Altirem Injection

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

Posology

GENERAL ANAESTHESIA

The administration of ALTIREM IV must be individualised based on the patientu2019s response. ALTIREM IV should be administered only by persons specifically trained in the use of anaesthetic medicines and the recognition and management of the expected adverse effects of potent opioids, including respiratory and cardiac resuscitation such as the establishment and maintenance of a patent airway and assisted ventilation.

Adults

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

Indication Bolus Infusion of ALTIREM IV (u03bcg/kg) Continuous infusion of ALTIREM IV (u03bcg/kg/min) Starting Rate Range With induction of anaesthesia in ventilated patients 1 (given over not less than 30 seconds) 0,5 to 1,0 - Maintenance of anaesthesia in ventilated patients Isoflurane (starting dose 0,5 MAC) 0,5 to 1,0 0,25 0,05 to 0,5 Propofol (starting dose 100 u03bcg/kg/min) 0,5 to 1,0 0,25 0,05 to 0,5

At the doses recommended, ALTIREM IV significantly reduced the amount of hypnotic medicine 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

ALTIREM IV should be administered with a hypnotic medicine, such as isoflurane, for the induction of anaesthesia. ALTIREM IV should be administered at an infusion rate of 0,5 - 1,0 u03bcg/kg/min with or without an initial bolus infusion of 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 ALTIREM IV infusion, then a bolus infusion is not necessary.

Maintenance of anaesthesia

After endotracheal intubation, the infusion rate of ALTIREM IV 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 ALTIREM IV, 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 obtain the desired level of u03bc-opioid receptor response. In response to light anaesthesia, supplemental bolus infusions may be administered every 2 to 5 minutes. The use of ALTIREM IV 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 as in ALTIREM IV, 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 ALTIREM IV. 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.

Concomitant medication

ALTIREM IV decreases the amounts or doses of inhaled anaesthetics, hypnotics and benzodiazepines required for anaesthesia (see section 4.5).

Paediatric patients (1 - 12 years of age)

Induction of anaesthesia

ALTIREM IV 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) (see Table 1 below).

Table 1: Dosing guidelines for maintenance of anaesthesia in paediatric patients (1 - 12 years of age) Concomitant anaesthetic medicine Bolus Infusion of ALTIREM IV (u03bcg/kg) Continuous Infusion of ALTIREM IV (u03bcg/kg/min) Starting Rate Typical Maintenance Rates Halothane (starting dose 0,3 MAC) 1 0,25 0,05 to 1,3 Sevoflurane (starting dose 0,3 MAC) 1 0,25 0,05 to 0,9 Isoflurane (starting dose 0,5 MAC) 1 0,25 0,06 to 0,09

When given by bolus infusion, ALTIREM IV should be administered over not less than 30 seconds.

Surgery should not commence until at least 5 minutes after the start of ALTIREM IV 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, remifentanil significantly reduces the amount of hypnotic medicine 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.

Guidelines for discontinuation

Following discontinuation of the infusion, the offset of analgesic effect of ALTIREM IV is rapid and similar to that seen in adult patients. Appropriate post-operative analgesic requirements should be anticipated and implemented (see Adults u2013 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.

CARDIAC ANAESTHESIA

Adults (see Table 2 below)

Table 2: Cardiac anaesthesia: Adults: Dosing guidelines for cardiac anaesthesia Indication Bolus Infusion of ALTIREM IV (u03bcg/kg) Continuous Infusion of ALTIREM IV (u03bcg/kg/min) Starting Rate Typical Infusion Rates Intubation Not recommended 1 - Maintenance of anaesthesia Isoflurane (starting dose 0,4 MAC) 0,5 to 1 1 0,003 to 4 Propofol (starting dose 50 u03bcg/kg/min) 0,5 to 1 1 0,01 to 4,3

Continuation of post-operative analgesia, prior to extubation Not recommended 1 0 to 1

Induction period of anaesthesia

After administration of a hypnotic medicine to achieve loss of consciousness, ALTIREM IV should be administered at an initial infusion rate of 1 u03bcg/kg/min. The use of bolus infusions of ALTIREM IV 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 ALTIREM IV should be titrated according to patient need. Supplemental bolus doses may also be given as required. High risk cardiac patients, such as those with poor ventricular function, should be administered a maximum bolus dose of 0,5 u03bcg/kg. These dosing recommendations also apply during hypothermic cardiopulmonary bypass (see section 5.2 u2013 Cardiac anaesthesia).

Concomitant medication

At the doses recommended above, ALTIREM IV significantly reduces the amount of hypnotic medicine 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 ALTIREM IV.

Continuation of post-operative analgesia prior to extubation

It is recommended that the infusion of ALTIREM IV 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 infusion should be maintained initially at a rate of 1 u03bcg/kg/min until the patient is ready to be weaned from the ventilator.

Guidelines for discontinuation

Prior to discontinuation of ALTIREM IV, patients must be given alternative analgesic and sedative medicine at a sufficient time in advance. The choice and dose of medicine(s) should be appropriate for the patientu2019s level of post-operative care. It is recommended that the ALTIREM IV infusion is discontinued by reducing the infusion rate in three to four steps of 50 % at 10 minute intervals. During weaning from the ventilator, the ALTIREM IV infusion should not be increased and only down titration should occur, supplemented as required with alternative analgesics. It is recommended that haemodynamic changes such as hypertension and tachycardia should be treated with alternative medicines, as appropriate.

Paediatric patients

There are insufficient data to make a dosage recommendation for use during cardiac surgery.

USE IN INTENSIVE CARE

ALTIREM IV can be used for the provision of analgesia for up to 72 hours and as an aid to short-term sedation in mechanically ventilated intensive care patients. It is recommended that ALTIREM IV is initiated at an infusion rate of 0,1 u03bcg/kg/min (6 u03bcg/kg/h) to 0,15 u03bcg/kg/min (9 u03bcg/kg/h). The infusion rate should be titrated in increments of 0,025 u03bcg/kg/min (1,5 u03bcg/kg/h) to achieve the desired level of analgesia. A period of at least 5 minutes should be allowed between dose adjustments. The level of analgesia should be carefully monitored, regularly reassessed and the ALTIREM IV infusion rate adjusted accordingly. If an infusion rate of 0,2 u03bcg/kg/min (12 u03bcg/kg/h) is reached and the desired level of sedation is not achieved, it is recommended that dosing with an appropriate sedative medicine is initiated (see below). The dose of sedative medicine should be titrated to obtain the desired level of sedation.

Further increases to the ALTIREM IV infusion rate in increments of 0,025 u03bcg/kg/min (1,5 u03bcg/kg/h) may be made if additional analgesia is required.

Table 3 summarises the starting infusion rates and typical dose range for provision of analgesia and sedation in individual patients:

Table 3: Dosing guidelines for use of ALTIREM IV within the intensive care setting Continuous Infusion u03bcg/kg/min (u03bcg/kg/h) Starting rate Range 0,1 (6) to 0,15 (9) 0,006 (0,36) to 0,74 (44,4)

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

The use of ALTIREM IV will reduce the dosage requirements of any concomitant sedative medicine by approximately 50 %. Typical starting doses for sedative medicine, if required are given in Table 4 below.

Table 4: Recommended starting dose of sedative medicines, if required. Sedative medicine Bolus (mg/kg) Infusion (mg/kg/h) Propofol Up to 0,5 0,5 Midazolam Up to 0,03 0,03

To allow separate titration of the respective medicines, sedative medicines should not be administered as an admixture.

Additional analgesia for ventilated patients undergoing stimulating procedures

An increase in the existing ALTIREM IV 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 ALTIREM IV infusion rate of at least 0,1 u03bcg/kg/min (6 u03bcg/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 u03bcg/kg/min (15 u03bcg/kg/h), maximum 0,75 u03bcg/kg/min (45 u03bcg/kg/h), has been administered for provision of additional anaesthesia during stimulating procedures.

Establishment of alternative analgesia prior to discontinuation of ALTIREM IV

Due to the very rapid offset of action of ALTIREM IV, no residual opioid activity will be present within 5 to 10 minutes after discontinuation regardless of the duration of infusion. Prior to discontinuation of ALTIREM IV, patients must be given alternative analgesic and sedative medicines at a sufficient time in advance, to allow the therapeutic effects of these medicines to become established. It is therefore recommended that the choice of medicine(s), the dose and the time of administration, are planned prior to discontinuation of ALTIREM IV.

Guidelines for extubation and discontinuation of ALTIREM IV

In order to ensure a smooth emergence from an ALTIREM IV-based regimen, it is recommended that the infusion rate of ALTIREM IV is titrated in stages to 0,1 u03bcg/kg/min (6 u03bcg/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 ALTIREM IV infusion should not be increased and only down titration should occur, supplemented as required with alternative analgesics.

Upon discontinuation of ALTIREM IV, the IV cannula should be cleared or removed to prevent subsequent inadvertent administration.

When other opioid medicines are administered as part of the regimen for transition to alternative analgesia, the patient must be carefully monitored. The benefit of providing adequate analgesia must always be balanced against the potential risk of respiratory depression with these medicines.

Paediatric intensive care patients

There are no data available on use in paediatric patients.

Renally-impaired intensive care patients

No adjustments to the doses recommended above are necessary in renally-impaired patients including those undergoing renal replacement therapy.

Special populations

Elderly (over 65 years of age)

General anaesthesia

The initial starting dose of ALTIREM IV should be half the recommended adult dose and then 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 above Cardiac Anaesthesia: Dosing guidelines).

Intensive care

No initial dose reduction is required (see Use in Intensive care).

Obese patients

For obese patients (greater than 30 % over their ideal body weight) the dosage of ALTIREM IV should be reduced and based upon ideal body weight, as the clearance and volume of distribution of remifentanil are better correlated with ideal body weight than actual body weight in this population.

Renal impairment

No dosage adjustment is necessary in patients with impaired renal function, including intensive care patients.

Hepatic impairment

No dosage adjustment is necessary. However, patients with severe hepatic impairment may be more sensitive to the respiratory depressant effects of remifentanil. These patients should be closely monitored and the dose of ALTIREM IV titrated to individual patient need.

Neurosurgery

Limited clinical experience in patients undergoing neurosurgery has shown that no special dosage recommendations of ALTIREM IV 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 ALTIREM IV in this population. Initial dosage reduction and subsequent titration to effect is therefore recommended.

Cardiac anaesthesia

No initial dose reduction is required (see Cardiac Anaesthesia: Dosing guidelines).

Long-term use in the ICU

No data are available on the long-term (longer than 72 hours) use of ALTIREM IV in ICU patients.

Method of administration

After reconstitution, solutions of ALTIREM IV are clear and colourless. Continuous infusion of ALTIREM IV 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 ALTIREM IV after use (see section 4.4). ALTIREM IV is for intravenous use only and must not be administered by epidural or intrathecal injection (see section 4.3). Refer to section 6.6 for reconstitution instruction and further handling.

• hypersensitivity to remifentanil, other fentanyl analogues or to any of the ingredients of ALTIREM IV listed in section 6.1
• Safety in pregnancy and lactation has not been established
• ALTIREM IV should not be used with nitrous oxide and oxygen alone, at altitudes above sea level
• ALTIREM IV should not be used unless artificial ventilation is planned.

ALTIREM IV is not recommended for use as the sole medicine in general anaesthesia. The use of ALTIREM IV in mechanically ventilated intensive care patients is not recommended for a duration of treatment greater than 3 days. As glycine is present in the formulation, ALTIREM IV is contraindicated for epidural and intrathecal use. ALTIREM IV should be administered only by persons specifically trained in the use of anaesthetic medicines and the recognition and management of the expected adverse effects of potent opioids, including respiratory and cardiac resuscitation such as the establishment and maintenance of a patent airway and assisted ventilation.

Patients with a known hypersensitivity to opioids of a different class may exhibit a hypersensitivity reaction following administration of remifentanil as in ALTIREM IV. Caution should be exercised before using ALTIREM IV in these patients.

Interference with daily activities may continue for up to 24 hours and no legal/contractual decisions should be entered into for 24 hours after receiving anaesthetic/conscious sedation. Alcohol use should also be avoided for the same time period.

Rapid offset of action/ Transition to alternative analgesia: Due to the very rapid offset of action of ALTIREM IV no residual opioid activity will be present within 5 to10 minutes after discontinuation of ALTIREM IV. For those patients undergoing surgical procedures where post-operative pain is anticipated, analgesics should be administered prior to or immediately following discontinuation of ALTIREM IV. The possibility of tolerance, hyperalgesia and associated haemodynamic changes should be considered when used in Intensive Care Unit. Prior to discontinuation of ALTIREM IV, patients must be given alternative analgesic and sedative medicines. Sufficient time must be allowed to reach the maximum effect of the longer acting analgesic. The choice of analgesic(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.

Risk from concomitant use of sedative medicines such as benzodiazepines or related medicines: Concomitant use of remifentanil as in ALTIREM IV and sedative medicines such as benzodiazepines or related medicines may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe ALTIREM IV concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible. The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

Discontinuation of Treatment Symptoms following withdrawal of remifentanil as in ALTIREM IV including tachycardia, hypertension and agitation have been reported infrequently upon abrupt cessation, particularly after prolonged administration of more than 3 days. The use of ALTIREM IV in mechanically ventilated intensive care patients is not recommended for duration of treatment greater than 3 days.

Inadvertent administration A sufficient amount of remifentanil as in ALTIREM IV 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 medicines. This may be avoided by administering ALTIREM IV into a fast-flowing IV line or via a dedicated IV line, which is adequately cleared of residual medicine or which is removed upon discontinuation of ALTIREM IV.

Muscle rigidity: prevention and management At the doses of remifentanil as in ALTIREM IV recommended, muscle rigidity may occur. The incidence is related to the dose and rate of administration. Therefore, bolus infusions should be administered over not less than 30 seconds. Muscle rigidity induced by remifentanil as in ALTIREM IV must be treated in the context of the patientu2019s 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 medicine and/or additional hypnotic medicines. Muscle rigidity seen during the use of remifentanil as in ALTIREM IV as an analgesic may be treated by stopping or decreasing the rate of administration of ALTIREM IV. Resolution of muscle rigidity after discontinuing the infusion of ALTIREM IV occurs within minutes. Alternatively, an opioid antagonist may be administered, however this may reverse or attenuate the analgesic effect of remifentanil.

Respiratory depression: management Analgesia is accompanied by marked respiratory depression. Therefore, ALTIREM IV 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 a discontinuation of the infusion. 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 that full consciousness and adequate spontaneous ventilation are achieved before the patient is discharged from the recovery area. Patients with impaired lung function and with severe hepatic impairment are more sensitive to the respiratory depressant effects.

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 ALTIREM IV or the dose of concurrent anaesthetics or by using IV fluids, vasopressor or anticholinergic medicines as appropriate. Debilitated, hypovolaemic and elderly patients are more sensitive to the cardiovascular effects of remifentanil, as in ALTIREM IV.

Serotonin Syndrome Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of remifentanil with serotonergic medicines. Serotonergic medicines include selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, medicines that affect the serotonergic neurotransmitter system, and medicines that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). This may occur within the recommended dosage range. Serotonin syndrome symptoms may include mental status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g. hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea). The onset of symptoms generally occurs within several hours to a few days of concomitant use but may occur later than that. If serotonin syndrome is suspected, rapid discontinuation of remifentanil should be considered.

Dependency As with other opioids, remifentanil as in ALTIREM IV may produce dependency. There is an increased risk of addiction in patients with a personal or family history of substance abuse or mental health disorders.

Paediatric population There is limited data available on use in neonates/infants under 1 year of age.

CNS depressant medicine Remifentanil as in ALTIREM IV is not metabolised by plasma cholinesterase and therefore interactions with medicines metabolised by the enzyme are not anticipated. Remifentanil, decreases the doses of inhaled and IV anaesthetics and benzodiazepines required for anaesthesia. If doses of concomitantly administered CNS depressant medicines such as alcohol, anaesthetics, anxiolytics, hypnotics, or antipsychotics are not reduced, patients may experience an increased incidence of adverse effects associated with these medicines.

Other opioids The concomitant use of opioids with sedative medicines such as benzodiazepines or related medicines increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).

Cardiac depressant medicine, (e.g., beta-blockers and calcium channel blocking agents) The cardiovascular effect of remifentanil as in ALTIREM IV (hypotension and bradycardia) may be exacerbated in patients receiving concomitant cardiac depressant medicines, such as beta blockers and calcium channel blocking medicines.

Serotonergic medicine Co-administration of remifentanil such as ALTIREM IV with medicine that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome, a potentially life-threatening condition. Serotonergic medicines include selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, medicine that effect the serotonin neurotransmitter system (e.g. mirtazapine, trazodone, tramadol) and monoamine oxidase (MAO) inhibitors. Caution should be exercised with concomitant use of MAOIs. Irreversible MAOIs should be discontinued at least 2 weeks prior to remifentanil use.

Alcohol After receiving ALTIREM IV, it is advisable that alcoholic drink is avoided.

Pregnancy Safety of remifentanil as in ALTIREM IV in pregnancy and lactation has not been established and is therefore not recommended (see section 4.3).

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

Breastfeeding It is not known whether remifentanil, as in ALTIREM IV, 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 ALTIREM IV.

Fertility There is no data on fertility with ALTIREM IV.

Remifentanil such as ALTIREM IV 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 following treatment with remifentanil as in ALTIREM IV, patients should be advised not to drive or operate machinery as remifentanil as in ALTIREM IV can impair cognitive function. 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, as contained in ALTIREM IV, are direct extensions of u03bc-opioid agonist pharmacology. These adverse events resolve within minutes of discontinuing or decreasing the rate of ALTIREM IV administration.

Tabulated list of adverse effects

System Organ Class Frequency Side effects Immune system disorders Less frequent Frequency unknown Allergic reactions including anaphylaxis have been reported in patients receiving ALTIREM IV in conjunction with one or more anaesthetic agents Anaphylactic shock Psychiatric disorders Frequency unknown Medicine dependence Nervous system disorders Frequent Less frequent Frequency unknown Skeletal muscle rigidity Sedation (during recovery from general anaesthesia), headache Convulsions, serotonin syndrome Cardiac disorders Frequent Less frequent Frequency unknown Bradycardia Asystole/cardiac arrest, usually preceded by bradycardia has been reported in patients receiving remifentanil in conjunction with other anaesthetic agents Atrioventricular block Vascular disorders Frequent Hypotension, post-operative hypertension Respiratory, thoracic and mediastinal disorders Frequent Less frequent Acute respiratory depression, apnoea, difficulty in breathing, cough Hypoxia Gastrointestinal disorders Frequent Less frequent Nausea, vomiting Constipation, abdominal pain*, pancreatitis* Skin and subcutaneous tissue disorders Frequent Pruritus General disorders and administrative site conditions Frequent Less frequent Frequency unknown Post-operative shivering Post-operative aches Medicine tolerance Investigations Frequent Less frequent Weight gain, elevations in serum transaminases (ALT, AST) Elevations in gamma-GT levels, elevations in non-fasting serum triglyceride levels, elevations in total cholesterol *Post-marketing experience.

a. Description of selected adverse reactions 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.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals 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. An email can be sent directly to the company, [email protected], to ensure safety of the product.

Signs and symptoms: Overdose with remifentanil, as in ALTIREM IV, would be manifested by an extension of the pharmacological actions of remifentanil i.e. respiratory depression, bradycardia, hypotension and skeletal muscle rigidity. Due to the very short duration of action of remifentanil, as in ALTIREM IV, the potential for deleterious effects due to overdose are limited to the immediate time period following administration. Response to discontinuation is rapid with return to baseline within ten minutes.

Management of overdose: In the event of suspected overdosage, the following actions are to be taken:

• discontinue administration of ALTIREM IV
• maintain the patent su2019 airway
• initiate assisted or controlled ventilation with oxygen
• maintain adequate cardiovascular function. If depressed respiration is associated with muscle rigidity, a neuromuscular blocking medicine may be required to facilitate assisted or controlled respiration. Intravenous fluids and vasopressor medicines for the treatment of hypotension and other supportive measures may be employed.
• Intravenous administration of an opioid antagonist such as naloxone may be given to manage severe respiratory depression and muscle rigidity. The duration of respiratory depression following overdose with remifentanil as in ALTIREM IV is unlikely to exceed the duration of action of the opioid antagonist.