Prescription Drug Information: PROCAINAMIDE HYDROCHLORIDE

PROCAINAMIDE HYDROCHLORIDE- procainamide hydrochloride injection
HF Acquisition Co LLC, DBA HealthFirst

SPL UNCLASSIFIED

Rx Only

DESCRIPTION

Procainamide Hydrochloride Injection, USP, is a sterile, nonpyrogenic solution of procainamide hydrochloride in Water for Injection. It is available in 100 mg per mL concentration. The 100 mg per mL potency contains 0.9% w/v benzyl alcohol and 0.09% sodium bisulfite as preservatives. The solution may contain hydrochloric acid and/or sodium hydroxide for pH adjustment. pH 5.0 (4.0 to 6.0). Headspace nitrogen gassed.

Procainamide hydrochloride, a Group 1A cardiac antiarrhythmic drug, is ρ-amino-N-[2-(diethylamino) ethyl] benzamide mono-hydrochloride. It has the following structural formula:

STRUCTURE
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M.W. 271.79

*(locus for acetylation to N-acetyl procainamide).

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.

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.

Following intramuscular injection, procainamide is rapidly absorbed into the bloodstream, and plasma levels peak in 15 to 60 minutes, considerably faster than orally administered procainamide hydrochloride tablets or capsules which produce peak plasma levels in 90 to 120 minutes. Intravenous administration of Procainamide Hydrochloride Injection can produce therapeutic procainamide levels within minutes after infusion is started. 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. It is not known if 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-acetylprocainamide (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 ρ-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 mcg/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 mcg/mL) of PA were found necessary for adequate control.

INDICATIONS & USAGE

Procainamide hydrochloride injection is indicated for the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia, that, in the judgement of the physician, are life-threatening. Because of the proarrhythmic effects of procainamide, its use with lesser arrhythmias is generally not recommended. Treatment of patients with asymptomatic ventricular premature contractions should be avoided.

Initiation of 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.)

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.

WARNINGS

WARNINGS
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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 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.

Sulfite Sensitivity
Procainamide Hydrochloride 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 sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

PRECAUTIONS

Blood-Pressure and ECG Monitoring

Blood pressure should be monitored with the patient supine during parenteral, especially intravenous, administration of PA (see DOSAGE AND ADMINISTRATION). There is a possibility that relatively high although transient plasma levels of PA may be attained and cause hypotension before the PA can be distributed from the plasma volume to its full apparent volume of distribution which is approximately 50 times greater. Therefore, caution should be exercised to avoid overly rapid administration of PA. If the blood pressure falls 15 mm Hg or more, PA administration should be temporarily discontinued. Electrocardiographic (ECG) monitoring is advisable as well, both for observation of the progress and response of the arrhythmia under treatment, and for early detection of any tendency to excessive widening of the QRS complex, prolongation of the P-R interval, or any signs of heart block (see OVERDOSAGE). Parenteral therapy with PA should be limited to use in hospitals in which monitoring and intensive supportive care are available, or to emergency situations in which equivalent observation and treatment can be provided.

General

Immediately after initiation of PA therapy, patients should be closely observed for possible hypersensitivity reactions. 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 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 interruption of the PA infusion 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 or infusion rate 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.

Information for Patients

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 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.

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.

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.

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, 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 pediatric patients have not been established.

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