Lexiscan - Regadenoson injection, Solution

Dosage and Administration (

Warnings and Precautions, Myocardial Ischemia (

LEXISCAN^® (regadenoson) injection is a pharmacologic stress agent indicated for radionuclide myocardial perfusion imaging (MPI) in patients unable to undergo adequate exercise stress.

• •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 DRUG INTERACTIONS

  No formal pharmacokinetic drug interaction studies have been conducted with LEXISCAN.

  • •Methylxanthines, e.g., caffeine, aminophylline and theophylline, interfere with the activity of LEXISCAN .
  • •Aminophylline may be used to attenuate severe and/or persistent adverse reactions to LEXISCAN .
  • •Dipyridamole may increase the activity of LEXISCAN. When possible, withhold dipyridamole for at least two days prior to LEXISCAN administration .

  7.1 Effects of Other Drugs on LEXISCAN

  • •Methylxanthines (e.g., caffeine, aminophylline and theophylline) are non-specific adenosine receptor antagonists that interfere with the vasodilation activity of LEXISCAN [
    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 LEXISCAN administration. Aminophylline may be used to attenuate severe or persistent adverse reactions to LEXISCAN [
    see Overdosage
    ].
  • •In clinical studies, LEXISCAN 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 LEXISCAN. When possible, withhold dipyridamole for at least two days prior to LEXISCAN administration.

  7.2 Effect of LEXISCAN on Other Drugs

  Regadenoson does not inhibit the metabolism of substrates for CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 in human liver microsomes, indicating that it is unlikely to alter the pharmacokinetics of drugs metabolized by these cytochrome P450 enzymes.

  (

  7.1 Effects of Other Drugs on LEXISCAN

  • •Methylxanthines (e.g., caffeine, aminophylline and theophylline) are non-specific adenosine receptor antagonists that interfere with the vasodilation activity of LEXISCAN [
    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 LEXISCAN administration. Aminophylline may be used to attenuate severe or persistent adverse reactions to LEXISCAN [
    see Overdosage
    ].
  • •In clinical studies, LEXISCAN 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 LEXISCAN. When possible, withhold dipyridamole for at least two days prior to LEXISCAN administration.

  ) and

  12 CLINICAL PHARMACOLOGY

  12.1 Mechanism of Action

  Regadenoson is a low affinity agonist (K_i≈ 1.3 µM) for the A_2Aadenosine receptor, with at least 10-fold lower affinity for the A₁adenosine receptor (K_i> 16.5 µM), and weak, if any, affinity for the A_2Band A₃adenosine receptors. Activation of the A_2Aadenosine receptor by regadenoson produces coronary vasodilation and increases coronary blood flow (CBF).

  12.2 Pharmacodynamics

  Coronary Blood Flow

  LEXISCAN 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

  ].

  Myocardial uptake of the radiopharmaceutical is proportional to CBF. Because LEXISCAN increases blood flow in normal coronary arteries with little or no increase in stenotic arteries, LEXISCAN causes relatively less uptake of the radiopharmaceutical in vascular territories supplied by stenotic arteries. MPI intensity after LEXISCAN 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 LEXISCAN in patients undergoing cardiac catheterization, was shown to shorten the duration of the coronary blood flow response to LEXISCAN as measured by pulsed-wave Doppler ultrasonography [

  see Overdosage

  ].

  Effect of Caffeine

  Ingestion 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 LEXISCAN 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 LEXISCAN. Maximum hemodynamic changes after LEXISCAN and ADENOSCAN in Studies 1 and 2 are summarized in Table 5.

  Table 5 Hemodynamic Effects in Studies 1 and 2

  Vital Sign Parameter	LEXISCAN 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, LEXISCAN was administered for MPI following inadequate exercise stress. More patients with LEXISCAN administration three minutes following inadequate exercise stress had an increase in heart rate and a decrease in systolic blood pressure compared with LEXISCAN 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 LEXISCAN 3 minutes following exercise (N=575)	Group 2 / MPI 1 LEXISCAN 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 LEXISCAN compared to placebo. Moderate (2.5%) or severe (< 1%) respiratory reactions were observed more frequently in the LEXISCAN group compared to placebo [

  see Adverse Reactions

  ].

  12.3 Pharmacokinetics

  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 LEXISCAN 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

  ]. 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.

  Specific 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.

  (

  12.2 Pharmacodynamics

  Coronary Blood Flow

  LEXISCAN 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

  ].

  Myocardial uptake of the radiopharmaceutical is proportional to CBF. Because LEXISCAN increases blood flow in normal coronary arteries with little or no increase in stenotic arteries, LEXISCAN causes relatively less uptake of the radiopharmaceutical in vascular territories supplied by stenotic arteries. MPI intensity after LEXISCAN 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 LEXISCAN in patients undergoing cardiac catheterization, was shown to shorten the duration of the coronary blood flow response to LEXISCAN as measured by pulsed-wave Doppler ultrasonography [

  see Overdosage

  ].

  Effect of Caffeine

  Ingestion 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 LEXISCAN 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 LEXISCAN. Maximum hemodynamic changes after LEXISCAN and ADENOSCAN in Studies 1 and 2 are summarized in Table 5.

  Table 5 Hemodynamic Effects in Studies 1 and 2

  Vital Sign Parameter	LEXISCAN 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, LEXISCAN was administered for MPI following inadequate exercise stress. More patients with LEXISCAN administration three minutes following inadequate exercise stress had an increase in heart rate and a decrease in systolic blood pressure compared with LEXISCAN 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 LEXISCAN 3 minutes following exercise (N=575)	Group 2 / MPI 1 LEXISCAN 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 LEXISCAN compared to placebo. Moderate (2.5%) or severe (< 1%) respiratory reactions were observed more frequently in the LEXISCAN 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 LEXISCAN if it contains particulate matter or is discolored.
• •Administer LEXISCAN 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 LEXISCAN.
• •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 LEXISCAN.

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

There are no available data on LEXISCAN use in pregnant women to inform a drug-associated risk. In animal reproduction studies, adverse developmental outcomes were observed with the administration of regadenoson to pregnant rats and rabbits during organogenesis only at doses that produced maternal toxicity (

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Reproductive studies in rats showed that regadenoson doses 10 and 20 times the maximum recommended human dose (MRHD) based on body surface area caused reduced fetal body weights and significant ossification delays in fore- and hind limb phalanges and metatarsals; maternal toxicity also occurred at these doses. Skeletal variations were increased in all treated groups. In rabbits, maternal toxicity occurred at regadenoson doses administered during organogenesis at 4 times the MRHD; however, there were no teratogenic effects in offspring at this dose. At higher doses, 12 and 20 times the MRHD, maternal toxicity occurred along with increased embryo-fetal loss and fetal malformations.