Adenosine Injection - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Adenosine Injection - Scientific Information

Manufacture: Fresenius Kabi USA, LLC
Country: Canada
Condition: Radionuclide Myocardial Perfusion Study, Supraventricular Tachycardia, Wolff-Parkinson-White Syndrome
Class: Antiarrhythmic agents, Cardiac stressing agents, Group V antiarrhythmics
Form: Liquid solution, Intravenous (IV)
Ingredients: adenosine, sodium chloride in water for Injection

Pharmaceutical Information

Drug Substance

Common Name: Adenosine
Chemical Name: 6-amino-9-β-D-ribofuranosyl-9-H-purine; Adenine riboside
Structural Formula:
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: Adenosine Injection, USP is a sterile solution for rapid bolus intravenous injection and is available in 6 mg/2 mL vials. 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 Injection, USP does not contain preservatives, colours or additives.

Stability and Storage Recommendations

Adenosine Injection, USP should be stored at controlled room temperature (15 - 30°C). Single-dose vials. Discard unused portion. 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

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.

Vial stoppers do not contain natural rubber latex.

Pharmacology

Animal Studies

Cardiac Electrophysiology

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.

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.

Human Studies

Adenosine at a dose of 83 µg/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 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.

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 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 Multidose Intravenous Toxicity

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 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.

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.