Inamrinone Lactate

CHF

Short-term management of CHF.1 2 8 27 28 29 59 60 In most clinical studies, used in patients with NYHA class III or IV CHF who continued to receive therapy with cardiac glycosides (e.g., digoxin) and/or diuretics.2 8

Not found to be safe and effective in the long-term (>48 hours) treatment of CHF.59 60 (See Mortality Associated with Long-term Use under Cautions.)

Some clinicians recommend reserving inamrinone therapy for patients with heart failure whose condition is refractory to or who are intolerant to therapy with cardiac glycosides, diuretics, and/or vasodilators.1 2 27

ACC and AHA strongly discourage use of intermittent infusions of positive inotropic agents 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.63 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.63

Has been used for treatment of heart failure associated with cardiac surgery†.65

CPR

An alternative therapy 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.55 66

Used in conjunction with sympathomimetic agents (e.g., dobutamine) and volume titration for treatment of drug-induced cardiogenic shock.66

AMI†

Not recommended for use during the acute phase following MI;1 30 60 not included in the ACC and AHA recommendations for management of AMI.62

Has been used in children with myocardial dysfunction and increased systemic or pulmonary vascular resistance†66

Administration

Administer IV.1 60

For ACLS during CPR†, may be administered by intraosseous injection† in pediatric patients without reliable/immediate IV access.66

Has been administered orally†,2 16 18 33 36 37 38 but the high frequency of adverse GI effects has precluded use of this route of administration.35

IV Administration

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

Administer by slow direct IV injection and/or by continuous IV infusion.1 60

May be administered undiluted for direct IV injection.1 60 Use direct IV injection for initial loading dose and supplemental bolus doses.1 60

Continuous IV infusion: Dilute to a final concentration of 1–3 mg/mL in 0.45 or 0.9% sodium chloride.1 60

Administer the appropriate initial and/or supplemental bolus doses slowly (see Dosage) directly into a vein or the tubing of a freely flowing compatible IV solution.1 60

Usually, infuse maintenance dosage continuously IV at a rate of 5–10 mcg/kg per minute.1 60

Adjust rate of IV infusion according to clinical response of the patient and tolerance to adverse effects.1 60

Dosage

Available as inamrinone lactate; dosage expressed in terms of inamrinone.1 60

Individualize dosage based on clinical response (cardiac output, pulmonary wedge pressure, central venous pressure, urine output, body weight, orthopnea, dyspnea, fatigue) and tolerance to adverse effects.1 60

Pediatric Patients

Initially, approximately 0.75–1 mg/kg over 5 minutes which may be repeated up to 2 times, followed by an infusion of 2–20 mcg/kg per minute.66

Adults

Initially, 0.75 mg/kg as a slow (over 2–3 minutes) direct injection; if warranted, may administer a supplemental direct IV dose of 0.75 mg/kg 30 minutes after the initial dose.1 60 Direct IV injection is followed by an IV infusion of 5–10 mcg/kg per minute.1 Duration of therapy determined by clinical response and tolerance to adverse effects.1 60

Initially, approximately 0.75 mg/kg over 10–15 minutes (may administer over 2–3 minutes in absence of ventricular dysfunction), followed by an IV infusion of 5–15 mcg/kg per minute adjusted to desired clinical effect.66 May administer an additional bolus in 30 minutes.66

Prescribing Limits

Adults

Maximum total dosage (including initial and supplemental doses and cumulative infused dose) usually 10 mg/kg daily.1 Higher dosages (up to 18 mg/kg daily) have been administered for short periods in a limited number of patients.1 29 60

Special Populations

Renal Impairment

Consider dosage reduction.65

Contraindications

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

• Known hypersensitivity to sulfiting agents (i.e., sulfur dioxide, potassium or sodium bisulfite, potassium or sodium metabisulfite, sodium sulfite).1 65

• Some experts state that inamrinone is contraindicated in patients with heart valve stenosis that limits cardiac output.66

Warnings/Precautions

Warnings

Not found to be safe and effective for long-term (>48 hours) treatment of CHF;59 60 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.59 60

Sensitivity Reactions

Apparent hypersensitivity reactions associated with prolonged oral† therapy.1

Marked alterations in liver function test results1 11 51 52 and symptoms suggestive of an idiopathic hypersensitivity reaction (e.g., eosinophilia) reported.1 51 Promptly discontinue therapy if liver function test results and clinical symptoms suggestive of an idiosyncratic hypersensitivity reaction occur.1 Evaluate nonspecific hepatic changes (e.g., moderate alterations in liver function test results without clinical symptoms of hepatotoxicity) on an individual basis and consider the potential risk versus benefit of continued inamrinone therapy.1

Some formulations contain sulfites, which may cause allergic-type reaction (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.41 42 43 44 45 46 56 60

General Precautions

Dose-dependent thrombocytopenia (platelet counts less than 100,000–150,000/mm3)1 11 15 17 18 20 27 reported with short-term IV administration of usual dosages of inamrinone.1 30

Monitor platelet counts prior to and frequently during therapy.1 If thrombocytopenia occurs, decrease dosage, although platelet counts may return to pretreatment levels without dosage adjustment.1 Discontinue if possible risk of thrombocytopenia outweighs potential benefit of therapy.1

Possible hypotension.1 2 10 32

Close monitoring of BP and heart rate recommended, especially in patients with CHF and compromised renal and hepatic perfusion.1 Decrease or stop the IV infusion if excessive decreases in BP occur.1

Should not replace surgical removal of the obstruction in patients with severe aortic or pulmonic valvular disease.1 Use with caution in patients with hypertrophic subaortic stenosis since the drug may aggravate outflow tract obstruction.1

Possible slight increase in conduction velocity through AV node; may result in increased ventricular response in undigitalized patients with atrial flutter or fibrillation.1 40 Prior administration of cardiac glycosides recommended in patients with atrial flutter or fibrillation.1 60

Potential for increased risk for ventricular and supraventricular arrhythmias in some high-risk patients with severe CHF.1 40

Observe patients closely for changes in fluid and electrolyte balance and renal function.1

Inamrinone-induced increases in cardiac output with resultant diuresis may require dosage reduction of diuretics to prevent excessive potassium loss.1 Hypokalemia may predispose digitalized patients to cardiac arrhythmias.1 Correct hypokalemia by potassium supplementation prior to and/or during inamrinone therapy.1

Correct or adjust fluid and electrolyte balance to optimize response to inamrinone therapy.1 May increase fluid and electrolyte intake cautiously in patients who have received vigorous diuretic therapy prior to inamrinone administration, since cardiac filling pressure may be insufficient for adequate response to the drug.1

Use not recommended during the acute phase following MI.1 30 60 (See AMI under Uses.)

Specific Populations

Category C.60

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

Safety and efficacy not established in children <18 years of age.1 40 The drug has been used in children with myocardial dysfunction and increased systemic or pulmonary vascular resistance† (e.g., postoperative cardiac surgical patients with CHF, patients with dilated cardiomyopathy, selected children with septic shock and myocardial dysfunction with a high systemic vascular resistance).61

Carefully monitor hemodynamic response in patients with CHF who have hepatic impairment, since plasma concentrations of inamrinone may increase during IV infusion of the drug.1 60

Carefully monitor hemodynamic response in patients with CHF who have renal impairment, since plasma concentrations of inamrinone may increase during IV infusion of the drug.1 60

Common Adverse Effects

Thrombocytopenia,1 60 arrhythmias,1 60 hypotension,1 60 nausea,1 60 vomiting, 60 fever.60

Absorption

Onset

Following IV administration, cardiovascular effects usually apparent within 2–5 minutes;4 7 peak effects generally occur within 10 minutes at all dosages.1 7

Duration

Approximately 0.5 or 2 hours at IV dosages of 0.75 or 3 mg/kg, respectively.1

Plasma Concentrations

Plasma inamrinone concentrations appear to correlate with cardiovascular effects.2 21 39 Therapeutic plasma inamrinone concentrations range from 0.5–7 mcg/mL.1 3 21 40

Dosing generally aimed at maintaining a steady-state plasma concentration of about 3 mcg/mL.1 40

Distribution

Extent

May be distributed to some extent into tissues.1 22

Not known whether inamrinone crosses the blood-brain barrier.3

Not known whether inamrinone crosses the placenta3 or is distributed into milk.1 3

Plasma Protein Binding

Approximately 10–49%.1 60

Elimination

Metabolism

Metabolized in the liver to several metabolites; mainly involves conjugate formation.2 25

Elimination Route

Excreted principally in urine as unchanged drug and metabolites.1 3

Half-life

Biphasic;1 22 mean terminal half-life is about 3.6 hours in healthy adults.1 22 Terminal half-life averaged 5.8 hours in patients with CHF.1

• Inhibits cyclic adenosine monophosphate (cAMP) phosphodiesterase activity in cardiac and vascular muscles, resulting in increased cellular concentrations of cAMP;1 2 5 8 such increases in cAMP may be associated with increased intracellular ionized calcium and result in increased myocardial contractility.1 2 4 5 6 7 8 14 19 64

• In addition to its inotropic effect, the drug has vasodilatory activity.1 2 6 7 8 9 10 11 14 39 48 49 50

• Increases cardiac output1 4 7 8 13 27 30 49 50 and decreases left ventricular end-diastolic pressure,4 10 14 pulmonary wedge pressure,1 4 7 8 11 13 systemic vascular resistance,1 4 7 11 and systemic arterial1 4 10 11 and diastolic pressures.1 2 11

• Does not increase myocardial oxygen consumption (MVO2).8

• Heart rate generally remains unchanged1 2 4 7 8 11 14 or increases slightly.2 10

• May slightly increase conduction velocity through the AV node.1 40