Prescription Drugs

CLINICAL PHARMACOLOGY Procainamide (PA) increases the effective refractory period of the atria, and to a lesser extent the bundle of His-Purkinje system and ventricles of the heart. It reduces impulse conduction velocity in the atria, His-Purkinje fibers, and ventricular muscle, but has variable effects on the atrioventricular (A-V) node, a direct slowing action and a weaker vagolytic effect which may speed A-V conduction slightly. Myocardial excitability is reduced in the atria. Purkinje fibers, papillary muscles, and ventricles by an increase in the threshold for excitation, combined with inhibition of ectopic pacemaker activity by retardation of the slow phase of diastolic depolarization, thus decreasing automaticity especially in ectopic sites. Contractility of the undamaged heart is usually not affected by therapeutic concentrations, although slight reduction of cardiac output may occur, and may be significant in the presence of myocardial damage. Therapeutic levels of PA may exert vagolytic effects and produce slight acceleration of heart rate, while high or toxic concentrations may prolong A-V conduction time or induce A-V block, or even cause abnormal automaticity and spontaneous firing, by unknown mechanisms. The electrocardiogram may reflect these effects by showing slight sinus tachycardia (due to the anticholinergic action) and widened QRS complexes and, less regularly, prolonged Q-T and P-R intervals (due to longer systole and slower conduction), as well as some decrease in QRS and T wave amplitude. These direct effects of PA on electrical activity, conduction, responsiveness, excitability and automaticity are characteristic of a Group 1A antiarrhythmic agent, the prototype for which is quinidine; PA effects are very similar. However, PA has weaker vagal blocking action than does quinidine, does not induce alpha-adrenergic blockade, and is less depressing to cardiac contractility. Ingested PA is resistant to digestive hydrolysis, and the drug is well absorbed from the entire small intestinal surface, but individual patients vary in their completeness of absorption of PA. Following oral administration q6h, procainamide hydrochloride extended-release tablets achieve a mean steady state of procainamide (as well as procainamide plus N-acetyl procainamide) serum concentrations approximately equivalent to those from a comparable dose of an immediate-release (conventional) dosage form given q3h. Procainamide hydrochloride extended-release tablets result in a significantly later time to peak plasma concentration when compared to immediate-release dosage forms. About 15 to 20 percent of PA is reversibly bound to plasma proteins, and considerable amounts are more slowly and reversibly bound to tissues of the heart, liver, lung, and kidney. The apparent volume of distribution eventually reaches about 2 liters per kilogram body weight with a half-time of approximately five minutes. While PA has been shown in the dog to cross the blood-brain barrier, it did not concentrate in the brain at levels higher than in plasma. PA crosses the placenta. Plasma esterases are far less active in hydrolysis of PA than of procaine. The half-time for elimination of PA is three to four hours in patients with normal renal function, but reduced creatinine clearance and advancing age each prolong the half-time of elimination of PA. A significant fraction of the circulating PA may be metabolized in hepatocytes to N-acetyl procainamide (NAPA), ranging from 16 to 21 percent of an administered dose in “slow acetylators” to 24 to 33 percent in “fast-acetylators”. Since NAPA also has significant antiarrhythmic activity and somewhat slower renal clearance than PA, both hepatic acetylation rate capability and renal function, as well as age, have significant effects on the effective biologic half-time of therapeutic action of administered PA and the NAPA derivative. Trace amounts may be excreted in the urine as free and conjugated p-aminobenzoic acid, 30 to 60 percent as unchanged PA, and 6 to 52 percent as the NAPA derivative. Both PA and NAPA are eliminated by active tubular secretion as well as by glomerular filtration. Action of PA on the central nervous system is not prominent, but high plasma concentrations may cause tremors. While therapeutic plasma levels for PA have been reported to be 3 to 10 µg/mL, certain patients such as those with sustained ventricular tachycardia, may need higher levels for adequate control. This may justify the increased risk of toxicity (see OVERDOSAGE). Where programmed ventricular stimulation has been used to evaluate efficacy of PA in preventing recurrent ventricular tachyarrhythmias, higher plasma levels (mean, 13.6 µg/mL) of PA were found necessary for adequate control.

PRONESTYL (procainamide hydrochloride) Capsule, Gelatin Coated PRONESTYL (procainamide hydrochloride) Tablet, Film Coated WARNING 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. DESCRIPTION PRONESTYL (procainamide hydrochloride), a Group 1A cardiac antiarrhythmic drug, is p-amino-N-{2-(diethylamino)ethyl}-benzamide monohydrochloride, molecular weight 271.79; its graphic formula is: *(locus for acetylation to N-acetylprocainamide) It differs from procaine which is the p-aminobenzoyl ester of 2-(diethylamino)-ethanol. Procainamide as the free base has a pKa of 9.23; the monohydrochloride is very soluble in water. PRONESTYL (procainamide hydrochloride) is supplied for oral administration as capsules and tablets in potencies of 250, 375, and 500 mg. Inactive ingredients: Tablets—calcium silicate, microcrystalline cellulose, colorants (FD&C Yellow No. 5 (tartrazine) and Yellow No. 6), flavor, povidone, pregelatinized starch, stearic acid, and other ingredients. Capsules—colorants (D&C Yellow No. 10, except 375 mg; FD&C Yellow No. 6), gelatin, lactose (except 500 mg); magnesium stearate, talc, and titanium dioxide.

INDICATIONS PRONESTYL (procainamide hydrochloride) is indicated for the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia, that, in the judgment of the physician, are life-threatening. Because of the proarrhythmic effects of PRONESTYL (procainamide) , its use with lesser arrhythmias is generally not recommended. Treatment of patients with asymptomatic ventricular premature contractions should be avoided. Initiation of PRONESTYL (procainamide) treatment, as with other antiarrhythmic agents used to treat life-threatening arrhythmias, should be carried out in the hospital. Antiarrhythmic drugs have not been shown to enhance survival in patients with ventricular arrhythmias. Because procainamide has the potential to produce serious hematological disorders (0.5 percent) particularly leukopenia or agranulocytosis (sometimes fatal), its use should be reserved for patients in whom, in the opinion of the physician, the benefits of treatment clearly outweigh the risks. (See WARNINGS and Boxed WARNING.) DOSAGE AND ADMINISTRATION The oral dose and interval of administration should be adjusted for the individual patient, based on clinical assessment of the degree of underlying myocardial diseased, the patient's age, and renal function. As a general guide, for younger adult patients with normal renal function, an initial total daily oral dose of up to 50 mg/kg of body weight of PRONESTYL (procainamide) Capsules or Tablets may be used, given in divided doses, every three hours, to maintain therapeutic blood levels. For older patients, especially those over 50 years of age, or for patients with renal, hepatic, or cardiac insufficiency, lesser amounts or longer intervals may produce adequate blood levels, and decrease the probability of occurrence of dose-related adverse reactions. The total daily dose should be administered in divided doses at three, four, or six hour intervals and adjusted according to the patient's response. To provide approximately 50 mg per kg of body weight per day* Patients weighing lb kg 88-110 40-50 250 mg q3h to 500 mg q6h 132-154 60-70 375 mg q3h to 750 mg q6h 176-198 80-90 500 mg q3 hr to 1 g q6h > 220 > 100 625 mg q3h to 1.25 g q6h *Initial dosage schedule guide only, to be adjusted for each patient individually, based on age, cardiorenal function, blood level (if available), and clinical response. HOW SUPPLIED PRONESTYL Capsules (Procainamide Hydrochloride Capsules USP) 250 mg: two-piece yellow gelatin capsules printed with 758 bottles of 100 NDC 0003-0758-50 bottles of 1000 NDC 0003-0758-80 cartons of 100 Unimatic* unit-dose capsules NDC 0003-0758-53 375 mg: white and orange gelatin capsules printed with 756 bottles of 100 NDC 0003-0756-50 cartons of 100 Unimatic* unit-dose capsules NDC 0003-0756-53 500 mg: yellow and orange gelatin capsules printed with 757 bottles of 100 NDC 0003-0757-50 bottles of 1000 NDC 0003-0757-80 cartons of 100 Unimatic* unit-dose capsules NDC 0003-0757-53 PRONESTYL Tablets (Procainamide Hydrochloride Tablets USP) 250 mg: yellow FILMLOK® tablets debossed with 431 bottles of 100 NDC 0003-0431-50 375 mg: orange FILMLOK® tablets debossed with 434 bottles of 100 NDC 0003-0434-50 500 mg: red FILMLOK® tablets debossed with 438 bottles of 100 NDC 0003-0438-50 Storage Store at room temperature; avoid excessive heat (104° F); protect from moisture. APOTHECON® A Bristol-Myers Squibb Company, Princeton, NJ 08540.

PATIENT INFORMATION The physician is advised to explain to the patient that close cooperation in adhering to the prescribed dosage schedule is of great importance in controlling the cardiac arrhythmia safely. The patient should understand clearly that more medication is not necessarily better and may be dangerous, that skipping doses or increasing intervals between doses to suit personal convenience may lead to loss of control of the heart problem, and that “making up” missed doses by doubling up later may be hazardous. The patient should be encouraged to disclose any past history of drug sensitivity, especially to procaine or other local anesthetic agents, or aspirin, and to report any history of kidney disease, congestive heart failure, myasthenia gravis, liver disease, or lupus erythematosus. The patient should be counseled to report promptly any symptoms of arthralgia, myalgia, fever, chills, skin rash, easy bruising, sore throat or sore mouth, infections, dark urine or icterus, wheezing, muscular weakness, chest or abdominal pain, palpitations, nausea, vomiting, anorexia, diarrhea, hallucinations, dizziness, or depression.

OVERDOSE Progressive widening of the QRS complex, prolonged Q-T and P-R intervals, lowering of the R and T waves, as well as increasing A-V block, may be seen with doses which are excessive for a given patient. Increased ventricular extrasystoles, or even ventricular tachycardia or fibrillation may occur. After intravenous administration but seldom after oral therapy, transient high plasma levels of PA may induce hypotension, affecting systolic more than diastolic pressures, especially in hypertensive patients. Such high levels may also produce central nervous depression, tremor, and even respiratory depression. Plasma levels above 10 µg/mL are increasingly associated with toxic findings, which are seen occasionally in the 10 to 12 µg/mL range, more often in the 12 to 15 µg/mL range, and commonly in patients with plasma levels greater than 15 µg/mL. Overdosage symptoms may result following a single 2 g dose while 3 g may be dangerous, especially if the patient is a slow acetylator, has decreased renal function, or underlying organic heart disease. Treatment of overdosage or toxic manifestations includes general supportive measures, close observation, monitoring of vital signs and possibly intravenous pressor agents and mechanical cardiorespiratory support. If available, PA and NAPA plasma levels may be helpful in assessing the potential degree of toxicity and response to therapy. Both PA and NAPA are removed from the circulation by hemodialysis but not peritoneal dialysis. No specific antidote for PA is known. CONTRAINDICATIONS Complete Heart Block Procainamide should not be administered to patients with complete heart block because of its effects in suppressing nodal or ventricular pacemakers and the hazard of asystole. It may be difficult to recognize complete heart block in patients with ventricular tachycardia, but if significant slowing of ventricular rate occurs during PA treatment without evidence of A-V conduction appearing, PA should be stopped. In cases of second degree A-V block or various types of hemiblock, PA should be avoided or discontinued because of the possibility of increased severity of block, unless the ventricular rate is controlled by an electrical pacemaker. Idiosyncratic Hypersensitivity In patients sensitive to procaine or other ester-type local anesthetics, cross sensitivity to PA is unlikely; however, it should be borne in mind, and PA should not be used if it produces acute allergic dermatitis, asthma, or anaphylactic symptoms. Lupus Erythematosus An established diagnosis of systemic lupus erythematosus is a contraindication to PA therapy, since aggravation of symptoms is highly likely. Torsades de Pointes In the unusual ventricular arrhythmia called “les torsades de pointes” (Twistings of the points), characterized by alternation of one or more ventricular premature beats in the directions of the QRS complexes on ECG in persons with prolonged Q-T and often enhanced U waves, Group 1A antiarrhythmic drugs are contraindicated. Administration of PA in such cases may aggravate this special type of ventricular extrasystole or tachycardia instead of suppressing it.

SIDE EFFECTS Cardiovascular Hypotension following oral PA administration is rare. Hypotension and serious disturbances of cardiorhythm such as ventricular asystole or fibrillation are more common after (see OVERDOSAGE, WARNINGS). Second degree heart block has been reported in 2 of almost 500 patients taking PA orally. Multisystem A lupus erythematosus-like syndrome of arthralgia, pleural or abdominal pain, and some-times arthritis, pleural effusion, pericarditis, fever, chills, myalgia, and possibly related hematologic or skin lesions (see below) is fairly common after prolonged PA administration, perhaps more often in patients who are slow acetylators (see Boxed WARNINGS and PRECAUTIONS). While some series have reported less than 1 in 500, others have reported the syndrome in up to 30 percent of patients on long term oral PA therapy. If discontinuation of PA does not reverse the lupoid symptoms, corticosteroid treatment may be effective. Hematologic Neutropenia, thrombocytopenia, or hemolytic anemia may rarely be encountered. Agranulocytosis has occurred after repeated use of PA, and deaths have been reported. (See Boxed WARNING, WARNINGS section.) Skin Angioneurotic edema, urticaria, pruritus, flushing, and maculopapular rash have also occurred occasionally. Gastrointestinal Anorexia, nausea, vomiting, abdominal pain, bitter taste, or diarrhea may occur in 3 to 4 percent of patients taking oral procainamide. Elevated Liver Enzymes Elevations of transaminase with and without elevations of alkaline phosphatase and bilirubin have been reported. Some patients have had clinical symptoms (e.g., malaise, right upper quadrant pain). Deaths from liver failure have been reported. Nervous System Dizziness or giddiness, weakness, mental depression, and psychosis with hallucinations have been reported occasionally. DRUG INTERACTIONS If other antiarrhythmic drugs are being used, additive effects on the heart may occur with PA administration, and dosage reduction may be necessary (see WARNINGS). Anticholinergic drugs administered concurrently with PA may produce additive antivagal effects on A-V nodal conduction, although this is not as well documented for PA as for quinidine. Patients taking PA who require neuromuscular blocking agents such as succinylcholine may require less than usual doses of the latter, due to PA effects on reducing acetylcholine release. Drug/Laboratory Test Interactions Suprapharmacologic concentrations of lidocaine and meprobamate may inhibit fluorescence of PA and NAPA, and propranolol shows a native fluorescence close to the PA/NAPA peak wavelengths, so that tests which depend on fluorescence measurement may be affected.

WARNINGS Mortality In the National Heart, Lung and Blood Institute's Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multicentered, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had had myocardial infarctions more than six days but less than two years previously, an excessive mortality or non-fatal cardiac arrest rate was seen in patients treated with encainide or flecainide (56/730) compared with that seen in patients assigned to matched placebo-treated groups (22/725). The average duration of treatment with encainide or flecainide in this study was ten months. The applicability of these results to other populations (e.g., those without recent myocardial infarctions) or to other antiarrhythmic drugs is uncertain, but at present it is prudent to consider any antiarrhythmic agent to have a significant risk in patients with structural heart disease. Blood Dyscrasias Agranulocytosis, bone marrow depression, neutropenia, hypoplastic anemia and thrombocytopenia in patients receiving procainamide hydrochloride have been reported at a rate of approximately 0.5 percent. Most of these patients received procainamide within the recommended dosage range. Fatalities have occurred (with approximately 20-25 percent 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 three 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 these hematologic disorders are identified, procainamide therapy should be discontinued. Blood counts usually return to normal within one month of discontinuation. Caution should be used in patients with pre-existing marrow failure of cytopenia of any type. (See ADVERSE REACTIONS.) Digitalis Intoxication Caution should be exercised in the use of procainamide in arrhythmias associated with digitalis intoxication. Procainamide can suppress digitalis-induced arrhythmias; however, if there is concomitant marked disturbance of atrioventricular conduction, additional depression of conduction and ventricular asystole or fibrillation may result. Therefore, use of procainamide should be considered only if discontinuation of digitalis, and therapy with potassium, lidocaine, or phenytoin are ineffective. First Degree Heart Block Caution should be exercised also if the patient exhibits or develops first degree heart block while taking PA, and dosage reduction is advised in such cases. If the block persists despite dosage reduction, continuation of PA administration must be evaluated on the basis of current benefit versus risk of increased heart block. Predigitalization for Atrial Flutter or Fibrillation Patients with atrial flutter or fibrillation should be cardioverted or digitalized prior to PA administration to avoid enhancement of A-V conduction which may result in ventricular rate acceleration beyond tolerable limits. Adequate digitalization reduces but does not eliminate the possibility of sudden increase in ventricular rate as the atrial rate is slowed by PA in these arrhythmias. Congestive Heart Failure For patients in congestive heart failure, and those with acute ischemic heart disease or cardiomyopathy, caution should be used in PA therapy, since even slight depression of myocardial contractility may further reduce cardiac output of the damaged heart. Concurrent Other Antiarrhythmic Agents Concurrent use of PA with other Group 1A antiarrhythmic agents such as quinidine or disopyramide may produce enhanced prolongation of conduction or depression of contractility and hypotension, especially in patients with cardiac decompensation. Such use should be reserved for patients with serious arrhythmias unresponsive to a single drug and employed only if close observation is possible. Renal insufficiency Renal insufficiency may lead to accumulation of high plasma levels from conventional oral doses of PA, with effects similar to those of overdosage (see OVERDOSAGE), unless dosage is adjusted for the individual patient. Myasthenia Gravis Patients with myasthenia gravis may show worsening of symptoms from PA due to its procaine-like effect on diminishing acetylcholine release at skeletal muscle motor nerve endings, so that PA administration may be hazardous without optimal adjustment of anticholinesterase medications and other precautions. PRECAUTIONS General Immediately after initiation of PA therapy, patients should be closely observed for possible hypersensitivity reactions, especially if procaine or local anesthetic sensitivity is suspected, and for muscular weakness if myasthenia gravis is a possibility. In conversion of atrial fibrillation to normal sinus rhythm by any means, dislodgement of mural thrombi may lead to embolization, which should be kept in mind. After a day or so, steady state plasma PA levels are produced following regular oral administration of a given dose of PRONESTYL (Procainamide Hydrochloride Tablets; Procainamide Hydrochloride Capsules) at set intervals, with peak plasma concentrations at about 90 to 120 minutes after each dose. After achieving and maintaining therapeutic plasma concentrations and satisfactory electrocardiographic and clinical responses, continued frequent periodic monitoring of vital signs and electrocardiograms is advised. If evidence of QRS widening of more than 25 percent or marked prolongation of the Q-T interval occurs, concern for overdosage is appropriate, and reduction in dosage is advisable if a 50 percent increase occurs. Elevated serum creatinine or urea nitrogen, reduced creatinine clearance, or history of renal insufficiency, as well as use in older patients (over age 50), provide grounds to anticipate that less than the usual dosage and longer time intervals between doses may suffice, since the urinary elimination of PA and NAPA may be reduced, leading to gradual accumulation beyond normally predicted amounts. If facilities are available for measurement of plasma PA and NAPA, or acetylation capability, individual dose adjustment for optimal therapeutic levels may be easier, but close observation of clinical effectiveness is the most important criterion. In the longer term, periodic complete blood counts are useful to detect possible idiosyncratic hematologic effects of PA on neutrophil, platelet or red cell homeostasis; agranulocytosis has been reported to occur occasionally in patients on long-term PA therapy. A rising titer of serum ANA may precede clinical symptoms of the lupoid syndrome (see Boxed WARNINGS and ADVERSE REACTIONS). If the lupus erythematosus-like syndrome develops in a patient with recurrent life-threatening arrhythmias not controlled by other agents, corticosteroid suppressive therapy may be used concomitantly with PA. Since the PA-induced lupoid syndrome rarely includes the dangerous pathologic renal changes, PA therapy may not necessarily have to be stopped unless the symptoms of serositis and the possibility of further lupoid effects are of greater risk then the benefit of PA in controlling arrhythmias. Patients with rapid acetylation capability are less likely to develop the lupoid syndrome after prolonged PA therapy. PRONESTYL Tablets (Procainamide Hydrochloride Tablets) contain FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity. Laboratory Tests Laboratory tests such as complete blood count (CBC), electrocardiogram, and serum creatinine or urea nitrogen may be indicated, depending on the clinical situation, and periodic rechecking of the CBC and ANA may be helpful in early detection of untoward reactions. Carcinogenesis, Mutagenesis, Impairment of Fertility Long term studies in animals have not been performed. Teratogenic Effects: Pregnancy Category C Animal reproduction studies have not been conducted with PA. It also is not known whether PA can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PA should be given to a pregnant woman only if clearly needed. Nursing Mothers Both PA and NAPA are excreted in human milk, and absorbed by the nursing infant. Because of the potential for serious adverse reactions in nursing infants, a decision to discontinue nursing or the drug should be made, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in children have not been established.