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INAMRINONE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Inamrinone is a phosphodiesterase inhibitor which has positive inotropic and vasodilatory properties, different in structure and mode of action from either digitalis glycosides or catecholamines.

Specific Substances

    1) Amrinone
    2) Amrinone
    3) Amrinona
    4) Amrinoni
    5) Amrinonum
    6) Inamrinone lactate
    7) 5-Amino-3,4'-bipyridyl-6(1H)-one
    8) WIN-40680
    9) Molecular Formula: C10-H9-N3-O
    10) CAS 60719-84-8

Available Forms Sources

    A) FORMS
    1) As of April 2000, the name of amrinone was changed to "inamrinone" to reduce the number of accidental injuries and deaths associated with the cardiac drug names amrinone and amiodarone (Anon, 2000).
    2) Inamrinone lactate is available as an injectable 5 mg/mL of inamrinone and 0.25 mg/mL of sodium metabisulfite (Prod Info inamrinone lactate iv injection, 2002).
    B) USES
    1) Inamrinone is used for the treatment of severe acute congestive heart failure refractory to other treatment modalities, including digitalis glycosides and vasodilators (Prod Info inamrinone lactate iv injection, 2002).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH THERAPEUTIC USE
    1) Thrombocytopenia and hepatotoxicity are dose-related side effects, occurring most commonly during chronic exposure, and may be a hypersensitivity reaction.
    B) WITH POISONING/EXPOSURE
    1) Effects in overdose are largely unknown. Hypotension and tachycardia may be expected due to its vasodilating properties.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Dysrhythmias were reported in 3% of patients following therapeutic use. Ventricular arrhythmias may be associated with high serum levels following IV use.
    B) WITH POISONING/EXPOSURE
    1) Hypotension is the primary effect of IV overdose.
    0.2.6) RESPIRATORY
    A) WITH THERAPEUTIC USE
    1) Pulmonary infiltrates, with and without vasculitis, have been noted with chronic oral therapy.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Headache may occur due to vasodilator effects.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Nausea, vomiting, abdominal pain, anorexia, and diarrhea have been reported during clinical use.
    0.2.9) HEPATIC
    A) WITH THERAPEUTIC USE
    1) Dose related liver function test elevations and hepatic necrosis have been described during long term oral dosing.
    0.2.11) ACID-BASE
    A) WITH THERAPEUTIC USE
    1) Metabolic acidosis has been reported.
    0.2.12) FLUID-ELECTROLYTE
    A) WITH THERAPEUTIC USE
    1) Diuresis and hypokalemia may be noted.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Dose related thrombocytopenia may occur in patients receiving therapeutic doses.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Bright yellow discoloration of the nails has been described.
    0.2.20) REPRODUCTIVE
    A) Inamrinone is classified in pregnancy risk category C.

Laboratory Monitoring

    A) Monitor serum electrolytes, particularly potassium, platelet count, liver and renal function tests.
    B) Monitor vital signs. Institute continuous cardiac monitoring and obtain an ECG.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    B) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    C) VENTRICULAR DYSRHYTHMIAS/SUMMARY: Institute continuous cardiac monitoring, obtain an ECG, and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders. Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.
    D) Monitor central venous or pulmonary wedge pressure in severely symptomatic patients.

Range Of Toxicity

    A) THERAPEUTIC DOSE - 0.75 mg/kg as an IV loading dose followed by an infusion at 5 to 10 mcg/kg/minute.
    B) INCREASED SIDE EFFECTS - Doses of 450 mg daily orally are associated with a higher incidence of thrombocytopenia.
    C) LETHAL DOSE - 840 mg infused over 3 hours was fatal in an adult. Infusion of 1.2 g over 31 hrs was fatal in a 2.5-year-old with congenital heart disease.
    D) THERAPEUTIC LEVELS - 0.5 to 7 mcg/mL; the manufacturer recommends a steady-state plasma level of 3 mcg/mL.

Clinical Effects

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) Thrombocytopenia and hepatotoxicity are dose-related side effects, occurring most commonly during chronic exposure, and may be a hypersensitivity reaction.
    B) WITH POISONING/EXPOSURE
    1) Effects in overdose are largely unknown. Hypotension and tachycardia may be expected due to its vasodilating properties.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Fever has been described as a side effect of inamrinone therapy (Wilmshurst & Webb-Peploe, 1983; Treadway, 1985).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Reduced tear secretion has been reported with inamrinone (Wilmshurst & Webb-Peploe, 1983).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) Dysosmia may occur (Kinney et al, 1982).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Dysrhythmias were reported in 3% of patients following therapeutic use. Ventricular arrhythmias may be associated with high serum levels following IV use.
    B) WITH POISONING/EXPOSURE
    1) Hypotension is the primary effect of IV overdose.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypotension is the primary effect of overdose with intravenous inamrinone and is due to its vasodilator properties (Bottorff et al, 1985; Lebovitz et al, 1995).
    b) Severe refractory hypotension was the predominant effect observed in a pediatric patient following the inadvertent and ultimately fatal overdose of inamrinone (Lebovitz et al, 1995). The patient had received 10 times the usual therapeutic dosage resulting in inamrinone plasma concentration of 75.9 micrograms/milliliters (normal 2-7 micrograms/milliliter) two hours after discontinuation of the intravenous infusion.
    B) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Dysrhythmias were reported in 3% of patients following therapeutic use. Ventricular dysrhythmias were associated with high serum levels following IV administration (Prod Info Inocor(R), inamrinone, 1999).
    b) Premature ventricular contractions were described in a pregnant 34-year-old woman with congestive heart failure, following intravenous administration of inamrinone (loading dose of 0.5 milligram/kilogram, followed by 2 micrograms/kilogram/minute) (Jelsema et al, 1991).

Respiratory

    3.6.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Pulmonary infiltrates, with and without vasculitis, have been noted with chronic oral therapy.
    3.6.2) CLINICAL EFFECTS
    A) PNEUMONITIS
    1) WITH THERAPEUTIC USE
    a) Pulmonary infiltrates with and without vasculitis, have been noted with chronic oral therapy (Wilmshurst & Webb-Peploe, 1983).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Headache may occur due to vasodilator effects.
    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache may occur due to vasodilator effects.

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Nausea, vomiting, abdominal pain, anorexia, and diarrhea have been reported during clinical use.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting have been reported during clinical use in 0.5 to 2 percent of patients receiving intravenous inamrinone (Mancini et al, 1985; Leier et al, 1982).
    B) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain has been reported during clinical use in 0.5 to 2 percent of patients (Mancini et al, 1985).
    C) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) Anorexia has been noted (Kinney et al, 1982).
    D) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea has also been reported (Silverman et al, 1989).
    E) LOSS OF TASTE
    1) WITH THERAPEUTIC USE
    a) Hypogeusia may occur (Kinney et al, 1982).

Hepatic

    3.9.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Dose related liver function test elevations and hepatic necrosis have been described during long term oral dosing.
    3.9.2) CLINICAL EFFECTS
    A) LIVER DAMAGE
    1) WITH THERAPEUTIC USE
    a) Dose-related LFT elevations and hepatic necrosis has been described in dogs receiving 9 to 32 mg/kg/day IV and in man during long-term oral dosing (Prod Info Inocor(R), inamrinone, 1999).
    b) Inamrinone-induced hepatotoxicity was described in a 49-year-old male following inamrinone therapy 100 mg orally every 8 hours for approximately 38 days (Gilman & Margolis, 1984).

Acid-Base

    3.11.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Metabolic acidosis has been reported.
    3.11.2) CLINICAL EFFECTS
    A) METABOLIC ACIDOSIS
    1) WITH THERAPEUTIC USE
    a) Metabolic acidosis was described in a pregnant 34-year-old woman with congestive heart failure, following intravenous administration of inamrinone (Loading dose of 0.5 milligram/kilogram, followed by 2 micrograms/kilogram/minute) (Jelsema et al, 1991).

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Dose related thrombocytopenia may occur in patients receiving therapeutic doses.
    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Dose-related thrombocytopenia occurs in approximately 2.4% of patients receiving therapeutic doses, and is more common during chronic therapy (Treadway, 1985).
    b) A 50% incidence of thrombocytopenia was reported in a study involving 18 children receiving continuous infusion of inamrinone following cardiac surgery. It has been suggested that inamrinone's primary metabolite N-acetylamrinone may be the mediator of thrombocytopenia. Rapid inamrinone acetylation and a rapid acetylator phenotype may be associated with a greater risk of developing thrombocytopenia in patients receiving inamrinone (Ross et al, 1993).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Bright yellow discoloration of the nails has been described.
    3.14.2) CLINICAL EFFECTS
    A) DISCOLORATION OF SKIN
    1) WITH THERAPEUTIC USE
    a) Bright yellow discoloration of nails has been described following therapeutic use (Wilmshurst & Webb-Peploe, 1983).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) Several cases of apparent hypersensitivity to oral inamrinone have been reported, effects have included pericarditis, pleuritis, ascites, myositis with interstitial shadowing on chest x-ray, vasculitis with nodular pulmonary densities, hypoxemia, and jaundice. Fatality occurred in one patient (Prod Info Inocor(R), inamrinone, 1999; Wilmshurst & Webb-Peploe, 1983).

Reproductive

    3.20.1) SUMMARY
    A) Inamrinone is classified in pregnancy risk category C.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    INAMRINONEC
    Reference: Briggs et al, 1998

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serum electrolytes, particularly potassium, platelet count, liver and renal function tests.
    B) Monitor vital signs. Institute continuous cardiac monitoring and obtain an ECG.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Serum electrolytes, particularly potassium, should be monitored. Renal and liver function tests are also advised.
    B) HEMATOLOGIC
    1) Platelet counts are also advised.
    4.1.3) URINE
    A) OTHER
    1) Monitor urine output.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Monitor serum electrolytes, particularly potassium, platelet count, liver and renal function tests.
    B) Monitor vital signs. Institute continuous cardiac monitoring and obtain an ECG.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    4) Monitoring central venous pressure may be useful in assessing hypotension and fluid balance.
    B) VENTRICULAR ARRHYTHMIA
    1) VENTRICULAR DYSRHYTHMIAS SUMMARY
    a) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.
    2) LIDOCAINE
    a) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    b) LIDOCAINE/DOSE
    1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    c) LIDOCAINE/MAJOR ADVERSE REACTIONS
    1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    3) AMIODARONE
    a) AMIODARONE/INDICATIONS
    1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).
    b) AMIODARONE/ADULT DOSE
    1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).
    c) AMIODARONE/PEDIATRIC DOSE
    1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).
    d) ADVERSE EFFECTS
    1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).
    4) PROCAINAMIDE
    a) PROCAINAMIDE/INDICATIONS
    1) An alternative drug in the treatment of PVCs or recurrent ventricular tachycardia when lidocaine is contraindicated or not effective. It should be avoided when the ingestion involves agents with quinidine-like effects (e.g. tricyclic antidepressants, phenothiazines, chloroquine, antidysrhythmics) and when the ECG reveals QRS widening or QT prolongation suspected to be secondary to overdose(Neumar et al, 2010; Vanden Hoek,TLet al,null).
    b) PROCAINAMIDE/ADULT LOADING DOSE
    1) 20 to 50 milligrams/minute IV until dysrhythmia is suppressed or toxicity develops from procainamide (hypotension develops or the QRS is widened by 50%), or a total dose of 17 milligrams/kilogram is given (1.2 grams for a 70 kilogram person) (Neumar et al, 2010).
    2) ALTERNATIVE DOSING: 100 mg every 5 minutes until dysrhythmia is controlled, or toxicity develops from procainamide (hypotension develops or the QRS is widened by 50%) or 17 mg/kg have been given (Neumar et al, 2010).
    3) MAXIMUM DOSE: 17 milligrams/kilogram (Neumar et al, 2010).
    c) PROCAINAMIDE/CONTROLLED INFUSION
    1) In conscious patients, procainamide should be administered as a controlled infusion (20 milligrams/minute) because of the risk of QT prolongation and its hypotensive effects (Link et al, 2015)
    d) PROCAINAMIDE/ADULT MAINTENANCE DOSE
    1) 1 to 4 milligrams/minute via an intravenous infusion (Neumar et al, 2010).
    e) PROCAINAMIDE/PEDIATRIC LOADING DOSE
    1) 15 milligrams/kilogram IV/Intraosseously over 30 to 60 minutes; discontinue if hypotension develops or the QRS widens by 50% (Kleinman et al, 2010).
    f) PROCAINAMIDE/PEDIATRIC MAINTENANCE DOSE
    1) Initiate at 20 mcg/kg/minute and increase in 10 mcg/kg/minute increments every 15 to 30 minutes until desired effect is achieved; up to 80 mcg/kg/minute (Bouhouch et al, 2008; Ratnasamy et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).
    g) PROCAINAMIDE/PEDIATRIC MAXIMUM DOSE
    1) 2 grams/day (Bouhouch et al, 2008; Ratnasamy et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).
    h) MONITORING PARAMETERS
    1) ECG, blood pressure, and blood concentrations (Prod Info procainamide HCl IV, IM injection solution, 2011). Procainamide can produce hypotension and QT prolongation (Link et al, 2015).
    i) AVOID
    1) Avoid in patients with QT prolongation and CHF (Neumar et al, 2010).

Enhanced Elimination

    A) PERITONEAL DIALYSIS
    1) Peritoneal dialysis did not remove significant amounts (less than one percent of the total body store) of inamrinone in an infant with severe congenital heart disease who developed refractory hypotension and renal failure after inamrinone overdose (Lebovitz et al, 1995). Peritoneal clearance in this infant was 0.26 milliliters/minute/kilogram compared with a total body clearance of 2.6 milliliters/minute/kilogram in normal children.
    B) HEMOFILTRATION
    1) In a 6-year-old with toxic shock syndrome and multiorgan system failure continuous arteriovenous hemofiltration achieved an inamrinone clearance of 0.1 to 0.6 milliliters/kilogram/minute (ultrafiltrate rate 0.17 and 0.40 milliliters/kilogram/minute respectively) compared with a total body clearance of 2.6 ml/kg/min in normal children (Lawless et al, 1993).

Range Of Toxicity

Summary

    A) THERAPEUTIC DOSE - 0.75 mg/kg as an IV loading dose followed by an infusion at 5 to 10 mcg/kg/minute.
    B) INCREASED SIDE EFFECTS - Doses of 450 mg daily orally are associated with a higher incidence of thrombocytopenia.
    C) LETHAL DOSE - 840 mg infused over 3 hours was fatal in an adult. Infusion of 1.2 g over 31 hrs was fatal in a 2.5-year-old with congenital heart disease.
    D) THERAPEUTIC LEVELS - 0.5 to 7 mcg/mL; the manufacturer recommends a steady-state plasma level of 3 mcg/mL.

Therapeutic Dose

    7.2.1) ADULT
    A) INTRAVENOUS: The recommended adult dosage for inamrinone is an initial IV loading dose of 0.75 mg/kg over 2 to 3 min followed by a continuous infusion of 5 to 10 mcg/kg/min. A supplemental IV bolus of 0.75 mg/kg may be repeated 30 min after the initial bolus, if required. Total daily dosage not to exceed 10 mg/kg/day (including boluses) (Prod Info inamrinone intravenous solution, 2002). An alternate mode of administration, reportedly associated with a lesser incidence of hypotension, is 40 mcg/kg/min over the first hour, followed by a maintenance infusion of 10 mcg/kg/min has been reported (Mancini et al, 1985).
    7.2.2) PEDIATRIC
    A) The safety and effectiveness of inamrinone in the pediatric population has not been established (Prod Info inamrinone intravenous solution, 2002).
    1) Inamrinone lactate 0.75 mg/kg was administered intravenously as an initial dose (over 5 min) followed by an IV infusion of 5 mcg/kg/min in one case for the treatment of congestive heart failure in a premature infant. The drug was continued at 5 mcg/kg/min for 15 days, thereafter the dose was decreased by 50% (2.5 mcg/kg/min) for 5 additional days, without deterioration of the patient's clinical status (Walker et al, 1987).
    2) Initial inamrinone bolus injections of 3 to 4.5 mg/kg in divided doses, followed by a continuous IV infusion of 5 to 10 mcg/kg/min to maintain plasma levels of 2 to 7 mcg/mL has been reported in a studies involving infants. In the same studies, neonates received a similar bolus dose, with a lower infusion rate of 3 to 5 mcg/kg/min (Lawless et al, 1991; Lawless et al, 1989; Lawless et al, 1988).

Minimum Lethal Exposure

    A) CASE REPORTS
    1) An accidental overdosage of 840 milligrams over 3 hours by bolus plus infusion had a fatal outcome, but causal relation is uncertain (Prod Info Inocor(R), inamrinone, 1999).
    2) A 2.5-month-old infant with severe congenital heart disease died after receiving an infusion of 90 to 198 mcg/kg/min infusion for 31 hours (total dose approximately 1.2 grams) (Lebovitz et al, 1995).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) Doses of 450 milligrams daily orally were associated with a higher incidence of thrombocytopenia (LeJemtel et al, 1980).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL
    a) Toxic inamrinone plasma concentrations have not been established.
    b) Increases in cardiac index show a linear correlation with plasma concentrations of 0.5 to 7 micrograms/milliliter; when measurement is feasible.

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (ORAL)MOUSE:
    a) 288 mg/kg (RTECS, 2002)
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) 212 mg/kg (RTECS, 2002)
    3) LD50- (ORAL)RAT:
    a) 102 mg/kg (RTECS, 2002)
    4) LD50- (SUBCUTANEOUS)RAT:
    a) 150 mg/kg (RTECS, 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Inamrinone lactate is a positive inotropic agent with vasodilator activity. Its exact mechanism is unknown. However, it is postulated that its inotropic activity is due to the inhibition of myocardial cyclic adenosine monophosphate (c-AMP) phosphodiesterase and increasing cellular levels of c-AMP while its vasodilator activity is due to the reduction of afterload and preload through its direct relaxant effect on vascular smooth muscle (Prod Info inamrinone intravenous solution, 2002).

Physicochemical

Physical Characteristics

    A) A pale yellow to tan powder, odorless or with a faint odor; practically insoluble in water (Sweetman, 2002).

Molecular Weight

    A) 187.2 (Sweetman, 2002)

References

General Bibliography

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