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英文药名：Lexiscan(Regadenoson Injection) 中文药名：瑞加德松预灌封注射器 生产厂家： 安斯泰来制药美国公司
The frequency of rhythm or conduction abnormalities following Lexiscan or Adenoscan is shown in Table 2 [see Warnings and Precautions (5.2)]. Table 2 Rhythm or Conduction Abnormalities* in Studies 1 and 2
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 (Study 3) of 999 subjects 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 Lexiscan group compared to the placebo group (p < 0.001). Most respiratory adverse reactions resolved without therapy; a few subjects 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 in Study 3*
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 subjects (Lexiscan 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. 6.2 Post-Marketing Experience 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, 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 Lexiscan 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 Lexiscan 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 Lexiscan 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 Lexiscan 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. Respiratory Respiratory arrest, dyspnea and wheezing have been reported following Lexiscan administration. 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 Lexiscan exposure. 7 DRUG INTERACTIONS No formal pharmacokinetic drug interaction studies have been conducted with Lexiscan. 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 (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 Lexiscan administration. Aminophylline may be used to attenuate severe or persistent adverse reactions to Lexiscan [ see Overdosage (10)]. • 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. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C: There are no adequate well-controlled studies with Lexiscan in pregnant women. Lexiscan should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus. 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; however, maternal toxicity also occurred at these doses. Skeletal variations were increased in all treated groups. In rabbits, there were no teratogenic effects in offspring at regadenoson doses 4 times the MRHD, although signs of maternal toxicity occurred at this dose. At regadenoson doses equivalent to 12 and 20 times the MRHD, maternal toxicity occurred along with increased embryo-fetal loss and fetal malformations. It is not clear whether malformations that occurred at maternally toxic doses of regadenoson in both animal species were due to fetal drug effects or only to the maternal toxic effects. Because animals received repeated doses of regadenoson, their exposure was significantly higher than that achieved with the standard single dose administered to humans [see Nonclinical Toxicology (13.2)]. 8.3 Nursing Mothers It is not known whether Lexiscan is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from Lexiscan in nursing infants, the decision to interrupt nursing after administration of Lexiscan or not to administer Lexiscan, should take into account the importance of the drug to the mother. Based on the pharmacokinetics of Lexiscan, it should be cleared 10 hours after administration. Therefore, nursing women may consider interrupting nursing for 10 hours after administration. 8.4 Pediatric Use Safety and effectiveness in pediatric patients (< 18 years of age) have not been established. 8.5 Geriatric Use Of the 1,337 patients receiving Lexiscan in Studies 1 and 2, 56% were 65 years of age and over and 24% were 75 years of age and over. Older patients (> 75 years of age) had a similar adverse event profile compared to younger patients (< 65 years of age), but had a higher incidence of hypotension (2% vs. ≤ 1%). 8.6 Renal Impairment Lexiscan was assessed in a randomized, placebo-controlled trial of patients with NKFK/DOQI Stage III or IV renal impairment (defined as a GFR 15-59 mL/min/1.73 m2). No serious adverse events were reported through the 24-hour follow-up period [see Adverse Reactions (6.1)]. 10 OVERDOSAGE Lexiscan overdosage may result in serious reactions [see Warnings and Precautions (5)]. In a study of healthy volunteers, symptoms of flushing, dizziness and increased heart rate were assessed as intolerable at Lexiscan doses greater than 0.02 mg/kg. Aminophylline to Reverse Effects Methylxanthines, such as caffeine, aminophylline, and theophylline, are competitive adenosine receptor antagonists and aminophylline has been used to terminate persistent pharmacodynamic effects. Aminophylline may be administered in doses ranging from 50 mg to 250 mg by slow intravenous injection (50 mg to 100 mg over 30–60 seconds). Methylxanthine use is not recommended in patients who experience a seizure in association with Lexiscan administration. 11 DESCRIPTION Regadenoson is an A2A adenosine receptor agonist that is a coronary vasodilator [see Clinical Pharmacology (12.1)]. Regadenoson is chemically described as adenosine, 2-[4-[(methylamino)carbonyl]-1H-pyrazol-1-yl]-, monohydrate. Its structural formula is:
The A2B and A3 adenosine 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 A2B and A3 adenosine receptors. In a randomized, placebo-controlled clinical trial (Study 3) of 999 subjects 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 (6.1)]. 12.3 Pharmacokinetics In healthy volunteers, 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 (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 subjects 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. 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. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, 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 Lexiscan's carcinogenic potential or potential effects on fertility. 13.2 Animal Toxicology and/or Pharmacology Reproductive Toxicology Studies Reproduction studies were conducted in rabbits and rats using doses of Lexiscan that were 2 to 20 times (rats) and 4 to 20 times (rabbits) the maximum recommended human dose (MRHD), based on body surface area comparison. When administered to rabbits during organogenesis, regadenoson caused maternal toxicity including tachypnea, soft, liquid or scant feces, and localized alopecia in all treated groups, and caused reduction in body weight and feed consumption at 0.3 and 0.5 mg/kg/day (12 and 20 X MRHD, respectively). At regadenoson doses equivalent to 12 and 20 times the MRHD, maternal toxicity occurred along with decreased number of live fetuses, reduced fetal body weight, and occurrence of fetal variations and malformations. At regadenoson doses equivalent to 20 times the MRHD, resorptions were increased and fetal body weights reduced. Fetal malformations included microphthalmia (1/116 at 20 X MRHD), interrelated vertebrae/rib alterations (2/145 and 2/116 each at 12 and 20 X MRHD), and misaligned caudal vertebrae (3/145 at 12 X MRHD). Fetal toxicity was only observed at maternally toxic doses. The no effect dose level for fetal toxicity is 0.1 mg/kg (4 X MRHD). A no effect dose level was not identified for maternal toxicity. When regadenoson was administered to pregnant rats during the period of major organogenesis, 4/25 rats from the 1.0 mg/kg/day group (20 X MRHD) and 1/25 rats from the 0.8 mg/kg (16 X MRHD) group died immediately following the first dose of regadenoson. All dams had decreased motor activity and one was gasping post-dosing. At doses ≥ 0.5 mg/kg (10 X MRHD), maternal toxicity included decreased motor activity, increased limb extension, excess salivation, and reduction in body weight and feed consumption. At doses ≥ 0.5 mg/kg, fetal body weights were significantly reduced and significant ossification delays were observed in fore- and hind limb phalanges and metatarsals. Skeletal malformations included delayed ossification of the skull (1/167), and hemivertebra present at a thoracic vertebra (1/167), observed at 16-20 X MRHD, and small arches of a lumbar and sacral vertebrae (1/174) observed at 2 X MRHD. The no effect dose level for maternal toxicity is 0.1 mg/kg/day (2 X MRHD). 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 Lexiscan 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 Lexiscan 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 Lexiscan to rabbits resulted in hemorrhage, acute inflammation, and necrosis; on day 8 muscle fiber regeneration was observed. 14 CLINICAL STUDIES The efficacy and safety of Lexiscan 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 Lexiscan 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. Image Agreement Comparison of the images obtained with Lexiscan 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 Lexiscan or Adenoscan. The agreement rate for the image obtained with Lexiscan 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 Lexiscan 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 Lexiscan is similar to Adenoscan in assessing the extent of reversible perfusion abnormalities (Table 5). Table 5 Agreement Rates in Studies 1 and 2
Lexiscan is supplied as a sterile, preservative-free solution containing 0.08 mg/mL regadenoson in the following package: • Single-use 5 mL pre-filled plastic Ansyr ® syringes with luer-lock fitting (NDC 0469-6501-89). Store at controlled room temperature, 25°C (77°F); excursions permitted to 15° to 30°C (59°–86°F). 17 PATIENT COUNSELING INFORMATION Advise patients that they may be at increased risk of fatal and nonfatal heart attacks, abnormal heart rhythms, cardiac arrest, significant increase or decrease in blood pressure, hypersensitivity reactions, seizures, bronchoconstriction, or cerebrovascular accidents (stroke) with the use of Lexiscan [see Warnings and Precautions (5.1), (5.3), (5.4), (5.5), (5.6), (5.8) and (5.9)]. 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. Question patients about a history of seizures. Prior to Lexiscan administration, patients should be informed of the most common reactions (such as shortness of breath, headache and flushing) that have been reported in association with Lexiscan during MPI. Patients with COPD or asthma should be informed to discuss their respiratory history and administration of pre-and post-study bronchodilator therapy with their clinician before scheduling an MPI study with Lexiscan. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=057289f4-2e18-4c1e-bed4-6c1858e2ef16 心血管造影剂瑞加德松（Lexiscan）被列入FDA观察名单 美国食品药品管理局（FDA）已将瑞加德松(Lexiscan, 阿斯特拉斯制药美国) 列入其最新的监控产品季度名单，该药物是一种心血管造影剂，有潜在的心肌梗死 (MI) 和死亡风险迹象，FDA 于上个月这样宣布说。 瑞加德松（Regadenoson）是一种选择性腺苷受体激动剂，可使冠状动脉产生舒张。这款药物用于不能接受运动压力测试患者的放射性核素心肌灌注显像。临床医师也超适用症将其用于CT影像。 FDA通过其不良事件报告系统 (FAERS) 数据库收到报告称在2013年第二季度期间，瑞加德松可能与心肌梗死和死亡有关联。自从这款药物于2008年获得FDA批准，其标签内容中已加入了心肌梗死风险警告。 FDA提醒，不能仅因为FDA将一款药物加入其观察名单就认为FDA已经断定这款药物能造成所报道的健康风险。当然，FDA将调查这之间是否确实存在因果关系。如果答案属实，FDA将考虑作出回应，如收集更多数据以更好地描述风险，修订药物的标签，或要求一个风险评估和减灾战略。 FDA一直强调，将一款药物列入观察名单不表明临床医师应该停止使用这款药物，或患者应该停止使用这款药物。瑞加德松在2011年时，因其可能的QT间期延长信号也曾被列入观察名单。这款药物的标签内容中一直有警告提示其存在危及生命的室性心律失常风险。 --------------------------------------------- 产地国家: 美国 原产地英文商品名: LEXISCAN injection 0.4mg/5ml(0.08mg/mL)/syringes 1vial 原产地英文药品名: REGADENOSON 中文参考商品译名: LEXISCAN 0.4毫克/5毫升（0.08毫克/毫升）/注射器 1瓶 中文参考药品译名: 瑞加德松 生产厂家中文参考译名: 安斯泰来制药美国公司 生产厂家英文名: Astellas | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
