Regadenoson (regadenoson)

Regadenoson is commercially available as the monohydrate; dosage is expressed in terms of regadenoson.

The recommended adult dose of regadenoson when used as an adjunct to radionuclide myocardial perfusion imaging in patients unable to exercise adequately is 0.4 mg (5 mL) as a rapid IV injection (i.e., over approximately 10 seconds), followed by a flush with 5 mL of 0.9% sodium chloride injection. The radionuclide myocardial perfusion imaging agent should be administered 10-20 seconds after the 0.9% sodium chloride injection flush; the radionuclide may be injected directly into the same catheter as regadenoson. (See Dosage and Administration: Administration.)

Regadenoson is administered by rapid IV injection (i.e., over approximately 10 seconds) into a peripheral vein using a 22-gauge or larger catheter or needle, followed by a flush with 5 mL of 0.9% sodium chloride injection. The radionuclide myocardial perfusion imaging agent should be administered 10-20 seconds after the 0.9% sodium chloride injection flush; the radionuclide may be injected directly into the same catheter as regadenoson. (See Dosage and Administration: Dosage.)

Some clinicians suggest that blood pressure should be monitored every minute during infusion and 3-5 minutes into recovery. In addition, electrocardiogram (ECG) monitoring should be performed as with exercise stress testing, and a 12-lead ECG should be recorded every minute during the infusion.

Some clinicians state that the indications for reversal of regadenoson infusion include severe hypotension (systolic blood pressure less than 80 mm Hg), development of symptomatic, persistent second-degree or complete heart block, wheezing, severe chest pain associated with ST-depression of 2 mm or greater, signs of poor perfusion (pallor, cyanosis, cold skin), technical problems with the monitoring equipment, and the patient's request to stop. The manufacturer recommends that the regadenoson infusion be reversed if the patient complains of any adverse effect.

Regadenoson injection should be stored at 25degreesC with excursions of 15-30degreesC permitted. Regadenoson injection should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit. Prefilled syringes of regadenoson are intended for single use only.

No dosing information is available for this tab.

No dosing information is available for this tab.

No formal pharmacokinetic drug interaction studies have been performed with regadenoson to date.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Adenosine; Hexobendine; Regadenoson/Xanthine Derivatives

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Xanthine derivatives may antagonize the effects of endogenous(1) and exogenous adenosine,(2,3) regadenoson,(4) and hexobendine.(5)

CLINICAL EFFECTS: Concurrent use of a xanthine derivative use may result in decreased effectiveness of adenosine, hexobendine and regadenoson. Aminophylline may increase the risk of adenosine-induced seizures.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with adenosine and a xanthine derivative should be monitored for decreased effectiveness of adenosine. The dosage of adenosine may need to be increased. Whenever possible, withhold xanthine derivatives for 5 half-lives prior to using adenosine in cardiac stress tests.(6) Methylxanthines should not be used to reverse the effects of adenosine in patients who experience adenosine-induced seizures.(3) Concurrent therapy with hexobendine and a xanthine oxidase derivative should also be monitored for decreased effectiveness of hexobendine.(5) The US manufacturer of regadenoson recommends that patients avoid methylxanthines (e.g. caffeine, pentoxifylline, and theophylline) for 12 hours prior to regadenoson administration. Aminophylline may be used to attenuate severe and/or persistent adverse reactions to regadenoson.(4)

DISCUSSION: In a study in six healthy subjects, theophylline significantly reduced the heart-rate response to adenosine. In addition, theophylline reduced the amount of abdominal and chest discomfort reported by subjects, allowing significantly higher infusion rates of adenosine.(7) Theophylline has also been reported to antagonize the vasorelaxant action of adenosine in human forearm arterioles.(8) In a study in five subjects, theophylline decreased the amounts of adenosine-induced side effects, including chest pain. There was no change in blood pressure or respiratory rate during concurrent adenosine and theophylline.(9) In a study in ten dog and twelve human subjects, the administration of adenosine after hexobendine increased coronary sinus blood flow. Aminophylline administration significantly decreased the coronary vasodilation response to adenosine and hexobendine.(5) In a study in ten healthy subjects, caffeine reduced the mean adenosine-induced increases in systolic blood pressure by 7.2 mmHg and heart rate by 8.4 beats/min when compared to placebo.(2) In another study in ten healthy subjects, caffeine was shown to lower the adenosine-induced response of blood pressure and heart rate.(3) Caffeine has also been reported to reduced adenosine-induced changes in minute ventilation and tidal volume.(3) Aminophylline has been shown to shorten the duration of coronary blood flow response to regadenoson.(3) Coronary flow reserve was 8% lower in patients who received caffeine (200 mg single dose) 2 hours prior to regadenoson administration when compared to subjects who received placebo instead of caffeine.(4)

Adenosine; Regadenoson/Dipyridamole

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Dipyridamole inhibits cellular transport of adenosine.(1-3) Also, dipyridamole has been shown to increase intrinsic adenosine levels indicating that dipyridamole inhibits the intrinsic metabolism of adenosine.(4) Regadenoson is a derivative of adenosine.(5)

CLINICAL EFFECTS: Concurrent dipyridamole may increase serum concentrations and potentiate the cardiovascular effects of adenosine. Conversely, significant bradycardia has occurred following rapid bolus injections of adenosine.(1-8) Dipyridamole may increase the effects of regadenoson.(1,2,5)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The recommendations for concurrent use of adenosine or regadenoson with dipyridamole is dependent on the indication. -For Cardioversion: The Australian manufacturer of adenosine states the use of adenosine for cardioversion is contraindicated in patients receiving dipyridamole. Discontinue the use of dipyridamole 24 hours prior to adenosine bolus dosing.(7) The US manufacturer of adenosine states smaller doses of adenosine may be effective with dipyridamole.(6) Lower the dose of adenosine in patients receiving dipyridamole.(1,2) Monitor for increased effects of adenosine. -For Stress Testing: Clinical practice guidelines from the American Society of Nuclear Cardiology state dipyridamole use within the previous 48 hours is a contraindication to adenosine or regadenoson stress testing.(9,10) The US manufacturer of dipyridamole recommends stopping dipyridamole for 48 hours prior to stress testing with intravenous dipyridamole or other adenosinergic agents (e.g. adenosine or regadenoson).(1) The Australian manufacturer of dipyridamole recommends stopping dipyridamole for 24 hours prior to stress testing with adenosine.(2) The US manufacturer of regadenoson recommends withholding dipyridamole for at least 2 days prior to regadenoson administration.(5)

DISCUSSION: In a prospective, placebo-controlled single blinded study in eight healthy subjects, all patients were randomized to receive adenosine infusion on two separate days. Heart rate and skin temperature increased in a dose-related manner following adenosine administration. An increase in heart rate of 15 bpm occurred with 0.005 mg/kg/min of adenosine following administration of dipyridamole but did not change following saline. Blood pressure remained unchanged throughout the study.(11) According to another prospective, non-placebo controlled, non-blinded study, five healthy volunteers received a five-day course of oral dipyridamole 100 mg every 6 hours. Plasma adenosine levels were measured for a five day control period as a baseline and also during the five-day course of dipyridamole. It was found during the baseline studies that adenosine levels vary significantly between individuals but seem to be constant within the same individual. During the five-day course, the average increase in endogenous adenosine concentration was 60%. It was concluded that administration of oral dipyridamole significantly increases plasma adenosine levels in normal human subjects. Also, there was a positive correlation between adenosine and dipyridamole levels (p = 0.001).(12)

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

Second- or third-degree AV block (except in patients with a functioning artificial pacemaker).

Sinus node dysfunction (except in patients with a functioning artificial pacemaker).

Known hypersensitivity to regadenoson or any ingredient in the formulation.

• Severe hypotension
• Wheezing

• Autonomic neuropathy
• Bradycardia
• Cerebrovascular accident
• Complete atrioventricular block
• Congenital long QT syndrome
• Hypotension
• Myocardial ischemia
• Second degree atrioventricular heart block
• Sick sinus syndrome
• Sinus bradycardia
• Unstable angina pectoris

• Aortic valve stenosis
• Atrial fibrillation
• Bronchospastic pulmonary disease
• Carotid artery stenosis
• Chronic obstructive pulmonary disease
• Hypertension
• Hypovolemia
• Left main coronary artery disease
• Pericardial effusion
• Pericarditis
• Prolonged QT interval
• Seizure disorder
• Transient cerebral ischemia

Adverse effects reported in 5% or more of patients receiving regadenoson include dyspnea, headache, flushing, chest discomfort, angina pectoris or ST-segment depression, dizziness, chest pain, nausea, abdominal discomfort, dysgeusia, and warm feeling.

More Frequent

• Abnormal ECG
• Angina

Rare or Very Rare

• Acute myocardial infarction
• Acute respiratory failure
• Anaphylaxis
• Angioedema
• Atrial fibrillation
• Atrial flutter
• Atrioventricular block
• Bronchospastic pulmonary disease
• Cardiac arrest
• Cerebrovascular accident
• Heart block
• Hypertension
• Hypotension
• Intracranial bleeding
• Seizure disorder
• Syncope
• Tachycardia
• Throat constriction
• Transient cerebral ischemia
• Urticaria
• Ventricular arrhythmias

More Frequent

• Chest discomfort
• Chest pain
• Dizziness
• Dyspnea
• Flushing
• Headache disorder
• Nausea

Less Frequent

• Dysgeusia

Rare or Very Rare

• Acute abdominal pain
• Bradycardia
• Diarrhea
• Musculoskeletal pain
• Myalgia
• Skin rash
• Tremor
• Vomiting
• Wheezing

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Safety and efficacy of regadenoson have not been established in pediatric patients younger than 18 years of age.

Category C. (See Users Guide.)

It is not known whether regadenoson is distributed into milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions from regadenoson in nursing infants, the decision to interrupt nursing after administering regadenoson or not to administer the drug, should take into account the importance of the drug to the woman. The manufacturer states that, based on the pharmacokinetics of regadenoson, the drug should be cleared from circulation 10 hours after administration; therefore, nursing women may consider interrupting nursing for 10 hours following drug administration.

Patients 75 years of age or older had a similar adverse effect profile compared with younger patients (i.e., patients younger than 65 years of age), however, older patients had a higher incidence of hypotension (2% versus less than 1%).

Based on a population pharmacokinetic analysis, age has a minimal influence on the pharmacokinetics of regadenoson; however, a general trend toward decreasing renal clearance was observed with increasing age. (See Dosage and Administration: Special Populations.)