DEXISUN Concentrated solution for infusion Ref.[50700] Active ingredients: Dexmedetomidine

DEXISUN should be administered only by healthcare professionals skilled in the management of patients in the intensive care setting and who have received complete training in the use of DEXISUN in the ICU setting.

Continuous electrocardiogram (ECG), blood pressure and oxygen saturation monitoring are mandatory during infusion of DEXISUN.

Safety and efficacy of DEXISUN in non-surgical intensive care patients have not been reported.

Clinical events of bradycardia and sinus arrest have been associated with DEXISUN administration in some young, healthy volunteers with high vagal tone, or with different routes of administration including rapid intravenous or bolus administration of DEXISUN. Bolus injections of DEXISUN should not be used, in order to minimise undesirable pharmacological side effects.

Respiration should be monitored in non-intubated patients due to the risk of respiratory depression and in some case apnoea (see section 4.8).

The time to recovery after the use of dexmedetomidine as in DEXISUN was reported to be approximately one hour. When used in an outpatient setting close monitoring should continue for at least one hour (or longer based on the patient condition), with medical supervision continued for at least one further hour to ensure the safety of the patient.

Caution should be exercised in patients with pre-existing severe bradycardia disorders (i.e. advanced heart block), or patients with pre-existing severe ventricular dysfunction (e.g. ejection fraction <30%) including congestive heart failure and cardiac failure in whom sympathetic tone is critical for maintaining haemodynamic balance (see section 4.3).

Hypotension, Bradycardia and Sinus arrest:

Decreased blood pressure and/or heart rate may occur with the administration of DEXISUN. Based on clinical experience with DEXISUN, if medical intervention is required, treatment may include decreasing or stopping the infusion of DEXISUN, increasing the rate of intravenous fluid administration, elevation of the lower extremities and use pressor agents. Because DEXISUN has the potential to augment bradycardia induced by vagal stimuli, medical practitioners should be prepared to intervene. The intravenous administration of anticholinergic agents should be considered to modify vagal tone. In clinical trials, atropine and glycopyrrolate were effective in the treatment of most episodes of DEXISUN-induced bradycardia. However, in some patients with significant cardiovascular dysfunction, more advanced resuscitative measures were required.

DEXISUN decreases sympathetic nervous activity and therefore, these effects may be expected to be most pronounced in patients with desensitised autonomic nervous system control (i.e. elderly, diabetes, chronic hypertension, severe cardiac disease).

Prevention of hypotension and bradycardia should take into consideration the haemodynamic stability of the patient and normovolaemia must be ensured prior to the administration of DEXISUN. Patients who are hypovolaemic may become hypotensive under DEXISUN therapy. Therefore, fluid supplementation should be administered prior to and during the administration of DEXISUN.

Additionally, in situations where the vasodilators or negative chronotropic agents are administered, co-administration of DEXISUN could have an additive pharmacodynamics effect and should be administered with caution and careful titration (see section 4.5).

Clinical events of bradycardia or hypotension may be potentiated when DEXISUN is used concurrently with propofol or midazolam. Therefore, consider a dose reduction of propofol or midazolam (see section 4.5).

Transient Hypertension

Transient hypertension has been observed primarily during the loading infusion, associated with initial peripheral vasoconstrictive effects of DEXISUN and relatively higher plasma concentrations achieved during the loading infusion. If intervention is necessary, reduction of the loading infusion rate may be considered. Following the loading infusion, the central effects of DEXISUN dominate and the blood pressure usually decreases.

DEXISUN may cause reduced lacrimation. Lubrication of the patient’s eyes may be considered when administering DEXISUN to avoid corneal dryness.

DEXISUN should not be given as a bolus dose and in the ICU a loading dose is not recommended. Users should therefore be ready to use an alternative sedative for acute control of agitation or during procedures, especially during the first few hours of treatment.

During procedural sedation a small bolus of another sedative may be used if a rapid increase in sedation level is required.

Some patients receiving dexmedetomidine as in DEXISUN have been reported to be arousable and alert when stimulated. This alone should not be considered as evidence of lack of efficacy in the absence of other clinical signs and symptoms.

Dexmedetomidine as in DEXISUN normally does not cause deep sedation and patients may be easily roused. DEXISUN is therefore not suitable in patients who will not tolerate this profile of effects, for example those requiring continuous deep sedation.

DEXISUN should not be used as a general anaesthetic induction agent for intubation or to provide sedation during muscle relaxant use.

DEXISUN lacks the anticonvulsant action of some other sedatives and so will not suppress underlying seizure activity.

Care should be taken if combining DEXISUN with other substances with sedative or cardiovascular actions as additive effects may occur. DEXISUN is not recommended for patient controlled sedation. Adequate data is not available.

When DEXISUN is used in an outpatient setting patients should normally be discharged into the care of a suitable third party. Patients should be advised to refrain from driving or other hazardous tasks and where possible to avoid the use of other agents that may sedate (e.g. benzodiazepines, opioids, alcohol) for a suitable period of time based on reported effects of dexmedetomidine, the procedure, concomitant medications, the age and the condition of the patient.

Patients with hepatic impairment

Care should be taken in severe hepatic impairment as excessive dosing may increase the risk of adverse reactions, over-sedation or prolonged effect as a result of reduced dexmedetomidine clearance.

Patients with neurological disorders

Experience of dexmedetomidine as in DEXISUN in severe neurological disorders such as head injury and after neurosurgery is limited and it should be used with caution here, especially if deep sedation is required. DEXISUN may reduce cerebral blood flow and intracranial pressure and this should be considered when selecting therapy.

Other

Alpha-2 agonists have less frequently been associated with withdrawal reactions when stopped abruptly after prolonged use. This possibility should be considered if the patient develops agitation and hypertension shortly after stopping DEXISUN.

DEXISUN may induce hyperthermia that may be resistant to traditional cooling methods. Dexmedetomidine treatment should be discontinued in the event of a sustained unexplained fever and is not recommended for use in malignant hyperthermia-sensitive patients.

Elderly

The elderly are more prone to cardiovascular adverse events e.g. hypotension and bradycardia and the dose must be carefully titrated to obtain the desired effect. Close cardiovascular system (CVS) monitoring is required. Elderly patients (over 65 years) often require lower doses of DEXISUN.

Cytochrome P-450

In vitro studies indicated that clinically relevant cytochrome P450 mediated interactions are unlikely.

Anaesthetics / Sedatives / Hypnotics / Opioids

Co-administration of DEXISUN is likely to lead to an enhancement of effects with anaesthetics, sedatives, hypnotics, and opioids. Specific studies have confirmed these enhanced effects with sevoflurane, isoflurane, propofol, alfentanil, and midazolam.

No pharmacokinetic interactions between dexmedetomidine and isoflurane, propofol, alfentanil and midazolam have been demonstrated. However, due to pharmacodynamic effects, when co-administered with DEXISUN, a reduction in dosage of these agents may be required.

Neuromuscular Blockers

No clinically meaningful increases in the magnitude of neuromuscular blockade and no pharmacokinetic interactions were observed with DEXISUN and rocuronium administration.

The possibility of enhanced hypotensive and bradycardic effects should be considered in patients receiving other medicines causing these effects, for example beta blockers, although additional effects in an interaction study with esmolol were modest.

The safety in pregnancy and lactation has not been established.

Pregnancy

There are no adequate and well-controlled studies in pregnant women. The use of DEXISUN is not recommended in pregnancy.

Labour and delivery

The safety of DEXISUN in labour and delivery has not been studied and it is therefore not recommended for obstetrics, including caesarean section deliveries.

Breastfeeding

It is not known whether DEXISUN is excreted in human milk. The use of DEXISUN is not recommended in lactating women.

Fertility

In the reported rat fertility study, dexmedetomidine had no effect on male or female fertility.

No human data on fertility are available.

The patient should not drive or operate machinery or make legal decisions until 24 hours after recovery from surgical procedure in which DEXISUN was used.

a. Summary of the safety profile

The most frequently reported adverse reactions with DEXISUN are hypotension, hypertension, bradycardia, nausea, dry mouth and hypoxia (see section 4.4).

The following side effects have been reported during clinical trials and post-marketing surveillance and are listed by system organ class and frequencies indicated:

b. Tabulated list of adverse reactions

Table 1. Adverse Events with an Incidence >2% - ICU Sedation Population:

Table 2. Adverse Events with an Incidence >2% - Conscious Sedation Population:

The majority of the adverse events were assessed as mild in severity. The most frequent adverse events were hypotension, bradycardia, and dry mouth. (See section 4.4).

Post marketing adverse reactions:

c. Description of selected adverse reactions

Withdrawal

ICU Sedation

Although not specifically studied, withdrawal symptoms similar to those reported for another alpha₂ adrenergic agent (clonidine) may result when DEXISUN is administered in excess of 24 hours and stopped abruptly.

These symptoms include nervousness, agitation and headache accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma.

Conscious Sedation

Withdrawal symptoms were not seen after discontinuation of short-term infusions of dexmedetomidine such as DEXISUN (<6 hours).

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. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the ‘6.04 Adverse Drug Reaction Reporting form’, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/index/8.

DEXISUN must not be mixed with other medicinal products or diluents except those mentioned in section 6.6.