Milrinone Injection

General

Milrinone should not be used in patients with severe obstructive aortic or pulmonic valvular disease in lieu of surgical relief of the obstruction. Like other inotropic agents, it may aggravate outflow tract obstruction in hypertrophic subaortic stenosis.

Supraventricular and ventricular arrhythmias have been observed in the high-risk population treated. In some patients, injections of milrinone and oral milrinone have been shown to increase ventricular ectopy, including nonsustained ventricular tachycardia. The potential for arrhythmia, present in congestive heart failure itself, may be increased by many drugs or combinations of drugs. Patients receiving milrinone should be closely monitored during infusion.

Milrinone produces a slight shortening of AV node conduction time, indicating a potential for an increased ventricular response rate in patients with atrial flutter/fibrillation which is not controlled with digitalis therapy.

During therapy with milrinone, blood pressure and heart rate should be monitored and the rate of infusion slowed or stopped in patients showing excessive decreases in blood pressure.

If prior vigorous diuretic therapy is suspected to have caused significant decreases in cardiac filling pressure, milrinone should be cautiously administered with monitoring of blood pressure, heart rate, and clinical symptomatology.

There is no experience in controlled trials with infusions of milrinone for periods exceeding 48 hours. Cases of infusion site reaction have been reported with intravenous milrinone therapy (see ADVERSE REACTIONS). Consequently, careful monitoring of the infusion site should be maintained to avoid possible extravasation.

Use in acute myocardial infarction

No clinical studies have been conducted in patients in the acute phase of post myocardial infarction. Until further clinical experience with this class of drugs is gained, milrinone is not recommended in these patients.

Laboratory Tests

Fluid and electrolyte changes and renal function should be carefully monitored during therapy with milrinone. Improvement in cardiac output with resultant diuresis may necessitate a reduction in the dose of diuretic. Potassium loss due to excessive diuresis may predispose digitalized patients to arrhythmias. Therefore, hypokalemia should be corrected by potassium supplementation in advance of or during use of milrinone.

Drug Interactions

No untoward clinical manifestations have been observed in limited experience with patients in whom milrinone was used concurrently with the following drugs: digitalis glycosides; lidocaine, quinidine; hydralazine, prazosin; isosorbide dinitrate, nitroglycerin; chlorthalidone, furosemide, hydrochlorothiazide, spironolactone; captopril; heparin, warfarin, diazepam, insulin; and potassium supplements.

Chemical Interactions

There is an immediate chemical interaction which is evidenced by the formation of a precipitate when furosemide is injected into an intravenous line of an infusion of milrinone. Therefore, furosemide should not be administered in intravenous lines containing milrinone.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Twenty-four months of oral administration of milrinone to mice at doses up to 40 mg/kg/day (about 50 times the human oral therapeutic dose in a 50 kg patient) was unassociated with evidence of carcinogenic potential. Neither was there evidence of carcinogenic potential when milrinone was orally administered to rats at doses up to 5 mg/kg/day (about 6 times the human oral therapeutic dose) for twenty-four months or at 25 mg/kg/day (about 30 times the human oral therapeutic dose) for up to 18 months in males and 20 months in females. Whereas the Chinese Hamster Ovary Chromosome Aberration Assay was positive in the presence of a metabolic activation system, results from the Ames Test, the Mouse Lymphoma Assay, the Micronucleus Test, and the in vivo Rat Bone Marrow Metaphase Analysis indicated an absence of mutagenic potential. In reproductive performance studies in rats, milrinone had no effect on male or female fertility at oral doses up to 32 mg/kg/day.

Animal Toxicity

Oral and intravenous administration of toxic dosages of milrinone to rats and dogs resulted in myocardial degeneration/fibrosis and endocardial hemorrhage, principally affecting the left ventricular papillary muscles. Coronary vascular lesions characterized by periarterial edema and inflammation have been observed in dogs only. The myocardial/endocardial changes are similar to those produced by beta-adrenergic receptor agonists such as isoproterenol, while the vascular changes are similar to those produced by minoxidil and hydralazine. Doses within the recommended clinical dose range (up to 1.13 mg/kg/day) for congestive heart failure patients have not produced significant adverse effects in animals.

Pregnancy Category C

Oral administration of milrinone to pregnant rats and rabbits during organogenesis produced no evidence of teratogenicity at dose levels up to 40 mg/kg/day and 12 mg/kg/day, respectively. Milrinone did not appear to be teratogenic when administered intravenously to pregnant rats at doses up to 3 mg/kg/day (about 2.5 times the maximum recommended clinical intravenous dose) or pregnant rabbits at doses up to 12 mg/kg/day, although an increased resorption rate was apparent at both 8 mg/kg/day and 12 mg/kg/day (intravenous) in the latter species. There are no adequate and well-controlled studies in pregnant women. Milrinone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Caution should be exercised when milrinone is administered to nursing women, since it is not known whether it is excreted in human milk.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Use in Elderly Patients

There are no special dosage recommendations for the elderly patient. Ninety percent of all patients administered milrinone in clinical studies were within the age range of 45 to 70 years, with a mean age of 61 years. Patients in all age groups demonstrated clinically and statistically significant responses. No age-related effects on the incidence of adverse reactions have been observed. Controlled pharmacokinetic studies have not disclosed any age-related effects on the distribution and elimination of milrinone.

Cardiovascular Effects

In patients receiving milrinone 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 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 was not shown to be arrhythmogenic in an electrophysiology study. Supraventricular arrhythmias were reported in 3.8% of the patients receiving milrinone. 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.

Other Effects

Other adverse reactions reported, but not definitely related to the administration of milrinone 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 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

100 mL
NDC 0409-2776-23

(20 mg/100 mL)

MILRINONE LACTATE INJECTION
200 mcg (0.2 mg)/mL*
IN 5% DEXTROSE INJECTION

SINGLE-DOSE FLEXIBLE CONTAINER

* EACH mL CONTAINS MILRINONE LACTATE
EQUIVALENT TO 0.2 mg MILRINONE, 0.282 mg
LACTIC ACID, 49.4 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. NO PRESERVATIVES
ADDED. USE ONLY IF SOLUTION IS CLEAR,
COLORLESS TO PALE YELLOW AND CONTAINER IS
UNDAMAGED. DISCARD UNUSED PORTION. EACH
FLEXIBLE CONTAINER IS FOR ONE INFUSION ONLY.
FOR I.V. USE. USUAL DOSAGE: SEE INSERT. MUST
NOT BE USED IN SERIES CONNECTIONS.

Rx ONLY

3
V
CONTAINS DEHP

Hospira

©HOSPIRA 2004
PRINTED IN USA
IM-0247 (5/04)

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

TO OPEN TEAR AT NOTCH

100 mL
NDC 0409-2776-23

20 mg/100 mL

Milrinone Lactate Injection
200 mcg (0.2 mg)/mL*
in 5% Dextrose Injection

* Each mL contains milrinone lactate equivalent to 0.2 mg milrinone,
0.282 mg lactic acid, 49.4 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. No preservatives added.

Use only if solution is clear, colorless to pale yellow, and container is
undamaged. Single-dose container. For Intravenous Use. Usual dosage: See
insert. Discard unused portion. Each flexible container is for one infusion
only. MUST NOT BE USED IN SERIES CONNECTIONS.

The overwrap is a moisture barrier. Do not remove unit from overwrap until
ready for use. After removing the overwrap, check for minute leaks by
squeezing container firmly. If leaks are found, discard unit as sterility may be
impaired. Use unit promptly when pouch is opened. Store at 20 to 25°C
(68 to 77°F). [See USP Controlled Room Temperature.] Protect from freezing.

Rx only

F WR-0284 (4/08)

Printed in USA
Hospira, Inc., Lake Forest, IL 60045 USA

Hospira

200 mL

NDC 0409-2776-02

MILRINONE LACTATE INJECTION
200 mcg (0.2 mg)/mL*
IN 5% DEXTROSE INJECTION
40 mg/200 mL

SINGLE-DOSE FLEXIBLE CONTAINTER

* EACH mL CONTAINS MILRINONE LACTATE
EQUIVALENT TO 0.2 mg MILRINONE,
0.282 mg LACTIC ACID, 49.4 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. NO
PRESERVATIVES ADDED. USE ONLY IF
SOLUTION IS CLEAR, COLORLESS TO PALE
YELLOW AND CONTAINER IS UNDAMAGED.
DISCARD UNUSED PORTION. EACH
FLEXIBLE CONTAINER IS FOR ONE INFUSION
ONLY. FOR I.V. USE. USUAL DOSAGE: SEE
INSERT. MUST NOT BE USED IN SERIES
CONNECTIONS.

Rx ONLY

CONTAINS DEHP

Hospira

©HOSPIRA 2004
IM-0246 (5/04)

HOSPIRA, INC., LAKE FOREST, IL 60045 USA
PRINTED IN USA

TO OPEN TEAR AT NOTCH

200 mL

NDC 0409-2776-02

Milrinone Lactate Injection

200 mcg (0.2 mg) / mL*

In 5% Dextrose Injection

40 mg/ 200 mL

* Each mL contains milrinone lactate equivalent to 0.2 mg
milrinone, 0.282 mg lactic acid, 49.4 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. No preservatives
added.

Use only if solution is clear, colorless to pale yellow, and
container is undamaged. Single-dose container. For Intravenous
Use. Usual dosage: See insert. Discard unused portion. Each
flexible container is for one infusion only. MUST NOT BE USED IN
SERIES CONNECTIONS.

The overwrap is a moisture barrier. Do not remove unit from
overwrap until ready for use. After removing the overwrap, check
for minute leaks by squeezing container firmly. If leaks are found,
discard unit as sterility may be impaired. Use unit promptly when
pouch is opened. Store at 20 to 25°C (68 to 77°F). [See USP
Controlled Room Temperature.] Protect from freezing.

Rx only

F WR-0285 (4/08)

Printed in USA
Hospira, Inc., Lake Forest, IL 60045 USA

Hospira