Adenoscan

Name: Adenoscan

Adenoscan Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

More common
  • Chest discomfort
  • difficult or labored breathing
  • lightheadedness or dizziness
  • throat, neck, or jaw discomfort
  • tightness in the chest
Less common
  • Chest pain
  • confusion
  • dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
  • fainting
  • fast, slow, or irregular heartbeat
  • sweating
  • troubled breathing
  • unusual tiredness or weakness
Rare
  • Fast, irregular, pounding, or racing heartbeat or pulse
  • headache
  • nervousness
  • pounding in the ears

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Diarrhea
  • feeling of warmth
  • indigestion
  • loss of appetite
  • nausea or vomiting
  • passing of gas
  • redness of the face, neck, arms, and occasionally, upper chest
  • stomach pain, fullness, or discomfort
Rare
  • Area of decreased vision
  • cough
  • discomfort in the back, ears, or tongue
  • drowsiness
  • dry mouth
  • metallic taste
  • mood changes
  • shakiness in the legs, arms, hands, or feet
  • stuffy nose
  • trembling or shaking of the hands or feet

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Consumer Information Use and Disclaimer

  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else's drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Check with your pharmacist about how to throw out unused drugs.
  • Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Adenoscan, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Adenoscan. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Adenoscan (adenosine).

Review Date: October 4, 2017

Indications and Usage for Adenoscan

Adenoscan (adenosine) is indicated as an adjunct to thallium-201 myocardial perfusion scintigraphy in patients unable to exercise adequately.

Use in specific populations

Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with adenosine; nor have studies been performed in pregnant women. Because it is not known whether Adenoscan can cause fetal harm when administered to pregnant women, Adenoscan should be used during pregnancy only if clearly needed.

Nursing Mothers

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

Pediatric Use

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

Geriatric Use

Clinical studies with Adenoscan 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.

Overdosage

The half-life of adenosine is less than 10 seconds and adverse reactions of Adenoscan usually resolve quickly when the infusion is discontinued, although delayed or persistent reactions have been observed. Methylxanthines, such as caffeine, aminophylline, and theophylline, are competitive adenosine receptor antagonists and theophylline has been used to terminate persistent adverse reactions. In clinical trials, theophylline (50-125 mg slow intravenous injection) was used to attenuate Adenoscan adverse reactions in approximately 2% of patients. Methylxanthine use is not recommended in patients who experience seizures in association with Adenoscan [see Drug Interactions (7.1)].

Adenoscan - Clinical Pharmacology

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 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).

Pharmacodynamics

Hemodynamic Effects
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 [see Warnings and Precautions (5.4)].

Pharmacokinetics

Distribution
Intravenously administered adenosine distributes 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.

Metabolism
Intracellular adenosine is 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.

Elimination
While extracellular adenosine is primarily cleared from plasma 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.

Specific Populations

Renal Impairment
As adenosine does not require renal function for its activation or inactivation, renal impairment would not be expected to alter its effectiveness or tolerability.

Hepatic Impairment
As adenosine does not require hepatic function for its activation or inactivation, hepatic impairment would not be expected to alter its effectiveness or tolerability.

Clinical Studies

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 the two studies, 193 patients also had recent coronary arteriography for comparison (healthy volunteers were not catheterized). The sensitivity 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. The specificity 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 0.14 mg/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.

For the Consumer

Applies to adenosine: intravenous solution

Along with its needed effects, adenosine (the active ingredient contained in Adenoscan) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking adenosine:

More common
  • Chest discomfort
  • difficult or labored breathing
  • lightheadedness or dizziness
  • throat, neck, or jaw discomfort
  • tightness in the chest
Less common
  • Chest pain
  • confusion
  • dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
  • fainting
  • fast, slow, or irregular heartbeat
  • sweating
  • troubled breathing
  • unusual tiredness or weakness
Rare
  • Fast, irregular, pounding, or racing heartbeat or pulse
  • headache
  • nervousness
  • pounding in the ears

Some side effects of adenosine may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Diarrhea
  • feeling of warmth
  • indigestion
  • loss of appetite
  • nausea or vomiting
  • passing of gas
  • redness of the face, neck, arms, and occasionally, upper chest
  • stomach pain, fullness, or discomfort
Rare
  • Area of decreased vision
  • cough
  • discomfort in the back, ears, or tongue
  • drowsiness
  • dry mouth
  • metallic taste
  • mood changes
  • shakiness in the legs, arms, hands, or feet
  • stuffy nose
  • trembling or shaking of the hands or feet

Clinical Pharmacology

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 A 1 and A 2 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 A 2 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 A 1 -receptor agonism, and produces peripheral vasodilation, presumably due to A 2 -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 K m and V max 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.

Precautions

Drug Interactions

Intravenous Adenoscan (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, Adenoscan should be used with caution in the presence of these agents.

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

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

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 Adenoscan.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies in animals have not been performed to evaluate the carcinogenic potential of Adenoscan (adenosine injection). 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. Fertility studies in animals have not been conducted with adenosine.

Pregnancy Category C

Animal reproduction studies have not been conducted with adenosine; nor have studies been performed in pregnant women. Because it is not known whether Adenoscan can cause fetal harm when administered to pregnant women, Adenoscan should be used during pregnancy only if clearly needed.

Pediatric Use

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

Geriatric Use

Clinical studies of Adenoscan 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. Greater sensitivity of some older individuals, however, cannot be ruled out.

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