Pr ADENOSINE INJECTION, USP 3 mg/mL 6 mg/2 mL Vial 12 mg/4 mL Vial
Pharmaceutical Partners of Canada Inc. Date of Preparation: 45 Vogell Road, Suite 200 January 14, 2008 Richmond Hill, ON L4B 3P6 Control No: 119244
PRODUCT MONOGRAPH
Pr ADENOSINE INJECTION, USP
6 mg/2 mL Vial 12 mg/4 mL Vial
Antiarrhythmic
ACTION AND CLINICAL PHARMACOLOGY
Adenosine is an endogenous nucleoside occurring in all cells of the body. When injected intravenously, adenosine slows atrioventricular (AV) nodal conduction, can interrupt the reentry pathways through the AV 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 adenosine, 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 adenosine. Reports in the medical literature indicate success in treating PSVT in pediatric patients (including newborns) with adenosine in doses equivalent by weight to those used in adults. Adenosine is not effective in converting rhythms other than PSVT, such as atrial flutter, atrial fibrillation, or ventricular tachycardia to normal sinus rhythm.
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 adenosine 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 adenosine should be unaffected by hepatic or renal insufficiency.
INDICATIONS AND CLINICAL USE
Adenosine Injection, USP 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 adenosine administration. Adenosine is indicated to aid in the diagnosis of broad or narrow complex supraventricular tachycardia. Although adenosine 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 adenosine actually reaches the systemic circulation (see DOSAGE AND ADMINISTRATION). Adenosine does not convert atrial flutter, atrial fibrillation or ventricular tachycardia to normal sinus rhythm. Adenosine should only be used with appropriate cardiac monitoring.
Adenosine Injection, USP 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.
Heart Block
Adenosine exerts its effect by decreasing conduction through the AV 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 Adenosine 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 adenosine 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. Adenosine 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 bypass 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 AV 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
Adenosine 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 adenosine should be avoided in patients with COPD or asthma. Adenosine therapy should be discontinued in any patient who develops severe respiratory difficulties.
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 adenosine 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 adenosine 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 BIBLIOGRAPHY.)
Drug Interactions
Adenosine 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.
(see
). Because of the synergistic depressant effects on the SA and AV nodes, adenosine should be used with caution in the presence of these agents.
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.
Adenosine effects are potentiated by dipyridamole. Thus, smaller doses of adenosine may be effective in the presence of dipyridamole.
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 AV node, higher degrees of heart block may be produced in the presence of carbamazepine.
In controlled clinical trials, 268 patients received 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, and 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, and head pressure (less than 1%).
Central Nervous System:
Lightheadedness (2%), dizziness, tingling in arms, numbness (1%), apprehension, blurred vision, burning sensation, heaviness in arms, and neck and back pain (less than 1%).
Gastrointestinal:
Nausea (3%) and metallic taste, tightness in throat, pressure in groin (less than 1%).
In postmarketing clinical experience with adenosine, cases of prolonged asystole, ventricular tachycardia including torsades de pointes (see WARNINGS), ventricular fibrillation, transient increase in blood pressure, bradycardia, atrial fibrillation, and bronchospasm have been reported.
No cases of overdosage associated with the use of adenosine have been reported. It is unlikely that the true overdosage will occur because adenosine has a short half-life (< 10 seconds) and adenosine is dosed by a rapid bolus injection. If prolonged adverse events associated with the use of adenosine 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 adenosine. 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.
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- to 2-second time period. Additional doses: If the initial dose does not terminate supraventricular 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
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 0.30 mg/kg. For pediatric patients who require single intravenous doses less than 0.6 mg (0.2 mL of 3 mg/mL solution), Adenosine Injection may be further diluted with normal saline to a final concentration range from 0.3 to 1.0 mg/mL in a suitable glass container as follows:
| Desired Concentration (mg/mL) | Volume of Adenosine Injection, 3 mg/mL Required (mL) | Volume of Diluent Required (mL) | Final Volume of Diluted Solution (mL) |
| 0.3 | 1 | 9 | 10 |
| 1.0 | 1 | 2 | 3 |
Diluted solutions should be used immediately. Discard unused portion. As with all parenteral products, intravenous admixtures should be inspected for clarity of solutions, particulate matter, precipitate, discolouration, and leakage prior to administration whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used.
Administer the adult dose. Single bolus injections greater than 12 mg are not recommended for adult or pediatric patients.
Adenosine Injection should be inspected visually for particulate matter and discolouration prior to administration.
Adenosine Injection 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.
Drug Substance
Adenosine
6-amino-9-b-D-ribofuranosyl-9-H-purine
267.2
Molecular Formula: C10H13N5O4
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 - 238degC.
Adenosine Injection, USP is a sterile solution for rapid bolus intravenous injection and is available in 6 mg/2 mL vial and 12 mg/4 mL vial. 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. Adenosine does not contain preservatives, colours or additives.
Adenosine Injection should be stored at controlled room temperature (15 - 30degC). Single use vials. Discard unused portion.
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.
Adenosine Injection, USP is supplied as a sterile nonpyrogenic solution in normal saline as single-dose vial. Product Code: C605102 2 mL single-dose flip-top vials containing 6 mg adenosine/2 mL solution (3 mg/mL) in a package of 10. C605104 4 mL single-dose flip-top vials containing 12 mg adenosine/4 mL solution (3 mg/mL) in a package of 10. Vial stoppers do not contain natural rubber latex.
Animal Studies
Adenosine exerts pronounced negative chronotropic and dromotropic effects on cardiac pacemakers and atrioventricular (AV) 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 AV node is more sensitive to adenosine than 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.
Adenosine was administered intravenously to three conscious male beagle dogs at an initial dose of 4.8 mg/kg and a second dose of 9.6 mg/kg administered 2 - 3 hours later. All dogs were observed for seven days. Examinations conducted both pre- and post-injection demonstrated no electrocardiographic changes.
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.
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.
Human Studies
Adenosine at a dose of 83 mg/kg terminated electrically-induced PSVT. However, it was ineffective in terminating either intra-atrial 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 mg/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 mg/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 mg/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. 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.
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 postmortem 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
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 postdose, 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.
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.
Belardinelli L, Linden J, Berne RM. The cardiac effects of adenosine. Prog Cardiovascular Disease 1989; 32:73.
Caruso AC. Supraventricular tachycardia. Postgrad Med 1991; 96:73.
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.
Dimarco JP, Sellers TD, et al. Diagnostic and therapeutic use of adenosine in patients with supraventricular tachyarrhythmias. JACC 1985; 6:417.
Dipalma JR. Adenosine for paroxysmal supraventricular tachycardia. Am Fam Physicians 1991; 44:929.
Evoniuk G, Von Borezet RW, Wurtman RJ. Antagonism of the cardiovascular effects of adenosine by caffeine or 8-(p-sulfophenyl)theophylline. J Pharmacol Exp Ther 1987; 240:428.
Faulds D, Chrisp P, Buchley M. Adenosine. An evaluation of its use in cardiac diagnostic procedures, and in the treatment of paroxysmal supraventricular tachycardia. Drugs 1991; 41(4):596.
Pelleg A, Porter RS. The pharmacology of adenosine. Pharmacother 1990; 10:157.
Plagemann P. Transport and Metabolism of Adenosine in Human Erythrocytes: Effect of Transport Inhibitors and Regulation by Phosphate. Jour. Cell. Physio. 1986; 128:491 - 500.
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.
Vidrio H, Bracia-Marguez F, Magos GA. Repeated administration of adenosine increases its cardiovascular effects in rats. Eur J Pharm 1987; 54:227.
Paul T, and Pflammater J-P. Adenosine: an effective and safe antiarrhythmic drug in pediatrics. Pediatr. Cardiol. 1997; 18:118 - 126.
Adenocard(r) (adenosine injection, USP, 3 mg/mL), Innovator Product Monograph, Fujisawa Canada Inc., October 24, 2003.