Corlopam

fenoldopam mesylate

Dosage Form: injection, solution
Corlopam®

brand of Fenoldopam Mesylate Injection, USP

Rx only

Corlopam Description

Corlopam (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-(4-hydroxyphenyl)-[1H]-3-benzazepine-7,8-diol methanesulfonate with the following structure:

fenoldopam mesylate

Fenoldopam mesylate is a white to off-white powder with a molecular weight of 401.87 and a molecular formula of C16H16ClNO3•CH3SO3H. It is sparingly soluble in water, ethanol and methanol, and is soluble in propylene glycol.

Each 1 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.

Corlopam - 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 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 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: In children, aged 1 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 3 to 5 minutes and 3 L/h/kg, respectively.

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 produced dose-related reductions in systolic and diastolic blood pressures. 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 1 hour response in all groups. There was some suggestion of partial tolerance at 48 hours in the 2 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

	Drug Dosage (mcg/kg/min)
Time Point and Mean Change From Time Zero ± SE	Placebo n = 7	0.04 n = 7	0.1 n = 7	0.4 n = 5	0.8 n = 6
* Mean change from time zero ± S.E.
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 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

	Drug Dosage mcg/kg/min
Time Point and Pharmacodynamic Parameters	0.01 n = 25	0.03 n = 24	0.1 n = 22	0.3 n = 23
* Mean change from baseline ± S.E.
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 Infusion*
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 Infusion*
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 thirty-six (236) severely hypertensive adult patients (DBP ≥ 120 mm Hg), with or without end-organ compromise, were randomized to receive in 2 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 to 8 mcg/kg/min. As in the study in mild to moderate hypertensives, most of the effect seen at 1 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: In a randomized, multi-center, double-blind, placebo-controlled, dose-ranging study, pediatric patients were randomized in equal proportions to 1 of 5 treatment groups: 0.05, 0.2, 0.8, or 3.2 mcg/kg/min fenoldopam or placebo. Fenoldopam or placebo was administered as a blinded continuous IV infusion for 30 minutes. Following this, open-label titration of fenoldopam was given to induce hypotension or normotension (defined as mean arterial pressure, 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 1 and 2) were treated for at least two hours. Of these, 2 were < 1 month of age, 25 were between 1 month of age and 1 year of age, 7 were between 1 and 2 years of age, and 43 were between 2 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 3). Changes in blood pressure and heart rate occurred as early as 5 minutes after starting infusion. Doses as high as 4 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 4 hours of infusion. When the infusion was discontinued, blood pressure and heart rates approached baseline values during the following 30 minutes.

Table 3 PHARMACODYNAMIC EFFECTS OF FENOLDOPAM IN PEDIATRIC PATIENTS

Baseline Mean and Mean Change ± SE
	Drug Dosage (mcg/kg/min)
	Placebo n = 16	0.05 n = 15*	0.2 n = 16	0.8 n = 15	3.2 n = 15
* For Mean Arterial Pressure, n=14; otherwise, n=15. § Dropouts were accounted for using the Last Observation Carried Forward (LOCF) method of analysis.
	Pre-Infusion Baseline
Mean Arterial Pressure	81 ± 4	77 ± 5	76 ± 4	88 ± 6	74 ± 4
Systolic BP	108 ± 5	103 ± 6	104 ± 6	117 ± 7	98 ± 4
Diastolic BP	62 ± 4	61 ± 4	57 ± 3	69 ± 6	56 ± 3
Heart rate	106 ± 8	110 ± 7	119 ± 7	125 ± 6	122 ± 6
Change at 5 Minutes of Infusion
Mean Arterial Pressure	4 ± 2	3 ± 3	-2 ± 2	-3 ± 3	-6 ± 3
Systolic BP	5 ± 3	3 ± 3	-2 ± 3	-5 ± 3	-8 ± 3
Diastolic BP	4 ± 2	6 ± 2	-1 ± 2	-2 ± 2	-4 ± 2
Heart rate	2 ± 3	-2 ± 3	-1 ± 3	4 ± 3	-2 ± 3
Change at 30 Minutes of Infusion (LOCF §)
Mean Arterial Pressure	0 ± 3	-1 ± 3	-2 ± 3	-10 ± 3	-10 ± 3
Systolic BP	-3 ± 4	0 ± 4	-3 ± 4	-12 ± 4	-10 ± 4
Diastolic BP	0 ± 3	1 ± 3	-2 ± 3	-8 ± 3	-6 ± 3
Heart rate	-6 ± 4	-4 ± 4	5 ± 4	7 ± 4	14 ± 4

Indications and Usage for Corlopam

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 any time after blood pressure is stable during fenoldopam infusion.

Pediatric Patients: Fenoldopam is indicated for the in-hospital, short-term (up to 4 hours) reduction in blood pressure (See CLINICAL PHARMACOLOGY/Pediatric Patients).

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 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 infusion, the IOP returned to baseline values within 2 hours. Fenoldopam administration to patients with glaucoma or intraocular hypertension should be undertaken with caution.

Tachycardia: Fenoldopam causes a dose-related tachycardia (Table 2 and Table 3), 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 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 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 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:

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 is administered to a nursing woman.

Pediatric Use:

Anti-hypertensive effects of fenoldopam have been studied in pediatric patients age < 1 month (at least 2 kg or full term) to 12 years old requiring blood pressure reduction (see Pharmacodynamics and Clinical Studies, Pediatric Patients).

Clinical studies of fenoldopam did not include subjects ages 12 to 16 years of age to determine if they respond differently from younger subjects or adults. The pharmacokinetics of fenoldopam are independent of age when corrected for body weight. Dose selection for patients 12 to 16 years of age should consider the patient’s clinical condition and concomitant drug therapy.

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 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 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 4 ADVERSE EVENTS* FROM FIXED-DOSE INFUSION STUDIES BY DOSAGE GROUP

Body System	Fenoldopam Dosage (mcg/kg/min)(Adults)
	Event	Placebo (n = 7)	0.01 (n = 26)	0.03 to 0.04 (n = 31)	0.1 (n = 28)	0.3 to 0.4 (n = 29)	0.6 to 0.8 (n = 11)
*Includes events reported by 2 or more patients receiving fenoldopam treatment across all dose groups. **Investigator defined; no protocol definition.
Body, General	Headache	1	5	4	7	8	6
	Injection site reaction	0	1	3	0	3	2
Cardiovascular	ST-T abnormalities (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