Milrinone Lactate - Milrinone Lactate injection, Solution prescribing information
INDICATIONS AND USAGE
Milrinone Lactate Injection is indicated for the short-term intravenous treatment of patients with acute decompensated heart failure. Patients receiving milrinone lactate 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 lactate has been in patients receiving digoxin and diuretics.
DOSAGE AND ADMINISTRATION
Milrinone Lactate Injection, USP 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
| Loading Dose (mL) Using 1 mg/mL Concentration | ||||||||||
| Patient Body Weight (kg) | ||||||||||
| kg | 30 | 40 | 50 | 60 | 70 | 80 | 90 | 100 | 110 | 120 |
| mL | 1.5 | 2 | 2.5 | 3 | 3.5 | 4 | 4.5 | 5 | 5.5 | 6 |
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.
| Infusion Rate | Total Daily Dose (24 Hours) | ||
| Minimum | 0.375 mcg/kg/min | 0.59 mg/kg | Administer as a continuous intravenous infusion |
| Standard | 0.5 mcg/kg/min | 0.77 mg/kg | |
| Maximum | 0.75 mcg/kg/min | 1.13 mg/kg |
Milrinone lactate 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.
| Desired Infusion Concentration mcg/mL | Milrinone Lactate Injection 1 mg/mL (mL) | Diluent (mL) | Total Volume (mL) |
| 200 | 10 | 40 | 50 |
| 200 | 20 | 80 | 100 |
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: See Dosage 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.
| Maintenance Dose (mcg/kg/min) | Patient Body Weight (kg) | |||||||||
| 30 | 40 | 50 | 60 | 70 | 80 | 90 | 100 | 110 | 120 | |
| 0.375 | 3.4 | 4.5 | 5.6 | 6.8 | 7.9 | 9 | 10.1 | 11.3 | 12.4 | 13.5 |
| 0.4 | 3.6 | 4.8 | 6 | 7.2 | 8.4 | 9.6 | 10.8 | 12 | 13.2 | 14.4 |
| 0.5 | 4.5 | 6 | 7.5 | 9 | 10.5 | 12 | 13.5 | 15 | 16.5 | 18 |
| 0.6 | 5.4 | 7.2 | 9 | 10.8 | 12.6 | 14.4 | 16.2 | 18 | 19.8 | 21.6 |
| 0.7 | 6.3 | 8.4 | 10.5 | 12.6 | 14.7 | 16.8 | 18.9 | 21 | 23.1 | 25.2 |
| 0.75 | 6.8 | 9 | 11.3 | 13.5 | 15.8 | 18 | 20.3 | 22.5 | 24.8 | 27 |
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 lactate. 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:
| Creatinine Clearance (mL/min/1.73m 2 ) | Infusion Rate (mcg/kg/min) |
| 5 | 0.2 |
| 10 | 0.23 |
| 20 | 0.28 |
| 30 | 0.33 |
| 40 | 0.38 |
| 50 | 0.43 |
CONTRAINDICATIONS
Milrinone Lactate Injection is contraindicated in patients who are hypersensitive to it.
ADVERSE REACTIONS
Cardiovascular Effects
In patients receiving milrinone lactate in Phase II and III clinical trials, ventricular arrhythmias were reported in 12.1%: Ventricular ectopic activity, 8.5%; nonsustained ventricular tachycardia, 2.8%; sustained ventricular tachycardia, 1% and ventricular fibrillation, 0.2% (2 patients experienced more than one type of arrhythmia). Holter recordings demonstrated that in some patients injection of milrinone lactate increased ventricular ectopy, including nonsustained ventricular tachycardia. Life-threatening arrhythmias were infrequent and when present have been associated with certain underlying factors such as preexisting arrhythmias, metabolic abnormalities (e.g. hypokalemia), abnormal digoxin levels and catheter insertion. Milrinone lactate was not shown to be arrhythmogenic in an electrophysiology study. Supraventricular arrhythmias were reported in 3.8% of the patients receiving milrinone lactate. The incidence of both supraventricular and ventricular arrhythmias has not been related to the dose or plasma milrinone concentration.
Other cardiovascular adverse reactions include hypotension, 2.9% and angina/chest pain, 1.2%.
In the post marketing experience, there have been rare cases of “torsades de pointes” reported.
CNS Effects
Headaches, usually mild to moderate in severity, have been reported in 2.9% of patients receiving milrinone lactate.
Other Effects
Other adverse reactions reported, but not definitely related to the administration of milrinone lactate include hypokalemia, 0.6%; tremor, 0.4%; and thrombocytopenia, 0.4%.
Isolated spontaneous reports of bronchospasm and anaphylactic shock have been received; and in the post-marketing experience, liver function test abnormalities and skin reactions such as rash have been reported.
Post-Marketing Adverse Event Reports
In addition to adverse events reported from clinical trials, the following events have been reported from worldwide post-marketing experience with milrinone: Isolated spontaneous reports of bronchospasm and anaphylactic shock. Liver function test abnormalities and skin reactions such as rash. Administration site conditions: Infusion site reaction. To report SUSPECTED ADVERSE REACTIONS, contact Shandong New Time Pharmaceutical Co., Ltd., at 1-866-XXX-XXXX or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DESCRIPTION
Milrinone lactate injection is a member of a class of bipyridine inotropic/vasodilator agents with phosphodiesterase inhibitor activity, distinct from digitalis glycosides or catecholamines. Milrinone lactate is designated chemically as 1,6-dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5-carbonitrile lactate and has the following structure:
Milrinone is an off-white to tan crystalline compound with a molecular weight of 211.2 and an empirical formula of C 12 H 9 N 3 O. It is slightly soluble in methanol, and very slightly soluble in chloroform and in water. As the lactate salt, it is stable and colorless to pale yellow in solution. Milrinone lactate is available as sterile aqueous solutions of the lactate salt of milrinone for injection or infusion intravenously.
Sterile, single-dose vials: Single-dose vials of 10 and 20 mL contain in each mL milrinone lactate equivalent to 1 mg milrinone and 47 mg Dextrose, Anhydrous, USP, in Water for Injection, USP. The pH is adjusted to between 3.2 and 4.0 with lactic acid or sodium hydroxide. The total concentration of lactic acid can vary between 0.95 mg/mL and 1.29 mg/mL. These vials require preparation of dilutions prior to administration to patients intravenously.
CLINICAL PHARMACOLOGY
Milrinone lactate is a positive inotrope and vasodilator, with little chronotropic activity different in structure and mode of action from either the digitalis glycosides or catecholamines.
Milrinone lactate, at relevant inotropic and vasorelaxant concentrations, is a selective inhibitor of peak III cAMP phosphodiesterase isozyme in cardiac and vascular muscle. This inhibitory action is consistent with cAMP mediated increases in intracellular ionized calcium and contractile force in cardiac muscle, as well as with cAMP dependent contractile protein phosphorylation and relaxation in vascular muscle. Additional experimental evidence also indicates that milrinone lactate is not a beta-adrenergic agonist nor does it inhibit sodium-potassium adenosine triphosphatase activity as do the digitalis glycosides.
Clinical studies in patients with congestive heart failure have shown that milrinone lactate produces dose-related and plasma drug concentration-related increases in the maximum rate of increase of left ventricular pressure. Studies in normal subjects have shown that milrinone lactate produces increases in the slope of the left ventricular pressure-dimension relationship, indicating a direct inotropic effect of the drug. Milrinone lactate also produces dose-related and plasma concentration-related increases in forearm blood flow in patients with congestive heart failure, indicating a direct arterial vasodilator activity of the drug.
Both the inotropic and vasodilatory effects have been observed over the therapeutic range of plasma milrinone concentrations of 100 ng/mL to 300 ng/mL.
In addition to increasing myocardial contractility, milrinone lactate improves diastolic function as evidenced by improvements in left ventricular diastolic relaxation.
The acute administration of intravenous milrinone has also been evaluated in clinical trials in excess of 1600 patients, with chronic heart failure, heart failure associated with cardiac surgery, and heart failure associated with myocardial infarction. The total number of deaths, either on therapy or shortly thereafter (24 hours) was 15, less than 0.9%, few of which were thought to be drug-related.
PHARMACOKINETICS
Following intravenous injections of 12.5 mcg/kg to 125 mcg/kg to congestive heart failure patients, milrinone lactate had a volume of distribution of 0.38 liters/kg, a mean terminal elimination half-life of 2.3 hours, and a clearance of 0.13 liters/kg/hr. Following intravenous infusions of 0.2 mcg/kg/min to 0.7 mcg/kg/min to congestive heart failure patients, the drug had a volume of distribution of about 0.45 liters/kg, a mean terminal elimination half-life of 2.4 hours, and a clearance of 0.14 liters/kg/hr. These pharmacokinetic parameters were not dose-dependent, and the area under the plasma concentration versus time curve following injections was significantly dose-dependent.
Milrinone lactate has been shown (by equilibrium dialysis) to be approximately 70% bound to human plasma protein.
The primary route of excretion of milrinone lactate in man is via the urine. The major urinary excretions of orally administered milrinone lactate in man are milrinone (83%) and its 0-glucuronide metabolite (12%). Elimination in normal subjects via the urine is rapid, with approximately 60% recovered within the first two hours following dosing and approximately 90% recovered within the first eight hours following dosing. The mean renal clearance of milrinone lactate is approximately 0.3 liters/min, indicative of active secretion.
Pharmacodynamics
In patients with heart failure due to depressed myocardial function, milrinone lactate produced a prompt dose and plasma concentration related increase in cardiac output and decreases in pulmonary capillary wedge pressure and vascular resistance, which were accompanied by mild-to-moderate increases in heart rate. Additionally, there is no increased effect on myocardial oxygen consumption. In uncontrolled studies, hemodynamic improvement during intravenous therapy with milrinone lactate was accompanied by clinical symptomatic improvement, but the ability of milrinone lactate to relieve symptoms has not been evaluated in controlled clinical trials. The great majority of patients experience improvements in hemodynamic function within 5 to 15 minutes of the initiation of therapy.
In studies in congestive heart failure patients, milrinone lactate when administered as a loading injection followed by a maintenance infusion produced significant mean initial increases in cardiac index of 25 percent, 38 percent, and 42 percent at dose regimens of 37.5 mcg/kg/0.375 mcg/kg/min, 50 mcg/kg/0.5 mcg/kg/min, and 75 mcg/kg/0.75 mcg/kg/min, respectively. Over the same range of loading injections and maintenance infusions, pulmonary capillary wedge pressure significantly decreased by 20 percent, 23 percent, and 36 percent, respectively, while systemic vascular resistance significantly decreased by 17 percent, 21 percent, and 37 percent. Mean arterial pressure fell by up to 5 percent at the two lower dose regimens, but by 17 percent at the highest dose. Patients evaluated for 48 hours maintained improvements in hemodynamic function, with no evidence of diminished response (tachyphylaxis). A smaller number of patients have received infusions of milrinone lactate for periods up to 72 hours without evidence of tachyphylaxis.
The duration of therapy should depend upon patient responsiveness.
Milrinone lactate has a favorable inotropic effect in fully digitalized patients without causing signs of glycoside toxicity. Theoretically, in cases of atrial flutter/fibrillation, it is possible that milrinone lactate may increase ventricular response rate because of its slight enhancement of AV node conduction. In these cases, digitalis should be considered prior to the institution of therapy with milrinone lactate.
Improvement in left ventricular function in patients with ischemic heart disease has been observed. The improvement has occurred without inducing symptoms or electrocardiographic signs of myocardial ischemia.
The steady-state plasma milrinone concentrations after approximately 6 to 12 hours of unchanging maintenance infusion of 0.5 mcg/kg/min are approximately 200 ng/mL. Near maximum favorable effects of milrinone lactate on cardiac output and pulmonary capillary wedge pressure are seen at plasma milrinone concentrations in the 150 ng/mL to 250 ng/mL range.
HOW SUPPLIED
Milrinone Lactate Injection, USP is supplied as 10 mL single-dose vials in a box of 10, NDC 42677-313-10; as 20 mL single-dose vials box of 10, NDC 42677-314-10, containing a sterile, clear, colorless to pale yellow solution. Each mL contains milrinone lactate equivalent to 1 mg milrinone.
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Avoid freezing.
Discard unused portion.
Manufactured by: Shandong New Time Pharmaceutical Co., Ltd., No. 1, North Outer Ring Road, Feixian, Shandong 273400, China. Revised: 08/2022 LBL 128
