Corlopam

Overdose

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

Contraindications

None.

Undesirable effects

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical 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 5. There was no clear dose relationship, except possibly for headache, nausea, flushing.

Table 5: Adverse reactions in fixed-dose studies occurring in > 5% of subjects on fenoldopam

The following additional adverse reactions were observed more frequently in patients treated with fenoldopam

Metabolism and Nutrition Disorders — Hypokalaemia

Psychiatric Disorders — Nervousness/Anxiety, insomnia

Nervous System Disorders — Dizziness

Cardiac Disorders — Extrasystoles, palpitations, cardiac failure, ischemic heart disease, myocardial infarction, angina pectoris, tachycardia

Gastrointestinal Disorders — Abdominal pain

Skin and Subcutaneous Tissue Disorders — Hyperhidrosis

Musculoskeletal and Connective Tissue Disorders —Muscle spasms

Renal and Urinary Disorders — Oliguria

General Disorders and Administration Site Conditions —Chest pain, pyrexia

Investigations — Blood urea increased, blood creatinine increased, blood glucose increased, transaminases increased, blood lactate dehydrogenase increased

The following adverse reactions have been identified during post approval use of Corlopam. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure. Voluntary reports of adverse reactions temporally associated with Corlopam that have been received since market introduction and that may have no causal relationship with the drug include the following:

Cardiac Disorders — Cardiogenic shock

Vascular Disorders — Hypotension

Gastrointestinal Disorders — Abdominal distension

Investigations — Electrocardiogram ST segment depression, oxygen saturation decreased

Therapeutic indications

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.

Fenoldopam is indicated for in-hospital, short-term (up to 4 hours) reduction in blood pressure [ CLINICAL PHARMACOLOGY].

Pharmacodynamic properties

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 6 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 6: Change in Blood Pressure and Heart Rate (mean ± SE) with Fenoldopam in Mildly to Moderately Hypertensive Adults

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 7).

Table 7. Change in Blood Pressure and Heart Rate (mean ± SE) with Fenoldopam in Adults with Hypertensive Emergencies

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).

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 8). 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 8: Change in Blood Pressure and Heart Rate (mean ± SE) with Fenoldopam in Hypertensive Pediatric Patients

Pharmacokinetic properties

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.

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.

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.

Date of revision of the text

Name of the medicinal product

Fertility, pregnancy and lactation

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. There are, however, 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.

Qualitative and quantitative composition

10 mg/mL solution in single-dose vial 10 mg/mL solution in single-dose ampule

Store at 2 to 30°C (35.6 to 86°F).

Hospira, Inc., Lake Forest, IL 60045 USA. Revised: Dec 2015

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

Fenoldopam causes a 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.

Hypokalemia has been observed after less than 6 hours of fenoldopam infusion. Hypokalemia reflects a pressure natriuresis with enhanced potassium-sodium exchange or a direct drug effect. Monitor serum potassium levels.

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.

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.

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 fibroosseous 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.

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. There are, however, 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.

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, discontinue nursing or fenoldopam.

Safety and effectiveness of fenoldopam have been established in the age groups age < 1 month (at least 2 kg or full term) to 12 years old requiring blood pressure reduction. 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.

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.

Dosage (Posology) and method of administration

Initiate dosing at 0.01 to 0.3 mcg/kg/min as a 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 ; 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.

Initiate dosing at 0.2 mcg/kg/minute and titrate dose by 0.3 to 0.5 mcg/kg/min every 20-30 minutes to a maximum dose of 0.8 mcg/kg/minute. Higher doses generally produced no further decreases in MAP but did worsen tachycardia.

Dilute contents of ampules or vials with 0.9% Sodium Chloride Injection or 5% Dextrose in Water before infusion. Each ampule or vial is for single use only. Discard diluted solution if not being administered to a patient after 4 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 Adults

Table 2: Dilution Instructions for Pediatric Patients

Rates of infusion in mL/hour for fenoldopam may be calculated using the following formula:

Example calculations for infusion rates are as follows:

Example 1: for a 60 kg patient at an initial dose of 0.01 mcg/kg/min using a 40 mcg/mL concentration, the infusion rate would be as follows:

Example 2: for a 10 kg patient at a dose of 0.2 mcg/kg/min using a 60 mcg/mL concentration, the infusion rate would be as follows:

Interaction with other medicinal products and other forms of interaction

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical 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 5. There was no clear dose relationship, except possibly for headache, nausea, flushing.

Table 5: Adverse reactions in fixed-dose studies occurring in > 5% of subjects on fenoldopam

The following additional adverse reactions were observed more frequently in patients treated with fenoldopam

Metabolism and Nutrition Disorders — Hypokalaemia

Psychiatric Disorders — Nervousness/Anxiety, insomnia

Nervous System Disorders — Dizziness

Cardiac Disorders — Extrasystoles, palpitations, cardiac failure, ischemic heart disease, myocardial infarction, angina pectoris, tachycardia

Gastrointestinal Disorders — Abdominal pain

Skin and Subcutaneous Tissue Disorders — Hyperhidrosis

Musculoskeletal and Connective Tissue Disorders —Muscle spasms

Renal and Urinary Disorders — Oliguria

General Disorders and Administration Site Conditions —Chest pain, pyrexia

Investigations — Blood urea increased, blood creatinine increased, blood glucose increased, transaminases increased, blood lactate dehydrogenase increased

The following adverse reactions have been identified during post approval use of Corlopam. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure. Voluntary reports of adverse reactions temporally associated with Corlopam that have been received since market introduction and that may have no causal relationship with the drug include the following:

Cardiac Disorders — Cardiogenic shock

Vascular Disorders — Hypotension

Gastrointestinal Disorders — Abdominal distension

Investigations — Electrocardiogram ST segment depression, oxygen saturation decreased

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.