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CORLOPAM Clinical Pharmacology (fenoldopam mesylate injection, USP)

12 CLINICAL PHARMACOLOGY

12.1 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.

12.2 Pharmacodynamics

Mild to Moderate Hypertension

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 4 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 4. Change in Blood Pressure and Heart Rate (mean ± SE) with Fenoldopam in Mildly to Moderately Hypertensive Adults

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 (mmHg)

0 ± 6

-15 ± 6

-19 ± 8

-14 ± 4

-24 ± 6

Diastolic BP (mmHg)

0 ± 2

-5 ± 3

-12 ± 4

-15 ± 3

-20 ± 4

Heart rate (bpm)

+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

Hypertensive Emergencies

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 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 Emergencies

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 (mmHg)

210 ± 21

208 ± 26

205 ± 24

211 ± 17

Diastolic BP (mmHg)

136 ± 16

135 ± 11

133 ± 14

136 ± 15

Heart rate (bpm)

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

Severe Hypertension

Two hundred thirty-six (236) severely hypertensive adult patients (DBP ≥120 mmHg), 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 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 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).

Hypertension in 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 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 6). 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 6. Change in Blood Pressure and Heart Rate (mean ± SE) with Fenoldopam in Hypertensive Pediatric Patients
*
For Mean Arterial Pressure, n=14; otherwise, n=15.

Drug Dosage (mcg/kg/min)

Placebo

0.05

0.2

0.8

3.2

n = 16

n = 15*

n = 16

n = 15

n = 15

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

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

12.3 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.

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