Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3800
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Corlopam (Injection, Solution)
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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 adult patients. An initial
fenoldopam dose may be chosen from Tables 2 and 3 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 usefulin 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 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 infusion. In clinical trials, fenoldopam
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
infusion can be abruptly discontinued or gradually tapered prior to discontinuation.
Oral antihypertensive agents can be added during fenoldopam infusion or following
its discontinuation. Patients in controlled clinical trials have received
intravenous fenoldopam for as long as 48 hours. PREPARATION OF INFUSION SOLUTION WARNING: CONTENTS OF AMPULES MUST BE DILUTED BEFORE INFUSION.
EACH AMPULE IS FOR SINGLE USE ONLY. Dilution: Adult
Patients: The fenoldopam injection ampule concentrate must be diluted
in 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, 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 5 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: 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: Fenoldopam should
be administered intravenously to pediatric patients by a continuous infusion
pump appropriate for the delivery of low infusion rates. Monitoring of blood
pressure should be continuous, usually by way of an intra-arterial line. Heart
rate should also be continuously monitored. In the clinical trial, the usual
starting dose was 0.2 mcg/kg/min with an effect on MAP evident within 5 minutes.
At a constant infusion rate the effect was maximal after 20 to 25 minutes.
Increased dosages of up to 0.3 to 0.5 mcg/kg/min every 20 to 30 minutes were
generally well tolerated. Tachycardia without further decrease in MAP occurred
at dosages greater than 0.8 mcg/kg/min. Upon discontinuation of the fenoldopam
infusion after an average of 4 hours of therapy, blood pressure and heart
rate returned to near baseline within 30 minutes. PREPARATION OF INFUSION SOLUTION WARNING: CONTENTS OF AMPULES MUST BE DILUTED BEFORE INFUSION.
EACH AMPULE IS FOR SINGLE USE ONLY. Dilution: Pediatric
Patients: Table 6 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. As low flow rates (e.g.,<0.5 mL/hr)
may not be practical, and due to volume overload, it may be necessary to increase
the concentration of fenoldopam in the infused solutions. Infusion
Rates: 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.
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dailymed-instance:descripti... |
Corlopam (Fenoldopam Mesylate Injection, USP) is a dopamine
D-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 CHClNO���CHSOH.
It is sparingly soluble in water, ethanol and methanol, and is soluble in
propylene glycol. Ampules: 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.
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Mechanism of Action Fenoldopam
is a rapid-acting vasodilator. It is an agonist for D-like dopamine
receptors and binds with moderate affinity to��-adrenoceptors.
It has no significant affinity for D-like receptors,��and��adrenoceptors, 5HTand 5HTreceptors, 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 D-like receptors than does the S-isomer. In non-clinical studies,
fenoldopam had no agonist effect on presynaptic D-like dopamine
receptors, or��- or��-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 theR (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 theblood-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. * Mean change from time zero��S.E. 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). * Mean change from baseline��S.E. 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 highas 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. * For Mean Arterial Pressure, n=14; otherwise, n=15. ��Dropouts
were accounted for using the Last Observation Carried Forward (LOCF) method
of analysis.
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None known.
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Store at 2 to 30��C (35.6 to 86��F). Revised:
March, 2005 HOSPIRA, INC., LAKE FOREST,
IL 60045 USA
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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 withglaucoma 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.<br/>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.<br/>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).<br/>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.<br/>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.<br/>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.<br/>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.<br/>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.
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Intentional fenoldopam overdosage has not been reported.
The most likely reaction would be excessive hypotension which should be treated
with drug discontinuation and appropriate supportive measures.
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Fenoldopam Mesylate
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Corlopam (Injection, Solution)
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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. *Includes events reported by 2 or more patients receiving
fenoldopam treatment across all dose groups. **Investigator
defined; no protocol definition. Adverse
effects in overall data base The adverse event
incidences listed below are based on observations of over 1,000 fenoldopam
treated adult patients and not listed in Table 4 above. Events reported with a frequency between 0.5 to 5% in patients
treated with IV fenoldopam Pediatric Patients:
In pediatric patients, the most common adverse events reported
during short-term administration in controlled trials (30 minutes) were hypotension
and tachycardia. However, because of the short exposure, there is limited
experience with defining adverse events in children. The long-term effects
of fenoldopam on growth and development have not been studied.
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dailymed-instance:warning |
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.
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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).
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Corlopam
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