ULTIVA Powder for concentrate for solution for infusion Ref.[8163] Active ingredients: Remifentanil

Ultiva shall 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.

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 to 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.

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs

Concomitant use of Ultiva and sedative medicines such as benzodiazepines or related drugs 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 Ultiva 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).

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 section 4.3).

Discontinuation of treatment and withdrawal syndrome

Repeated administration at short term intervals for prolonged periods may result in the development of withdrawal syndrome after cessation of therapy. 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. 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.

Muscle rigidity – prevention and management

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

Muscle rigidity induced by Ultiva must be treated in the context of the patients clinical condition with appropriate supporting measures. Excessive muscle rigidity occurring during the induction of anaesthesia should be treated by the administration of a neuromuscular blocking agent and/or additional hypnotic agents. Muscle rigidity seen during the use of Ultiva as an analgesic may be treated by stopping or decreasing the rate of administration of Ultiva. Resolution of muscle rigidity after discontinuing the infusion of Ultiva occurs within minutes. Alternatively an opioid antagonist may be administered, however this may reverse or attenuate the analgesic effect of Ultiva.

Respiratory depression – prevention and management

As with all potent opioids, profound analgesia is accompanied by marked respiratory depression. Therefore, Ultiva shall only be used in areas where facilities for monitoring and dealing with respiratory depression are available. Special care should be taken in patients with respiratory dysfunction. The appearance of respiratory depression shall be managed appropriately, including decreasing the rate of infusion by 50%, or a temporary discontinuation of the infusion. Unlike other fentanyl analogues, Ultiva 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, which may rarely lead to asystole/cardiac arrest (see section 4.5 and 4.8) 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, hypotensive and elderly patients may be more sensitive to the cardiovascular effects of Ultiva.

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.

Neonates/infants

There is limited data available on use in neonates/infants under 1 year of age (see sections 4.2.1.3 and 5.1).

Tolerance and opioid use disorder (abuse and dependence)

Tolerance, physical and psychological dependence, and opioid use disorder (OUD) may develop upon repeated administration of opioids. Abuse or intentional misuse of opioids may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders).

Ultiva contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium-free’.

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

As with other opioids, Ultiva decreases the doses of inhaled and IV anaesthetics, and benzodiazepines required for anaesthesia (see section 4.2). If doses of concomitantly administered CNS depressant drugs are not reduced, patients may experience an increased incidence of adverse effects associated with these agents.

Sedative medicines such as benzodiazepines or related drugs: The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs 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). The concomitant use of opioids and gabapentinoids (gabapentin and pregabalin) increases the risk of opioid overdose, respiratory depression and death.

Co-administration of remifentanil 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.

The cardiovascular effects of Ultiva (hypotension and bradycardia – see sections 4.4 and 4.8) may be exacerbated in patients receiving concomitant cardiac depressant drugs, such as beta-blockers and calcium channel blocking agents.

After receiving Ultiva, it is advisable that alcoholic drink is avoided.

Pregnancy

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.

Labour and delivery

There are insufficient data to recommend Ultiva 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).

Breast-feeding

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 Ultiva.

After anaesthesia with Ultiva 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.

Summary of the safety profile

The most common undesirable effects associated with Ultiva are direct extensions of mu-opioid agonist pharmacology. These adverse events resolve within minutes of discontinuing or decreasing the rate of remifentanil administration.

Tabulated list of adverse reactions

The frequencies below 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).

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 section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Website: www.hpra.ie.

Ultiva should only be reconstituted and diluted with those infusion solutions recommended (see section 6.6).

It should not be reconstituted, 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 as non-specific esterase 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.