Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/268
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Milrinone Lactate (Injection, Solution)
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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 a molecular weight
of 211.22 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 Injection is available as
a sterile aqueous solution of the lactate
salt of milrinone for intravenous use. Each mL of the 10 mL and 20 mL single dose
vials contains milrinone lactate equivalent
to 1 mg milrinone and 47 mg Dextrose,
Anhydrous, USP in Water for Injection, USP.
The pH is adjusted 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.
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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 dothe
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.<br/>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 0.2
mcg/kg/min to 0.7 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.<br/>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
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/0.5mcg/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 at the 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 0.5
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 Injection is
contraindicated in patients who are
hypersensitive to it.
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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 site
reaction have been reported
with intravenous milrinone
therapy (see ADVERSE
REACTIONS).
Consequently, careful monitoring
of the infusion site
should be
maintained to
avoid possible
extravasation.<br/>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:<br/>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
observed in 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.<br/>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 and Mutagenesis and
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. Whereas the 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:<br/>Teratogenic
Effects: 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/>Geriatric Use: There are no special dosage
recommendations for the
geriatric 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 of adverse
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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Milrinone Lactate (Injection, Solution)
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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 ClassIV symptoms appeared to
be 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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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 intravenous
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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