Regadenoson .08 mg/mL Injection, Solution — NDC 68083-175-10 (Billing 68083-0175-10)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Regadenoson is a low affinity agonist (K i ≈ 1.3 μM) for the A 2A adenosine receptor, with at least 10- fold lower affinity for the A 1 adenosine receptor (K i > 16.5 μM), and weak, if any, affinity for the A 2B and A 3 adenosine receptors. Activation of the A 2A adenosine receptor by regadenoson produces coronary vasodilation and increases coronary blood flow (CBF).

12.2Pharmacodynamics 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 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 subjects 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 I n a clinical study, Regadenoson injection was administered for MPI following inadequate exercise stress.

More patients with Regadenoson injection administr… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Regadenoson is a low affinity agonist (K i ≈ 1.3 μM) for the A 2A adenosine receptor, with at least 10- fold lower affinity for the A 1 adenosine receptor (K i > 16.5 μM), and weak, if any, affinity for the A 2B and A 3 adenosine receptors. Activation of the A 2A adenosine receptor by regadenoson produces coronary vasodilation and increases coronary blood flow (CBF).

12.3Pharmacokinetics In healthy subjects, the regadenoson plasma concentration-time profile is multi-exponential in nature and best characterized by 3-compartment model. The maximal plasma concentration of regadenoson is achieved within 1 to 4 minutes after injection of Regadenoson injection and parallels the onset of the pharmacodynamic response. The half-life of this initial phase is approximately 2 to 4 minutes.

An intermediate phase follows, with a half-life on average of 30 minutes coinciding with loss of the pharmacodynamic effect. The terminal phase consists of a decline in plasma concentration with a half-life of approximately 2 hours [see Clinical Pharmacology (12.2)]. Within the dose range of 0.3–20 μg/kg in healthy subjects, clearance, terminal half-life or volume of distribution do not appear dependent upon the dose.

A population pharmacokinetic analysis including data from subjects and patients demonstrated that regadenoson clearance decreases in parallel with a reduction in creatinine clearance and clearance increases with increased body weight. Age, gender, and race have minimal effects on the pharmacokinetics of regadenoson. Special Populations Renally Impaired Patients: The disposition of regadenoson was studied in 18 patients with various degrees of renal function and in 6 healthy subjects.

With increasing renal impairment, from mild (CLcr 50 to < 80 mL/min) to moderate (CLcr 30 to < 50 mL/min) to severe renal impairment (CLcr < 30 mL/min), the fraction of regadenoson excreted unchanged in urine and the renal clearance decreased, resulting in increased elimination half-lives and AUC values compared to healthy subjects (CLcr ≥ 80 mL/min). However, the maximum observed plasma concentrations as well as volumes of distribution estimates were similar across the groups. The plasma concentration-time profiles were not significantly altered in the early stages after dosing when most pharmacologic effects are observed.

No dose adjustment is needed in patients with renal impairment. Patients with End Stage Renal Disease: The pharmacokinetics of regadenoson in patients on dialysis has not been assessed; however, in an in vitro study regadenoson was found to be dialyzable. Hepatically Impaired Patients : The influence of hepatic impairment on the pharmacokinetics of regadenoson has not been evaluated.

Because greater than 55% of the dose is excreted in the urine as unchanged drug and factors that decrease clearance do not affect the plasma concentration in the early stages after dosing when clinically meaningful pharmacologic effects are observed, no dose adjustment is needed in patients with hepatic impairment. Geriatric Patients : Based on a population pharmacokinetic analysis, age has a minor influence on the pharmacokinetics of regadenoson. No dose adjustment is needed in elderly patients.

Metabolism The metabolism of regadenoson is unknown in humans. Incubation with rat, dog, and human liver microsomes as well as human hepatocytes produced no detectable metabolites of regadenoson. Excretion In healthy volunteers, 57% of the regadenoson dose is excreted unchanged in the urine (range 19–77%), with an average plasma renal clearance around 450 mL/min, i.e., in excess of the glomerular filtration rate.

This indicates that renal tubular secretion plays a role in regadenoson elimination.

12.2Pharmacodynamics 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 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 subjects 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 I n 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/MP1… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES Agreement between Regadenoson injection and ADENOSCAN The efficacy and safety of Regadenoson injection were determined relative to ADENOSCAN in two randomized, double-blind studies (Studies 1 and 2) in 2,015 patients with known or suspected coronary artery disease who were indicated for pharmacologic stress MPI. A total of 1,871 of these patients had images considered valid for the primary efficacy evaluation, including 1,294 (69%) men and 577 (31%) women with a median age of 66 years (range 26–93 years of age).

Each patient received an initial stress scan using ADENOSCAN (6-minute infusion using a dose of 0.14 mg/kg/min, without exercise) with a radionuclide gated SPECT imaging protocol. After the initial scan, patients were randomized to either Regadenoson injection or ADENOSCAN, and received a second stress scan with the same radionuclide imaging protocol as that used for the initial scan. The median time between scans was 7 days (range of 1–104 days).

The most common cardiovascular histories included hypertension (81%), CABG, PTCA or stenting (51%), angina (63%), and history of myocardial infarction (41%) or arrhythmia (33%); other medical history included diabetes (32%) and COPD (5%). Patients with a recent history of serious uncontrolled ventricular arrhythmia, myocardial infarction, or unstable angina, a history of greater than first-degree AV block, or with symptomatic bradycardia, sick sinus syndrome, or a heart transplant were excluded. A number of patients took cardioactive medications on the day of the scan, including β-blockers (18%), calcium channel blockers (9%), and nitrates (6%).

In the pooled study population, 68% of patients had 0–1 segments showing reversible defects on the initial scan, 24% had 2–4 segments, and 9% had ≥ 5 segments. Comparison of the images obtained with Regadenoson injection to those obtained with ADENOSCAN was performed as follows. Using the 17-segment model, the number of segments showing a reversible perfusion defect was calculated for the initial ADENOSCAN study and for the randomized study obtained using Regadenoson injection or ADENOSCAN.

The agreement rate for the image obtained with Regadenoson injection or ADENOSCAN relative to the initial ADENOSCAN image was calculated by determining how frequently the patients assigned to each initial ADENOSCAN category (0–1, 2–4, 5–17 reversible segments) were placed in the same category with the randomized scan. The agreement rates for Regadenoson injection and ADENOSCAN were calculated as the average of the agreement rates across the three categories determined by the initial scan. Studies 1 and 2 each demonstrated that Regadenoson injection is similar to ADENOSCAN in assessing the extent of reversible perfusion abnormalities (Table 7).

Table 7 Agreement Rates in Studies 1 and 2 Study 1 Study 2 ADENOSCAN – ADENOSCAN Agreement Rate (± SE) 61 ± 3% 64 ± 4% ADENOSCAN – Regadenoson injection Agreement Rate (±SE) 62 ± 2% 63 ± 3% Rate Difference (Regadenoson injection– ADENOSCAN) (± SE) 95% Confidence Interval 1 ± 4% -7.5, 9.2% -1 ± 5% -11.2, 8.7% Use of Regadenoson injection in Patients with Inadequate Exercise Stress The efficacy and safety of Regadenoson injection administered 3 minutes (Group 1) or 1 hour (Group 2) following inadequate exercise stress were evaluated in an open-label randomized, multi-center, non-inferiority study.

Adequate exercise was defined as ≥ 85% maximum predicted heart rate and ≥ 5 METS. SPECT MPI was performed 60-90 minutes after Regadenoson injection administration in each group (MPI 1). Patients returned 1-14 days later to undergo a second stress MPI with Regadenoson injection without exercise (MPI 2).

All patients were referred for evaluation of coronary artery disease. Of the 1,147 patients randomized, a total of 1,073 patients received Regadenoson injection and had interpretable SPECT scans at all visits; 538 in Group 1 and 535 in Group 2. The median age of the patients was 62 years (range 28 to… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Regadenoson was negative in the Ames bacterial mutation assay, chromosomal aberration assay in Chinese hamster ovary (CHO) cells, and mouse bone marrow micronucleus assay. Long-term animal studies have not been conducted to evaluate Regadenoson injection's carcinogenic potential or potential effects on fertility.

13.2Animal Toxicology and /or Pharmacology Cardiomyopathy : Minimal cardiomyopathy (myocyte necrosis and inflammation) was observed in rats following single-dose administration of regadenoson . Increased incidence of minimal cardiomyopathy was observed on day 2 in males at doses of 0.08, 0.2 and 0.8 mg/kg (1/5, 2/5, and 5/5) and in females (2/5) at 0.8 mg/kg. In a separate study in male rats, the mean arterial pressure was decreased by 30 to 50% of baseline values for up to 90 minutes at regadenoson doses of 0.2 and 0.8 mg/kg, respectively.

No cardiomyopathy was noted in rats sacrificed 15 days following single administration of regadenoson. The mechanism of the cardiomyopathy induced by regadenoson was not elucidated in this study but was associated with the hypotensive effects of regadenoson. Profound hypotension induced by vasoactive drugs is known to cause cardiomyopathy in rats.

Local Irritation : Intravenous administration of Regadenoson injection to rabbits resulted in perivascular hemorrhage, vein vasculitis, inflammation, thrombosis and necrosis, with inflammation and thrombosis persisting through day 8 (last observation day). Perivascular administration of Regadenoson injection to rabbits resulted in hemorrhage, inflammation, pustule formation and epidermal hyperplasia, which persisted through day 8 except for the hemorrhage which resolved. Subcutaneous administration of Regadenoson injection to rabbits resulted in hemorrhage, acute inflammation, and necrosis; on day 8 muscle fiber regeneration was observed.