Dexithera 2 Ml/4 Ml/10 Ml/200 mg/400 mg Solution

DEXITHERA 100 u03bcg/mL is an alpha2 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: DEXITHERA 100 u03bcg/mL should be administered only by health professionals 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 DEXITHERA 100 u03bcg/mL.

In order to minimise undesirable pharmacologic side effects, bolus injections of DEXITHERA 100 u03bcg/mL should not be used. Clinically significant events of bradycardia and sinus arrest have been associated with dexmedetomidine hydrochloride administration in young healthy volunteers with high vagal tone, or with different routes of administration including rapid intravenous or bolus administration of dexmedetomidine hydrochloride.

DEXITHERA 100 u03bcg/mL should be administered by continuous intravenous infusion not to exceed 24 hours. Fluid supplementation should be administered prior to and during administration of DEXITHERA 100 u03bcg/mL to ensure normovolaemia. DEXITHERA 100 u03bcg/mL 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 DEXITHERA 100 u03bcg/mL. Patients receiving DEXITHERA 100 u03bcg/mL have been observed to be arousable and alert when stimulated. This is an expected component of dexmedetomidine sedation and should not be considered as evidence of lack of efficacy in the absence of other clinical signs and symptoms. DEXITHERA 100 u03bcg/mL has been continuously infused in mechanically ventilated patients prior to extubation, during extubation, and post extubation. It is not necessary to discontinue dexmedetomidine prior to extubation.

Posology

Adults

ICU sedation

DEXITHERA 100 u03bcg/mL dosage should be individualised and titrated to the desired clinical effect.

Initiation: For adult patients, it is recommended to initiate DEXITHERA 100 u03bcg/mL 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/h. 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/h 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). DEXITHERA 100 u03bcg/mL dosing should be individualised and titrated to the desired clinical effect.

Initiation For adult patients, DEXITHERA 100 u03bcg/mL 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 micrograms/kg over 10 minutes may be suitable.

Maintenance of conscious sedation (MAC): MAC - Following the load, maintenance dosing of DEXITHERA 100 u03bcg/mL should generally be initiated at 0,6 micrograms/kg/h and titrated to achieve desired clinical effect with doses ranging from 0,2 to 1 micrograms/kg/h 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 micrograms/kg/h should be used.

Dosage adjustment Due to possible pharmacodynamic interactions a reduction in dosage of DEXITHERA 100 u03bcg/mL 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 DEXITHERA 100 u03bcg/mL 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 DEXITHERA 100 u03bcg/mL dosage reductions may need to be considered.

Paediatric population Safety and efficacy of DEXITHERA 100 u03bcg/mL has not been studied in children and adolescents and is therefore not recommended for patients under 18 years of age.

Method of administration For intravenous infusion

A controlled infusion device should be used to administer DEXITHERA 100 u03bcg/mL. Parenteral products should be inspected visually for particulate matter and discolouration prior to administration. Ampoules/vials are intended for single patient use only. For instructions on the dilution of DEXITHERA 100 u03bcg/mL before administration, see section 6.6.

DEXITHERA 100 u03bcg/mL is contraindicated in:

• Hypersensitivity to dexmedetomidine or to any of the excipients listed in section 6.1.
• Patients with sepsis.
• Unstable trauma patients.
• Hypovolaemic patients.
• Heart block.
• Uncontrolled cardiac failure.
• Imminent hepatic failure.

DEXITHERA 100 u03bcg/mL is intended for use in an intensive care setting, operating room and during diagnostic procedures. The use in other environments is not recommended. DEXITHERA 100 u03bcg/mL should only be administered by health care providers skilled in the management of patients in these settings and who have received complete training in the use of DEXITHERA 100 u03bcg/mL in these environments.

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.

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

Monitoring During the infusion of DEXITHERA 100 u03bcg/mL, all patients should receive continuous cardiac monitoring. Continuous electrocardiogram (ECG), blood pressure and oxygen saturation monitoring are mandatory during DEXITHERA 100 u03bcg/mL infusion. Due to the risk of respiratory depression and in some cases apnoea (see section 4.8), respiration should be monitored in non-intubated patients. The safety and efficacy of DEXITHERA 100 u03bcg/mL in non-surgical intensive care patients have not been established. The time to recovery after the use of DEXITHERA 100 u03bcg/mL 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.

General precautions DEXITHERA 100 u03bcg/mL should not be given as bolus dose and in the ICU a loading dose is not recommended. Users should 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 DEXITHERA 100 u03bcg/mL 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. Dexmedetomidine normally does not cause deep sedation and patients may be easily roused. DEXITHERA 100 u03bcg/mL is therefore not suitable in patients who will not tolerate this profile of effects, for example those requiring continuous deep sedation. DEXITHERA 100 u03bcg/mL should not be used as a general anaesthetic induction medicine for intubation or to provide sedation during muscle relaxant use. DEXITHERA 100 u03bcg/mL lacks the anticonvulsant action of some other sedatives and so will not suppress underlying seizure activity. Care should be taken if combining DEXITHERA 100 u03bcg/mL with other substances with sedative or cardiovascular actions as additive effects may occur. DEXITHERA 100 u03bcg/mL is not recommended for patient controlled sedation due to a lack of adequate data. When DEXITHERA 100 u03bcg/mL 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 medicines or substances that may sedate (e.g, benzodiazepines, opioids, alcohol) for a suitable period of time (see section 4.7), based on observed effects of DEXITHERA 100 u03bcg/mL, the procedure, concomitant medications, the age and the condition of the patient.

Cardiovascular effects and precautions DEXITHERA 100 u03bcg/mL reduces heart rate and blood pressure through central sympatholysis but at higher concentrations causes peripheral vasoconstriction leading to hypertension (see section 5.1). DEXITHERA 100 u03bcg/mL is therefore not suitable in patients with severe cardiovascular instability. Clinical events of bradycardia or hypotension may be potentiated when DEXITHERA 100 u03bcg/mL is used concurrently with propofol or midazolam (see section 4.5). Caution should be exercised when administering DEXITHERA 100 u03bcg/mL to patients with pre-existing bradycardia disorders (i.e., advanced heart block). Data on the effects of DEXITHERA 100 u03bcg/mL 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. In clinical trials, atropine and glycopyrrolate were found to be effective in the treatment of most episodes of DEXITHERA 100 u03bcg/mL-induced bradycardia. More resuscitative measures were however required in some patients with significant cardiovascular dysfunction. 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 dexmedetomidine 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 (e.g., ejection fraction < 30 %), including congestive heart failure and cardiac failure and the elderly. Hypotension does not normally require specific treatment but, where needed, users should be ready to intervene with dose reduction, fluids and/or vasoconstrictors. Treatment may include dose reduction or discontinuation of DEXITHERA 100 u03bcg/mL, elevation of the lower extremities, increasing the rate of IV fluid administration and/or administration of vasoconstrictors. DEXITHERA 100 u03bcg/mL is contraindicated for use in patients with hypovolaemia (see section 4.3). Patients who are hypovolaemic may become hypotensive during DEXITHERA 100 u03bcg/mL treatment. Normovolaemia must therefore be ensured prior to administration of DEXITHERA 100 u03bcg/mL (see section 4.2). Patients with impaired peripheral autonomic activity (e.g., due to spinal cord injury) may have more pronounced haemodynamic changes after starting DEXITHERA 100 u03bcg/mL and so should be treated with care. Transient hypertension has been observed primarily during the loading dose in association with the peripheral vasoconstrictive effects of dexmedetomidine. Treatment of hypertension has generally not been necessary but decreasing the continuous infusion rate may be advisable. Following the loading infusion, the central effects of DEXITHERA 100 u03bcg/mL dominate and the blood pressure usually decreases. The use of DEXITHERA 100 u03bcg/mL may enhance the pharmacodynamic effect of vasodilators or negative chronotropic medicines when co-administered. In these cases, DEXITHERA 100 u03bcg/mL should be administered with caution and careful titration is advised (see section 4.5). 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 DEXITHERA 100 u03bcg/mL together with spinal or epidural anaesthesia due to possible increased risk of hypotension or bradycardia.

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 DEXITHERA 100 u03bcg/mL clearance.

Patients with neurological disorders Experience of dexmedetomidine 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. DEXITHERA 100 u03bcg/mL may reduce cerebral blood flow and intracranial pressure, and this should be considered when selecting therapy.

Elderly patients Caution should be exercised when administering DEXITHERA 100 u03bcg/mL to elderly patients. Elderly patients over 65 years of age may be more prone to hypotension with the administration of DEXITHERA 100 u03bcg/mL, including a loading dose, for procedures. Close cardiovascular monitoring is required in these patients and the dose of DEXITHERA 100 u03bcg/mL must be carefully titrated until the desired effect is obtained. Elderly patients often require lower doses of DEXITHERA 100 u03bcg/mL.

Other Alpha-2 agonists have rarely been associated with withdrawal reactions when stopped abruptly after prolonged use (in excess of 24 hours). This possibility should be considered if the patient develops agitation and hypertension shortly after stopping DEXITHERA 100 u03bcg/mL. Other symptoms of withdrawal may include headache, nervousness and elevated catecholamine concentrations in the plasma. DEXITHERA 100 u03bcg/mL may induce hyperthermia that may be resistant to traditional cooling methods. DEXITHERA 100 u03bcg/mL treatment should be discontinued in the event of a sustained unexplained fever or pyrexia and is not recommended for use in malignant hyperthermia-sensitive patients.

Treatment with DEXITHERA 100 u03bcg/mL may result in decreased lacrimation. To avoid corneal dryness, lubrication of the patientu2019s eyes may be considered when administering DEXITHERA 100 u03bcg/mL.

Sodium DEXITHERA 100 u03bcg/mL contains less than 1 mmol sodium (23 mg) per mL infusion, i.e., it is essentially sodium-free. Each 10 mL vial of concentrate for solution for infusion contains 37 mg sodium, equivalent to 2 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Interaction studies have only been performed in adults. Co-administration of DEXITHERA 100 u03bcg/mL with anaesthetics, sedatives, hypnotics, and opioids is likely to lead to an enhancement of effects, including sedative, anaesthetic and cardiorespiratory effects. Specific studies have confirmed enhanced effects with isoflurane, propofol, alfentanil, and midazolam. No pharmacokinetic interactions between dexmedetomidine and isoflurane, propofol, alfentanil and midazolam have been demonstrated. However, due to possible pharmacodynamic interactions, when co-administered with DEXITHERA 100 u03bcg/mL, a reduction in dosage of DEXITHERA 100 u03bcg/mL or the concomitant anaesthetic, sedative, hypnotic or opioid may be required.

Inhibition of cytochrome P (CYP) enzymes including CYP2B6 by dexmedetomidine has been studied in human liver microsome incubations. In vitro study suggests that interaction potential in vivo exists between DEXITHERA 100 u03bcg/mL 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. 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. Following the co-administration of DEXITHERA 100 u03bcg/mL and rocuronium, no clinically meaningful increases in the extent of neuromuscular blockade and no pharmacokinetic interactions can be observed.

Pregnancy Safety of use during pregnancy has not been established. There are no or limited amount of data from the use of DEXITHERA 100 u03bcg/mL in pregnant women. Studies in animals have shown reproductive toxicity. DEXITHERA 100 u03bcg/mL should not be used during pregnancy.

Labour and delivery The safety of DEXITHERA 100 u03bcg/mL in labour and delivery has not been studied and it is therefore not recommended for obstetrics, including caesarean section deliveries.

Breastfeeding Dexmedetomidine is excreted in human milk, however levels will be below the limit of detection by 24 hours following treatment discontinuation. A risk to infants cannot be excluded. The use of DEXITHERA 100 u03bcg/mL is not recommended in breastfeeding women.

Fertility In the rat fertility study, dexmedetomidine had no effect on male or female fertility. No human data on fertility are available.

Dexmedetomidine has major impact on the ability to drive and use machines. Patients should be advised to refrain from driving, operating machines, undertaking any other hazardous tasks or make legal decisions for at least 24 hours after receiving DEXITHERA 100 u03bcg/mL.

Summary of the safety profile

Sedation of adult ICU patients In the ICU setting, the most frequent reported adverse reactions are hypotension, hypertension, bradycardia, nausea, dry mouth and hypoxia. Hypotension and bradycardia were the most frequent dexmedetomidine-related serious adverse reactions occurring in ICU patients.

Procedural/conscious sedation The most frequent adverse events reported in procedural sedation are hypotension, respiratory depression, bradycardia and dry mouth. Most of the adverse reactions were assessed to be mild in severity.

The following undesirable effects have been reported during clinical trials in the ICU setting

Blood and lymphatic system disorders Frequent: anaemia

Metabolism and nutrition disorders Frequent: hyperglycaemia, hypoglycaemia, hypovolaemia Less frequent: metabolic acidosis, hypoalbuminemia, hypocalcaemia

Psychiatric disorders Frequent: agitation Less frequent: hallucination

Cardiac disorders Frequent: bradycardia 1, 2 , myocardial ischaemia or infarction, tachycardia 2 , atrial fibrillation Less frequent: atrioventricular block 1 , cardiac output decreased, cardiac arrest 1 , sinus tachycardia, ventricular tachycardia

Vascular disorders Frequent: hypotension 1, 2 , hypertension 1, 2

Respiratory, thoracic and mediastinal disorders Frequent: respiratory depression 2 , atelectasis, pleural effusion, hypoxia 3 , bradypnoea 3 Less frequent: dyspnoea, apnoea, pulmonary oedema, wheezing

Gastrointestinal disorders Frequent: nausea 2 , vomiting, dry mouth 2 Less frequent: abdominal distention

Renal and urinary disorders Frequency unknown: polyuria

General disorders and administration site conditions Frequent: withdrawal syndrome, hyperthermia, pyrexia, chills Less frequent: medicine ineffective, thirst, peripheral oedema

Investigations Less frequent: urine output decreased

Injury, poisoning and procedural complications Frequent: post-procedural haemorrhage

1 See section on Description of selected adverse reactions.

2 Adverse reaction observed also in procedural/conscious sedation studies.

3 Adverse reaction only observed in procedural/conscious sedation studies.

Post-marketing experience Table 3: Adverse events experienced during post-approval use of DEXITHERA

Body System (WHORT) Preferred Term Body as 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

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

Description of selected adverse reactions Clinically significant bradycardia or hypotension should be treated as described in section 4.4.

When treated with dexmedetomidine, bradycardia has occasionally led to sinus arrest or pause in relatively healthy, non-ICU subjects. A response in symptoms resulted from leg raising and the administration of anticholinergic medicine, such as atropine or glycopyrrolate. In patients with pre-existing bradycardia, isolated cases have been reported of bradycardia progressing to periods of asystole. 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 reproduced by avoiding such a loading dose or reducing the infusion rate or size of the loading dose.

First-degree AV block and second-degree heart block may occur. Bradycardia, with or without hypotension, and cardiac arrest may occur. Because DEXITHERA has the potential to augment bradycardia induced by vagal stimuli, clinicians should be prepared to intervene.