Adenosine 30mg/10ml Solution For Infusion
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Adenosine 30 mg/10 ml Solution for Infusion
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 10 ml vial of Adenosine Solution for Infusion contains 30 mg of adenosine (3 mg/ml)
Excipient: each vial contains 90 mg of sodium chloride (9 mg/ml).
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Solution for infusion
Adenosine Solution for Infusion is a sterile clear, colourless solution free from visible particles.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Intravenous (IV) Adenosine Solution for Infusion is a coronary vasodilator for use in conjunction with radionuclide myocardial perfusion imaging in patients who cannot exercise adequately or for whom exercise is inappropriate
4.2 Posology and method of administration
Adenosine Solution for Infusion is intended for use in hospitals with monitoring and cardio-respiratory resuscitation equipment available for immediate use if necessary.
It should be administered following the same procedure as for exercise testing where facilities for cardiac monitoring and cardio-respiratory resuscitation are available. During administration of Adenosine Solution for Infusion continuous ECG control is necessary as life-threatening arrhythmia might occur. Heart rate and blood pressure should be monitored every minute.
Adults :
1. Adenosine Solution for Infusion should be administered undiluted as a continuous peripheral intravenous infusion at a dose of 140 pg/kg/min for six minutes using an infusion pump. Separate venous sites for Adenosine Solution for Infusion and radionuclide administration are recommended to avoid an adenosine bolus effect.
2. After three minutes of Adenosine Solution for Infusion, the radionuclide is injected to ensure sufficient time for peak coronary blood flow to occur. The optimal vasodilator protocol is achieved with six minutes of Adenosine Solution for Infusion.
3. To avoid an adenosine bolus effect, blood pressure should be measured in the arm opposite to the Adenosine Solution for Infusion.
The table below is given as a guide for adjustment of the infusion rate of undiluted Adenosine Solution for Infusion, in line with bodyweight (total dose 0.84 mg/kg).
|
Patient Weight (kg) |
Infusion Rate (ml/min) |
|
45 - 49 |
2.1 |
|
50 - 54 |
2.3 |
|
55 - 59 |
2.6 |
|
60 - 64 |
2.8 |
|
65 - 69 |
3.0 |
|
70 - 74 |
3.3 |
|
75 - 79 |
3.5 |
|
80 - 84 |
3.8 |
|
85 - 89 |
4.0 |
|
90 - 94 |
4.2 |
|
95 - 99 |
4.4 |
|
100 - 104 |
4.7 |
Paediatric population:
The safety and efficacy of adenosine in children aged 0-18 years old have not been established. No data are available.
Elderly:
See dosage recommendations for adults.
4.3 Contraindications
Adenosine Solution for Infusion is contra-indicated in patients suffering from:
Hypersensitivity to the active substance or to any of the excipients.
Second or third degree atrioventricular (AV) block, sick sinus syndrome except in patients with a functioning artificial pacemaker
Long QT syndrome
Severe hypotension
Unstable angina not successfully stabilised with medical therapy Decompensated states of heart failure
Chronic obstructive lung disease with evidence of bronchospasm (e.g. asthma bronchiale)
Concomitant use of dipyridamole (see section 4.5).
4.4 Special warnings and precautions for use
Adenosine is intended for use in a hospital setting with monitoring and cardiorespiratory resuscitation equipment available for immediate use if necessary. During administration, continuous ECG monitoring is necessary as life-threatening arrhythmia might occur (section 4.2).
Because it has the potential to cause significant hypotension, Adenosine Solution for Infusion should be used with caution in patients with left main coronary stenosis, uncorrected hypovolemia, stenotic valvular heart disease, left to right shunt, pericarditis or pericardial effusion, autonomic dysfunction or stenotic carotid artery disease with cerebrovascular insufficiency. Adenosine Solution for Infusion should be discontinued in any patient who develops persistent or symptomatic hypotension.
Adenosine Solution for Infusion should be used with caution in patients with recent myocardial infarction or severe heart failure. Adenosine Solution for Infusion should be used with caution in patients with minor conduction defects (first degree AV block, bundle branch block) that could be transiently aggravated during infusion.
Adenosine may trigger convulsions in patients who are susceptible to convulsions.
Adenosine Solution for Infusion should be used with caution in patients with atrial fibrillation or flutter and especially in those with an accessory by-pass tract since particularly the latter may develop increased conduction down the anomalous pathway.
Rare cases of severe bradycardia have been reported. Some occurred in early posttransplant patients; in the other cases occult sino-atrial disease was present. The occurrence of severe bradycardia should be taken as a warning of underlying disease and should lead to treatment discontinuation. Severe bradycardia would favour the occurrence of torsades de pointes, especially in patients with prolonged QT intervals. But to date, no case of torsades de pointes has been reported when adenosine is continuously infused.
The occurrence of respiratory failure (potentially fatal), asystole/cardiac arrest (potentially fatal), angina, severe bradycardia or severe hypotension should also lead to treatment discontinuation.
In patients with recent heart transplantation (less than 1 year) an increased sensitivity of the heart to adenosine has been observed.
Adenosine may precipitate or aggravate bronchospasm (see sections 4.3 and 4.8).
Adenosine Solution for Infusion contains 9 mg sodium chloride per ml (corresponding to 3.54 mg sodium per ml).
To be taken into consideration by patients on a controlled sodium diet.
4.5 Interaction with other medicinal products and other forms of interaction
Dipyridamole inhibits adenosine cellular uptake and metabolism, and potentiates the action of Adenosine Solution for Infusion. In one study dipyridamole was shown to produce a 4 fold increase in adenosine actions. It is therefore suggested that Adenosine Solution for Infusion should not be administered to patients receiving dipyridamole; if use of Adenosine Solution for Infusion is essential, dipyridamole should be stopped 24 hours before hand, or the dose of Adenosine Solution for Infusion should be greatly reduced.
Aminophylline, theophylline and other xanthines are competitive adenosine antagonists and should be avoided for 24 hours prior to use of Adenosine Solution for Infusion.
Food and drinks containing xanthines (tea, coffee, chocolate and cola) should be avoided for at least 12 hours prior to use of Adenosine Solution for Infusion.
Adenosine may interact with drugs tending to impair cardiac conduction.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no or limited amount of data from the use of adenosine in pregnant women. Animal studies are insufficient with respect to reproductive toxicity. Adenosine is not recommended during pregnancy unless the physician considers the benefits to outweigh the potential risks.
Lactation
It is unknown whether adenosine metabolites are excreted in human milk. Adenosine Solution for Infusion should not be used during breast-feeding.
4.7 Effects on ability to drive and use machines
Not relevant.
4.8 Undesirable effects
Effects related to the known pharmacology of adenosine are frequent, but usually self-limiting and of short duration. Discontinuation of infusion may be necessary if the effect is intolerable.
Methylxanthines, such as IV aminophylline or theophylline have been used to terminate persistent side effects (50-125 mg by slow intravenous injection).
Adverse events are ranked under the heading of the frequency:
Very common (>1/10), Common (>1/100, <1/10), Uncommon (>1/1000, <1/100), Rare (>1/10000, <1/1000), Very rare (<1/10000), Not known (cannot be estimated from available data).
Cardiac Disorders:
- common: hypotension, sometimes severe (see section 4.4), ST segment depression, sustained or non-sustained ventricular tachycardia, AV block (see section 4.4).
If sustained second or third degree AV block develops the infusion should be discontinued. If first degree AV block occurs, the patient should be observed carefully as a quarter of patients will progress to a higher degree of block.
- uncommon: bradycardia sometimes severe (see section 4.4)
- not known: asystole /Cardiac arrest (sometimes fatal, especially in patients with underlying ischemic heart disease/cardiac disorders, see section 4.4): sinus tachycardia, atrial fibrillation, ventricular fibrillation
Nervous system disorders:
- very common: headache
- common: dizziness, light-headedness, paraesthesia,
- rare: tremor, drowsiness
- not known: loss of consciousness / syncope, convulsions, especially in predisposed patients (see section 4.4)
Eye disorders:
- rare: blurred vision
Ear and labyrinth disorders:
- rare: tinnitus
Respiratory, thoracic and mediastinal disorders:
- very common: dyspnea (or the urge to breathe deeply)
- rare: bronchospasm (see section 4.4), nasal congestion
- very rare: respiratory failure (see section 4.4)
- not known: apnea/respiratory arrest
Cases with fatal outcome of respiratory failure, of bronchospasm, and of apnea / respiratory arrest have been reported
Gastro-intestinal disorders:
- very common: abdominal discomfort
- common: dry mouth
- uncommon: metallic taste
- not known: nausea, vomiting
Renal and Urinary disorders:
- rare: urinary urgency
Vascular disorders:
- very common: flushing
General disorders and administration site conditions:
- very common: chest pain or pressure, feeling of thoracic constriction/oppression
- common: throat, neck and jaw discomfort
- uncommon: sweating, discomfort in the leg, arm or back, feeling of general discomfort, weakness/pain
- very rare: injection site reactions
Reproductive system and breast disorders: - rare: nipple discomfort
Psychiatric disorders:
- uncommon: nervousness
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 www.mhra.gov .uk/yellowcard.
4.9 Overdose
Overdose would cause severe hypotension, bradycardia or asystole. The half-life of adenosine in blood is very short, and side effects of Adenosine Solution for Infusion (when they occur) would quickly resolve when the infusion is discontinued. Administration of IV aminophylline or theophylline may be needed.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other Cardiac Preparations, ATC code: C01EB 10 Endogenous nucleoside with peripheral vasodilator / antiarrhythmic effect
Adenosine is a potent vasodilator in most vascular beds, except in renal afferent arterioles and hepatic veins where it produces vasoconstriction. Adenosine exerts its pharmacological effects through activation of purine receptors (cell-surface A1 and A2 adenosine receptors). Although the exact mechanism by which adenosine receptor activation relaxes vascular smooth muscle is not known, there is evidence to support both inhibition of the slow inward calcium current reducing calcium uptake, and activation of adenylate cyclase through A2 receptors in smooth muscle cells. Adenosine may reduce vascular tone by modulating sympathetic neurotransmission. The intracellular uptake of adenosine is mediated by a specific transmembrane nucleoside transport system. Once inside the cell, adenosine is rapidly phosphorylated by adenosine kinase to adenosine monophosphate, or deaminated by adenosine deaminase to inosine. These intracellular metabolites of adenosine are not vasoactive.
Intracoronary Doppler flow catheter studies have demonstrated that intravenous
Adenosine Solution for Infusion at 140 pg/kg/min produces maximum coronary hyperaemia (relative to intracoronary papaverine) in approximately 90% of cases within 2-3 minutes of the onset of the infusion. Coronary blood flow velocity returns
to basal levels within 1-2 minutes of discontinuing the Adenosine Solution for Infusion.
The increase in blood flow caused by Adenosine Solution for Infusion in normal coronary arteries is significantly more than that in stenotic arteries. Adenosine Solution for Infusion redirects coronary blood flow from the endocardium to the epicardium and may reduce collateral coronary blood flow thereby inducing regional ischaemia.
Continuous infusion of adenosine in man has been shown to produce a mild dose-dependent fall in mean arterial pressure and a dose-related positive chronotropic effect, most likely caused by sympathetic stimulation. The onset of this reflex increase in heart rate occurs later than the negative chronotropic/dromotropic effect. This differential effect is mostly observed after bolus injection thus explaining the potential use of adenosine as a treatment for supraventricular arrhythmias when administered as a bolus or as a coronary vasodilator when administered as an infusion.
Although Adenosine Solution for Infusion affects cardiac conduction, it has been safely and effectively administered in the presence of other cardioactive or vasoactive drugs such as beta adrenergic blocking agents, calcium channel antagonists, nitrates, ACE inhibitors, diuretics, digitalis or anti-arrhythmics.
5.2 Pharmacokinetic properties
It is impossible to study adenosine in classical pharmacokinetic studies. It is present in various forms in all the cells of the body where it plays an important role in energy production and utilisation systems. An efficient salvage and recycling system exists in the body, primarily in erythrocytes and blood vessel endothelial cells. The half-life in vitro is estimated to be less than 10 seconds. The in vivo half-life may be even shorter.
Since neither the kidney nor the liver are involved in the degradation of exogenous adenosine, the efficacy of Adenosine Solution for Infusion should be unaffected by hepatic or renal insufficiency.
5.3 Preclinical safety data
Because adenosine is naturally present in all living cells, studies in animals to evaluate the carcinogenic potential of Adenosine Solution for Infusion (adenosine) have not been performed.
No controlled reproductive studies were conducted in animals with adenosine.
6.1 List of excipients
Sodium Chloride Water for Injection
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
The shelf life of the unopened product is 24 months The product should be used immediately after opening
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
See section 6.3
6.5 Nature and contents of container
Clear, type I glass vials with chlorobutyl rubber stoppers secured with aluminium caps with flip-off seals.
Pack of 6 vials in a plastic tray.
6.6 Special precautions for disposal
See section 4.2.
The product is for single use only.
The product should be inspected visually for particulate matter and colouration prior to administration. Where the visual appearance of the product may have changed, the vial should be discarded.
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Mercury Pharmaceuticals Ltd,
Capital House,
85 King William Street,
London EC4N 7BL, UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 12762/0471
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
09/09/2013
10 DATE OF REVISION OF THE TEXT
21/03/2014