MILRINONE STRAGEN

Heart failure is a multifactorial condition that affects roughly 1-2% of the adult population.

Often the result of long-term myocardial ischemia, cardiomyopathy, or other cardiac insults, heart failure results from an inability of the heart to perfuse peripheral tissues with sufficient oxygen and metabolites, resulting in complex systemic pathologies.

Heart failure is underpinned by numerous physiological changes, including alteration in β-adrenergic signalling and cyclic adenosine monophosphate (cAMP) production, which affects the heart's contractile function and cardiac output.

Milrinone is a second-generation bipyridine phosphodiesterase (PDE) inhibitor created through chemical modification of amrinone.

As a

PDE-III inhibitor, milrinone results in increased cAMP levels and improves cardiac function and peripheral vasodilation in acute decongested heart failure. 3, 7, 1, 2, 4, 8 Milrinone was originally synthesized at the Sterling Winthrop Research Institute in the 1980s.

It was approved by the FDA on December 31, 1987, and was marketed under the trademark PRIMACOR® by Sanofi-Aventis US before being discontinued.

Milrinone is indicated for the short-term (48 hours or less) treatment of patients with acute decompensated heart failure.

Milrinone administration should occur together with close monitoring using appropriate electrocardiographic equipment and should occur in a facility equipped for the immediate treatment of potential cardiac events, including ventricular arrhythmias.

Milrinone is a bipyridine derivative with positive inotropic and lusitropic effects that also results in peripheral vasodilation with minimal chronotropic effects over a therapeutic range of 100-300 ng/mL. 8, 6 As such, milrinone is used in decompensated congestive heart failure.

Studies have demonstrated that milrinone exhibits sigmoidal effects, such that increasing milrinone plasma concentrations beyond a certain level results in no further hemodynamic changes.

Despite milrinone's benefits, both intravenous and oral use has been associated with increased frequency of ventricular arrhythmias, and long-term oral use has been associated with an increased risk of sudden death; in general, there are no data to support the safety or efficacy of milrinone use beyond 48 hours and patients should be monitored closely for cardiac dysfunction.

Also, as milrinone is primarily excreted renally, dose adjustments may be required in patients with impaired renal function.

cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A Inhibitor.

When administered as an

Intravenous bolus dose of 10-100 μg/kg, milrinone induces hemodynamic effects within 60 seconds reaching a peak effect by 2-5 minutes.

The plasma

AUC is significantly dose-dependent.

Milrinone administered

Intravenous to congestive heart failure patients had a volume of distribution of 0.38 L/kg (injections between 12.5-125 μg/kg) and 0.45 L/kg (infusions between 0.2-0.7 μg/kg/min.

Animal studies suggest that two oxidative pathways are involved in milrinone metabolism, albeit only involving a small proportion of the administered dose.

The major metabolite is the

O-glucuronide metabolite. 2, 8.

Milrinone is primarily excreted in the urine, with 60% of a dose recovered after two hours and 90% within eight hours.

Approximately 83% of milrinone recovered in urine is unchanged while 12% is present as the main O-glucuronide metabolite. 2, 6, 8.

Milrinone administered

Intravenous to congestive heart failure patients had a mean terminal elimination half-life of 2.3 hours (injections between 12.5-125 μg/kg) and 2.4 hours (infusions between 0.2-0.7 μg/kg/min.

Milrinone administered

Intravenous to congestive heart failure patients had a clearance of 0.13 L/kg/hr (injections between 12.5-125 μg/kg) and 0.14 L/kg/hr (infusions between 0.2-0.7 μg/kg/min.

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information regarding milrinone is not readily available.

Patients experiencing an overdose are at an increased risk of severe adverse effects such as hypotension and adverse cardiac events such as ventricular arrhythmias.

Whether given orally or by continuous or intermittent intravenous infusion, milrinone lactate 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 lactate was associated with no improvement in symptoms and an increased risk of hospitalization and death.

In this study, patients with Class IV symptoms appeared to be at particular risk of life-threatening cardiovascular reactions.

There is no evidence that milrinone lactate given by long-term continuous or intermittent infusion does not carry a similar risk.

The use of milrinone lactate 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 lactate should be observed closely with the use of continuous electrocardiographic monitoring to allow the prompt detection and management of ventricular arrhythmias.

Injection is contraindicated in patients who are hypersensitive to it.

Injection, USP should be administered with a loading dose followed by a continuous infusion (maintenance dose) according to the following guidelines: LOADING DOSE 50 mcg/kg: Administer slowly over 10 minutes The table below shows the loading dose in milliliters (mL) of milrinone lactate (1mg/mL) by patient body weight (kg).

Dose (mL) Using 1 mg/mL Concentration Patient Body Weight (kg) kg 30 40 50 60 70 80 90 100 110 120 mL 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 The loading dose may be given undiluted, but diluting to a rounded total volume of 10 or 20 mL may simplify the visualization of the injection rate.

Dose (24 Hours) Minimum 0.375 mcg/kg/min 0.59 mg/kg Administer as a continuous intravenous infusion Standard 0.5 mcg/kg/min 0.77 mg/kg Maximum 0.75 mcg/kg/min 1.13 mg/kg Milrinone lactate 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.

Concentration mcg/mL Milrinone Lactate Injection 1 mg/mL (mL) Diluent (mL) Total Volume (mL) 200 10 40 50 200 20 80 100 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.

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.

Rate (mL/hr) Using 200 mcg/mL Concentration Maintenance Dose (mcg/kg/min) Patient Body Weight (kg) 30 40 50 60 70 80 90 100 110 120 0.375 3.4 4.5 5.6 6.8 7.9 9 10.1 11.3 12.4 13.5 0.4 3.6 4.8 6 7.2 8.4 9.6 10.8 12 13.2 14.4 0.5 4.5 6 7.5 9 10.5 12 13.5 15 16.5 18 0.6 5.4 7.2 9 10.8 12.6 14.4 16.2 18 19.8 21.6 0.7 6.3 8.4 10.5 12.6 14.7 16.8 18.9 21 23.1 25.2 0.75 6.8 9 11.3 13.5 15.8 18 20.3 22.5 24.8 27 When administering milrinone lactate by continuous infusion, it is advisable to use a calibrated electronic infusion device.

Intravenous drug products should be inspected visually and should not be used if particulate matter or discoloration is present.

Data obtained from patients with severe renal impairment (creatinine clearance = 0 to 30 mL/min) but without congestive heart failure have demonstrated that the presence of renal impairment significantly increases the terminal elimination half-life of milrinone lactate.

Reductions in infusion rate may be necessary in patients with renal impairment.

For patients with clinical evidence of renal impairment, the recommended infusion rate can be obtained from the following table: Creatinine Clearance (mL/min/1.73m 2 ) Infusion Rate (mcg/kg/min) 5 0.2 10 0.23 20 0.28 30 0.33 40 0.38 50 0.43.

Injection, USP is supplied as 10 mL single-dose vials in a box of 10, NDC 83301-0016-2; as 20 mL single-dose vials box of 10, NDC 83301-0017-2, containing a sterile, clear, colorless to pale yellow solution.

Each mL contains milrinone lactate equivalent to 1 mg milrinone.

Store at 20° to 25°C (68° to 77°F) .

Avoid freezing.

Discard unused portion after initial use.

Manufactured for

Pasadena, CA 91101.