Regadenoson - Regadenoson injection, Solution

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

  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 (12.2)and Patient Counseling Information (17)

  ]. 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      (10 )

  ].
  
  • In clinical studies, Regadenoson injection was administered to patients taking other cardioactive drugs (i.e., β-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

  12.2 Pharmacodynamics

  
  
  

  Coronary Blood Flow

  
  
  

  R

  egadenoson 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 mcg/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 pulsed-wave Doppler ultrasonography

  [see Overdosage (10)]

  .
  
  

  Effect of Caffeine

  
  
  

  I

  ngestion of caffeine decreases the ability to detect reversible ischemic defects. In a placebo-controlled, 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 (7.1)and Patient Counseling Information (17)]

  .
  
  

  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 (6.1)].

  ]
  .
• 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 vial: clear, colorless solution containing regadenoson 0.4 mg /5 mL (0.08 mg /mL).

• Myocardial Ischemia. Fatal cardiac events have occurred. Avoid use in patients with symptoms or signs of acute myocardial ischemia, for example unstable angina or cardiovascular instability, who may be at greater risk. Cardiac resuscitation equipment and trained staff should be available before administration (