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Fenoldopam (Systemic)


VA CLASSIFICATION
Primary: CV402
Secondary: CV500

Commonly used brand name(s): Corlopam.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antihypertensive. —

Indications

Accepted

Hypertension (treatment)—Fenoldopam is indicated for the in-hospital, short-term (up to 48 hours) management of severe hypertension (including malignant hypertension with deteriorating end-organ function) when rapid, but quickly reversible, emergency reduction of blood pressure is clinically indicated {01}. Transition to orally administered antihypertensive therapy can begin at any time after blood pressure is stable during infusion of fenoldopam {01}.
—For additional information on initial therapeutic guidelines related to the treatment of hypertension, see Appendix III.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    401.87 {01}

Mechanism of action/Effect:

Fenoldopam is a rapid-acting vasodilator with agonist effects on dopamine D 1-like receptors, and only moderate affinity for the alpha 2-adrenergic receptors {01}. Fenoldopam is a racemic mixture, with the R-isomer having an approximate 250-fold higher affinity for D 1-like receptors than the S-isomer {01}. Fenoldopam has no agonist effect on presynaptic D 2-like dopamine receptors or on alpha- or beta-adrenergic receptors, and does not appear to affect angiotensin-converting enzyme activity {01}. In animals, fenoldopam dilates coronary, renal, mesenteric, and peripheral arteries, although vasodilation is not equal in all vascular beds {01}. In normal and hypertensive patients, fenoldopam appears to dilate renal efferent and afferent arterioles, thereby increasing renal blood flow; however, a beneficial clinical effect on renal fuction in patients with heart failure or hepatic or severe renal disease has not been demonstrated {01}.


Other actions/effects:

Fenoldopam may increase norepinephrine plasma concentrations {01}.

Distribution:

Steady-state plasma concentrations of intravenous fenoldopam are proportional to the infusion rates when fenoldopam is administered at a constant infusion rate ranging from 0.01 to 1.6 mcg per kg of body weight (mcg/kg) per minute {01}. In rats, approximately 0.005% of a fenoldopam dose crosses the blood-brain barrier {01}.

Biotransformation:

Metabolism of fenoldopam is by conjugation and does not involve cytochrome P450 enzymes {01}. Methylation, glucuronidation, and sulfation are the main routes of conjugation {01}. The resulting metabolites are considered to be inactive {01}. Approximately 4% of a fenoldopam dose is eliminated as unchanged drug {01}.

Half-life:


Elimination:

Approximately 5 minutes in patients with mild to moderate hypertension {01}.


Elimination:
    Renal—Approximately 90% {01}.
    Fecal—Approximately 10% {01}.


In dialysis—
        In patients with end-stage renal disease, continuous ambulatory peritoneal dialysis does not affect the clearance of fenoldopam {01}. It is not known if fenoldopam is removable by hemodialysis {01}.



Precautions to Consider

Carcinogenicity

No increase in the incidence of neoplasms was found in a 2-year study in mice given daily oral fenoldopam doses of 12.5, 25, or 50 mg per kg of body weight (mg/kg) for the first 208 days of the study and then given oral daily fenoldopam doses of 25 mg/kg for the remainder of study {01}. An increased incidence and degree of severity of a fibro-osseous lesion of the sternum occurred in female mice in the highest-dose group {01}. A higher incidence and degree of severity of chronic nephritis occurred in female mice in the middle- and upper-dose groups {01}. These pathologic findings did not occur in male mice treated with fenoldopam {01}.

In rats, no increase in the incidence or type of neoplasms was found in a 2-year study that used daily oral fenoldopam doses of 5, 10, or 20 mg/kg for the first 371 days of the study and then increased the doses of the mid- and high-dose groups to daily fenoldopam doses of 15 or 25 mg/kg, respectively, thereafter {01}. A higher incidence of hyperplasia of collecting duct epithelium at the tip of the renal papilla occurred in rats in the mid- and high-dose groups {01}.

Mutagenicity

Mutagenicity was not detected in the in vitro Ames test or Chinese hamster ovary (CHO) cell assay {01}. Fenoldopam was associated with statistically significant and dose-dependent increases in chromosomal aberrations and in the proportion of aberrant metaphases in the in vitro chromosomal aberration assay with CHO cells {01}. However, chromosomal damage was not seen in the in vivo mice micronucleus or bone marrow assays {01}.

Pregnancy/Reproduction
Fertility—
Impairment of fertility or reproduction performance was not found in fertility and general reproduction performance studies in male and female rats given oral daily doses of fenoldopam of 12.5, 37.5, or 75 mg/kg {01}.

Pregnancy—
Adequate and well-controlled studies in pregnant women have not been done {01}. No evidence of impaired fertility or harm to the fetus was found in reproduction studies in rats and rabbits given daily oral fenoldopam doses of 12.5 to 200 mg/kg and 6.25 to 25 mg/kg, respectively {01}. However, maternal toxicity occurred at the highest doses tested {01}. Because animal reproduction studies are not always predictive of human response, fenoldopam should be used in pregnant patients only if absolutely necessary {01}.

FDA Pregnancy Category B {01}.

Breast-feeding

It is not known whether fenoldopam is distributed into breast milk {01}. However, fenoldopam is distributed into the milk of lactating rats {01}. Caution should be used when fenoldopam is administered to a nursing woman {01}.

Pediatrics

No information is available on the relationship of age to the effects of fenoldopam in pediatric patients. Safety and efficacy have not been established {01}.


Geriatrics


The pharmacokinetics of fenoldopam are unaffected by patient age {01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Beta-adrenergic blocking agents{01}    (concurrent use with fenoldopam has not been studied in hypertensive patients {01} and is not recommended; unexpected hypotension may result from beta-adrenergic blocking agent inhibition of the reflex response [tachycardia] to fenoldopam {01})


Alpha-adrenergic blocking agents{01} or
Angiotensin-converting enzyme (ACE) inhibitors{01} or
Calcium channel blocking agents{01} or
Diuretics, loop{01} or
Diuretics, thiazide{01}    (there is limited experience in the concurrent use of these agents with fenoldopam {01})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Electrolytes, serum{01} , especially
Potassium, serum{01}    (decreases in serum potassium to concentrations below 3 mEq per liter (mEq/L) have occurred after less than 6 hours of fenoldopam administration {01}; it is not known if hypokalemia results from a pressure natriuresis with enhanced potassium-sodium exchange or as a direct effect of the drug {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Glaucoma, open-angle{01} or
Hypertension, ocular (mean baseline intraocular pressure of 29.2 mm Hg with a range of 22 to 33 mm Hg){01}    (in 12 patients with open-angle glaucoma or ocular hypertension, infusion of fenoldopam in escalating doses ranging from 0.05 to 0.5 mcg per kg of body weight [mcg/kg] per minute over a 3.5-hour period resulted in a dose-dependent increase in intraocular pressure [IOP] {01}; the maximum mean increase in intraocular pressure that occurred was 6.5 mm Hg [range -2 to +8.5 mm Hg, corrected for placebo effect] {01}; the IOP returned to baseline within 2 hours after discontinuation of fenoldopam {01}; fenoldopam should be administered with caution in these patients {01})


Cerebral infarction or hemorrhage, acute{01}    (because fenoldopam may cause hypotension, close monitoring during fenoldopam administration is necessary in these patients {01})


Sensitivity to fenoldopam
Sensitivity to sulfites{01}    (fenoldopam injection contains sodium metabisulfite, which may cause allergic- or anaphylactic-type reactions and life-threatening or less severe asthmatic episodes in individuals who are sensitive to sulfites {01}; sensitivity to sulfites is more common in asthmatic patients than in nonasthmatic patients {01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Electrolytes, serum{01} , especially
Potassium, serum{01}    (monitoring at 6-hour intervals is recommended {01}; decreases in serum potassium to concentrations below 3 mEq/L have occurred after less than 6 hours of fenoldopam administration {01})


» Heart rate determinations{01}
» Blood pressure determinations{01}    (monitoring at frequent intervals, such as every 15 minutes, is recommended {01}
Note: Intra-arterial blood pressure monitoring was not used in clinical trials in emergency hypertension {01}

)




Side/Adverse Effects

Note: ST-T wave abnormalities, primarily T-wave inversion, have occurred with administration of fenoldopam {01}.
Arterial lesions characterized by medial necrosis and hemorrhage have occurred in renal and splanchnic arteries of rats given a continuous intravenous infusion of fenoldopam in doses of 1 to 100 mcg per kg of body weight (mcg/kg) per minute for 24 hours {01}. The lesions are morphologically identical to those observed in rats given intravenous infusions of dopamine, and have a dose-related incidence {01}. The occurrence of these lesions may involve activation of D 1-like dopaminergic receptors {01}. Lesions have not been seen in dogs given continuous intravenous infusion of fenoldopam in doses of up to 100 mcg/kg per minute for 24 hours, or in dogs given the same dose for 6 hours daily for 24 days {01}. No evidence of similar lesions have been observed in humans {01}.
A higher incidence of polyarteritis nodosa occurred in rats given oral daily doses of fenoldopam of 10 to 15 mg per kg (mg/kg) or 20 to 25 mg/kg for 24 months {01}. These lesions were not seen in rats given oral daily doses of fenoldopam of 5 mg/kg for 24 months or in mice given oral daily doses of fenoldopam of up to 50 mg/kg for 24 months {01}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Hypotension{01} (lightheadedness or fainting)
    
tachycardia{01} (fast heartbeat)

Note: In clinical studies in patients with severe hypertension and end-organ damage, 3% of patients withdrew because of excessive hypotension {01}.
Tachycardia is dose-related and could lead to ischemic cardiac events or worsened heart failure in certain individuals, although these events have not been observed {01}. Tachycardia is more prevalent with infusion rates above 0.1 mcg/kg per minute and decreases over time, but remains significant at higher fenoldopam doses {01}.


Incidence less frequent
    
Vomiting{01}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Flushing{01} (sudden reddening of the face, neck, and occasionally, upper chest)
    
headache{01}
    
nausea{01}

Incidence less frequent
    
Abdominal pain and/or sensation of fullness{01}
    
back pain
    
constipation{01}
    
diarrhea{01}
    
dizziness{01}
    
insomnia{01}
    
nasal congestion{01}
    
nervousness and/or anxiety{01}
    
sweating{01}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and/or chronic
    
Hypotension, severe{01}


Treatment of overdose
Fenoldopam should be discontinued and treatment should be symptomatic and supportive {01}.


General Dosing Information
Fenoldopam should be administered by continuous intravenous infusion using a calibrated mechanical infusion pump that can deliver the desired infusion rate accurately and reliably {01}. A bolus dose should not be used {01}. Hypotension and rapid decreases of blood pressure should be avoided {01}.

For treatment of adverse effects
Recommended treatment consists of the following:    • Hypokalemia may be treated with either oral or intravenous potassium supplementation {01}.



Parenteral Dosage Forms

FENOLDOPAM MESYLATE INJECTION

Note: Fenoldopam infusion can be discontinued abruptly or tapered gradually prior to discontinuation {01}. Orally administered antihypertensive agents can be added during fenoldopam infusion or following its discontinuation {01}.


Usual adult dose
Hypertension (treatment)
The optimal magnitude and rate of blood pressure reduction in acutely hypertensive patients have not been determined precisely {01}. In clinical studies, doses ranging from 0.01 to 1.6 mcg per kg per minute have been used {01}. Doses below 0.1 mcg per kg per minute have very limited effects and may be only minimally useful {01}. In general, as the initial dose increases, blood pressure reduction is greater and more rapid {01}. Lower initial doses, such as 0.03 to 0.1 mcg per kg per minute, titrated slowly, have been associated with less reflex tachycardia than have higher initial doses (³ 0.3 mcg per kg per minute) {01}. Most of the effect of a given infusion rate is attained within 15 minutes {01}. The initial dose should be titrated upward or downward, no more frequently than every 15 minutes (and less frequently as goal blood pressure is approached), to achieve the desired therapeutic effect {01}. The recommended increments for titration are 0.05 to 0.1 mcg per kg per minute {01}. Blood pressure and heart rate should be monitored at frequent intervals, e.g., every 15 minutes {01}.

For initial doses of fenoldopam used in clinical trials to produce a desired magnitude and rate of blood pressure reduction in a given clinical situation, see prescriber information {01}.

The drug dose rate must be individualized according to the patient's body weight and according to the desired rapidity and extent of pharmacodynamic effect {01}. The following table provides the calculated infusion volume in mL per minute (mL/min) for a range of drug doses and body weights {01}.



Infusion rates (mL/min) to achieve a given drug dose rate (mcg/kg/min) 
Body weight (kg)  Desired drug dose 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 
Recommended infusion rate (mL/min) 
40  0.025  0.05  0.1  0.2  0.3 
50  0.031  0.06  0.13  0.25  0.38 
60  0.038  0.08  0.15  0.3  0.45 
70  0.044  0.09  0.18  0.35  0.53 
80  0.05  0.1  0.2  0.4  0.6 
90  0.056  0.11  0.23  0.45  0.68 
100  0.063  0.13  0.25  0.5  0.75 
110  0.069  0.14  0.28  0.55  0.83 
120  0.075  0.15  0.3  0.6  0.9 
130  0.081  0.16  0.33  0.65  0.98 
140  0.088  0.18  0.35  0.7  1.05 
150  0.094  0.19  0.38  0.75  1.13 



Usual adult prescribing limits
1.6 mcg per kg per minute {01}. Fenoldopam infusion has been administered to patients for as long as 48 hours {01}.

Usual pediatric dose
Safety and efficacy have not been established.

Strength(s) usually available
U.S.—


10 mg per mL (Rx) [Corlopam (citric acid) (propylene glycol) (sodium citrate dihydrate) (sodium metabisulfite)]

Packaging and storage:
Store between 2 and 30 ºC (36 and 86 ºF) {01}.

Preparation of dosage form:
The contents of ampuls must be diluted before infusion {01}. Each ampul is for single use only {01}. Concentrated fenoldopam must be diluted in 0.9% Sodium Chloride Injection USP or 5% Dextrose Injection USP using the following dilution schedule:

Preparation of infusion solution 
Volume of concentrate (amount of drug)  Added to volume of 0.9% Sodium Chloride Injection USP or 5% Dextrose Injection USP  To make a final concentration of 
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 
.

Stability:
The diluted solution is stable under normal ambient light and temperature conditions for at least 24 hours {01}. Diluted solution that is not used within 24 hours of preparation should be discarded {01}. Parenteral products should be inspected visually {01}. If particulate matter or cloudiness is observed, the drug should be discarded {01}.

Additional information:
Fenoldopam injection contains sodium metabisulfite, which may cause allergic- or anaphylactic-type reactions and life-threatening or less severe asthmatic episodes in individuals who are sensitive to sulfites {01}. Sensitivity to sulfites is more common in asthmatic patients than in nonasthmatic patients {01}.



Developed: 03/10/1998



References
  1. Corlopam package insert (Neurex—U.S.), New 9/97, Rec 11/97.
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