5.1 Cardiac Arrest, Ventricular Arrhythmias, and Myocardial Infarction

Fatal and nonfatal cardiac arrest, sustained ventricular tachycardia (requiring resuscitation), and myocardial infarction have occurred following adenosine infusion. Avoid use in patients with symptoms or signs of acute myocardial ischemia, for example, unstable angina or cardiovascular instability; these patients may be at greater risk of serious cardiovascular reactions to adenosine. Appropriate resuscitative measures should be available [see Overdosage (10)].

5.2 Sinoatrial and Atrioventricular Nodal Block

Adenosine exerts a direct depressant effect on the SA and AV nodes and may cause first-, second- or third-degree AV block, or sinus bradycardia. In clinical trials, approximately 6% of patients developed AV block following adenosine administration (first-degree heart block developed in 3%, second-degree in 3%, and third-degree in 0.8% of patients) [see Clinical Trials Experience (6.1)].

Use adenosine with caution in patients with pre-existing first-degree AV block or bundle branch block. Do not use in patients with high-grade AV block or sinus node dysfunction (except in patients with a functioning artificial pacemaker). Discontinue adenosine in any patient who develops persistent or symptomatic high-grade AV block.

5.3 Bronchoconstriction

Adenosine administration can cause dyspnea, bronchoconstriction, and respiratory compromise. Adenosine should be used with caution in patients with obstructive lung disease not associated with bronchoconstriction (e.g., emphysema, bronchitis). Do not use in patients with bronchoconstriction or bronchospasm (e.g., asthma). Discontinue adenosine in any patient who develops severe respiratory difficulties. Resuscitative measures should be available prior to adenosine administration [see Clinical Trials Experience (6.1), Overdosage (10), and Clinical Pharmacology (12.2)].

5.4 Hypotension

Adenosine is a potent peripheral vasodilator and can induce significant hypotension. The risk of serious hypotension may be higher in patients with autonomic dysfunction, hypovolemia, stenotic valvular heart disease, pericarditis or pericardial effusions, or stenotic carotid artery disease with cerebrovascular insufficiency. Discontinue adenosine in any patient who develops persistent or symptomatic hypotension.

5.5 Cerebrovascular Accident

Hemorrhagic and ischemic cerebrovascular accidents have occurred. Hemodynamic effects of adenosine including hypotension or hypertension can be associated with these adverse reactions [see Warnings and Precautions (5.4) and (5.9)].

5.6 Seizures

New-onset or recurrence of convulsive seizures has occurred following adenosine. Some seizures are prolonged and require emergent anticonvulsive management. Aminophylline may increase the risk of seizures associated with adenosine. Methylxanthine use is not recommended in patients who experience seizures in association with adenosine administration [see Overdosage (10)].

5.7 Hypersensitivity, Including Anaphylaxis

Dyspnea, throat tightness, flushing, erythema, rash, and chest discomfort have occurred. Symptomatic treatment may be required. Have personnel and appropriate treatment available. Resuscitative measures may be necessary if symptoms progress [see Post-Marketing Experience (6.2)].

5.8 Atrial Fibrillation

Adenosine can cause atrial fibrillation in patients with or without a history of atrial fibrillation. Atrial fibrillation typically began 1.5 to 3 minutes after initiation of adenosine, lasted for 15 seconds to 6 hours, and spontaneously converted to normal sinus rhythm [see Post-Marketing Experience (6.2)].

5.9 Hypertension

Adenosine can induce clinically significant increases in systolic and diastolic blood pressure. Most increases resolved spontaneously within several minutes, but in some cases, hypertension lasted for several hours [see Clinical Trials Experience (6.1)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following adverse reactions, with an incidence of at least 1%, were reported with adenosine among 1,421 patients in clinical trials. 11% of the adverse reactions occurred several hours after adenosine administration. 8% of the adverse reactions began with adenosine infusion and persisted for up to 24 hours.

The most common (incidence ≥ 10%) adverse reactions to adenosine are flushing, chest discomfort, shortness of breath, headache, throat, neck or jaw discomfort, gastrointestinal discomfort, and dizziness (Table 2).

Adverse reactions to adenosine of any severity reported in less than 1% of patients include:

6.2 Post-Marketing Experience

The following adverse reactions have been reported from marketing experience with adenosine. Because these reactions 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.

7.1 Effects of Other Drugs on Adenosine

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The vasoactive effects of adenosine are inhibited by adenosine receptor antagonists, (such as methylxanthines (e.g., caffeine, aminophylline, and theophylline). The safety and efficacy of adenosine in the presence of these agents has not been systematically evaluated [see Overdosage (10)].

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The vasoactive effects of adenosine are potentiated by nucleoside transport inhibitors such as dipyridamole. The safety and efficacy of adenosine in the presence of dipyridamole has not been systematically evaluated.

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Whenever possible, drugs that might inhibit or augment the effects of adenosine should be withheld for at least five half-lives prior to the use of adenosine.

7.2 Effects of Adenosine on Other Drugs

Adenosine injection has been given with other cardioactive drugs (such as beta adrenergic blocking agents, cardiac glycosides, and calcium channel blockers) without apparent adverse interactions, but its effectiveness with these agents has not been systematically evaluated. Because of the potential for additive or synergistic depressant effects on the SA and AV nodes, however, adenosine should be used with caution in the presence of these agents [see Warnings and Precautions (5.2)].

8.1 Pregnancy

8.3 Nursing Mothers

It is not known whether adenosine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from adenosine in nursing infants, the decision to interrupt nursing after administration of adenosine or not to administer adenosine, should take into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness of adenosine in patients less than 18 years of age have not been established.

8.5 Geriatric Use

Clinical studies with adenosine did not include sufficient numbers of subjects aged younger than 65 years to determine whether they respond differently. Other reported experience has not revealed clinically relevant differences of the response of elderly in comparison to younger patients.

12.1 Mechanism of Action

Adenosine causes cardiac vasodilation which increases cardiac blood flow. Adenosine is thought to exert 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 also lessen 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.

Myocardial uptake of thallium-201 is directly proportional to coronary blood flow. Since adenosine significantly increases blood flow in normal coronary arteries with little or no increase in stenotic arteries, adenosine causes relatively less thallium-201 uptake in vascular territories supplied by stenotic coronary arteries i.e., a greater difference is seen after adenosine between areas served by normal and areas served by stenotic vessels than is seen prior to adenosine.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies in animals have not been performed to evaluate adenosine's carcinogenic potential or potential effects on fertility. Adenosine was negative for genotoxic potential in the Salmonella (Ames Test) and Mammalian Microsome Assay.

Adenosine, however, like other nucleosides at millimolar concentrations present for several doubling times of cells in culture, is known to produce a variety of chromosomal alterations.

16.1 How Supplied

Adenosine Injection, USP is supplied as 20 mL and 30 mL single-dose vials of sterile, nonpyrogenic solution in normal saline as follows:

16.2 Storage and Handling

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature.]

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.

Discard unused portion.

Sterile, Nonpyrogenic, Preservative-free.

The container closure is not made with natural rubber latex.