Adenoscan

Mechanism Of Action

Adenosine is a potent vasodilator in most vascular beds, except in renal afferent arterioles and hepatic veins where it produces vasoconstriction. 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 Adenoscan significantly increases blood flow in normal coronary arteries with little or no increase in stenotic arteries, Adenoscan causes relatively less thallium-201 uptake in vascular territories supplied by stenotic coronary arteries i.e., a greater difference is seen after Adenoscan between areas served by normal and areas served by stenotic vessels than is seen prior to Adenoscan.

Hemodynamics

Adenosine produces a direct negative chronotropic, dromotropic and inotropic effect on the heart, presumably due to A1-receptor agonism, and produces peripheral vasodilation, presumably due to A2-receptor agonism. The net effect of Adenoscan in humans is typically a mild to moderate reduction in systolic, diastolic and mean arterial blood pressure associated with a reflex increase in heart rate. Rarely, significant hypotension and tachycardia have been observed.

Pharmacokinetics

Intravenously administered adenosine is rapidly cleared from the circulation via cellular uptake, primarily by erythrocytes and vascular endothelial cells. This process involves a specific transmembrane nucleoside carrier system that is reversible, nonconcentrative, and bidirectionally symmetrical. 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. Since adenosine kinase has a lower Km and Vmax than adenosine deaminase, deamination plays a significant role only when cytosolic adenosine saturates the phosphorylation pathway. Inosine formed by deamination of adenosine can leave the cell intact or can be degraded to hypoxanthine, xanthine, and ultimately uric acid. Adenosine monophosphate formed by phosphorylation of adenosine is incorporated into the high-energy phosphate pool. While extracellular adenosine is primarily cleared by cellular uptake with a half-life of less than 10 seconds in whole blood, excessive amounts may be deaminated by an ecto-form of adenosine deaminase. As Adenoscan requires no hepatic or renal function for its activation or inactivation, hepatic and renal failure would not be expected to alter its effectiveness or tolerability.

Clinical Trials

In two crossover comparative studies involving 319 subjects who could exercise (including 106 healthy volunteers and 213 patients with known or suspected coronary disease), Adenoscan and exercise thallium images were compared by blinded observers. The images were concordant for the presence of perfusion defects in 85.5% of cases by global analysis (patient by patient) and up to 93% of cases based on vascular territories. In these two studies, 193 patients also had recent coronary arteriography for comparison (healthy volunteers were not catheterized). The sensitivity (true positive Adenoscan divided by the number of patients with positive (abnormal) angiography) for detecting angiographically significant disease ( ≥ 50% reduction in the luminal diameter of at least one major vessel) was 64% for Adenoscan and 64% for exercise testing, while the specificity (true negative divided by the number of patients with negative angiograms) was 54% for Adenoscan and 65% for exercise testing. The 95% confidence limits for Adenoscan sensitivity were 56% to 78% and for specificity were 37% to 71%.

Intracoronary Doppler flow catheter studies have demonstrated that a dose of intravenous Adenoscan of 140 mcg/kg/min produces maximum coronary hyperemia (relative to intracoronary papaverine) in approximately 95% of cases within two to three minutes of the onset of the infusion. Coronary blood flow velocity returns to basal levels within one to two minutes of discontinuing the Adenoscan infusion.

In the U.S.

• Adenocard
• Adenoscan

Available Dosage Forms:

• Solution

Therapeutic Class: Antiarrhythmic

Pharmacologic Class: Adenosine Receptor Agonist

This section provides information on the proper use of a number of products that contain adenosine. It may not be specific to Adenoscan. Please read with care.

A nurse or other trained health professional will give you this medicine. This medicine is given through a needle placed into one of your veins.

It is very important that your doctor check your progress very closely while you are receiving this medicine. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to receive it.

Heart attack and death may occur after receiving this medicine. Make sure your doctor knows if you have any heart problems (eg, unstable angina or cardiovascular instability) before you have a heart stress test. Check with your doctor right away if you have chest pain or discomfort, nausea, pain or discomfort in arms, jaw, back or neck, sweating, or vomiting.

Do not take anything that contains caffeine before you receive this medicine. This includes medicines, foods, and beverages with caffeine, such as coffee, tea, and cola drinks.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

• If you need to store this medicine at home, talk with your doctor, nurse, or pharmacist about how to store it.

Contraindications

Hypersensitivity

2nd or 3rd degree AV block (except those on pacemakers)

Sinus node disease, such as sick sinus syndrome or symptomatic bradycardia (except in patients with a functioning artificial pacemaker)

Adenoscan: Contraindicated in bronchoconstrictive or bronchospastic lung disease (eg, asthma)

Cautions

Symptomatic bradycardia, cardiac arrest, heart block, heart transplant patients, HTN, hypotension, MI, proarrhythmic events, unstable angina

Adenocard: Caution with bronchoconstrictive or bronchospastic lung disease (eg, asthma)

Cerebrovascular accident hemorrhagic and ischemic cerebrovascular accidents reported; hemodynamic effects of adenosine including hypotension or hypertension possibly associated with these adverse reactions

Nucleoside transport inhibitors (eg, dipyridamole) and potentiate the vasoactive effects of adenosine; withhold for 5 half-lives before adenosine administration

Methylxanthines (eg, caffeine, theophylline) are adenosine receptor antagonists and inhibit adenosine’s vasoactive effects; withhold methylxanthines for 5 half-lives before adenosine administration

New-onset or recurrence of convulsive seizures reported following adenosine; some seizures are prolonged and require emergent anticonvulsive management; aminophylline may increase risk of seizures associated with adenosine; methylxanthine use not recommended in patients who experience seizures in association with adenosine administration

Dyspnea, throat tightness, flushing, erythema, rash, and chest discomfort reported that may require symptomatic treatment; resuscitative measures may be necessary if symptoms progress; have trained personnel and treatment available during treatment

Arrhythmia at time of cardioversion (Adenocard): Ventricular fibrillation reported following 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

Risk for myocardial infarction and death

• Avoid use for cardiac nuclear stress tests in patients with signs or symptoms of acute myocardial ischemia (eg, unstable angina, cardiovascular instability); use may increase risk of fatal MI
• Screen all nuclear stress test candidates for risks

The recommended Adenoscan dose is 0.14 mg/kg/min infused over six minutes (total dose of 0.84 mg/kg) (Table 1).

Visually inspect Adenoscan for particulate matter and discoloration prior to administration. Do not administer Adenoscan if it contains particulate matter or is discolored.

There are no data on the safety or efficacy of alternative Adenoscan infusion protocols. The safety and efficacy of Adenoscan administered by the intracoronary route have not been established.

The nomogram displayed in Table 1 was derived from the following general formula:

                                                     0.14 (mg/kg/min) x
                                                   total body weight (kg)          =       Infusion rate
                                                Adenoscan concentration                     (mL/min)
                                                           (3 mg/mL)

Adenoscan for injection is supplied as 20 mL and 30 mL single-dose vials containing a sterile, nonpyrogenic, clear solution of adenosine 3 mg/mL.

The following adverse reactions are discussed in more detail in other sections of the prescribing information:

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 Adenoscan among 1,421 patients in clinical trials. Eleven percent (11%) of the adverse reactions occurred several hours after Adenoscan administration. Eight percent (8%) of the adverse reactions began with Adenoscan infusion and persisted for up to 24 hours.

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

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

Body as a Whole:                     back discomfort, lower extremity discomfort, weakness
Cardiovascular System:           myocardial infarction, ventricular arrhythmia, third-degree AV block,
                                                 bradycardia, palpitation, sinus exit block, sinus pause, T-wave changes,
                                                 hypertension (systolic blood pressure > 200 mm Hg)
Respiratory System:                 cough
Central Nervous System:         drowsiness, emotional instability, tremors
Genital/Urinary System:          vaginal pressure, urgency
Special Senses:                         blurred vision, dry mouth, ear discomfort, metallic taste, nasal
                                                 congestion, scotomas, tongue discomfort

Post-Marketing Experience

The following adverse reactions have been reported from marketing experience with Adenoscan. 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.

Cardiac Disorders:                                                              cardiac arrest, atrial fibrillation, cardiac failure,
                                                                                            myocardial infarction, tachycardia, ventricular arrhythmia
Gastrointestinal Disorders:                                                 nausea and vomiting
General Disorders and Administration Site Conditions:   chest pain, injection site reaction, infusion site pain
Immune System Disorders:                                                hypersensitivity
Nervous System Disorders:                                                cerebrovascular accident including intracranial hemorrhage,
                                                                                            seizure activity including tonic-clonic (grand mal) seizures, loss
                                                                                            of consciousness
Respiratory, Thoracic and Mediastinal Disorders:             bronchospasm, respiratory arrest, throat tightness

Adenoscan is part of the drug class:

• Miscellaneous Cardiac Preparations