Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2336
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Milrinone Lactate (Injection, Solution)
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Milrinone should be administered with a loading dose
followed by a continuous infusion (maintenance dose) according to
the following guidelines: The table below shows the loading dose in milliliters
(mL) of milrinone (1mg/mL) by patient body weight (kg). The loading dose may be given undiluted, but diluting
to a rounded total volume of 10 or 20 mL (see Maintenance Dose
for diluents) may simplify the visualization of the injection rate. Milrinone drawn from vials should be diluted prior
to maintenance dose administration. The diluents that may be used
are 0.45% Sodium Chloride Injection USP, 0.9% Sodium Chloride Injection
USP, or 5% Dextrose Injection USP. The table below shows the volume
of diluent in milliliters (mL) that must be used to achieve 200 mcg/mL
concentration for infusion, and the resultant total volumes. The infusion rate should be adjusted according
to hemodynamic and clinical response. Patients should be closely monitored.
In controlled clinical studies, most patients showed an improvement
in hemodynamic status as evidenced by increases in cardiac output
and reductions in pulmonary capillary wedge pressure. Note: See���Dosage Adjustment in Renally Impaired Patients.���Dosage may be titrated to the maximum hemodynamic effect and should
not exceed 1.13 mg/kg/day. Duration of therapy should depend upon
patient responsiveness. The maintenance dose
in mL/hr by patient body weight (kg) may be determined by reference
to the following table. Note: Milrinone supplied in 100 mL and 200 mL Flexible Containers
(200 mcg/mL in 5% Dextrose Injection) need not be diluted prior to
use. When administering milrinone lactate by continuous
infusion, it is advisable to use a calibrated electronic infusion
device. The Flexible Container has a concentration
of milrinone equivalent to 200 mcg/mL in 5% Dextrose Injection and
is more convenient to use than dilutions prepared from the vials.
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dailymed-instance:descripti... |
Milrinone lactate injection is a member of a new
class of bipyridine inotropic/vasodilator agents with phosphodiesterase
inhibitor activity, distinct from digitalis glycosides or catecholamines.
Milrinone lactate is designated chemically as 1,6-dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5-carbonitrile
lactate and has the following structure: Milrinone is an off-white to tan crystalline compound with an empirical
weight of 211.2 and a molecular formula of CHNO. It is slightly soluble in methanol, and very slightly
soluble in chloroform and in water. As the lactate salt, it is stable
and colorless to pale yellow in solution. Milrinone lactate is available
as sterile aqueous solutions of the lactate salt of milrinone for
injection or infusion intravenously. Sterile, Single-Dose Vials: Single-dose
vials of 10 and 20 mL contain in each mL milrinone lactate equivalent
to 1 mg milrinone and 51.7 mg Dextrose, Hydrous, USP, in Water for
Injection, USP. The pH is adjusted to between 3.2 and 4.0 with lactic
acid or sodium hydroxide. The total concentration of lactic acid can
vary between 0.95 mg/mL and 1.29 mg/mL. These vials require preparation
of dilutions prior to administration to patients intravenously. Pre-Mix Flexible Containers: The Flexible Containers provide two ready-to-use dilutions of milrinone
in volumes of 100 mL and 200 mL of 5% Dextrose Injection. Each mL
contains milrinone lactate equivalent to 200 mcg milrinone. The nominal
concentration of lactic acid is 0.282 mg/mL. Each mL also contains
49.4 mg Dextrose, Anhydrous, USP. The pH is adjusted to between 3.2
and 4.0 with lactic acid or sodium hydroxide. The flexible plastic container is fabricated from a specially formulated
polyvinylchloride. Water can permeate from inside the container into
the overwrap but not in amounts sufficient to affect the solution
significantly. Solutions in contact with the plastic container may
leach out certain chemical components from the plastic invery small
amounts; however, biological testing was supportive of the safety
of the plastic container materials. Exposure to temperatures above
25��C/77��F during transport and storage will lead to minor
losses in moisture content. Higher temperatures lead to greater losses.
It is unlikely that these minor losses will lead to clinically significant
changes within the expiration period.
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dailymed-instance:clinicalP... |
Milrinone is a positive inotrope and vasodilator,
with little chronotropic activity different in structure and mode
of action from either the digitalis glycosides or catecholamines. Milrinone, at relevant inotropic and vasorelaxant concentrations,
is a selective inhibitor of peak III cAMP phosphodiesterase isozyme
in cardiac and vascular muscle. This inhibitory action is consistent
with cAMP mediated increases in intracellular ionized calcium and
contractile force in cardiac muscle, as well as with cAMP dependent
contractile protein phosphorylation and relaxation in vascular muscle.
Additional experimental evidence also indicates that milrinone is
not a beta-adrenergic agonist nor does it inhibit sodium-potassium
adenosine triphosphatase activity as do the digitalis glycosides. Clinical studies in patients with congestive heart failure
have shown that milrinone produces dose-related and plasma drug concentration-related
increases in the maximum rate of increase of left ventricular pressure.
Studies in normal subjects have shown that milrinone produces increases
in the slope of the left ventricular pressure-dimension relationship,
indicating a direct inotropic effect of the drug. Milrinone also produces
dose-related and plasma concentration-related increases in forearm
blood flow in patients with congestive heart failure, indicating a
direct arterial vasodilator activity of the drug. Both the inotropic and vasodilatory effects have been observed over
the therapeutic range of plasma milrinone concentrations of 100 ng/mL
to 300 ng/mL. In addition to increasing myocardial
contractility, milrinone improves diastolic function as evidenced
by improvements in left ventricular diastolic relaxation. The acute administration of intravenous milrinone has
also been evaluated in clinical trials in excess of 1600 patients,
with chronic heart failure, heart failure associated with cardiac
surgery, and heart failure associated with myocardial infarction.
The total number of deaths, either on therapy or shortly thereafter
(24 hours) was 15, less than 0.9%, few of which were thought to be
drug-related. Pharmacokinetics Following intravenous injections of 12.5 mcg/kg
to 125 mcg/kg to congestive heart failure patients, milrinone had
a volume of distribution of 0.38 liters/kg, a mean terminal elimination
half-life of 2.3 hours, and a clearance of 0.13 liters/kg/hr.
Following intravenous infusions of 0.20 mcg/kg/min to 0.70 mcg/kg/min
to congestive heart failure patients, the drug had a volume of distribution
of about 0.45 liters/kg, a mean terminal elimination half-life of
2.4 hours, and a clearance of 0.14 liters/kg/hr. These pharmacokinetic
parameters were not dose-dependent, and the area under the plasma
concentration versus time curve following injections was significantly
dose-dependent. Milrinone has been shown (by
equilibrium dialysis) to be approximately 70% bound to human plasma
protein. The primary route of excretion of milrinone
in man is via the urine. The major urinary excretions of orally administered
milrinone in man are milrinone (83%) and its 0-glucuronide metabolite
(12%). Elimination in normal subjects via the urine is rapid, with
approximately 60% recovered within the first two hours following dosing
and approximately 90% recovered within the first eight hours following
dosing. The mean renal clearance of milrinone is approximately 0.3 liters/min,
indicative of active secretion. Pharmacodynamics In patients with heart failure due to depressed myocardial function,
milrinone produced a prompt dose and plasma concentration related
increase in cardiac output and decreases in pulmonary capillary wedge
pressure and vascular resistance, which were accompanied by mild-to-moderate
increases in heart rate. Additionally, there is no increased effect
on myocardial oxygen consumption. In uncontrolled studies, hemodynamic
improvement during intravenous therapy with milrinone was accompanied
by clinical symptomatic improvement, but the ability of milrinone
to relieve symptoms has not been evaluated in controlled clinical
trials. The great majority of patients experience improvements in
hemodynamic function within 5 to 15 minutes of the initiation
of therapy. In studies in congestive heart failure
patients, milrinone when administered as a loading injection followed
by a maintenance infusion produced significant mean initial increases
in cardiac index of 25 percent, 38 percent, and 42 percent at dose
regimens of 37.5 mcg/kg/0.375 mcg/kg/min, 50 mcg/kg/0.50 mcg/kg/min,
and 75 mcg/kg/0.75 mcg/kg/min, respectively. Over the same range of
loading injections and maintenance infusions, pulmonary capillary
wedge pressure significantly decreased by 20 percent, 23 percent,
and 36 percent, respectively, while systemic vascular resistance significantly
decreased by 17 percent, 21 percent, and 37 percent. Mean arterial
pressure fell by up to 5 percent atthe two lower dose regimens, but
by 17 percent at the highest dose. Patients evaluated for 48 hours
maintained improvements in hemodynamic function, with no evidence
of diminished response (tachyphylaxis). A smaller number of patients
have received infusions of milrinone for periods up to 72 hours without
evidence of tachyphylaxis. The duration of therapy
should depend upon patient responsiveness. Milrinone
has a favorable inotropic effect in fully digitalized patients without
causing signs of glycoside toxicity. Theoretically, in cases of atrial
flutter/fibrillation, it is possible that milrinone may increase ventricular
response rate because of its slight enhancement of AV node conduction.
In these cases, digitalis should be considered prior to the institution
of therapy with milrinone. Improvement in left
ventricular function in patients with ischemic heart disease has been
observed. The improvement has occurred without inducing symptoms or
electrocardiographic signs of myocardial ischemia. The steady-state plasma milrinone concentrations after approximately
6 to 12 hours of unchanging maintenance infusion of 0.50 mcg/kg/min
are approximately 200 ng/mL. Near maximum favorable effects of milrinone
on cardiac output and pulmonary capillary wedge pressure are seen
at plasma milrinone concentrations in the 150 ng/mL to 250 ng/mL range.
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Milrinone lactate is contraindicated in patients
who are hypersensitive to it.
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dailymed-instance:supply |
Milrinone Lactate Injection is supplied as follows: Milrinone Lactate Injection in 5% Dextrose is supplied
as follows: Use only if solution is clear, colorless to pale
yellow, and container is undamaged. Store at
20��to 25��C (68��to 77��F). [See USP Controlled
Room Temperature]. Avoid freezing.
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General: Milrinone should not be used in patients with severe
obstructive aortic or pulmonic valvular disease in lieu of surgical
relief of the obstruction. Like other inotropic agents, it may aggravate
outflow tract obstruction in hypertrophic subaortic stenosis. Supraventricular and ventricular arrhythmias have been
observed in the high-risk population treated. In some patients, injections
of milrinone and oral milrinone have been shown to increase ventricular
ectopy, including nonsustained ventricular tachycardia. The potential
for arrhythmia, present in congestive heart failure itself, may be
increased by many drugs or combinations of drugs. Patients receiving
milrinone should be closely monitored during infusion. Milrinone produces a slight shortening of AV node conduction
time, indicating a potential for an increased ventricular response
rate in patients with atrial flutter/fibrillation which is not controlled
with digitalis therapy. During therapy with
milrinone, blood pressure and heart rate should be monitored and the
rate of infusion slowed or stopped in patients showing excessive decreases
in blood pressure. If prior vigorous diuretic
therapy is suspected to have caused significant decreases in cardiac
filling pressure, milrinone should be cautiously administered with
monitoring of blood pressure, heart rate, and clinical symptomatology. There is no experience in controlled trials with infusions
of milrinone for periods exceeding 48 hours. Cases of infusion sitereaction have been reported with intravenous milrinone therapy (see
ADVERSE REACTIONS). Consequently, careful
monitoring of the infusion site should be maintained to
avoid possible extravasation. Use in acute myocardial infarction No clinical studies have been conducted in patients in
the acute phase of post myocardial infarction. Until further clinical
experience with this class of drugs is gained, milrinone is not recommended
in these patients.<br/>Laboratory Tests: Fluid and Electrolytes: Fluid and electrolyte changes and renal function should be carefully
monitored during therapy with milrinone. Improvement in cardiac output
with resultant diuresis may necessitate a reduction in the dose of
diuretic. Potassium loss due to excessive diuresis may predispose
digitalized patients to arrhythmias. Therefore, hypokalemia should
be corrected by potassium supplementation in advance of or during
use of milrinone.<br/>Drug Interactions: No untoward clinical manifestations have been observedin limited experience with patients in whom milrinone was used concurrently
with the following drugs: digitalis glycosides; lidocaine, quinidine;
hydralazine, prazosin; isosorbide dinitrate, nitroglycerin; chlorthalidone,
furosemide, hydrochlorothiazide, spironolactone; captopril; heparin,
warfarin, diazepam, insulin; and potassium supplements. Chemical Interactions There is an immediate chemical interaction
which is evidenced by the formation of a precipitate when furosemide
is injected into an intravenous line of an infusion of milrinone.
Therefore, furosemide should not be administered in intravenous lines
containing milrinone.<br/>Carcinogenesis, Mutagenesis,
Impairment of Fertility: Twenty-four months of oral administration of milrinone
to mice at doses up to 40 mg/kg/day (about 50 times the human oral
therapeutic dose in a 50 kg patient) was unassociated with evidence
of carcinogenic potential. Neither was there evidence of carcinogenic
potential when milrinone was orally administered to rats at doses
up to 5 mg/kg/day (about 6 times the human oral therapeutic dose)
for twenty-four months or at 25 mg/kg/day (about 30 times the human
oral therapeutic dose) for up to 18 months in males and 20 months
in females. Whereasthe Chinese Hamster Ovary Chromosome Aberration
Assay was positive in the presence of a metabolic activation system,
results from the Ames Test, the Mouse Lymphoma Assay, the Micronucleus
Test, and the in vivo Rat Bone
Marrow Metaphase Analysis indicated an absence of mutagenic potential.
In reproductive performance studies in rats, milrinone had no effect
on male or female fertility at oral doses up to 32 mg/kg/day.<br/>Animal Toxicity: Oral and intravenous administration of toxic dosages
of milrinone to rats and dogs resulted in myocardial degeneration/fibrosis
and endocardial hemorrhage, principally affecting the left ventricular
papillary muscles. Coronary vascular lesions characterized by periarterial
edema and inflammation have been observed in dogs only. The myocardial/endocardial
changes are similar to those produced by beta-adrenergic receptor
agonists such as isoproterenol, while the vascular changes are similar
to those produced by minoxidil and hydralazine. Doses within the recommended
clinical dose range (up to 1.13 mg/kg/day) for congestive heart failure
patients have not produced significant adverse effects in animals.<br/>Pregnancy Category C: Oral administration of milrinone to pregnant rats
and rabbits during organogenesis produced no evidence of teratogenicity
at dose levels up to 40 mg/kg/day and 12 mg/kg/day, respectively.
Milrinone did not appear to be teratogenic when administered intravenously
to pregnant rats at doses up to 3 mg/kg/day (about 2.5 times
the maximum recommended clinical intravenous dose) or pregnant rabbits
at doses up to 12 mg/kg/day, although an increased resorption rate
was apparent at both 8 mg/kg/day and 12 mg/kg/day (intravenous) in
the latter species. There are no adequate and well-controlled studies
in pregnant women. Milrinone should be used during pregnancy only
if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers: Caution should be exercised when milrinone is administered
to nursing women, since it is not known whether it is excreted in
human milk.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have
not been established.<br/>Use in Elderly Patients: There are no special dosage recommendations for the
elderly patient. Ninety percent of all patients administered milrinone
in clinical studies were within the age range of 45 to 70 years, with
a mean age of 61 years. Patients in all age groups demonstrated clinically
and statistically significant responses. No age-related effects on
the incidence ofadverse reactions have been observed. Controlled
pharmacokinetic studies have not disclosed any age-related effects
on the distribution and elimination of milrinone.
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Doses of milrinone may produce hypotension because
of its vasodilator effect. If this occurs, administration of milrinone
should be reduced or temporarily discontinued until the patient's
condition stabilizes. No specific antidote is known, but general measures
for circulatory support should be taken.
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Milrinone Lactate
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dailymed-instance:fullName |
Milrinone Lactate (Injection, Solution)
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dailymed-instance:adverseRe... |
Cardiovascular Effects: In patients receiving milrinone in Phase II and III clinical trials,
ventricular arrhythmias were reported in 12.1%: Ventricular ectopic
activity, 8.5%; nonsustained ventricular tachycardia, 2.8%; sustained
ventricular tachycardia, 1% and ventricular fibrillation, 0.2% (2
patients experienced more than one type of arrhythmia). Holter recordings
demonstrated that in some patients injection of milrinone increased
ventricular ectopy, including nonsustained ventricular tachycardia.
Life-threatening arrhythmias were infrequent and when present have
been associated with certain underlying factors such as preexisting
arrhythmias, metabolic abnormalities (e.g. hypokalemia), abnormal
digoxin levels and catheter insertion. Milrinone was not shown to
be arrhythmogenic in an electrophysiology study. Supraventricular
arrhythmias were reported in 3.8% of the patients receiving milrinone.
The incidence of both supraventricular and ventricular arrhythmias
has not been related to the dose or plasma milrinone concentration. Other cardiovascular adverse reactions include hypotension,
2.9% and angina/chest pain, 1.2%. In the post
marketing experience, there have been rare cases of���torsades
de pointes���reported. CNS Effects Headaches,
usually mild to moderate in severity, have been reported in 2.9% of
patients receiving milrinone. Other Effects Other
adverse reactions reported, but not definitely related to the administration
of milrinone include hypokalemia, 0.6%; tremor, 0.4%; and thrombocytopenia,
0.4%. Isolated spontaneous reports of bronchospasm
and anaphylactic shock have been received; and in the post-marketing
experience, liver function test abnormalities have been reported. Post-Marketing Adverse Event
Reports In addition to adverse events
reported from clinical trials, the following events have been reported
from worldwide post-marketing experience with milrinone: Isolated spontaneous reports of bronchospasm and anaphylactic
shock. Liver function test abnormalities and
skin reactions such as rash. Administration
site conditions: Infusion site reaction
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dailymed-instance:warning |
Whether given orally or
by continuous or intermittent intravenous infusion, milrinone has
not been shown to be safe or effective in the longer (greater than
48 hours) treatment of patients with heart failure. In a multicenter
trial of 1088 patients with Class III and IV heart failure, long-term
oral treatment with milrinone was associated with no improvement in
symptoms and an increased risk of hospitalization and death. In this
study, patients with Class IV symptoms appeared tobe at particular
risk of life-threatening cardiovascular reactions. There is no evidence
that milrinone given by long-term continuous or intermittent infusion
does not carry a similar risk. The use of milrinone both intravenously and orally
has been associated with increased frequency of ventricular arrhythmias,
including nonsustained ventricular tachycardia.Long-term oral use
has been associated with an increased risk of sudden death. Hence,
patients receiving milrinone should be observed closely with the use
of continuous electrocardiographic monitoring to allow the prompt
detection and management of ventricular arrhythmias.
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dailymed-instance:indicatio... |
Milrinone lactate injection is indicated for the
short-term intravenous treatment of patients with acute decompensated
heart failure. Patients receiving milrinone should be observed closely
with appropriate electrocardiographic equipment. The facility for
immediate treatment of potential cardiac events, which may include
life threatening ventricular arrhythmias, must be available. The majority
of experience with milrinone has been in patients receiving digoxin
and diuretics. There is no experience in controlled trials with infusions
of milrinone for periods exceeding 48 hours.
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Milrinone Lactate
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