Remifentanil 1 Mg/2 Mg/5 Mg Solution

REMIFENTANIL B. BRAUN is indicated as a narcotic analgesic or adjuvant for use during induction and/or maintenance of inhalation anaesthesia during surgical procedures, including cardiac surgery. REMIFENTANIL B. BRAUN is indicated for the provision of analgesia as an aid to sedation (up to 72 hours sedation) in mechanically ventilated intensive care patients. Safety and efficacy beyond 72 hours has not been demonstrated.

Posology Continuous infusion of REMIFENTANIL B. BRAUN 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. Care should be taken to avoid obstruction or disconnection of infusion lines and to adequately clear the lines to remove residual REMIFENTANIL B. BRAUN after use (see section 4.4). REMIFENTANIL B. BRAUN is for intravenous use only and must not be administered by epidural or intrathecal injection. Reconstitution: See section 6.6.

GENERAL ANAESTHESIA: The administration of REMIFENTANIL B. BRAUN must be individualized based on the patient's response. Adults: The following table summarises the starting infusion rates and dosage range:

Dosing Guidelines for Adults

At the doses recommended, REMIFENTANIL B. BRAUN significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane should be administered as recommended above to avoid excessive depth of anaesthesia (see section 4.5).

Induction of anaesthesia: REMIFENTANIL B. BRAUN should be administered with a hypnotic agent, such as isoflurane, for the induction of anaesthesia. REMIFENTANIL B. BRAUN can be administered at an infusion rate of 0,5 - 1,0 u03bcg/kg/min with or without an initial bolus infusion 1 u03bcg/kg over not less than 30 seconds. If endotracheal intubation is to occur more than 8 to 10 minutes after the start of the REMIFENTANIL B. BRAUN infusion, then a bolus infusion is not necessary. Maintenance of anaesthesia: After endotracheal intubation, the infusion rate of REMIFENTANIL B. BRAUN should be decreased, according to the anaesthetic technique, as indicated in the above table. Due to the fast onset and short duration of action of REMIFENTANIL B. BRAUN, the rate of administration during anaesthesia can be titrated upward in 25 - 100 % increments or downward in 25 - 50 % decrements, every 2 to 5 minutes to attain the desired level of u03bc-opioid response. In response to light anaesthesia, supplemental bolus infusions may be administered every 2 to 5 minutes. The use of REMIFENTANIL B. BRAUN to treat pain during the post-operative period is not recommended in patients who are breathing spontaneously. Guidelines for discontinuation: Due to the very rapid offset of action of REMIFENTANIL B. BRAUN, residual opioid activity will be reduced 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, or immediately following discontinuation of REMIFENTANIL B. BRAUN. 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.

Concomitant medication: REMIFENTANIL B. BRAUN decreases the amounts or doses of inhaled anaesthetics, hypnotics and benzodiazepines required for anaesthesia (see section 4.5).

Paediatric population Paediatric patients (1 - 12 years of age): Induction of anaesthesia: REMIFENTANIL B. BRAUN is not recommended for the induction of anaesthesia as insufficient data are available. Maintenance of anaesthesia: Dosing Guidelines for Maintenance of Anaesthesia in Paediatric Patients (1 - 12 years of age) Concomitant Anaesthetic Agent Bolus Infusion of REMIFENTANIL B. BRAUN Continuous Infusion of REMIFENTANIL B. BRAUN (u03bcg/kg/min) Starting Rate Typical Maintenance Rates Halothane (starting dose 0,3 MAC) Sevoflurane (starting dose 0,3 MAC) Isoflurane (starting dose 0,5 MAC) 1 1 1 0,25 0,25 0,25 0,05 to 1,3 0,05 to 0,9 0,06 to 0,9

When given by bolus infusion, REMIFENTANIL B. BRAUN should be administered over not less than 30 seconds. Surgery should not commence until at least 5 minutes after the start of the REMIFENTANIL B. BRAUN 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 above, the REMIFENTANIL B. BRAUN 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 the REMIFENTANIL B. BRAUN. Guidelines for discontinuation: Following discontinuation of infusion, the onset of analgesic effect of the REMIFENTANIL B. BRAUN is rapid and similar to that seen in adult patients. Appropriate post-operative analgesic requirements should be anticipated and implemented (see Adults - Guidelines for discontinuation).

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 of body weight differences. However, there are insufficient clinical data to make dosage recommendations for this age group.

As glycine is present in the formulation, REMIFENTANIL B. BRAUN is contra- indicated for epidural and intrathecal use (see section 5.3)

• Hypersensitivity to the remifentanil and other fentanyl analogues or to any of the excipients listed in section 6.1.
• Safety in pregnancy and lactation has not been established (see section 4.6).
• REMIFENTANIL B. BRAUN should not be used with nitrous oxide and oxygen alone at altitudes above sea level.
• REMIFENTANIL B. BRAUN should not be used unless artificial ventilation is planned.

Remifentanil, such as REMIFENTANIL B. BRAUN, 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 medicine 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 (see section 4.2). As mechanically ventilated, intensive care patients were not studied beyond three days, no evidence of safety and efficacy for longer treatment has been established. Therefore, a longer usage is not recommended in intensive care patients.

Rapid offset of action/transition to alternative analgesia: Due to the very rapid offset of action of remifentanil such as REMIFENTANIL B. BRAUN, patients merge rapidly from anaesthesia and no residual opioid activity will be present within 5 - 10 minutes after the discontinuation of REMIFENTANIL B. BRAUN. During administration of remifentanil such as REMIFENTANIL B. BRAUN as a u03bc-opioid agonist the potential for the development of tolerance and hyperalgesia should be paid attention to. Therefore, prior to discontinuation of REMIFENTANIL B. BRAUN, 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 more established and to prevent hyperalgesia and concomitant haemodynamic changes. For those patients undergoing surgical procedures where post-operative pain is anticipated, analgesics should be administered prior to discontinuation of REMIFENTANIL B. BRAUN. 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: Symptoms following withdrawal of remifentanil such as REMIFENTANIL B. BRAUN including tachycardia, hypertension and agitation have been reported infrequently upon abrupt cessation, particularly after prolonged administration of 3 days. Where reported, re-introduction and tapering of the infusion has been beneficial.

The use of REMIFENTANIL B. BRAUN in mechanically ventilated intensive care patients is not recommended for duration of treatment greater than 3 days.

Muscle rigidity - prevention and management: At the doses recommended muscle rigidity 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 such as REMIFENTANIL B. BRAUN 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 B. BRAUN as an analgesic may be treated by stopping or decreasing the rate of administration of REMIFENTANIL B. BRAUN. Resolution of muscle rigidity after discontinuing the infusion of remifentanil such as REMIFENTANIL B. BRAUN occurs within minutes. Alternatively, a u03bc-opioid antagonist may be administered; however this may reverse or attenuate the analgesic effect of REMIFENTANIL B. BRAUN.

Respiratory depression - preventive measures and treatment: As with all potent opioids, profound analgesia is accompanied by marked respiratory depression. Therefore, REMIFENTANIL B. BRAUN should only be used in areas where facilities for monitoring and dealing with respiratory depression are available. Special care should be taken in patients with impaired lung function and with severe hepatic impairment. These patients may be slightly more sensitive to the respiratory depressant effects of remifentanil such as REMIFENTANIL B. BRAUN. They should be closely monitored and the dose of REMIFENTANIL B. BRAUN titrated to individual patient need. 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 such as REMIFENTANIL B. BRAUN has not been shown to cause recurrent respiratory depression even after prolonged administration. However in the presence of confounding factors (e.g. inadvertent administration of bolus doses and concomitant administration of longer acting opioids), respiratory depression occurring up to 50 minutes after discontinuation of infusion has been reported (see also section 4.5). 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, which can give rise to asystole and cardiac arrest (see section 4.5 and section 4.8), may be managed by reducing the rate of infusion of REMIFENTANIL B. BRAUN or the dose of concurrent anaesthetics or by using IV fluids, vasopressor or anticholinergic agents as appropriate. Debilitated, hypovolaemic, hypotensive and elderly patients may be more susceptible to the cardiovascular effects of remifentanil such as REMIFENTANIL B. BRAUN.

Inadvertent administration: An amount of REMIFENTANIL B. BRAUN may be present in the dead space of the IV line and/or cannula that may be sufficient to cause respiratory depression, apnoea and/or muscle rigidity if the line is flushed with IV fluids or other medicine. This may be avoided by administering REMIFENTANIL B. BRAUN into a fast flowing IV line or via a dedicated IV line which is removed when REMIFENTANIL B. BRAUN is discontinued.

Drug abuse: As with other opioids, remifentanil such as REMIFENTANIL B. BRAUN may produce dependence.

Paediatric populations Neonates and infants: There is limited data available on use in neonates/infants under 1 year of age (see section 4.2 and section 5.1). REMIFENTANIL B. BRAUN is not recommended for use as the sole agent in general anaesthesia.

Remifentanil such as REMIFENTANIL B. BRAUN is not metabolised by plasma cholinesterase, therefore, interactions with medicine metabolised by this enzyme are not anticipated.

• CNS depressant medicine: As with other opioids, remifentanil such as REMIFENTANIL B. BRAUN, 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). If doses of concomitantly administered CNS depressant medicine are not reduced patients may experience an increased incidence of adverse effects associated with these agents. The concomitant use of opioids and gabapentinoids (gabapentin and pregabalin) increases the risk of opioid overdose, respiratory depression and death.
• Other opioids: Information of medicine interactions with other opioids in relation to anaesthesia is very limited.
• Cardiac depressant medicine, such as beta-blockers and calcium channel blocking agents: The cardiovascular effects of remifentanil such as REMIFENTANIL B. BRAUN (hypotension and bradycardia), may be exacerbated in patients receiving concomitant cardiac depressant medicine, such as beta-blockers and calcium channel blocking agents (see also sections 4.4).
• Serotonergic medicine: Co-administration of remifentanil such as REMIFENTANIL B. BRAUN with a serotonergic agent, such as Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) or Monoamine Oxidase Inhibitors (MAOIs) may increase the risk of serotonin syndrome, a potentially life-threatening condition. Caution should be exercised with concomitant use of MAOIs. Irreversible MAOIs should be discontinued at least 2 weeks prior to remifentanil use.

Pregnancy: There are no data from the use of remifentanil such as REMIFENTANIL B. BRAUN in pregnant women.

Labour and Delivery: There are insufficient data to recommend remifentanil such as REMIFENTANIL B. BRAUN for use during labour and caesarean section. It is known that remifentanil crosses the placental barrier and fentanyl analogues can cause respiratory depression in the child. In case remifentanil is administered nevertheless, the patient and the neonate must be monitored for signs of excess sedation or respiratory depression (see section 4.4).

Breastfeeding: It is not known whether remifentanil such as REMIFENTANIL B. BRAUN 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 breastfeeding for 24 hours following administration of REMIFENTANIL B. BRAUN.

Fertility: No data available.

Remifentanil such as REMIFENTANIL B. BRAUN has major influence on the ability to drive and use machines. The physician has to decide when these activities may be resumed. If an early discharge is envisaged after application of REMIFENTANIL B. BRAUN, following treatment using anaesthetic agents, patient should be advised not to drive or operate machinery. It is advisable that the patient is accompanied when returning home and that alcoholic drink is avoided.

Summary of the safety profile The most common undesirable effects associated with remifentanil such as REMIFENTANIL B. BRAUN are direct extensions of u03bc-opioid agonist activities. These adverse events resolve within minutes of discontinuing or decreasing the rate of REMIFENTANIL B. BRAUN administration.

Tabulated summary of adverse reactions

Immune System Disorders: allergic reactions including anaphylaxis have been reported in patients receiving REMIFENTANIL B. BRAUN in conjunction with one or more anaesthetic agents.

Cardiac Disorders: cardiac arrest, asystole usually preceded by bradycardia, have been reported in patients receiving REMIFENTANIL B. BRAUN in conjunction with other anaesthetic agents. Patients with severe hepatic impairment are more sensitive to the respiratory depressant effects.

Rapid offset of action: Due to the very rapid offset of action of REMIFENTANIL B. BRAUN no residual opioid activity will be present within 5 to 10 minutes after discontinuation of REMIFENTANIL B. BRAUN. For those patients undergoing surgical procedures where post-operative pain is anticipated, analgesic should be administered prior to or immediately following discontinuation of REMIFENTANIL B. BRAUN. Sufficient time must be allowed to reach the maximum effect of the longer acting analgesic. The choice of analgesic should be appropriate for the patientu2019s surgical procedure and the level of post-operative care.

Reporting of suspected adverse reactions Reporting suspected adverse reaction after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who- umc.org) found on SAHPRA website.

Symptoms: As with all potent opioid analgesics, overdose would be manifested by an extension of the pharmacologically predictable actions of remifentanil such as REMIFENTANIL B. BRAUN i.e. respiratory depression, bradycardia, hypotension and skeletal muscle rigidity. Due to the very short duration of action of remifentanil such as REMIFENTANIL B. BRAUN, the potential for deleterious effects due to overdose is limited to the immediate time period following medicine administration. Response to discontinuation of the medicine is rapid, with return baseline within ten minutes.

Treatment: In the event of overdose, or suspected overdose, the following actions should be taken:

• discontinue administration of REMIFENTANIL B. BRAUN,
• maintain a patent airway,
• initiate assisted or controlled ventilation with oxygen,
• 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 and muscle rigidity. The duration of respiratory depression following overdose with REMIFENTANIL B. BRAUN is unlikely to exceed the duration of action of opioid antagonist.