Dilution Milrinone (Primacor ®)

Milrinone (Primacor ®)

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Usual Diluents

D5W, NS

Standard Dilutions [Amount of drug] [Infusion volume] [Infusion rate]

Remove 50 ml from 250ml bag.
(Final volume =250 ml)
[50 mg] [200 ml] [Titrate]

Also available as a pre-pack:
PRIMACOR Flexible Containers (200 mcg/mL in 5% Dextrose Injection) are supplied:
100 mL (200 mcg/mL) NDC 0024-1203-11 in 5% Dextrose Injection single units.

200 mL (200 mcg/mL) NDC 0024-1203-22 in 5% Dextrose Injection single units.

Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. It is recommended that the Flexible Containers be stored at room temperature, 25 C (77 F), however, brief exposure up to 40 C (104 F) does not adversely affect the product.

Stability / Miscellaneous

EXP: 3 DAYS (RT).

Dosing: initially give loading dose: 50 mcg/kg IV over 10 minutes, followed by continuous infusion: 0.375 to 0.75 mcg/kg/min (usually 0.5 mcg/kg/min).
Lower doses are required in renal failure (0.2 to 0.23 mcg/kg/min for crcl <10 ml/min, crcl 10-30 ml/min-0.23 to 0.33 mcg/kg/min).

Venodilator: 0 Arterial dilator: ++ Inotropic effect: +++
Calculation of drip rate:
50 mg/250ml (ml/hr) = wt (kg) x 0.3 x mcg/kg/min

Recommended infusion rates: renal insufficiency

Creatinine Clearance (mL/min/1.73 m ²)	Infusion Rate (mcg/kg/min)
5	0.20
10	0.23
20	0.28
30	0.33
40	0.38
50	0.43

CLINICAL PHARMACOLOGY
PRIMACOR is a positive inotrope and vasodilator, with little chronotropic activity different in structure and mode of action from either the digitalis glycosides or catecholamines.

PRIMACOR, 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 PRIMACOR 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 PRIMACOR 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 PRIMACOR produces increases in the slope of the left ventricular pressure-dimension relationship, indicating a direct inotropic effect of the drug. PRIMACOR 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, PRIMACOR 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, 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 0.13 liters/kg/hr. Following intravenous infusions of 0.20 mcg/kg/min to 0.70 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.

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

The primary route of excretion of PRIMACOR in man is via the urine. The major urinary excretions of orally administered PRIMACOR 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 PRIMACOR is approximately 0.3 liters/min, indicative of active secretion.

INDICATIONS AND USAGE
PRIMACOR is indicated for the short-term intravenous treatment of patients with acute decompensated heart failure. Patients receiving PRIMACOR 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 PRIMACOR has been in patients receiving digoxin and diuretics. There is no experience in controlled trials with infusions of PRIMACOR for periods exceeding 48 hours.

DOSAGE AND ADMINISTRATION
PRIMACOR (milrinone lactate) 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

Note: PRIMACOR Flexible Containers (200 mcg/mL in 5% Dextrose Injection) are for intravenous infusion only and should not be used for a loading dose. Dosage recommendations using a 1mg/mL concentration of milrinone are included for informational purposes only. The loading dose should be administered using a milrinone 1mg/mL vial.

The table below shows the loading dose in milliliters (mL) of milrinone (1mg/mL) by patient body weight (kg).

**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	2.0	2.5	3.0	3.5	4.0	4.5	5.0	5.5	6.0

MAINTENANCE DOSE

	Infusion Rate	Total Daily Dose (24 Hours)
Minimum	0.375 mcg/kg/min	0.59 mg/kg	Administer as a
Standard	0.50 mcg/kg/min	0.77 mg/kg	continuous
Maximum	0.75 mcg/kg/min	1.13 mg/kg	intravenous infusion

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 at top of page.... 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.

Manufactured by:
Hospira Inc.
Lake Forest, IL 60045

Manufactured for:
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807

Revised March 2007B

Source: [package insert]