ECCLADEX Concentrated solution for intravenous infusion Ref.[115322] Active ingredients: Dexmedetomidine

Monitoring

ECCLADEX should be administered only by healthcare providers skilled in the management of patients in the intensive care setting and who have received complete training in the use of ECCLADEX in the ICU setting. The use in other environments is not recommended. All patients should have continuous cardiac monitoring during ECCLADEX infusion. Respiration should be monitored in non-intubated patients due to the risk of respiratory depression and in some cases apnoea (see section 4.8).

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

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

General precautions

Some patients receiving ECCLADEX have been observed 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. ECCLADEX normally does not cause deep sedation and patients may be easily roused. ECCLADEX is therefore not suitable in patients who will not tolerate this profile of effects, for example those requiring continuous deep sedation.

ECCLADEX should not be used as a general anaesthetic induction medicine for intubation or to provide sedation during muscle relaxant use. ECCLADEX lacks the anticonvulsant action of some other sedatives and so will not suppress underlying seizure activity. Care should be taken if combining ECCLADEX with other medicines with sedative or cardiovascular actions as additive effects may occur. ECCLADEX is not recommended for patient controlled sedation. Adequate data is not available.

Cardiovascular effects and precautions

ECCLADEX reduces heart rate and blood pressure through central sympatholysis but at higher concentrations causes peripheral vasoconstriction leading to hypertension (see section 5.1). ECCLADEX is therefore not suitable in patients with severe cardiovascular instability (see section 4.3).

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).

Data on the effects of ECCLADEX in patients with heart rate <60 are very limited and particular care should be taken with such patients. Bradycardia does not normally require treatment, but has commonly responded to anti-cholinergic medicine or dose reduction where needed. Patients with high physical fitness and slow resting heart rate may be particularly sensitive to bradycardic effects of alpha-2 receptor agonists and cases of transient sinus arrest have been reported. Also cases of cardiac arrest, often preceded by bradycardia or atrioventricular block, have been reported (see section 4.8). The hypotensive effects of ECCLADEX may be of greater significance in those patients with pre-existing hypotension (especially if not responsive to vasopressors), hypovolaemia, chronic hypotension or reduced functional reserve such as patients with severe ventricular dysfunction and the elderly and special care is warranted in these cases. Hypotension does not normally require specific treatment but, where needed, users should be ready to intervene with dose reduction, fluids and/or vasoconstrictors. Patients with impaired peripheral autonomic activity (e.g. due to spinal cord injury) may have more pronounced haemodynamic changes after starting ECCLADEX and so should be treated with care.

Hypotension, bradycardia and sinus arrest

Clinical events of bradycardia and sinus arrest have been associated with ECCLADEX administration in young, healthy volunteers with high vagal tone, or with different routes of administration including rapid intravenous or bolus administration of ECCLADEX. Decreased blood pressure and/or heart rate may occur with the administration of ECCLADEX. Based on clinical experience with ECCLADEX, if medical intervention is required, treatment may include decreasing or stopping the infusion of ECCLADEX, increasing the rate of intravenous fluid administration, elevation of the lower extremities and use of pressor medicines. Because ECCLADEX has the potential to augment bradycardia induced by vagal stimuli, healthcare providers should be prepared to intervene. The intravenous administration of anticholinergic medicines should be considered to modify vagal tone. In clinical trials, atropine and glycopyrrolate were effective in the treatment of most episodes of ECCLADEX- induced bradycardia. However, in some patients with significant cardiovascular dysfunction, more advanced resuscitative measures were required. ECCLADEX 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 ECCLADEX. Patients who are hypovolaemic may become hypotensive under ECCLADEX therapy.

Therefore, fluid supplementation should be administered prior to and during the administration of ECCLADEX. Additionally,in situations where other vasodilators or negative chronotropic medicines are administered, coadministration of ECCLADEX could have an additive pharmacodynamic effect and should be administered with caution and careful titration (see section 4.5). Clinical events of bradycardia or hypotension may be potentiated when ECCLADEX is used concurrently with propofol or midazolam. Therefore, consider a dose reduction of propofol or midazolam (see section 4.5).

Non-surgical ICU patients

Safety and efficacy of ECCLADEX in non-surgical intensive care patients have not been established.

Transient hypertension

Transient hypertension has been observed primarily during the loading infusion, associated with initial peripheral vasoconstrictive effects of ECCLADEX 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 ECCLADEX dominate and the blood pressure usually decreases.

Local vasoconstriction at higher concentration may be of greater significance in patients with ischaemic heart disease or severe cerebrovascular disease who should be monitored closely. Dose reduction or discontinuation should be considered in a patient developing signs of myocardial or cerebral ischaemia. Caution is advised when administering ECCLADEX together with spinal or epidural anaesthesia due to possible increased risk of hypotension or bradycardia.

Reduced lacrimation

ECCLADEX may cause reduced lacrimation. Lubrication of the patient's eyes may be considered when administering dexmedetomidine to avoid corneal dryness.

Patients with neurological disorders

Experience of ECCLADEX 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. ECCLADEX may reduce cerebral blood flow and intracranial pressure and this should be considered when selecting therapy (see section 4.3).

Other

Alpha-2 agonists, such as ECCLADEX have 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 ECCLADEX.

ECCLADEX may induce hyperthermia that may be resistant to traditional cooling methods. Dexmedetomidine, as contained in ECCLADEX treatment should be discontinued in the event of a sustained unexplained fever and is not recommended for use in malignant hyperthermia-sensitive patients. Diabetes insipidus has been reported in association with dexmedetomidine treatment. If polyuria occurs, it is recommended to stop dexmedetomidine and check serum sodium level and urine osmolality.

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 ECCLADEX clearance (see section 4.2).

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 CVS monitoring is required. Elderly patients (over 65 years) often require lower doses of ECCLADEX (see section 4.2).

Sodium content

ECCLADEX contains less than 1 mmol sodium (23 mg) per ml.

Paediatric population

Safety and efficacy of ECCLADEX has not been adequately studied in children and adolescents and is therefore not recommended for patients under 18 years of age.

Interaction studies have only been performed in adults.

Cytochrome P-450

Inhibition of CYP enzymes including CYP2B6 by dexmedetomidine, as contained in ECCLADEX has been studied in human liver microsome incubations. In vitro study suggests that interaction potential in vivo exists between dexmedetomidine and substrates with dominant CYP2B6 metabolism.

Induction of dexmedetomidine in vitro was observed on CYP1A2, CYP2B6, CYP2C8, CYP2C9 and CYP3A4, and induction in vivo cannot be excluded. The clinical significance is unknown.

Anaesthetics/Sedatives/Hypnotics/Opioids

Co-administration of ECCLADEX is likely to lead to an enhancement of effects with anaesthetics, sedatives, hypnotics and opioids such as sedative, anaesthetic and cardiorespiratory effects. Specific studies have confirmed these effects with sevoflurane, isoflurane, propofol, alfentanil, and midazolam. No pharmacokinetic interactions between dexmedetomidine and isoflurane, propofol, alfentanil, and midazolam were demonstrated. However, due to pharmacodynamic effects, when co-administered with ECCLADEX a reduction in dosage of these medicines may be required.

Neuromuscular blockers

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

Medicines causing hypotension and bradycardia

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.

Safety in pregnancy and lactation has not been established.

Pregnancy

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

Labour and delivery

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

Breastfeeding

Dexmedetomidine, as contained in ECCLADEX is excreted in breast milk.

The use of ECCLADEX is not recommended in lactating women.

Fertility

No data is available in humans.

ECCLADEX has major influence on the ability to drive and use machines and patients should not drive or operate machinery or make legal decisions until 24 hours after recovery from surgical procedure in which ECCLADEX was used.

a) Summary of the safety profile

Sedation of adult ICU (Intensive Care Unit) patients

The most frequently reported adverse reactions with ECCLADEX in ICU setting are hypotension, hypertension and bradycardia. Hypotension and bradycardia were also the most frequent dexmedetomidine-related serious adverse reactions.

Procedural/awake sedation

The most frequently reported adverse reactions with dexmedetomidine in procedural sedation were:

• Hypotension
• Respiratory depression
• Bradycardia

b) Tabulated list of adverse reactions

¹ See section on Description of selected adverse reactions
² Adverse reaction observed also in procedural sedation studies
³ Incidence 'common' in ICU sedation studies
^* Post-marketing data

c) Description of selected adverse reactions

Clinically significant hypotension or bradycardia should be treated as described in section 4.4.

In relatively healthy non-ICU patients treated with dexmedetomidine, bradycardia has occasionally led to sinus arrest or pause. The symptoms responded to leg raising and anticholinergics such as atropine or glycopyrrolate. Inisolated cases bradycardia has progressed to periods of asystole in patients with pre-existing bradycardia. Also cases of cardiac arrest, often preceded by bradycardia or atrioventricular block, have been reported. Hypertension has been associated with the use of a loading dose and this reaction can be reduced by avoiding such a loading dose or reducing the infusion rate or size of the loading dose.

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 providers are asked to report any suspected adverse reactions to: SAHPRA: https://www.sahpra.org.za/health-products-vigilance/

Aspen Pharmacare:

E-mail: Drugsafety@aspenpharma.com
Tel: 0800 118 088

This medicine must not be mixed with other medicines except those mentioned in section 6.6.