Drug class: Cardiotonic Agents
VA class: CV900
Chemical name: 1,6-Dihydro-2-methyl-6-oxo-[3,4′-bipyridine]-5-carbonitrile
Molecular formula: C₁₂H₉N₃O
CAS number: 78415-72-2

Medically reviewed by Drugs.com on Feb 22, 2024. Written by ASHP.

Introduction

Positive inotropic agent that has vasodilating effects; a selective phosphodiesterase (PDE) inhibitor.

Uses for Milrinone

Heart Failure

Short-term management of acute decompensated heart failure. In most clinical studies, used in patients with NYHA class III or IV CHF who were receiving cardiac glycosides (e.g., digoxin) and diuretics. No evidence to date that milrinone decreases mortality.

Not found to be safe and effective in the long-term (>48 hours) treatment of heart failure. (See Mortality Associated with Long-term Use under Cautions.) Some clinicians recommend reserving milrinone therapy for patients with severe heart failure whose condition is refractory to therapy with cardiac glycosides, diuretics, ACE inhibitors, and/or β-adrenergic blocking agents.

Because positive inotropic agents have not demonstrated improved outcomes and can be potentially harmful (e.g., increased risk of arrhythmias in patients with heart failure), the ACCF and AHA recommend that these drugs be reserved for patients with severe systolic dysfunction who have low cardiac index and evidence of systemic hypoperfusion and/or congestion, or for palliative therapy in those with end-stage heart failure. To minimize risk of adverse effects, use lowest possible dosage and evaluate regularly for need for continued inotropic therapy.

Has been used for treatment of heart failure associated with cardiac surgery^{† [off-label]}.

Advanced Cardiovascular Life Support (ACLS)

Also has been used for postresuscitation stabilization^{† [off-label]} in patients who require additional cardiac output and BP support following cardiac arrest.

Milrinone Dosage and Administration

Administration

Administer by slow IV injection followed by IV infusion.

Has been administered orally^{† [off-label]} (oral dosage form not commercially available in US), but increased morbidity and mortality have precluded continued study of this route of administration. Also has been administered by intraosseous (IO) injection^{† [off-label]} in the setting of ACLS.

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer as a slow IV injection followed by a continuous IV infusion.

Administer initial dose undiluted or diluted (for better visualization of injection rate).

Administer IV infusions via a calibrated electronic controlled-infusion device.

Do not use premixed IV solution in flexible plastic containers in series connections. For administration instructions for premixed solutions, consult manufacturers’ labelings.

Dilution

Initial dose: May dilute initial dose with 0.45% sodium chloride injection, 0.9% sodium chloride injection, or 5% dextrose injection to a total volume of 10 or 20 mL.

Continuous IV infusion: Dilute contents of vial containing milrinone 10, 20, or 50 mg with 40, 80, or 200 mL, respectively, of 0.45% sodium chloride injection, 0.9% sodium chloride injection, or 5% dextrose injection to provide a solution containing approximately 200 mcg/mL. Alternatively, use premixed solution containing 200 mcg/mL of milrinone in 5% dextrose injection without further dilution.

Rate of Administration

Administer initial dose slowly (e.g., over 10 minutes) as a direct IV injection.

Adjust rate of IV infusion according to hemodynamic and clinical response, including assessment of cardiac output and pulmonary capillary wedge pressure.

Dosage

Available as milrinone lactate; dosage expressed in terms of milrinone.

Pediatric Patients

ACLS

IV/IO

For postresuscitation stabilization^{† [off-label]}, initial loading dose of 50 mcg/kg over 10–60 minutes, followed by an infusion of 0.25–0.75 mcg/kg per minute, has been administered.

Adults

Heart Failure

Acute Decompensated Heart Failure

IV

Initially, 50 mcg/kg as a slow, direct injection, followed by an IV infusion of 0.375– 0.75 mcg/kg per minute. Duration of therapy depends on clinical response.

ACLS

IV

For postresuscitation stabilization^†, initial loading dose of 50 mcg/kg as a direct injection over 10 minutes, followed by an infusion of 0.375 mcg/kg per minute, usually administered.

Prescribing Limits

Adults

Heart Failure

Acute Decompensated Heart Failure

IV

Maximum total dosage (including initial and cumulative doses) 1.13 mg/kg daily.

Special Populations

Renal Impairment

Heart Failure

IV

Reduce rate of continuous IV infusion in patients with Cl_cr≤50 mL/minute.

Geriatric Patients

No dosage adjustments except those related to renal impairment. (See Renal Impairment under Dosage and Administration.)

Cautions for Milrinone

Contraindications

• Known hypersensitivity to milrinone or any ingredient in the formulation.

Warnings/Precautions

Warnings

Mortality Associated with Long-term Use

Not found to be safe and effective for long-term (>48 hours) treatment of heart failure; chronic oral therapy did not consistently alleviate symptoms and was associated with increased risk of hospitalization and sudden death, particularly in patients with NYHA class IV disease. No evidence to indicate that long-term IV therapy (either continuous or intermittent infusion) would not be associated with similar risks.

Mechanism for increased mortality not fully elucidated; long-term therapy may result in increased cellular cAMP concentrations (with resultant toxicity to myocardial cells and enhanced electrophysiologic mechanisms leading to arrhythmias, including ventricular arrhythmias). (See Arrhythmogenic Effects under Cautions.)

Arrhythmogenic Effects

Potential for increased frequency of supraventricular and ventricular arrhythmias (e.g., nonsustained ventricular tachycardia). Close monitoring, including continuous ECG monitoring, recommended to allow for prompt detection and management of ventricular arrhythmias.

General Precautions

Obstructive Valvular Disease

May aggravate outflow track obstruction; use with caution in patients with hypertrophic subaortic stenosis.

Should not replace surgical intervention necessary to relieve obstruction in patients with severe obstructive aortic or pulmonic valvular disease.

Effects on Cardiac Conduction

Possible slight shortening of AV conduction velocity; may result in increased ventricular response rate in patients with atrial flutter or fibrillation not controlled with cardiac glycoside therapy. Consider cardiac glycoside therapy prior to use in patients with atrial flutter or fibrillation.

Hemodynamic Effects

Possible excessive decreases in BP. Close monitoring of BP, heart rate, and clinical symptomatology recommended, especially in patients with substantial decreases in cardiac filling pressure associated with prior vigorous diuretic therapy. Decrease or stop the IV infusion if necessary.

MI

Use not recommended during the acute phase following MI.

Fluid and Electrolyte Imbalance

Observe patient closely for changes in fluid and electrolyte balance and renal function. Milrinone-induced increases in cardiac output with resultant diuresis may require dosage reduction of diuretics to prevent excessive potassium loss. Hypokalemia may predispose digitalized patients to cardiac arrhythmias; correct hypokalemia by potassium supplementation prior to and/or during milrinone therapy.

Specific Populations

Pregnancy

Category C.

Lactation

Not known whether milrinone is distributed into milk. Caution advised if used in nursing women.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.

Renal Impairment

Clearance may be decreased; dosage adjustments necessary depending on degree of renal impairment. (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Ventricular arrhythmias (e.g., ventricular ectopy, nonsustained ventricular tachycardia ), supraventricular arrhythmias, hypotension, headache.

Drug Interactions

Administered concomitantly with cardiac glycosides, lidocaine, quinidine, hydralazine, prazosin, isosorbide dinitrate, nitroglycerin, chlorthalidone, furosemide, hydrochlorothiazide, spironolactone, captopril, heparin, warfarin, diazepam, insulin, and potassium supplements without unusual adverse effects.

Milrinone Pharmacokinetics

Absorption

Onset

Following IV administration, improvement in hemodynamic function usually occurs within 5–15 minutes.

Duration

Hemodynamic responses usually are maintained during continuous IV infusion for 48–72 hours; no evidence of tachyphylaxis observed.

Plasma Concentrations

Plasma milrinone concentrations appear to correlate with cardiovascular effects. Inotropic and vasodilatory effects occur with plasma milrinone concentrations of 100–300 ng/mL.

Distribution

Plasma Protein Binding

Approximately 70%.

Elimination

Elimination Route

Excreted principally in urine as unchanged drug (83%) and its O-glucuronide metabolite (12%). Only small amounts are excreted in feces.

Half-life

Approximately 2.4 hours.

Special Populations

In patients with renal impairment (but without CHF), elimination half-life is substantially increased.

Stability

Storage

Parenteral

Injection, for IV use

15–25°C; do not freeze.

Injection, for IV infusion (premixed solution)

25°C; may be exposed briefly to temperatures up to 40°C. Do not freeze.

Compatibility

Parenteral

Solution CompatibilityHID

Drug Compatibility

Actions

• Selectively inhibits cyclic adenosine monophosphate (cAMP) phosphodiesterase activity in cardiac and vascular muscles, resulting in increased intracellular concentrations of cAMP; such increases in cAMP may be associated with increased intracellular ionized calcium and result in increased myocardial contractility.

• Has vasodilatory activity; however, has little chronotropic activity.

• Increases cardiac output and decreases pulmonary capillary wedge pressure and vascular resistance; produces minor changes in heart rate or myocardial oxygen consumption.

Advice to Patients

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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