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Procainamide

Pronunciation

Pronunciation

(pro KANE a mide)

Index Terms

  • PCA (error-prone abbreviation)
  • Procainamide Hydrochloride
  • Procaine Amide Hydrochloride
  • Procanbid
  • Pronestyl

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Injection, as hydrochloride:

Generic: 100 mg/mL (10 mL); 500 mg/mL (2 mL)

Pharmacologic Category

  • Antiarrhythmic Agent, Class Ia

Pharmacology

Decreases myocardial excitability and conduction velocity and may depress myocardial contractility, by increasing the electrical stimulation threshold of ventricle, His-Purkinje system and through direct cardiac effects

Distribution

Vd: Children: 2.2 L/kg; Adults: 2 L/kg; decreased with congestive heart failure or shock

Metabolism

Hepatic via acetylation to produce N-acetyl procainamide (NAPA) (active metabolite)

Excretion

Urine (30% to 60% unchanged procainamide; 6% to 52% as NAPA); feces (<5% unchanged procainamide. Note: >80% of formed NAPA is renally eliminated in contrast to procainamide which is ~50% renally eliminated (Gibson, 1977).

Onset of Action

IM 10 to 30 minutes

Time to Peak

Serum: IM: 15 to 60 minutes

Half-Life Elimination

Procainamide (hepatic acetylator, phenotype, cardiac and renal function dependent): Children: 1.7 hours; Adults: 2.5 to 4.7 hours; Anephric: 11 hours

NAPA (renal function dependent): Children: 6 hours; Adults: 6 to 8 hours; Anephric: 42 hours

Protein Binding

15% to 20%

Special Populations: Renal Function Impairment

Elimination half-life is prolonged.

Special Populations: Elderly

Elimination half-life is prolonged.

Use: Labeled Indications

Intravenous: Treatment of life-threatening ventricular arrhythmias

Oral [Canadian product]: Treatment of supraventricular arrhythmias. Note: In the treatment of atrial fibrillation, use only when preferred treatment is ineffective or cannot be used. Use in paroxysmal atrial tachycardia when reflex stimulation or other measures are ineffective.

Use: Unlabeled

Paroxysmal supraventricular tachycardia (PSVT); prevent recurrence of ventricular tachycardia

Treatment of the following arrhythmias in adults with preserved left ventricular function (ACLS): Stable monomorphic VT, pre-excited atrial fibrillation, and stable wide complex regular tachycardia (likely VT)

Treatment of the following arrhythmias in children (PALS): Tachycardia with pulses and poor perfusion (probable SVT [unresponsive to vagal maneuvers and adenosine or synchronized cardioversion], probable VT [unresponsive to synchronized cardioversion or adenosine])

Contraindications

Hypersensitivity to procainamide, procaine, other ester-type local anesthetics, or any component of the formulation; complete heart block; second-degree AV block or various types of hemiblock (without a functional artificial pacemaker); SLE; torsade de pointes

Dosing: Adult

Dose must be titrated to patient's response.

Antiarrhythmic:

IM: 50 mg/kg/day divided every 3 to 6 hours or 0.5 to 1 g every 4 to 8 hours (Koch-Weser, 1971)

IV:

Loading dose: 15 to 18 mg/kg administered as slow infusion over 25 to 30 minutes or 100 mg/dose at a rate not to exceed 50 mg/minute repeated every 5 minutes as needed to a total dose of 1 g.

Hemodynamically stable monomorphic VT or pre-excited atrial fibrillation (ACLS, 2010): Loading dose: Infuse 20 to 50 mg/minute or 100 mg every 5 minutes until arrhythmia controlled, hypotension occurs, QRS complex widens by 50% of its original width, or total of 17 mg/kg is given. Follow with a continuous infusion of 1 to 4 mg/minute. Note: Not recommended for use in ongoing ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) due to prolonged administration time and uncertain efficacy.

Maintenance dose: 1 to 4 mg/minute by continuous infusion. Maintenance infusions should be reduced by one-third in patients with moderate renal or cardiac impairment and by two-thirds in patients with severe renal or cardiac impairment.

Oral [Canadian product]: Sustained release formulation (Procan SR®): Maintenance: 50 mg/kg/24 hours given in divided doses every 6 hours

Suggested Procan SR® maintenance dose:

<55 kg: 500 mg every 6 hours

55 to 91 kg: 750 mg every 6 hours

>91 kg: 1000 mg every 6 hours

Dosing: Geriatric

Refer to adult dosing. Initiate doses at lower end of dosage range.

Dosing: Pediatric

Must be titrated to patient's response:

Arrhythmias:

IM: 20 to 30 mg/kg/day divided every 4 to 6 hours; maximum: 4 g/day

IV:

Load: 3 to 6 mg/kg/dose over 5 minutes not to exceed 100 mg/dose; may repeat every 5 to 10 minutes to maximum of 15 mg/kg/load

Maintenance as continuous IV infusion: 20 to 80 mcg/kg/minute; maximum: 2 g/24 hours

Possible VT (PALS, 2010): IV; I.O.: 15 mg/kg over 30 to 60 minutes

Dosing: Renal Impairment

Oral [Canadian product]:

Manufacturer’s labeling: Manufacturer recommends increasing dosing interval; specific interval increase not described

Alternate dosing:

CrCl >50 mL/minute: No dosage adjustment necessary (Bauer, 2008)

CrCl 10 to 50 mL/minute: Reduce initial daily dose by 25% to 50% (Bauer, 2008)

CrCl <10 mL/minute: Reduce initial daily dose by 50% to 75% (Bauer, 2008). Monitor procainamide/NAPA concentrations closely.

IV:

Manufacturer’s labeling: Manufacturer recommends dosage reduction; specific dosage reduction not described, however, close monitoring of procainamide and NAPA concentrations and clinical effectiveness recommended

Alternate dosing:

CrCl >50 mL/minute: No dosage adjustment necessary (Bauer, 2008)

CrCl 10–50 mL/minute: Reduce continuous infusion dose by 25% to 50% (Bauer, 2008)

CrCl <10 mL/minute: Reduce continuous infusion dose by 50% to 75% (Bauer, 2008). Monitor procainamide/NAPA concentrations closely.

Dialysis:

Procainamide: Moderately hemodialyzable (20% to 50%); NAPA: Not dialyzable (0% to 5%): Monitor procainamide/N-acetylprocainamide (NAPA) concentrations; supplementation may be necessary (Aronoff, 2007)

Procainamide/NAPA: Not peritoneal dialyzable (0% to 5%) (Aronoff, 2007)

Continuous renal replacement therapy (CRRT): In patients with chronic kidney disease receiving CRRT, reduce maintenance dose by 50%. In patients with anuria receiving CRRT, further dosage reduction may be required; use of an initial 1 mg/minute continuous infusion dose has been suggested. Monitor procainamide/NAPA concentrations closely (Mohamed, 2013).

Dosing: Hepatic Impairment

Manufacturer’s labeling: Manufacturer recommends reduction in frequency of administration; specific frequency reduction not described; however, close monitoring of procainamide and NAPA concentrations and clinical effectiveness recommended.

Alternate dosing (Bauer, 2008):

Oral [Canadian product]:

Child-Pugh score 8–10: Reduce initial daily dose by 25%. Monitor procainamide/NAPA concentrations closely.

Child-Pugh score >10: Reduce initial daily dose by 50%. Monitor procainamide/NAPA concentrations closely.

IV:

Child-Pugh score 8–10: Reduce continuous infusion dose by 25%. Monitor procainamide/NAPA concentrations closely.

Child-Pugh score >10: Reduce continuous infusion dose by 50%. Monitor procainamide/NAPA concentrations closely.

Reconstitution

IV: Dilute loading dose to a maximum concentration of 20 mg/mL.

Administration

Oral: Do not crush or chew sustained release drug products [Canadian product].

IV: Must dilute prior to IV administration. Dilute loading dose to a maximum concentration of 20 mg/mL; administer loading dose at a maximum rate of 50 mg/minute

Compatibility

Stable in 1/2NS, NS, sterile water for injection; variable stability (consult detailed reference) in D5NS, D5W. Note: Some information indicates that procainamide may be subject to greater decomposition in D5W unless the admixture is refrigerated or the pH is adjusted. Procainamide is believed to form an association complex with dextrose - the bioavailability of procainamide in this complex is not known and the complex formation is reversible (Raymond, 1988).

Y-site administration: Incompatible with milrinone.

Storage

Store at 20°C to 25°C (68°F to 77°F). The solution is initially colorless but may turn slightly yellow on standing. Injection of air into the vial causes solution to darken. Discard solutions darker than light amber. Color formation may occur upon refrigeration. When admixed in NS or D5W to a final concentration of 2 to 4 mg/mL, solution is stable at room temperature for 24 hours and for 7 days under refrigeration.

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification

Amiodarone: May enhance the QTc-prolonging effect of Antiarrhythmic Agents (Class Ia). Amiodarone may increase the serum concentration of Antiarrhythmic Agents (Class Ia). Management: Avoid whenever possible. While considered contraindicated in some places, amiodarone U.S. prescribing information suggests that use could be considered under some circumstances, with careful monitoring. Reduce quinidine or procainamide dose by one third. Avoid combination

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates. Consider therapy modification

BuPROPion: May increase the serum concentration of OCT2 Substrates. Monitor therapy

Cimetidine: May increase the serum concentration of Procainamide. Management: Consider an alternative H2-receptor antagonist in patients taking procainamide. If combined, monitor for increased therapeutic effects/toxicity of procainamide. Consider therapy modification

Cobicistat: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Consider therapy modification

Darunavir: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Fingolimod: May enhance the arrhythmogenic effect of Antiarrhythmic Agents (Class Ia). Avoid combination

Highest Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Highest Risk QTc-Prolonging Agents. Avoid combination

Imatinib: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Indapamide: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Consider therapy modification

Ivabradine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

LamoTRIgine: May increase the serum concentration of Procainamide. Management: Consider monitoring for increased procainamide concentrations and/or systemic effects in patients receiving procainamide with lamotrigine. The lamotrigine Canadian product monograph states that coadministration of these agents is not recommended. Monitor therapy

Lurasidone: May enhance the QTc-prolonging effect of Procainamide. Management: Consider alternatives to procainamide in patients with acute lurasidone overdose. If procainamide treatment cannot be avoided, monitor for excessive QTc interval prolongation. Consider therapy modification

MiFEPRIStone: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Neuromuscular-Blocking Agents: Procainamide may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Monitor therapy

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Perhexiline: CYP2D6 Substrates may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Propafenone: May enhance the arrhythmogenic effect of Antiarrhythmic Agents (Class Ia). Management: Concurrent use of propafenone with quinidine, amiodarone, or other class IA or class III antiarrhythmics should be avoided. Treatment with such agents should be withheld for at least 5 half-lives prior to initiation of propafenone. Avoid combination

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

RaNITIdine: May increase the serum concentration of Procainamide. Ranitidine may also increase the concentration of the active N-acetyl-procainamide (NAPA) metabolite. Monitor therapy

Trimethoprim: May increase serum concentrations of the active metabolite(s) of Procainamide. Trimethoprim may increase the serum concentration of Procainamide. Consider therapy modification

Vinflunine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Test Interactions

In the presence of propranolol or suprapharmacologic concentrations of lidocaine or meprobamate, tests which depend on fluorescence to measure procainamide/NAPA concentrations may be affected.

Adverse Reactions

>1%:

Cardiovascular: Hypotension (IV up to 5%)

Dermatologic: Rash

Gastrointestinal: Diarrhea (oral: 3% to 4%), nausea (oral: 3% to 4%), taste disorder (oral: 3% to 4%), vomiting (oral: 3% to 4%)

Miscellaneous: Positive ANA (≤50%), SLE-like syndrome (≤30%, increased incidence with long-term therapy or slow acetylators; syndrome may include abdominal pain, arthralgia, arthritis, chills, fever, hepatomegaly, myalgia, pericarditis, pleural effusion, pulmonary infiltrates, rash)

<1% (Limited to important or life-threatening): Agranulocytosis, alkaline phosphatase increased, angioedema, anorexia, aplastic anemia, arrhythmia exacerbated, arthralgia, asystole, bone marrow suppression, cerebellar ataxia, confusion, demyelinating polyradiculoneuropathy, disorientation, dizziness, drug fever, fever, first degree heart block, flushing, granulomatous hepatitis, hallucinations, hemolytic anemia, hepatic failure, hyperbilirubinemia, hypoplastic anemia, intrahepatic cholestasis, leukopenia, lightheadedness, maculopapular rash, mania, mental depression, myasthenia gravis worsened, myocardial contractility depressed, myocarditis, myopathy, neuromuscular blockade, neutropenia, pancreatitis, pancytopenia, paradoxical increase in ventricular rate in atrial fibrillation/flutter, peripheral/polyneuropathy, pleural effusion, positive Coombs' test, proarrhythmia, pseudo-obstruction, psychosis, pulmonary embolism, QTc-interval prolongation, pruritus, rash, respiratory failure due to myopathy, second-degree heart block, tachycardia, thrombocytopenia, torsade de pointes, transaminases increased, urticaria, vasculitis, ventricular fibrillation, weakness

ALERT: U.S. Boxed Warning

Drug-induced lupus erythematosus-like syndrome:

The prolonged administration of procainamide often leads to the development of a positive antinuclear antibody (ANA) test, with or without symptoms of a lupus erythematosus-like syndrome. If a positive ANA titer develops, the benefits versus risks of continued procainamide therapy should be assessed.

Mortality:

In the National Heart, Lung and Blood Institute's Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multicenter, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had myocardial infarction more than 6 days but less than 2 years previously, an excessive mortality or nonfatal cardiac arrest rate (7.7%) was seen in patients treated with encainide or flecainide compared with that seen in patients assigned to matched placebo-treated group (3%). The average duration of treatment with encainide or flecainide in this study was 10 months.

The applicability of the cast results to other populations (eg, those without recent myocardial infarctions) is uncertain. Considering the known proarrhythmic properties of procainamide and the lack of evidence of improved survival for any antiarrhythmic drug in patients without life-threatening arrhythmias, the use of procainamide as well as other antiarrhythmic agents should be reserved for patients with life-threatening ventricular arrhythmias.

Blood dyscrasias:

Agranulocytosis, bone marrow depression, neutropenia, hypoplastic anemia and thrombocytopenia in patients receiving procainamide HCl have been reported at a rate of approximately 0.5%. Most of these patients received procainamide within the recommended dosage range. Fatalities have occurred (with approximately 20 to 25% mortality in reported cases of agranulocytosis). Since most of these events have been noted during the first 12 weeks of therapy, it is recommended that complete blood counts including white cell, differential and platelet counts be performed at weekly intervals for the first 3 months of therapy, and periodically thereafter. Complete blood counts should be performed promptly if the patient develops any signs of infection (such as fever, chills, sore throat or stomatitis), bruising or bleeding. If any of those hematologic disorders are identified, procainamide therapy should be discontinued. Blood counts usually return to normal within 1 month of discontinuation. Caution should be used in patients with preexisting marrow failure or cytopenia of any type.

Warnings/Precautions

Concerns related to adverse effects:

• Blood dyscrasias: [US Boxed Warning]: Potentially fatal blood dyscrasias (eg, agranulocytosis) have occurred with therapeutic doses; weekly monitoring is recommended during the first 3 months of therapy and periodically thereafter. Discontinue procainamide if this occurs.

• Conduction disturbances: Reduce dose if first-degree heart block occurs.

• Drug-induced lupus erythematosus-like syndrome: [US Boxed Warning]: Long-term administration leads to the development of a positive antinuclear antibody (ANA) test in 50% of patients which may result in a drug-induced lupus erythematosus-like syndrome (in 20% to 30% of patients); discontinue procainamide with rising ANA titers or with SLE symptoms and choose an alternative agent.

• Proarrhythmic effects: Watch for proarrhythmic effects; monitor and adjust dose to prevent QTc prolongation. Avoid use in patients with QT prolongation (ACLS, 2010).

Disease-related concerns:

• Atrial fibrillation/flutter: May increase ventricular response rate in patients with atrial fibrillation or flutter; control AV conduction before initiating.

• Electrolyte imbalance: Correct electrolyte disturbances, especially hypokalemia or hypomagnesemia, prior to use and throughout therapy.

• Heart failure (HF): Use with caution or avoid (ACLS, 2010) in patients with HF; may precipitate or exacerbate condition due to negative inotropic actions.

• Myasthenia gravis: Avoid use in myasthenia gravis; may worsen condition.

• Renal impairment: Use with caution in patients with renal impairment; dosage reduction recommended.

Concurrent drug therapy issues:

• Antiarrhythmics: Use caution with concurrent use of other antiarrhythmics; may exacerbate or increase the risk of conduction disturbances.

• Drugs with QT prolongation potential: Avoid concurrent use with other drugs known to prolong QTc interval.

Dosage form specific issues:

• Sodium metabisulfite: The injectable product contains sodium metabisulfite which may cause allergic-type reactions, including anaphylactic symptoms and life-threatening asthmatic episodes in susceptible people; this is seen more frequently in asthmatics. Note: Canadian injectable product does not contain sodium metabisulfite.

Special populations:

• Elderly: Use caution and dose cautiously; renal clearance of procainamide/NAPA declines in patients ≥50 years of age (independent of creatinine clearance reductions) and in the presence of concomitant renal impairment.

Other warnings/precautions:

• CAST trial: [US Boxed Warning] In the Cardiac Arrhythmia Suppression Trial (CAST), recent (>6 days but <2 years ago) myocardial infarction patients with asymptomatic, non-life-threatening ventricular arrhythmias did not benefit and may have been harmed by attempts to suppress the arrhythmia with flecainide or encainide. An increased mortality or nonfatal cardiac arrest rate (7.7%) was seen in the active treatment group compared with patients in the placebo group (3%). The applicability of the CAST results to other populations is unknown. Procainamide should be reserved for patients with life-threatening ventricular arrhythmias.

Monitoring Parameters

ECG, blood pressure, renal function; with prolonged use monitor CBC with differential, platelet count; procainamide and NAPA blood concentrations in patients with hepatic impairment, renal impairment, or receiving constant infusion >3 mg/minute for longer than 24 hours; ANA titers

Consult individual institutional policies and procedures.

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted. Procainamide crosses the placenta (Dumesic 1982; Oudijk 2002); procainamide and its active metabolite (N-acetyl procainamide) can be detected in the cord blood and neonatal serum (Pittard 1983). Intravenous procainamide may be considered for the acute treatment of SVT in pregnant women. Due to adverse events (lupus-like syndrome), long term therapy should be avoided unless other options are not available (Page [ACC/AHA/HRS 2015]).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience injection site pain or irritation. Have patient report immediately to prescriber signs of infection, bruising, bleeding, signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), angina, depression, mood changes, hallucinations, severe nausea, vomiting, joint pain, joint edema, diarrhea, severe dizziness, passing out, tachycardia, bradycardia, arrhythmia, mouth sores, muscle pain, muscle weakness, seizures, or shortness of breath (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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