Eusedex 1 mL Concentrated solution for intravenous infusion.

EUSEDEX is an alpha 2 adrenoreceptor agonist sedative with analgesic properties indicated for:

• Intensive care unit sedation
• Sedation of intubated and mechanically ventilated adult post-surgical patients during treatment in an intensive care setting.
• Monitored anaesthesia care (MAC) / Conscious sedation in a theatre or intensive care setting for:
• Minor surgical procedures under local anaesthesia
• Fibreoptic intubation

Efficacy and safety have not been studied in children under 18 years of age.

NOTE: EUSEDEX should be administered only by health care providers skilled in the management of patients in the intensive care setting. Continuous monitoring of vital signs, in particular blood pressure, heart rate and oxygen saturation is mandatory during infusion of EUSEDEX.

In order to minimise undesirable pharmacologic side effects, bolus injections of EUSEDEX should not be used. Clinically significant events of bradycardia and sinus arrest have been associated with EUSEDEX administration in young healthy volunteers with high vagal tone, or with different routes of administration including rapid intravenous or bolus administration of EUSEDEX.

EUSEDEX should be administered by continuous intravenous infusion not to exceed 24 hours. Fluid supplementation should be administered prior to and during administration of EUSEDEX to ensure normovolaemia. EUSEDEX has been administered to patients requiring mechanical ventilation as well as to patients breathing spontaneously after extubation. There is no respiratory depression associated with the administration of EUSEDEX. Patients receiving EUSEDEX have been observed to be arousable and alert when stimulated. This is an expected component of EUSEDEX sedation and should not be considered as evidence of lack of efficacy in the absence of other clinical signs and symptoms. EUSEDEX has been continuously infused in mechanically ventilated patients prior to extubation, during extubation, and post extubation. It is not necessary to discontinue EUSEDEX prior to extubation.

Posology

Adults

ICU sedation

EUSEDEX dosage should be individualised and titrated to the desired clinical effect.

Initiation

For adult patients, it is recommended to initiate EUSEDEX with a loading dose of 1,0 microgram/kg over ten minutes.

Maintenance of ICU sedation

Adult patients will generally require a maintenance infusion in the range of 0,2 to 0,7 microgram/kg/hr. The rate of the maintenance infusion can be adjusted in order to achieve the desired clinical effect. Dosages as low as 0,05 micrograms/kg/hr have been used in clinical studies.

A dose reduction for both the loading and maintenance infusions should be considered in patients with impaired hepatic or renal function and in patients over 65 years of age (see sections 4.3, 4.4 and 5.2).

Conscious sedation

Monitored anaesthesia care (MAC) with an adequate nerve block and awake fibreoptic intubation (AFI) EUSEDEX dosing should be individualised and titrated to the desired clinical effect.

Initiation

For adult patients, EUSEDEX is generally initiated with a loading infusion of 1 (one) microgram/kg over 10 minutes. For patients over 65 years of age or those undergoing less invasive procedures such as ophthalmic surgery, a loading infusion of 0,5 microgram/kg over 10 minutes may be suitable.

Maintenance of conscious sedation

MAC Following the load, maintenance dosing of EUSEDEX should generally be initiated at 0,6 microgram/kg/hr and titrated to achieve desired clinical effect with doses ranging from 0,2 to 1 microgram/kg/hr for all procedures. The rate of the maintenance infusion should be adjusted to achieve the targeted level of sedation.

AFI Following the load in awake fibreoptic intubation, a fixed maintenance dose of 0,7 microgram/kg/hr should be used.

Dosage adjustment

Due to possible pharmacodynamic interactions a reduction in dosage of EUSEDEX or other concomitant anaesthetics, sedatives, hypnotics or opioids may be required when co-administered (see section 4.5).

Special populations

Impaired hepatic function

Dosage reductions may need to be considered for patients with hepatic impairment, as EUSEDEX is metabolised primarily in the liver.

Impaired renal function

Since the majority of metabolites are excreted in the urine, dosage reductions may need to be considered for patients with renal impairment.

Elderly population

Since the elderly are more sensitive to the effects of EUSEDEX, dosage reductions may need to be considered.

Paediatric population

Safety and efficacy of EUSEDEX have not been studied in children and adolescents and it is therefore not recommended for patients under 18 years of age.

Method of administration

For intravenous infusion. For instructions on preparation and dilution of the product before administration, see section 6.6.

EUSEDEX is contraindicated in

• patients with a known hypersensitivity to dexmedetomidine or to any of the excipients of EUSEDEX listed in section 6.1
• patients with sepsis
• unstable trauma patients
• hypovolaemic patients
• heart block
• uncontrolled cardiac failure
• imminent hepatic failure

EUSEDEX should be administered only by health care providers skilled in the management of patients in the intensive care setting and who have received complete training in the use of EUSEDEX in the ICU setting. Safety and efficacy of EUSEDEX in non-surgical intensive care patients have not been established.

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

Elderly population

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 EUSEDEX.

Special precautions

NOTE: EUSEDEX should be administered only by health care providers skilled in the management of patients in the intensive care setting. Continuous electrocardiogram (ECG), blood pressure and oxygen saturation monitoring are mandatory during infusion of EUSEDEX.

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

Clinical events of bradycardia and sinus arrest have been associated with EUSEDEX administration in young, healthy volunteers with high vagal tone, or with different routes of administration including rapid intravenous or bolus administration of EUSEDEX (see boxed warning above). Decreased blood pressure and/or heart rate may occur with the administration of EUSEDEX. Based on clinical experience with EUSEDEX, if medical intervention is required, treatment may include decreasing or stopping the infusion of EUSEDEX, increasing the rate of intravenous fluid administration, elevation of the lower extremities and use of pressor medicines. Because EUSEDEX has the potential to augment bradycardia induced by vagal stimuli, clinicians 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 EUSEDEX-induced bradycardia. However, in some patients with significant cardiovascular dysfunction, more advanced resuscitative measures were required.

EUSEDEX 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 EUSEDEX. Patients who are hypovolaemic may become hypotensive under EUSEDEX therapy. Therefore, fluid supplementation should be administered prior to and during the administration of EUSEDEX. Additionally, in situations where other vasodilators or negative chronotropic medicines are administered, co-administration of EUSEDEX 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 EUSEDEX 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 EUSEDEX 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 EUSEDEX dominate and the blood pressure usually decreases.

Hyperthermia or pyrexia

EUSEDEX may induce hyperthermia or pyrexia, which may be resistant to traditional cooling methods, such as administration of cooled intravenous fluids and antipyretic medicines. Discontinue EUSEDEX if medicine-related hyperthermia or pyrexia is suspected and monitor patients until body temperature normalizes.

EUSEDEX may cause reduced lacrimation. Lubrication of the patientu2019s eyes may be considered when administering EUSEDEX to avoid corneal dryness.

Cytochrome P-450

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

Anaesthetics/sedatives/hypnotics/opioids

Co-administration of EUSEDEX is likely to lead to an enhancement of effects with anaesthetics, sedatives, hypnotics and opioids. Specific studies have confirmed these effects with sevoflurane, isoflurane, propofol, alfentanil, and midazolam. No pharmacokinetic interactions between EUSEDEX and isoflurane, propofol, alfentanil, and midazolam were demonstrated. However, due to pharmacodynamic effects, when co-administered with EUSEDEX 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 EUSEDEX and rocuronium administration.

Safety in pregnancy and lactation has not been established.

Pregnancy

Available data from published randomized controlled trials and case reports over several decades of use with intravenously administered dexmedetomidine during pregnancy have not identified a drug-associated risk of major birth defects and miscarriage; however, the reported exposures occurred after the first trimester. Most of the available data are based on studies with exposures that occurred at the time of caesarean section delivery, and these studies have not identified an adverse effect on maternal outcomes or infant Apgar scores. Available data indicate that dexmedetomidine crosses the placenta.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

Labour and delivery

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

Breastfeeding

Available published literature reports the presence of EUSEDEX in human milk following intravenous administration. There is no information regarding the effects of EUSEDEX on the breastfed infant or the effects on milk production. Advise women to monitor the breastfed infant for irritability. The developmental and health benefits of breastfeeding should be considered along with the motheru2019s clinical need for EUSEDEX and any potential adverse effects on the breastfed infant from EUSEDEX or from the underlying condition.

In two published clinical studies, a total of 14 women were given intravenous dexmedetomidine 6 micrograms/kg/hour for 10 minutes followed by continuous infusion of 0,2 u2013 0,7 microgram/kg/hour. Breast milk and maternal blood samples were collected at 0, 6, 12, and 24 hours after discontinuation of dexmedetomidine. Plasma and milk dexmedetomidine concentrations were detectable up to 6 hours in most subjects, up to 12 hours in one subject and undetectable in all at 24 hours. The milk-to-plasma ratio from single paired maternal milk and plasma concentrations at each time point ranged from 0,53 to 0,95. The relative infant dose was estimated to range from 0,02 to 0,098 %.

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

Tabulated summary of adverse reactions ICU sedation

Adverse event information is derived from the continuous infusion trials of EUSEDEX when dosed at a maintenance dose range of 0,2 to 0,7 microgram/kg/hr to achieve the desired clinical effect for sedation in the ICU setting. 1007 patients received EUSEDEX. Treatment-emergent adverse events occurring at an incidence of > 2 % are provided in Table 1. The adverse reactions are displayed by system organ class. The most frequently observed treatment-emergent adverse events include hypotension, hypertension, bradycardia, nausea, dry mouth and hypoxia (see section 4.4).

Table 1: Adverse events with an incidence > 2 % - ICU sedation population

Body System (MedDRA)/ Adverse Event All EUSEDEX N = 1007 Randomised EUSEDEX N = 798 Placebo N = 400 n (%) n (%) n (%) Blood and lymphatic system disorders Anaemia 19 (1,9 %) 18 (2,3 %) 7 (1,8 %) Metabolism and nutrition disorders Hypovolaemia Hyperglycaemia Hypocalcaemia Acidosis 31 (3,1 %) 17 (1,7 %) 7 (0,7 %) 6 (0,6 %) 22 (2,8 %) 15 (1,9 %) 7 (0,9 %) 5 (0,6 %) 9 (2,3 %) 7 (1,8 %) 0 4 (1,0 %) Psychiatric disorders Agitation 20 (2,0 %) 16 (2,0 %) 11 (2,8 %) Cardiac disorders Bradycardia Atrial fibrillation Tachycardia Sinus tachycardia Ventricular tachycardia 52 (5,2 %) 44 (4,4 %) 20 (2,0 %) 6 (0,6 %) 4 (0.4 %) 36 (4,5 %) 37 (4,6 %) 15 (1,9 %) 6 (0,8 %) 4 (0,5 %) 10 (2,5 %) 13 (3,3 %) 17 (4,3 %) 2 (0,5 %) 3 (0,8 %)

Vascular disorders Hypotension Hypertension 248 (24,6 %) 123 (12,2 %) 191 (23,9 %) 101 (12,7 %) 48 (12,0 %) 76 (19,0 %) Respiratory, thoracic and mediastinal disorders Atelectasis Pleural effusion Hypoxia Pulmonary oedema Wheezing 29 (2,9 %) 23 (2,3 %) 16 (1,6 %) 9 (0,9 %) 4 (0,4 %) 23 (2,9 %) 16 (2,0 %) 13 (1,6 %) 9 (1,1 %) 4 (0,5 %) 13 (3.3 %) 4 (1,0 %) 8 (2,0 %) 3 (0,8 %) 1 (0,3 %) Gastrointestinal disorders Nausea Dry mouth Vomiting 90 (8,9 %) 35 (3,5 %) 34 (3,4 %) 73 (9,1 %) 22 (2,8 %) 26 (3,3 %) 36 (9,0 %) 4 (1,0 %) 21 (5,3 %) General disorders and administration site conditions Pyrexia Hyperthermia Chills Peripheral oedema 35 (3,5 %) 19 (1,9 %) 17 (1,7 %) 4 (0,4 %) 31 (3,9 %) 16 (2,0 %) 14 (1,8 %) 2 (0,3 %) 15 (3,8 %) 12 (3,0 %) 13 (3,3 %) 2 (0,5 %) Investigations Decreased urine output 6 (0,6 %) 6 (0,8 %) 0 Injury, poisoning and procedural complications Post-procedural haemorrhage 15 (1,5 %) 13 (1,6 %) 10 (2,5 %)

Conscious sedation

Adverse event information is derived from the two primary Phase III trials for conscious sedation in which 318 patients received EUSEDEX. Treatment-emergent adverse events occurring at an incidence of > 2 % are provided in Table 2. The adverse reactions are displayed by system organ class. 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)

Table 2: Adverse events with an incidence > 2 % - conscious sedation population

Body System (MedDRA) / Adverse Event EUSEDEX N = 318 n (%) Cardiac disorders Bradycardia 3 Tachycardia 4 45 (14,2 %) 17 (5,3 %) Vascular disorders Hypotension 1 Hypertension 2 173 (54,4 %) 41 (12,9 %) Respiratory, thoracic and mediastinal disorders Respiratory depression 5 Hypoxia 6 Bradypnoea 117 (36,8 %) 7 (2,2 %) 5 (1,6 %)

1. Hypotension was defined in absolute and relative terms as systolic blood pressure of < 80 mmHg or < 30 % lower than pre-study medicine infusion value, or diastolic blood pressure of < 50 mmHg.

2. Hypertension was defined in absolute and relative terms as systolic blood pressure > 180 mmHg or > 30 % higher than pre-study medicine infusion value or diastolic blood pressure of > 100 mmHg.

3. Bradycardia was defined in absolute and relative terms as < 40 bpm or < 30 % lower than pre-study medicine infusion value.

4. Tachycardia was defined in absolute and relative terms as > 120 bpm or > 30 % greater than pre-study medicine infusion value.

5. Respiratory depression was defined in absolute and relative terms as RR 25 % decrease from baseline.

6. Hypoxia was defined in absolute and relative terms as SpO2 < 90 % or 10 % decrease from baseline.

Post-marketing experience

Table 3: Adverse events experienced during post-approval use of EUSEDEX

Body system (WHOART) Preferred term Body as a whole u2013 general disorders Allergic reaction, ascites, fever, hyperpyrexia, hypovolaemia, light anaesthesia, oedema, peripheral oedema, pain, syncope, withdrawal syndrome, rigors

Cardiovascular disorders, General Blood pressure fluctuation, circulatory failure, cyanosis, abnormal ECG, heart disorder, hypertension, aggravated hypertension, pulmonary hypertension, hypotension, postural hypotension, pulmonary hypertension, myocardial infarction

Central and peripheral nervous system disorders Convulsion, dizziness, headache, neuralgia, neuritis, neuropathy, paraesthesia, paralysis, paresis, speech disorder

Gastrointestinal system disorders Abdominal pain, diarrhoea, eructation, mucosal ulceration, nausea, vomiting

Heart rate and rhythm disorders Dysrhythmia, atrial dysrhythmia, atrial fibrillation, AV block, bradycardia, bundle branch block, cardiac arrest, extrasystoles, heart block, hypoxia, supraventricular tachycardia,T wave inversion, tachycardia, ventricular dysrhythmia, ventricular tachycardia

Liver and biliary system disorders Increased AG ratio, increased GGT, abnormal hepatic function, hyperbilirubinaemia, increased aspartate transaminase (AST), increased alanine transaminase (ALT), jaundice

Metabolic and nutritional disorders Acidosis, lactic acidosis, respiratory acidosis, diabetes mellitus, hyperglycaemia, hypoglycaemia, hypokalaemia, hyperkalaemia, hypoproteinaemia, increased alkaline phosphatase, increased non-protein nitrogen (NPN), thirst

Musculoskeletal system disorders Muscle weakness

Myo-, endo-, pericardial & valve disorders Angina pectoris, myocardial infarction, myocardial ischaemia

Platelet, bleeding & clotting disorders Coagulation disorders, disseminated intravascular coagulation, haematoma, abnormal platelets, decreased prothrombin, thrombocytopenia

Psychiatric disorders Agitation, anxiety, confusion, delirium, depression, hallucination, illusion, nervousness

Red blood cell disorders Anaemia

Renal disorders Increased blood urea, oliguria

Resistance mechanism disorders Infection, fungal infection, sepsis

Respiratory system disorders Adult respiratory distress syndrome, apnoea, bronchial obstruction, bronchospasm, coughing, dyspnoea, emphysema, haemoptysis, hypercapnia, hypoventilation, hypoxia, pharyngitis, pleurisy, pneumonia, pneumothorax, pulmonary congestion, pulmonary oedema, respiratory depression, respiratory disorder, respiratory insufficiency, increased sputum, stridor

Skin and appendages disorders Rash erythematous, increased sweating

Urinary system disorders Haematuria, acute renal failure, abnormal renal function, urinary retention

Vascular (extracardiac) disorders Haemorrhage, cerebral haemorrhage, peripheral ischaemia, vascular disorder, vasodilation

Vision disorders Diplopia, photopsia, abnormal vision

White cell & RES disorders Leukocytosis

First-degree AV block and second-degree heart block may occur. Bradycardia, with or without hypotension, and cardiac arrest may occur.

Because EUSEDEX has the potential to augment bradycardia induced by vagal stimuli, clinicians should be prepared to intervene. In clinical trials, atropine and glycopyrrolate were effective in the treatment of EUSEDEX-induced bradycardia.