MILRINONE IN 5% DEXTROSE

General Administration Information
For storage information, see the specific product information within the How Supplied Section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Milrinone is a clear, colorless to pale yellow solution.
Intravenous Administration
Loading Dose

-Dilution of the 1 mg/mL solution is not necessary; however, diluting to a total volume of 10 to 20 mL may ease administration.
-Administer over 10 to 60 minutes.
-May divide loading dose into 5 equal aliquots and administer each aliquot over 10 minutes if blood pressure remains within an acceptable range.

Continuous IV Infusion
-Dilute to a final concentration of 200 mcg/mL using either 0.45% Sodium Chloride Injection, 0.9% Sodium Chloride Injection, or 5% Dextrose Injection.
-Administer with a controlled infusion device.
-Titrate the infusion according to hemodynamic and clinical response.
-Observe the patient closely with appropriate electrocardiographic equipment. Immediate treatment for cardiac events, including life-threatening ventricular arrhythmias, must be available.
-Do not administer simultaneously with blood or furosemide. Furosemide is incompatible with milrinone; precipitation may occur if given together in the same line.

Other Injectable Administration
Intraosseous Administration
NOTE: Milrinone is not FDA-approved for intraosseous administration.
-The same milrinone dosage may be given via the intraosseous route when IV access is not available. Of note, intraosseous lines are not commonly used in neonates because of the availability of the umbilical vein, the fragility of small bones, and the small intraosseous space available.
-After injection, flush with saline to promote medication entry into the central circulation.

Milrinone can cause hypotension (2.9%) and reflex sinus tachycardia due to its vasodilatory effects. Monitor blood pressure and heart rate during milrinone infusion; slow or stop the infusion in patients showing excessive decreases in blood pressure.

Milrinone has been associated with an increased frequency of ventricular and atrial arrhythmias. Monitor patients receiving milrinone closely with the use of continuous electrocardiographic monitoring to allow the prompt detection and management of ventricular arrhythmias. An increased risk of hospitalization and sudden death has been observed in patients on long-term oral milrinone therapy; there is no evidence that long-term continuous or intermittent infusion does not carry a similar risk. Ventricular arrhythmias (12.1%), premature ventricular contractions (PVCs) (8.5%), nonsustained ventricular tachycardia (2.8%), sustained ventricular tachycardia (1%), ventricular fibrillation (0.2%), supraventricular tachycardia (SVT) (3.8%), and angina/chest pain (unspecified) (1.2%) were reported in adult patients during clinical trials. Life-threatening arrhythmias were infrequent and usually associated with other precipitating factors. Torsade de pointes has been reported rarely with postmarketing use. New atrial arrhythmias occurred more frequently in patients receiving milrinone compared to placebo (4.6% vs. 1.5%) in an adult trial assessing clinical outcomes of patients hospitalized for acute exacerbation of chronic heart failure. Pediatric trials have reported a wide variance in the incidence of arrhythmia associated with milrinone. While some trials have reported no to rare occurrences of tachyarrhythmia (e.g., ventricular arrhythmia, supraventricular tachycardia), a study including 603 infants receiving milrinone postoperatively after congenital heart disease surgery reported that 50% experienced an arrhythmia. The most common arrhythmias were monomorphic ventricular tachycardia (12%), junctional ectopic tachycardia (10%), accelerated junctional rhythm (8%), and atrial tachyarrhythmias including atrial fibrillation, atrial flutter, and ectopic or chaotic atrial tachycardia (8%). After multivariate logistic regression analysis, milrinone use on admission to the cardiac intensive care unit remained independently associated with an increase in the odds of postoperative tachyarrhythmia resulting in an intervention (OR 2.8, 95% CI 1.3 to 6, p = 0.007).

Cases of injection site reaction have been reported with intravenous milrinone therapy. Carefully monitor the infusion site to avoid possible extravasation.

Milrinone is less likely to cause thrombocytopenia than inamrinone; in adult trials, thrombocytopenia was reported in 0.4% of patients but is not definitely related to the administration of milrinone. Pediatric trials have reported a wide variance in the incidence of thrombocytopenia associated with milrinone. Some trials including neonates, infants, and children have reported no new occurrence or progression (n = 12) or no difference in incidence when compared to placebo (n = 277). In another study of 19 infants and children who underwent open-heart surgery, 58% developed thrombocytopenia (defined as platelet count 100,000 cells/mm3 or less) during the postoperative milrinone infusion. The incidence of thrombocytopenia was 21% at 24 hours, 47% at 36 hours, and 42% at 48 hours of milrinone infusion. Platelet transfusion was required for 2 infants while receiving milrinone.

Headache, usually mild to moderate in severity, has been reported in 2.9% of patients receiving milrinone.

Tremor (0.4%) has been reported but is not definitely related to the administration of milrinone. Additionally, skin reactions, such as rash, and isolated spontaneous reports of bronchospasm and anaphylactic shock have been reported with postmarketing use. Nausea and vomiting may also occur.

Hypokalemia (0.6%) has been reported but is not definitely related to the administration of milrinone. Monitor fluid and electrolyte changes carefully during therapy with milrinone. Correct hypokalemia by potassium supplementation during use of milrinone. Additionally, elevated hepatic enzymes have been reported with postmarketing use.

Milrinone is contraindicated in patients with a milrinone hypersensitivity. Solutions containing dextrose may be contraindicated in those with a known corn hypersensitivity.

Do not use milrinone in patients with severe obstructive aortic or pulmonic valvular heart disease in lieu of surgical relief of the obstruction. Inotropes may aggravate outflow tract obstruction in patients with idiopathic hypertrophic subaortic stenosis.

Milrinone use has been associated with ventricular arrhythmias, including ventricular tachycardia. Milrinone produces a slight shortening of AV node conduction time, indicating a potential for an increased ventricular response rate in patients with atrial flutter or atrial fibrillation which is not controlled with digitalis therapy. Observe patients closely with continuous ECG monitoring to allow for prompt detection and management of ventricular arrhythmias. Correct hypovolemia and hypokalemia to minimize the potential of significant hypotension and/or arrhythmia. Milrinone has not been shown to be safe or effective when used for more than 48 hours in patients with heart failure. An increased risk of hospitalization and death has been observed in patients on long-term oral milrinone therapy; there is no evidence that long-term continuous or intermittent infusion does not carry a similar risk.

Milrinone use is not recommended during acute myocardial infarction. The effects of milrinone during the acute phase after myocardial infarction are unknown.

Severe renal impairment significantly increases the half-life of milrinone. Infusion rate reductions are recommended for patients with renal impairment or renal failure (CrCl 50 mL/minute or less). Monitor renal function during milrinone infusion.

Description: Milrinone is a parenteral positive inotrope and vasodilator with phosphodiesterase inhibitor activity and minimal chronotropic activity. These properties make it a useful alternative to traditional catecholamines in patients with low cardiac output. In pediatric patients, milrinone is used for acute heart failure and the prevention of low cardiac output syndrome (LCOS) after cardiac surgery. It is also used for patients with fluid-refractory septic shock, persistent hypoperfusion, and cardiac dysfunction despite the use of other vasoactive agents or in shock associated with cardiac dysfunction and high systemic vascular resistance (e.g., cardiogenic shock). Pediatric advanced life support (PALS) guidelines support its use for maintaining cardiac output and post-resuscitation stabilization. Inotropes can induce hypotension and arrhythmias. Milrinone is more likely to cause hypotension and less likely to cause tachyarrhythmias when compared to dobutamine and low-dose dopamine; however, milrinone may cause reflex tachycardia. Milrinone is primarily eliminated by the kidneys and requires dosage adjustment in patients with renal insufficiency. Although not FDA-approved for pediatric use, milrinone is used off-label in patients as young as neonates.

For the short-term treatment of low cardiac output states (e.g., acute heart failure*, septic shock*, cardiogenic shock*, low cardiac output syndrome (LCOS)* after cardiac surgery):
Continuous Intravenous or Intraosseus Infusion dosage:
Premature Neonates: 0.75 mcg/kg/minute continuous IV infusion for 3 hours, then 0.2 mcg/kg/minute for 18 hours.
Neonates: 50 mcg/kg IV/IO load, then 0.25 to 1 mcg/kg/minute continuous IV/IO infusion. Some experts choose not to bolus milrinone in patients with septic shock to decrease the risk of hypotension.
Infants, Children, and Adolescents: 50 mcg/kg IV/IO load, then 0.25 to 1 mcg/kg/minute continuous IV/IO infusion. Some experts choose not to bolus milrinone in patients with septic shock to decrease the risk of hypotension.

For the treatment of persistent pulmonary hypertension of the newborn (PPHN)* in patients with poor response to nitric oxide:
Continuous Intravenous Infusion dosage:
Neonates: 50 mcg/kg IV load, then 0.33 to 0.5 mcg/kg/minute continuous IV infusion, initially. Titrate by 0.33 mcg/kg/minute every 2 hours until clinical response is attained. Max: 1 mcg/kg/minute. Avoid loading dose to minimize the risk of hypotension.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established; however, up to 1 mcg/kg/minute continuous IV infusion has been used.
-Infants
Safety and efficacy have not been established; however, up to 1 mcg/kg/minute continuous IV infusion has been used.
-Children
Safety and efficacy have not been established; however, up to 1 mcg/kg/minute continuous IV infusion has been used.
-Adolescents
Safety and efficacy have not been established; however, up to 1 mcg/kg/minute continuous IV infusion has been used.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
CrCl more than 50 mL/minute: No dosage adjustment needed.
CrCl 30 to 50 mL/minute: Initiate at a rate of 0.33 to 0.43 mcg/kg/minute continuous IV infusion and titrate until clinical response is attained.
CrCl 10 to 29 mL/minute: Initiate at a rate of 0.23 to 0.33 mcg/kg/minute continuous IV infusion and titrate until clinical response is attained.
CrCl less than 10 mL/minute: Initiate at a rate of 0.2 mcg/kg/minute continuous IV infusion and titrate until clinical response is attained.

Intermittent hemodialysis
It is not known whether milrinone is removed by hemodialysis.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Milrinone is a positive inotrope and vasodilator with little chronotropic activity. Milrinone selectively inhibits phosphodiesterase III, preventing breakdown of cyclic adenosine monophosphate (cAMP) in cardiac and vascular muscle cells. This results in increased myocardial contractility and vasodilation. Milrinone also improves diastolic relaxation (lusitropy), thus reducing preload, afterload, and systemic vascular resistance.

Pharmacokinetics: Milrinone is administered by intravenous infusion. Milrinone has a Vd of about 0.45 L/kg, a mean elimination half-life of 2.4 hours, and a clearance of 0.14 L/kg/hour after continuous infusion in adult patients with congestive heart failure. Milrinone is approximately 70% bound to human plasma protein. It is primarily eliminated via the urine, with 83% excreted as the parent drug and 12% as its O-glucuronide metabolite. Elimination is rapid; approximately 60% is recovered in the urine within 2 hours of dosing and 90% is recovered within 8 hours. The mean renal clearance of milrinone is approximately 0.3 L/minute, indicating active secretion.

Affected cytochrome P450 isoenzymes and drug transporters: none


-Route-Specific Pharmacokinetics
Intravenous Route
Onset of action occurs in 2 to minutes, peaking around 10 minutes, with a variable duration ranging from 1.5 to 5 hours. Inotropic and vasodilatory effects of milrinone have been observed over the therapeutic range of 100 to 300 ng/mL.


-Special Populations
Pediatrics
Premature Neonates
Estimated half-life is approximately 5-times longer in premature neonates compared to children or adults. In a prospective, open-label pilot study in 29 very preterm neonates (gestational age younger than 29 weeks, postnatal age younger than 12 hours), the population mean (95% CI) clearance estimate was 0.64 mL/kg/minute, the population mean Vd was 0.576 L/kg, and the half-life estimate was 10.3 hours.

Infants
Compared to adults, infants have a larger Vd, faster clearance, and prolonged half-life of milrinone. Although Vd is similar, clearance is significantly faster in children compared to infants. Vd was 0.9 +/- 0.4 L/kg, clearance was 3.8 +/- 1 mL/kg/minute, and half-life was 3.15 +/- 2 hours in a prospective, open-label study in infants after open-heart surgery (n = 12). In pediatric patients with septic shock (n = 11, age: 8 months to 15 years), Vd was 1.47 +/- 1.03 L/kg, mean clearance was 11 +/- 9.6 mL/kg/minute, and median half-life was 1.47 hours (0.62 to 10.85 hours).

Children and Adolescents
Compared to adults, children have a larger Vd, faster clearance, and similar half-life of milrinone. Although Vd is similar, clearance is significantly faster in children compared to infants. Vd was 0.7 +/- 0.2 L/kg, clearance was 5.9 +/- 2 mL/kg/minute, and half-life was 1.86 +/- 2 hours in a prospective, open-label study in children after open-heart surgery (n = 7, age: 1 to 13 years). In pediatric patients with septic shock (n = 11, age: 8 months to 15 years), Vd was 1.47 +/- 1.03 L/kg, mean clearance was 11 +/- 9.6 mL/kg/minute, and median half-life was 1.47 hours (0.62 to 10.85 hours).

Renal Impairment
Renal impairment (CrCl 30 mL/minute or less) significantly increases the half-life of milrinone.