Dexsedate 100 Μg/Ml 100 μg Concentrate for solution for infusion

DEXSEDATE is an alpha 2 adrenoreceptor agonist sedative with analgesic properties. DEXSEDATE 100 u03bcg/ml should not be used outside an Intensive Care Unit setting or surgical operating theatres. There should be continuous monitoring of vital parameters.

indicated for:

• Intensive care unit sedation
• u2022 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 case setting for:
• u2022 Minor surgical procedures under local anaesthesia
• u2022 Fibreoptic intubation

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

Posology

NOTE: DEXSEDATE should be administered only by health care 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 DEXSEDATE. In order to minimise undesirable pharmacologic side effects, bolus injection of DEXSEDATE should not be used. Clinically significant events of bradycardia and sinus arrest have been associated with DEXSEDATE administration in young healthy volunteers with high vagal tone, or with different routes of administration including rapid intravenous or bolus administration of DEXSEDATE. DEXSEDATE should be administered by continuous intravenous infusion not to exceed 24 hours. Fluid supplementation should be administered prior to and during administration of DEXSEDATE to ensure normovolaemia.

DEXSEDATE 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 DEXSEDATE. Patients receiving DEXSEDATE 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. DEXSEDATE has been continuously infused in mechanically ventilated patients prior to extubation, during extubation, and post extubation. It is not necessary to discontinue DEXSEDATE prior to extubation.

Posology

Adults

ICU sedation

DEXSEDATE dosage should be individualised and titrated to the desired clinical effect. Initiation For adult patients, it is recommended to initiate DEXSEDATE 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 micrograms/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.

Conscious sedation

Monitored anaesthesia care (MAC) with an adequate nerve block and awake fibreoptic intubation (AFI). DEXSEDATE dosing should be individualised and titrated to the desired clinical effect. Initiation For adult patients, DEXSEDATE 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 Following the load, maintenance dosing of DEXSEDATE 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 pharmacodynamics interactions a reduction in dosage of DEXSEDATE 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 DEXSEDATE 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 DEXSEDATE dosage reductions may need to be considered. Paediatric population Safety and efficacy of DEXSEDATE 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. For instructions on preparation and dilution of the product before administration, see section 6.6.

DEXSEDATE is contraindicated in:

• u2022 Patients with a known hypersensitivity to dexmedetomidine or to any of the excipients (see section 6.1)
• u2022 Patients with sepsis
• u2022 Unstable trauma patients
• u2022 Hypovolaemic patients
• u2022 Heart block
• u2022 Uncontrolled cardiac failure
• u2022 Imminent hepatic failure
• u2022 Uncontrolled hypotension
• u2022 Acute cerebrovascular conditions

DEXSEDATE 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 DEXSEDATE in the ICU setting. Safety and efficacy of DEXSEDATE in non-surgical intensive care patients have not been established. Clinical events of bradycardia and sinus arrest have been associated with DEXSEDATE administration in some young, healthy volunteers with high vagal tone, or with different routes of administration including rapid intravenous or bolus administration of DEXSEDATE. Bolus injections of DEXSEDATE 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 DEXSEDATE.

Special precautions

NOTE: DEXSEDATE 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 DEXSEDATE. 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 DEXSEDATE administration in some young, healthy volunteers with high vagal tone, or with different routes of administration including rapid intravenous or bolus administration of DEXSEDATE. Bolus injections of DEXSEDATE should not be used, in order to minimise undesirable pharmacological side effects. Decreased blood pressure and/or heart rate may occur with the administration of DEXSEDATE. If medical intervention is required, treatment may include decreasing or stopping the infusion of DEXSEDATE, increasing the rate of intravenous fluid administration, elevation of the lower extremities and use pressor medicines. Because DEXSEDATE has the potential to augment bradycardia induced by vagal stimuli, medical practitioners 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 dexmedetomidine-induced bradycardia. However, in some patients with significant cardiovascular dysfunction, more advanced resuscitative measures were required. DEXSEDATE 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 DEXSEDATE. Patients who are hypovolaemic may become hypotensive under DEXSEDATE therapy. Therefore, fluid supplementation should be administered prior to and during the administration of DEXSEDATE. Additionally, in situations where other vasodilators or negative chronotropic medicines are administered, co-administration of DEXSEDATE 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 DEXSEDATE is used concurrently with propofol or midazolam. Therefore, consider a dose reduction of propofol or midazolam (see section 4.5). Patients with impaired peripheral autonomic activity (e.g. due to spinal cord injury) may have more pronounced haemodynamic changes after starting DEXSEDATE and so should be treated with care.

Transient hypertension Transient hypertension has been observed primarily during the loading infusion, associated with initial peripheral vasoconstrictive effects of DEXSEDATE 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 DEXSEDATE 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 DEXSEDATE together with spinal or epidural anaesthesia due to possible increased risk of hypotension or bradycardia. DEXSEDATE may cause reduced lacrimation. Lubrication of the patientu2019s eyes may be considered when administering DEXSEDATE to avoid corneal dryness. 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 DEXSEDATE clearance. Patients with neurological disorders Experience of DEXSEDATE 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. DEXSEDATE 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 DEXSEDATE. DEXSEDATE may induce hyperthermia that may be resistant to traditional cooling methods. DEXSEDATE 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 DEXSEDATE treatment. If polyuria occurs, it is recommended to stop DEXSEDATE and check serum sodium level and urine osmolality. DEXSEDATE contains less than 1 mmol sodium (23 mg) per ml, essentially u201csodium freeu201d.

Cytochrome P-450 Inhibition of GYP enzymes including CYP2B6 by dexmedetomidine 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.

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.

Anaesthetics/sedatives/hypnotics/opioids Co-administration of DEXSEDATE 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 DEXSEDATE and isoflurane, propofol, alfentanil, and midazolam were demonstrated. However, due to pharmacodynamic effects, when co-administered with DEXSEDATE 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 DEXSEDATE 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 DEXSEDATE 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 DEXSEDATE in human milk following intravenous administration. There is no information regarding the effects of DEXSEDATE 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 DEXSEDATE and any potential adverse effects on the breastfed infant from DEXSEDATE 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 after delivery 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 %.

Fertility In a rat fertility study, there was 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 a surgical procedure in which DEXSEDATE was used.

a. Summary of the safety profile ICU sedation The most frequently reported adverse reactions with dexmedetomidine in ICU setting are hypotension, hypertension, bradycardia, nausea, dry mouth and hypoxia (see section 4.4). Conscious sedation 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)

b. Tabulated summary of adverse reactions The frequency of adverse reactions listed below is defined using the following convention: frequent; less frequent or frequency unknown (cannot be estimated from the available data).

MedDRA system organ class Frequency Adverse reactions Infections and infestations Frequency unknown Infection, fungal infection, sepsis

MedDRA system organ class Frequency Adverse reactions Blood and lymphatic system disorders Frequent Anaemia Frequency unknown Coagulation disorders, disseminated intravascular coagulation, haematoma, abnormal platelets, decreased prothrombin, thrombocytopenia, leukocytosis

Endocrine disorders Frequency unknown Diabetes mellitus, diabetes insipidus

Metabolism and nutrition disorders Frequent Hypoglycaemia, hyperglycaemia Less frequent Hypocalcaemia, hypoalbuminaemia, metabolic acidosis Frequency unknown Lactic acidosis, respiratory acidosis, hypokalaemia, hyperkalaemia, hypoproteinaemia, increased alkaline phosphatase, increased nonprotein nitrogen (NPN)

Psychiatric disorders Frequent Agitation Frequency unknown Anxiety, confusion, delirium, depression, illusion, nervousness, hallucination

Nervous system disorders Frequency unknown Convulsion, dizziness, headache, neuralgia, neuritis, neuropathy, paraesthesia, paralysis, paresis, speech disorder

Eye disorders Frequency unknown Diplopia, photopsia, abnormal vision

Cardiac disorders Frequent Atrial fibrillation, bradycardia, tachycardia Less frequent Sinus tachycardia, ventricular tachycardia, decreased cardiac output Frequency unknown Dysrhythmia, atrial dysrhythmia, AV block, bundle branch block, extrasystoles, heart block, supraventricular tachycardia, T-wave inversion, ventricular dysrhythmia, angina pectoris, abnormal ECG, heart disorder, myocardial ischaemia or infarction, atrioventricular block, cardiac arrest

Vascular disorders Frequent Hypovolaemia, hypotension, hypertension Frequency unknown Blood pressure fluctuation, circulatory failure, cyanosis, aggravated hypertension, pulmonary hypertension, postural hypotension, pulmonary hypertension, haemorrhage, cerebral haemorrhage, peripheral ischaemia, vascular disorder, vasodilation

Respiratory, thoracic and mediastinal disorders Frequent Atelectasis, pleural effusion, hypoxia, bradypnoea, respiratory depression Less frequent Pulmonary oedema, wheezing, dyspnoea, apnoea Frequency unknown Syncope, adult respiratory distress syndrome, bronchial obstruction, bronchospasm, coughing, emphysema, haemoptysis, hypercapnia, hypoventilation, pharyngitis, pleurisy, pneumonia, pneumothorax, pulmonary congestion, respiratory disorder, respiratory insufficiency, increased sputum, stridor

Gastrointestinal disorders Frequent Nausea, vomiting, dry mouth Less frequent Abdominal distension Frequency unknown Abdominal pain, diarrhoea, eructation, mucosal ulceration

Hepato-biliary disorders Frequency unknown Increased AG ratio, increased GGT, abnormal hepatic function, hyperbilirubinaemia, increased aspartate transaminase (AST), increased alanine transaminase (ALT), jaundice

Skin and subcutaneous tissue disorders Frequency unknown Rash erythematous, increased sweating

Musculoskeletal and connective tissue disorders Frequency unknown Muscle weakness

Renal and urinary disorders Frequency unknown Increased blood urea, oliguria, haematuria, acute renal failure, abnormal renal function, urinary retention

General disorders and administration site conditions Frequent Pyrexia, chills, hyperthermia Less frequent Peripheral oedema, medicine ineffective Frequency unknown Allergic reaction, ascites, hyperpyrexia, light anaesthesia, oedema, pain, rigors, thirst, withdrawal syndrome

Investigations Less frequent Decreased urine output

Injury, poisoning and procedural complications Frequent Post-procedural haemorrhage

Withdrawal ICU sedation Although not specifically studied, withdrawal symptoms similar to those reported for another alpha 2 adrenergic medicine (clonidine) may result when DEXSEDATE 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 DEXSEDATE (< 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 requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who - umc.org) found on SAHPRA website.

First-degree AV block and second-degree heart block may occur. Bradycardia, with or without hypotension, and cardiac arrest may occur. Because DEXSEDATE has the potential to augment bradycardia induced by vagal stimuli, medical practitioners should be prepared to intervene. In clinical trials, atropine and glycopyrrolate were effective in the treatment of DEXSEDATE-induced bradycardia.