Regadenoson
REGADENOSON- regadenoson injection, solution
Almaject, Inc.
1 INDICATIONS AND USAGE
Regadenoson injection is a pharmacologic stress agent indicated for radionuclide myocardial perfusion imaging (MPI) in patients unable to undergo adequate exercise stress.
2 DOSAGE AND ADMINISTRATION
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) and Clinical Pharmacology (12.2) ].
- 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.
3 DOSAGE FORMS AND STRENGTHS
Single-dose vial: clear, colorless solution containing regadenoson 0.4 mg /5 mL (0.08 mg /mL).
4 CONTRAINDICATIONS
Do not administer Regadenoson injection to patients with:
· Second- or third-degree AV block, or
· Sinus node dysfunction unless these patients have a functioning artificial pacemaker [see Warnings and Precautions (5.2) ] .
5 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 (2) ]. As noted in an animal study, longer injection times may increase the duration and magnitude of increase in coronary blood flow [see Clinical Pharmacology (12.2) ]. 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 (10) ].
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 (6.2) ].
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 (6.2) ].
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 A dverse Reactions (6.1) ]. Have personnel and resuscitative equipment immediately available.
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 (6.2) ].
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 (12.2) ]. 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 (6.2) ].
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 Regadenoson injection administration [see Adverse Reactions (6.1), Clinical Pharmacology (12.2), Overdosage (10) and Patient Counseling Information (17)].
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.
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 (5.5) and (5.6) ].
6 ADVERSE REACTIONS
The following adverse reactions are discussed in more detail in other sections of the labeling.
• Myocardial Ischemia [see Warnings and Precautions (5.1) ]
• Sinoatrial and Atrioventricular Nodal Block [see Warnings and Precautions (5.2) ]
• Atrial Fibrillation/Atrial Flutter [see Warnings and Precautions (5.3)]
• Hypersensitivity, Including Anaphylaxis [see Warnings and Precautions (5.4) ]
• Hypotension [see Warnings and Precautions (5.5) ]
• Hypertension [see Warnings and Precautions (5.6) ]
• Bronchoconstriction [see Warnings and Precautions (5.7) ]
• Seizure [see Warnings and Precautions (5.8) ] • Cerebrovascular Accident (Stroke) [see Warnings and Precautions (5.9) ]
6.1 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.
During clinical development, 1,651 patients were exposed to Regadenoson injection, with most receiving 0.4 mg as a rapid (≤ 10 seconds) intravenous injection. Most of these patients received Regadenoson injection in two clinical studies that enrolled patients who had no history of bronchospastic lung disease as well as no history of a cardiac conduction block of greater than first-degree AV block, except for patients with functioning artificial pacemakers. In these studies (Studies 1 and 2), 2,015 patients underwent myocardial perfusion imaging after administration of Regadenoson injection (N = 1,337) or ADENOSCAN® (N = 678). The population was 26–93 years of age (median 66 years), 70% male and primarily Caucasian (76% Caucasian, 7% African American, 9% Hispanic, 5% Asian). Table 1 shows the most frequently reported adverse reactions.
Overall, any adverse reaction occurred at similar rates between the study groups (80% for the Regadenoson injection group and 83% for the ADENOSCAN group). Aminophylline was used to treat the reactions in 3% of patients in the Regadenoson injection group and 2% of patients in the ADENOSCAN group. Most adverse reactions began soon after dosing, and generally resolved within approximately 15 minutes, except for headache which resolved in most patients within 30 minutes.
Table 1 Adverse Reactions in Studies 1 and 2 Pooled (Frequency ≥ 5%)
| Regadenoson Injection N = 1,337 | A DENO SCAN N = 678 | |
| Dyspnea | 28% | 26% |
| Headache | 26% | 17% |
| Flushing | 16% | 25% |
| Chest Discomfort | 13% | 18% |
| Angina Pectoris or ST Segment Depression | 12% | 18% |
| Dizziness | 8% | 7% |
| Chest Pain | 7% | 10% |
| Nausea | 6% | 6% |
| Abdominal Discomfort | 5% | 2% |
| Dysgeusia | 5% | 7% |
| Feeling Hot | 5% | 8% |
ECG Abnormalities:
The frequency of rhythm or conduction abnormalities following Regadenoson injection or ADENOSCAN is shown in Table 2 [see Warnings and Precautions (5.2) ].
Table 2 Rhythm or Conduction Abnormalities* in Studies 1 and 2
| Regadenoson Injection N / N evaluable (%) | ADENOSCAN N / N evaluable (%) | |
| Rhythm or conduction abnormalities # | 332/1275 (26%) | 192/645 (30%) |
| Rhythm abnormalities | 260/1275 (20%) | 131/645 (20%) |
| PACs | 86/1274 (7%) | 57/645 (9%) |
| PVCs | 179/1274 (14%) | 79/645 (12%) |
| First-degree AV block (PR prolongation > 220 msec) | 34/1209 (3%) | 43/618 (7%) |
| Second-degree AV block | 1/1209 (0.1%) | 9/618 (1%) |
| AV conduction abnormalities (other than AV blocks) | 1/1209 (0.1%) | 0/618 (0%) |
| Ventricular conduction abnormalities | 64/1152 (6%) | 31/581 (5%) |
* 12-lead ECGs were recorded before and for up to 2 hours after dosing.
# includes rhythm abnormalities (PACs, PVCs, atrial fibrillation/flutter, wandering atrial pacemaker, supraventricular or ventricular arrhythmia) or conduction abnormalities, including AV block.
Respiratory Abnormalities
In a randomized, placebo-controlled trial of 999 patients with asthma (n=532) or stable chronic obstructive pulmonary disease (n=467), the overall incidence of pre-specified respiratory adverse reactions was greater in the Regadenoson injection group compared to the placebo group (p < 0.001). Most respiratory adverse reactions resolved without therapy; a fewpatients received aminophylline or a short-acting bronchodilator. No differences were observed between treatment arms in the reduction of >15% from baseline at two-hours in FEV1 (Table 3).Table 3 Respiratory Adverse Effects*
| Asthma Cohort | Chronic Obstructive Pulmonary Disease (COPD) Cohort | |||
| Regadenoson Injection (N=356) | Placebo (N=176) | Regadenoson Injection (N=316) | Placebo (N=151) | |
| Overall Pre-specified Respiratory Adverse Reaction # | 12.9% | 2.3% | 19.0% | 4.0% |
| Dyspnea | 10.7% | 1.1% | 18.0% | 2.6% |
| Wheezing | 3.1% | 1.1% | 0.9% | 0.7% |
| FEV1 reduction >15% @ | 1.1% | 2.9% | 4.2% | 5.4% |
* All patients continued the use of their respiratory medications as prescribed prior to administration of Regadenoson injection.
# Patients may have reported more than one type of adverse reaction. Adverse reactions were collected up to 24 hours following drug administration. Pre-specified respiratory adverse reactions included dyspnea, wheezing, obstructive airway disorder, dyspnea exertional, and tachypnea.
@ Change from baseline at 2 hours
Renal Impairment
In a randomized, placebo-controlled trial of 504 patients (Regadenoson injection n=334 and placebo n=170) with a diagnosis or risk factors for coronary artery disease and NKFK/DOQI Stage III or IV renal impairment (defined as GFR 15-59 mL/min/1.73 m2), no serious adverse events were reported through the 24-hour follow-up period.
Inadequate Exercise Stress
In an open-label, multi-center trial evaluating Regadenoson injection administration following inadequate exercise stress, 1,147 patients were randomized into one of two groups. Each group underwent two Regadenoson injection stress myocardial perfusion imaging (MPI) procedures. Group 1 received Regadenoson injection 3 minutes following inadequate exercise in the first Regadenoson injection stress (MPI 1). Group 2 rested 1 hour after inadequate exercise to allow hemodynamics to return to baseline prior to receiving Regadenoson injection (MPI 1). Both groups returned for a second stress MPI 1-14 days later and received Regadenoson injection without exercise (MPI 2).
The most common adverse reactions are similar in type and incidence to those in Table 1 above for both Groups. The timing of the administration of Regadenoson injection following inadequate exercise did not alter the common adverse reaction profile.
Table 4 shows a comparison of cardiac events of interest for the two groups [see Warnings and Precautions (5.1) ]. The cardiac events were numerically higher in Group 1.Table 4 Cardiac Events of Interest in Inadequate Exercise Stress Study
| Cardiac Event* | Group 1/MPI 1 Regadenoson Injection 3 minutes following exercise (N=575) | Group 2/MPI 1 Regadenoson Injection 1 hour following exercise (N=567) |
| 17 (3.0%) | 3 (0.5%) | |
| Holter/12-Lead ECG Abnormality | ||
| ST-T Depression (≥ 2 mm) | 13 (2.3%) | 2 (0.4%) |
| ST-T Elevation (≥ 1 mm) | 3 (0.5%) | 1 (0.2%) |
| Acute coronary syndrome | 1 (0.2%) | 0 |
| Myocardial infarction | 1 (0.2%) | 0 |
*A clinically significant cardiac event was defined as any of the following events found on the Holter ECG/12-lead ECGwithin one hour after regadenoson administration: ventricular arrhythmias (sustained ventricular tachycardia, ventricularfibrillation, Torsade de Pointes, ventricular flutter); ST-T depression (≥ 2 mm); ST-T elevation (≥ 1 mm); AV block (2:1 AV block, AV Mobitz I, AV Mobitz II, complete heart block); sinus arrest > 3 seconds in durationOr
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