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Pronunciation

(MIL ri none)

Generic Available (U.S.)

Yes

Index Terms

• Milrinone Lactate

Brand Names: Canada

• Milrinone Lactate Injection
• Primacor®

Pharmacologic Category

• Phosphodiesterase Enzyme Inhibitor

Pharmacologic Category Synonyms

• PDE Inhibitor

Use: Labeled Indications

Short-term I.V. therapy of acutely-decompensated heart failure

Use: Unlabeled

Inotropic therapy for patients unresponsive to other acute heart failure therapies (eg, dobutamine); outpatient inotropic therapy for heart transplant candidates; palliation of symptoms in end-stage heart failure patients who cannot otherwise be discharged from the hospital and are not transplant candidates

Pregnancy Risk Factor

C

Pregnancy Considerations

Teratogenic effects have not been observed in animal reproduction studies; however, increased resorption was reported in some studies.

Lactation

Excretion in breast milk unknown/use caution

Contraindications

Hypersensitivity to milrinone, inamrinone, or any component of the formulation; concurrent use of inamrinone

Warnings/Precautions

Concerns related to adverse effects:

• Arrhythmias: Observe for arrhythmias in this very high-risk patient population. Ventricular or atrial arrhythmias may persist even after discontinuation of inamrinone especially in patients with renal dysfunction. 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.

• Hepatic effects: Discontinue therapy if dose-related elevations in LFTs and clinical symptoms of hepatotoxicity occur; monitor liver function.

• Hypotension: Monitor blood pressure/ heart rate closely. Mean arterial pressure decreases by ∼5% at doses between 0.375-5 mcg/kg/minute and by 17% at 0.75 mcg/kg/minute (includes loading doses ranging between 37.5-75 mcg/kg). Infusion may require reduction in dose or temporary discontinuation if hypotension occurs. Hypotension may be prolonged especially in patients with renal dysfunction. Vigorous diuresis may contribute to hypotension; cautious administration of fluids may be required to prevent hypotension.

Disease-related concerns:

• Electrolyte imbalance: Correct electrolyte disturbances, especially hypokalemia or hypomagnesemia, prior to use and throughout therapy.

• Myocardial infarction (MI): Not recommended in acute MI treatment.

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment recommended. Hypotension may be prolonged in patients with renal dysfunction.

Other warnings/precautions:

• Long-term therapy: According to the ACC/AHA 2009 heart failure guidelines, long-term, regularly-scheduled intermittent infusions are strongly discouraged.

• Monitoring: Monitor fluid status closely; patients may require adjustment of diuretic and electrolyte replacement therapy.

Adverse Reactions

>10%: Cardiovascular: Ventricular arrhythmia (ectopy 9%, NSVT 3%, sustained ventricular tachycardia 1%, ventricular fibrillation <1%)

1% to 10%:

Cardiovascular: Supraventricular arrhythmia (4%), hypotension (3%), angina/chest pain (1%)

Central nervous system: Headache (3%)

<1% (Limited to important or life-threatening): Atrial fibrillation, hypokalemia, MI, thrombocytopenia, tremor, ventricular fibrillation

Postmarketing and/or case reports: Anaphylaxis, bronchospasm, injection site reaction, liver function abnormalities, rash, torsade de pointes

Metabolism/Transport Effects

None known.

Drug Interactions

There are no known significant interactions.

Storage

Store at 15°C to 30°C (59°F to 86°F); avoid freezing. Stable at 0.2 mg/mL in 1/2NS, NS, or D₅W for 72 hours at room temperature in normal light.

Reconstitution

Standard dilution: For a final concentration of 0.2 mg/mL: Dilute Primacor® 1 mg/mL (20 mL) with 80 mL diluent (final volume: 100 mL) of 1/2 NS, NS or D₅W. May also dilute 1 mg/mL (10 mL) with 40 mL diluent (final volume: 50 mL).

Compatibility

Stable in D₅W, LR, 1/2NS, NS.

Y-site administration: Compatible: Acyclovir, amikacin, amiodarone, ampicillin, argatroban, atracurium, bivalirudin, bumetanide, calcium chloride, calcium gluconate, caspofungin, cefazolin, cefepime, cefotaxime, ceftazidime, cefuroxime, cimetidine, ciprofloxacin, clindamycin, dexamethasone sodium phosphate, dexmedetomidine, digoxin, diltiazem, dobutamine, dopamine, doripenem, epinephrine, fenoldopam, fentanyl, gentamicin, heparin, hetastarch in lactate electrolyte injection (Hextend®), hydromorphone, insulin (regular), isoproterenol, labetalol, lorazepam, magnesium sulfate, meropenem, methylprednisolone sodium succinate, metoprolol, metronidazole, micafungin, midazolam, morphine, nesiritide, nicardipine, nitroglycerin, nitroprusside, norepinephrine, oxacillin, pancuronium, piperacillin, piperacillin/tazobactam, potassium chloride, propofol, propranolol, quinidine gluconate, ranitidine, rocuronium, sodium bicarbonate, telavancin, theophylline, thiopental, ticarcillin/clavulanate, tobramycin, torsemide, vancomycin, vasopressin, vecuronium, verapamil. Incompatible: Furosemide, imipenem/cilastin, procainamide.

Compatibility in syringe: Compatible: Atropine, calcium chloride, digoxin, epinephrine, lidocaine, morphine, propranolol, sodium bicarbonate, verapamil. Incompatible: Furosemide.

Mechanism of Action

A selective phosphodiesterase inhibitor in cardiac and vascular tissue, resulting in vasodilation and inotropic effects with little chronotropic activity.

Pharmacodynamics/Kinetics

Onset of action: I.V.: 5-15 minutes

Distribution: V_dss: 0.32-0.45 L/kg

Protein binding, plasma: ~70%

Metabolism: Hepatic (12%)

Half-life elimination: Normal renal function: ~2.5 hours; CVVH: 20.1 hours (Taniguchi, 2000)

Excretion: Urine (85% as unchanged drug) within 24 hours; active tubular secretion is a major elimination pathway for milrinone

Dosage

Adults: I.V.: Loading dose (optional; see "Note"): 50 mcg/kg administered over 10 minutes followed by a maintenance dose titrated according to hemodynamic and clinical response; Maintenance dose: I.V. infusion: 0.375-0.75 mcg/kg/minute; lower initial doses of 0.1 mcg/kg/minute (with final doses of 0.2-0.3 mcg/kg/minute) have also been recommended (Lindenfeld, 2010).

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, 2011).

Dosing adjustment in renal impairment:

Manufacturer recommended adjustment:

Cl_cr 50 mL/minute/1.73 m²: Administer 0.43 mcg/kg/minute

Cl_cr 40 mL/minute/1.73 m²: Administer 0.38 mcg/kg/minute

Cl_cr 30 mL/minute/1.73 m²: Administer 0.33 mcg/kg/minute

Cl_cr 20 mL/minute/ 1.73 m²: Administer 0.28 mcg/kg/minute

Cl_cr 10 mL/minute/1.73 m²: Administer 0.23 mcg/kg/minute

Cl_cr 5 mL/minute/1.73 m²: Administer 0.2 mcg/kg/minute

Administration: I.V.

Infuse via infusion pump.

Administration: I.V. Detail

Injectable solution and premixed solution: pH: 3.2-4.0

Monitoring Parameters

Platelet count, CBC, electrolytes (especially potassium and magnesium), liver function and renal function tests; ECG, CVP, SBP, DBP, 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.

Patient Education

This drug can only be given intravenously. Weigh daily and report weight gain. Report pain at infusion site; numbness, tingling, or swelling of extremities; or respiratory difficulty.

Anesthesia and Critical Care Concerns/Other Considerations

Clinical Pearls/Comments: If hypotension is a problem, loading doses may be omitted and maintenance infusions initiated. There is some delay in hemodynamic effects, but it is minimal (1-3 hours). Lower initial maintenance infusions have also been used (0.18-0.25 mcg/kg/minute).

Evidence-Based Information: Milrinone is ~85% renally eliminated and therefore requires dosage adjustment in patients with renal impairment. In patients with decompensated heart failure (HF) receiving CVVH, it has been demonstrated that milrinone continuous infusions (0.25 mcg/kg/minute) resulted in steady-state concentrations >4 times the concentrations obtained in patients with normal renal function. In addition, the half-life is prolonged (~20.1 hours vs 2.5 hours) (Taniguchi, 2000).

Cardiovascular Considerations

Milrinone may be useful for severe HF patients on a beta-blocker and require an I.V. inotrope. Long-term use of phosphodiesterase enzyme inhibitor therapy in heart failure provides some symptomatic relief but is associated with clear cut increases in mortality. Milrinone has been used for short-term improvement in hemodynamics. Chronic administration of milrinone does not confer beneficial effects on cardiovascular morbidity and mortality.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

None reported

Mental Health: Effects on Psychiatric Treatment

May cause hypotension; concurrent use with a psychotropic may further this risk; monitor. May rarely cause thrombocytopenia; use caution with valproic acid; monitor.

Nursing: Physical Assessment/Monitoring

Monitor cardiac/hemodynamic status continuously during therapy and serum potassium at regular intervals. Monitor for fluid retention.

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Infusion, premixed in D₅W: 200 mcg/mL (100 mL, 200 mL)

Injection, solution: 1 mg/mL (10 mL, 20 mL, 50 mL)

Injection, solution [preservative free]: 1 mg/mL (10 mL, 20 mL)

References

Aronoff GR, Bennett WM, Berns JS, et al, Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children, 5th ed. Philadelphia, PA: American College of Physicians; 2007, p 45, 145.

Baruch L, Patacsil P, Hameed A, et al, “Pharmacodynamic Effects of Milrinone With and Without a Bolus Loading Infusion,” Am Heart J, 2001, 141(2):266-73.

Cuffe MS, Califf RM, Adams KF Jr, et al, “Short-Term Intravenous Milrinone for Acute Exacerbation of Chronic Heart Failure: A Randomized Controlled Trial,” JAMA, 2002, 287(12):1541-7.

Cusick DA, Pfeifer PB, and Quigg RJ, “Effects of Intravenous Milrinone Followed by Titration of High-Dose Vasodilator Therapy on Clinical Outcome and Rehospitalization Rates in Patients With Severe Heart Failure,” Am J Cardiol, 1998, 82(9):1060-5.

Felker GM, Benza RL, Chandler AB, et al, “Heart Failure Etiology and Response to Milrinone in Decompensated Heart Failure: Results From the OPTIME-CHF Study,” J Am Coll Cardiol, 2003, 41(6):997-1003.

Hatzizacharias A, Makris T, Krespi P, et al, “Intermittent Milrinone Effect on Long-Term Hemodynamic Profile in Patients With Severe Congestive Heart Failure,” Am Heart J, 1999, 138(2 Pt 1):241-6.

Hunt SA, Abraham WT, Chin MH, et al, “2009 Focused Update Incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation,” J Am Coll Cardiol, 2009, 53(15):e1-90.

Lindenfeld J, Albert NM, Boehmer JP, et al, “HFSA 2010 Comprehensive Heart Failure Practice Guideline,” J Card Fail, 2010, 16(6):e1-194.

Pamboukian SV, Carere RG, Webb JG, et al, “The Use of Milrinone in Pretransplant Assessment of Patients With Congestive Heart Failure and Pulmonary Hypertension,” J Heart Lung Transplant, 1999, 18(4):367-71.

Stevenson LW, “Inotropic Therapy for Heart Failure,” N Engl J Med, 1998, 339(25):1848-50.

Taniguchi T, Shibata K, Saito S, et al, “Pharmacokinetics of Milrinone in Patients With Congestive Heart Failure During Continuous Venovenous Hemofiltration,” Intensive Care Med, 2000, 26(8):1089-93.

International Brand Names

• Coritrope (ID)
• Corotrop (AT, CH, CZ, ES, SE)
• Corotrope (AR, BE, CN, CO, ES, FR, GR, HN, LU, NL, PE, PL, UY, VE)
• Inovad (ID)
• Lunan Likang (CL)
• Milicor (IN)
• Primacor (AU, BR, GB, HK, IL, IN, KP, MX, MY, NZ, PH, TH, TW)

Lexi-Comp.com

Last full review/revision February 2012