufficient data, the administration of Ultiva by TCI for the management of post-operative analgesia is not recommended.

Intensive Care - 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 (6 microgram/kg/h) to 0.15 microgram/kg/min (9 microgram/kg/h). The infusion rate should be titrated in increments of 0.025 microgram/kg/min (1.5 microgram/kg/h) to achieve the desired level of sedation and analgesia. A period of at least 5 minutes should be allowed between dose adjustments. The level of sedation and analgesia should be carefully monitored, regularly reassessed and the Ultiva infusion rate adjusted accordingly. If an infusion rate of 0.2 microgram/kg/min (12 microgram/kg/h) is reached and the desired level of sedation is not achieved, it is recommended that dosing with an appropriate sedative agent is initiated (see below). The dose of sedative agent should be titrated to obtain the desired level of sedation. Further increases to the Ultiva infusion rate in increments of 0.025 microgram/kg/min (1.5 microgram/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. As patients were not studied beyond three days, no evidence of safety and efficacy for longer treatment has been established.

The following table summarises the starting infusion rates and typical dose range for provision of analgesia and sedation in individual patients:

DOSING GUIDELINES FOR USE OF ULTIVA WITHIN THE INTENSIVE CARE SETTING

Bolus doses of Ultiva are not recommended in the intensive care setting.

The use of Ultiva will reduce the dosage requirement of any concomitant sedative agents. Typical starting doses for sedative agents, if required, are given below:

RECOMMENDED STARTING DOSE OF SEDATIVE AGENTS, IF REQUIRED

To allow separate titration of the respective agents sedative agents should not be 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 microgram/kg/min (6 microgram/kg/h) should be maintained for at least 5 minutes prior to the start of the stimulating procedure. Further dose adjustments may be made every 2 to 5 minutes in increments of 25%-50% in anticipation of, or in response to, additional requirement for analgesia. A mean infusion rate of 0.25 microgram/kg/min (15 microgram/kg/h), maximum 0.75 microgram/kg/min (45 microgram/kg/h), has been administered for provision of additional analgesia during stimulating procedures.

Establishment of alternative analgesia prior to discontinuation of Ultiva: Due to the very rapid offset of action of Ultiva, no residual opioid activity will be present within 5 to 10 minutes after discontinuation regardless of the duration of infusion. 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 prior to discontinuation of Ultiva.

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 microgram/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.

Ultiva TCI has not been studied in intensive care patients

Intensive Care - Paediatric patients

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

Renally-impaired intensive care patients

No adjustments to the doses recommended above are necessary in renally-impaired patients, including those undergoing renal replacement therapy (see Section 5.2 Pharmacokinetic properties).

Neurosurgery

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

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.

For TCI, a lower initial target of 1.5 to 4 nanograms/ml should be used in ASA III or IV patients and subsequently titrated to response.

Cardiac anaesthesia: No initial dose reduction is required.

Obese patients

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

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, remifentanil TCI should be titrated carefully to individual response.

Renal impairment

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

Hepatic impairment

No adjustment of the initial dose, relative to that used in healthy adults, is necessary as the pharmacokinetic profile of remifentanil is unchanged in this patient population. However, patients with severe hepatic impairment may be slightly more sensitive to the respiratory depressant effects of remifentanil. These patients should be closely monitored and the dose of Ultiva titrated to individual patient need.

As glycine is present in the formulation Ultiva is contra-indicated for epidural and intrathecal use.

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

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

Ultiva should be administered only in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function, and by persons specifically trained in the use of anaesthetic drugs and the recognition and management of the expected adverse effects of potent opioids, including respiratory and cardiac resuscitation. Such training must include the establishment and maintenance of a patent airway and assisted ventilation.

Rapid offset of action

Due to the very rapid offset of action of Ultiva, patients may emerge rapidly from anaesthesia and no residual opioid activity will be present within 5-10 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. Sufficient time must be allowed to reach the maximum effect of the longer acting analgesic. The choice of analgesic should be appropriate for the patient's surgical procedure and the level of post-operative care. 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

Common post-operative events associated with the emergence from general anaesthesia, such as shivering, agitation, tachycardia, hypertension, may occur earlier following discontinuation of Ultiva.

Symptoms including tachycardia, hypertension and agitation have been reported infrequently upon abrupt cessation, particularly after prolonged administration of Ultiva. Where reported, re-introduction 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. 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.

Muscle rigidity - prevention and management

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

Muscle rigidity induced by remifentanil must be treated in the context of the patient's clinical condition with appropriate supporting measures including ventilatory support. 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 - management

As with all potent opioids, profound analgesia is accompanied by marked respiratory depression. Therefore, remifentanil should only be used in areas where facilities for monitoring and dealing with respiratory depression are available. The appearance of respiratory depression should be managed appropriately, including decreasing the rate of infusion by 50%, or by 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 (see section 4.8 Undesirable Effects) 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.

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

Drug abuse

As with other opioids remifentanil may produce dependency.

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

As with other opioids remifentanil, whether given by manually-controlled infusion or TCI, decreases the amounts or doses of inhaled and IV anaesthetics, and benzodiazepines required for anaesthesia (see section 4.2 Posology and method of administration, General Anaesthesia – Adults, Paediatric Patients, and Cardiac Surgery). If doses of concomitantly administered CNS depressant drugs are not reduced patients may experience an increased incidence of adverse effects associated with these agents.

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.

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 remifentanil-related material was found in rat milk after dosing with remifentanil, caution should be exercised when remifentanil is administered to a nursing mother.

For a summary of the reproductive toxicity study findings please refer to Section 5.3 Preclinical safety data.

Labour and delivery

The safety profile of remifentanil during labour or delivery has not been demonstrated. There are insufficient data to recommend remifentanil for use during labour and Caesarean section. Remifentanil crosses the placental barrier and fentanyl analogues can cause respiratory depression in the child.

If an early discharge is envisaged, following treatment using anaesthetic agents, patients should be advised not to drive or operate machinery.

The most common adverse events associated with remifentanil are direct extensions of μ-opioid agonist pharmacology. These are acute respiratory depression, bradycardia, hypotension and/or skeletal muscle rigidity. These adverse events resolve within minutes of discontinuing or decreasing the rate of remifentanil administration.

Post-operative shivering, apnoea, hypertension, hypoxia, pruritis, constipation, aches, sedation, nausea and vomiting have also been reported.

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

In common with other opioids, very rare cases of asystole, usually preceded by severe bradycardia, have been reported in patients receiving remifentanil in conjunction with other anaesthetic agents.

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

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

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

Remifentanil is a selective μ-opioid agonist with a rapid onset and very short duration of action. The μ-opioid activity, of remifentanil, is antagonised 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 microgram/kg.

Following administration of the recommended doses of remifentanil, the effective biological half-life is 3-10 minutes. The average clearance of remifentanil in young healthy adults is 40ml/min/kg, the central volume of distribution is 100ml/kg and the steady-state volume of distribution is 350ml/kg. In children aged 1 to 12 years, remifentanil clearance and volume of distribution decreases with increasing age; the values of these parameters in neonates are approximately twice those of healthy young adults.

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 2.5nanograms/ml. Remifentanil is approximately 70% bound to plasma proteins.

Metabolism

Remifentanil is an esterase metabolised opioid that is susceptible to metabolism by non-specific blood and tissue esterases. The metabolism of remifentanil results in the formation of an essentially inactive carboxylic acid metabolite (1/4600th as potent as remifentanil). 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.

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 centigrade.

Renal impairment

The rapid recovery from remifentanil-based sedation and analgesia is 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 reach approximately 100-fold the level of remifentanil at steady-state. Clinical data demonstrate that the 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 25 - 35 %.

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. Patients with severe hepatic impairment may be slightly more sensitive 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 need.

Paediatric patients

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 elimination half-life of remifentanil in neonates is not significantly different from that of young healthy adults. Changes in analgesic effect after changes in infusion rate of remifentanil should be rapid and similar to those seen in young healthy adults. The pharmacokinetics of the carboxylic acid metabolite in paediatric patients 2-17 years of age are similar to those seen in adults after correcting for differences in body weight.

Elderly

The clearance of remifentanil is slightly reduced (approximately 25%) in elderly patients>65 years) compared to young patients. The pharmacodynamic activity of remifentanil increases with increasing age. Elderly patients have a remifentanil EC50 for formation of delta waves on the electroencephalogram (EEG) that is 50% lower than 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 need.

Intrathecal administration of the glycine formulation without remifentanil to dogs caused agitation, pain and hind limb dysfunction and incoordination. These effects are believed to be secondary to the glycine excipient. Glycine is a commonly used excipient in intravenous products and this finding has no relevance for intravenous administration of Ultiva.

Remifentanil, like other opioid agonists, produced increases in action potential duration (APD) in dog isolated Purkinje fibres. For remifentanil, the effects were seen at concentrations of 1μM or higher (which are higher than plasma concentrations seen in clinical practice). There were no effects at a concentration of 0.1μM.

The major metabolite remifentanil acid had no effect on APD up to the maximum tested concentration of 10μM.

Reproductive toxicity studies

Remifentanil has been shown to reduce fertility in male rats when administered daily by intravenous injection for at least 70 days at a dose of 0.5mg/kg, or approximately 250 times the maximum recommended human bolus dose of 2 microgram/kg. The fertility of female rats was not affected at doses up to 1mg/kg when administered for at least 15 days prior to mating. No teratogenic effects have been observed with remifentanil at doses up to 5mg/kg in rats and 0.8mg/kg in rabbits. Administration of remifentanil to rats throughout late gestation and lactation at doses up to 5mg/kg IV had no significant effect on the survival, development, or reproductive performance of the F1 generation.

Genotoxicity

Remifentanil was devoid of genotoxic activity in bacteria and in rat liver or mouse bone marrow cells in vivo. However, a positive response was seen in vitro in different mammalian cell systems in the presence of a metabolic activation system. This activity was seen only at concentrations more than three orders of magnitude higher than therapeutic blood levels.

Glycine Ph. Eur.

Hydrochloric acid Ph. Eur.

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

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. Non-specific esterases 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 for Injection 1mg: 18 months

Ultiva for Injection 2mg: 2 years

Ultiva for Injection 5mg: 3 years

Store at or below 25°C.

The reconstituted solution of Ultiva is chemically and physically stable for 24 hours at room temperature. However, Ultiva does not contain an antimicrobial preservative and thus care must be taken to assure the sterility of prepared solutions, reconstituted product should be used promptly, and any unused material discarded.

Ultiva for Injection 1mg for intravenous use is available as 1mg of Remifentanil lyophilised powder in 3ml vials, in cartons of 5.

Ultiva for Injection 2mg for intravenous use is available as 2mg of Remifentanil lyophilised powder in 5ml vials, in cartons of 5.

Ultiva for Injection 5mg for intravenous use is available as 5mg of Remifentanil lyophilised powder in 10ml vials, in cartons of 5.

Ultiva is stable for 24 hours at room temperature after reconstitution and further dilution 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

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 patents aged 1 year and over).

For TCI the recommended dilution of Ultiva is 20 to 50 micrograms/ml.

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

Lactated Ringer's Injection

Lactated Ringer's and 5% Dextrose Injection

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

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

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

Table 2 Ultiva for Injection Infusion Rates (ml/h) for a 25 microgram/ml Solution

Table 3. Ultiva for Injection Infusion Rates (ml/h) for a 50 microgram/ml Solution

Table 4. Ultiva for Injection Infusion Rates (ml/h) for a 250 microgram/ml Solution

The following table provides the equivalent blood remifentanil concentration using a TCI approach for various manually-controlled infusion rates at steady state:

Table 5. Remifentanil Blood Concentrations (nanograms/ml) estimated using the Minto (1997) Pharmacokinetic Model in a 70 kg, 170 cm, 40 Year Old Male Patient for Various Manually-Controlled Infusion rates (micrograms /kg/min) at Steady State.

GlaxoSmithKline UK Ltd

980 Great West Rd

Brentford

Middlesex

TW8 9GS

19494/0026 < Ultiva for Injection 1mg>

19494/0027 <Ultiva for Injection 2mg>

19494/0028 < Ultiva for Injection 5mg>

01 May 2004

17 September 2009