Ultiva

Remifentanil hydrochloride.

Ultiva is a sterile, endotoxin-free, preservative-free, white to off white, lyophilized powder, to be reconstituted before use.
Ultiva 1 mg: 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 remifentanil base.
Excipients/Inactive Ingredients: Glycine Ph. Eur, Hydrochloric acid Ph. Eur.

Pharmacology: Pharmacodynamics: Remifentanil is a selective μ-opioid agonist with a rapid onset and very short duration of action. The μ-opioid activity, of Remifentanil, is antagonized by narcotic antagonists such as naloxone.
Assays of histamine in patients and normal volunteers have shown no elevation in histamine levels after administration of remifentanil in bolus doses up to 30 µg/kg.
Neonates/infants (aged less than 1 year): In a randomised (ratio of 2:1, remifentanil:halothane), open label, parallel group, multicentre study in 60 young infants and neonates ≤8 weeks of age (mean 5.5 weeks) with an ASA physical status of I-II who were undergoing pyloromyotomy, the efficacy and safety of remifentanil (given as a 0.4 μg/kg/min initial continuous infusion plus supplemental doses or infusion rate changes as needed) was compared with halothane (given at 0.4% with supplemental increases as needed). Maintenance of anaesthesia was achieved by the additional administration of 70% nitrous oxide (N20) plus 30% oxygen. Recovery times were superior in the remifentanil relative to the halothane groups (not significant).
Use for Total Intravenous anaesthesia (TIVA) - children aged 6 months to 16 years.
TIVA with remifentanil in paediatric surgery was compared to inhalation anaesthesia in three randomised, open-label studies. The results are summarised in the table as follows. (See Table 1.)

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In the study in lower abdominal/urological surgery comparing remifentanil/propofol with remifentanil/sevoflurane, hypotension occurred significantly more often under remifentanil/sevoflurane, and bradycardia occurred significantly more often under remifentanil/propofol. In the study in ENT surgery comparing remifentanil/propofol with desflurane/nitrous oxide, a significantly higher heart rate was seen in subjects receiving desflurane/nitrous oxide compared with remifentanil/propofol and with baseline values.
Pharmacokinetics: 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 40 mL/min/kg, the central volume of distribution is 100 mL/kg and the steady-state volume of distribution is 350 mL/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 µg/kg/min increase in infusion rate, the blood concentration of remifentanil will rise 2.5 ng/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 may exceed 250-fold the level of remifentanil at steady-state in some patients. Clinical data demonstrates that accumulation of the metabolite does not result in clinically relevant μ-opioid effects even after administration of remifentanil infusions for up to 3 days in these patients.
There is no evidence that remifentanil is extracted during renal replacement therapy.
The carboxylic acid metabolite is extracted during haemodialysis by at least 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 to 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.
Placental and milk transfer: In a human clinical trial, the mean ratio of maternal arterial to umbilical venous concentration indicated that the neonate was exposed to approximately 50% concentration of remifentanil to that in the mother. The mean umbilical arteriovenous ratio of remifentanil concentrations was approximately 30% suggesting metabolism of remifentanil in the neonate.
Toxicology: Pre-clinical Safety Data: 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 1 µM or higher (which are higher than plasma concentrations seen in clinical practice). There were no effects at a concentration of 0.1 µM.
The major metabolite remifentanil acid had no effect on APD up to the maximum tested concentration of 10 µM.
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 0.5 mg/kg, or approximately 250 times the maximum recommended human bolus dose of 2 µg/kg. The fertility of female rats was not affected at doses up to 1 mg/kg when administered for at least 15 days prior to mating. No teratogenic effects have been observed with remifentanil at doses up to 5 mg/kg in rats and 0.8 mg/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.

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.
Continuous infusions of Ultiva must be administered by a calibrated infusion device into a fast flowing IV line or via a dedicated IV line. This infusion line should be connected at, or close to, the venous cannula and primed, to minimise the potential dead space (see Instructions for use/handling under Cautions for Usage for additional information, including tablets with examples of infusion rates by body weight to help titrate Ultiva to the patient's anaesthetic needs.)
Care should be taken to avoid obstruction or disconnection of infusion lines and to adequately clear the lines to remove residual Ultiva after use (see Precautions).
Ultiva is for intravenous use only and must not be administered by epidural or intrathecal injection (see Contraindications).
Dilution: Ultiva may be further diluted after reconstitution (see Cautions for Usage and Storage for storage conditions of the reconstituted/diluted product and the recommended diluents).
For manually-controlled infusion Ultiva can be diluted to concentrations of 20 to 250 µg/mL (50 µg/mL is the recommended dilution for adults and 20 to 25 µg/mL for paediatric patients aged 1 year and over) (see Instructions for Use/Handling under Cautions for Usage for additional information, including tables to help titrate Ultiva to the patient's anaesthetic needs).
General Anaesthesia: The administration of Ultiva must be individualised based on the patient's response. Specific dosing guidelines for patients undergoing cardiac surgery are provided as follows.
Adults: Administration by Manually-Controlled Infusion:The following table summarises the starting infusion rates and dose range: (See Table 2.)

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When given by bolus injection at induction Ultiva should be administered over not less than 30 seconds.
At the doses recommended previously, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended previously to avoid an increase of haemodynamic effects such as hypotension and bradycardia (see Concomitant medication as follows).
Induction of anaesthesia: Ultiva should be administered with a standard dose of an hypnotic agent, such as propofol, thiopentone, or isoflurane, for the induction of anaesthesia. Administering Ultiva after a hypnotic agent will reduce the incidence of muscle rigidity. Ultiva can be administered at an infusion rate of 0.5 to 1 μg/kg/min, with or without an initial slow bolus injection of 1 μg/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 slow bolus injections may be administered every 2 to 5 minutes.
Anaesthesia in spontaneously breathing anaesthetized patients with a secured airway (e.g. laryngeal mask anaesthesia): In spontaneously breathing anaesthetized 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 anaesthetized patients is 0.04 μg/kg/min with titration to effect. A range of infusion rates from 0.025 to 0.1 μg/kg/min has been studied. Bolus injections are not recommended in spontaneously breathing anaesthetized patients.
Ultiva should not be used as an analgesic in procedures where patients remain conscious or do not receive any airway support during the procedure.
Concomitant medication: Ultiva decreases the amounts or doses of inhaled anaesthetics, hypnotics and benzodiazepines required for anaesthesia (see 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 remifentanil.
Guidelines for discontinuation / continuation into the immediate post-operative period: 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 Precautions).
In the event that longer acting analgesia has not been established prior to the end of surgery, Ultiva may need to be continued to maintain analgesia during the immediate post-operative period until longer acting analgesia has reached its maximum effect.
Guidance on provision of analgesia and sedation in mechanically ventilated intensive care patients is provided as follows.
In patients who are breathing spontaneously, the infusion rate of Ultiva should initially be decreased to a rate of 0.1 µg/kg/min. The infusion rate may then be increased or decreased by not greater than 0.025 µg/kg/min every five minutes, to balance the patient's level of analgesia and respiratory rate. Ultiva should only be used in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function, under the close supervision of persons specifically trained in the recognition and management of the respiratory effects of potent opioids.
The use of bolus injections of Ultiva to treat pain during the post-operative period is not recommended in patients who are breathing spontaneously.
Paediatric patients (1-12 years of age): Co-administration of Ultiva and an intravenous anaesthetic agent for induction of anaesthesia has not been studied in detail and is therefore not recommended.
When given by bolus injection Ultiva should be administered over not less than 30 seconds. Surgery should not commence until at least 5 minutes after the start of the Ultiva infusion, if a simultaneous bolus dose has not been given. For sole administration of nitrous oxide (70%) with Ultiva, typical maintenance infusion rates should be between 0.4 and 3 µg/kg/min, and although not specifically studied, adult data suggest that 0.4 µg/kg/min is an appropriate starting rate. Paediatric patients should be monitored and the dose titrated to the depth of analgesia appropriate for the surgical procedure.
Induction of anaesthesia: The use of remifentanil for induction of anesthesia in patients aged 1-12 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: (See Table 3.)

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Concomitant medication: At the doses recommended previously, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane, halothane and sevoflurane should be administered as recommended previously to avoid an increase of haemodynamic effects such as hypotension and bradycardia. No data are available for dosage recommendations for simultaneous use of other hypnotics other than those listed in the table with remifentanil (see Adults - Concomitant medication previously mentioned).
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 Precautions).
Neonates/infants (aged less than 1 year): There is limited clinical trial experience of remifentanil in neonates and infants (aged under 1 year old; see Pharmacology: Pharmacodynamics under Actions). The pharmacokinetic profile of remifentanil in neonates/infants (aged less than 1 year) is comparable to that seen in adults after correction for body weight differences (see Pharmacology: Pharmacokinetics under Actions). However, because there are insufficient clinical data, the administration of Ultiva is not recommended for this age group.
Use for Total Intravenous anaesthesia (TIVA): There is limited clinical trial experience of remifentanil for TIVA in infants (see Pharmacology: Pharmacodynamics under Actions). However, there are insufficient clinical data to make dosage recommendations.
Cardiac Anaesthesia: Administration by Manually-Controlled Infusion: (See Table 4.)

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Induction period of anaesthesia: After administration of hypnotic to achieve loss of consciousness, Ultiva should be administered at an initial infusion rate of 1 µg/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 slow bolus doses, administered over not less than 30 seconds, may also be given every 2 to 5 minutes as required. High risk cardiac patient, such as those with poor ventricular function or undergoing valve surgery, should be administered a maximum bolus dose of 0.5 µg/kg. These dosing recommendations also apply during hypothermic cardiopulmonary bypass (see Pharmacology: Pharmacokinetics under Actions-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 previously to avoid excessive depth of anaesthesia. No data are available for dosage recommendations for simultaneous use of other hypnotics other than those listed in the table with remifentanil (see Adults - Concomitant medication previously mentioned).
Guidelines for post-operative patient management: 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 Use in intensive Care as follows for further information on management of intensive care patients).
Establishment of alternative analgesia prior to discontinuation of Ultiva: Due to the very rapid offset of action of Ultiva, no residual opioid activity will be present within 5 to 10 minutes after discontinuation. Prior to discontinuation of Ultiva, patients must be given alternative analgesic and sedative agents at a sufficient time in advance to allow the therapeutic effects of these agents to become established. It is therefore recommended that the choice of agent(s), the dose and the time of administration are planned, before weaning the patient from the ventilator.
Guidelines for discontinuation of Ultiva: Due to the very rapid offset of action of Ultiva, hypertension, shivering and aches have been reported in cardiac patients immediately following discontinuation of Ultiva (see Adverse Reactions). To minimize the risk of these occurring, adequate alternative analgesia must be established (as described previously), before the Ultiva infusion is discontinued. The infusion rate should be reduced by 25% decrements in at least 10-minutes intervals until the infusion is discontinued.
During weaning from the ventilator the Ultiva infusion should not be increased and only down titration should occur, supplemented as required with alternative analgesics. Haemodynamic changes such as hypertension and tachycardia should be treated with alternative agents as appropriate.
When other opioid agents are administered as part of the regimen for transition to alternative analgesia, the patient must be carefully monitored. The benefit of providing adequate post-operative analgesia must always be balanced against the potential risk of respiratory depression with these agents.
Use in Intensive Care: Ultiva can be used for the provision of analgesia in mechanically ventilated intensive care patients. Sedative agents should be used as appropriate.
Ultiva has been studied in mechanically ventilated 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. Therefore, the use of Ultiva is not recommended for a duration of treatment greater than 3 days.
In adults, it is recommended that Ultiva is initiated at an infusion rate of 0.1 µg/kg/min (6 µg/kg/h) to 0.15 µg/kg/min (9 µg/kg/h). The infusion rate should be titrated in increments of 0.025 µg/kg/min (1.5 µg/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 µg/kg/min (12 µg/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 as follows). 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 µg/kg/min (1.5 µg/kg/h) may be made if additional analgesia is required.
The following table summarises the starting infusion rates and typical dose range for provision of analgesia and sedation in individual patients: (See Table 5.)

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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 as follows: (See Table 6.)

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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 µg/kg/min (6 µg/kg/h) should be maintained for at least 5 minutes prior to the start of the stimulating procedure. Further dose adjustments may be made every 2 to 5 minutes in increments of 25% to 50% in anticipation of, or in response to, additional requirement for analgesia. A mean infusion rate of 0.25 µg/kg/min (15 µg/kg/h), maximum 0.75 µg/kg/min (45 µg/kg/h), has been administered for provision of additional anaesthesia during stimulating procedures.
Establishment of alternative analgesia prior to discontinuation of Ultiva: Due to the very rapid offset of action of Ultiva, no residual opioid activity will be present within 5 to 10 minutes after discontinuation regardless of the duration of infusion. Following administration of Ultiva, the possibility of tolerance and hyperalgesia should be considered. Therefore, prior to discontinuation of Ultiva, patients must be given alternative analgesic and sedative agents to prevent hyperalgesia and associated haemodynamic changes. These agents must be given at a sufficient time in advance to allow the therapeutic effects of these agents to become established. The range of options for analgesia includes long acting oral, intravenous, or regional analgesics controlled by the nurse or the patient. These techniques should always be titrated to individual patient needs as the infusion of Ultiva is reduced. It is recommended that the choice of agent(s), the dose and the time of administration are planned prior to discontinuation of Ultiva.
There is a potential for the development of tolerance with time during prolonged administration of µ-opioid agonists.
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 µg/kg/min (6 µg/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-minutes 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.
Paediatric Intensive Care 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; however the clearance of the carboxylic acid metabolite is reduced in patients with renal impairment. (See Pharmacology: Pharmacokinetics under Actions).
Special patient populations: Elderly (over 65 years of age): General anaesthesia: The initial starting dose of remifentanil administered to patients over 65 should be half the recommended adult dose and then shall be titrated to individual patient need as an increased sensitivity to the pharmacological effects of remifentanil has been seen in this patient population. This dose adjustment applies to use in all phases of anaesthesia including induction, maintenance, and immediate post-operative analgesia.
Cardiac anaesthesia: No initial dose reduction is required (see Cardiac Anaesthesia previously mentioned).
Intensive care: No initial dose reduction is required (see Use in Intensive Care previously mentioned).
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.
Renal impairment: On the basis of investigations carried out to date, a dose adjustment in patients with impaired renal function, including intensive care patients is not necessary.
Hepatic impairment: Studies carried out with a limited numbers of patients with impaired liver function, do not justify any special dosage recommendations. However, patients with severe hepatic impairment may be slightly more sensitive to the respiratory depressant effects of remifentanil (see Precautions). These patients should be closely monitored and the dose of remifentanil shall be titrated to individual patient need.
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. In paediatric patients, there are insufficient data to make a dosage recommendation.
Cardiac anaesthesia: No initial dose reduction is required (see Cardiac Anaethesia mentioned previously).

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

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. The use of Ultiva in mechanically ventilated intensive care patients is not recommended for a duration of treatment greater than 3 days.
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 remifentanil in these patients (see Contraindications).
Rapid offset of action/Transition to alternative analgesia: Due to the very rapid offset of action of Ultiva, no residual opioid activity will be present within 5-10 minutes after the discontinuation of Ultiva. For those patients undergoing surgical procedures where post-operative pain is anticipated, analgesics should be administered prior to discontinuation of Ultiva. The possibility of tolerance, hyperalgesia and associated haemodynamic changes should be considered when used in Intensive Care Unit. Prior to discontinuation of Ultiva, patients must be given alternative analgesic and sedative agents. Sufficient time must be allowed to reach the therapeutic effect of the longer acting analgesic. The choice of agent(s), the dose and the time of administration should be planned in advance and individually tailored to be appropriate for the patient's surgical procedure and the level of post-operative care anticipated. When other opioid agents are administered as part of the regimen for transition to alternative analgesia, the benefit of providing adequate post-operative analgesia must always be balanced against the potential risk of respiratory depression with these agents.
Discontinuation of Treatment: Symptoms following withdrawal of Ultiva including tachycardia, hypertension and agitation have been reported infrequently upon abrupt cessation, particularly after prolonged administration of more than 3 days. Where reported, re-introduction and tapering of the infusion has been beneficial. The use of Ultiva in mechanically ventilated intensive care patients is not recommended for duration of treatment greater than 3 days.
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 - prevention and 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: The risk of cardiovascular effects such as hypotension and bradycardia (see Adverse Reactions), which may rarely lead to asystole/cardiac arrest may be reduced by lowering the rate of infusion of Ultiva or the dose of concurrent anaesthetics or by using IV fluids, vasopressor or anticholinergic agents as appropriate.
Debilitated, hypovolaemic, and elderly patients may be more sensitive to the cardiovascular effects of remifentanil.
Neonates/infants: There is limited data available on use in neonates/infants under 1 year of age (see Pharmacology: Pharmacodynamics under Actions and Dosage & Administration).
Drug abuse: As with other opioids remifentanil may produce dependency.
Effects on ability to drive and use machines: After anaesthesia with remifentanil the patient should not drive or operate machinery. The physician should decide when these activities may be resumed. It is advisable that the patient is accompanied when returning home and that alcoholic drink is avoided.
This medicine can impair cognitive function and can affect a patient's ability to drive safely.

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, nursing mothers should be advised to discontinue breast-feeding for 24 hours following administration of remifentanil.
For a summary of the reproductive toxicity study findings please refer to Pharmacology: Toxicology: Preclinical safety data under Actions.
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.

The most common adverse events associated with remifentanil are direct extensions of µ-opioid agonist pharmacology. These adverse events resolve within minutes of discontinuing or decreasing the rate of Remifentanil administration.
The frequencies as follows are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000), not known (cannot be estimated from the available data).
Immune System Disorders: Rare: Allergic reactions including anaphylaxis have been reported in patients receiving remifentanil in conjunction with one or more anaesthetic agents.
Psychiatric disorders: Not known: Drug dependence.
Nervous System Disorders: Very common: Skeletal muscle rigidity.
Rare: Sedation (during recovery from general anaesthesia).
Not known: Convulsions
Cardiac Disorders: Common: Bradycardia.
Rare: Asystole/cardiac arrest, usually preceded by bradycardia, has been reported in patients receiving remifentanil in conjunction with other anaesthetic agents.
Not known: Atrioventricular block.
Vascular Disorders: Very common: Hypotension.
Common: Post-operative hypertension.
Respiratory, Thoracic and Mediastinal Disorders: Common: Acute respiratory depression, apnoea.
Uncommon: Hypoxia.
Gastrointestinal Disorders: Very common: Nausea, vomiting.
Uncommon: Constipation.
Skin and Subcutaneous Tissue Disorders: Common: Pruritus.
General Disorders and Administration Site Conditions: Common: Post-operative shivering.
Uncommon: Post-operative aches.
Not known: Drug tolerance.
Discontinuation of Treatment: Symptoms following withdrawal of remifentanil including tachycardia, hypertension and agitation have been reported infrequently upon abrupt cessation, particularly after prolonged administration of more than 3 days (see Precautions).

Remifentanil is not metabolised by plasmacholinesterase, therefore, interactions with drugs metabolised by this enzyme are not anticipated.
As with other opioids, remifentanil decreases the amounts or doses of inhaled and IV anaesthetics, and benzodiazepines required for anaesthesia (see Dosage & 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.

Instructions for use/handling: Ultiva should be prepared for intravenous use by adding, as appropriate 1 mL of diluent to give a reconstituted solution with a concentration of 1 mg/mL remifentanil. The reconstituted solution is clear, colourless, and practically free from particulate material. After reconstitution, visually inspect the product (where the container permits) for particulate material, discolouration or damage of container. Discard any solution where such defects are observed. Reconstituted product is for single use only. Any unused material should be discarded.
Ultiva should not be administered by manually-controlled infusion without further dilution to 20 to 250 µg/mL (50 µg/mL is recommended dilution for adults and 20-25 µg/mL in paediatric patients aged 1 year and over).
The dilution is dependent upon the technical capability of the infusion device and the anticipated requirements of the patient.
One of the following IV fluids listed as follows should be used for dilution: Water for Injections; Glucose 5% solution for injection; Glucose 5% and Sodium Chloride 0.9% solution for injection; Sodium Chloride 0.9% solution for injection; Sodium Chloride 0.45% solution for injection.
After dilution, visually inspect the product to ensure it is clear, colourless, practically free from particulate matter and the container is undamaged.
Discard any solution where such defects are observed.
Ultiva has been shown to be compatible with the following intravenous fluids when administered into running IV catheter of: Lactated Ringer's solution for injection; Lactated Ringer's and Glucose 5% solution for injection.
Ultiva has been shown to be compatible with propofol when administered into running IV catheter.
The following tables give guidelines for infusion rates of Ultiva for manually-controlled infusion: (See Tables 7, 8, 9, 10 and 11.)

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Incompatibilities: Ultiva should only be reconstituted and diluted with those infusion solutions recommended (see Instructions for use/handling).
It should not be reconstitute, diluted, or mixed with Lactated Ringer's Injection or Lactated Ringer's and 5% Dextrose 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 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.

Store at or below 25°C.
The reconstituted solution of Ultiva is chemically and physically stable for 24 hours at room temperature (25°C). 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.

Anaesthetics - Local & General

N01AH06 - remifentanil ; Belongs to the class of opioid anesthetics. Used as general anesthetics.

DD, P₁S₁S₃

Inj (vial, sterile, endotoxin-free, preservative-free, white to off-white, lyophilized powder) 1 mg x 5's. 2 mg x 5's.