PROCAINAMIDE HCL

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-According to the product labeling, procainamide injection is compatible in D5W. However, data indicate procainamide may quickly form an association complex with dextrose. The clinical implications of this complexation are unknown. Refrigeration and pH adjustment may reduce the rate of complexation. Other sources indicate procainamide also is not compatible with D5WNS but is compatible with NS and 0.45% NS.
-Monitor blood pressure and ECG continuously during administration.
-Adjust dosage according to patient response, renal function, serum procainamide concentrations, and, when indicated, serum NAPA concentrations.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Intermittent IV Infusion
-Dilute to a maximum concentration of 20 mg/ml.
-Inject slowly over 20-60 minutes. Faster administration can cause toxic concentrations and significant hypotension.

Continuous IV Infusion
-Concentrations of 2-4 mg/ml are recommended in the product labeling for continuous infusion.
-A slight yellow color may be present but it does not alter potency. Discard any solution that has a color darker than light amber or contains a precipitate.
-Procainamide at concentrations of 2-4 mg/ml is stable for 24 hours at room temperature or 7 days under refrigeration (2-8 degrees Celsius) in NS or D5W.

Other Injectable Administration
Intraosseous infusion
NOTE: Procainamide is not approved by the FDA for intraosseous administration.
-During cardiopulmonary resuscitation in pediatric patients, the same dosage may be given via the intraosseous route when IV access is not available.

Adverse central nervous system effects have been occasionally reported in adults receiving procainamide. These effects have included depression, dizziness, psychosis with hallucinations, and asthenia (weakness).

Bone marrow suppression and blood dyscrasias (0.5%) including severe neutropenia (leukopenia), agranulocytosis, aplastic anemia, pancytopenia, and thrombocytopenia, are relatively rare complications of procainamide therapy, which have been reported more frequently with the use of sustained-release preparations. Most of these events have been noted during the first 12 weeks of procainamide therapy. Since several fatalities have been attributed to bone marrow depression, it is recommended that patients taking sustained-release preparations of the drug receive a complete blood count with differential and platelet count weekly for the first 3 months of treatment, then periodically thereafter. CBCs should also be obtained in patients who develop unexplained fever while receiving procainamide. Although the exact mechanism responsible for procainamide-induced neutropenia has not been established, the reaction appears to be due to bone marrow depression rather than to an immune-mediated mechanism. Other hematologic adverse reactions that occur rarely but require medical attention include Coombs' positive hemolytic anemia (possibly associated with the SLE-like syndrome). If any serious hematologic disorder is identified, procainamide should be discontinued. Blood counts usually return to normal within one month of drug discontinuation.

Procainamide has a direct anticholinergic effect on the atrioventricular node. In addition, it slows the atrial rate by increasing the effective refractory period and the action potential duration in the atria, ventricles, and His-Purkinje system, sometimes resulting in a reflex sympathetic response. ECG changes associated with procainamide include PR prolongation, widening of the QRS interval, and QT prolongation. Arrhythmia exacerbation may occur during procainamide therapy. Cardiovascular adverse reactions, each occurring in 2 (9%) pediatric patients (n = 22, age 0 days to 19 years) with various tachyarrhythmias receiving continuous intravenous (IV) procainamide, included hypotension, bradycardia, AV block, ventricular ectopy, and QRS prolongation. Cardiac arrhythmias associated with procainamide administration in adults include ventricular asystole, ventricular fibrillation, or ventricular tachycardia. Fatalities have resulted when the drug is administered too rapidly or in excessive doses. Torsade de pointes is well described for the class Ia antiarrhythmic agents, a group which includes procainamide although this reaction may occur more frequently with quinidine than with procainamide. Torsade de pointes has been associated with both procainamide and its metabolite, N-acetylprocainamide (NAPA). ECG monitoring (e.g., QRS complex, QT interval) and blood pressure monitoring is recommended during IV procainamide administration. Transient but severe hypotension can occur following IV administration of procainamide, which may be related to the dosage or rate of IV drug administration. If the blood pressure decreases by >= 15 mmHg or QT prolongation or QRS widening of > 50% occurs, temporarily discontinue the procainamide infusion. Procainamide may decrease cardiac contractility and can decrease left ventricular function in patients with myocardial disease or worsen congestive heart failure in patients with pre-existing severe heart failure or ventricular dysfunction. These effects occur particularly in patients with cardiomyopathy, preexisting severe heart failure, or decreased left ventricular ejection fractions.

Lupus-like symptoms, manifested by abdominal pain, fever, chills, arthralgia or arthritis, myalgia, pericarditis, pleuritis, and/or skin rash (unspecified) have been reported in adults during procainamide therapy. Hematological or dermatological effects may also occur with the lupus-like syndrome. Limited data indicate this lupus-like syndrome may occur in up to 30% of adult patients on long-term oral procainamide therapy. Slow acetylation status may indicate a higher risk for SLE symptoms or rate of development of positive antinuclear antibodies, especially in patients with renal impairment. The lupus-like syndrome is reversible following discontinuance of the drug. If necessary, corticosteroid treatment may be used to treat unresolved symptoms following drug withdrawal. Although infrequent, dermatological reactions have been associated with procainamide therapy in adults, including urticaria, pruritus, flushing, and maculopapular rash. Angioedema has been rarely reported in adults during procainamide therapy.

Evidence of drug-induced hepatic injury including elevated hepatic enzymes and hyperbilirubinemia have been associated with procainamide therapy in adults. Fatalities due to hepatic failure have been reported.

In laboratory testing, supratherapeutic concentrations of lidocaine and meprobamate may inhibit fluorescence of procainamide and NAPA. In addition, propranolol shows a native fluorescence close to the procainamide/NAPA peak wavelengths; tests which depend on fluorescence measurement may be affected.

Procainamide should be used with caution in patients with ester local anesthetic hypersensitivity as patients may display cross-sensitivity, although this is unlikely. Procainamide is contraindicated in patients with idiosyncratic hypersensitivity to procainamide (e.g., previous reactions such as anaphylactic symptoms, bronchospasm, or acute allergic dermatitis to procainamide).

Fast rates of intravenous administration of procainamide may be associated with hypotension; caution is advised and care should be taken to avoid overly rapid administration of procainamide, especially in patients with significant hypotension or shock states (e.g., anaphylactic shock, cardiogenic shock, hemorrhagic shock).

Procainamide is contraindicated in patients with second- or third-degree AV block unless controlled by a pacemaker due to the risk of additive cardiac depression. In general, use procainamide cautiously in patients with certain types of cardiac disease. Procainamide has proarrhythmic properties and can induce or worsen cardiac arrhythmias. Procainamide should not be used in patients with preexisting heart block, such as first-degree AV block, bundle-branch block, or severe digitalis toxicity, because it can worsen the conduction defect or cause ventricular asystole or fibrillation. Antiarrhythmic agents with proarrhythmic properties (arrhythmia exacerbation), including procainamide and other Class I agents, should not be used in patients with asymptomatic non-life-threatening ventricular arrhythmias, especially in patients at risk for proarrhythmic effects such as heart failure, myocardial infarction, or cardiomegaly. Procainamide has not been shown to reduce mortality in patients with non-life-threatening ventricular arrhythmias. There is, however, evidence of an increased risk of mortality and non-fatal cardiac arrest with the use of flecainide after myocardial infarction in adult patients with asymptomatic PVCs or non-sustained ventricular tachycardia. Considering the known proarrhythmic properties of procainamide and the lack of evidence of improved survival for antiarrhythmic drugs in patients without life-threatening arrhythmias, the use of procainamide should be reserved for patients with life-threatening ventricular arrhythmias. Procainamide should also be used with caution in patients with congestive heart failure, left ventricular dysfunction, acute ischemic heart disease, or cardiomyopathy, since even slight depression of myocardial contractility may further reduce the cardiac output of the damaged heart. In addition, patients with congestive heart failure can have undiagnosed heart block, and the administration of procainamide to such patients would be hazardous. The use of procainamide is contraindicated in patients with torsade de pointes as procainamide can actually aggravate this arrhythmia instead of suppressing it. Similarly, procainamide should be avoided when possible in patients with QT prolongation due to the increased risk of proarrhythmic effects. Use procainamide with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus, and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.

Procainamide is contraindicated in patients with an established diagnosis of systemic lupus erythematosus (SLE), as aggravation of symptoms is likely to occur. However, in SLE patients with recurrent life-threatening arrhythmias not controlled by other agents, procainamide may be used in combination with corticosteroid suppressive therapy. The procainamide-induced SLE-like syndrome rarely results in pathologic renal changes; therefore, procainamide may not have to be terminated unless the symptoms of serositis and the possibility of further lupoid effects are a greater risk than the benefit of procainamide in controlling life-threatening arrhythmias. The prolonged administration of procainamide often leads to the development of a positive antinuclear antibodies (ANA) test (more common in patients who are slow acetylators), with or without symptoms of a SLE-like syndrome. If a positive ANA titer develops, assess the benefits versus risks of continued procainamide therapy. SLE may also increase the risk of prolonging the QT interval when using procainamide.

In patients with hepatic disease, lower doses or longer dosing intervals of procainamide may be needed due to reduced procainamide elimination. Procainamide is about 15 to 35% metabolized by N-acetylation, depending on genetic acetylation status. Slow acetylation status may indicate a higher risk for procainamide accumulation and toxicity (e.g., SLE symptoms, rate of development of ANA antibodies), especially in patients with renal impairment. Procainamide should be used with extreme caution in patients with renal disease (renal failure, renal impairment) because drug accumulation and toxicity can occur. Approximately 65% of a dose is excreted as unchanged drug (procainamide). The active metabolite, NAPA, is also significantly excreted unchanged in the urine.

Use procainamide cautiously in patients with myasthenia gravis because it has been reported to exacerbate muscle weakness associated with this condition. Patients with myasthenia gravis may show worsening of symptoms from procainamide due to its procaine-like effect on diminishing acetylcholine release at skeletal muscle motor nerve endings. Procainamide administration may be hazardous without optimal adjustment of anticholinesterase medications and other precautions.

Procainamide should be used with caution in patients with pre-existing marrow failure or cytopenia of any type, including agranulocytosis, aplastic anemia, hemolytic anemia, neutropenia, leukopenia, pancytopenia, and/or thrombocytopenia. Severe bone marrow suppression, agranulocytosis, neutropenia, hypoplastic anemia, and thrombocytopenia have been reported in patients receiving procainamide 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, complete blood counts including white cell, differential, and platelet counts should be performed weekly for the first 3 months of therapy, and periodically thereafter. Complete blood counts should be performed immediately if the patient develops any signs of infection, bruising, or bleeding. If any of these hematologic disorders are identified, procainamide hydrochloride should be discontinued. Blood counts usually return to normal within 1 month of discontinuation.

Use procainamide injection cautiously in patients with a sulfite hypersensitivity. Procainamide injection contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite hypersensitivity is seen more frequently in patients with asthma.

It is recommended that patients with atrial flutter or atrial fibrillation be adequately digitalized or have undergone cardioversion prior to therapy with procainamide in order to avoid enhancement of AV conduction and acceleration of ventricular rate. Digitalization in these patients reduces but does not eliminate the possibility of ventricular rate increases.

Description: Procainamide is a parenteral class Ia antiarrhythmic agent used in the treatment of several cardiac arrhythmias (e.g., ventricular tachycardia and supraventricular tachycardia [SVT]). Because of the proarrhythmic effects of procainamide and the lack of evidence of improved survival for any antiarrhythmic drug in persons without life-threatening arrhythmias, its use for lesser arrhythmias is generally not recommended. Pediatric Advanced Life Support (PALS) guidelines recommend procainamide for the treatment of SVT unresponsive to vagal maneuvers and adenosine and/or electric cardioversion and for the treatment of wide-complex ventricular tachycardia. Procainamide is associated with serious and sometimes fatal hematologic adverse events, particularly agranulocytosis or leukopenia; reserve use for persons in whom the benefits clearly outweigh the risks. Although not FDA-approved in pediatric patients, procainamide has been used in patients as young as neonates.

-When using procainamide for non-emergent indications, adjust the dose according to patient response, renal function, serum procainamide concentrations, and, when indicated, serum NAPA concentration.

For the treatment of wide-complex ventricular tachycardia*:
Intravenous or Intraosseus dosage:
Infants, Children, and Adolescents: 15 mg/kg/dose (Max: 100 mg/dose) IV or IO as a single dose. Consider procainamide for the treatment of wide-complex tachycardia in hemodynamically stable patients.

For the treatment of supraventricular tachycardia (SVT)*:
-for the treatment of SVT* excluding during cardiopulmonary resuscitation:
Intravenous dosage:
Neonates: 3.5 to 10 mg/kg/dose IV as a single dose, then 10 to 80 mcg/kg/minute continuous IV infusion has been studied for various tachyarrhythmias.
Infants, Children, and Adolescents: 3.5 to 15 mg/kg/dose (Max: 100 mg/dose) IV as a single dose, then 10 to 80 mcg/kg/minute continuous IV infusion. Max: 2 g/day.
-for the treatment of SVT* during cardiopulmonary resuscitation:
Intravenous or Intraosseus dosage:
Infants, Children, and Adolescents: 15 mg/kg/dose (Max: 100 mg/dose) IV or IO as a single dose. Additional doses may be administered if there is no effect and no toxicity from the initial dose; however, a maximum dose is not provided. Adult guidelines recommend a maximum dose of 17 mg/kg. Consider procainamide for SVT unresponsive to vagal maneuvers and adenosine and/or electric cardioversion.

Therapeutic Drug Monitoring:
-Although a therapeutic range for procainamide has not been established in pediatric patients, a range of 3 to 10 mcg/mL is recommended for most adult patients. Certain patients, such as those with sustained ventricular tachycardia, may require higher concentrations.
-Adverse reactions are occasionally seen at serum concentrations more than 10 mcg/mL and become more common as concentrations increase to more than 15 mcg/mL.
-N-acetylprocainamide (NAPA) is one-third as potent as the parent drug. Monitoring of serum NAPA concentrations is primarily indicated in patients with impaired renal function, as NAPA can accumulate in this patient population. In general, do not exceed combined total concentrations of 40 mcg/mL. In neonates, NAPA concentrations of 6 to 20 mcg/mL (with a sum of NAPA plus procainamide concentration not to exceed 30 mcg/mL) have been suggested as therapeutic.

Maximum Dosage Limits:
Procainamide has a narrow therapeutic index. In all populations, dosage is individualized based on patient weight, renal function, clinical goals, patient response, serum procainamide concentrations and, when needed, serum N-acetylprocainamide (NAPA) concentrations.

Patients with Hepatic Impairment Dosing
Although no specific guidelines are available for pediatric patients, dosage reduction may be needed in individual patients with hepatic impairment. Adjust dosage based on serum procainamide and NAPA concentrations.

Patients with Renal Impairment Dosing
Reduction of dosage is required due to accumulation of procainamide and NAPA. Although no specific guidelines are available for pediatric patients, use lower initial doses and make dosage adjustments in conjunction with monitoring of procainamide and NAPA levels, in addition to other factors such as clinical response, renal status, and hepatic function.

Intermittent hemodialysis
Procainamide and NAPA are removed from the circulation by hemodialysis. Adjust dose based on procainamide and NAPA concentrations.

Peritoneal dialysis
Procainamide and NAPA are not removed from the circulation by peritoneal dialysis.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Like procaine, procainamide inhibits the influx of sodium through membrane pores. Procainamide exerts its effects on 'fast' channels of the myocardial cell membrane, prolonging the recovery period after repolarization. The effective refractory period and the action potential duration in the atria, ventricles, and His-Purkinje system are prolonged. The effective refractory period is increased more than the action potential duration; therefore, the myocardium remains refractory even after the resting membrane potential has been restored. The drug decreases myocardial automaticity, excitability, conduction velocity, and possibly contractility. Procainamide also exhibits anticholinergic properties that may modify its myocardial effects, however these actions are less pronounced than for either quinidine or disopyramide.

The net effect of procainamide is to suppress ectopy in atrial and ventricular tissue. Because nodal tissue is more dependent on calcium influx, procainamide has little use in arrhythmias of nodal origin.

Pharmacokinetics: Procainamide is administered parenterally. Procainamide distributes widely throughout the body and is approximately 15% to 20% bound to plasma proteins. Procainamide is partially metabolized in hepatocytes to the active metabolite N-acetylprocainamide (NAPA). The extent of metabolism is dependent on the activity of acetyl transferase. Metabolic rate is greater in patients who are rapid acetylators. Significant amounts of both unchanged procainamide (30% to 60%) and NAPA (6% to 52%) are eliminated renally by glomerular filtration and active tubular secretion.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Intravenous Route
Therapeutic concentrations of procainamide are achieved within minutes of starting an intravenous infusion.


-Special Populations
Pediatrics
Neonates
In patients receiving continuous intravenous procainamide, the mean clearance was significantly lower and the mean NAPA:procainamide ratio was significantly higher in premature neonates (n = 7, gestational age younger than 37 weeks) compared to term neonates (n = 14). The mean clearance and NAPA:procainamide ratio in premature neonates was 5.2 +/- 0.25 mL/kg/minute and 0.78 +/- 0.06, respectively, versus 8.22 +/- 0.35 mL/kg/minute and 0.55 +/- 0.04, respectively, in term neonates. Procainamide clearance correlated with creatinine clearance (CrCl). Five patients in the study had supratherapeutic procainamide concentrations (more than 10 mg/L). Four of the 5 were premature neonates; all 5 had a CrCl less than 30 mL/minute/1.73 m2. The half-life of procainamide calculated from concentrations in 3 patients ranged from 5.4 to 28.6 hours; however, all of these patients had a CrCl of 30 mL/minute/1.73m2 or less.

Children
Based on the result of a small pharmacokinetic study (n = 5, age 7 to 12 years) in patients receiving a single intravenous dose of procainamide, children have a higher clearance and shorter half-life, but a similar Vd compared to adult patients. The mean plasma clearance, half-life, and Vd were 19.4 +/- 2 mL/kg/minute, 1.7 +/- 0.1 hours, and 2.2 +/- 0.3 L/kg, respectively, in children compared to 8.32 to 9.3 mL/kg/minute, 2.5 to -4.7 hours, and 1.2 to 1.93 L/kg, respectively, reported in adults.

Hepatic Impairment
The clearance of procainamide and NAPA may be reduced in patients with hepatic impairment. In adult patients with cirrhosis receiving a single oral dose of procainamide, the urinary recovery of NAPA was reduced by a factor of 3 and the index of procainamide acetylation and hydrolysis were reduced by about 40% and 60%, respectively. These changes did not correlate with the degree of hepatic impairment.

Renal Impairment
The clearance of procainamide was correlated with CrCl in a small study of neonatal patients. In adult patients with end-stage renal failure, the half-life of procainamide and NAPA increased to 10 to 20 hours and 31 to 50 hours, respectively, after a single IV infusion of 6.5 mg/kg.