Rapid conversion to a normal sinus rhythm of paroxysmal supraventricular tachycardias, including those associated with accessory by‐pass tracts (Wolff‐Parkinson‐White Syndrome). 

Paediatric population
Rapid conversion to a normal sinus rhythm of paroxysmal supraventricular tachycardia in children aged 0 to 18 years.

Diagnostic Indications
Aid to diagnosis of broad or narrow complex supraventricular tachycardias. Although Xoria will not convert atrial flutter, atrial fibrillation or ventricular tachycardia to sinus rhythm, the slowing of AV conduction helps diagnosis of atrial activity.
Sensitisation of intra‐cavitary electrophysiological investigations.

Xoria is intended for hospital use only with monitoring and cardiorespiratory resuscitation equipment available for immediate use.

Method of administration

It should be administered by rapid IV bolus injection according to the ascending dosage schedule below. To be certain the solution reaches the systemic circulation administer either directly into a vein or into an IV line. If given into an IV line it should be injected as proximally as possible, and followed by a rapid saline flush.
Xoria should only be used when facilities exist for cardiac monitoring. Patients who develop high‐level AV block at a particular dose should not be given further dosage increments.

Posology

Adult:

Initial dose:           3 mg given as a rapid intravenous bolus (over 2 seconds).

Second dose:        If the first dose does not result in elimination of the supraventricular tachycardia within 1 to 2 minutes, 6mg should be given also as a                                      rapid intravenous bolus.

Third dose:            If the second dose does not result in elimination of the supraventricular tachycardia within 1 to 2 minutes. 12 mg should be given also                                     as a rapid intravenous bolus.

Additional or higher doses are not recommended.

Paediatric population
During administration of adenosine cardio‐respiratory resuscitation equipment must be available for immediate use if necessary.
Adenosine is intended for use with continuous monitoring and ECG recording during administration.
The dosing recommended for the treatment of paroxysmal supraventricular tachycardia in the paediatric population is:

• First bolus of 0.1 mg/kg body weight (maximum dose of 6 mg)
• Increments of 0.1 mg/kg body weight as needed to achieve termination of supraventriculartachycardia (maximum dose of 12 mg).

Method of administration
Adenosine should be administered by rapid intravenous (IV) bolus injection into a vein or into an IV line. If given into an IV line it should be injected through as proximally as possible, and followed by a rapid saline flush. If administered through a peripheral vein, a large bore cannula should be used.

Elderly
See dosage recommendations for adults.

Diagnostic dose
The   above   ascending   dosage   schedule   should   be   employed   until   sufficient   diagnostic information has been obtained.
Method of administration: Rapid intravenous injection only.
 

Xoria is contraindicated for patients presenting: • Known hypersensitivity to adenosine or to any of the excipients. • Sick sinus syndrome, second or third degree Atrio‐Ventricular (AV) block (except in patients with a functioning artificial pacemaker). • Chronic obstructive lung disease with evidence of bronchospasm (e.g. asthma bronchiale) • Long QT syndrome • Severe hypotension • Decompensated states of heart failure

Special warnings: Due to the possibility of transient cardiac arrhythmias arising during conversion of the supraventricular tachycardia to normal sinus rhythm, administration should be carried out in a hospital setting with monitoring and cardio‐respiratory 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 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. There have been reports of cerebrovascular accident/transient ischemic attack, secondary to the haemodynamic effects of adenosine.

Adenosine should be used with caution in patients with recent myocardial infarction, severe heart failure, or in patients with minor conduction defects (first degree A‐V block, bundle branch block) that could be transiently aggravated during infusion.

Adenosine 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  post  heart transplant 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  could potentially favour the occurrence of torsades de pointes, especially in patients with prolonged QT intervals.

In  patients  with  recent  heart  transplantation  (less  than  1  year)  an  increased sensitivity  of  the heart to adenosine has been observed.

Since neither the kidney nor the liver are involved in the degradation of exogenous adenosine, Adenosine's efficacy should be unaffected by hepatic or renal insufficiency.

As  dipyridamole  is  a  known  inhibitor  of  adenosine  uptake,  it  may  potentiate  the  action  of adenosine.  It  is  therefore  suggested  that  adenosine should  not  be  administered  to patients receiving  dipyridamole;  if  use  of  adenosine  is  essential,  dipyridamole  should  be stopped  24 hours  before hand,  or  the  dose  of  adenosine  should  be  greatly  reduced.  (see  Section  4.5 Interactions with other Medicaments and other forms of Interaction). 

Precautions:
The   occurrence   of   angina,   severe   bradycardia,   severe   hypotension,   respiratory failure (potentially  fatal),   or   asystole/cardiac   arrest   (potentially   fatal),   should lead   to   immediate discontinuation of administration.

Adenosine  may  trigger  convulsions  in  patients  who  are  susceptible  to  convulsions.  In patients with   history  of   convulsions/seizures,   the   administration   of   adenosine   should  be   carefully monitored.

Because of the possible risk of torsades de pointes, Xoria should be used with caution in patients with  a  prolonged  QT  interval,  whether  this  is  drug induced  or  of  metabolic  origin. Xoria  is contraindicated in patients with Long QT syndrome (see section 4.3).

Adenosine may precipitate or aggravate bronchospasm (see sections 4.3 and 4.8).

Adenosine contains sodium. To be taken into consideration by patients on a controlled sodium diet.

Paediatric population
Adenosine  may  trigger  atrial  arrhythmias  and  thus  might  lead  to  ventricular  acceleration in children with Wolff‐Parkinson‐White (WPW) syndrome. Also see section 5.1.
The efficacy of intraosseus administration has not been established.
 

Dipyridamole inhibits adenosine cellular uptake and metabolism, and potentiates the action of adenosine.  In one  study  dipyridamole  was  shown  to  produce  a  4  fold  increase  in adenosine actions. Asystole has been reported following concomitant administration.

It is therefore  suggested  that  adenosine  should  not  be  administered  to  patients receiving dipyridamole; if use of adenosine is essential, dipyridamole should be stopped 24 hours before hand, or the dose of adenosine should be greatly reduced. See Section 4.4 Special Warnings and Precautions for Use.

Aminophylline,  theophylline  and  other  xanthines  are  competitive  adenosine  antagonists  and should be avoided for 24 hours prior to use of adenosine.

Food and drinks containing xanthines (tea, coffee, chocolate and cola) should be avoided for at least 12 hours prior to use of adenosine.

Xoria may interact with drugs tending to impair cardiac conduction.
 

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
Ademocor should not be used during breast‐feeding.

Not applicable.

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).

These  side  effects  are  generally  mild,  of  short  duration  (usually  less  than  1  minute) and  well tolerated by the patient. However severe reactions can occur.
Methylxanthines,  such  as  IV  aminophylline  or  theophylline  have   been  used  to  terminate persistent side effects (50‐125 mg by slow intravenous injection).

Frequency	Applicable to Adenosine 6mg/2ml
Immune system disorders
Not known	‐Anaphylactic reaction (including angioedema and skin reactions such as urticaria and rash).
Cardiac Disorders
Very common	‐ Bradycardia ‐ Sinus pause, skipped beats ‐ Atrial extrasystoles ‐ Atrio‐Ventricular block ‐ Ventricular excitability disorders such as ventricular extrasystoles, non‐sustained ventricular tachycardia
Uncommon	‐ Sinus tachycardia ‐ Palpitations
Very rare	‐ Atrial fibrillation ‐ Severe bradycardia not corrected by atropine and possibly requiring temporary pacing ‐ Ventricular excitability disorders Including ventricular fibrillation and torsade de pointes (see section 4.4)
Not known	‐ Hypotension sometimes severe ‐ asystole /Cardiac arrest, sometimes fatal especially in patients with underlying ischemic heart disease /cardiac disorder (see section 4.4)
Nervous System disorders
Common	‐ Headache ‐ Dizziness, light‐headedness
Uncommon	‐ Head pressure
Very rare	‐Transient and hypertension spontaneously rapidly reversible worsening of intracranial
Not known	‐ Loss of consciousness / syncope ‐ Convulsions, especially in predisposed patients (see section 4.4)
Eye disorders
Uncommon	‐ Blurred vision
Respiratory, thoracic and mediastinal disorders
Very common	‐ Dyspnea (or the urge to take a deep breath)

Uncommon	‐ Hyperventilation
Very rare	‐ Bronchospasm (see section 4.4)
Not known	‐ Respiratory failure (see section 4.4) ‐ Apnea / Respiratory arrest,
Cases of Respiratory failure, bronchospasm, apnea, and respiratory arrest with fatal outcome have been reported.
Gastrointestinal disorders
Common	‐ Nausea
Uncommon	‐ Metallic taste
Not known	‐ Vomiting
Vascular disorders
Very common	‐ Flushing
General disorders and Administration Site conditions
Very common	‐Chest pressure/pain, feeling of thoracic constriction/oppression
Common	‐ Burning sensation
Uncommon	‐ Sweating ‐ Feeling of general discomfort / weakness / pain
Very rare	‐ Injection site reactions
Psychiatric disorders
Common	‐ Apprehension

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:

• Saudi Arabia

The National Pharmacovigilance Center (NPC)

Fax: + (966‐11) 2057662

Call NPC at: + (966‐11) 2038222, Exts: 2317‐2356‐2340.

SFDA Call Center: 19999

e‐mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa/

• Other GCC States

Please contact the relevant competent authority

Overdosage would cause severe hypotension, bradycardia or asystole. The half life of adenosine in blood is very short, and side effects (when they occur) would quickly resolve. Administration of IV aminophylline or theophylline may be needed. Pharmacokinetic evaluation indicates that methyl xanthines are competitive antagonists to adenosine, and that therapeutic concentrations of theophylline block its exogenous effects.
 

Pharmacotherapeutic group: Other Cardiac Preparations: ATC Code: C01EB 10

Endogenous nucleoside with peripheral vasodilator/antiarrhythmic effect

Antiarrhythmic drug.

Adenosine is a purine nucleoside which is present in all cells of the body. Animal pharmacology studies have in several species shown that Adenosine has a negative dromotropic effect on the atrioventricular (AV) node.

In man Xoria (Adenosine) administered by rapid intravenous injection slows conduction through the AV node. This action can interrupt re‐entry circuits involving the AV node and restore normal sinus rhythm in patients with paroxysmal supraventricular tachycardias. Once the circuit has been interrupted, the tachycardia stops and normal sinus rhythm is re‐established.

One acute interruption of the circuit is usually sufficient to arrest the tachycardia.

Since atrial fibrillation and atrial flutter do not involve the AV node as part of a re‐entry circuit, Adenosine will not terminate these arrhythmias.

By transiently slowing AV conduction, atrial activity is easier to evaluate from ECG recordings and therefore the use of Adenosine can aid the diagnosis of broad or narrow complex tachycardias.

Adenosine may be useful during electrophysiological studies to determine the site of AV block or to determine in some cases of pre‐excitation, whether conduction is occurring by an accessory pathway or via the AV node.

Paediatric population
No controlled studies have been conducted in paediatric patients with adenosine for the conversion of paroxysmal supraventricular tachycardia (PSVT). However, the safety and efficacy of  adenosine  in  children  aged  0  to  18  years  with  PSVT  is  considered  established  based on extensive clinical use and literature data (open label studies, case reports, clinical guidelines).

Literature  review  identified  14  studies  where  IV  adenosine  was  used  for  acute  termination  of supraventricular tachycardia (SVT) in around a total of 450 paediatric patients aged 6 hours to 18 years. Studies were heterogenic in terms of age, and dosing schedules. SVT was terminated in 72 to 100% of cases in most of the published studies. Dosages used varied from 37.5 mcg/kg to 400 mcg/kg. Several studies discussed a lack of response to starting doses less than 100mcg/kg.

Depending on the child's clinical history, symptoms and ECG diagnosis, adenosine has been used in clinical   practice   under   expert   supervision   in   children   with   stable   wide‐QRS complex tachycardia and Wolff‐Parkinson‐White syndrome however the currently available data does not support  a  paediatric  indication.  In  total  6  cases  of  adenosine‐induced  arrhythmias (3  atrial fibrillation, 2 atrial flutter, 1 ventricular fibrillation) have been described in 6 children aged 0 to 16 years with manifest or concealed WPW syndrome, of which 3 spontaneously recovered and 3 needed amiodarone +/‐ cardioversion (see also section 4.4).

Adenosine has  been  used as  an  aid  to  diagnosis  of  broad  or narrow complex supraventricular tachycardias   in   same   doses as   for   treatment   of   supraventricular   tachycardia.   Although adenosine  will  not  convert  atrial  flutter,  atrial  fibrillation  or ventricular  tachycardia  to  sinus rhythm, the slowing of AV conduction helps diagnosis of atrial activity. However, the currently available data does not support a paediatric indication for the use of adenosine for diagnostic purposes.
 

Adenosine is impossible to study via classical ADME protocols. It is present in various forms in all 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 the erythrocytes and blood vessel endothelial cells. The half‐life in vitro is estimated to be <10 seconds. The in vivo half‐life may be even shorter.

There are no pre‐clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

‐ Sodium chloride
‐ Water for injection

Compatibility with other medicines is not known.

24 months Any portion of the vial not used at once should be discarded.

Do not store above 30 ᵒC. Do not refrigerate.

3 ml type I clear glass ampoules with a 12.75 mm diameter, with orange one‐point‐cut (OPC).

None.