Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Orion Corporation, Orionintie 1, FI-02200 Espoo, Finland
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.
Dexdor is intended for use in an intensive care setting, operating room and during diagnostic procedures. The use in other environments is not recommended. All patients should have continuous cardiac monitoring during Dexdor 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.
Dexdor should not be given as a 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 Dexdor 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.
Dexdor should not be used as a 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.
Dexdor is not recommended for patient controlled sedation. Adequate data is not available.
When Dexdor 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.
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.
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 Dexdor 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.
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 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 in 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.
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.
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.
Dexdor contains less than 1 mmol sodium (23 mg) per ml.
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.
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). Dexdor should not be used during pregnancy unless the clinical condition of the woman requires treatment with dexmedetomidine.
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.
In the rat fertility study, dexmedetomidine had no effect on male or female fertility. No human data on fertility are available.
Patients should be advised to refrain from driving or other hazardous tasks for a suitable period of time after receiving Dexdor for procedural sedation.
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.
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).
The adverse reactions listed in Table 1 have been accumulated from pooled data of clinical trials in intensive care.
Adverse reactions are ranked under headings of frequency, the most frequent first, 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).
Table 1. Adverse reactions:
Common: Hyperglycaemia, hypoglycaemia
Uncommon: Metabolic acidosis, hypoalbuminaemia
Common: Agitation
Uncommon: Hallucination
Very common: Bradycardia1,2
Common: Myocardial ischaemia or infarction, tachycardia
Uncommon: Atrioventricular block first degree, cardiac output decreased
Very common: Hypotension1,2, hypertension1,2
Very common: Respiratory depression2,3
Uncommon: Dyspnoea, apnoea
Common: Nausea2, vomiting, dry mouth2
Uncommon: Abdominal distension
Not known: Polyuria
Common: Withdrawal syndrome, hyperthermia
Uncommon: 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
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.
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.
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 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 national reporting system listed in Appendix V.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
Compatibility studies have shown potential for adsorption of dexmedetomidine to some types of natural rubber. Although dexmedetomidine is dosed to effect, it is advisable to use components with synthetic or coated natural rubber gaskets.
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