Cardiology Adenocard^®

PRODUCT MONOGRAPH

ADENOCARD®
(adenosine injection, USP, 3 mg/mL)

6 mg/2 mL Vial
6 mg/2 mL Prefilled Syringe
12 mg/4 mL Prefilled Syringe

THERAPEUTIC CLASSIFICATION
Antiarrhythmic

Astellas Pharma Canada, Inc.
675 Cochrane Drive, Suite 500
West Tower
Markham, Ontario
L3R 0B8

Date of Preparation: August 24, 2005

Date of Revision: September 26, 2005

Control Nos: 099774

ACTION AND CLINICAL PHARMACOLOGY

Adenocard (adenosine) is an endogenous nucleoside occurring in all cells of the body. When injected intravenously adenosine slows atrioventricular (A-V) nodal conduction, can interrupt the reentry pathways through the A-V node and can restore normal sinus rhythm in patients with paroxysmal supraventricular tachycardia (PSVT), including PSVT associated with Wolff-Parkinson-White syndrome.

Adenosine is antagonized competitively by methylxanthines such as caffeine and theophylline and potentiated by blockers of nucleoside transport such as dipyridamole. Adenosine is not blocked by atropine.

In controlled clinical trials, cumulative 60% and 92% of patients converted to normal sinus rhythm within one minute after 6 mg and 12 mg bolus doses of Adenocard, respectively. In other controlled clinical trials with bolus doses of 3, 6, 9 and 12 mg some patients with paroxysmal supraventricular tachycardia converted to normal sinus rhythm on 3 mg of Adenocard®. Reports in the medical literature indicate success in treating PSVT in pediatric patients (including newborns) with Adenocard in doses equivalent by weight to those used in adults.

Adenocard is not effective in converting rhythms other than PSVT, such as atrial flutter, atrial fibrillation, or ventricular tachycardia to normal sinus rhythm.

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Hemodynamics
Adenosine is a potent vasodilator in most vascular beds, except in renal afferent arterioles and hepatic veins where it produces vasoconstriction. The intravenous bolus dose of 6 or 12 mg Adenocard usually has no systemic hemodynamic effects. When larger doses are given by infusion, adenosine decreases blood pressure by decreasing peripheral resistance.

Pharmacokinetics
Intravenously administered adenosine is rapidly cleared from the circulation via cellular uptake, primarily by erythrocytes and vascular endothelial cells, with a half life of less than 10 seconds. Intracellular adenosine is rapidly metabolized either via phosphorylation to adenosine monophosphate by adenosine kinase, or via deamination to inosine by adenosine deaminase in the cytosol. Adenosine monophosphate formed by phosphorylation of adenosine is incorporated into the high-energy phosphate pool. Inosine formed by deamination of adenosine can leave the cell intact or can be metabolized to hypoxanthine, xanthine and ultimately uric acid.

Since neither the kidney nor the liver are required for the metabolism or elimination of adenosine, the activity of ADENOCARD® should be unaffected by hepatic or renal insufficiency.

INDICATIONS AND CLINICAL USE

Adenocard (adenosine) is indicated for the conversion to sinus rhythm of paroxysmal supraventricular tachycardia (PSVT), including that associated with accessory bypass tracts (Wolff-Parkinson-White Syndrome). When clinically advisable, appropriate vagal maneuvers (e.g. Valsalva maneuver) should be attempted prior to Adenocard administration.

Adenocard (adenosine) is indicated to aid in the diagnosis of broad or narrow complex supraventricular tachycardia. Although Adenocard is not effective in converting atrial flutter, atrial fibrillation or ventricular tachycardia to sinus rhythm, the transient atrioventricular nodal block produced helps diagnosis of atrial activity.

It is essential to ascertain that Adenocard actually reaches the systemic circulation (see DOSAGE AND ADMINISTRATION).

Adenocard does not convert atrial flutter, atrial fibrillation or ventricular tachycardia to normal sinus rhythm.

Adenocard should only be used with appropriate cardiac monitoring.

CONTRAINDICATIONS

Adenocard (adenosine) is contraindicated in:

• Second or third degree AV block (except in patients with a functioning artificial pacemaker).
• Sick sinus syndrome(except in patients with a functioning artificial pacemaker).
• Symptomatic bradycardia (except in patients with a functioning artificial pacemaker).
• Known hypersensitivity to adenosine.

WARNINGS
Heart Block
Adenocard (adenosine) exerts its effect by decreasing conduction through the A-V node and may produce a short lasting first-, second- or third-degree heart block. Appropriate therapy should be instituted as needed. Patients who develop high level block on one dose of Adenocard should not be given additional doses. Because of the very short half-life of adenosine (<10 seconds), these effects are generally self-limiting.

Rarely, ventricular fibrillation/flutter has been reported following Adenocard administration, including both resuscitated and fatal events. In most instances, these cases were associated with the concomitant use of digoxin and, less frequently with digoxin and verapamil. Adenocard should be used with caution in patients receiving digoxin or digoxin and verapamil in combination. Appropriate resuscitative measures should be available.

Patients with atrial fibrillation/flutter and an accessory by-pass tract may develop increased conduction down the anomalous pathway.

Arrhythmias at Time of Conversion
At the time of conversion to normal sinus rhythm, a variety of new rhythms may appear on the electrocardiogram. They generally last only a few seconds without intervention, and may take the form of premature ventricular contractions, polymorphic ventricular tachycardia, torsades de pointes, atrial premature contractions, sinus bradycardia, sinus tachycardia, skipped beats, and varying degrees of A-V nodal block. These arrhythmias and conduction disturbances were observed in about 55% of patients.

Asystole
Transient or prolonged episodes of asystole have been reported with fatal outcomes in some cases.

Bronchoconstriction
Adenocard has been administered to a limited number of patients with asthma and serious exacerbation of their symptoms has been reported in some patients. Respiratory compromise has occurred during adenosine infusion in patients with chronic obstructive pulmonary disease (COPD). Therefore, the use of Adenocard should be avoided in patients with COPD or asthma.

Adenocard therapy should be discontinued in any patient who develops severe respiratory difficulties.

PRECAUTIONS

Use in Pregnancy
Adenosine is a substance naturally present in the body and therefore no fetal effects would be anticipated. However, since it is not known whether Adenocard can cause fetal harm when administered to pregnant women, it should not be used during pregnancy unless potential benefits outweigh the potential risks to the fetus.

Use in Children
No controlled studies have been conducted in pediatric patients to establish the safety and efficacy of Adenocard for the conversion of paroxysmal supraventricular tachycardia (PSVT). However, open-label studies carried out by independent investigators indicated that intravenous adenosine can be used safely in neonates, infants, children and adolescents. (See Dosage and Administration - Pediatric Patients, and Selected Reference.)

Use in Elderly
Clinical studies of Adenocard did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, Adenocard in geriatric patients should be used with caution since this population may have a diminished cardiac function, nodal dysfunction, concomitant diseases or drug therapy that may alter hemodynamic function and produce severe bradycardia or AV block.

Drug Interactions
(a) Cardioactive Drugs
Adenocard has been effectively administered in the presence of other cardioactive drugs, such as quinidine, beta-adrenergic blocking agents, calcium channel blocking agents and angiotensin converting enzyme inhibitors, without any change in the adverse reaction profile. Digoxin and verapamil use may be rarely associated with ventricular fibrillation when combined with Adenocard (see WARNINGS). Because of the synergistic depressant effects on the SA and AV nodes, Adenocard should be used with caution in the presence of these agents.

(b) Methylxanthines
The effects of adenosine are antagonized by methylxanthines (such as caffeine and theophylline). In the presence of methylxanthines, larger doses of adenosine may be required or adenosine may not be effective.

(c) Dipyridamole
Adenosine effects are potentiated by dipyridamole. Thus, smaller doses of adenosine may be effective in the presence of dipyridamole.

(d) Carbamazepine
Carbamazepine has been reported to increase the degree of heart block produced by other agents. Since the primary effect of adenosine is to decrease conduction through the A-V node, higher degrees of heart block may be produced in the presence of carbamazepine.

ADVERSE REACTIONS

In controlled clinical trials 268 patients received Adenocard (adenosine). One hundred and two patients (38%) experienced one or more adverse events. These adverse events appeared immediately after administration of adenosine and usually lasted less than one minute. The most common adverse reactions were: facial flushing (18%), dyspnea (12%), chest pressure (7%) and nausea (3%).

Cardiovascular: Facial flushing (18%), headache (2%), sweating, palpitations, chest pain, hypotension (less than 1%). A variety of arrhythmias and conduction disturbances were observed in about 55% of patients at the time of conversion to normal sinus rhythm.
Respiratory: Shortness of breath/dyspnea (12%), chest pressure (7%), hyperventilation, head pressure (less than 1%).

Central Nervous System: Lightheadedness (2%), dizziness, tingling in arms, numbness (1%), apprehension, blurred vision, burning sensation, heaviness in arms, neck and back pain (less than 1%).

Gastrointestinal: Nausea (3%), metallic taste, tightness in throat, pressure in groin (less than 1%).

The following adverse events have been reported from marketing experience with Adenocard. Because these events are reported voluntarily from a population of uncertain size, are associated with concomitant diseases and multiple drug therapies and surgical procedures, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these events in labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2) frequency of the reporting, (3) strength of causal connection to the drug, or a combination of these factors.

Cardiovascular: Prolonged asystole, ventricular tachycardia, ventricular fibrillation, transient increase in blood pressure, bradycardia, atrial fibrillation, and Torsade de Pointes (See Warnings and Precautions).

Respiratory: Bronchospasm

Central Nervous System: Convulsions, grand mal and tonic clonic seizures

SYMPTOMS AND TREATMENT OF OVERDOSAGE

No cases of overdosage associated with the use of Adenocard (adenosine) have been reported. It is unlikely that the true overdosage will occur because adenosine has a short half-life (<10 seconds) and Adenocard is dosed by a rapid bolus injection. If prolonged adverse events associated with the use of Adenocard occur, treatment should be individualized and directed toward the specific event. To date, no patient has required administration of adenosine antagonists such as aminophylline to counteract adverse events associated with the use of Adenocard.

In clinical studies on the use of adenosine as a diagnostic agent in imaging, less than 0.1% of the patients exposed to adenosine were described as having severe, prolonged, adverse events. These prolonged adverse events were treated with aminophylline after discontinuation of the adenosine infusion. The usual concentration of aminophylline used was 1.25 mg/mL (125 mg in 100 mL) administered intravenously over five to six minutes. An additional 1.25 mg/mL (125 mg in 100 mL) can be administered, but clinical experience has demonstrated that this is rarely required.

DOSAGE AND ADMINISTRATION

Adenocard (adenosine) should only be used with appropriate cardiac monitoring.

ADENOCARD SHOULD BE GIVEN AS A RAPID BOLUS INTRAVENOUS INJECTION. TO BE CERTAIN THE SOLUTION REACHES THE SYSTEMIC CIRCULATION, IT SHOULD BE ADMINISTERED EITHER DIRECTLY INTO A PERIPHERAL VEIN OR, IF GIVEN INTO AN IV LINE, IT SHOULD BE GIVEN AS CLOSE TO THE PATIENT AS POSSIBLE AND FOLLOWED BY A RAPID SALINE FLUSH.

Adult Patients
The recommended intravenous doses for adults are as follows:

Initial dose: 6 mg administered as a rapid intravenous bolus given over a 1-2 second time period.
Additional doses: If the initial dose does not terminate supra-ventricular tachycardia within 1-2 minutes, 12 mg dose should be given as a rapid intravenous bolus. This 12 mg dose may be repeated a second time if required. Single bolus injections greater than 12 mg are not recommended.

Pediatric Patients
Pediatric patients with a body weight < 50 kg:
Initial Dose: Give 0.05-0.10 mg/kg as a rapid intravenous bolus given either centrally or peripherally.

Additional Doses: If conversion of PSVT does not occur within 1-2 minutes, additional bolus injections of adenosine can be administered at incrementally higher doses, increasing the amount given by 0.05-0.10 mg/kg. Follow each bolus with a saline flush. This process should be continued until sinus rhythm is established or up to a maximum dose of 0.3 mg/kg.

For pediatric patients who require single intravenous doses less than 0.6 mg (0.2 mL), Adenocard may be further diluted with normal saline to a final concentration range from 0.3 to 1 mg/mL.

Patient with a body weight =50 kg:
Administer the adult dose.

Single bolus injections greater than 12 mg are not recommended for adult or pediatric patients.

NOTE: Adenocard injection should be inspected visually for particulate matter and discoloration prior to administration.

Adenocard should not be refrigerated as crystallization may occur. If crystallization has occurred, dissolve crystals by warming to room temperature. The solution must be clear at the time of use.

PHARMACEUTICAL INFORMATION

Drug Substance
Structural formula:

Common Name: Adenosine

Chemical Name: 6-amino-9-β-D-ribofuranosyl-9-H-purine; Adenine riboside

Molecular Weight: 267.2

Molecular Formula: C10H13N5O4

Description:
Adenosine is a white crystalline powder. It is soluble in water (7 mg/mL at pH 7.0) and practically insoluble in alcohol. Solubility increases by warming and by lowering the pH. The melting point is 233-238°C.

Composition:
Adenocard is a sterile solution for rapid bolus intravenous injection and is available in 6 mg/2 mL vials and 6 mg/2 mL and 12 mg/4 mL prefilled syringes. Each mL contains 3 mg adenosine and 9 mg Sodium Chloride in Water for Injection. The pH of the solution is between 4.5 and 7.5. Adenocard does not contain preservatives, colours or additives.

The Ansyr® plastic syringe is molded from a specially formulated polypropylene. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. Solution in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the syringe material.

Stability and Storage Recommendations:
Adenocard (adenosine injection) is supplied as a sterile non-pyrogenic solution in normal saline and should be stored at controlled room temperature 15°C - 30° C. DO NOT REFRIGERATE as crystallization may occur. If crystallization has occurred, dissolve crystals by warming to room temperature. The solution must be clear at the time of use.

Availability of Dosage Forms:
Adenocard is supplied in 2 mL single-dose flip-top vials containing 6 mg adenosine/2 mL solution (3 mg/mL) in a package of ten; and 6 mg in 2 mL (fill volume) and 12 mg in 4 mL (fill volume) Ansyr® plastic disposable syringes, in a package of ten.

Instructions for Syringe Use:
The new Ansyr® syringe delivery system, easily adapts to most peripheral line connection valves without the use of a needle. A needle is not provided with the Adenocard Ansyr syringe delivery system. Should you require the use of a needle to inject Adenocard directly into a vein, the adaptable Luer Lock tip can accomodate an 18 or 20 gauge needle. To use the syringe, remove luer cover. Hold plunger and push barrel forward to relieve any resistance that may be present. Pull the barrel down until air is expelled from the syringe. Adenocard is now ready to be administered. (See DOSAGE AND ADMINISTRATION Section). Syringes and vials, are intended for single use only. To prevent needle-stick injuries needles should not be recapped, purposely bent or broken by hand. Ansyr® is a latex free, plastic delivery system and is a registered trademark of Hospira Inc.. Any portion of the vial or syringe not used at once should be discarded. For additional information pertaining to the use of the Adenocard Ansyr® syringe, please refer to the drug carton diagrams.

PHARMACOLOGY

A. Animal Studies

Cardiac Electrophysiology
Adenosine exerts pronounced negative chronotropic and dromotropic effects on cardiac pacemakers and atrioventricular (A-V) nodal conduction, respectively. Junctional pacemakers appear to be more sensitive to adenosine than sinus pacemakers, and ventricular pacemakers more sensitive than junctional pacemakers.

Significant species variability was observed in animal experiments with regard to adenosine effects on the heart. In the guinea pig, the A-V node is more sensitive to adenosine then the sinus node, while the opposite is true in the dog. Dipyridamole potentiates the action of adenosine in the guinea pig, but not in the rat heart. Species variability has also been observed with regard to the indirect anti-adrenergic action of adenosine.

Acute Cardiovascular Effects of Adenosine
Adenosine was administered intravenously to three conscious male beagle dogs at an initial dose of 4.8 mg/kg and a second dose, administered 2-3 hours later, of 9.6 mg/kg. All dogs were observed for seven days. Examinations conducted both pre and post injection demonstrated no electrocardiographic changes.

Other Effects
Adenosine can induce bronchoconstriction in rats.

Increased levels of intrarenal adenosine caused a significant decrease in glomerular filtration rate, sodium excretion and renin release. Direct administration of adenosine into the cerebral ventricles resulted in ataxia, muscular weakness, sleepiness and change in behaviour.

Adenosine modulates sympathetic neurotransmission through actions at various sites including ganglia, presynaptic noradrenergic nerve terminals and postsynaptic target organs receiving sympathetic innervation. Adenosine can also affect cholinergic neurotransmission.

Pharmacokinetics
Adenosine is a naturally occurring nucleoside which is present in various forms in all cells of the body. Any intravenously administered dose of adenosine is minute in comparison to the existing body pool.

Adenosine may be converted to its base adenine and then to AMP, or directly to AMP. Adenosine may also be deaminated to inosine and then converted to AMP. Under normal circumstances adenosine is generated by breakdown of ATP and by biosynthesis in the liver. The biochemical pathways seem to be the same for all species. It appears that erythrocytes serve as the transporting vehicle for adenosine.

A system exists to conserve and recycle adenosine in the body. The major components of this salvage system appear to be the endothelial cells of the blood vessels and the erythrocytes themselves.

B. Human Studies
Adenosine at a dose of 83 μg/kg terminated electrically induced PSVT. However, it was ineffective in terminating either intraatrial tachycardia or atrial fibrillation (AF).

Bolus injections of adenosine, ranging from 3 to 12 mg, exert negative chronotropic and dromotropic effects on sinoatrial and atrioventricular nodes, respectively, without significant changes in blood pressure.

Continuous intravenous infusion, for 6 minutes, of 10-140 μg/kg/min in conscious human subjects resulted in increased heart rate (by 33 beats/min), increased systolic blood pressure (by 13 mmHg) and decreased diastolic blood pressure (by 8 mmHg). In addition, it caused pronounced increases in plasma norepinephrine and epinephrine levels.

When adenosine 70-90 μg/kg/min infusion was administered to conscious human subjects, both heart rate and skin temperature increased without a change in the blood pressure.

Systemic infusion of adenosine at dosages that affect myocardial blood flow, 40-50 μg/kg/min, had no effect on glomerular filtration rate or total renal blood flow in healthy subjects.

Inhalation of adenosine caused a concentration dependent bronchoconstriction in asthmatic patients, but not in non-asthmatics.

Adenocard (adenosine) is a respiratory stimulant (probably through activation of carotid body chemoreceptors) and intravenous administration in man has been shown to increase minute ventilation (Ve) and reduce arterial PCO2 causing respiratory alkalosis.

The short half-life of intravenously administered adenosine of less than 10 seconds makes it impossible to perform the standard pharmacokinetic studies in man.

TOXICOLOGY

Acute Single Dose Intravenous Toxicity
Adenosine was administered as a single intravenous injection to five male and five female Charles River CD-1 mice at a dose of 6 mg per animal, and to five male and five female Sprague-Dawley rats at a dose of 12 mg per animal.

No mortalities and no visible abnormalities or post-mortem abnormalities were observed in these studies.

The LD50 value was estimated to be greater than 240 mg/kg in mice and greater than 48 mg/kg in rats.

Acute Multi-Dose Intravenous Toxicity
(a) Rats
Adenosine was administered intravenously to 10 male and 10 female Charles River CD rats at a dosage level of 200 mg/kg. Total dosage was administered in five approximately equal amounts, one minute apart. Control group received the vehicle.

Immediately following drug administration, most animals exhibited decreased activity which persisted for approximately 30 minutes. In addition, ataxia was observed in some animals. Four hours post dose, all surviving animals appeared normal.

One female from the treated group was found dead at the 30 minute observation interval. Prostration was noted prior to death. Red foci were observed in the thymus and left lobe of the lung of this animal. All other animals survived to study termination.

(b) Dogs
Adenosine was administered intravenously to four male and four female beagle dogs at a dosage of 50 mg/kg. Total dosage was administered in five approximately equal amounts one minute apart. Control group received the vehicle. Higher incidence of decreased activity and ptyalism was seen in the treated group during the first hour after dosing. All dogs survived to study termination.

Long Term Toxicity and Carcinogenicity
Because adenosine is administered as a single dose and because it is a normal component of the body, no chronic toxicity studies and no carcinogenicity studies were performed.

Mutagenicity
Adenosine was tested in the Salmonella/Mammalian Microsome Plate Incorporation Mutagenicity Assay for its ability to induce back mutations at selected loci of several strains of Salmonella typhimurium in the presence and absence of rat liver microsomal enzymes. The tester strains used were TA98, TA100, TA1535, TA1537 and TA1538. Adenosine did not cause a positive response in any of the tester strains either in the presence or absence of microsomal enzymes.

Reproduction and Teratology
Adenosine present at millimolar concentrations in cell cultures produces a variety of chromosomal alterations. In rats and mice, adenosine administered intraperitoneally once a day for five days at 50, 100 and 150 mg/kg [10-30 (rats) and 5-15 (mice) times human dosage on a mg/M2 basis] caused decreased spermatogenesis and increased the number of abnormal sperm, a reflection of the ability of adenosine to produce chromosomal damage.

SELECTED BIBLIOGRAPHY

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3. Dimarco JP, Miles W, Akhtar M, et al. Adenosine for paroxysmal supraventricular tachycardia: dose ranging and comparison with verapamil. Ann Int Med 1990;113:104.

4. Dimarco JP, Sellers TD, et al. Diagnostic and therapeutic use of adenosine in patients with supraventricular tachyarrhythmias. JACC 1985;6:417.

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10. Solti F, Juhasz-Nagy S, Kecakemeti V, Czako E. The effect of adenosine on impulse formation and propagation in the heart. Cor Vasa 1984;26:296.

11. Vidrio H, Bracia-Marguez F, Magos GA. Repeated administration of adenosine increases its cardiovascular effects in rats. Eur J Pharm 1987;54:227.

12. Paul T, and Pflammater J-P. Adenosine: an effective and safe antiarrhythmic drug in pediatrics. Pediatr. Cardiol. 1997;18:118-126.