Milrinone Lactate in Dextrose Injection

Milrinone lactate injection is indicated for the short-term intravenous treatment of patients with acute decompensated heart failure.  Patients receiving milrinone should be observed closely with appropriate electrocardiographic equipment.  The facility for immediate treatment of potential cardiac events, which may include life threatening ventricular arrhythmias, must be available.  The majority of experience with intravenous milrinone has been in patients receiving digoxin and diuretics.  There is no experience in controlled trials with infusions of milrinone for periods exceeding 48 hours.

Whether given orally or by continuous or intermittent intravenous infusion, milrinone 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 1,088 patients with Class III and IV heart failure, long-term oral treatment with milrinone 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 given by long-term continuous or intermittent infusion does not carry a similar risk.

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

General

Milrinone should not be used in patients with severe obstructive aortic or pulmonic valvular disease in lieu of surgical relief of the obstruction.  Like other inotropic agents, it may aggravate outflow tract obstruction in hypertrophic subaortic stenosis.

Supraventricular and ventricular arrhythmias have been observed in the high-risk population treated.  In some patients, injections of milrinone and oral milrinone have been shown to increase ventricular ectopy, including nonsustained ventricular tachycardia.  The potential for arrhythmia, present in congestive heart failure itself, may be increased by many drugs or combinations of drugs.  Patients receiving milrinone should be closely monitored during infusion.

Milrinone produces a slight shortening of AV node conduction time, indicating a potential for an increased ventricular response rate in patients with atrial flutter/fibrillation which is not controlled with digitalis therapy.

During therapy with milrinone blood pressure and heart rate should be monitored and the rate of infusion slowed or stopped in patients showing excessive decreases in blood pressure.

If prior vigorous diuretic therapy is suspected to have caused significant decreases in cardiac filling pressure, milrinone should be cautiously administered with monitoring of blood pressure, heart rate, and clinical symptomatology.

Use in Acute Myocardial Infarction

No clinical studies have been conducted in patients in the acute phase of post myocardial infarction.  Until further clinical experience with this class of drugs is gained, milrinone is not recommended in these patients.

Laboratory Tests

Fluid and Electrolytes: Fluid and electrolyte changes and renal function should be carefully monitored during therapy with milrinone.  Improvement in cardiac output with resultant diuresis may necessitate a reduction in the dose of diuretic.  Potassium loss due to excessive diuresis may predispose digitalized patients to arrhythmias.  Therefore, hypokalemia should be corrected by potassium supplementation in advance of or during use of milrinone.

Drug Interactions

No untoward clinical manifestations have been observed in limited experience with patients in whom milrinone was used concurrently with the following drugs: digitalis glycosides; lidocaine, quinidine; hydralazine, prazosin; isosorbide dinitrate, nitroglycerin; chlorthalidone, furosemide, hydrochlorothiazide, spironolactone; captopril; heparin, warfarin, diazepam, insulin; and potassium supplements.

Chemical Interactions

There is an immediate chemical interaction which is evidenced by the formation of a precipitate when furosemide is injected into an intravenous line of an infusion of milrinone.  Therefore, furosemide should not be administered in intravenous lines containing milrinone.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Twenty-four months of oral administration of milrinone to mice at doses up to 40 mg/kg/day (about 50 times the human oral therapeutic dose in a 50 kg patient) was unassociated with evidence of carcinogenic potential.  Neither was there evidence of carcinogenic potential when milrinone was orally administered to rats at doses up to 5 mg/kg/day (about six times the human oral therapeutic dose) for 24 months or at 25 mg/kg/day (about 30 times the human oral therapeutic dose) for up to 18 months in males and 20 months in females.  Whereas the Chinese Hamster Ovary Chromosome Aberration Assay was positive in the presence of a metabolic activation system, results from the Ames Test, the Mouse Lymphoma Assay, the Micronucleus Test, and the in vivo Rat Bone Marrow Metaphase Analysis indicated an absence of mutagenic potential.  In reproductive performance studies in rats, milrinone had no effect on male or female fertility at oral doses up to 32 mg/kg/day.

Animal Toxicity

Oral and intravenous administration of toxic dosages of milrinone to rats and dogs resulted in myocardial degeneration/fibrosis and endocardial hemorrhage, principally affecting the left ventricular papillary muscles.  Coronary vascular lesions characterized by periarterial edema and inflammation have been observed in dogs only.  The myocardial/endocardial changes are similar to those produced by beta-adrenergic receptor agonists such as isoproterenol, while the vascular changes are similar to those produced by minoxidil and hydralazine.  Doses within the recommended clinical dose range (up to 1.13 mg/kg/day) for congestive heart failure patients have not produced significant adverse effects in animals.

Pregnancy Category C

Oral administration of milrinone to pregnant rats and rabbits during organogenesis produced no evidence of teratogenicity at dose levels up to 40 mg/kg/day and 12 mg/kg/day, respectively.  Milrinone did not appear to be teratogenic when administered intravenously to pregnant rats at doses up to 3 mg/kg/day (about 2.5 times the maximum recommended clinical intravenous dose) or pregnant rabbits at doses up to 12 mg/kg/day, although an increased resorption rate was apparent at both 8 mg/kg/day and 12 mg/kg/day (intravenous) in the latter species.  There are no adequate and well-controlled studies in pregnant women.  Milrinone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Caution should be exercised when milrinone is administered to nursing women, since it is not known whether it is excreted in human milk.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Use in Elderly Patients

There are no special dosage recommendations for the elderly patient.  Ninety percent of all patients administered milrinone in clinical studies were within the age range of 45 to 70 years, with a mean age of 61 years.  Patients in all age groups demonstrated clinically and statistically significant responses.  No age-related effects on the incidence of adverse reactions have been observed.  Controlled pharmacokinetic studies have not disclosed any age-related effects on the distribution and elimination of milrinone.

Doses of milrinone may produce hypotension because of its vasodilator effect.  If this occurs, administration of milrinone should be reduced or temporarily discontinued until the patient’s condition stabilizes.  No specific antidote is known, but general measures for circulatory support should be taken.

Milrinone 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 (1 mg/mL) by patient body weight (kg).

                  
Loading Dose (mL) Using 1 mg/mL Concentration

The loading dose may be given undiluted, but diluting to a rounded total volume of 10 or 20 mL (see Maintenance Dose for diluents) may simplify the visualization of the injection rate.

                                             MAINTENANCE DOSE

Milrinone 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.

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.

Note: SeeDosage 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.

Milrinone Infusion Rate (mL/hr) Using 200 mcg/mL Concentration

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.

Dosage Adjustment in Renally Impaired Patients

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.  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:

Milrinone Lactate Injection is supplied as follows:

This container closure is not made with natural rubber latex.

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].  Avoid freezing.

45917D

Revised: August 2014

PACKAGE LABEL - PRINCIPAL DISPLAY - Milrinone 10 mL Single Dose Vial Label

NDC 63323-617-10

601710

Milrinone Lactate Injection

10 mg per 10 mL  (1 mg per mL)*

For Intravenous Use Only

Rx only

10 mL Single Dose Vial

PACKAGE LABEL - PRINCIPAL DISPLAY - Milrinone 10 mL Single Dose Vial Tray Label

NDC 63323-617-10

601710

Milrinone Lactate Injection

10 mg per 10 mL  (1 mg per mL)*

For Intravenous Use Only

10 mL Single Dose Vial

10 Vials

Rx only