中文名称：甲磺酸非诺多泮 中文别名：6-氯-2,3,4,5-四氢-1-(4-羟苯基)-1H-3-苯并氮杂卓-7,8-二醇甲磺酸盐 英文名称：Fenoldopam mesylate 英文别名：8-Chloro-2-(4-hydroxyphenyl)-4-azabicyclo[5.4.0]undeca-7,9,11-triene-9,10-diol methanesulphonate 用途：非诺多泮可以增加去甲肾上腺素的血浆浓度。主要刺激DA1受体诱导小动脉扩张。既可降低动脉压，又可扩张肾血管致肾血流增加。 药理作用：非诺多泮是一快速作用的血管扩张剂，是 DA1 受体激动剂，与 α2- 肾上腺素受体有中度结合力，与 DA2 、 α1 和 β 肾上腺素受体、 5HT1 和 5HT2 受体或毒覃碱受体没有明显亲和力。非诺多泮是一种消旋混合物， R －异构体具有生物活性。 R- 异构体与 DA1 受体的亲和力较 S- 异构体高 250 倍。非诺多泮研究中，本品对突触前 DA2 受体、 α 或 β- 肾上腺素受体没有亲和力，对血管紧张素转化酶也无活性。非诺多泮可以增加去甲肾上腺素的血浆浓度。 　　本品主要刺激 DA1 受体诱导小动脉扩张。既可降低动脉压，又可扩张肾血管致肾血流增加。此外，本品作用于肾小细胞，具有直接的促尿钠排泄和利尿特性，特别是对高血压病人此作用更为明显。 　　本品静脉注射起效时间约为 5 分钟，约 20 分钟达到稳态血药浓度，经肝脏迅速代谢为无活性代谢产物，而后大部分由尿排泄，血浆清除半衰期约为 5 分钟。 适应症：严重高血压的紧急短期处理。 项目概述：一项随机双盲、安慰剂 对照研究中， 32 名轻中度原发性高血压患者（舒张期血压在 95-119mmHg 之间）分为 5 组，患者的平均基础血压 154/98mmHg ，心率为 75 下 / 分钟，以恒定的速率静脉滴注非诺多泮，收缩期和舒张期血压产生剂量相关性减少。以固定速率滴注 48 小时。所有滴速均快速产生反应，所有试验组中 15 分钟产生的效应是 1 小时时产生效应的 50 － 100 ％。在两个高剂量组中 48 小时时产生部分耐受，但是实质性影响持续至 48 小时。当滴注停止后血压渐渐恢复至治疗前水平，并未出现反跳现象。这一研究表明以 0.8μg/kg/min 的速率滴注并不比 0.4μg/kg/min 速率滴注反应强。 　　一项多中心、随机、双盲比较试验中， 94 名高血压急症患者（定义为舒张压 ≥120mmHg ，伴有末端器官损害，包括心血管、肾脏、大脑和视网膜系统）以 4 种速率（ 0.01 、 0.03 、 0.1 、 0.3μg/kg/min ）静脉滴注非诺多泮 24 小时。如果临床允许，在滴注后 1 小时滴速可加倍。结果显示收缩压和舒张压出现剂量依赖性快速降低，心率增加。 　　一项有 153 例严重高血压（舒张压 ≥16kPa ）病人参与的随机开放性多中心研究发现，本品与硝普钠疗效相仿。本品灌注引起的剂量相关性动脉压降低可达 24 小时，未见耐受性方面的不良反应，也未见停药反跳现象和明显的心率变化。对某些严重高血压伴肾功能损害的病人，本品可改善其肾功能。本品还可降低接受心脏或非心脏外科手术病人的术后高血压，能维持或增加排尿量。 市场分析：近些年，严重高血压的治疗在临床上越来越受到关注和重视，成为心血管科医生和新药开发机构研究的重要目标。目前，国内临床上常用的此类药物主要是硝普钠。但是，硝普钠在临床使用过程中存在很多问题，给患者和医生带来极大的不方便。如在使用硝普钠过程中可出现不同程度的恶心、呕吐、精神不安、肌肉痉挛、头痛、厌食、皮疹、出汗、发热等。长期或大量使用，特别是在肾功能衰竭病人中，可能引起硫氰化物蓄积而导致甲状腺功能减退，甚至出现险峻的低血压症。突然停药可出现反跳现象。再加上硝普钠性质不稳定，使用过程中见光易变质，这些缺点在很大程度上限制了它的使用。而非诺多泮由于性质稳定、疗效可靠，安全性高、不良反应甚微等优势在上市后的短短两年间就被收载进了美国药典（ USP ） 24 版（ 2000 年）增补版。总之，随着严重高血压的发病人群不断扩增，随着人们对严重高血压的认识不断加深，非诺多泮必将作为治疗该病的一线药物取代硝普钠的市场。 原产地英文商品名: FENOLDOPAM(Corlopam GENERIC)10mg/ml/ampule 原产地英文药品名: FENOLDOPAM MESYLATE 原产地英文化合物名称: 8-Chloro-2-(4-hydroxyphenyl)-4-azabicyclo[5.4.0]undeca-7,9,11-triene-9,10-diol methanesulphonate 中文参考商品译名: 非诺多泮(Corlopam仿制药)10毫克/毫升/安醅 中文参考药品译名: 甲磺酸非诺多泮 中文参考化合物名称: 6-氯-2,3,4,5-四氢-1-(4-羟苯基)-1H-3-苯并氮杂卓-7,8-二醇甲磺酸盐 Fenoldopam Generic Name: Fenoldopam mesylate Dosage Form: injection Fenoldopam MESYLATE INJECTION USP Rx ONLY Fenoldopam Description  Fenoldopam Mesylate Injection USP is a dopamine D1-like receptor agonist. The product is formulated as a solution to be diluted for intravenous infusion. Chemically it is 6-chloro-2,3,4,5-tetrahydro-1-(p-hydroxy-phenyl)-1H-3-benzazepine-7,8-diol methanesulfonate (salt) with the following structure: Fenoldopam mesylate is a white to off-white powder with a molecular weight of 401.87 and a molecular formula of C17H20CINO6S. It is sparingly soluble in water, ethanol and methanol, and is soluble in propylene glycol. Each mL contains, in sterile aqueous solution, citric acid 3.44 mg; Fenoldopam mesylate equivalent to Fenoldopam 10 mg; propylene glycol 518 mg; sodium citrate dihydrate 0.61 mg; sodium metabisulfite 1 mg. The pH range is 2.8 to 3.8. Fenoldopam - Clinical Pharmacology Mechanism of Action Fenoldopam is a rapid-acting vasodilator. It is an agonist for D1-like dopamine receptors and binds with moderate affinity to α2-adrenoceptors. It has no significant affinity for D2-like receptors, α1 and β adrenoceptors, 5HT1 and 5HT2 receptors, or muscarinic receptors. Fenoldopam is a racemic mixture with the R-isomer responsible for the biological activity. The R-isomer has approximately 250-fold higher affinity for D1-like receptors than does the S-isomer. In non-clinical studies, Fenoldopam had no agonist effect on presynaptic D2-like dopamine receptors, or α- or β-adrenoceptors, nor did it affect angiotensin-converting enzyme activity. Fenoldopam may increase norepinephrine plasma concentration. In animals, Fenoldopam has vasodilating effects in coronary, renal, mesenteric and peripheral arteries. All vascular beds, however, do not respond uniformly to Fenoldopam. Vasodilating effects have been demonstrated in renal efferent and afferent arterioles. Pharmacokinetics Adult Patients: Fenoldopam, administered as a constant infusion at dosages of 0.01 to 1.6 mcg/kg/min, produced steady-state plasma concentrations that were proportional to infusion rates. The elimination half-life was about 5 minutes in mild to moderate hypertensives, with little difference between the R (active) and S isomers. Steady state concentrations are attained in about 20 minutes (4 half-lives). The steady state plasma concentrations of Fenoldopam, at comparable infusion rates, were similar in normotensive subjects and in patients with mild to moderate hypertension or hypertensive emergencies. The pharmacokinetics of Fenoldopam were not influenced by age, gender, or race in adult patients with a hypertensive emergency. There have been no formal drug-drug interaction studies using intravenous Fenoldopam. Clearance of parent (active) Fenoldopam is not altered in adult patients with end-stage renal disease on continuous ambulatory peritoneal dialysis (CAPD) and is not altered in adult patients with severe hepatic failure. The effects of hemodialysis on the pharmacokinetics of Fenoldopam have not been evaluated. Pediatric Patients: Information related to the pharmacokinetics of Fenoldopam injection in pediatric patients is approved for Abbott Laboratories’ Fenoldopam drug products. However, due to Abbott’s marketing exclusivity rights, this drug product is not labeled for pediatric use. In radiolabeled studies in rats, no more than 0.005% of Fenoldopam crossed the blood-brain barrier. Excretion and Metabolism Radiolabeled studies show that about 90% of infused Fenoldopam is eliminated in urine, 10% in feces. Elimination is largely by conjugation, without participation of cytochrome P-450 enzymes. The principal routes of conjugation are methylation, glucuronidation, and sulfation. Only 4% of the administered dose is excreted unchanged. Animal data indicate that the metabolites are inactive. Pharmacodynamics and Clinical Studies Adult Patients: In a randomized double-blind, placebo-controlled, 5-group study in 32 patients with mild to moderate essential hypertension (diastolic blood pressure between 95 and 119 mm Hg), and a mean baseline pressure of about 154/98 mm Hg, and heart rate of about 75 bpm, fixed-rate IV infusions of Fenoldopam mesylate produced dose-related reductions in systolic and diastolic blood pressure. Infusions were maintained at a fixed rate for 48 hours. Table 1 shows the results of the study. The onset of response was rapid at all infusion rates, with the 15-minute response representing 50 to 100% of the one-hour response in all groups. There was some suggestion of partial tolerance at 48 hours in the two higher dose infusions, but a substantial effect persisted through 48 hours. When infusions were stopped, blood pressure gradually returned to pretreatment values with no evidence of rebound. This study suggests that there is no greater response to 0.8 mcg/kg/min than to 0.4 mcg/kg/min. Table 1 PHARMACODYNAMIC EFFECTS OF Fenoldopam IN MILD TO MODERATE ADULT HYPERTENSIVE PATIENTS Mean change from time zero ± SE Time Point and Mean Change From Time Zero ± SE Drug Dosage (mcg/kg/min) Placebo n=7 0.04 n=7 0.1 n=7 0.4 n=5 0.8 n=6 15 Minutes of Infusion Systolic BP 0±6 -15±6 -19±8 -14±4 -24±6 Diastolic BP 0±2 -5±3 -12±4 -15±3 20±4 Heart rate +2±2 +3±2 +5±1 +16±3 +19±3 30 Minutes of Infusion Systolic BP -6±5 -17±6 -18±6 -14±8 -26±6 Diastolic BP -6±3 -7±3 -16±4 -14±3 -20±2 Heart rate +2±2 +3±2 +10±2 +18±3 +23±3 1 Hour of Infusion Systolic BP -15±4 -22±7 -22±7 -26±9 -22±9 Diastolic BP -5±3 -9±2 -18±4 -19±4 -21±1 Heart rate +1±3 +5±2 +12±3 +19±4 +25±4 4 Hours of Infusion Systolic BP -14±5 -16±9 -31±15 -22±11 -25±7 Diastolic BP -14±8 -8±4 -19±9 -25±3 -20±1 Heart rate +5±3 +6±3 +10±4 +21±2 +27±7 24 Hours of Infusion Systolic BP -20±6 -23±8 -35±7 -22±6 -23±11 Diastolic BP -11±6 -11±5 -23±10 -22±5 -13±3 Heart rate +6±3 +5±3 +13±2 +17±4 +15±3 48 Hours of Infusion Systolic BP -12±8 -31±6 -22±8 -9±6 -14±10 Diastolic BP -9±5 -10±6 -9±7 -9±2 -9±3 Heart rate +1±2 0±4 +1±4 +12±3 +8±3  In a multicenter, randomized, double-blind comparison of four infusion rates, Fenoldopam mesylate was administered as constant rate infusions of 0.01, 0.03, 0.1 and 0.3 mcg/kg/min for up to 24 hours to 94 adult patients experiencing hypertensive emergencies (defined as diastolic blood pressure ≥120 mm Hg with evidence of compromise of end-organ function involving the cardiovascular, renal, cerebral or retinal systems). Infusion rates could be doubled after one hour if clinically indicated. There were dose-related, rapid-onset, decreases in systolic and diastolic blood pressures and increases in heart rate (Table 2). Table 2 PHARMACODYNAMIC EFFECTS OF Fenoldopam IN ADULT HYPERTENSIVE EMERGENCY PATIENTS Mean change from baseline ± SE Time Point and Pharmacodynamic Parameters Drug Dosage (mcg/kg/min) 0.01 n=25 0.03 n=24 0.1 n=22 0.3 n=23 Pre-Infusion Baseline Systolic BP- mean±SE 210±21 208±26 205±24 211±17 Diastolic BP- mean±SE 136±16 135±11 133±14 136±15 Heart rate- mean±SE 87±20 84±14 81±19 80±14 15 Minutes of Infusion Systolic BP -5±4 -7±4 -16±4 -19±4 Diastolic BP -5±3 -8±3 -12±2 -21±2 Heart rate -2±3 +1±1 +2±1 +11±2 30 Minutes of Infusion Systolic BP -6±4 -11±4 -21±3 -16±4 Diastolic BP -10±3 -12±3 -17±3 -20±2 Heart rate -2±3 -1±1 +3±2 +12±3 1 Hour of Infusio n Systolic BP -5±3 -9±4 -19±4 -22±4 Diastolic BP -8±3 -13±3 -18±2 -23±2 Heart rate -1±3 0±2 +3±2 +11±3 4 Hours of Infusio n Systolic BP -14±4 -20±5 -23±4 -37±4 Diastolic BP -12±3 -18±3 -21±3 -29±3 Heart rate -2±4 0±2 +4±2 +11±2 Two hundred and thirty six severely hypertensive adult patients (DBP ≥120 mm Hg), with or without end-organ compromise, were randomized to receive in two open-label studies either Fenoldopam or nitroprusside. The response rate was 79% (92/117) in the Fenoldopam group and 77% (90/119) in the nitroprusside group. Response required a decline in supine diastolic blood pressure to less than 110 mm Hg if the baseline were between 120 and 150 mm Hg, inclusive, or by ≥40 mm Hg if the baseline were ≥150 mm Hg. Patients were titrated to the desired effect. For Fenoldopam, the dose ranged from 0.1 to 1.5 mcg/kg/min; for nitroprusside, the dose ranged from 1.0 to 8.0 mcg/kg/min. As in the study in mild to moderate hypertensives, most of the effect seen at one hour is present at 15 minutes. The additional effect seen after 1 hour occurs in all groups and may not be drug-related (there was no placebo group for evaluation). Pediatric Patients: Information related to the pharmacodynamics of Fenoldopam injection in pediatric patients is approved for Abbott Laboratories’ Fenoldopam drug products. However, due to Abbott’s marketing exclusivity rights, this drug product is not labeled for pediatric use. Indications and Usage for Fenoldopam Adult Patients: Fenoldopam is indicated for the in-hospital, short-term (up to 48 hours) management of severe hypertension when rapid, but quickly reversible, emergency reduction of blood pressure is clinically indicated, including malignant hypertension with deteriorating end-organ function. Transition to oral therapy with another agent can begin at anytime after blood pressure is stable during Fenoldopam mesylate infusion. Pediatric Patients: Information related to the indicated use of Fenoldopam injection in pediatric patients is approved for Abbott Laboratories’ Fenoldopam drug products. However, due to Abbott’s marketing exclusivity rights, this drug product is not labeled for pediatric use. Contraindications None known. Warnings Contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. Precautions Intraocular Pressure In a clinical study of 12 patients with open-angle glaucoma or ocular hypertension (mean baseline intraocular pressure was 29.2 mm Hg with a range of 22 to 33 mm Hg), infusion of Fenoldopam mesylate at escalating doses ranging from 0.05 to 0.5 mcg/kg/min over a 3.5 hour period caused a dose-dependent increase in intraocular pressure (IOP). At the peak effect, the intraocular pressure was raised by a mean of 6.5 mm Hg (range -2 to +8.5 mm Hg, corrected for placebo effect). Upon discontinuation of the Fenoldopam mesylate infusion, the IOP returned to baseline values within 2 hours. Fenoldopam mesylate administration to patients with glaucoma or intraocular hypertension should be undertaken with caution. Tachycardia Fenoldopam mesylate causes a dose-related tachycardia (Table 2), particularly with infusion rates above 0.1 mcg/kg/min. Tachycardia in adults diminishes over time but remains substantial at higher doses. Tachycardia in pediatric patients at doses ≥ 0.8 mcg/kg/min persists at least for 4 hours. Hypotension Fenoldopam mesylate may occasionally produce symptomatic hypotension and close monitoring of blood pressure during administration is essential. (See ADVERSE REACTIONS.) It is particularly important to avoid systemic hypotension when administering the drug to patients who have sustained an acute cerebral infarction or hemorrhage. In pediatric patients, Fenoldopam mesylate was only administered to patients with an indwelling intraarterial line. Hypokalemia   Decreases in serum potassium occasionally to values below 3 mEq/L were observed after less than 6 hours of Fenoldopam infusion. It is not clear if the hypokalemia reflects a pressure natriuresis with enhanced potassium-sodium exchange or a direct drug effect. During clinical trials, electrolytes were monitored at intervals of 6 hours. Hypokalemia was treated with either oral or intravenous potassium supplementation. Patient management should include appropriate attention to serum electrolytes. Intracranial Pressure The effect of Fenoldopam in the presence of increased intracranial pressure has not been studied. Drug Interactions with Beta-Blockers Concomitant use of Fenoldopam with beta-blockers should be avoided. If the drugs are used together, caution should be exercised because unexpected hypotension could result from beta-blocker inhibition of the sympathetic reflex response to Fenoldopam. Drug Interactions, General Although there have been no formal interaction studies, intravenous Fenoldopam mesylate has been administered safely with drugs such as digitalis and sublingual nitroglycerin. There is limited experience with concomitant antihypertensive agents such as alpha-blockers, calcium channel-blockers, ACE inhibitors, and diuretics (both thiazide-like and loop). Carcinogenesis, Mutagenesis, Impairment of Fertility In a 24-month study, mice treated orally with Fenoldopam at 12.5, 25, or 50 mg/kg/day, reduced to 25 mg/kg/day on day 209 of study, showed no increase above controls in the incidence of neoplasms. Female mice in the highest dose group had an increased incidence and degree of severity of a fibro-osseous lesion of the sternum compared with control or low-dose animals. Compared to controls, female mice in the middle- and upper-dose groups had a higher incidence and degree of severity of chronic nephritis. These pathologic lesions were not seen in male mice treated with Fenoldopam. In a 24-month study, rats treated orally with Fenoldopam at 5, 10 or 20 mg/kg/day, with the mid- and high-dose groups increased to 15 or 25 mg/kg/day, respectively, on day 372 of the study, showed no increase above controls in the incidence or type of neoplasms. Compared with the controls, rats in the mid- and high-dose groups had a higher incidence of hyperplasia of collecting duct epithelium at the tip of the renal papilla. Fenoldopam did not induce bacterial gene mutation in the Ames test or mammalian gene mutation in the Chinese hamster ovary (CHO) cell assay. In the in vitro chromosomal aberration assay with CHO cells, Fenoldopam was associated with statistically significant and dose-dependent increases in chromosomal aberrations, and in the proportion of aberrant metaphases. However, no chromosomal damage was seen in the in vivo mice micronucleus or bone marrow assays. Oral fertility and general reproduction performance studies in male and female rats at 12.5, 37.5 or 75 mg/kg/day revealed no impairment of fertility or reproduction performance due to Fenoldopam. Pregnancy Teratogenic Effects; Pregnancy Category B. Oral reproduction studies have been performed in rats and rabbits at doses of 12.5 to 200 mg/kg/day and 6.25 to 25 mg/kg/day, respectively. Studies have revealed maternal toxicity at the highest doses tested but no evidence of impaired fertility or harm to the fetus due to Fenoldopam. However, there are no adequate and well-controlled studies in pregnant women. Since animal reproduction studies are not always predictive of human response, Fenoldopam should be used in pregnancy only if clearly needed. Nursing Mothers Fenoldopam is excreted in milk in rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Fenoldopam mesylate is administered to a nursing woman. Pediatric Use Clinical study information related to the safety and effectiveness of Fenoldopam injection in pediatric patients ages < 1 month to 12 years old is approved for Abbott Laboratories’ Fenoldopam drug products. However, due to Abbott’s marketing exclusivity rights, this drug product is not labeled for pediatric use. Geriatric Use Clinical studies of Fenoldopam did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Adverse Reactions Adult Patients: Fenoldopam mesylate causes a dose-related fall in blood pressure and increase in heart rate (see PRECAUTIONS; Tachycardia, and Hypotension). In controlled clinical studies of severe hypertension in patients with end-organ damage, 3% (4/137) of patients withdrew because of excessive falls in blood pressure. Increased heart rate could, in theory, lead to ischemic cardiac events or worsened heart failure, although these events have not been observed. The most common events reported as associated with Fenoldopam mesylate use are headache, cutaneous dilation (flushing), nausea, and hypotension, each reported in more than 5% of patients. Adverse reactions in controlled trials in hypertensive adult patients Adverse events occurring more than once in any dosing group (once if potentially important or plausibly drug-related) in the fixed-dose constant-infusion studies are presented in the following Table by infusion-rate group. There was no clear dose relationship, except possibly for headache, nausea, flushing. Table 3 ADVERSE EVENTS* FROM FIXED-DOSE INFUSION STUDIES BY DOSAGE GROUP Includes events reported by 2 or more patients receiving Fenoldopam mesylate treatment across all dose groups. Investigator defined; no protocol definition. Fenoldopam Mesylate Dosage (mcg/kg/min) (Adults) Body System Event Placebo (n=7) 0.01 (n=26) 0.03-0.04 (n=31) 0.1 (n=28) 0.3-0.4 (n=29) 0.6-0.8 (n=11) Body, General Headache 1 5 4 7 8 6 Injection site reaction 0 1 3 0 3 2 Cardiovascular ST-T abnormalitites (primarily T-wave inversion) 0 2 4 0 1 0 Flushing 0 0 0 0 1 3 Hypotension 0 0 0 2 0 2 Postural hypotension 0 2 0 0 0 0 Tachycardia 0 0 0 0 0 2 Digestive Nausea 0 3 0 3 5 4 Vomiting 0 2 0 2 1 2 Abdominal pain/fullness 0 2 0 0 2 1 Constipation 0 0 0 0 0 2 Diarrhea 0 0 0 0 2 0 Metabolic and Nutritional Increased creatinine 0 0 2 0 0 0 Hypokalemia 0 2 2 0 1 0 Nervous Nervousness/anxiety 0 0 1 0 0 2 Insomnia 0 2 0 0 0 0 Dizziness 0 1 1 2 2 0 Respiratory Nasal congestion 0 0 0 0 0 2 Skin and Appendages Sweating 0 0 0 1 1 2 Urogenital Urinary tract infection 0 2 0 1 0 0 Musculoskeletal Back pain 0 1 0 1 2 2 Adverse effects in overall database The adverse event incidences listed below are based on observations of over 1,000 Fenoldopam mesylate treated adult patients and not listed in the Table 3 above. Events reported with a frequency between 0.5 to 5% in patients treated with IV Fenoldopam mesylate Cardiovascular: extrasystoles, palpitations, bradycardia, heart failure, ischemic heart disease, myocardial infarction, angina pectoris Metabolic: elevated BUN, elevated serum glucose, elevated transaminase, elevated LDH General Body: non-specific chest pain, pyrexia Hematologic/Lymphatic: leukocytosis, bleeding Respiratory: dyspnea, upper respiratory disorder Genitourinary: oliguria Musculoskeletal: limb cramp Pediatric Patients: Information relating to treatment-emergent adverse events of Fenoldopam injection in pediatric patients is approved for Abbott Laboratories’ Fenoldopam drug products. However, due to Abbott’s marketing exclusivity rights, this drug product is not labeled for pediatric use. Animal Toxicology Unusual toxicologic findings (arterial lesions in the rat) with Fenoldopam are summarized below. These findings have not been observed in mice or dogs. No evidence of a similar lesion in humans has been observed. Arterial lesions characterized by medial necrosis and hemorrhage have been seen in renal and splanchnic arteries of rats given Fenoldopam mesylate by continuous intravenous infusion at doses of 1 to 100 mcg/kg/min for 24 hours. The incidence of these lesions is dose related. Arterial lesions morphologically identical to those observed with Fenoldopam have been reported in rats infused with dopamine. Data suggest that the mechanism for this injury involves activation of D1-like dopaminergic receptors. Such lesions have not been seen in dogs given doses up to 100 mcg/kg/min by continuous intravenous infusion for 24 hours, nor were they seen in dogs infused at the same dose for 6 hours daily for 24 days. The clinical significance of this finding is not known. Oral administration of Fenoldopam doses of 10 to 15 mg/kg/day or 20 to 25 mg/kg/day to rats for 24 months induced a higher incidence of polyarteritis nodosa compared to controls. Such lesions were not seen in rats given 5 mg/kg/day of Fenoldopam or in mice given the drug at doses up to 50 mg/kg/day for 24 months. Overdosage Intentional Fenoldopam mesylate overdosage has not been reported. The most likely reaction would be excessive hypotension which should be treated with drug discontinuation and appropriate supportive measures. Fenoldopam Dosage and Administration Adult Patients: The optimal magnitude and rate of blood pressure reduction in acutely hypertensive patients have not been rigorously determined, but, in general, both delay and too rapid decreases appear undesirable in sick patients. An initial Fenoldopam mesylate injection dose may be chosen from Tables 1 and 2 in the CLINICAL PHARMACOLOGY section that produces the desired magnitude and rate of blood pressure reduction in a given clinical situation. Doses below 0.1 mcg/kg/min have very modest effects and appear only marginally useful in this population. In general, as the initial dose increases, there is a greater and more rapid blood pressure reduction. However, lower initial doses (0.03 to 0.1 mcg/kg/min) titrated slowly have been associated with less reflex tachycardia than have higher initial doses (≥0.3 mcg/kg/min). In clinical trials, doses from 0.01 to 1.6 mcg/kg/min have been studied. Most of the effect of a given infusion rate is attained in 15 minutes. Fenoldopam mesylate injection should be administered by continuous intravenous infusion. A bolus dose should not be used. Hypotension and rapid decreases of blood pressure should be avoided. The initial dose should be titrated upward or downward, no more frequently than every 15 minutes (and less frequently as goal pressure is approached) to achieve the desired therapeutic effect. The recommended increments for titration are 0.05 to 0.1 mcg/kg/min. Use of a calibrated, mechanical infusion pump is recommended for proper control of infusion rate during Fenoldopam mesylate injection infusion. In clinical trials, Fenoldopam mesylate injection treatment was safely performed without the need for intra-arterial blood pressure monitoring; blood pressure and heart rate were monitored at frequent intervals, typically every 15 minutes. Frequent blood pressure monitoring is recommended. Fenoldopam mesylate injection infusion can be abruptly discontinued or gradually tapered prior to discontinuation. Oral antihypertensive agents can be added during Fenoldopam mesylate injection infusion or following its discontinuation. Patients in controlled clinical trials have received intravenous Fenoldopam mesylate injection for as long as 48 hours. PREPARATION OF INFUSION SOLUTION WARNING: CONTENTS OF VIALS MUST BE DILUTED BEFORE INFUSION. EACH VIAL IS FOR SINGLE USE ONLY. Dilution: Adult Patients: The Fenoldopam mesylate injection vial concentrate must be diluted in 0.9% Sodium Chloride Injection or 5% Dextrose Injection using the following dilution schedule: mL of Concentrate (mg of drug) Added to Final Concentration 4 mL (40 mg) 1000 mL 40 mcg/mL 2 mL (20 mg) 500 mL 40 mcg/mL 1 mL (10 mg) 250 mL 40 mcg/mL The drug dose rate must be individualized according to body weight and according to the desired rapidity and extent of pharmacodynamic effect. Table 4 provides the calculated infusion volume in mL/hour for a range of drug doses and body weights. The infusion should be administered using a calibrated mechanical infusion pump that can accurately and reliably deliver the desired infusion rate. Infusion Rates: Table 4 Fenoldopam ADULT INFUSION RATES (mL/hour) DRUG DOSAGE FOR ADULTS > 40 KG, USING 40 MCG/ML CONCENTRATION NOTE: CONCENTRATION IS DIFFERENT FROM PEDIATRIC PATIENTS, SEE BELOW: PEDIATRIC PATIENTS Body Weight (kg) Infusion Rate 0.025 mcg/kg/min 0.05 mcg/kg/min 0.1 mcg/kg/min 0.2 mcg/kg/min 0.3 mcg/kg/min Infusion Rate (mL/hour) of 40 mcg/mL solution 40 1.5 3 6 12 18 50 1.9 3.8 7.5 15 22.5 60 2.3 4.5 9.0 18 27 70 2.6 5.3 10.5 21 31.5 80 3 6 12 24 36 90 3.4 6.8 13.5 27 40.5 100 3.8 7.5 15 30 45 110 4.1 8.3 16.5 33 49.5 120 4.5 9 18 36 54 130 4.9 9.8 19.5 39 58.5 140 5.3 10.5 21 42 63 150 5.6 11.3 22.5 45 67.5 Table 4 (continued) Fenoldopam ADULT INFUSION RATES (mL/hour) DRUG DOSAGE FOR ADULTS > 40 KG, USING 40 MCG/ML CONCENTRATION NOTE: CONCENTRATION IS DIFFERENT FROM PEDIATRIC PATIENTS, SEE BELOW: PEDIATRIC PATIENTS Body Weight (kg) Infusion Rate 0.5 mcg/kg/min 0.8 mcg/kg/min 1 mcg/kg/min 1.2 mcg/kg/min 1.4 mcg/kg/min 1.6 mcg/kg/min 40 Infusion Rate (mL/hour) of 40 mcg/mL solution 30 48 60 72 84 96 50 37.5 60 75 90 105 120 60 45 72 90 108 126 144 70 52.5 84 105 126 147 168 80 60 96 120 144 168 192 90 67.5 108 135 162 189 216 100 75 120 150 180 210 240 110 82.5 132 165 198 231 264 120 90 144 180 216 252 288 130 97.5 156 195 234 273 312 140 105 168 210 252 294 336 150 112.5 180 225 270 315 360 The diluted solution is stable under normal ambient light and temperature conditions for at least 24 hours. Diluted solution that is not used within 24 hours of preparation should be discarded. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter or cloudiness is observed, the drug should be discarded. Pediatric Patients: Information related to the dosing and administration of Fenoldopam injection in pediatric patients is approved for Abbott Laboratories’ Fenoldopam drug products. However, due to Abbott’s marketing exclusivity rights, this drug product is not labeled for pediatric use. How is Fenoldopam Supplied Fenoldopam Mesylate Injection USP is supplied in single-dose vials as follows: NDC 55390-071-01, 10 mg/mL; 1 mL vial, individually boxed. NDC 55390-072-01, 10 mg/mL; 2 mL vial, individually boxed. Store at 2° to 30°C (35.6° to 86°F). Discard unused portion. Manufactured by:                                                                                                  Manufactured for: Ben Venue Laboratories, Inc.                                                                       Bedford Laboratories™ Bedford, OH 44146                                                                                             Bedford, OH 44146 August 2004                                                                                                                        FDP - P01