Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous:
Generic: 200 mcg/mL (100 mL, 200 mL); 10 mg/10 mL (10 mL); 20 mg/20 mL (20 mL); 50 mg/50 mL (50 mL)
Solution, Intravenous [preservative free]:
Generic: 200 mcg/mL (100 mL, 200 mL); 20 mg/20 mL (20 mL)
Pharmacology
Mechanism of Action
A selective phosphodiesterase inhibitor in cardiac and vascular tissue, resulting in vasodilation and inotropic effects with little chronotropic activity.
Pharmacokinetics/Pharmacodynamics
Distribution
Vd beta:
Infants (after cardiac surgery): 0.9 ± 0.4 L/kg (Ramamoorthy 1998)
Children (after cardiac surgery): 0.7 ± 0.2 L/kg (Ramamoorthy 1998)
Adults:
After cardiac surgery: 0.3 ± 0.1 L/kg (Ramamoorthy 1998)
Heart failure (with single injection): 0.38 L/kg
Heart failure (with infusion): 0.45 L/kg
Metabolism
Hepatic (minor); majority is not metabolized (Rocci 1987)
Excretion
Urine (83% as unchanged drug; 12% as 0-glucuronide metabolite); active tubular secretion is a major elimination pathway for milrinone (Rocci 1987)
Clearance:
Infants (after cardiac surgery): 3.8 ± 1 mL/kg/minute (Ramamoorthy 1998)
Children (after cardiac surgery): 5.9 ± 2 mL/kg/minute (Ramamoorthy 1998)
Children (with septic shock): 10.6 ± 5.3 mL/kg/minute (Lindsay 1998)
Adults:
After cardiac surgery: 2 ± 0.7 mL/kg/minute (Ramamoorthy 1998)
Heart failure: 2.2 to 2.3 mL/kg/minute
Onset of Action
IV: 5 to 15 minutes
Half-Life Elimination
Infants (after cardiac surgery): 3.15 ± 2 hours (Ramamoorthy 1998)
Children (after cardiac surgery): 1.86 ± 2 hours (Ramamoorthy 1998)
Adults:
Heart failure: 2.3 to 2.4 hours; renal impairment prolongs half-life (Rocci 1987)
Severe heart failure undergoing continuous venovenous hemofiltration (CVVH): 20.1 ± 3.3 hours (Taniguchi 2000)
Protein Binding
Plasma: ~70%
Use: Labeled Indications
Inotropic support in heart failure: Short-term IV therapy of acutely-decompensated heart failure (HF)
Guideline recommendations:
Heart failure: Bridge therapy in stage D HF unresponsive to guideline-directed medical therapy and device therapy in patients awaiting heart transplant or mechanical circulatory support; short-term management of hospitalized patients with severe systolic dysfunction presenting with low blood pressure and significantly depressed cardiac output; long-term management (palliative therapy) in select patients with stage D HF unresponsive to guideline-directed medical therapy and device therapy who are not candidates for heart transplant or mechanical circulatory support (ACCF/AHA [Yancy 2013]).
Use: Off Label
Bridge to heart transplantationb
Data from several prospective trials and one observational study support the use of milrinone in patients awaiting heart transplant Aranda 2003, Bhat 2006, Brozena 2004, Upadya 2004. Additional trials may be necessary to further define the role of milrinone in this setting.
Cardiogenic shockyes
The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) heart failure guidelines and an American Heart Association scientific statement on management of cardiogenic shock recommend milrinone to maintain systemic perfusion and preserve end-organ performance in HF patients with reduced ejection fraction presenting with cardiogenic shock ACCF/AHA [Yancy 2013], AHA [van Diepen 2017].
Palliation of symptoms in end-stage heart failureyes
Based on the American College of Cardiology Foundation/American Heart Association guidelines for the management of heart failure, long-term, continuous use of positive inotropic drugs is acceptable for palliation of patients with end-stage heart failure (ie, stage D) who cannot be stabilized with standard medical treatment, including device therapy, and are not eligible for either mechanical circulatory support or cardiac transplantation.
Postoperative inotropic support for heart transplant recipientsyes
Based on The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients, milrinone given for the perioperative inotropic support of heart transplant recipients is suggested as a therapeutic option in this setting.
Contraindications
Hypersensitivity to milrinone or any component of the formulation
Dosage and Administration
Dosing: Adult
Inotropic support in heart failure: IV: Loading dose (optional, not recommended by ACCF/AHA 2013 heart failure guidelines; also see "Note"): 50 mcg/kg administered over 10 minutes followed by a maintenance dose titrated according to hemodynamic and clinical response; Maintenance dose: IV infusion: 0.375 to 0.75 mcg/kg/minute; lower initial doses of 0.1 mcg/kg/minute (with final maintenance doses of 0.2 to 0.3 mcg/kg/minute) have also been recommended (HFSA [Lindenfeld 2010]). The ACCF/AHA 2013 heart failure guidelines recommend a maintenance dose of 0.125 to 0.75 mcg/kg/minute (ACCF/AHA [Yancy 2013]).
Note: When initiating an infusion of 0.5 mcg/kg/minute without a loading dose, significant hemodynamic changes seen at 30 minutes with similar effects on pulmonary capillary wedge pressure and cardiac index seen at 2 and 3 hours, respectively, compared to loading dose regimen (Baruch 2001).
Bridge to heart transplantation (off-label use): IV: 0.1 to 0.75 mcg/kg/minute; titrate to optimize clinical condition (Aranda 2003; Bhat 2006; Upadya 2004)
Cardiogenic shock (off-label use): IV: 0.125 to 0.75 mcg/kg/minute (AHA [van Diepen 2017])
Postoperative inotropic support in heart transplant recipients (off-label use): IV: 0.375 to 0.75 mcg/kg/minute; use the lowest effective dose and wean as tolerated over the first 3 to 5 days (ISHLT [Costanzo 2010]).
Dosing: Geriatric
Refer to adult dosing.
Dosing: Pediatric
Hemodynamic support (eg, acute decompensated heart failure, cardiogenic shock, septic shock): Limited data available; optimal dosing not established: Note: Dosing should be individualized and titrated to effect due to interpatient variability in clearance, with or without low cardiac output syndrome or acute kidney injury (Bailey 2004; Garcia Guerra 2013; Gist 2015; Vogt 2014):
Infants, Children, and Adolescents: IV, Intraosseous: Loading dose (optional): 50 mcg/kg administered over 10 to 60 minutes followed by a continuous IV or intraosseous infusion; infusion dose range: 0.25 to 0.75 mcg/kg/minute; titrate dose to effect (PALS [Kleinman 2010]). Due to the risk of hypotension, some centers do not utilize a loading dose (ACCM [Davis 2017]).
Low cardiac output syndrome (LCOS) following CHD corrective surgery, prevention: Limited data available: Infants and Children: IV: Loading dose: 25 or 75 mcg/kg administered over 60 minutes followed by a continuous IV infusion of 0.25 or 0.75 mcg/kg/minute (Hoffman 2003). Dosing based on a double-blind, placebo-controlled trial which randomized 227 postoperative cardiac surgery patients (age range: 2 days to 6.9 years, median: 3 months) at high risk for LCOS to low-dose milrinone (loading dose: 25 mcg/kg, continuous infusion: 0.25 mcg/kg/minute), high-dose milrinone (loading dose: 75 mcg/kg, continuous infusion: 0.75 mcg/kg/minute), and placebo; results showed patients in the high-dose milrinone group had a 64% relative risk reduction for the development of LCOS compared to placebo; the low-dose milrinone group had a statistically insignificant trend toward reducing the development of LCOS (Hoffman 2003).
Reconstitution
Loading dose (optional): May administer undiluted; diluting to a rounded total volume of 10 or 20 mL may simplify the visualization of the injection rate.
Maintenance dose: For a final concentration of 0.2 mg/mL: Dilute 1 mg/mL (20 mL) with 80 mL diluent (final volume: 100 mL) of 1/2NS, NS or D5W. May also dilute 1 mg/mL (10 mL) with 40 mL diluent (final volume: 50 mL).
Administration
IV: For IV use only. Administer loading dose (optional) undiluted slowly over 10 minutes; diluting to a rounded total volume of 10 or 20 mL may simplify the visualization of the injection rate. Infuse maintenance dose via continuous infusion pump.
Storage
Store at 20°C to 25°C (68°F to 77°F); avoid freezing. Minimize exposure to heat; avoid excessive heat. Brief exposure up to 40°C (104°F) will not adversely affect drug. Stable at 0.2 mg/mL in 1/2NS, NS, or D5W for 72 hours at room temperature in normal light (Wilson 1986).
Drug Interactions
Anagrelide: May enhance the adverse/toxic effect of Milrinone. Avoid combination
Riociguat: Milrinone may enhance the hypotensive effect of Riociguat. Management: Riociguat is contraindicated with nonselective phosphodiesterase (PDE) inhibitors and PDE type 5 inhibitors. Other types of PDE inhibitors are not contraindicated, but caution is advised and patients should be monitored for hypotension. Monitor therapy
Adverse Reactions
>10%: Cardiovascular: Ventricular arrhythmia (ventricular ectopy: 9%, nonsustained ventricular tachycardia: 3%, ventricular tachycardia: 1%, ventricular fibrillation: <1%)
1% to 10%:
Cardiovascular: Supraventricular cardiac arrhythmia (4%), hypotension (3%), angina pectoris (≤1%), chest pain (≤1%)
Central nervous system: Headache (3%)
<1%, postmarketing, and/or case reports: Anaphylaxis, atrial fibrillation, bronchospasm, hepatic insufficiency, hypokalemia, injection site reaction, myocardial infarction, skin rash, thrombocytopenia, torsades de pointes, tremor
Warnings/Precautions
Concerns related to adverse effects:
- Arrhythmias: Ventricular arrhythmias, including nonsustained ventricular tachycardia and supraventricular arrhythmias, have been reported. Observe closely for arrhythmias in this very high-risk patient population; sudden cardiac death has been observed. Due to the prolonged half-life as compared to other inotropic agents, ventricular or atrial arrhythmias may persist even after discontinuation of milrinone especially in patients with renal dysfunction (Cox 2013; Leier 1998). Ensure that ventricular rate is controlled in atrial fibrillation/flutter before initiating; may increase ventricular response rate. In heart transplant candidates, institute appropriate measures to protect patient against risks of sudden cardiac death (Brozena 2004).
- Hypotension: Hypotension may occur. Monitor blood pressure closely. Hypotension may be prolonged especially in patients with renal dysfunction (Cox 2013; Leier 1998). Vigorous diuresis may contribute to hypotension; cautious administration of fluids may be required to prevent hypotension. Omitting the bolus dose may decrease the risk of hypotension (Baruch 2001; Cuffe 2002). If hypotension occurs, consider dose reduction or temporary discontinuation.
Disease-related concerns:
- Cardiovascular disease: Avoid use in patients with severe obstructive aortic or pulmonic valvular disease in lieu of surgical relief of the obstruction; may aggravate outflow tract obstruction in hypertrophic cardiomyopathy with outflow tract obstruction.
- Electrolyte imbalance: Correct electrolyte disturbances, especially hypokalemia or hypomagnesemia, prior to use and throughout therapy to minimize the risk of arrhythmias.
- Renal impairment: Use with caution in patients with renal impairment; reduction in infusion rate recommended. Hypotension may be prolonged in patients with renal dysfunction (Cox 2013; Leier 1998).
Other warnings/precautions:
- Appropriate use: A facility for immediate treatment of potential cardiac events, including life-threatening ventricular arrhythmias, must be available. Safe and effective use beyond 48 hours (prolonged use) has not been demonstrated. An increased risk of death and hospitalization has been observed with prolonged use in NYHA Class III/IV heart failure patients. Sudden cardiac death has been reported with prolonged use. Continuous electrocardiographic monitoring is recommended.
- Long-term therapy: According to the ACCF/AHA 2013 heart failure guidelines, long-term use of intravenous inotropic therapy without a specific indication or for reasons other than palliation is potentially harmful (ACCF/AHA [Yancy 2013]).
Monitoring Parameters
Platelet count, electrolytes (especially potassium and magnesium) and fluid status, renal function; ECG, blood pressure, heart rate; infusion site
If pulmonary artery catheter is in place, monitor cardiac index, stroke volume, systemic vascular resistance, pulmonary capillary wedge pressure and pulmonary vascular resistance.
Consult individual institutional policies and procedures.
Pregnancy
Pregnancy Risk Factor
C
Pregnancy Considerations
Adverse events have not been observed in animal reproduction studies; however, increased resorption was reported in some studies.
Patient Education
What is this drug used for?
- It is used to treat heart failure (weak heart).
Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:
- Fast heartbeat
- Severe dizziness
- Passing out
- Abnormal heartbeat
- Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.
Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.
Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.
