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Inamrinone (Systemic)


VA CLASSIFICATION
Primary: CV900

Commonly used brand name(s): Inocor.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Cardiotonic —

Indications

Accepted

Congestive heart failure (treatment)—inamrinone is indicated for the short-term management of congestive heart failure in patients who have not responded adequately to digitalis, diuretics, and/or vasodilators. {01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    187.20 {06}

Mechanism of action/Effect:

Not precisely known; {01} {09} {10} but seems to be peripheral vasodilation, reducing both preload and afterload, {01} {21} and possibly also direct stimulation of cardiac contractility (positive inotropic effect) {01} {02} {07} {08} {09} {14} as a result of phosphodiesterase inhibition {01} {07} {09} {14}.


Other actions/effects:

Slightly increases atrioventricular (AV) conduction velocity. {01} {21}

Protein binding:

Low to moderate (10 to 49%). {01}

Biotransformation:

Hepatic. {01} {10}

Half-life:


Adults:

Healthy volunteers: Approximately 3.6 hours. {01} {11} {13}

Congestive heart failure: Approximately 5.0 to 8.3 hours. {01} {12} {13} {15} {16}



Neonates and infants:

Less than 4 weeks: 12.7 to 22.2 hours. {17} {19}

More than 4 weeks: 3.8 to 6.8 hours. {17} {19}


Time to peak effect

Within 10 minutes. {01}

Duration of action:


Dose-related:

750 mcg (0.75 mg) per kg of body weight (mcg/kg): 30 minutes. {01}

3 mg per kg of body weight (mg/kg): 2 hours. {01}


Elimination:
    Renal—About 63%, as unchanged drug (10 to 40%) {01} {10} {21} and metabolites. {01}
    Fecal—About 18%. {01}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to bisulfites may also be sensitive to inamrinone lactate injection, which contains sodium metabisulfite. {01}

Carcinogenicity

A 2-year study in rats found no evidence of carcinogenicity. {01}

Mutagenicity

Positive results were obtained in the mouse micronucleus test (at 7.5 to 10 times the maximum human dose) and in the Chinese hamster ovary chromosome aberration assay, indicating clastogenic potential and suppression of the number of polychromatic erythrocytes. However, negative results were obtained in the Ames Salmonella assay, mouse lymphoma study, and cultured human lymphocyte metaphase analysis. {01}

Pregnancy/Reproduction

Pregnancy—
Adequate and well-controlled studies in humans have not been done.

Studies in New Zealand white rabbits at oral doses of 16 and 50 mg per kg of body weight (mg/kg) have shown that inamrinone causes fetal skeletal and gross external malformations. These effects did not occur in French Hy/Cr rabbits at oral doses of 32 mg/kg per day or in rats receiving intravenous doses approximately equivalent to the recommended daily human dose.

In mutagenicity studies, gestation levels in rats were slightly prolonged at doses of 50 and 100 mg/kg per day. At the higher dose, dystocia occurred in dams and the incidence of stillbirths, decreased litter size, and poor pup survival was increased.

FDA Pregnancy Category C.

Breast-feeding

It is not known whether inamrinone is excreted in breast milk. However, problems in humans have not been documented.

Pediatrics

Studies and case reports of inamrinone use for pulmonary hypertension, congestive heart failure, and postoperative low cardiac output in approximately 30 neonates and infants and 6 children up to 24 months of age have not demonstrated pediatrics-specific problems that would limit the usefulness of inamrinone in pediatric patients. {17} {18} {19} {20}


Geriatrics


Although appropriate studies on the relationship of age to the effects of inamrinone have not been performed in the geriatric population, no geriatrics-specific problems have been documented to date. However, elderly patients are more likely to have age-related renal function impairment, which may require adjustment of dosage in patients receiving inamrinone.


Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Blood pressure {01} {10} and
Potassium concentrations, serum {01}    (may be decreased)


Hepatic enzymes {01}    (serum concentrations may be increased)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Aortic or pulmonic valvular disease, severe {01} {10}    (surgical relief of obstruction required)


Risk-benefit should be considered when the following medical problems exist
Hepatic function impairment {01} {10}    (elimination reduced; dosage adjustment may be necessary)


» Hypertrophic cardiomyopathy {01} {10}    (inamrinone may aggravate outflow tract obstruction)


Renal function impairment {01} {10}    (elimination reduced; dosage adjustment may be necessary)


Sensitivity to inamrinone {05}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Blood pressure and
» Heart rate    (determinations at periodic intervals in patients receiving inamrinone; inamrinone infusion should be slowed or stopped in patients who develop an excessive fall in blood pressure)


» Body weight    (determinations recommended at periodic intervals to confirm efficacy of inamrinone)


Cardiac index and
Central venous pressure and
Pulmonary capillary wedge pressure    (determinations recommended at periodic intervals to confirm efficacy of inamrinone)


Hepatic function determinations and
Renal function determinations and
Serum electrolyte, especially potassium, concentrations    (recommended at periodic intervals in patients receiving inamrinone; hypokalemia secondary to improved cardiac output and resultant diuresis may contribute to risk of arrhythmias {01})

    (dosage adjustment may be necessary in patients with existing or developing renal or hepatic function impairment)


» Platelet counts    (recommended prior to initiation and at periodic intervals during inamrinone therapy. Dosage of inamrinone may need to be reduced if thrombocytopenia occurs; in some cases, platelet levels stabilize with continuation at the same dose; any decision regarding a change in dosage should be based on monitoring of platelet counts; in some patients, withdrawal of inamrinone may be necessary)




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Arrhythmias (irregular heartbeat)
    
hypotension (dizziness)

Incidence rare
    
Burning at site of injection{01}{10}
    
chest pain{01}{10}{22}
    
hepatotoxicity (yellow eyes or skin)
    
thrombocytopenia (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)

Note: Thrombocytopenia occurs in about 2.4% of patients but is rarely symptomatic; more common with high doses or prolonged treatment.




Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent or rare
    
Abdominal pain (stomach pain)
    
fever{01}{10}
    
nausea or vomiting{01}{10}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Contol Center Listing ).

Treatment of overdose
Treatment of overdose consists of general measures for circulatory support. {01} {10}


General Dosing Information
Pretreatment with digitalis is recommended in patients with atrial flutter/fibrillation since inamrinone may increase ventricular response rates because of its slight enhancement of atrioventricular (AV) conduction. {01}

Patients who have received vigorous diuretic therapy may need cautiously liberalized fluid and electrolyte intake to ensure an adequate cardiac filling pressure for response to inamrinone. {01}

Caution is recommended to avoid extravasation of inamrinone infusion.

Tachyphylaxis to the hemodynamic effects of inamrinone occurs commonly, usually within 72 hours of initiation of therapy {03} {04}.


Parenteral Dosage Forms

Note: The dosing and strengths of the dosage forms available are expressed in terms of inamrinone base (not the lactate salt).


INAMRINONE LACTATE INJECTION

Usual adult dose
Initial—Intravenous, 750 mcg (0.75 mg) (base) per kg of body weight, undiluted, given slowly over 2 to 3 minutes; may be repeated after thirty minutes if necessary. {01} {10}

Maintenance—Intravenous infusion, 5 to 10 mcg (0.005 to 0.01 mg) (base) per kg of body weight per minute, the dosage being adjusted according to clinical response. {01} {10}

Usual adult prescribing limits
Up to 10 mg (base) per kg of body weight per day, although some patients have been given doses up to 18 mg per kg per day for short durations. {01}

Usual pediatric dose


Neonates:
Initial: Intravenous, 3.0 to 4.5 mg per kg of body weight in divided doses. {17} {19} {24}

Maintenance: Intravenous infusion, 3 mcg (0.003 mg) to 5 mcg (0.005 mg) per kg of body weight per minute. {17} {19} {24}



Infants:
Initial: Intravenous, 3.0 to 4.5 mg per kg of body weight in divided doses. {19} {24}

Maintenance: Intravenous infusion, 10 mcg (0.01 mg) per kg of body weight per minute. {19} {24}


Strength(s) usually available
U.S.—


5 mg (base) per mL (Rx) [Inocor (sodium metabisulphite)]

Canada—


5 mg (base) per mL (Rx) [Inocor (sodium metabisulphite)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light. Protect from freezing. {01}

Preparation of dosage form:
For administration by intravenous infusion, inamrinone lactate injection may be diluted in 0.45% or 0.9% sodium chloride injection, to produce a solution containing 1 to 3 mg of amrinone (base) per mL. {01}

Stability:
Diluted solutions should be used within 24 hours. {01}

Incompatibilities:
Inamrinone lactate injection should not be diluted with solutions containing dextrose since a chemical interaction occurs, developing slowly over 24 hours. However, inamrinone lactate injection may be injected into running dextrose infusions through a Y-connector or directly into the tubing where preferable. {01}

Furosemide should not be administered in intravenous lines containing inamrinone, since an immediate precipitate is formed. {01}



Revised: 06/17/1992



References
  1. Inocor package insert, Winthrop-Breon, Rev 1/90, Rec 11/91.
  1. Konstam MA, Cohen SR, Weiland DS, et al. Relative contribution of inotropic and vasodilator effects to inamrinone-induced hemodynamic improvement in congestive heart failure. Am J Cardiol 1986; 57: 242-8.
  1. Maisel AS, Wright CM, Carter SM, Ziegler M, Motulsky HJ. Tachyphylaxis with inamrinone therapy: association with sequestration and down-regulation of lymphocyte beta-adrenergic receptors. Ann Intern Med 1989; 110(3): 195-201.
  1. Per responses to Cardiovascular and Renal Drugs Advisory Panel (1985–1990) memorandum Number 21, 1990 revision.
  1. General precaution per DID policy.
  1. USAN and the USP dictionary of drug names, 29th Edition. United States Pharmacopeial Convention, Inc. 1992; 47.
  1. Honerjager, P. Pharmacology of bipyridine phosphodiesterase III inhibitors. Am Heart J 1991; 121(6 part 2): 1939-44.
  1. Jafri SM, Goldstein S. Phosphodiesterase inhibitors in CHF. What role will they play? Hosp Ther 1987, June: 31-40.
  1. DiBianco, R. Acute positive inotropic intervention: the phosphodiesterase inhibitors. Am Heart J 1991; 121(6 part 1): 1871-5.
  1. Bottorff MB, Rutledge DR, Pieper JA. Evaluation of intravenous inamrinone: the first of a new class of positive inotropic agents with vasodilator properties. Pharmacotherapy 1985; 5(5): 227-37.
  1. Park GB, Kershner RP, Angellotti J, et al. Oral bioavailability and intravenous pharmacokinetics of inamrinone in humans. J Pharm Sci 1983; 72(7): 817-9.
  1. Edelson J, LeJemtel TH, Alousi AA, et al. Relationship between inamrinone plasma concentration and cardiac index. Clin Pharmacol Ther 1981; 29(6): 723-8.
  1. Intravenous inamrinone for congestive heart failure. Med Lett Drugs Ther 1984; 26: 104-5.
  1. Mancini D, LeJemtel T, Sonnenblick E. Intravenous use of inamrinone for the treatment of the failing heart. Am J Cardiol 1985; 56: 8B.
  1. Wilson H, Rocci ML, Weber KT. Pharmacokinetics of oral inamrinone in patients with chronic cardiac failure. Clin Pharmacol Ther 1982; Feb: 282.
  1. Benotti JR, Lesko LJ, McCue JE. Acute pharmacodynamics and pharmacokinetics of oral inamrinone. J Clin Pharmacol 1982; 22: 425-32.
  1. Lawless S, Burckart G, Diven W, Thompson A, Siewers R. inamrinone in neonates and infants after cardiac surgery. Crit Care Med 1989; 17(8): 751-4.
  1. Walker PC, Perry BL, Shankaran S. Safety of inamrinone for treating congestive heart failure in a premature neonate. Clin Pharm 1987; 327-31.
  1. Lawless S, Burckart G, Diven W, Thompson A, Siewers R. inamrinone pharmacokinetics in neonates and infants. J Clin Pharmacol 1988; 28: 283-4.
  1. Lawless ST, Zaritsky A, Miles M. The acute pharmacokinetics and pharmacodynamics of inamrinone in pediatric patients. J Clin Pharmacol 1991; 31: 800-3.
  1. Ward A, Brogden RN, Heel RC, Speight TM, Avery GS. inamrinone. A preliminary review of its pharmacological properties and therapeutic use. Drugs 1983; 26: 468-502.
  1. Leier CV, Dalpiaz K, Huss P, et al. inamrinone therapy for congestive heart failure in outpatients with idiopathic dilated cardiomyopathy. Am J Cardiol 1983; 52: 304-8.
  1. A symposium: inamrinone. November 11, 1984, Miami, Florida. Am J Cardiol 1985 Jul 22; 56: 1B-42B.
  1. Reviewers" responses to monograph revision of 3/92.
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