Corlopam ® -fenoldopam

FENOLDOPAM (CORLOPAM ®)

Usual Diluents

Standard Dilutions   [Amount of drug] [Infusion volume] [Infusion rate]

Stability / Miscellaneous

Stability / Miscellaneous
EXP: 1 Day (refrigerated),  4 hrs (RT).

Indications: Short term treatment (up to 48hrs) of severe hypertension when rapid, but quickly reversible, emergency reduction of blood pressure is indicated. May be discontinued abruptly or tapered gradually.

Dosing: Usual initial rate: 0.1 mcg/kg/min, increased by increments of 0.05 to 0.1 mcg/kg/min at 15-20min intervals until target blood pressure reached. Usual effective doses: 0.1 to 1.6 mcg/kg/min. Generally, lower initial doses (0.03 to 0.1 mcg/kg/min) titrated slowly, have been associated with less reflex tachycardia.
Never given by IV bolus.

MOA: Selective dopamine (D1) agonist which decreases peripheral vascular resistance; increases renal blood flow; increased diuresis and natriuresis. 6 times as potent as dopamine in producing renal vasodilation.
Onset: 10 minutes.

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Mechanism of Action
Fenoldopam is a rapid-acting vasodilator. It is an agonist for D1-like dopamine receptors and binds with moderate affinity to α2-adrenoceptors. It has no significant affinity for D2-like receptors, α1 and β adrenoceptors, 5HT1 and 5HT2 receptors, or muscarinic receptors. Fenoldopam is a racemic mixture with the R-isomer responsible for the biological activity. The R-isomer has approximately 250-fold higher affinity for D1-like receptors than does the S-isomer. In non-clinical studies, fenoldopam had no agonist effect on presynaptic D2-like dopamine receptors, or α- or β-adrenoceptors, nor did it affect angiotensin-converting enzyme activity. Fenoldopam may increase norepinephrine plasma concentration.

In animals, fenoldopam has vasodilating effects in coronary, renal, mesenteric and peripheral arteries. All vascular beds, however, do not respond uniformly to fenoldopam. Vasodilating effects have been demonstrated in renal efferent and afferent arterioles.

Pharmacokinetics
Adult Patients: Fenoldopam, administered as a constant infusion at dosages of 0.01 to 1.6 mcg/kg/min, produced steady-state plasma concentrations that were proportional to infusion rates. The elimination half-life was about 5 minutes in mild to moderate hypertensives, with little difference between the R (active) and S isomers. Steady state concentrations are attained in about 20 minutes (4 half-lives). The steady state plasma concentrations of fenoldopam, at comparable infusion rates, were similar in normotensive subjects and in patients with mild to moderate hypertension or hypertensive emergencies.

The pharmacokinetics of fenoldopam were not influenced by age, gender, or race in adult patients with a hypertensive emergency. There have been no formal drug-drug interaction studies using intravenous fenoldopam. Clearance of parent (active) fenoldopam is not altered in adult patients with end-stage renal disease on continuous ambulatory peritoneal dialysis (CAPD) and is not altered in adult patients with severe hepatic failure. The effects of hemodialysis on the pharmacokinetics of fenoldopam have not been evaluated.

INDICATIONS AND USAGE
Adult Patients: Fenoldopam is indicated for the in-hospital, short-term (up to 48 hours) management of severe hypertension when rapid, but quickly reversible, emergency reduction of blood pressure is clinically indicated, including malignant hypertension with deteriorating end-organ function. Transition to oral therapy with another agent can begin at anytime after blood pressure is stable during fenoldopam mesylate infusion.

Pediatric Patients: Information related to the indicated use of fenoldopam injection in pediatric patients is approved for Abbott Laboratories’ fenoldopam drug products. However, due to Abbott’s marketing exclusivity rights, this drug product is not labeled for pediatric use.

Pharmacodynamics and Clinical Studies
Adult Patients: In a randomized double-blind, placebo-controlled, 5-group study in 32 patients with mild to moderate essential hypertension (diastolic blood pressure between 95 and 119 mm Hg), and a mean baseline pressure of about 154/98 mm Hg, and heart rate of about 75 bpm, fixed-rate IV infusions of fenoldopam mesylate produced dose-related reductions in systolic and diastolic blood pressure. Infusions were maintained at a fixed rate for 48 hours. Table 1 shows the results of the study. The onset of response was rapid at all infusion rates, with the 15-minute response representing 50 to 100% of the one-hour response in all groups. There was some suggestion of partial tolerance at 48 hours in the two higher dose infusions, but a substantial effect persisted through 48 hours. When infusions were stopped, blood pressure gradually returned to pretreatment values with no evidence of rebound. This study suggests that there is no greater response to 0.8 mcg/kg/min than to 0.4 mcg/kg/min.

Table 1 PHARMACODYNAMIC EFFECTS OF FENOLDOPAM IN MILD TO MODERATE ADULT HYPERTENSIVE PATIENTS

In a multicenter, randomized, double-blind comparison of four infusion rates, fenoldopam mesylate was administered as constant rate infusions of 0.01, 0.03, 0.1 and 0.3 mcg/kg/min for up to 24 hours to 94 adult patients experiencing hypertensive emergencies (defined as diastolic blood pressure ≥120 mm Hg with evidence of compromise of end-organ function involving the cardiovascular, renal, cerebral or retinal systems). Infusion rates could be doubled after one hour if clinically indicated. There were dose-related, rapid-onset, decreases in systolic and diastolic blood pressures and increases in heart rate (Table 2).

Table 2 PHARMACODYNAMIC EFFECTS OF FENOLDOPAM IN ADULT HYPERTENSIVE EMERGENCY PATIENTS

Two hundred and thirty six severely hypertensive adult patients (DBP ≥120 mm Hg), with or without end-organ compromise, were randomized to receive in two open-label studies either fenoldopam or nitroprusside. The response rate was 79% (92/117) in the fenoldopam group and 77% (90/119) in the nitroprusside group. Response required a decline in supine diastolic blood pressure to less than 110 mm Hg if the baseline were between 120 and 150 mm Hg, inclusive, or by ≥40 mm Hg if the baseline were ≥150 mm Hg. Patients were titrated to the desired effect. For fenoldopam, the dose ranged from 0.1 to 1.5 mcg/kg/min; for nitroprusside, the dose ranged from 1.0 to 8.0 mcg/kg/min. As in the study in mild to moderate hypertensives, most of the effect seen at one hour is present at 15 minutes. The additional effect seen after 1 hour occurs in all groups and may not be drug-related (there was no placebo group for evaluation).

Pediatric Patients: Information related to the pharmacodynamics of fenoldopam injection in pediatric patients is approved for Abbott Laboratories’ fenoldopam drug products. However, due to Abbott’s marketing exclusivity rights, this drug product is not labeled for pediatric use.

DOSAGE AND ADMINISTRATION
Adult Patients: The optimal magnitude and rate of blood pressure reduction in acutely hypertensive patients have not been rigorously determined, but, in general, both delay and too rapid decreases appear undesirable in sick patients. An initial fenoldopam mesylate injection dose may be chosen from Tables 1 and 2 in the CLINICAL PHARMACOLOGY section that produces the desired magnitude and rate of blood pressure reduction in a given clinical situation. Doses below 0.1 mcg/kg/min have very modest effects and appear only marginally useful in this population. In general, as the initial dose increases, there is a greater and more rapid blood pressure reduction. However, lower initial doses (0.03 to 0.1 mcg/kg/min) titrated slowly have been associated with less reflex tachycardia than have higher initial doses (≥0.3 mcg/kg/min). In clinical trials, doses from 0.01 to 1.6 mcg/kg/min have been studied. Most of the effect of a given infusion rate is attained in 15 minutes.

Fenoldopam mesylate injection should be administered by continuous intravenous infusion. A bolus dose should not be used. Hypotension and rapid decreases of blood pressure should be avoided. The initial dose should be titrated upward or downward, no more frequently than every 15 minutes (and less frequently as goal pressure is approached) to achieve the desired therapeutic effect. The recommended increments for titration are 0.05 to 0.1 mcg/kg/min.

Use of a calibrated, mechanical infusion pump is recommended for proper control of infusion rate during fenoldopam mesylate injection infusion. In clinical trials, fenoldopam mesylate injection treatment was safely performed without the need for intra-arterial blood pressure monitoring; blood pressure and heart rate were monitored at frequent intervals, typically every 15 minutes. Frequent blood pressure monitoring is recommended.

Fenoldopam mesylate injection infusion can be abruptly discontinued or gradually tapered prior to discontinuation. Oral antihypertensive agents can be added during fenoldopam mesylate injection infusion or following its discontinuation. Patients in controlled clinical trials have received intravenous fenoldopam mesylate injection for as long as 48 hours.

PREPARATION OF INFUSION SOLUTION
WARNING: CONTENTS OF VIALS MUST BE DILUTED BEFORE INFUSION. EACH VIAL IS FOR SINGLE USE ONLY.

Dilution:
Adult Patients: The fenoldopam mesylate injection vial concentrate must be diluted in 0.9% Sodium Chloride Injection or 5% Dextrose Injection using the following dilution schedule:

The drug dose rate must be individualized according to body weight and according to the desired rapidity and extent of pharmacodynamic effect. Table 4 provides the calculated infusion volume in mL/hour for a range of drug doses and body weights. The infusion should be administered using a calibrated mechanical infusion pump that can accurately and reliably deliver the desired infusion rate.

Infusion Rates:
Table 4 FENOLDOPAM ADULT INFUSION RATES (mL/hour) DRUG DOSAGE FOR ADULTS > 40 KG, USING 40 MCG/ML CONCENTRATION NOTE: CONCENTRATION IS DIFFERENT FROM PEDIATRIC PATIENTS, SEE BELOW: PEDIATRIC PATIENTS

Table 4 (continued) FENOLDOPAM ADULT INFUSION RATES (mL/hour) DRUG DOSAGE FOR ADULTS > 40 KG, USING 40 MCG/ML CONCENTRATION NOTE: CONCENTRATION IS DIFFERENT FROM PEDIATRIC PATIENTS, SEE BELOW: PEDIATRIC PATIENTS

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

Pediatric Patients: Information related to the dosing and administration of fenoldopam injection in pediatric patients is approved for Abbott Laboratories’ fenoldopam drug products. However, due to Abbott’s marketing exclusivity rights, this drug product is not labeled for pediatric use.

HOW SUPPLIED
Fenoldopam Mesylate Injection USP is supplied in single-dose vials as follows:
NDC 55390-071-01, 10 mg/mL; 1 mL vial, individually boxed.
NDC 55390-072-01, 10 mg/mL; 2 mL vial, individually boxed.

Store at 2° to 30°C (35.6° to 86°F). Discard unused portion.

Manufactured by:
Ben Venue Laboratories, Inc.
Bedford, OH 44146
August 2004 FDP-P01

Source: [package insert]