4.1. Therapeutic indications

Dexmedetomidine 4 micrograms/ml solution for infusion is indicated in:

1. For sedation of adult ICU (Intensive Care Unit) patients requiring a sedation level not deeper than arousal in response to verbal stimulation (corresponding to Richmond Agitation-Sedation Scale (RASS) 0 to -3).

2. For sedation of non-intubated adult patients prior to and/or during diagnostic or surgical procedures requiring sedation, i.e. procedural/awake sedation.

4.2. Posology and method of administration

Indication 1. For sedation of adult ICU (Intensive Care Unit) patients requiring a sedation level not deeper than arousal in response to verbal stimulation (corresponding to Richmond Agitation-Sedation Scale (RASS) 0 to -3).

For hospital use only. Dexmedetomidine 4 micrograms/ml solution for infusion should be administered by healthcare professionals skilled in the management of patients requiring intensive care.

Posology

Patients already intubated and sedated may switch to dexmedetomidine with an initial infusion rate of 0.7 micrograms/kg/h which may then be adjusted stepwise within the dose range 0.2 to 1.4 micrograms/kg/h in order to achieve the desired level of sedation, depending on the patient's response. A lower starting infusion rate should be considered for frail patients. Dexmedetomidine is very potent and the infusion rate is given per hour. After dose adjustment, a new steady state sedation level may not be reached for up to one hour.

Maximum dose

The maximum dose of 1.4 micrograms/kg/h should not be exceeded. Patients failing to achieve an adequate level of sedation with the maximum dose of dexmedetomidine should be switched to an alternative sedative agent.

Use of a loading dose of Dexmedetomidine 4 micrograms/ml solution for infusion in ICU sedation is not recommended and is associated with increased adverse reactions. Propofol or midazolam may be administered if needed until clinical effects of dexmedetomidine are established.

Duration

There is no experience in the use of Dexmedetomidine 4 micrograms/ml solution for infusion for more than 14 days. The use of Dexmedetomidine 4 micrograms/ml solution for infusion for longer than this period should be regularly reassessed.

Indication 2. For sedation of non-intubated adult patients prior to and/or during diagnostic or surgical procedures requiring sedation, i.e. procedural/awake sedation.

Dexmedetomidine 4 micrograms/ml solution for infusion should be administered only by health care professionals skilled in the anaesthetics management of patients in the operating room or during diagnostic procedures. When Dexmedetomidine 4 micrograms/ml solution for infusion is administered for conscious sedation, patients should be continuously monitored by persons not involved in the conduct of the diagnostic or surgical procedure. Patients should be monitored continuously for early signs of hypotension, hypertension, bradycardia, respiratory depression, airway obstruction, apnoea, dyspnoea and/or oxygen desaturation (see section 4.8). Supplemental oxygen should be immediately available and provided when indicated. The oxygen saturation should be monitored. by pulse oximetry.

Dexmedetomidine 4 micrograms/ml solution for infusion is given as a loading infusion followed by maintenance infusion. Depending on the procedure concomitant local anaesthesia or analgesia may be needed in order to achieve the desired clinical effect. Additional analgesia or sedatives (e.g. opioids, midazolam or propofol) are recommended in case of painful procedures or if increased depth of sedation is necessary. The pharmacokinetic distribution half –life of Dexmetomidine has been estimated to be around 6 min, which can be taken into consideration, together with the effects of other administered medications, when assessing the appropriate time needed for titration to desired clinical effect of Dexmedetomidine.

Initiation of Procedural Sedation:

A loading infusion of 1.0 microgram/kg over 10 minutes. For less invasive procedures such as ophthalmic surgery, a loading infusion of 0.5 micrograms/kg given over 10 minutes may be suitable

Maintenance of Procedural Sedation:

The maintenance infusion is generally initiated at 0.6-0.7 microgram/kg/hour and titrated to achieve desired clinical effect with doses ranging from 0.2 to 1 microgram/kg/hour. The rate of the maintenance infusion should be adjusted to achieve the targeted level of sedation.

Special populations

Elderly

No dose adjustment is normally required for elderly patients (see section 5.2). Elderly patients appear to have an increased risk for hypotension (see section 4.4) but the limited data available from procedural sedation do not suggest a clear dose dependency.

Renal impairment

No dose adjustment is required for patients with renal impairment.

Hepatic impairment

Dexmedetomidine is metabolised in the liver and should be used with caution in patients with hepatic impairment. A reduced maintenance dose may be considered (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of dexmedetomidine in children aged 0 to 18 years have not been established. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

Method of administration

Dexmedetomidine 4 micrograms/ml solution for infusion should not be diluted before use: it is supplied ready to use. It should not be mixed with other medicines.

Dexmedetomidine must be administered only as an intravenous infusion using a controlled infusion device.

Dexmedetomidine should not be given as a bolus dose. See also general precautions, section 4.4

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Advanced heart block (grade 2 or 3) unless paced.

Uncontrolled hypotension.

Acute cerebrovascular conditions.

4.4. Special warnings and precautions for use

Monitoring

Dexmedetomidine is intended for use in an intensive care setting operating room or during diagnostic procedures. The use in other environments is not recommended. All patients should have continuous cardiac monitoring during Dexmedetomidine infusion. 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 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

Dexmedetomidine should not be given as 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 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.

Dexmedetomidine is therefore not suitable in patients who will not tolerate this profile of effects, for example those requiring continuous deep sedation.

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

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

Care should be taken if combining dexmedetomidine with other substances with sedative or cardiovascular actions as additive effects may occur.

Dexmedetomidine is not recommended for patient controlled sedation. Adequate data is not available.

When Dexmedetomidine 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 observed effects of dexmedetomidine, the procedure,concomitant medications, the age and the condition of the patient

Elderly

Caution should be exercised when administering dexmedetomidine to elderly patients.

Elderly patients over 65 years of age may be more prone to hypotension with the administration of dexmedetomidine, including a loading dose, for procedures. A dose reduction should be considered. Please refer to section 4.2.

Mortality in ICU patients ≤ 65 years old

In the SPICE III pragmatic randomised controlled trial of 3 904 critically ill adult ICU patients there was no overall difference in 90-day mortality between the dexmedetomidine and usual care group (mortality 29.1% in both groups), but a heterogeneity of effect from age on mortality was observed. Dexmedetomidine was associated with an increased mortality in the age-group ≤ 65 years (odds ratio 1.26; 95% credibility interval 1.02 to 1.56) compared to alternative sedatives. While the mechanism is unclear, this heterogeneity of effect on mortality from age was most prominent in cases with early use of dexmedetomidine in high dose to achieve deep sedation in patients admitted for other reasons than postoperative care and increased with increasing APACHE II scores. The effect on mortality was not detectable when dexmedetomidine was used for light sedation. These findings should be weighed against the expected clinical benefit of dexmedetomidine compared to alternative sedatives in younger patients.

Cardio-vascular effects and precautions

Dexmedetomidine reduces heart rate and blood pressure through central sympatholysis but at higher concentrations causes peripheral vasoconstriction leading to hypertension (see section 5.1).

Dexmedetomidine is therefore not suitable in patients with severe cardiovascular instability.

Caution should be exercised when administering dexmedetomidine to patients with pre-existing bradycardia. Data on the effects of Dexmedetomidine 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 dexmedetomidine may be of greater significance in those patients with preexisting 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 (see section 4.3). 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 dexmedetomidine 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 and a loading dose is not recommended for ICU sedation. Treatment of hypertension has generally not been necessary but decreasing the continuous infusion rate may be advisable.

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 dexmedetomidine 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 dexmedetomidine 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.

Dexmedetomidine may reduce cerebral blood flow and intracranial pressure and this should be considered when selecting therapy.

Other

Alpha-2 agonists have rarely 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 dexmedetomidine.

Dexmedetomidine 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.

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.

Excipients with recognised action/effect:

Dexmedetomidine 4 micrograms/ml solution for infusion contains 5.5 g glucose per 100 ml. This should be taken into account in patients with diabetes mellitus.

4.5. Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Co-administration of dexmedetomidine 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 dexmedetomidine, a reduction in dosage of dexmedetomidine or the concomitant anaesthetic, sedative, hypnotic or opioid may be required.

Inhibition of 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 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 medicinal products causing these effects, for example beta blockers, although additional effects in an interaction study with esmolol were modest.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of dexmedetomidine in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3).

Dexmedetomidine should not be used during pregnancy unless the clinical condition of the woman requires treatment with dexmedetomidine.

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. A decision must be made whether to discontinue breastfeeding or to discontinue dexmedetomidine therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

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

4.7. Effects on ability to drive and use machines

Dexmedetomidine has major impact on the ability to drive and use machines. Patients should be advised to refrain from driving or other hazardous tasks for a suitable period of time after receiving Dexmedetomidine for procedural sedation.

4.8. Undesirable effects

Summary of the safety profile

Indication 1: Sedation of adult ICU (Intensive Care Unit) patients:

The most frequently reported adverse reactions with dexmedetomidine in ICU setting are hypotension, hypertension and bradycardia, occurring in approximately 25%, 15% and 13% of patients respectively.

Hypotension and bradycardia were also the most frequent dexmedetomidine-related serious adverse reactions occurring in 1.7% and 0.9% of randomised Intensive Care Unit (ICU) patients respectively.

Indication 2: Procedural/awake sedation

The most frequently reported adverse reactions with dexmedetomidine in procedural sedation are listed below (the protocols of phase III studies contained pre-defined thresholds for reporting changes in blood pressure, respiratory rate and heart rate as AEs).

- Hypotension (55 % in dexmedetomidine-group vs. 30 % in placebo-group receiving rescue midazolam and fentanyl))

- Respiratory depression ( 38 % in dexmedetomidine-group vs. 35 % in placebo-group receiving rescue midazolam and fentanyl))

- Bradycardia (14 % in dexmedetomidine-group vs. 4 % in placebo-group receiving rescue midazolam and fentanyl))

Tabulated list of adverse reactions

The adverse reactions listed in Table 1 have been accumulated from pooled data of clinical trials in intensive care.

The frequency of adverse reactions listed below is defined using the following convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000), very rare (<1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

MedDRA System Organ Class (SOC)

Very common

Common

Uncommon

Rare

Not known

Metabolism and nutrition disorders

Hyperglycaemia, Hypoglycaemia

Metabolic acidosis

Hypoalbuminaemia

Endocrine disorders

Diabetes insipidus

Psychiatric disorders

Agitation

Hallucination

Cardiac disorders

Bradycardia 1,2

Myocardial ischaemia or infaction

Tachycardia

Atrioventricular block1 ,cardiac output decreased, cardiac arrest1

Vascular disorders

Hypotension 1,2

Hypertension1,2

Respiratory, thoracic and mediastinal disorders

Respiratory depression 2,3

Dyspnoea apnoea

Gastrointestinal disorders

Nausea2 vomiting, dry mouth2

Abdominal distension

General disorders and administration site conditions

Withdrawal syndrome, hyperthermia

Drug ineffective, thirst

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

Description of selected adverse reactions

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

In relatively healthy non-ICU subjects 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. In isolated 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.

Paediatric population

Children > 1 month post-natal, predominantly post-operative, have been evaluated for treatment up to 24 hours in the ICU and demonstrated a similar safety profile as in adults. Data in new-born infants (28 – 44 weeks gestation) is very limited and restricted to maintenance doses ≤ 0.2 mcg/kg/h. A single case of hypothermic bradycardia in a neonate has been reported in the literature.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

Several cases of dexmedetomidine overdose have been reported both in the clinical trial and the postmarketing data. The reported highest infusion rates of dexmedetomidine in these cases have reached up to 60 µg/kg/h for 36 minutes and 30 µg/kg/h for 15 minutes in a 20-month-old child and in an adult, respectively. The most common adverse reactions reported in conjunction with overdose includ bradycardia, hypotension, hypertension, oversedation, respiratory depression and cardiac arrest.

Management

In cases of overdose with clinical symptoms, dexmedetomidine infusion should be reduced or stopped. Expected effects are primarily cardiovascular and should be treated as clinically indicated (see section 4.4). At high concentration hypertension may be more prominent than hypotension. In clinical studies, cases of sinus arrest reversed spontaneously or responded to treatment with atropine and glycopyrrolate. Resuscitation was required in isolated cases of severe overdose resulting in cardiac arrest.