Adcopres Injection

ADCOPRES 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 of ADCOPRES has not been studied in children under 18 years of age.

Posology
ADCOPRES 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 ADCOPRES. Patients in receipt of ADCOPRES have been observed to be arousable and alert when stimulated. This is a predictable component of dexmedetomidine sedation and should not be considered as evidence of lack of efficacy in the absence of other clinical signs and symptoms. ADCOPRES has been continuously infused in mechanically ventilated patients before extubation, during extubation, and after extubation. It is not deemed necessary to cease dexmedetomidine prior to extubation. In order to minimise undesirable pharmacologic side effects, bolus injections of ADCOPRES should not be used. The administration of ADCOPRES may be associated with clinical signs of bradycardia and sinus arrest in young, healthy volunteers with high vagal tone, or by administration through different routes, including rapid intravenous or bolus administration of ADCOPRES. ADCOPRES should be administered by continuous intravenous infusion not to exceed 24 hours. To ensure normovolaemia, the supplementation of fluid should be administered prior to and during administration of ADCOPRES.

Adults
ICU Sedation
Dosage of ADCOPRES should be individualised and titrated to the desired clinical effect. Initiation: For initiation in adult patients, a loading dose of 1,0 mcg/kg over a period of 10 minutes is recommended. Maintenance of ICU sedation: A maintenance infusion, ranging of 0,2 to 0,7 microgram/kg/hr will generally be required in adults. The infusion maintenance rate can be adjusted in order to achieve the desired clinical effect. Dosages as low as 0,05 micrograms/kg/hr may be used. A reduction in dose for both the loading and maintenance infusions should be considered in patients with impaired hepatic or renal function and in elderly patients (over 65 years of age) (see section 4.3, 4.4 and 5.2).

Conscious Sedation
Monitored anaesthesia care (MAC) with an adequate nerve block and awake fibreoptic intubation (AFI). Dosage of ADCOPRES should be individualised and titrated to the preferred clinical effect. Initiation: For initiation in adult patients, a loading dose of 1,0 mcg/kg over a period of 10 minutes is recommended. For elderly patients (over 65 years of age) or those undergoing less invasive procedures such as ophthalmic surgery, a loading infusion of 0,5 mcg/kg over 10 minutes may suitable. Maintenance of Conscious Sedation: For MAC, following the load, a maintenance dose of ADCOPRES should generally be initiated at 0,6 mcg/kg/hr and titrated to achieve desired clinical effect with doses ranging from 0,2 to 1 mcg/kg/hr for every procedure. The infusion rate for maintenance should be adjusted to achieve the targeted level of sedation. For AFI, following the load in awake fibreoptic intubation, a fixed maintenance dose of 0,7 mcg/kg/hr should be used.

Special Populations
Paediatrics
Safety and efficacy of ADCOPRES has not been established. ADCOPRES is not suitable for administration to individuals below 18 years of age.
Elderly
Elderly patients (over 65 years) often require lower doses of dexmedetomidine as in ADCOPRES.
Impaired Hepatic Function
The dose may have to be reduced when considering patients with hepatic impairment, ADCOPRES is primarily metabolised in the liver.
Impaired Renal Function
Considering that the majority of metabolites are eliminated in the urine, dose reductions may be needed for patients with renal impairment.
Dosage Adjustment
Due to possible pharmacodynamic interactions a reduction in dosage of ADCOPRES or other concomitant anaesthetics, sedatives, hypnotics or opioids may be required when co-administered (see section 4.5).

Method of Administration
For intravenous infusion
Only a controlled infusion device is to be used when ADCOPRES is administered. A visual inspection should be performed on parenteral products, prior to administration for any particulate matter and discolouration. Glass vials are intended for single patient use ONLY. For instructions on dilution of the medicine before administration, see section 6.6.

ADCOPRES is contraindicated in

• patients known to be hypersensitive to dexmedetomidine or to any of the excipients listed in section 6.1
• patients with sepsis
• patients with unstable trauma
• hypovolaemic patients
• heart block
• uncontrolled cardiac failure
• imminent hepatic failure
• pregnancy and lactation

ADCOPRES shouldnu2019t be used outside an Intensive Care Unit setting or surgical operating theatres. The vital parameters of the patient must be monitored constantly. Administration of ADCOPRES should only be performed by health professionals experienced in the management of patients in the intensive care setting. Continuous cardiac monitoring is vital during infusion of ADCOPRES. In order to minimise undesirable pharmacological side effects, bolus injections of ADCOPRES should not be used. ADCOPRES glass vials are intended for single patient use only. Safety and efficacy of ADCOPRES in non-surgical intensive care patients have not been established.

Respiration should be monitored in non-intubated patients due to the risk of respiratory depression and in some case apnoea.

Special Precautions
Elderly
Elderly patients are more susceptible to cardiovascular adverse events e.g., hypotension and bradycardia and the dosage must be carefully titrated to ensure the desired effect is obtained. Continuous monitoring of the cardiovascular system is required.
Cardio-vascular effects
Dexmedetomidine as in ADCOPRES reduces heart rate and blood pressure through central sympatholysis but at higher concentrations causes peripheral vasoconstriction leading to hypertension (see section 5.1). Dexmedetomidine as in ADCOPRES is therefore not suitable in patients with severe cardiovascular instability. Caution should be exercised when administering dexmedetomidine to patients with pre-existing bradycardia disorders (i.e., advanced heart block). 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 pre-existing severe ventricular dysfunction including congestive heart failure and cardiac failure in whom sympathetic tone is critical for maintaining haemodynamic balance. Patients with high physical fitness and slow resting heart rate may be particularly sensitive to bradycardic effects of alpha-2 receptor agonists. Dose reduction or discontinuation should be considered in a patient developing signs of myocardial or cerebral ischaemia.

Patients with impaired peripheral autonomic activity (e.g., due to spinal cord injury) should be monitored closely, as they may have more pronounced haemodynamic changes after starting dexmedetomidine as in ADCOPRES. Local vasoconstriction, at higher concentration, may be of greater significance in patients with ischaemic heart disease or severe cerebrovascular disease. Care should be taken.

Hypotension, Bradycardia and Sinus arrest
Decreased blood pressure and/or heart rate may occur with the administration of ADCOPRES. Based on clinical experience with ADCOPRES, if medical intervention is required, treatment may include decreasing or stopping the infusion of ADCOPRES, increasing the rate of intravenous fluid administration, elevation of the lower extremities and use of pressor agents. Because ADCOPRES has the potential to augment bradycardia induced by vagal stimuli, medical practitioner should be prepared to intervene. The intravenous administration of anticholinergic agents 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. ADCOPRES 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 ADCOPRES. Patients who are hypovolaemic may become hypotensive under ADCOPRES therapy. Therefore, fluid supplementation should be administered prior to and during the administration of ADCOPRES.

Additionally, in situations where other vasodilators or negative chronotropic agents are administered, coadministration of ADCOPRES 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 ADCOPRES 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 ADCOPRES 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 ADCOPRES dominate and the blood pressure usually decreases.

Hyperthermia or pyrexia
ADCOPRES may induce hyperthermia or pyrexia, which may be resistant to traditional cooling methods, such as administration of cooled intravenous fluids and antipyretic medicines. Discontinue ADCOPRES if medicine-related hyperthermia or pyrexia is suspected and monitor patients until body temperature normalises. ADCOPRES may cause reduced lacrimation. Lubrication of the patientu2019s eyes may be considered when administering dexmedetomidine to avoid corneal dryness.

Hepatic impairment
Care should be taken in patients with severe hepatic impairment as excessive dosing may increase the risk of adverse reactions, over-sedation or prolonged effect as a result of reduced dexmedetomidine as in ADCOPRES clearance.

Patients with neurological disorders
Dexmedetomidine as in ADCOPRES may reduce cerebral blood flow and intracranial pressure and this should be considered when selecting therapy. Caution should be exercised when administering ADCOPRES to patients with severe neurological disorders such as head injury and after neurosurgery, especially if deep sedation is required. ADCOPRES 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.

ADCOPRES contains less than 1 mmol sodium (23 mg) per dose.

Anaesthetics/Sedatives/Hypnotics/Opioids
Co-administration of ADCOPRES with anaesthetics, sedatives, hypnotics and opioids is likely to lead to an enhancement of effects. Specific studies have confirmed these effects with sevoflurane, isoflurane, propofol, alfentanil, and midazolam. No pharmacokinetic interactions between dexmedetomidine and isoflurane, propofol, alfentanil, and midazolam were demonstrated. However, due to possible pharmacodynamic interaction, when co-administered with ADCOPRES a reduction in dosage of ADCOPRES or these medicines may be required.

Neuromuscular Blockers
No clinically significant increase in the magnitude of neuromuscular blockade and no pharmacokinetic interactions with ADCOPRES and rocuronium administration were observed.

Cardiovascular medicines
The possibility of enhanced hypotensive and bradycardic effects should be considered in patients receiving other medicines causing these effects, for example beta blockers.

Cytochrome P-450
In vitro studies indicate that clinically relevant cytochrome P450 mediated drug interactions are unlikely. 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.

Pregnancy
Safety of ADCOPRES in pregnancy and lactation has not been established. 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 ADCOPRES in labour and delivery has not been studied and it is therefore not recommended for obstetrics, including caesarean section deliveries.

Breastfeeding
Dexmedetomidine as in ADCOPRES is excreted in human milk, however levels will be below the limit of detection by 24 hours following treatment discontinuation. There is no information regarding the effects of ADCOPRES on the breastfed infant or the effects on milk production. The risk to infants cannot be excluded and therefore healthcare professionals must advise women to monitor the breastfed infant for irritability. A decision must be made whether to discontinue breastfeeding or to discontinue ADCOPRES therapy.

Fertility
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 ADCOPRES for procedural sedation.

a. Summary of the safety profile
ICU Sedation
The most frequently observed treatment-emergent adverse events include hypotension, hypertension, bradycardia, nausea, dry mouth and hypoxia (see section 4.4).
Procedural/awake sedation
The most frequently reported adverse reactions with ADCOPRES in procedural sedation are hypotension, respiratory depression, bradycardia.

b. Tabulated list of adverse reactions
The adverse reactions below are classified where appropriate by system organ class and frequency according to the following convention.

System Organ Class Frequency Adverse Event
Blood and lymphatic system disorders Frequent Anaemia
Metabolism and nutrition disorders Frequent Hyperglycaemia, hypercalcaemia, acidosis, hypovolaemia Less frequent Hypoalbuminaemia
Psychiatric disorders Frequent Agitation Less frequent Hallucination
Cardiac disorders Frequent Bradycardia, atrial fibrillation, sinus tachycardia, ventricular tachycardia, myocardial ischaemia or infarction, tachycardia Less frequent Atrioventricular block, cardiac output decreased, cardiac arrest
Vascular disorders Frequent Hypotension, hypertension
Respiratory, thoracic and mediastinal disorders Frequent Respiratory depression, atelectasis, pleural effusion, wheezing, pulmonary oedema, hypoxia Less frequent Dyspnoea, apnoea
Gastrointestinal disorders Frequent Nausea, vomiting, dry mouth Less frequent Abdominal distension
Renal and urinary disorders Less frequency Polyuria
General disorders and administration site conditions Frequent Withdrawal syndrome, hyperthermia, pyrexia, chills, oedema peripheral Less frequent Drug ineffective, thirst
Investigations Frequent Urine output decreased
Injury, poisoning and procedural complications Frequent Post-procedural haemorrhage

Post-marketing experience
System Organ Class Preferred term Infections and infestations Infection, fungal infection, sepsis Blood and the lymphatic system disorders Anaemia, leukocytosis, coagulation, disorders, disseminated intravascular coagulation, haematoma, abnormal platelets, decreased prothrombin, thrombocytopenia Immune system disorders Allergic reactions Metabolism and nutrition disorders Hyperglycaemia, hypoglycaemia, acidosis, lactic acidosis, respiratory acidosis, diabetes mellitus, hypokalaemia, hyperkalaemia, hypoproteinaemia, increased alkaline phosphate, increased Non-protein nitrogen (NPN), thirst Psychiatric disorders Agitation, anxiety, confusion, delirium, depression, hallucination, illusion, nervousness Nervous system disorders Convulsion, dizziness, headache, neuralgia, neuritis, neuropathy, paraesthesia, paralysis, paresis, speech disorder, syncope Eye disorders Diplopia, photopsia, abnormal vision Cardiac disorders Bradycardia, myocardial ischaemia, myocardial infarction, tachycardia, angina pectoris, dysrhythmia, atrial dysrhythmia, atrial fibrillation, AV block, bundle branch block, cardiac arrest, extrasystoles, heart block, hypoxia, supraventricular tachycardia, T-wave inversion, ventricular dysrhythmia, ventricular tachycardia
Vascular disorders Hypotension, hypertension, haemorrhage, cerebral haemorrhage, peripheral ischaemia, vascular disorder, vasodilation, circulatory failure, cyanosis, abnormal ECG, heart disorder, aggravated hypertension, pulmonary hypertension, postural hypotension, pulmonary hypertension
Respiratory, thoracic and mediastinal disorders Adult respiratory distress syndrome, apnoea, bronchial obstruction, bronchospasm, coughing, dyspnoea, emphysema, haemoptysis, hypercapnia, pharyngitis, pleurisy, pneumonia, pneumothorax, pulmonary congestion, pulmonary oedema, respiratory depression, respiratory disorder, respiratory insufficiency, increased sputum, stridor
Gastrointestinal disorders Abdominal pain, diarrhoea, eructation, mucosal ulceration, nausea, vomiting
Hepato-biliary disorders Increased albumin to globulin (AG) ratio, increased gamma-glutamyl transpepsidase (GGT), abnormal hepatic function, hyperbilirubinaemia, increased aspartate transaminase (AST), increased alanine transaminase (ALT), jaundice.
Skin and subcutaneous tissue disorders Rash erythematous, increased sweating
Musculoskeletal, connective tissue and disorders Muscle weakness
Renal and urinary disorders Increased blood urea, oliguria, haematuria, acute renal failure, abnormal renal function, urinary retention
General disorders and administration site conditions Ascites, fever, hyperpyrexia, hypovolaemia, light anaesthesia, oedema, peripheral oedema, pain, withdrawal syndrome, rigors.

c. Description of selected adverse reactions
Bradycardia and hypotension
Clinically significant hypotension or bradycardia should be treated as described in section 4.4. In relatively healthy non-ICU subjects treated with ADCOPRES, 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.

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 asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8 For reporting of side effects directly to the HCR, contact +27 11 635 0134 or email [email protected]

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