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Primacor

Generic Name: Milrinone Lactate
Class: Cardiotonic Agents
VA Class: CV900
Chemical Name: 1,6-Dihydro-2-methyl-6-oxo-[3,4′-bipyridine]-5-carbonitrile
Molecular Formula: C12H9N3O
CAS Number: 78415-72-2

Introduction

Positive inotropic agent that has vasodilating effects; a selective phosphodiesterase (PDE) inhibitor.1 7 8 9 10 11 13 14 15 22 23 26

Uses for Primacor

CHF

Short-term management of acutely decompensated heart failure.1 3 12 13 14 22 23 In most clinical studies, used in patients with NYHA class III or IV CHF who were receiving cardiac glycosides (e.g., digoxin) and diuretics.1 3 13 15 16 22 23 No evidence to date that milrinone decreases mortality associated with CHF.8 9 10 11 15 22

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Not found to be safe and effective in the long-term (>48 hours) treatment of CHF.1 2 9 10 11 15 19 22 23 (See Mortality Associated with Long-term Use under Cautions.) Some clinicians recommend reserving milrinone therapy for patients with severe heart failure whose condition is refractory to therapy with cardiac glycosides, diuretics, ACE inhibitors, and/or β-adrenergic blocking agents.11 12

ACC and AHA strongly discourage use of intermittent infusions of positive inotropic agents (e.g., milrinone) at home, in outpatient medical facilities (e.g., clinics), or in short-stay medical units for the long-term management of heart failure, even for advanced stages of the disease.24 However, ACC and AHA state that short-term continuous positive inotropic therapy can be considered for palliative therapy in patients with refractory end-stage heart failure.24 25

Has been used for treatment of heart failure associated with cardiac surgery.17

CPR

An alternative therapy (used in conjunction with catecholamines) in ACLS for improving cardiac output when catecholamine therapy alone is ineffective in patients with severe heart failure, cardiogenic shock, or other forms of shock.5 6 26

AMI

Not recommended for use during the acute phase following MI;1 22 not included in the ACC and AHA recommendations for management of AMI.20

Myocardial Dysfunction in Children

Has been used in children with myocardial dysfunction and increased systemic or pulmonary vascular resistance.26 (See Pediatric Use under Cautions.)

Primacor Dosage and Administration

General

  • Intermittent infusions for long-term management of heart failure are not recommended.24 However, short-term continuous IV therapy can be considered for palliative therapy in patients with refractory end-stage heart failure.24 25 (See CHF under Uses.)

Administration

Administer by slow IV injection followed by IV infusion.1 3 5 6 7 8 12 13 14 22 26

For ACLS during CPR, may be administered by intraosseous injection in pediatric patients without reliable/immediate IV access.26

Oral Administration

Has been administered orally (oral dosage form not commercially available in US), but increased morbidity and mortality have precluded continued study of this route of administration.1 2 15 22

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer as a slow IV injection followed by a continuous IV infusion.1 3 5 6 7 8 12 13 14 22 26

Administer initial dose undiluted or diluted (for better visualization of injection rate).1 22

Administer IV infusions via a calibrated electronic controlled-infusion device.1 22 23

Do not use premixed IV solution in flexible plastic containers in series connections.1 For administration instructions for premixed solutions, consult manufacturers’ labelings.1

Dilution

Initial dose: May dilute initial dose with 0.45% sodium chloride injection, 0.9% sodium chloride injection, or 5% dextrose injection to a total volume of 10 or 20 mL.1 22

Continuous IV infusion: Dilute contents of vial containing milrinone 10, 20, or 50 mg with 40, 80, or 200 mL, respectively, of 0.45% sodium chloride injection, 0.9% sodium chloride injection, or 5% dextrose injection to provide a solution containing approximately 200 mcg/mL.1 21 22 23 Alternatively, use premixed solution containing 200 mcg/mL of milrinone in 5% dextrose injection without further dilution.1

Rate of Administration

Administer initial dose slowly (e.g., over 10 minutes) as a direct IV injection.1 22

Adjust rate of IV infusion according to hemodynamic and clinical response, including assessment of cardiac output and pulmonary capillary wedge pressure.1 22

Dosage

Available as milrinone lactate; dosage expressed in terms of milrinone.1 22

Pediatric Patients

CPR
ACLS
IV or Intraosseous

Initially, 50–75 mcg/kg as a slow, direct injection over 10–60 minutes, followed by an infusion of 0.5–0.75 mcg/kg per minute.26

Adults

CHF
Decompensated CHF
IV

Initially, 50 mcg/kg as a slow, direct injection, followed by an IV infusion of 0.375– 0.75 mcg/kg per minute.1 22 Duration of therapy depends on clinical response.1 22

CPR
ACLS
IV

Initially, 50 mcg/kg as a slow, direct injection over 10 minutes, followed by an IV infusion of 0.375–0.75 mcg/kg per minute for 2–3 days.26

Prescribing Limits

Adults

CHF
Decompensated CHF
IV

Maximum total dosage (including initial and cumulative doses) 1.13 mg/kg daily.1 22

Special Populations

Renal Impairment

CHF
IV

Reduce rate of continuous IV infusion in patients with Clcr≤50 mL/minute.1 22 23

Recommended Rates of Continuous IV Infusion in Patients with Renal Impairment122

Clcr (mL/min)

Infusion Rate

50

0.43 mcg/kg per minute

40

0.38 mcg/kg per minute

30

0.33 mcg/kg per minute

20

0.28 mcg/kg per minute

10

0.23 mcg/kg per minute

5

0.2 mcg/kg per minute

Geriatric Patients

No dosage adjustments except those related to renal impairment.1 (See Renal Impairment under Dosage and Administration.)

Cautions for Primacor

Contraindications

  • Known hypersensitivity to milrinone or any ingredient in the formulation.1 22

  • Some experts state that milrinone is contraindicated in patients with heart valve stenosis that limits cardiac output.26

Warnings/Precautions

Warnings

Mortality Associated with Long-term Use

Not found to be safe and effective for long-term (>48 hours) treatment of CHF;1 2 9 10 11 15 19 22 23 chronic oral therapy did not consistently alleviate CHF symptoms and was consistently associated with increased risk of hospitalization and sudden death, particularly in patients with NYHA class IV disease.1 2 22 No evidence to indicate that long-term IV therapy (either continuous or intermittent infusion) would not be associated with similar risks.1 22

Mechanism for increased mortality not fully elucidated; long-term therapy may result in increased cellular cAMP concentrations (with resultant toxicity to myocardial cells and enhanced electrophysiologic mechanisms leading to arrhythmias, including ventricular arrhythmias).2 (See Arrhythmogenic Effects under Cautions.)

Arrhythmogenic Effects

Potential for increased frequency of supraventricular and ventricular arrhythmias (e.g., nonsustained ventricular tachycardia).1 7 12 22 23 Close monitoring, including continuous ECG monitoring, recommended to allow for prompt detection and management of ventricular arrhythmias.1 22

General Precautions

Obstructive Valvular Disease

May aggravate outflow track obstruction; use with caution in patients with hypertrophic subaortic stenosis.1 22

Should not replace surgical intervention necessary to relieve obstruction in patients with severe obstructive aortic or pulmonic valvular disease.1 22

Effects on Cardiac Conduction

Possible slight shortening of AV conduction velocity; may result in increased ventricular response rate in patients with atrial flutter or fibrillation not controlled with cardiac glycoside therapy.1 7 15 22 Consider cardiac glycoside therapy prior to use in patients with atrial flutter or fibrillation.1 22 23

Hemodynamic Effects

Possible excessive decreases in BP.1 22 Close monitoring of BP, heart rate, and clinical symptomatology recommended, especially in patients with substantial decreases in cardiac filling pressure associated with prior vigorous diuretic therapy.1 22 Decrease or stop the IV infusion if necessary.1 22

AMI

Use not recommended during the acute phase following MI.1 22 23 (See AMI under Uses.)

Fluid and Electrolyte Imbalance

Observe patient closely for changes in fluid and electrolyte balance and renal function.1 22 Milrinone-induced increases in cardiac output with resultant diuresis may require dosage reduction of diuretics to prevent excessive potassium loss.1 22 Hypokalemia may predispose digitalized patients to cardiac arrhythmias; correct hypokalemia by potassium supplementation prior to and/or during milrinone therapy.1 22

Specific Populations

Pregnancy

Category C.1 22

Lactation

Not known whether milrinone is distributed into milk.1 22 Caution advised if used in nursing women.1 22

Pediatric Use

Safety and efficacy not established.1 21 22 23

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.1 22 23

Renal Impairment

Clearance may be decreased; dosage adjustments necessary depending on degree of renal impairment.1 22 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Ventricular arrhythmias1 3 12 13 15 22 (e.g., ventricular ectopy,1 12 13 15 22 nonsustained ventricular tachycardia1 13 22 ), supraventricular arrhythmias,1 12 13 15 22 hypotension,1 3 13 15 22 headache.1 12 13 15 22

Interactions for Primacor

Administered concomitantly with cardiac glycosides, lidocaine, quinidine, hydralazine, prazosin, isosorbide dinitrate, nitroglycerin, chlorthalidone, furosemide, hydrochlorothiazide, spironolactone, captopril, heparin, warfarin, diazepam, insulin, and potassium supplements without unusual adverse effects.1 22

Primacor Pharmacokinetics

Absorption

Onset

Following IV administration, improvement in hemodynamic function usually occurs within 5–15 minutes.1 22

Duration

Hemodynamic responses usually are maintained during continuous IV infusion for 48–72 hours; no evidence of tachyphylaxis observed.1 22

Plasma Concentrations

Plasma milrinone concentrations appear to correlate with cardiovascular effects.7 Inotropic and vasodilatory effects occur with plasma milrinone concentrations of 100–300 ng/mL.1 22

Distribution

Plasma Protein Binding

Approximately 70%.1

Elimination

Elimination Route

Excreted principally in urine1 7 15 22 26 as unchanged drug (83%) and its O-glucuronide metabolite (12%).1 22 Only small amounts are excreted in feces.15

Half-life

Approximately 2.4 hours.1 22

Special Populations

In patients with renal impairment (but without CHF), elimination half-life is substantially increased.1 22

Stability

Storage

Parenteral

Injection, for IV use

15–25°C; do not freeze.1

Injection, for IV infusion (premixed solution)

25°C; may be exposed briefly to temperatures up to 40°C.1 Do not freeze.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID

Compatible

Dextrose 5% in water

Ringer’s injection, lactated

Sodium chloride 0.45 or 0.9%

Drug Compatibility
Admixture CompatibilityHID

Compatible

Quinidine gluconate

Incompatible

Procainamide HCl

Y-Site CompatibilityHID

Compatible

Acyclovir sodium

Amikacin sulfate

Amiodarone HCl

Ampicillin sodium

Argatroban

Atracurium besylate

Bivalirudin

Bumetanide

Calcium chloride

Calcium gluconate

Caspofungin acetate

Cefazolin sodium

Cefepime HCl

Cefotaxime sodium

Ceftaroline fosamil

Ceftazidime

Cefuroxime sodium

Ciprofloxacin

Clindamycin phosphate

Dexamethasone sodium phosphate

Dexmedetomidine HCl

Digoxin

Diltiazem HCl

Dobutamine HCl

Dopamine HCl

Doripenem

Epinephrine HCl

Fenoldopam mesylate

Fentanyl citrate

Gentamicin sulfate

Heparin sodium

Hetastarch in lactated electrolyte injection (Hextend)

Hydromorphone HCl

Insulin, regular human

Isoproterenol HCl

Labetalol HCl

Lorazepam

Magnesium sulfate

Meropenem

Methylprednisolone sodium succinate

Metoprolol tartrate

Metronidazole

Micafungin sodium

Midazolam HCl

Morphine sulfate

Nesiritide

Nicardipine HCl

Nitroglycerin

Norepinephrine bitartrate

Oxacillin sodium

Pancuronium bromide

Piperacillin sodium-tazobactam sodium

Potassium chloride

Propofol

Propranolol HCl

Quinidine gluconate

Ranitidine HCl

Rocuronium bromide

Sodium bicarbonate

Sodium nitroprusside

Telavancin HCl

Theophylline

Ticarcillin disodium-clavulanate potassium

Tobramycin sulfate

Torsemide

Vancomycin HCl

Vasopressin

Vecuronium bromide

Verapamil HCl

Incompatible

Furosemide

Imipenem-cilastatin sodium

Procainamide HCl

Actions

  • Selectively inhibits cyclic adenosine monophosphate (cAMP) phosphodiesterase activity in cardiac and vascular muscles, resulting in increased intracellular concentrations of cAMP; such increases in cAMP may be associated with increased intracellular ionized calcium and result in increased myocardial contractility.1 7 15 22

  • Has vasodilatory activity; however, has little chronotropic activity.1 7 22

  • Increases cardiac output and decreases pulmonary capillary wedge pressure and vascular resistance; produces minor changes in heart rate or myocardial oxygen consumption.1 7 8 12 13 15 22 23

Advice to Patients

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 22

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.1 22

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Milrinone Lactate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for IV use

1 mg (of milrinone) per mL (10, 20, and 50 mL)*

Milrinone Lactate Injection

Primacor (available as Carpuject cartridges or vials)

Sanofi-Aventis

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Milrinone Lactate in Dextrose

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for IV infusion

200 mcg (of milrinone) per mL in 5% Dextrose (100 and 200 mL)*

Milrinone Lactate Injection (in flexible containers)

Primacor (in flexible containers)

Sanofi-Aventis

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 10, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Sanofi-Synthelabo. Primacor (milrinone lactate) injection prescribing information. New York, NY; 2003 Jan.

2. Packer M, Carver JR, Rodeheffer RJ et al. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med. 1991; 325:1468-75. [IDIS 288125] [PubMed 1944425]

3. Cuffe MS, Califf RM, Adams KF Jr et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA. 2002; 287:1541-7. [IDIS 479076] [PubMed 11911756]

4. Poole-Wilson PA. Treatment of acute heart failure: out with the old, in with the new. JAMA. 2002; 287:1578-80. [IDIS 479079] [PubMed 11911762]

5. American Heart Association in collaboration with the International Liaison Committee on Resuscitation. Guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care. Part 6: Advanced cardiovascular life support. Circulation. 2000; 102(Suppl I): I-86-171.

6. American Heart Association in collaboration with the International Liaison Committee on Resuscitation. Guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care. Part 10: Pediatric advanced life support. Circulation. 2000; 102(Suppl I): I-291-342.

7. Shipley JB, Tolman D, Hastillo A et al. Milrinone: basic and clinical pharmacology and acute and chronic management: a review. Am J Med Sci. 1996; 311:286-91. [IDIS 369469] [PubMed 8659556]

8. White CM, Chow MSS. The role of positive inotropic agents in severe congestive heart failure. Formulary. 1997; 32:255-66.

9. Gheorghiade M, Benatar D, Konstam MA et al. Pharmacotherapy for systolic dysfunction: a review of randomized clinical trials. Am J Cardiol. 1997; 80:14H-27H. [IDIS 397429] [PubMed 9372994]

10. Skrabal MZ, Stading JA, Behmer-Miller KA et al. Advances in the treatment of congestive heart failure: new approaches for an old disease. Pharmacotherapy; 2000:787-804.

11. Felker GM, O’Connor CM. Inotropic therapy for heart failure: an evidence-based approach. Am Heart J. 2001; 142:393-401. [IDIS 469538] [PubMed 11526351]

12. Anderson JL, Baim DS, Fein SA et al. Efficacy and safety of sustained (48 hour) intravenous infusions of milrinone in patients with severe congestive heart failure: a multicenter study. J Am Coll Cardiol. 1987; 9:711-22. [PubMed 3549837]

13. Anderson JL. Hemodynamic and clinical benefits with intravenous milrinone in severe chronic heart failure: results of a multicenter study in the United States. Am Heart J. 1991; 121:1956-64. [IDIS 283368] [PubMed 2035427]

14. Rettig GF, Schieffer HJ. Acute effects of intravenous milrinone in heart failure. Eur Heart J. 1989; 10(Suppl C):39-43. [PubMed 2680496]

15. Hilleman DE, Forbes WP. Role of milrinone in the management of congestive heart failure. DICP. 1989; 23:357-62. [IDIS 254665] [PubMed 2658377]

16. Cuffe MS, Califf RM, Adams KF et al. Rationale and design of the OPTIME CHF trial: outcomes of a prospective trial of intravenous milrinone for exacerbations of chronic heart failure. Am Heart J. 2000; 139:15-22. [PubMed 10618557]

17. Wright EM, Skoyles J, Sherry KM. Milrinone in the treatment of low output states following cardiac surgery. Eur J Anaesthesiol. 1992; (Suppl 5):21-6.

18. Copp MV, Hill AJ, Feneck RO. Overview of the effects of intravenous milrinone in acute heart failure following surgery. Eur J Anaesthesiol. 1992; Suppl 5:21-6.

19. Ewy GA. Inotropic infusions for chronic congestive heart failure: medical miracles or misguided medicinals? J Am Coll Cardiol. 1999; 33:572-5.

20. Ryan TJ, Antman EM, Brooks NH et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction: 1999 update: a report of the American College of Cardiology/American Hart Association Task force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol. 1999; 34:890-911. [IDIS 434290] [PubMed 10483976]

21. Ben Venue Laboratories. Bedford, OH: Personal communication.

22. Bedford Laboratories. Milrinone lactate injection prescribing information. Bedford, OH; 2002 April.

23. Sanofi-Synthelabo., New York, New York: Personal communication

24. Hunt SA, Baker DW, Chin MH et al. ACC/AHA guidelines for the management of chronic heart failure in the adult: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol. 2001. From website.

25. Hunt SA, Baker DW, Chin MH et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol. 2001; 38:2101-13. [IDIS 474368] [PubMed 11738322]

26. The American Heart Association. Guidelines 2005 for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2005; 112(Suppl I):IV1-211.

HID. Trissel LA. Handbook on injectable drugs. 17th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2013:802-807.

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