DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS 10 mg/mL solution in single-dose vial. o10 mg/mL solution in single-dose vial (3).. o10 mg/mL solution in single-dose vial (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS Beta-blockers: Avoid concomitant use (7.1).. 7.1Beta-Blockers Avoid concomitant use of fenoldopam with beta-blockers. If the drugs are used together, blood pressure should be monitored frequently because hypotension could result from beta-blocker inhibition of the sympathetic reflex response to fenoldopam.

GERIATRIC USE SECTION.

8.5 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 start 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING Unit of SaleConcentrationNDC 0409-3373-0110 mg/mL1 Single-dose vial in cartonNDC 0409-3373-0220 mg/2 mL1 Single-dose vial in carton(10 mg/mL)Store at to 30C (35.6 to 86F).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE Fenoldopam injection is dopaminergic agonist indicated:oIn adult patients for short term management of severe hypertension when rapid and reversible reduction of blood pressure is clinically indicated, including for malignant hypertension with deteriorating end-organ function (1.1).oIn pediatric patients for short-term reduction in blood pressure (1.2).. oIn adult patients for short term management of severe hypertension when rapid and reversible reduction of blood pressure is clinically indicated, including for malignant hypertension with deteriorating end-organ function (1.1).. oIn pediatric patients for short-term reduction in blood pressure (1.2).. 1.1Adult Patients Fenoldopam is indicated for 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 any time after blood pressure is stable during fenoldopam infusion.. 1.2Pediatric Patients Fenoldopam is indicated for in-hospital, short-term (up to hours) reduction in blood pressure [see Clinical Pharmacology (12.2)].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The most common events (occurring in more than 5% of patients) reported associated with use are headache, cutaneous dilation (flushing), nausea, and hypotension (6.1).To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The most common reactions associated with fenoldopam use are headache, cutaneous dilation (flushing), nausea, and hypotension, each reported in more than 5% of patients.Adverse reactions 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 Table 3. There was no clear dose relationship, except possibly for headache, nausea, flushing.Table 3. Adverse reactions in fixed-dose studies occurring in 5% of subjects on fenoldopamEventPlacebo(n 7)Fenoldopam(n 125)n (%)n (%)Headache1 (14%)30 (24%)Nausea015 (12%)Vomiting07 (6%)Injection site reaction09 (7%)Electrocardiogram wave inversion07 (6%)The following additional adverse reactions were observed more frequently in patients treated with fenoldopamIncidence 0.5% to 5%Metabolism and Nutrition Disorders -- HypokalemiaPsychiatric Disorders -- Nervousness/Anxiety, insomniaNervous System Disorders -- DizzinessCardiac Disorders -- Extrasystoles, palpitations, cardiac failure, ischemic heart disease, myocardial infarction, angina pectoris, tachycardiaGastrointestinal Disorders -- Abdominal painSkin and Subcutaneous Tissue Disorders -- HyperhidrosisMusculoskeletal and Connective Tissue Disorders --Muscle spasmsRenal and Urinary Disorders -- OliguriaGeneral Disorders and Administration Site Conditions --Chest pain, pyrexiaInvestigations -- Blood urea increased, blood creatinine increased, blood glucose increased, transaminases increased, blood lactate dehydrogenase increased. 6.2Post-Marketing Experience The following adverse reactions have been identified during post approval use of CORLOPAM. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Voluntary reports of adverse reactions temporally associated with CORLOPAM that have been received since market introduction include the following:Cardiac Disorders -- Cardiogenic shock Vascular Disorders -- Hypotension Gastrointestinal Disorders -- Abdominal distension Investigations -- Electrocardiogram ST segment depression, oxygen saturation decreased.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology 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 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 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 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 higher incidence of polyarteritis nodosa compared to controls. Such lesions were not seen in rats given mg/kg/day of fenoldopam or in mice given the drug at doses up to 50 mg/kg/day for 24 months.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In 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 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 higher incidence and degree of severity of chronic nephritis. These pathologic lesions were not seen in male mice treated with fenoldopam.In 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 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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Fenoldopam is rapid-acting vasodilator. It is an agonist for D1-like dopamine receptors and binds with moderate affinity to 2-adrenoceptors. It has no significant affinity for D2-like receptors, and -adrenoceptors, 5HT1 and 5HT2 receptors, or muscarinic receptors. Fenoldopam is 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 or -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.. 12.2Pharmacodynamics Mild to Moderate HypertensionIn 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 mean baseline pressure of about 154/98 mm Hg, and heart rate of about 75 bpm, fixed-rate IV infusions of fenoldopam produced dose-related reductions in systolic and diastolic blood pressures. Infusions were maintained at fixed rate for 48 hours. Table 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 hour response in all groups. There was some suggestion of partial tolerance at 48 hours in the higher dose infusions, but 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 4. Change in Blood Pressure and Heart Rate (mean +- SE) with Fenoldopam in Mildly to Moderately Hypertensive AdultsDrug Dosage (mcg/kg/min)Placebon 70.04n 70.1n 70.4n 50.8n 615 Minutes of InfusionSystolic BP (mmHg)0 +- 6-15 +- 6-19 +- 8-14 +- 4-24 +- 6Diastolic BP (mmHg)0 +- 2-5 +- 3-12 +- 4-15 +- 3-20 +- 4Heart rate (bpm)+2 +- 2+3 +- 2+5 +- 1+16 +- 3+19 +- 330 Minutes of InfusionSystolic BP-6 +- 5-17 +- 6-18 +- 6-14 +- 8-26 +- 6Diastolic BP-6 +- 3-7 +- 3-16 +- 4-14 +- 3-20 +- 2Heart rate+2 +- 2+3 +- 2+10 +- 2+18 +- 3+23 +- 31 Hour of InfusionSystolic BP-15 +- 4-22 +- 7-22 +- 7-26 +- 9-22 +- 9Diastolic BP-5 +- 3-9 +- 2-18 +- 4-19 +- 4-21 +- 1Heart rate+1 +- 3+5 +- 2+12 +- 3+19 +- 4+25 +- 44 Hours of InfusionSystolic BP-14 +- 5-16 +- 9-31 +- 15-22 +- 11-25 +- 7Diastolic BP-14 +- 8-8 +- 4-19 +- 9-25 +- 3-20 +- 1Heart rate+5 +- 3+6 +- 3+10 +- 4+21 +- 2+27 +- 724 Hours of InfusionSystolic BP-20 +- 6-23 +- 8-35 +- 7-22 +- 6-23 +- 11Diastolic BP-11 +- 6-11 +- 5-23 +- 10-22 +- 5-13 +- 3Heart rate+6 +- 3+5 +- 3+13 +- 2+17 +- 4+15 +- 348 Hours of InfusionSystolic BP-12 +- 8-31 +- 6-22 +- 8-9 +- 6-14 +-10Diastolic BP-9 +- 5-10 +- 6-9 +- 7-9 +- 2-9 +- 3Heart rate+1 +- 20 +- 4+1 +- 4+12 +- 3+8 +- 3Hypertensive EmergenciesIn multicenter, randomized, double-blind comparison of four infusion rates, fenoldopam 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 mmHg 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 5).Table 5. Change in Blood Pressure and Heart Rate (mean +- SE) with Fenoldopam in Adults with Hypertensive EmergenciesDrug Dosage mcg/kg/min0.01n 250.03n 240.1n 220.3n 23Pre-Infusion BaselineSystolic BP (mmHg)210 +- 21208 +- 26205 +- 24211 +- 17Diastolic BP (mmHg)136 +- 16135 +- 11133 +- 14136 +- 15Heart rate (bpm)87 +- 2084 +- 1481 +- 1980 +- 1415 minutes of InfusionSystolic BP-5 +- 4-7 +- 4-16 +- 4-19 +- 4Diastolic BP-5 +- 3-8 +- 3-12 +- 2-21 +- 2Heart rate-2 +- 3+1 +- 1+2 +- 1+11 +- 230 Minutes of InfusionSystolic BP-6 +- 4-11 +- 4-21 +- 3-16 +- 4Diastolic BP-10 +- 3-12 +- 3-17 +- 3-20 +- 2Heart rate-2 +- 3-1 +- 1+3 +- 2+12 +- 31 Hour of InfusionSystolic BP-5 +- 3-9 +- 4-19 +- 4-22 +- 4Diastolic BP-8 +- 3-13 +- 3-18 +- 2-23 +- 2Heart rate-1 +- 30 +- 2+3 +- 2+11 +- 34 Hours of InfusionSystolic BP-14 +- 4-20 +- 5-23 +- 4-37 +- 4Diastolic BP-12 +- 3-18 +- 3-21 +- 3-29 +- 3Heart rate-2 +- 40 +- 2+4 +- 2+11 +- 2Severe HypertensionTwo hundred thirty-six (236) severely hypertensive adult patients (DBP >=120 mmHg), with or without end-organ compromise, were randomized to receive in 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 decline in supine diastolic blood pressure to less than 110 mmHg if the baseline were between 120 and 150 mmHg, inclusive, or by >=40 mmHg if the baseline were >=150 mmHg. 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 to mcg/kg/min. As in the study in mild to moderate hypertensives, most of the effect seen at hour is present at 15 minutes. The additional effect seen after hour occurs in all groups and may not be drug-related (there was no placebo group for evaluation).Hypertension in Pediatric PatientsIn randomized, multi-center, double-blind, placebo-controlled, dose-ranging study, pediatric patients were randomized in equal proportions to of treatment groups:0.05, 0.2, 0.8, or 3.2 mcg/kg/min fenoldopam or placebo. Fenoldopam or placebo was administered as blinded continuous IV infusion for 30 minutes. Following this, open-label titration of fenoldopam was given to induce hypotension or normotension (defined as MAP, between 50 and 80 mmHg for patients >1 month of age and MAP between 40 and 70 mmHg for patients <=1 month). Seventy-seven pediatric patients (up to 12 years of age Tanner Stages and 2) were treated for at least two hours. Of these, were <1 month of age, 25 were between month of age and year of age, were between and years of age, and 43 were between and 12 years of age. Of the 77 patients enrolled in the trial, 58 were enrolled in association with surgery, and 19 were treated in an ICU setting.The lowest dosage at which decreases in MAP were seen during blinded administration was 0.2 mcg/kg/min. The dose at which the maximum effect was seen was 0.8 mcg/kg/min. Doses higher than 0.8 mcg/kg/min generally produced no further decreases in MAP but did worsen tachycardia (Table 6). Changes in blood pressure and heart rate occurred as early as minutes after starting infusion. Doses as high as mcg/kg/min were administered during the open-label period. The effects increased with time for 15 to 25 minutes, and an effect could still be detected after an average of hours of infusion. When the infusion was discontinued, blood pressure and heart rates approached baseline values during the following 30 minutes.Table 6. Change in Blood Pressure and Heart Rate (mean +- SE) with Fenoldopam in Hypertensive Pediatric PatientsDrug Dosage (mcg/kg/min)Placebo0.050.20.83.2n 16n 15For Mean Arterial Pressure, n=14; otherwise, n=15.n 16n 15n 15Pre-Infusion BaselineMean Arterial Pressure81 +- 477 +- 576 +- 488 +- 674 +- 4Systolic BP108 +- 5103 +- 6104 +- 6117 +- 798 +- 4Diastolic BP62 +- 461 +- 457 +- 369 +- 656 +- 3Heart rate106 +- 8110 +- 7119 +- 7125 +- 6122 +- 6Change at Minutes of InfusionMean Arterial Pressure4 +- 23 +- 3-2 +- 2-3 +- 3-6 +- 3Systolic BP5 +- 33 +- 3-2 +- 3-5 +- 3-8 +- 3Diastolic BP4 +- 26 +- 2-1 +- 2-2 +- 2-4 +- 2Heart rate2 +- 3-2 +- 3-1 +- 34 +- 3-2 +- 3Change at 30 Minutes of InfusionMean Arterial Pressure0 +- 3-1 +- 3-2 +- 3-10 +- 3-10 +- 3Systolic BP-3 +- 40 +- 4-3 +- 4-12 +- 4-10 +- 4Diastolic BP0 +- 31 +- 3-2 +- 3-8 +- 3-6 +- 3Heart rate-6 +- 4-4 +- 45 +- 47 +- 414 +- 4. 12.3Pharmacokinetics Adult PatientsFenoldopam, administered as 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 minutes in mild to moderate hypertensives, with little difference between the (active) and 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 patients 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 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 PatientsIn children, aged month to 12 years old, steady-state fenoldopam plasma concentrations were proportional to dose (0.05 mcg/kg/min to 3.2 mcg/kg/min). The elimination half-life and clearance were to minutes and L/h/kg, respectively.In radiolabeled studies in rats, no more than 0.005% of fenoldopam crossed the blood-brain barrier.Excretion and MetabolismRadiolabeled 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.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS None.. None (4).

DESCRIPTION SECTION.

11 DESCRIPTION CORLOPAM (Fenoldopam Mesylate Injection, USP) is dopamine D1-like receptor agonist. The product is formulated as solution to be diluted for intravenous infusion. Chemically it is 6-chloro-2,3,4,5-tetrahydro-1-(4-hydroxyphenyl)-[1H]-3-benzazepine-7,8-diol methanesulfonate with the following structure:fenoldopam mesylateFenoldopam mesylate is white to off-white powder with molecular weight of 401.87 and molecular formula of C16H16ClNO3oCH3SO3H. 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 mg.. fenoldopam mesylate.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oAdults: Initiate dosing at 0.01 to 0.3 mcg/kg/min by continuous infusion. Dosing can be increased in increments of 0.05 to 0.1 mcg/kg/minute every 15 minutes or longer until target blood pressure is reached (2.1).oDilute prior to administration (2.1, 2.2).oPediatrics: Initiate dosing at 0.2 mcg/kg/minute by continuous infusion and titrate dose by 0.3 to 0.5 mcg/kg/min every 20-30 minutes to maximum dose of 0.8 mcg/kg/minute (2.1, 2.2).. oAdults: Initiate dosing at 0.01 to 0.3 mcg/kg/min by continuous infusion. Dosing can be increased in increments of 0.05 to 0.1 mcg/kg/minute every 15 minutes or longer until target blood pressure is reached (2.1).. oDilute prior to administration (2.1, 2.2).. oPediatrics: Initiate dosing at 0.2 mcg/kg/minute by continuous infusion and titrate dose by 0.3 to 0.5 mcg/kg/min every 20-30 minutes to maximum dose of 0.8 mcg/kg/minute (2.1, 2.2).. 2.1Recommended Dosage Adult PatientsInitiate dosing at 0.01 to 0.3 mcg/kg/min as continuous intravenous infusion. Dosing may be increased in increments of 0.05 to 0.1 mcg/kg/minute every 15 minutes or longer, until target blood pressure is reached [see Clinical Pharmacology (12.2)]; the maximal infusion rate reported in clinical studies was 1.6 mcg/kg/minute. Doses lower than 0.1 mcg/kg/min and slow up-titration have been associated with less reflex tachycardia. Maintenance infusions may be continued for up to 48 hours.Oral antihypertensive agents can be added during fenoldopam infusion or after discontinuation.Pediatric PatientsInitiate dosing at 0.2 mcg/kg/minute and titrate dose by 0.3 to 0.5 mcg/kg/min every 20-30 minutes to maximum dose of 0.8 mcg/kg/minute. Higher doses generally produced no further decreases in Mean Arterial Pressure (MAP) but did worsen tachycardia.. 2.2Preparation and Administration Dilute contents of vials with 0.9% Sodium Chloride Injection or 5% Dextrose in Water before infusion. Each vial is for single use only. Discard diluted solution if not being administered to patient after hours at room temperature or 24 hours at refrigerated temperature. Inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter or cloudiness is observed, discard the drug.Table 1. Dilution Instructions for AdultsmL of Concentrate (mg of drug)Added toFinal Concentration4 mL (40 mg)1000 mL40 mcg/mL2 mL (20 mg)500 mL40 mcg/mL1 mL (10 mg)250 mL40 mcg/mLTable 2. Dilution Instructions for Pediatric PatientsmL of Concentrate (mg of drug)Added toFinal Concentration3 mL (30 mg)500 mL60 mcg/mL1.5 mL (15 mg)250 mL60 mcg/mL0.6 mL (6 mg)100 mL60 mcg/mLRates of infusion in mL/hour for fenoldopam may be calculated using the following formula:Infusion Rate (mL/h) [Dose (mcg/kg/min) Weight (kg) 60 min/h] Concentration (mcg/mL)Example calculations for infusion rates are as follows:Example 1: for 60 kg patient at an initial dose of 0.01 mcg/kg/min using 40 mcg/mL concentration, the infusion rate would be as follows:Infusion Rate (mL/h) [0.01 (mcg/kg/min) 60 (kg) 60 (min/h)] 0.9 (mL/h) 40 (mcg/mL)Example 2: for 10 kg patient at dose of 0.2 mcg/kg/min using 60 mcg/mL concentration, the infusion rate would be as follows:Infusion Rate (mL/h) [0.2 (mcg/kg/min) 10 (kg) 60 (min/h)] 2.0 (mL/h) 60 (mcg/mL).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION oAdvise patients with underlying hypertension that they require continued follow up for their medical condition, and, if applicable, encourage patients to continue taking their oral antihypertensive medication(s) as directed.oAdvise patients to contact healthcare professional immediately for any of the following signs of new hypertensive emergency: neurological symptoms, visual changes, or evidence of congestive heart failure.. oAdvise patients with underlying hypertension that they require continued follow up for their medical condition, and, if applicable, encourage patients to continue taking their oral antihypertensive medication(s) as directed.. oAdvise patients to contact healthcare professional immediately for any of the following signs of new hypertensive emergency: neurological symptoms, visual changes, or evidence of congestive heart failure.

LACTATION SECTION.

8.2Lactation. Risk SummaryThere are no data on the presence of fenoldopam in human milk, the effects on the breastfed child, or the effects on milk production. Fenoldopam is present in rat milk. When drug is present in animal milk, it is likely that the drug will be present in human milk.Because of the potential for severe adverse reactions in the breastfed infant, advise women not to breastfeed during treatment with CORLOPAM.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action Fenoldopam is rapid-acting vasodilator. It is an agonist for D1-like dopamine receptors and binds with moderate affinity to 2-adrenoceptors. It has no significant affinity for D2-like receptors, and -adrenoceptors, 5HT1 and 5HT2 receptors, or muscarinic receptors. Fenoldopam is 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 or -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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In 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 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 higher incidence and degree of severity of chronic nephritis. These pathologic lesions were not seen in male mice treated with fenoldopam.In 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 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.. 13.2 Animal Toxicology and/or Pharmacology 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 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 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 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 higher incidence of polyarteritis nodosa compared to controls. Such lesions were not seen in rats given mg/kg/day of fenoldopam or in mice given the drug at doses up to 50 mg/kg/day for 24 months.

OVERDOSAGE SECTION.

10 OVERDOSAGE The most likely reaction in fenoldopam overdose would be excessive hypotension which should be treated with drug discontinuation and appropriate supportive measures.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 1 mL Vial Label. mL Single-dose Fliptop VialNDC 0409-3373-01CORLOPAM(R) Fenoldopam Mesylate Injection, USP 10 mg/mLRx onlyDilute before administering.Distributed by Hospira, Inc., Lake Forest, IL 60045 USAHospira. PRINCIPAL DISPLAY PANEL 1 mL Vial Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use Safety and effectiveness of fenoldopam have been established in the age groups age 1 month (at least kg or full term) to 12 years old requiring blood pressure reduction [see Clinical Pharmacology (12.2)]. The adverse event profile in pediatric patients is similar to that seen in adults.The pharmacokinetics of fenoldopam are independent of age when corrected for body weight.The long-term effects of fenoldopam on growth and development have not been studied.

PHARMACODYNAMICS SECTION.

12.2Pharmacodynamics Mild to Moderate HypertensionIn 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 mean baseline pressure of about 154/98 mm Hg, and heart rate of about 75 bpm, fixed-rate IV infusions of fenoldopam produced dose-related reductions in systolic and diastolic blood pressures. Infusions were maintained at fixed rate for 48 hours. Table 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 hour response in all groups. There was some suggestion of partial tolerance at 48 hours in the higher dose infusions, but 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 4. Change in Blood Pressure and Heart Rate (mean +- SE) with Fenoldopam in Mildly to Moderately Hypertensive AdultsDrug Dosage (mcg/kg/min)Placebon 70.04n 70.1n 70.4n 50.8n 615 Minutes of InfusionSystolic BP (mmHg)0 +- 6-15 +- 6-19 +- 8-14 +- 4-24 +- 6Diastolic BP (mmHg)0 +- 2-5 +- 3-12 +- 4-15 +- 3-20 +- 4Heart rate (bpm)+2 +- 2+3 +- 2+5 +- 1+16 +- 3+19 +- 330 Minutes of InfusionSystolic BP-6 +- 5-17 +- 6-18 +- 6-14 +- 8-26 +- 6Diastolic BP-6 +- 3-7 +- 3-16 +- 4-14 +- 3-20 +- 2Heart rate+2 +- 2+3 +- 2+10 +- 2+18 +- 3+23 +- 31 Hour of InfusionSystolic BP-15 +- 4-22 +- 7-22 +- 7-26 +- 9-22 +- 9Diastolic BP-5 +- 3-9 +- 2-18 +- 4-19 +- 4-21 +- 1Heart rate+1 +- 3+5 +- 2+12 +- 3+19 +- 4+25 +- 44 Hours of InfusionSystolic BP-14 +- 5-16 +- 9-31 +- 15-22 +- 11-25 +- 7Diastolic BP-14 +- 8-8 +- 4-19 +- 9-25 +- 3-20 +- 1Heart rate+5 +- 3+6 +- 3+10 +- 4+21 +- 2+27 +- 724 Hours of InfusionSystolic BP-20 +- 6-23 +- 8-35 +- 7-22 +- 6-23 +- 11Diastolic BP-11 +- 6-11 +- 5-23 +- 10-22 +- 5-13 +- 3Heart rate+6 +- 3+5 +- 3+13 +- 2+17 +- 4+15 +- 348 Hours of InfusionSystolic BP-12 +- 8-31 +- 6-22 +- 8-9 +- 6-14 +-10Diastolic BP-9 +- 5-10 +- 6-9 +- 7-9 +- 2-9 +- 3Heart rate+1 +- 20 +- 4+1 +- 4+12 +- 3+8 +- 3Hypertensive EmergenciesIn multicenter, randomized, double-blind comparison of four infusion rates, fenoldopam 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 mmHg 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 5).Table 5. Change in Blood Pressure and Heart Rate (mean +- SE) with Fenoldopam in Adults with Hypertensive EmergenciesDrug Dosage mcg/kg/min0.01n 250.03n 240.1n 220.3n 23Pre-Infusion BaselineSystolic BP (mmHg)210 +- 21208 +- 26205 +- 24211 +- 17Diastolic BP (mmHg)136 +- 16135 +- 11133 +- 14136 +- 15Heart rate (bpm)87 +- 2084 +- 1481 +- 1980 +- 1415 minutes of InfusionSystolic BP-5 +- 4-7 +- 4-16 +- 4-19 +- 4Diastolic BP-5 +- 3-8 +- 3-12 +- 2-21 +- 2Heart rate-2 +- 3+1 +- 1+2 +- 1+11 +- 230 Minutes of InfusionSystolic BP-6 +- 4-11 +- 4-21 +- 3-16 +- 4Diastolic BP-10 +- 3-12 +- 3-17 +- 3-20 +- 2Heart rate-2 +- 3-1 +- 1+3 +- 2+12 +- 31 Hour of InfusionSystolic BP-5 +- 3-9 +- 4-19 +- 4-22 +- 4Diastolic BP-8 +- 3-13 +- 3-18 +- 2-23 +- 2Heart rate-1 +- 30 +- 2+3 +- 2+11 +- 34 Hours of InfusionSystolic BP-14 +- 4-20 +- 5-23 +- 4-37 +- 4Diastolic BP-12 +- 3-18 +- 3-21 +- 3-29 +- 3Heart rate-2 +- 40 +- 2+4 +- 2+11 +- 2Severe HypertensionTwo hundred thirty-six (236) severely hypertensive adult patients (DBP >=120 mmHg), with or without end-organ compromise, were randomized to receive in 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 decline in supine diastolic blood pressure to less than 110 mmHg if the baseline were between 120 and 150 mmHg, inclusive, or by >=40 mmHg if the baseline were >=150 mmHg. 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 to mcg/kg/min. As in the study in mild to moderate hypertensives, most of the effect seen at hour is present at 15 minutes. The additional effect seen after hour occurs in all groups and may not be drug-related (there was no placebo group for evaluation).Hypertension in Pediatric PatientsIn randomized, multi-center, double-blind, placebo-controlled, dose-ranging study, pediatric patients were randomized in equal proportions to of treatment groups:0.05, 0.2, 0.8, or 3.2 mcg/kg/min fenoldopam or placebo. Fenoldopam or placebo was administered as blinded continuous IV infusion for 30 minutes. Following this, open-label titration of fenoldopam was given to induce hypotension or normotension (defined as MAP, between 50 and 80 mmHg for patients >1 month of age and MAP between 40 and 70 mmHg for patients <=1 month). Seventy-seven pediatric patients (up to 12 years of age Tanner Stages and 2) were treated for at least two hours. Of these, were <1 month of age, 25 were between month of age and year of age, were between and years of age, and 43 were between and 12 years of age. Of the 77 patients enrolled in the trial, 58 were enrolled in association with surgery, and 19 were treated in an ICU setting.The lowest dosage at which decreases in MAP were seen during blinded administration was 0.2 mcg/kg/min. The dose at which the maximum effect was seen was 0.8 mcg/kg/min. Doses higher than 0.8 mcg/kg/min generally produced no further decreases in MAP but did worsen tachycardia (Table 6). Changes in blood pressure and heart rate occurred as early as minutes after starting infusion. Doses as high as mcg/kg/min were administered during the open-label period. The effects increased with time for 15 to 25 minutes, and an effect could still be detected after an average of hours of infusion. When the infusion was discontinued, blood pressure and heart rates approached baseline values during the following 30 minutes.Table 6. Change in Blood Pressure and Heart Rate (mean +- SE) with Fenoldopam in Hypertensive Pediatric PatientsDrug Dosage (mcg/kg/min)Placebo0.050.20.83.2n 16n 15For Mean Arterial Pressure, n=14; otherwise, n=15.n 16n 15n 15Pre-Infusion BaselineMean Arterial Pressure81 +- 477 +- 576 +- 488 +- 674 +- 4Systolic BP108 +- 5103 +- 6104 +- 6117 +- 798 +- 4Diastolic BP62 +- 461 +- 457 +- 369 +- 656 +- 3Heart rate106 +- 8110 +- 7119 +- 7125 +- 6122 +- 6Change at Minutes of InfusionMean Arterial Pressure4 +- 23 +- 3-2 +- 2-3 +- 3-6 +- 3Systolic BP5 +- 33 +- 3-2 +- 3-5 +- 3-8 +- 3Diastolic BP4 +- 26 +- 2-1 +- 2-2 +- 2-4 +- 2Heart rate2 +- 3-2 +- 3-1 +- 34 +- 3-2 +- 3Change at 30 Minutes of InfusionMean Arterial Pressure0 +- 3-1 +- 3-2 +- 3-10 +- 3-10 +- 3Systolic BP-3 +- 40 +- 4-3 +- 4-12 +- 4-10 +- 4Diastolic BP0 +- 31 +- 3-2 +- 3-8 +- 3-6 +- 3Heart rate-6 +- 4-4 +- 45 +- 47 +- 414 +- 4.

PHARMACOKINETICS SECTION.

12.3Pharmacokinetics Adult PatientsFenoldopam, administered as 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 minutes in mild to moderate hypertensives, with little difference between the (active) and 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 patients 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 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 PatientsIn children, aged month to 12 years old, steady-state fenoldopam plasma concentrations were proportional to dose (0.05 mcg/kg/min to 3.2 mcg/kg/min). The elimination half-life and clearance were to minutes and L/h/kg, respectively.In radiolabeled studies in rats, no more than 0.005% of fenoldopam crossed the blood-brain barrier.Excretion and MetabolismRadiolabeled 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.

PREGNANCY SECTION.

8.1 Pregnancy Risk SummaryThere are insufficient data regarding CORLOPAM use in pregnancy to evaluate for drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.In animal studies, there was no evidence of teratogenicity or fetotoxicity when fenoldopam was orally administered to rats and rabbits during organogenesis (see Data). There are adverse effects on maternal and fetal outcomes associated with severe hypertension (see Clinical Considerations).The estimated background risk for major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Clinical Considerations. Disease-associated maternal and/or embryo/fetal riskSevere hypertension can result in maternal stroke, pulmonary edema, myocardial ischemia or death of the mother or fetus.. Data. Animal DataOral 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, administered during the period of organogenesis. Studies have revealed maternal toxicity at the highest doses tested but no evidence of harm to the fetus due to fenoldopam.

SPL UNCLASSIFIED SECTION.

1.1Adult Patients Fenoldopam is indicated for 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 any time after blood pressure is stable during fenoldopam infusion.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk SummaryThere are insufficient data regarding CORLOPAM use in pregnancy to evaluate for drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.In animal studies, there was no evidence of teratogenicity or fetotoxicity when fenoldopam was orally administered to rats and rabbits during organogenesis (see Data). There are adverse effects on maternal and fetal outcomes associated with severe hypertension (see Clinical Considerations).The estimated background risk for major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Clinical Considerations. Disease-associated maternal and/or embryo/fetal riskSevere hypertension can result in maternal stroke, pulmonary edema, myocardial ischemia or death of the mother or fetus.. Data. Animal DataOral 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, administered during the period of organogenesis. Studies have revealed maternal toxicity at the highest doses tested but no evidence of harm to the fetus due to fenoldopam.. 8.2Lactation. Risk SummaryThere are no data on the presence of fenoldopam in human milk, the effects on the breastfed child, or the effects on milk production. Fenoldopam is present in rat milk. When drug is present in animal milk, it is likely that the drug will be present in human milk.Because of the potential for severe adverse reactions in the breastfed infant, advise women not to breastfeed during treatment with CORLOPAM.. 8.4 Pediatric Use Safety and effectiveness of fenoldopam have been established in the age groups age 1 month (at least kg or full term) to 12 years old requiring blood pressure reduction [see Clinical Pharmacology (12.2)]. The adverse event profile in pediatric patients is similar to that seen in adults.The pharmacokinetics of fenoldopam are independent of age when corrected for body weight.The long-term effects of fenoldopam on growth and development have not been studied.. 8.5 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 start 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oFenoldopam causes dose-related tachycardia, particularly with infusion rates above 0.1 mcg/kg/min (5.1).oHypokalemia: Monitor potassium levels (5.2).oIncreased intraocular pressure in patients with glaucoma or intraocular hypertension (5.3).oContains sodium metabisulfite, sulfite that may cause allergic-type reactions including anaphylactic symptoms in susceptible patients (5.4).. oFenoldopam causes dose-related tachycardia, particularly with infusion rates above 0.1 mcg/kg/min (5.1).. oHypokalemia: Monitor potassium levels (5.2).. oIncreased intraocular pressure in patients with glaucoma or intraocular hypertension (5.3).. oContains sodium metabisulfite, sulfite that may cause allergic-type reactions including anaphylactic symptoms in susceptible patients (5.4).. 5.1Tachycardia Fenoldopam causes dose-related tachycardia, particularly with infusion rates above 0.1 mcg/kg/min in adults and >0.8 mcg/kg/min in pediatric patients. Tachycardia in adults may diminish with continued therapy at doses of fenoldopam of <0.1 mcg/kg/min.. 5.2Hypokalemia Hypokalemia has been observed after less than hours of fenoldopam infusion. Hypokalemia reflects pressure natriuresis with enhanced potassium-sodium exchange or direct drug effect. Monitor serum potassium levels.. 5.3Increased Intraocular Pressure In clinical study of 12 patients with open-angle glaucoma or ocular hypertension (mean baseline intraocular pressure was 29.2 mm Hg with range of 22 to 33 mm Hg), infusion of fenoldopam at escalating doses ranging from 0.05 to 0.5 mcg/kg/min over 3.5 hour period caused dose-dependent increase in intraocular pressure (IOP). At the peak effect, the intraocular pressure was raised by mean of 6.5 mm Hg (range -2 to +8.5 mm Hg, corrected for placebo effect). Upon discontinuation of the fenoldopam infusion, the IOP returned to baseline values within hours.. 5.4Allergic Reactions Associated with Sulfite Contains sodium metabisulfite, 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 non-asthmatic people.