(regadenoson injection)
The following adverse reactions are discussed in more detail in other sections of the labeling.
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 adenosine injection (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 adenosine injection group). Aminophylline was used to treat the reactions in 3% of patients in the regadenoson injection group and 2% of patients in the adenosine injection 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.
| Regadenoson Injection N = 1,337 | Adenosine Injection 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 adenosine injection is shown in Table 2 [see Warnings and Precautions (5.2)].
| Regadenoson Injection N/N evaluable (%) | Adenosine Injection N/N evaluable (%) | |
|---|---|---|
Rhythm or conduction abnormalities† | 332/1,275 (26%) | 192/645 (30%) |
Rhythm abnormalities | 260/1,275 (20%) | 131/645 (20%) |
PACs | 86/1,274 (7%) | 57/645 (9%) |
PVCs | 179/1,274 (14%) | 79/645 (12%) |
First-degree AV block (PR prolongation > 220 msec) | 34/1,209 (3%) | 43/618 (7%) |
Second-degree AV block | 1/1,209 (0.1%) | 9/618 (1%) |
AV conduction abnormalities (other than AV blocks) | 1/1,209 (0.1%) | 0/618 (0%) |
Ventricular conduction abnormalities | 64/1,152 (6%) | 31/581 (5%) |
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 few patients 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).
| 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% |
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.
| 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 |
The following adverse reactions have been reported from worldwide marketing experience with regadenoson. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Cardiovascular
Myocardial infarction, cardiac arrest, ventricular arrhythmias, supraventricular tachyarrhythmias including atrial fibrillation with rapid ventricular response (new-onset or recurrent), atrial flutter, heart block (including third-degree block), asystole, marked hypertension, symptomatic hypotension in association with transient ischemic attack, acute coronary syndrome (ACS), seizures and syncope [see Warnings and Precautions (5.1), (5.2), (5.3), (5.5), (5.6) and (5.8)] have been reported. Some events required intervention with fluids and/or aminophylline [see Overdosage (10)]. QTc prolongation shortly after regadenoson injection administration has been reported.
Central Nervous System
Tremor, seizure, transient ischemic attack, and cerebrovascular accident including intracranial hemorrhage [see Warnings and Precautions (5.8) and (5.9)].
Gastrointestinal
Abdominal pain, occasionally severe, has been reported a few minutes after regadenoson injection administration, in association with nausea, vomiting, or myalgias; administration of aminophylline, an adenosine antagonist, appeared to lessen the pain. Diarrhea and fecal incontinence have also been reported following regadenoson injection administration.
Hypersensitivity
Anaphylaxis, angioedema, cardiac or respiratory arrest, respiratory distress, decreased oxygen saturation, hypotension, throat tightness, urticaria, rashes have occurred and have required treatment including resuscitation [see Warnings and Precautions (5.4)].
Musculoskeletal
Musculoskeletal pain has occurred, typically 10–20 minutes after regadenoson injection administration; the pain was occasionally severe, localized in the arms and lower back and extended to the buttocks and lower legs bilaterally. Administration of aminophylline appeared to lessen the pain.
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