primacor

DESCRIPTION
PRIMACOR, brand of milrinone lactate injection, is a member of a new class ofbipyridine inotropic/vasodilator agents with phosphodiesterase inhibitor activity,distinct from digitalis glycosides or catecholamines primacor. PRIMACOR (milrinone lactate)is designated chemically as 1,6-dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5-carbonitrilelactate and has the following structure:

Milrinone is an off-white to tan crystalline compound with a molecular weightof 211.2 and an empirical formula of C 12 H 9 N 3 O primacor. It is slightly solublein methanol, and very slightly soluble in chloroform and in water primacor. As the lactatesalt, it is stable and colorless to pale yellow in solution primacor. PRIMACOR is availableas sterile aqueous solutions of the lactate salt of milrinone for injectionor infusion intravenously primacor.

Sterile, single-dose vials: Single-dose vials of 10, 20 and 50 mL, containin each mL milrinone lactate equivalent to 1 mg milrinone and 47 mg Dextrose,Anhydrous, USP, in Water for Injection, USP primacor. The pH is adjusted to between 3.2and 4.0 with lactic acid or sodium hydroxide primacor. The total concentration of lacticacid can vary between 0.95 mg/mL and 1.29 mg/mL primacor. These vials require preparationof dilutions prior to administration to patients intravenously primacor.

Pre-Mix Flexible Container: The Flexible Container provide two ready-to-usedilutions of milrinone in volumes of 100 and 200 mL of 5% Dextrose Injection primacor. Each mL contains milrinone lactate equivalent to 200 mcg milrinone primacor. The nominalconcentration of lactic acid is 0.282 mg/mL primacor. Each mL also contains 49.4 mg Dextrose,Anhydrous, USP primacor. The pH is adjusted to between 3.2 and 4.0 with lactic acid orsodium hydroxide primacor. The flexible plastic container is comprised of polyvinyl chloridewith a foil overwrap primacor. Water can permeate the plastic into the overwrap, butthe amount is insufficient to significantly affect the pre-mix solution primacor.

CLINICAL PHARMACOLOGY
PRIMACOR is a positive inotrope and vasodilator, with little chronotropic activitydifferent in structure and mode of action from either the digitalis glycosidesor catecholamines primacor.

PRIMACOR, at relevant inotropic and vasorelaxant concentrations, is a selectiveinhibitor of peak III cAMP phosphodiesterase isozyme in cardiac and vascularmuscle primacor. This inhibitory action is consistent with cAMP mediated increases inintracellular ionized calcium and contractile force in cardiac muscle, as wellas with cAMP dependent contractile protein phosphorylation and relaxation invascular muscle primacor. Additional experimental evidence also indicates that PRIMACORis not a beta-adrenergic agonist nor does it inhibit sodium-potassium adenosinetriphosphatase activity as do the digitalis glycosides primacor.

Clinical studies in patients with congestive heart failure have shown thatPRIMACOR produces dose-related and plasma drug concentration-related increasesin the maximum rate of increase of left ventricular pressure primacor. Studies in normalsubjects have shown that PRIMACOR produces increases in the slope of the leftventricular pressure-dimension relationship, indicating a direct inotropic effectof the drug primacor. PRIMACOR also produces dose-related and plasma concentration-relatedincreases in forearm blood flow in patients with congestive heart failure, indicatinga direct arterial vasodilator activity of the drug primacor.

Both the inotropic and vasodilatory effects have been observed over the therapeuticrange of plasma milrinone concentrations of 100 ng/mL to 300 ng/mL primacor.

In addition to increasing myocardial contractility, PRIMACOR improves diastolicfunction as evidenced by improvements in left ventricular diastolic relaxation primacor.

The acute administration of intravenous milrinone has also been evaluated inclinical trials in excess of 1600 patients, with chronic heart failure, heartfailure associated with cardiac surgery, and heart failure associated with myocardialinfarction primacor. 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 primacor.

Pharmacokinetics
Following intravenous injections of 12.5 mcg/kg to 125 mcg/kg to congestiveheart failure patients, PRIMACOR had a volume of distribution of 0.38 liters/kg,a mean terminal elimination half-life of 2.3 hours, and a clearance of 0.13liters/kg/hr primacor. Following intravenous infusions of 0.20 mcg/kg/min to 0.70 mcg/kg/minto congestive heart failure patients, the drug had a volume of distributionof about 0.45 liters/kg, a mean terminal elimination half-life of 2.4 hours,and a clearance of 0.14 liters/kg/hr primacor. These pharmacokinetic parameters werenot dose-dependent, and the area under the plasma concentration versus timecurve following injections was significantly dose-dependent primacor.

PRIMACOR has been shown (by equilibrium dialysis) to be approximately 70% boundto human plasma protein primacor.

The primary route of excretion of PRIMACOR in man is via the urine primacor. The majorurinary excretions of orally administered PRIMACOR in man are milrinone (83%)and its 0-glucuronide metabolite (12%) primacor. Elimination in normal subjects via theurine is rapid, with approximately 60% recovered within the first two hoursfollowing dosing and approximately 90% recovered within the first eight hoursfollowing dosing primacor. The mean renal clearance of PRIMACOR is approximately 0.3liters/min, indicative of active secretion primacor.

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