Presentation: Primacor Injection is available as a sterile, clear, colourless to pale yellow solution, in 10ml ampoules (containing 10mg milrinone as the lactate) for intravenous administration. Primacor also contains dextrose and lactic acid.

Uses: Primacor Injection is indicated for the short-term treatment of severe congestive heart failure unresponsive to conventional maintenance therapy and for the treatment of acute heart failure, including low output states, following cardiac surgery.

Action: Milrinone is a positive inotrope and vasodilator, with little chronotropic activity. It also improves left ventricular diastolic relaxation. It differs in structure and mode of action from the digitalis glycosides, catecholamines or angiotensin-converting enzyme inhibitors. It is a selective inhibitor of peak lil phosphodiesterase isoenzyme in cardiac and vascular muscle. It produces slight enhancement of A-V node conduction, but no other significant electrophysiological effects. In clinical studies Primacor Injection has been shown to produce prompt improvements in the haemodynamic indices of heart failure, including cardiac output, pulmonary capiilary wedge pressure and vascular resistance, without clinically significant effect on heart rate or myocardial oxygen consumption. These improvements are related to both dose and plasma concentration. Haemodynamic improvement during intravenous Primacor therapy in chronic heart failure is accompanied by clinical symptomatic improvement, as measured by changes in New York Heart Association classification.

Dosage and Administration: For intravenous administration.

Adults: Primacor Injection should be given as a loading dose of 50 microgrammes/kg administered over a period of 10 minutes followed by continuous maintenance infusion at a dosage titrated between 0.375 microgrammes/kg/min and 0.75 microgrammes/kg/min to give a maximum haemodynamic effect. Total dosage should not exceed 1.13mg/kg/day.

Note: In impaired renal function, lower rates of maintenance infusion are advised; see "Use in Impaired Renal Function".

The following provides a guide to maintenance infusion delivery rate based upon a solution containing milrinone 200 microarammes/ml*.

PRIMACOR INJECTION

Dose

(microgrammes/kg/min)

0.375

0.400

0.500

0.600

0.700

0.750

MAINTENANCE

INFUSION DELIVERY RATE

(ml/kghrr)

O.t1

O.t2

0.15

0.18

0.21

0.22

_

~A 200 microgrammes/ml solution is prepared by using 40ml

0.45% saline, 0.9% saline or 5% dextrose may be used as diluents. Solutions of different concentrations may be used according to patient fluid requirements. The duration of therapy should depend upon the patient's response. In chronic heart failure, patients have been maintained on treatment for several days although the usual period is 48 to 72 hours. In acute states following cardiac surgery it is unlikely that treatment need be maintained for more than 12 hours.

Use in Impaired Renal Function: Data obtained from patients with severe renal impaimment but without congestive heart failure have demonstrated that the presence of renal impairment significantly increases the terminal elimination half-life of milrinone. For patients with clinical evidence of renal impairment, the following maintenance infusion rates are recommended:

Creatinine Primacor Injection

clearance dose

(ml/min/1.73m2) (microgrammes/

kg/min))

5

10

20

30

40

50

0.20 0.23

0.28

0.33

0.38

0.43

Maintenance

infusion delivery

rate (for solution of

milrinone 200

microgrammes/ml)

(ml/kg/hr)

0.06

0.07

0.08

0.10

0.11

0.13

Adjustment of the infusion rate should be made according to haemodynamic response.

Use in Elderly Patients: Experience so far suggests that no special recommendations for the elderly patient are necessary.

Use in Children: Safety and effectiveness in children have not been established.

Contra-indications: Hypersensitivity to Primacor Injection is a contra-indication to its use.

Precautions: The use of Primacor Injection is not recommended immediately following acute myocardial infarction until safety and efficacy have been established in this situation.

In patients with severe obstructive aortic or pulmonary valvular disease or hypertrophic subaortic stenosis, Primacor Injection should not be used in place of surgical relief of the obstruction. In these conditions it is possible that a drug with inotropic/vasodilator properties might aggravate outflow obstruction .

agents to prolong A-V node conduction time should be considered.

Milrinone may induce hypotension through its vasodilatory actions. Particular caution should therefore be observed when initiating Primacor Injection therapy in patients who are hypotensive and in those in whom prior vigorous diuretic therapy is suspected of causing significant decreases in cardiac filling pressure. Blood pressure, heart rate, electrocardiogram, clinical state, fluid balance, electrolytes and renal function should be carefully monitored when initiabng and during Primacor Injection therapy. The infusion should be sbwed or stopped if arrhythmias develop or an excessive decrease in blood pressure occurs. Improvement in cardiac output with resultant diuresis may necessitate a reduction in the dose of diuretic. Potassium loss due to excessive diuresis may predispose digitalised patents to arrhythmias. Therefore, hypokalaemia should be corrected by potassium supplementation in advance of, or during, the use of Primacor Injection.

Use in Pregnancy and Lactation: Although animal studies have not revealed evidence of druginduced foetal damage or other deleterious effects on reproductive function, the safety of milrinone in human pregnancy has not yet been established. It should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. Caution should be exercised when Primacor Injection is administered to nursing women, since it is not known whether milrinone is excreted in human milk.

side Effects: Supraventricular and ventricular arrhythmias including nonsustained ventricular tachycardia have been reported during treatment with Primacor Injection. An increase in ventricular response rate in patients with atrial fibrillation may occur. The incidence of arrhythmias has not been related to dose or plasma levels of milrinone. Other reported side-effects include hypotension, angina/chest pain, headaches, hypokalaemia and tremor. Thrombocytopenia has also been observed but has not been definitely related to the administrabon of Primacor Injection.

Drug Interactions: No untoward clinical manifestations of drug interaction have been observed during Primacor Injection therapy. Whilst there is a theoretical potential interaction with calcium channel blockers, there has been no evidence of a clinically significant interaction to date. Milrinone has a favourable inotropic effect in fully digitalised patients without causing signs of glycoside toxicity.

Chemical Compatibility: Precipitabon occurs immediately when frusemide or bumetanide is mixed with milrinone solution. Therefore, frusemide or bumetanide should not be administered in intravenous lines containing Primacor Injection. Sodium bicarbonate intravenous infusion should not be used for dilution. Other drugs should not be mixed with Primacor Injection until further compatibility data are available.

antidote is known, but general measures for circulatory support should be taken.

Pharmaceutical Precautions: Store at room temperature; avoid freezing. Infusion solutions diluted as recommended with 0.45% saline,0.9% saline or 5% dextrose should be freshly prepared before use. Parenteral drug products should be examined visually and should not be used if particulate matter or discolouration are present.

Legal Category: POM.

Package Quantities: Boxes of 10 ampoules.

Further Information: In congestive heart failure, milrinone on intravenous administration has a volume of distribution of about 0.4 I/kg, a temminal elimination haH-life of about 2.3 hours and a clearance of about 0.13 I/kg/h. These pharmacokinetic parameters are not dose-dependent. Milrinone is approximately 70% bound to plasma protein and is primarily excreted unchanged via the kidney.

PRODUCT LICENCE No. PL 11723/0064

Sanofi Winthrop Limited One Onslow Street, Guildford Surrey GU1 4YS.

Date of Preparation:

February 1992

316/394