Milrinone Lactate Injection - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Milrinone Lactate Injection - Scientific Information

Manufacture: Fresenius Kabi USA, LLC
Country: Canada
Condition: Heart Failure (Congestive Heart Failure)
Class: Inotropic agents
Form: Liquid solution, Intravenous (IV)
Ingredients: Milrinone

Pharmaceutical Information

Drug Substance

Common Name: Milrinone (USAN)
Milrinone lactate is formed in situ.
Chemical Name: 1,6-dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5-carbonitrile
Structural Formula:
Molecular Formula: C12H9N3O
Molecular Weight: 211.22
Physical Form: Milrinone is an off-white to tan crystalline powder.
Solubility: Milrinone is soluble in acidic and basic aqueous solutions. It is also soluble in chloroform and methanol, slightly soluble in dimethylformamide, and not soluble in ethanol and ethyl ether.
pKa and pH values: The pKa value is 9.67. The pH is 6.35.

Composition

Milrinone Lactate Injection is provided as a sterile, clear, colourless to pale yellow solution. The pH of Milrinone Lactate Injection is adjusted to between 3.2 and 4.0 with lactic acid or sodium hydroxide. Each mL contains milrinone lactate equivalent to 1 mg milrinone and anhydrous dextrose USP 47 mg, in Water for Injection. The total concentration of lactic acid can vary between 0.95 and 1.29 mg/mL.

Stability and Storage Recommendations

Store Milrinone Lactate Injection vials at room temperature (15 °C to 30 °C). Avoid freezing.

Diluted Solutions

For ease of administration Milrinone Lactate Injection may be diluted with suitable diluents such as Normal or Half Normal Saline Injection or sterile 5% Dextrose Injection, or may be used undiluted if suitable equipment is available.

Dilution as described under Dosage and Administration, Drug Administration.

Vial Size Volume of Diluent to be Added to Vial Approximate Available Volume Nominal Concentration
20 mg vial
(20 mL)
180 mL 200 mL 100 μg/mL
20 mg vial
(20 mL)
113 mL 133 mL 150 μg/mL
20 mg vial
(20 mL)
80 mL 100 mL 200 μg/mL

Diluted solutions should be used within 24 hours at room temperature (15 °C to 30 °C) or 72 hours if refrigerated (2 °C to 8 °C).

For detailed information regarding dilution, see Dosage and Administration.

Precipitation occurs immediately when furosemide is mixed with milrinone solution. Therefore, furosemide should not be administered in intravenous lines containing Milrinone Lactate Injection.

Note: As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discolouration and leakage prior to administration, whenever solution and container permit. Solution showing haziness, particulate matter, precipitate, discolouration or leakage should not be used. Discard unused portion

Availability of Dosage Forms

Milrinone Lactate Injection is available in single-dose vials of 10 mL, 20 mL and 50 mL. Each mL contains milrinone lactate equivalent to 1 mg milrinone. The total concentration of lactic acid can vary between 0.95 and 1.29 mg/mL.

C601710 10 mL single-dose vials in packages of 10
C601720 20 mL single-dose vials in packages of 10
C601750 50 mL single-dose vials packaged individually

Pharmacology

Tissue Distribution and Biotransformation

Specific study of tissue distribution was conducted in the rat, following oral administration of milrinone at 4.5 mg/kg. At 30 minutes post-medication, the time of peak blood level, the only tissues, other than the G.I. tract, showing drug levels significantly higher than blood were the thyroid, kidney and liver. By 2 hrs, all tissue levels except the kidney were low and 45% of the dose had already been excreted in the urine.

The biotransformation of 14C-milrinone was studied in the rat, dog and monkey following oral administration. In all three species, milrinone was the major urinary excretion product, constituting from 67% (monkey) to 98% (rat) of urinary radioactivity. Five metabolites were observed and identified: the pyridyl-N-oxide, the carboxamide, and three glycosidic sugar conjugates of milrinone: a glucuronide, a glucoside and a riboside. The last two were observed only in the dog. Only the glucuronide might be considered a major metabolic pathway, representing 15% and 30% of urinary radioactivity in the dog and monkey, respectively.

Animal Pharmacology

The inotropic and chronotropic activities of milrinone were investigated in vitro, using isolated guinea pig, cat, rabbit, rat and hamster atria and papillary muscles. Milrinone, in concentrations ranging from 0.1 to 300 µg/mL, caused concentration-dependent increases in papillary muscle and atrial developed tension, with minimal increases in atrial rate. Compared with the in vitro inotropic activity of amrinone, milrinone was approximately 30 times more potent.

Milrinone does not increase the sensitivity of the myofibrillar proteins to calcium.

In the anesthetized dog, the intravenous bolus administration of milrinone in doses of 0.01 to 0.3 mg/kg caused dose-dependent increases in cardiac contractile force with a minimal effect on blood pressure and heart rate. Milrinone also increases the rate of myocardial relaxation in a dose-related manner (lusitropic effect).

In the failing dog heart model, milrinone significantly reversed propranolol, verapamil and pentobarbital induced heart failure.

In the isolated rabbit renal artery preparation milrinone and amrinone were approximately equipotent against both potassium and norepinephrine-induced contractions, with nifedipine being considerably more potent than either milrinone or amrinone in this preparation.

Drug Interaction Studies

The inotropic potency of milrinone was not affected in anesthetized dogs pretreated with sodium nitroprusside, furosemide or diazepam. Milrinone, at 10 - 100 µg/kg, increased cardiac contractile force in the presence of ouabain or dopamine.

Milrinone does potentiate the inotropic activity of beta adrenergic agonists.

Milrinone did not worsen or improve ouabain-induced arrhythmias and the inotropic response to milrinone was not altered in the presence of such arrhythmias.

In the canine hind limb preparations, milrinone, at doses of 0.03 to 0.3 mg/kg caused dose-related reductions in systolic and diastolic perfusion pressures. This effect was not blocked by either denervation, histamine receptor antagonists, cholinergic or beta adrenergic receptor antagonists or by prostaglandin synthetase inhibition.

In the 24 hour Harris dog model, in which arrhythmias are produced by ligation of the left anterior descending coronary artery, milrinone did not interfere with the antiarrhythmic effects of quinidine, procainamide and disopyramide and reduced their negative-inotropic and intracardiac conduction effects.

Toxicology

Acute Toxicity

The following intravenous 7-day LD50 values were determined:
Species Age Range Sex LD50 (mg base/kg)
Mouse Adults M 79
Mouse Adults F 79
Rat Adults M 76
Rat Adults M 73
Rat Adults F 76
Rabbit Young Adults F 44

Clinical observations for mice, rats and rabbits included ataxia, decreased motor activity, loss of righting reflex, tremors and clonic convulsions. In addition for mice and rats only, ptosis, lacrimation, salivation, spastic limb movements and loss of motor activity were observed. Observations made during necropsies of mice and rats treated with the highest dosages included: small black pitted areas in the glandular stomach, red or red-black material or mucus in the small intestine and lung consolidation (congestion). For rabbits, macroscopic and histomorphologic lesions: epicardial and endocardial hemorrhage, and papillary muscle fibrosis were observed at intravenous dosages of 12.6 mg base/kg and higher and were related to exaggerated pharmacologic effects of supra-therapeutic dosages.

Subacute/Chronic Toxicity

Toxicologic effects observed in oral and intravenous studies in various laboratory animal species including mice, rats, rabbits, dogs and monkeys were related to responses by animals with normal myocardial function to the exaggerated pharmacologic effects of inotropy and vasodilation. Clinical effects observed for one or more species included: increased heart rate, shortening of PR and QT intervals, conversion of sinus arrhythmia (common to dogs) to normal sinus rhythm, reddening of extremities, and decreases in systolic and diastolic blood pressure. Similarly, pathologic effects observed in various species were related to exaggerated pharmacologic responses by the normal heart to excessive inotropic and vasodilator stimulation and included: myocardial degeneration, necrosis and fibrosis principally affecting the left ventricular papillary muscles, perivasculitis and/or vasculitis of epicardial arteries and subendocardial hemorrhage. Results of intravenous studies in rats and dogs are summarized in the following table:

SUMMARY OF CARDIAC HISTOMORPHOLOGIC EFFECTS IN INTRAVENOUS TOXICITY STUDIES OF MILRINONE IN RATS AND DOGS
Dosage: mg base/kg/day
Species
(N/group)
Dosage
mg base/kg/day
Duration No Adverse Effect Threshold Toxicity
Sprague-Dawley Rat
Study 1
(N=10M, 10F)
2.5, 10, 40 Bolus inj. Daily (4 weeks) --- 2.5a - 10.0b 40.0c
Study 2
(N=10M, 10F)
0.01, 0.1, 1.0, 2.5 Bolus inj. Daily (4 weeks) 0.01, 0.1, 1.0, 2.5 --- ---
Beagle Dog
(N=2M, 2F) 2, 6, 18 4-Hr Infusion (10 doses in 12 days) --- 2.0d 6.0e 18.0e

a Minimal myocardial fibrosis even for 2/20 rats (one of each sex)

b Mild myocardial fibrosis and/or degeneration observed for 5/20 rats

c Mild to marked myocardial fibrosis observed for 19/19 rats

d Minimal myocardial degeneration and/or inflammation observed for 2/4 dogs: coronary arteritis for 1/4 dogs

e Minimal to moderate myocardial inflammation and/or fibrosis observed for 4/4 dogs at each dosage: coronary arteritis observed for 1/4 and 2/4 dogs at dosages of 6 and 18 mg base per kg/day, respectively.

Carcinogenicity, Mutagenicity, Teratogenicity, Impairment of Fertility

Milrinone was not carcinogenic in life-time (two-year) oral studies conducted in mice and rats.

Milrinone was not genotoxic in in vitro tests for potential to induce gene mutation (Ames tests and mouse lymphoma cell assay) or in in vivo tests for potential to induce chromosomal damage (micronucleus test and metaphase bone marrow analysis). An in vitro test for potential to induce chromosomal damage in Chinese Hamster Ovary cells was positive only when conducted in the presence of hepatic microsomes (metabolic activation). This single positive result in an in vitro test was not considered to be biologically important since a dose-dependent response was not observed, and negative results were obtained in in vitro tests conducted with dosages of milrinone that exceeded the recommended cumulative daily human oral and intravenous dosages by more than 25 fold.

Effects on fertility were not observed in male, female and 3-generation oral reproductive studies in rats. An increased rate of fetal resorptions was observed when milrinone was given as an intravenous bolus injection to rabbits at 7 times the cumulative maximum recommended human therapeutic dosage intended for administration by infusion during a period of 24 hours. Milrinone was not teratogenic when administered orally or intravenously to rats and rabbits.