Regadenoson

Regadenoson Injection is a pharmacologic stress agent indicated for radionuclide myocardial perfusion imaging (MPI) in patients unable to undergo adequate exercise stress.

The recommended dose of Regadenoson Injection is 5 mL (0.4 mg regadenoson) administered as an intravenous injection within 10 seconds.

• Patients should be instructed to avoid consumption of any products containing methylxanthines, including caffeinated coffee, tea or other caffeinated beverages, caffeine-containing drug products, aminophylline and theophylline for at least 12 hours before a scheduled radionuclide MPI [
  see Drug Interactions (

  7.1 Effects of Other Drugs on Regadenoson Injection

  • Methylxanthines (e.g., caffeine, aminophylline and theophylline) are non-specific adenosine receptor antagonists that interfere with the vasodilation activity of Regadenoson Injection [
    see Clinical Pharmacology and Patient Counseling Information
    ]. Patients should avoid consumption of any products containing methylxanthines as well as any drugs containing theophylline or aminophylline for at least 12 hours before Regadenoson Injection administration. Aminophylline may be used to attenuate severe or persistent adverse reactions to Regadenoson Injection [
    see Overdosage
    ].
  • In clinical studies, Regadenoson Injection was administered to patients taking other cardioactive drugs (i.e., ß-blockers, calcium channel blockers, ACE inhibitors, nitrates, cardiac glycosides, and angiotensin receptor blockers) without reported adverse reactions or apparent effects on efficacy.
  • Dipyridamole may change the effects of Regadenoson Injection. When possible, withhold dipyridamole for at least two days prior to Regadenoson Injection administration.

  ) and Clinical Pharmacology (

  12.2 Pharmacodynamics

  Coronary Blood Flow

  
  
  Regadenoson Injection causes a rapid increase in CBF which is sustained for a short duration. In patients undergoing coronary catheterization, pulsed-wave Doppler ultrasonography was used to measure the average peak velocity (APV) of coronary blood flow before and up to 30 minutes after administration of regadenoson (0.4 mg, intravenously). Mean APV increased to greater than twice baseline by 30 seconds and decreased to less than twice the baseline level within 10 minutes [

  see Clinical Pharmacology (12.3)

  ].

  Myocardial uptake of the radiopharmaceutical is proportional to CBF. Because Regadenoson Injection increases blood flow in normal coronary arteries with little or no increase in stenotic arteries, Regadenoson Injection causes relatively less uptake of the radiopharmaceutical in vascular territories supplied by stenotic arteries. MPI intensity after Regadenoson Injection administration is therefore greater in areas perfused by normal relative to stenosed arteries.

  Effect of duration of injection

  
  
  A study in dogs compared the effects of intravenous injection of 2.5 μg/kg regadenoson (in 10 mL) over 10 seconds and 30 seconds on CBF. The duration of a two-fold increase in CBF was 97±14 seconds (n=6) and 221±20 seconds (n=4), respectively, for the 10 second and 30 second injections. The peak effects (i.e., maximal increase) on CBF after the 10 second and 30 second injections were 217±15% and 297±33% above baseline, respectively. The times to peak effect on CBF were 17±2 seconds and 27±6 seconds, respectively.

  Effect of Aminophylline

  
  
  Aminophylline (100 mg, administered by slow intravenous injection over 60 seconds) injected 1 minute after 0.4 mg Regadenoson Injection in patients undergoing cardiac catheterization, was shown to shorten the duration of the coronary blood flow response to Regadenoson Injection as measured by pulsedwave Doppler ultrasonography [

  see Overdosage

  ].

  Effect of Caffeine

  
  
  Ingestion of caffeine decreases the ability to detect reversible ischemic defects. In a placebocontrolled, parallel group clinical study, patients with known or suspected myocardial ischemia received a baseline rest/stress MPI followed by a second stress MPI. Patients received caffeine or placebo 90 minutes before the second Regadenoson Injection stress MPI. Following caffeine administration (200 or 400 mg), the mean number of reversible defects identified was reduced by approximately 60%. This decrease was statistically significant [

  see Drug Interactions and Patient Counseling Information

  ].

  Hemodynamic Effects

  
  
  In clinical studies, the majority of patients had an increase in heart rate and a decrease in blood pressure within 45 minutes after administration of Regadenoson Injection. Maximum hemodynamic changes after Regadenoson Injection and ADENOSCAN in Studies 1 and 2 are summarized in Table 5.

  Table 5 Hemodynamic Effects in Studies 1 and 2

  Vital Sign Parameter	Regadenoson Injection N = 1,337	ADENOSCAN N = 678
  Heart Rate
  > 100 bpm	22%	13%
  Increase > 40 bpm	5%	3%
  Systolic Blood Pressure
  < 90 mm Hg	2%	3%
  Decrease > 35 mm Hg	7%	8%
  ≥ 200 mm Hg	1.9%	1.9%
  Increase ≥ 50 mm Hg	0.7%	0.8%
  ≥ 180 mm Hg and increase of ≥ 20 mm Hg from baseline	4.6%	3.2%
  Diastolic Blood Pressure
  < 50 mm Hg	2%	4%
  Decrease > 25 mm Hg	4%	5%
  ≥ 115 mm Hg	0.9%	0.9%
  Increase ≥ 30 mm Hg	0.5%	1.1%

  Hemodynamic Effects Following Inadequate Exercise

  
  
  In a clinical study, Regadenoson Injection was administered for MPI following inadequate exercise stress. More patients with Regadenoson Injection administration three minutes following inadequate exercise stress had an increase in heart rate and a decrease in systolic blood pressure compared with Regadenoson Injection administered at rest. The changes were not associated with any clinically significant adverse reactions. Maximum hemodynamic changes are presented in Table 6.

  Table 6 Hemodynamic Effects in Inadequate Exercise Stress Study

  Vital Sign Parameter	Group 1 / MPI 1 Regadenoson Injection 3 minutes following exercise (N=575)	Group 2 / MPI 1 Regadenoson Injection 1 hour following exercise (N=567)
  Heart Rate
  > 100 bpm	44%	31%
  Increase > 40 bpm	5%	16%
  Systolic Blood Pressure
  < 90 mm Hg	2%	4%
  Decrease > 35 mm Hg	29%	10%
  ≥ 200 mm Hg	0.9%	0.4%
  Increase ≥ 50 mm Hg	2%	0.4%
  ≥ 180 mm Hg and increase of ≥ 20 mm Hg from baseline	5%	2%
  Diastolic Blood Pressure
  < 50 mm Hg	3%	3%
  Decrease > 25 mm Hg	6%	5%
  ≥ 115 mm Hg	0.7%	0.4%
  Increase ≥ 30 mm Hg	2%	1%

  Respiratory Effects

  
  
  The A_2Band A₃adenosine receptors have been implicated in the pathophysiology of bronchoconstriction in susceptible individuals (i.e., asthmatics). In in vitro studies, regadenoson has not been shown to have appreciable binding affinity for the A_2Band A₃adenosine receptors.

  In a randomized, placebo-controlled clinical trial of 999 patients with a diagnosis, or risk factors for, coronary artery disease and concurrent asthma or COPD, the incidence of respiratory adverse reactions (dyspnea, wheezing) was greater with Regadenoson Injection compared to placebo. Moderate (2.5%) or severe (< 1%) respiratory reactions were observed more frequently in the Regadenoson Injection group compared to placebo [

  see Adverse Reactions

  ].

  )
  ].

• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Regadenoson Injection if it contains particulate matter or is discolored.

• Administer Regadenoson Injection as an intravenous injection within 10 seconds into a peripheral vein using a 22 gauge or larger catheter or needle.

• Administer a 5 mL saline flush immediately after the injection of Regadenoson Injection.

• Administer the radionuclide myocardial perfusion imaging agent 10–20 seconds after the saline flush. The radionuclide may be injected directly into the same catheter as Regadenoson Injection.

• Single-dose pre-filled syringe: clear, colorless solution containing regadenoson 0.4 mg/5 mL (0.08 mg/mL). 

The following adverse reactions are discussed in more detail in other sections of the labeling.

• Myocardial Ischemia [
  see Warnings and Precautions (

  5.1 Myocardial Ischemia

  Fatal and nonfatal myocardial infarction (MI), ventricular arrhythmias, and cardiac arrest have occurred following Regadenoson Injection. 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 Regadenoson Injection. Cardiac resuscitation equipment and trained staff should be available before administering Regadenoson Injection. Adhere to the recommended duration of injection [

  see Dosage and Administration

  ]. As noted in an animal study, longer injection times may increase the duration and magnitude of increase in coronary blood flow [

  see Clinical Pharmacology

  ]. If serious reactions to Regadenoson Injection occur, consider the use of aminophylline, an adenosine antagonist, to shorten the duration of increased coronary blood flow induced by Regadenoson Injection [

  see Overdosage

  ].

  )
  ]
• Sinoatrial and Atrioventricular Nodal Block [
  see Warnings and Precautions (

  5.2 Sinoatrial and Atrioventricular Nodal Block

  Adenosine receptor agonists, including Regadenoson Injection, can depress the SA and AV nodes and may cause first-, second- or third-degree AV block, or sinus bradycardia requiring intervention. In clinical trials first-degree AV block (PR prolongation > 220 msec) developed in 3% of patients within 2 hours of Regadenoson Injection administration; transient second-degree AV block with one dropped beat was observed in one patient receiving Regadenoson Injection. In post-marketing experience, third-degree heart block and asystole within minutes of Regadenoson Injection administration have occurred [

  see Adverse Reactions

  ].

  )
  ]
• Atrial Fibrillation/Atrial Flutter [
  see Warnings and Precautions (

  5.3 Atrial Fibrillation/Atrial Flutter

  New-onset or recurrent atrial fibrillation with rapid ventricular response and atrial flutter have been reported following Regadenoson Injection [

  see Adverse Reactions

  ].

  )
  ]
• Hypersensitivity, Including Anaphylaxis [
  see Warnings and Precautions (

  5.4 Hypersensitivity, Including Anaphylaxis

  Anaphylaxis, angioedema, cardiac or respiratory arrest, respiratory distress, decreased oxygen saturation, hypotension, throat tightness, urticaria and rashes have occurred. In clinical trials, hypersensitivity reactions were reported in fewer than 1 percent of patients [

  see Adverse Reactions

  ]. Have personnel and resuscitative equipment immediately available.

  )
  ]
• Hypotension [
  see Warnings and Precautions (

  5.5 Hypotension

  Adenosine receptor agonists, including Regadenoson Injection, induce arterial vasodilation and hypotension. In clinical trials, decreased systolic blood pressure (> 35 mm Hg) was observed in 7% of patients and decreased diastolic blood pressure (> 25 mm Hg) was observed in 4% of patients within 45 minutes of Regadenoson Injection administration. The risk of serious hypotension may be higher in patients with autonomic dysfunction, hypovolemia, left main coronary artery stenosis, stenotic valvular heart disease, pericarditis or pericardial effusions, or stenotic carotid artery disease with cerebrovascular insufficiency. In post-marketing experience, syncope, transient ischemic attacks and seizures have been observed [

  see Adverse Reactions

  ].

  )
  ]
• Hypertension [
  see Warnings and Precautions (

  5.6 Hypertension

  Administration of adenosine receptor agonists, including Regadenoson Injection, may result in clinically significant increases in blood pressure in some patients. Among patients who experienced an increase in blood pressure in clinical trials, the increase was observed within minutes of Regadenoson Injection administration. Most increases resolved within 10 to 15 minutes, but in some cases, increases were observed at 45 minutes following administration [

  see Clinical Pharmacology

  ]. In post-marketing experience, cases of potentially clinically significant hypertension have been reported, particularly with underlying hypertension and when low-level exercise was included in the MPI [

  see Adverse Reactions

  ].

  )
  ]
• Bronchoconstriction [
  see Warnings and Precautions (

  5.7 Bronchoconstriction

  Adenosine receptor agonists, including Regadenoson Injection, may cause dyspnea, bronchoconstriction, and respiratory compromise. Appropriate bronchodilator therapy and resuscitative measures should be available prior to and following Regadenoson Injection administration [

  see Adverse Reactions

  ,

  Clinical Pharmacology

  ,

  Overdosage and Patient Counseling Information

  ].

  )
  ]
• Seizure [
  see Warnings and Precautions (

  5.8 Seizure

  Regadenoson Injection may lower the seizure threshold; obtain a seizure history. New-onset or recurrence of convulsive seizures has occurred following Regadenoson Injection. Some seizures are prolonged and require emergent anticonvulsive management. Aminophylline may increase the risk of seizures associated with Regadenoson Injection. Methylxanthine use is not recommended in patients who experience a seizure in association with Regadenoson Injection administration.

  )
  ]
• Cerebrovascular Accident (Stroke) [
  see Warnings and Precautions (

  5.9 Cerebrovascular Accident (Stroke)

  Hemorrhagic and ischemic cerebrovascular accidents have occurred. Hemodynamic effects of Regadenoson Injection including hypotension or hypertension may be associated with these adverse reactions [

  see Warnings and Precautions and

  ].

  )
  ]

No formal pharmacokinetic drug interaction studies have been conducted with Regadenoson Injection.