VA Class:CV300
Procainamide hydrochloride is a class Ia antiarrhythmic agent.154
Procainamide hydrochloride is used for the treatment of ventricular arrhythmias (e.g., sustained ventricular tachycardia) that in the judgment of the physician are life-threatening, but the drug usually is not the antiarrhythmic of first choice.135, 147 Because of the drug's arrhythmogenic potential, the lack of evidence for improved survival for class I antiarrhythmic agents,135, 136, 137, 138 and the risk of serious (occurring in about 0.5% of patients), potentially fatal adverse hematologic effects (see Cautions: Hematologic Effects), particularly leukopenia or agranulocytosis, use of procainamide for less severe arrhythmias is not recommended by the manufacturer.135 Findings from the National Heart, Lung, and Blood Institute (NHLBI)'s Cardiac Arrhythmia Suppression Trial (CAST) study after an average of 10 months of follow-up have indicated that the rate of total mortality and nonfatal cardiac arrest in patients with recent myocardial infarction, mild-to-moderate left ventricular dysfunction, and asymptomatic or mildly symptomatic ventricular arrhythmias (principally frequent ventricular premature complexes [VPCs, PVCs]) who received encainide or flecainide increased substantially compared with placebo.121, 135, 139, 140 (See Cautions in Flecainide 24:04.04.12.). Therefore, therapy with selected antiarrhythmic agents (e.g., procainamide) should be reserved for the suppression and prevention of documented life-threatening ventricular arrhythmias and treatment of patients with asymptomatic VPCs should be avoided.135 The manufacturers state that procainamide therapy should be initiated only in a hospital setting.135
Procainamide has been used to suppress and prevent the recurrence of less severe but symptomatic ventricular arrhythmias†, including uniform, multiform, and/or coupled VPCs† and nonsustained ventricular tachycardia, and asymptomatic ventricular arrhythmias†; however, the arrhythmogenic potential of the drug and findings of the CAST study with other class I antiarrhythmic agents have called into question the safety of using such agents in arrhythmias that were not life-threatening.135, 139, 140, 141, 142, 143, 144, 145 Therefore, procainamide therapy should be reserved for life-threatening ventricular arrhythmias in carefully selected patients in whom the benefits of procainamide therapy outweigh the possible risks.135, 147
Life-Threatening Ventricular Arrhythmias and Advanced Cardiovascular Life Support
Antiarrhythmic drugs are used during cardiac arrest to facilitate the restoration and maintenance of a spontaneous perfusing rhythm in patients with refractory (i.e., persisting or recurring after at least one shock) ventricular fibrillation or pulseless ventricular tachycardia; however, there is no evidence that these drugs increase survival to hospital discharge when given routinely during cardiac arrest.400 High-quality cardiopulmonary resuscitation (CPR) and defibrillation are integral components of advanced cardiovascular life support (ACLS) and the only proven interventions to increase survival to hospital discharge.400, 401 Other resuscitative efforts, including drug therapy, are considered secondary and should be performed without compromising the quality and timely delivery of chest compressions and defibrillation.400, 401 The principal goal of pharmacologic therapy during cardiac arrest is to facilitate return of spontaneous circulation (ROSC), and epinephrine is considered the drug of choice for this use.400, 401 (See Uses: Advanced Cardiovascular Life Support and Cardiac Arrhythmias, in Epinephrine 12:12.12.) Antiarrhythmic drugs may be considered for the treatment of refractory ventricular fibrillation or pulseless ventricular tachycardia during cardiac resuscitation; however, experts generally recommend the use of amiodarone (or lidocaine).400, 401 Procainamide may be used for the management of regular wide-complex tachycardias during the periarrest period and is included as a recommended antiarrhythmic agent in current ACLS guidelines for adult and pediatric tachycardia.400, 401, 403
Monomorphic and Polymorphic Ventricular Tachycardia
Procainamide is one of several antiarrhythmic agents that may be used in the treatment of sustained, stable monomorphic ventricular tachycardia not associated with angina, pulmonary edema, or hypotension (blood pressure less than 90 mm Hg) in patients with preserved ventricular function.147, 159, 160 Drug regimens including amiodarone or procainamide may be used initially for the treatment of patients with episodes of sustained ventricular tachycardia that are somewhat better tolerated hemodynamically.147, 159, 160 If IV antiarrhythmic therapy is used for ventricular fibrillation or tachycardia, it probably should be discontinued (at least temporarily) after 6-24 hours so that the patient's ongoing need for antiarrhythmic drugs can be reassessed.147, 159
Although rare, episodes of drug-refractory sustained polymorphic ventricular tachycardia (“electrical storm”) have been reported in cases of acute myocardial infarction.147, 159 Some experts state that these episodes usually are treated with an IV β-adrenergic blocking agent, IV amiodarone, left stellate ganglion blockade, intra-aortic balloon counterpulsation (IABP), or emergency revascularization;147, 159 IV magnesium also may be used.159 However, other experts recommend revascularization and β-blockade followed by IV antiarrhythmic drugs, such as procainamide or amiodarone, for patients with recurrent or incessant polymorphic ventricular tachycardia due to acute myocardial ischemia.160
Ventricular Premature Complexes
Procainamide decreases the frequency of VPCs associated with acute myocardial infarction, but IV lidocaine is considered the drug of choice because normal doses of lidocaine do not decrease cardiac contractility or peripheral resistance or slow AV conduction to the degree produced by procainamide. Like other antiarrhythmic drugs, procainamide has not been shown to decrease mortality rate in patients with VPCs associated with acute myocardial infarction. The use of procainamide in the treatment of asymptomatic VPCs should be avoided.135 Procainamide generally is not used to treat cardiac glycoside-induced ventricular arrhythmias. (See Cautions: Precautions and Contraindications.)
Supraventricular Tachyarrhythmias
Procainamide has been used for the treatment of various supraventricular tachycardias (SVTs)†; because of a higher risk of toxicity and proarrhythmic effects, antiarrhythmic agents generally should be reserved for patients who do not respond to or cannot be treated with AV nodal blocking agents (β-adrenergic blocking agents and nondihydropyridine calcium-channel blocking agents).301, 401 Some experts state that procainamide may be useful for restoring sinus rhythm or slowing ventricular rate in patients with preexcited atrial fibrillation and rapid ventricular response associated with Wolff-Parkinson-White syndrome† since AV nodal blocking agents are contraindicated in such patients; however, direct-current cardioversion is the treatment of choice in hemodynamically compromised patients.300, 301 Procainamide also has been used in the management of junctional tachycardia†, but the drug has a more limited role in this arrhythmia and is usually considered only when IV β-adrenergic blocking agents are ineffective.300
IV procainamide has been used effectively in the treatment of malignant hyperthermia†. Procainamide is also used parenterally (preferably IM) in the treatment of arrhythmias that occur during surgery and anesthesia.
Procainamide hydrochloride may be administered by IM or IV injection or by IV infusion.161 ECG and blood pressure should be continuously monitored during IV administration of procainamide.152 IV administration may produce transient high plasma levels of the drug, which can cause severe hypotension.161
Procainamide may be administered by intraosseous (IO) injection† in the setting of pediatric advanced cardiovascular life support (PALS); onset of action and systemic concentrations are comparable to those achieved with venous administration.403 The drug also has been administered orally; however, an oral dosage form no longer is commercially available in the US.161, 400
Dosage of procainamide must be carefully adjusted according to individual requirements and response, age, renal function, and the general condition and cardiovascular status of the patient.152, 161 ECG monitoring of cardiac function and monitoring of renal function (i.e. creatinine clearance) is recommended during procainamide therapy,121, 135, 151, 152 especially when the drug is given IV or when it is given in patients with increased risk of adverse reactions to procainamide, such as patients older than 50 years of age and patients with severe heart disease, hypotension, or hepatic or renal disease.121, 151 Dosage should be reduced in patients with renal insufficiency135, 151, 152 and/or congestive heart failure and in critically ill patients; plasma concentrations of procainamide and its major metabolite N -acetyl procainamide (NAPA) should be determined and dosage should be adjusted to maintain desired concentrations.151
Ventricular and Supraventricular Arrhythmias
The usual initial adult IM dosage of procainamide hydrochloride is 50 mg/kg given in divided doses (every 3-6 hours).121, 152, 161 For the treatment of arrhythmias that occur during surgery and anesthesia, 100-500 mg of procainamide hydrochloride may be administered parenterally (preferably IM) in adults.121
To facilitate control of the rate of administration, it is recommended that commercially available injections of procainamide hydrochloride be diluted prior to direct IV injection.121, 161 Administration of the drug by IV injection should be done slowly at a rate not exceeding 50 mg/minute.161 If procainamide hydrochloride is administered by IV infusion, the drug should be diluted with a suitable IV infusion fluid (usually 5% dextrose injection) to a concentration of 20 mg/mL (for initial loading infusion) or 2 or 4 mg/mL (for maintenance infusion).121, 161 Blood pressure and ECG should be monitored continuously and the rate of administration adjusted accordingly. 152 If a fall in blood pressure of more than 15 mm Hg occurs, or if excessive widening of the QRS complex (greater than 50%) or prolongation of the PR interval occurs, or if severe adverse effects appear, the drug should be temporarily discontinued.
For initial control of arrhythmias in adults, IV doses of 100 mg of procainamide hydrochloride may be given every 5 minutes until the arrhythmia is controlled, adverse effects occur, or until a total of 500 mg has been administered, after which it may be advisable to wait 10 minutes or longer to allow for distribution of the drug before additional doses are given.121 Alternatively, a loading-dose IV infusion of 500-600 mg may be administered at a constant rate over a period of 25-30 minutes.121 Although it is unusual to require more than 600 mg to initially control an arrhythmia, the maximum recommended total dose given by either method of IV administration is 1 g.121 To maintain therapeutic plasma concentrations subsequently, a continuous IV infusion of 2-6 mg/minute may be administered.121 Alternatively, some clinicians have recommended a maintenance IV infusion of 0.02-0.08 mg/kg per minute.
If used in adults with cardiac arrest, some experts recommend an IV infusion of 20 mg/minute up to a total maximum dose of 17 mg/kg.403
Various dosages of procainamide hydrochloride have been given in the treatment of malignant hyperthermia†. The IV dosage has ranged from 200-900 mg and has generally been followed by a maintenance infusion.
Ventricular and Supraventricular Arrhythmias
The manufacturers have not established pediatric dosage recommendations for procainamide hydrochloride.
Pediatric parenteral dosage recommendations are variable, and clinicians should consult specialized references for specific information.152, 154, 157, 158 Some clinicians recommend a pediatric IV dose of 2-6 mg/kg (not to exceed 100 mg) as a loading dose administered over 5 minutes,152, 154, 157 repeated as necessary at intervals of 5-10 minutes152, 154 (not to exceed a total loading dose of 15 mg/kg or 500 mg in a 30-minute period).152, 154, 157 Also, some experts recommend a maintenance IV infusion dose of 0.02-0.08 mg (20-80 mcg)/kg per minute, up to a total maintenance infusion dose of 2 g in 24 hours.152, 154, 157 For pediatric resuscitation, some experts recommend an IV or IO† dose of 15 mg/kg given over 30-60 minutes with discontinuance of the drug if widening of the QRS complex (greater than 50%) from baseline occurs or hypotension develops.403 If the drug is administered IM, some clinicians recommend a pediatric dosage of 20-30 mg/kg daily (not to exceed 4 g in 24 hours),152, 154 given in divided doses (every 4-6 hours).152
Procainamide has numerous adverse effects which may necessitate cessation of therapy in many patients.
Prolonged use of procainamide often results in the development of positive antinuclear antibody (ANA) titers.135 ANA titers are found in at least 50% of patients receiving long-term procainamide therapy (usually within 2-18 months after starting therapy); the induction of ANA by the drug appears to be independent of the dosage. Patients with procainamide-induced increases in ANA titers may develop a syndrome resembling systemic lupus erythematosus (SLE),135, 152 characterized by polyarthralgia, arthritis, pleurisy, pleural effusion, dyspnea, fever, chills, myalgia, skin lesions (including urticaria, erythema multiforme, and morbilliform eruptions), headache, fatigue, weakness, abdominal pain, nausea, vomiting, pericarditis, pericardial effusion, pericardial tamponade, acute hepatomegaly, splenomegaly, lymphadenopathy, acute pancreatitis, and the presence of LE cells in the blood. Patients with procainamide-induced SLE may have a positive direct antiglobulin (Coombs') test.152, 157 Thrombocytopenia,152, 157 Coombs' positive hemolytic anemia,152, 157 increased serum concentrations of AST (SGOT), ALT (SGPT), and amylase rarely have been associated with procainamide-induced SLE.152 Procainamide-induced SLE syndrome probably represents a hypersensitivity reaction in which procainamide anti-DNA antibodies are formed.
If a positive ANA titer develops during procainamide therapy, the relative benefits and risks of continued therapy with the drug should be assessed.135 Procainamide should be discontinued in patients who develop symptoms of SLE and/or who have rising ANA titer, unless the benefit of antiarrhythmic therapy with the drug outweighs the potential risk. If procainamide-induced SLE develops in a patient with a life-threatening arrhythmia uncontrolled by other antiarrhythmic drugs, the manufacturers state that corticosteroid therapy may be used concomitantly with procainamide. Signs and symptoms of SLE usually regress when the drug is discontinued, but long-term treatment with corticosteroids may be necessary if symptoms do not regress. If arthralgia, fever, rash, malaise, or other unexplained symptoms occur, laboratory studies such as LE cell preparations and ANA titer determinations should be performed.
Serious adverse hematologic effects, including agranulocytosis, leukopenia, bone marrow depression, hypoplastic anemia, and thrombocytopenia, have been reported in 0.5% of patients receiving procainamide.118, 119, 120, 121, 135, 152, 157 Pure red cell aplasia also has been reported.124 In most reported cases, such effects occurred with usual recommended dosages of procainamide during the first 12 weeks of therapy.118, 119, 120, 121, 135 The drug should be discontinued if any of these adverse hematologic effects occurs.118, 119, 120, 121, 135 Although blood cell counts usually return to normal within 1 month after discontinuance of procainamide, adverse hematologic effects have been fatal in some cases (e.g., in about 20-25% of patients who developed agranulocytosis).118, 119, 120, 121, 135 Because of the risk of these effects, careful monitoring of hematologic status is necessary during procainamide therapy (see Cautions: Precautions and Contraindications), and use of the drug should be limited to patients in whom the potential benefits clearly outweigh the possible risks (see Uses).118, 119, 120, 121, 135
Leukopenia, hemolytic anemia, and eosinophilia also have occurred rarely in patients receiving procainamide. In at least one case, pancytopenia with generalized ecchymoses has been reported. Adverse hematologic effects also have been associated with a procainamide-induced syndrome resembling systemic lupus erythematosus. (See Cautions: Sensitivity Reactions.)
GI disturbances such as anorexia, bitter taste, abdominal pain, nausea, vomiting, and diarrhea may occur in patients receiving procainamide and are most common with dosages of 4 g or more daily.
Adverse nervous system effects of procainamide are rare and have included dizziness, giddiness, seizures, mental depression, confusion, and psychosis with hallucinations.
Urticaria, pruritus, and maculopapular rash have occurred occasionally in patients receiving procainamide. An urticarial vasculitis also has occurred.126
Paradoxically, an extremely rapid ventricular rate may occur when procainamide is used in the treatment of atrial fibrillation or flutter, because of a reduction in the degree of AV nodal block to a 1:1 ratio. Patients with atrial flutter or fibrillation should be cardioverted or digitalized prior to procainamide administration to avoid enhanced AV conduction, which may result in ventricular rate acceleration beyond tolerable limits.135 The anticholinergic action of the drug on the AV node may also increase the heart rate. Procainamide-induced ventricular tachycardia may be prevented by prior digitalization; however, in atrial flutter or fibrillation, adequate digitalization reduces but does not eliminate the possibility of sudden increase in ventricular rate as the atrial rate is slowed by procainamide.135 If cessation of atrial fibrillation is accompanied by depression of the normal pacemaker, an idioventricular rhythm (including ventricular tachycardia and fibrillation) may result. Procainamide-induced ventricular tachycardia is particularly hazardous in patients with extensive myocardial injury. Conversion of atrial fibrillation also may be associated with embolism. Therefore, anticoagulant therapy may be necessary before procainamide conversion of atrial fibrillation to normal sinus rhythm. (See Uses: Supraventricular Tachyarrhythmias.) The arrhythmogenic effect of procainamide may result in atypical ventricular tachycardia (torsades de pointes).147, 157 (See Cautions: Precautions and Contraindications.)
Procainamide cardiotoxicity is evidenced by conduction defects (50% widening of the QRS complex), ventricular tachycardia, frequent ventricular premature complexes, and complete AV block. When these ECG signs appear, procainamide should be discontinued and the patient should be monitored closely. Less frequently, ECG signs of toxicity may include prolongation of the PR and QT intervals and decreases in voltage of the QRS complexes and T waves.157 Adverse cardiac effects occur most commonly when procainamide is administered IV. The hazard of ventricular fibrillation increases with increasing dosage of procainamide and may be accompanied by ECG signs of toxicity. Large IV doses of the drug may cause heart block and asystole, and death has occurred rarely.
The manufacturers state that phenylephrine or norepinephrine should be available to treat severe hypotension caused by IV procainamide.
Other adverse effects of procainamide include fever,154, 157 flushing, angioedema, hypergammaglobulinemia, and, rarely, generalized or digital vasculitis, proximal myopathy, and Sjögren's syndrome. Hepatomegaly with increased serum aminotransferase concentrations has been reported after a single oral dose of the drug. Liver aminotransferase concentrations have been elevated, with or without elevations in alkaline phosphatase and bilirubin concentrations, in patients receiving oral procainamide.135 Abnormal liver function test results in some patients were accompanied by malaise, right upper-quadrant pain, liver failure, and death secondary to liver failure.135
Precautions and Contraindications
Findings from the postmarketing Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multicenter, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had had myocardial infarctions more than 6 days but less than 2 years previously, indicate that the rate of total mortality and nonfatal cardiac arrest was increased in patients treated with encainide or flecainide compared with that seen in patients who received placebo.135 The applicability of these results to other populations (e.g., those without recent myocardial infarction) is uncertain.135 The manufacturers state that because of the drug's arrhythmogenic potential, the lack of evidence for improved survival for class I antiarrhythmic agents,135, 136, 137, 138 and the risk of serious (occurring in about 0.5% of patients), potentially fatal adverse hematologic effects (see Cautions: Hematologic Effects), use of procainamide hydrochloride in patients with ventricular arrhythmias should be limited to those with life-threatening arrhythmias in carefully selected patients in whom benefits of procainamide therapy outweigh the possible risks, taking into account possible alternative antiarrhythmic therapy.135 Use of procainamide in less severe arrhythmias currently is not recommended and treatment of asymptomatic VPCs should be avoided.135
Since procainamide, like other antiarrhythmic agents, has been associated with the development or exacerbation of arrhythmias in some patients, clinical and ECG evaluations are essential prior to and during procainamide therapy to monitor for the appearance of arrhythmias and to determine the need for continued therapy.118, 119, 120, 121, 152 Procainamide should be used with extreme caution, if at all, in patients with marked disturbances of AV conduction, such as second- or third-degree heart block, bundle-branch block, or severe cardiac glycoside intoxication because procainamide may cause additional depression of conduction, resulting in ventricular asystole or fibrillation.152 The drug is contraindicated in patients with complete AV heart block and in patients with second- or third-degree AV nodal block unless an electrical pacemaker is operative. The dosage should be reduced in patients who exhibit or develop first-degree heart block with procainamide; if the block persists despite dosage reduction, risk versus benefit of continued therapy with increased heart block must be carefully evaluated.135 Procainamide should be administered with caution (especially parenterally) in the treatment of ventricular arrhythmias in patients with severe organic heart disease, since these patients may have undiagnosed complete heart block; if the ventricular rate is slowed by procainamide and normal AV conduction does not occur, the drug should be discontinued and the patient reevaluated, since asystole may result. Procainamide also is contraindicated in patients with atypical ventricular tachycardia (torsades de pointes), since class IA antiarrhythmic agents may aggravate this ventricular arrhythmia.152 The possibility that potentially serious cardiac arrhythmias, including torsades de pointes, could occur if procainamide were used concomitantly with other drugs that prolong the QTc interval also should be considered and such combined use should be avoided.146, 149 Procainamide should be used with extreme caution in the treatment of ventricular tachycardia occurring during coronary occlusion. Hypokalemia, hypoxia, and disorders of acid-base balance must be eliminated as potentiating factors in patients who require large doses of antiarrhythmic agents to control ventricular arrhythmias. Procainamide should be used with caution in patients with congestive heart failure, acute ischemic heart disease, or cardiomyopathy, since even slight depression of contractility may further decrease cardiac output.135, 152 Procainamide should be used with caution in patients with renal and hepatic disease, since accumulation of the drug may cause symptoms of overdosage, such as ventricular tachycardia and severe hypotension.
Commercially available formulations of procainamide hydrochloride injection may contain sulfites, which can cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.
Procainamide should be used with caution in patients with preexisting bone marrow depression or cytopenia of any type.118, 119, 120, 135 Because of the risk of potentially severe, sometimes fatal adverse hematologic effects, the manufacturers recommend that complete blood cell counts, including differential leukocyte counts and platelet counts, optimally be performed at weekly intervals during the first 3 months of therapy and periodically thereafter.118, 119, 120, 121, 135 If a serious adverse hematologic effect is identified, the drug should be discontinued.118, 119, 120, 121, 124, 135 Patients should be instructed to promptly report to their physician any sign of infection (e.g., sore mouth, throat, or gums; unexplained fever; chills),135 unusual bleeding or bruising,135 rash, arthralgia, myalgia, dark urine or icterus, wheezing, muscular weakness, chest or abdominal pain, palpitation, nausea, vomiting, anorexia, diarrhea, hallucinations, dizziness, or mental depression associated with procainamide therapy. If any of these signs and/or symptoms occur and granulocytopenia is present, the drug should be discontinued and appropriate treatment (e.g., measures to prevent infection) should be instituted immediately. Laboratory tests for detection of procainamide-induced SLE such as ANA titer determinations should be performed before and periodically during maintenance or prolonged procainamide therapy, even in asymptomatic patients. Procainamide is contraindicated in patients with an established diagnosis of SLE, since symptomatic aggravation is likely.135, 152
Procainamide is contraindicated in patients who are hypersensitive to the drug, and the possibility of cross-sensitivity to procaine and chemically related drugs (e.g., ester-type local anesthetics) must be considered,135 although cross-sensitivity is unlikely.135 Procainamide should not be used if it causes acute allergic dermatitis, asthma, or anaphylactic symptoms. Since procainamide has been reported to increase muscle weakness in patients with myasthenia gravis, the drug may be contraindicated in these patients. (See Drug Interactions: Anticholinesterase and Anticholinergic Agents.)
Safety and efficacy of procainamide in pediatric patients have not been established.135, 403 However, some experts state that procainamide may be considered in children with supraventricular tachycardia unresponsive to adenosine, vagal maneuvers, or electric cardioversion.154, 157, 158, 402 Procainamide also has been used during pediatric resuscitation; expert consultation prior to use in a hemodynamically stable patient is strongly recommended.403 In addition, the drug should not be used in combination with another agent that prolongs the QT interval (e.g., amiodarone) without expert consultation.403
Clinical studies of procainamide did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.135, 151 Because the drug is known to be substantially excreted by the kidney, patients with renal impairment may be at increased risk of procainamide-induced toxicity.135, 151, 155 In general, dosage should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range.135, 151 (See Dosage and Administration: Dosage.) The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.135, 151
Mutagenicity and Carcinogenicity
Studies to determine the mutagenic and carcinogenic potentials of procainamide have not been performed to date.
Animal reproduction studies have not been performed with procainamide. It is not known whether procainamide can cause fetal harm when administered to pregnant women or can affect reproduction capacity. Procainamide does cross the placenta, but the extent to which it does so has not been well characterized.100, 156 Procainamide should be used during pregnancy only when clearly needed.
Procainamide and NAPA are distributed into milk and can be absorbed by a nursing infant.135, 156 Because of the potential for serious adverse reactions to procainamide in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.135
Histamine H2-Receptor Antagonists
Concomitant administration of procainamide and cimetidine may result in increased plasma procainamide and NAPA concentrations and subsequent toxicity.101, 102, 107, 108, 111, 152, 157 This interaction may be more marked in geriatric patients and patients with renal impairment since such patients eliminate procainamide, NAPA, and cimetidine more slowly.101, 108, 111 Cimetidine decreases the renal clearance of procainamide and NAPA;101, 102, 107, 108 however, additional mechanisms also may contribute to this interaction.102, 107, 108 Limited evidence suggests that ranitidine also may increase plasma concentrations of procainamide and NAPA,101, 103, 104, 152 but to a lesser extent than cimetidine;103 the precise mechanisms for this interaction are complex and are not fully understood.103, 104, 105, 106 Evidence to date suggests that famotidine does not substantially interact with procainamide.109, 112 Caution should be exercised when either cimetidine or ranitidine is administered concomitantly with procainamide, particularly in geriatric patients and patients with renal impairment;101, 102, 103, 104, 107, 108, 111 the patient and plasma procainamide concentrations should be monitored closely and procainamide dosage adjusted accordingly.101, 102, 103, 104, 108, 111
Procainamide may enhance the effects of skeletal muscle relaxants.152 The drug may potentiate the effects of both nondepolarizing and depolarizing skeletal muscle relaxants, such as gallamine triethiodide (no longer commercially available in the US), metocurine iodide (no longer commercially available in the US), pancuronium bromide, succinylcholine chloride, and tubocurarine chloride. Although the clinical significance of this interaction has not been established, procainamide should be used with caution in conjunction with neuromuscular blocking agents.
Anticholinesterase and Anticholinergic Agents
Procainamide should be used with caution, if at all, in patients with myasthenia gravis and the dose of anticholinesterase drugs such as neostigmine and pyridostigmine may have to be increased. Theoretically, the anticholinergic effect of procainamide may be additive with anticholinergic drugs or procainamide may enhance the effects of anticholinergic agents.152
Since procainamide may reduce blood pressure, patients receiving hypotensive drugs and procainamide parenterally or in high oral doses should be observed for possible additive hypotensive effects. β-adrenergic blocking agents may increase plasma procainamide concentrations.152
Concomitant use of procainamide with drugs that prolong the QTc interval may result in potentially serious cardiac arrhythmias, including torsades de pointes.146, 149
Concurrent use of procainamide with class IA antiarrhythmics (e.g., disopyramide, quinidine) may enhance conduction prolongation, contractility depression, and hypotension, especially in patients with cardiac decompensation;135 combined use should be reserved for serious arrhythmias unresponsive to monotherapy and only if close observation is possible.135 When procainamide is administered with other antiarrhythmic drugs such as lidocaine, phenytoin, propranolol, or quinidine, the cardiac effects may be additive or antagonistic and toxic effects may be additive.
Concomitant use of procainamide and amiodarone may result in increased plasma procainamide and N -acetylprocainamide (NAPA) concentrations and subsequent toxicity.114, 115, 116, 152, 157 In a limited number of patients receiving 2-6 g of procainamide hydrochloride daily, initiation of amiodarone hydrochloride (1200 mg daily for 5-7 days and then 600 mg daily) increased plasma procainamide and NAPA concentrations by about 55 and 33%, respectively, during the first week of amiodarone therapy.114, 115, 116 The exact mechanism(s) has not been elucidated, but it has been suggested that amiodarone may decrease the renal clearance of procainamide or NAPA and/or inhibit the hepatic metabolism of procainamide.115, 116 In addition to a pharmacokinetic interaction, additive electrophysiologic effects, including increased QTc and QRS intervals, occur during concomitant use; adverse electrophysiologic effects (e.g., acceleration of ventricular tachycardia) may also occur.117 Pending further accumulation of data, it is recommended that procainamide dosage be reduced by 20-33% when amiodarone therapy is initiated in patients currently receiving procainamide or that procainamide therapy be discontinued.114, 116, 117
Concomitant administration of procainamide and trimethoprim may result in increased plasma procainamide and NAPA concentrations.135, 152
Because alcohol appears to enhance acetylation of procainamide to NAPA, alcohol consumption may reduce the half-life of procainamide.135
Ofloxacin may decrease the renal clearance of procainamide, which may result in an increase in the area under the serum concentration-time curve (AUC) and peak concentration of procainamide by 20-25%.155
Para-aminobenzoic acid may decrease the renal clearance of NAPA, which may result in an increase in the plasma concentration and half-life of NAPA.155
Overdosage of procainamide has produced hypotension, widening of the QRS complex, prolongation of PR and QT intervals, lowering of R and T waves, increasing AV block, ventricular extrasystole, ventricular tachycardia or fibrillation, junctional tachycardia, intraventricular conduction delay, oliguria, lethargy, confusion, nausea, and vomiting.135
Management of procainamide overdosage generally involves symptomatic and supportive care with ECG and blood pressure monitoring.135 There is no known antidote to procainamide.135 If ingestion of the drug is recent, gastric lavage or emesis may reduce absorption. Procainamide toxicity can usually be treated, if necessary, by administering vasopressors after adequate fluid volume replacement.135 IV infusion of (1/6) M sodium lactate injection reportedly reduces the cardiotoxic effects of procainamide. If procainamide toxicity causes severe hypotension and renal insufficiency, urinary elimination of procainamide and NAPA is decreased and hemodialysis may be necessary. Peritoneal dialysis is not effective. One patient who ingested approximately 7 g of procainamide hydrochloride recovered after treatment consisting of IV norepinephrine, IV furosemide, attempted volume expansion with albumin, and hemodialysis. Another patient recovered after ingestion of 19 g of procainamide hydrochloride; this patient was treated with IV isoproterenol and IV epinephrine.
Antiarrhythmic and Electrophysiologic Effects
Procainamide is an antiarrhythmic agent whose cardiac actions appear to be similar to those of quinidine. Procainamide is regarded as a myocardial depressant because it decreases myocardial excitability and conduction velocity, and may depress myocardial contractility. Procainamide, like disopyramide and quinidine, also possesses anticholinergic properties which may modify the direct myocardial effects of the drug.
The exact mechanism of antiarrhythmic action of procainamide has not been established, but the drug is considered a class I (membrane-stabilizing) antiarrhythmic agent.154 Like other class I antiarrhythmic agents, procainamide is believed to combine with fast sodium channels in their inactive state and thereby inhibit recovery after repolarization in a time- and voltage-dependent manner which is associated with subsequent dissociation of the drug from the sodium channels. Procainamide exhibits electrophysiologic effects characteristic of class IA antiarrhythmic agents. The electrophysiologic characteristics of the subgroups of class I antiarrhythmic agents may be related to quantitative differences in their rates of attachment to and dissociation from transmembrane sodium channels, with class IA agents exhibiting intermediate rates of attachment and dissociation. N -Acetylprocainamide (NAPA), a metabolite of procainamide, exhibits class III antiarrhythmic activity.147
Like lidocaine and quinidine, procainamide suppresses automaticity in the His-Purkinje system. In usual doses, procainamide may decrease the automaticity of ectopic pacemakers, but the extent of this effect also depends upon the anticholinergic effect of the drug on the sinoatrial (SA) node, atria, and atrioventricular (AV) node. Extremely high concentrations of procainamide may increase myocardial automaticity. The drug decreases conduction velocity in the atria, ventricles, and His-Purkinje system, and may decrease or cause no change in conduction velocity through the AV node. Procainamide probably suppresses atrial fibrillation or flutter by prolonging the effective refractory period (ERP) and increasing the action potential duration in atrial and ventricular muscle and in the His-Purkinje system. Because prolongation of the ERP is greater than the increase in the duration of the action potential, the cardiac tissue remains refractory even after restoration of the resting membrane potential. Procainamide shortens the ERP of the AV node, and the anticholinergic action of the drug may also increase the conductivity of the AV node. The effects of procainamide on refractoriness and the action potential duration of atrial fibers may be modified by the anticholinergic effects of the drug. Procainamide decreases cardiac excitability both in diastole and in the relative refractory period by increasing the threshold potential for electrical excitation. In therapeutic plasma concentrations, procainamide causes prolongation of the PR and QT intervals, but the QRS complex is usually not prolonged beyond the normal range.
The effect of procainamide on heart rate is unpredictable, but generally the drug causes no change or slightly increases heart rate. Procainamide may have a direct negative inotropic effect, but therapeutic plasma concentrations of the drug do not usually depress contractility in the normal heart. Cardiac output is not usually decreased, except in the presence of myocardial damage. Procainamide may reduce peripheral resistance and blood pressure as a result of peripheral vasodilation. Decreased blood pressure is most likely to occur with high plasma concentrations of the drug. IV procainamide may decrease pulmonary arterial pressure. At high plasma concentrations, procainamide may produce sinus tachycardia because of reflex sympathetic response to its hypotensive effect.
Procainamide has local anesthetic properties equal to but more sustained than those of procaine. Procainamide produces less CNS stimulation than does procaine.
Plasma procainamide concentrations of approximately 4-10 mcg/mL are required to suppress ventricular arrhythmias.152, 154, 155 Plasma procainamide concentrations exceeding 10 mcg/mL are increasingly associated with toxic findings, which are observed occasionally in the 10-12 mcg/mL range, more often in the 12-15 mcg/mL range, and commonly in patients with plasma concentrations greater than 15 mcg/mL;135 however, some clinicians state that plasma procainamide concentrations of 15-20 mcg/mL may be appropriate in selected patients with careful monitoring.155 With fixed dosage, there are large interindividual variations in the plasma concentrations of procainamide. Plasma concentrations of procainamide are approximately 25% higher than blood concentrations. N -Acetylprocainamide (NAPA), a metabolite of procainamide, has antiarrhythmic activity, and plasma concentrations of this metabolite may represent more than 50% of the total drug in the plasma. If renal excretion of procainamide is prolonged and conversion to NAPA is rapid, plasma concentrations of NAPA exceed procainamide concentrations at steady-state. The suggested therapeutic range for combined procainamide and NAPA concentrations is 5-30 mcg/mL.152, 154, 155
Absorption of procainamide after IM administration is rapid, and the drug appears in the plasma in 2 minutes. Peak plasma procainamide concentrations after IM administration of the drug average 30% higher than after oral administration of the same dose. In one study in healthy individuals, peak plasma procainamide concentrations of 5-8.5 mcg/mL were attained in 15-60 minutes and plasma concentrations of 2-3 mcg/mL persisted for 6 hours after a single 1-g IM dose. The onset of action after IM administration of a single dose of the drug occurs within 10-30 minutes. In one study in patients with atherosclerotic heart disease, plasma concentrations of the drug ranged from 5.8-16 mcg/mL at the end of an IV infusion of 500 mg of procainamide hydrochloride at a rate of 50 mg/minute.
Procainamide is rapidly distributed into the CSF, liver, spleen, kidneys, lungs, muscles, brain, and heart. The apparent volume of distribution of the drug at steady state is approximately 2 L/kg. The apparent volume of distribution of procainamide is decreased in patients with heart failure. Studies using radiolabeled procainamide indicate that 14-23% of the drug is bound to plasma proteins at therapeutic plasma concentrations.155 Procainamide crosses the placenta, but the extent to which it does has not been well characterized.100, 156 Procainamide and NAPA are distributed into milk and can be absorbed by a nursing infant.135, 156
After IV administration, procainamide has an initial half-life of 4-5 minutes and a terminal half-life of 2.5-4.7 hours in individuals with normal renal function.155 The elimination half-life of procainamide may be increased in patients with renal impairment and in geriatric patients. The half-life of NAPA is 6-7 hours in patients with normal renal function.155 In patients with congestive heart failure and/or renal insufficiency, plasma concentrations of procainamide are higher and decrease more gradually.
Procainamide is acetylated, presumably in the liver, to form NAPA.154 Acetylation of procainamide is related to genetic acetylator phenotype.155 The rate of acetylation is genetically determined and varies among individuals; however, it is constant for each person.155
The total amount of unchanged procainamide excreted in urine varies from 40-70% of a dose due to differences in acetylator phenotype and in renal excretion. NAPA and 2 unidentified metabolites are also excreted in urine. Less than 0.2% of the dose is excreted in urine as either p -acetamidobenzoic acid or aminobenzoic acid. Procainamide and NAPA are excreted by active tubular secretion and glomerular filtration. The rate of renal excretion of procainamide and NAPA is not affected by changes in urine pH nor by acetylator phenotype. Rapid and slow acetylators excrete approximately the same amount of procainamide as unchanged drug, but rapid acetylators excrete more of a dose as NAPA. In patients with renal insufficiency, excretion of procainamide and NAPA is decreased. Procainamide and NAPA are removed by hemodialysis but not by peritoneal dialysis. NAPA also is removed by arteriovenous hemofiltration and by arteriovenous hemodiafiltration.125
Procainamide hydrochloride is an antiarrhythmic agent. The drug differs structurally from procaine in the replacement of the ester group of procaine with an amide group. Procainamide hydrochloride occurs as a white to tan, hygroscopic, crystalline powder and is very soluble in water and soluble in alcohol. The drug has a pKa of 9.23.
Procainamide hydrochloride injection is a sterile solution of the drug in water for injection and is colorless or has not more than a slight yellow color. Hydrochloric acid and/or sodium hydroxide is used to adjust the pH of the commercially available injection to 4-6. At the time of manufacture, the air in the vials of procainamide hydrochloride injection is replaced with nitrogen. Sodium metabisulfite is present in the injection principally to prevent discoloration caused by oxidation of p -aminobenzoic acid (a procainamide degradation product) rather than to maintain product potency.134 Sodium metabisulfite is present in the injection principally to prevent discoloration caused by oxidation of p -aminobenzoic acid (a procainamide degradation product) rather than to maintain product potency.134
Procainamide hydrochloride injections are colorless or may turn slightly yellow on standing; injection of air into vials of the drug causes darkening of the solution. Solutions of procainamide that are darker than light amber or are otherwise discolored should not be used. Although procainamide hydrochloride injection may be stored at room temperature (10-27°C), refrigeration retards oxidation and associated development of color.
When procainamide hydrochloride injection is diluted with 0.9% sodium chloride injection or sterile water for injection, solutions containing 2-4 mg/mL are stable for 24 hours at room temperature or for 7 days at 2-8°C. While solutions diluted in 5% dextrose have been described as being less stable than this secondary to possible formation of an association complex between the drug and dextrose,/127, 128, 129, 130, 131, 132, 133 and such complexation may not be readily reversible, at least in vitro,128 this phenomenon has only been observed in vitro to date and its clinical importance, if any, remains unclear.127 There is in vitro evidence indicating that complexation is pH dependent130 and that its rate and extent can be minimized by adjusting the pH of procainamide hydrochloride in 5% dextrose solutions to 7.5 with sodium bicarbonate.129 However, because this complexation has not been observed in vivo and its clinical importance has not been established, the need for such precautions remains questionable.127 Therefore, the manufacturer currently states that procainamide hydrochloride that has been diluted to a final concentration of 2-4 mg/mL in 5% dextrose can be considered stable for at least 24 hours at room temperature or for 7 days when refrigerated.127 In addition, because use of IV procainamide hydrochloride generally is limited to clinical situations in which ECG and blood pressure are monitored continuously, any potential alterations in clinical bioavailability resulting from such dilutions probably would be readily apparent.127 Procainamide hydrochloride injection has been reported to be physically incompatible with some drugs, but the compatibility depends on several factors (e.g., concentrations of the drugs, specific diluents used, resulting pH, temperature). Specialized references should be consulted for specific compatibility information.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection | 100 mg/mL* | ||
500 mg/mL* | Procainamide Hydrochloride Injection |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
100. Dumesic DA, Silverman NH, Tobias S et al. Transplacental cardioversion of fetal supraventricular tachycardia with procainamide. N Engl J Med . 1982; 307:1128-31. [PubMed 7121530]
101. Parke-Davis. Procan® SR (procainamide hydrochloride) extended-release tablets prescribing information. In: Physicians' desk reference. 49th ed. Montvale, NJ: Medical Economics Company Inc; 1995(Suppl A):134-5.
102. Mangini RJ, ed. Drug interaction facts. St. Louis: JB Lippincott Co; 1985(Jan):468.
103. Mangini RJ, ed. Drug interaction facts. St. Louis: JB Lippincott Co; 1985(Oct):469a.
104. Somogyi A, Bochner F. Dose and concentration dependent effect of ranitidine on procainamide disposition and renal clearance in man. Br J Clin Pharmacol . 1984; 18:175-81. [PubMedCentral][PubMed 6091709]
105. Martin BK. Effect of ranitidine on procainamide disposition. Br J Clin Pharmacol . 1985; 19:858-60. [PubMedCentral][PubMed 4027133]
106. Somogyi A, Bochner F. Ranitidine and procainamide absorption. Br J Clin Pharmacol . 1985; 20:182-3. [PubMedCentral][PubMed 4041340]
107. Christian CD Jr, Meredith CG, Speeg KV. Cimetidine inhibits renal procainamide clearance. Clin Pharmacol Ther . 1984; 36:221-7. [PubMed 6204803]
108. Rodvold KA, Paloucek FP, Jung D et al. Interaction of steady-state procainamide with H2-receptor antagonists cimetidine and ranitidine. Ther Drug Monit . 1987; 9:378-83. [PubMed 2447687]
109. Klotz U, Arvela P, Rosenkranz B. Famotidine, a new H2-receptor antagonist, does not affect hepatic elimination of diazepam or tubular secretion of procainamide. Eur J Clin Pharmacol . 1985; 28:671-5. [PubMed 2866097]
110. Merck Sharp & Dohme. Pepcid® product monograph. West Point, PA; 1987 July.
111. Higbee MD, Wood JS, Mead RA. Procainamide-cimetidine interaction: a potential toxic interaction in the elderly. J Am Geriatr Soc . 1984; 32:162-4. [PubMed 6693705]
112. Chremos AN. Clinical pharmacology of famotidine: a summary. J Clin Gastroenterol . 1987; 9(Suppl 2):7-12. [PubMed 2887616]
113. Somogyi A, McLean A, Heinzow B. Cimetidine-procainamide pharmacokinetic interaction in man: evidence of competition for tubular secretion of basic drugs. Eur J Clin Pharmacol . 1983; 25:339-45. [PubMed 6194997]
114. Wyeth Laboratories Inc. Cordarone® (amiodarone hydrochloride) prescribing information. In: Huff BB, ed. Physicians' desk reference. 43rd ed. Oradell, NJ: Medical Economics Company Inc; 1989:2291-4.
115. Hansten PD, Horn JR, eds. Amiodarone drug interactions. Drug Interact Newsl . 1987; 7:13-6.
116. Saal AK, Werner JA, Greene HL et al. Effect of amiodarone on serum quinidine and procainamide levels. Am J Cardiol . 1984; 53:1264-7. [PubMed 6711425]
117. Windle J, Prystowsky EN, Miles WM et al. Pharmacokinetic and electrophysiologic interactions of amiodarone and procainamide. Clin Pharmacol Ther . 1987; 41:603-10. [PubMed 3581646]
118. Pronestyl-SR® tablets (procainamide hydrochloride) sustained released tablets prescribing information. In: Barnhart ER, publisher. Physicians' desk reference. 44th ed. Oradell, NJ: Medical Economics Company Inc; 1990:1699-1701.
119. Procan® SR (procainamide hydrochloride) sustained release tablets prescribing information. In: Barnhart ER, publisher. Physicians' desk reference. 44th ed. Oradell, NJ: Medical Economics Company Inc; 1990:1651-3.
120. Pronestyl® tablets and capsules prescribing information. In: Barnhart ER, publisher. Physicians' desk reference. 44th ed. Oradell, NJ: Medical Economics Company Inc; 1990:1697-9.
121. Geneva. Pronestyl® (procainamide hydrochloride) injection prescribing information. Princeton, NJ: 1997 May.
122. Pratt CM, Brater DC, Harrell FE et al (Cardiovascular and Renal Drugs Advisory Board to the Food and Drug Administration). Clinical and regulatory implications of the cardiac arrhythmia suppression trial. Am J Cardiol . 1990; 65:103-5. [PubMed 1688479]
123. Anon. Drugs for cardiac arrhythmias. Med Lett Drugs Ther . 1989; 31:35-40. [PubMed 2565011]
124. Giannone L, Kugler JW, Krantz SB. Pure red cell aplasia associated with administration of sustained-release procainamide. Arch Intern Med . 1987; 147:1179-80. [PubMed 3036033]
125. Domoto DT, Brown WW, Bruggensmith P. Removal of toxic levels of N -acetylprocainamide with continuous arteriovenous hemofiltration or continuous arteriovenous hemodiafiltration. Ann Intern Med . 1987; 106:550-2. [PubMed 2435200]
126. Knox JP, Welykyj SE, Gradini R et al. Procainamide-induced urticarial vasculitis. Cutis . 1988; 42:469-72. [PubMed 2973973]
127. Bristol-Myers Squibb Company, Pharmaceutical Group, Princeton, NJ: personal communication.
128. Henry DW, Lacerte JA, Klutman NE et al. Irreversibility of procainamide-dextrose complex in plasma in vitro. Am J Hosp Pharm . 1991; 48:2426-9. [PubMed 1746577]
129. Raymond GG, Reed MT, Teagarden JR et al. Stability of procainamide hydrochloride in neutralized 5% dextrose injection. Am J Hosp Pharm . 1988; 45:2513-7. [PubMed 3228104]
130. Gupta DV. Complexation of procainamide with dextrose. J Pharm Sci . 1982; 71:994-6. [PubMed 7131286]
131. Gupta VD. Complexation of procainamide with hydroxide-containing compounds. J Pharm Sci . 1983; 72:205-7. [PubMed 6834262]
132. Baaske DM, Malick AW, Carter JE et al. Stability of procainamide hydrochloride in dextrose solutions. Am J Hosp Pharm . 1980; 37:1050-2. [PubMed 7405932]
133. Kirschenbaum HL, Lesko LJ, Mendes RW et al. Stability of procainamide in 0.9% sodium chloride or dextrose 5% in water. Am J Hosp Pharm . 1979; 36:1464-5. [PubMed 517523]
134. Metras JI, Swenson CF McDermott MP. Stability of procainamide hydrochloride in an extemporaneously compounded oral liquid. Am J Hosp Pharm . 1988; 49:17,20-4.
135. Monarch Pharmaceuticals. Procanbid® (procainamide hydrochloride) extended-release tablets prescribing information. Bristol, TN: 2002 Jan.
136. Teo KK, Yusuf S, Furberg CD. Effects of prophylactic antiarrhythmic drug therapy in acute myocardial infarction. JAMA . 1993; 270:1589-95. [PubMed 8371471]
137. Pratt CM, Moye L. The Cardiac Arrhythmia Suppression Trial: implications for antiarrhythmic drug development. J Clin Pharmacol . 1990; 30:967-74. [PubMed 2122983]
138. Hine LK, Laird NM, Hewitt P et al. Meta-analysis of empirical long-term antiarrhythmic therapy after myocardial infarction. JAMA . 1989; 262:3037-40. [PubMed 2509746]
139. The Cardiac Arrhythmia Suppression Trial (CAST) investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. Engl J Med . 1989; 321:406-12.
140. Ruskin JN. The Cardiac Arrhythmia Suppression Trial (CAST). N Engl J Med . 1989; 321:386-8. [PubMed 2501683]
141. Vlay SC. Lessons from the past and reflections on the Cardiac Arrhythmia Suppression Trial. Am J Cardiol . 1990; 65:112-3. [PubMed 1688480]
142. Pratt CM, Brater DC, Harrell FE Jr et al. Clinical and regulatory implications of the Cardiac Arrhythmia Suppression Trial. Am J Cardiol . 1990; 65:103-5. [PubMed 1688479]
143. Morganroth J, Bigger JT Jr, Anderson JL. Treatment of ventricular arrhythmias by United States cardiologists: a survey before the Cardiac Arrhythmia Suppression Trial results were available. Am J Cardiol . 1990; 65:40-8. [PubMed 1688481]
144. Pratt C, Ward DE, Camm AJ. Lessons from the cardiac arrhythmia suppression trial. BMJ . 1989; 299:805-6. [PubMedCentral][PubMed 2510839]
145. Coyle JD, Schaal SF. An interim perspective on the removal of encainide and flecainide from the Cardiac Arrhythmia Suppression Trial. DICP . 1989; 23:478-9. [PubMed 2500783]
146. Glaxo Wellcome. Raxar® (grepafloxacin hydrochloride) tablets prescribing information. Research Triangle Park, NC; 1997 Nov.
147. Ryan TJ, Antman EM, Brooks NH et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). From ACC website. 1996; 28:1328-428. [Web]
149. Rhone-Poulenc Rorer Pharmaceuticals, Inc. Zagam® (sparfloxacin) tablets prescribing information. Collegeville, PA; 1996 Nov.
151. Food and Drug Administration. Procanbid (procainamide HCl) extended-release tablets [July 11, 2000: King]. MedWatch drug labeling changes. Rockville, MD; July 2000. From FDA website. [Web]
152. Siberry GK, Iannone R, eds. The Harriet Lane handbook: a manual for pediatric house officers. 15th ed. St. Louis: Mosby Publishers, Inc; 2000: 826-7.
154. Gal P, Reed MD. Appendix: Medications. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson textbook of pediatrics. 17th ed. Philadelphia: Saunders; 2004:2475.
155. Pieper JA. Procainamide. In: Murphy JE, ed. Clinical pharmacokinetics. 2nd ed. Bethesda, MD: American Society of Health-System Pharmacists; 2001:305-18.
156. Procainamide. In: Briggs GG, Freeman RK, Yaffe SJ, eds. Drugs in pregnancy and lactation. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2002:1159-60.
157. Dubin A. Disturbances of rate and rhythm of the heart. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson textbook of pediatrics. 17th ed. Philadelphia: Saunders; 2004:1555.
158. Mathers LH, Frankel LR. Pediatric emergencies and resuscitation. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson textbook of pediatrics. 17th ed. Philadelphia: Saunders; 2004:295.
159. Antman EM, Anbe DT, Armstrong PW et al. ACC/AHA guidelines for the management of patients with ST-elevation acute myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). J Am Coll Cardiol . 2004; 44:671-719. [PubMed 15358045]
160. Zipes DP, Camm AJ, Borggrefe M et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). Circulation . 2006; 114:e385-484. [PubMed 16935995]
161. Hospira. Procainamide hydrochloride injection prescribing information. Lake Forest, IL: 2007 Dec
300. Page RL, Joglar JA, Caldwell MA et al. 2015 ACC/AHA/HRS Guideline for the Management of Adult Patients With Supraventricular Tachycardia: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol . 2016; 67:e27-e115.
301. January CT, Wann LS, Alpert JS et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol . 2014; 64:e1-76. [PubMed 24685669]
400. Link MS, Berkow LC, Kudenchuk PJ et al. Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation . 2015; 132(18 Suppl 2):S444-64. [PubMedCentral]
401. Neumar RW, Otto CW, Link MS et al. Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation . 2010; 122(18 Suppl 3):S729-67.
402. de Caen AR, Berg MD, Chameides L et al. Part 12: Pediatric Advanced Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation . 2015; 132(18 Suppl 2):S526-42. [PubMed 26473000]
403. Kleinman ME, Chameides L, Schexnayder SM et al. Part 14: pediatric advanced life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation . 2010; 122(18 Suppl 3):S876-908. [PubMedCentral]