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Following
oral administration of Procan SR tablets every 6 hours, the mean
steady-state serum concentrations of procainamide and NAPA achieved
are approximately equivalent to those of a comparable dose of the
conventional immediate-release capsule administered every 3 hours.
When 500 mg sustained-release tablets
were administered for 3 days, approximately 48% and 15% were recovered
in the urine as procainamide and NAPA, respectively. Other metabolites
e.g. free and conjugated p-aminobenzoic acid which usually account
for about 10% of the dose, were not analyzed in this study.
INDICATIONS
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No antiarrhythmic drug has been shown
to reduce the incidence of sudden death in patients with asymptomatic
ventricular arrhythmias. Most antiarrhythmic drugs have the potential
to cause dangerous arrhythmias; some have been shown to be associated
with an increased incidence of sudden death. In light of the above,
physicians should carefully consider the risks and benefits of antiarrhythmic
therapy for all patients with ventricular arrhythmias.
Ventricular Arrhythmias: For the treatment of documented
life-threatening ventricular arrhythmias, such as sustained ventricular
tachycardia. Procainamide may also be used for the treatment of
patients with documented symptomatic ventricular arrhythmias when
the symptoms are of sufficient severity to require treatment. Because
of the proarrhythmic effects of procainamide its use should be reserved
for patients in whom, in the opinion of the physician, the benefit
of treatment clearly outweighs the risks.
For patients with sustained ventricular tachycardia, procainamide
therapy should be initiated in the hospital.
Hospitalization may also be required for certain other patients
depending on their cardiac status and underlying cardiac disease.
The effects of procainamide in patients with recent myocardial infarction
have not been adequately studied and, therefore, its use in this
condition cannot be recommended.
Supraventricular Arrhythmias: In the treatment of atrial
fibrillation, particularly if the condition is of recent development
and the treatments of choice cannot be used or are ineffective.
The drug may also be used in paroxysmal atrial tachycardia which
cannot be controlled by reflex stimulation or by other measures.
CONTRAINDICATIONS
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Hypersensitivity to procainamide is
an absolute contraindication; in this connection, cross-sensitivity
to procaine and related drugs must be borne in mind. Procainamide
should not be administered to patients with complete atrioventricular
heart block; it is also contraindicated in cases of second-degree
and third-degree AV block unless an electrical pacemaker is operative.
Procainamide is also contraindicated in patients with systemic lupus
erythematosus, and should not be used in patients having “les
torsades de pointes” ventricular arrhythmias.
It has been suggested that procainamide be contraindicated in patients
with myasthenia gravis.
WARNINGS
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Mortality: The results of the
Cardiac Arrhythmia Suppression Trial (CAST) in post-myocardial infarction
patients with asymptomatic ventricular arrhythmias showed a significant
increase in mortality and in non-fatal cardiac arrest rate in patients
treated with encainide or flecainide compared with a matched placebo-treated
group.
CAST was continued using a revised protocol with the moricizine
and placebo arms only. The trial was prematurely terminated because
of a trend towards an increase in mortality in the moricizine-treated
group.
The applicability of these results to other populations or other
antiarrhythmic agents is uncertain, but at present it is prudent
to consider these results when using any antiarrhythmic agent.
Blood Dyscrasias: Agranulocytosis, bonemarrow depression,
neutropenia, hypoplastic anemia and thrombocytopenia have been reported
at a rate of approximately 0.5% in patients receiving procainamide.
Most of these patients received procainamide within the recommended
dosage range. Fatalities have occurred (with approximately 20 to
25% mortality in reported cases of agranulocytosis). Since most
of these events have been noted during the first 12 weeks of therapy,
it is recommended that complete blood counts including white cell,
differential and platelet
counts be performed at weekly intervals for the first 3 months of
therapy; and periodically thereafter. Complete blood counts should
be performed promptly if the patient develops any signs of infection
(such as fever, chills, sore throat or stomatitis), bruising or
bleeding. If any of these hematologic disorders are identified,
procainamide should be discontinued. Blood counts usually return
to normal within 1 month of discontinuation. Caution should be used
in patients with pre-existing marrow failure or cytopenia of any
type (see Adverse Effects).
Patients should be instructed to report promptly any flu-type symptoms
such as malaise and aches, as well as any soreness of the mouth,
throat or gums, unexplained fever, skin rash, unusual bleeding or
bruising, symptoms that resemble arthritis or symptoms of an upper
respiratory tract infection.
Positive Antinuclear Antibody: The prolonged administration
of procainamide often leads to the development of a positive antinuclear
antibody (ANA) test with or without symptoms of lupus erythematosus-like
syndrome. If a positive ANA titer develops, the benefit/risk ratio
related to continued procainamide therapy should be assessed.
This may necessitate a discontinuation of procainamide and substitution
of alternative antiarrhythmic therapy.
PRECAUTIONS
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General:
During administration of procainamide, evidence of untoward myocardial
responses should be carefully watched for in all patients. In the
presence of an abnormal myocardium, procainamide may at times produce
untoward responses. In atrial fibrillation or flutter, the ventricular
rate may increase suddenly as the atrial rate is slowed.
Adequate digitalization reduces, but does not abolish, this danger.
If myocardial damage exists, ventricular tachycardia is particularly
hazardous.
Correction of atrial fibrillation, with resultant forceful contractions
of the atrium, may cause a dislodgment of mural thrombi and produce
an embolic episode. However, it has been suggested that, in a patient
who is already discharging emboli, procainamide is more likely to
stop than to aggravate the process.
Attempts to adjust the heart rate in a patient who has developed
ventricular tachycardia during an occlusive coronary episode should
be carried out with extreme caution. Caution is also required in
marked disturbances of atrioventricular conduction such as AV block,
bundle branch block, or severe digitalis intoxication, where the
use of procainamide may result in additional depression of conduction
and ventricular asystole or fibrillation. Widening of QRS complex
on ECG calls for extreme caution. The effects of procainamide in
digitalis intoxication, particularly where the arrhythmia is accompanied
by marked conduction disturbances, are unpredictable and fatalities
have occurred.
Because patients with severe organic heart disease and ventricular
tachycardia may also have complete heart block, which is difficult
to diagnose under these circumstances, this complication should
always be kept in mind when treating ventricular arrhythmias with
procainamide. If the ventricular rate is significantly slowed by
procainamide without attainment of regular atrioventricular conduction,
the drug should be stopped and the patient re-evaluated because
asystole may result under these circumstances.
Serious hypotension can result from peripheral vasodilation, and
by depressing myocardial contractility and cardiac output. At high
plasma levels, procainamidemay produce sinus tachycardia due to
reflex sympathetic response to its hypotensive effect. Large doses
may increase cardiac automaticity and can induce complete atrioventricular
block, cardiac standstill or ventricular extrasystoles that may
proceed to ventricular fibrillation. These effects on the myocardium
are reflected in the ECG; a widening of the QRS complex occurs most
consistently; less regularly,
the PR and QT intervals are prolonged; the QRS and T waves show
some decrease in voltage. These actions of procainamide may be intensified
in patients with congestive heart failure.
Plasma procainamide and NAPA concentrations rise markedly with increases
in blood urea nitrogen and correlate well with creatinine clearance.
Should patients with impaired kidney function and/or liver disease
receive unadjusted dosage, symptoms of overdosage (principally ventricular
tachycardia and severe hypotension) may occur due to drug accumulation.
Similarly, plasma concentrations have been found to be increased
in elderly patients possibly due to declining renal function in
this age group. The frequency of administration should be reduced
in patients with
renal or hepatic insufficiency or in elderly patients.
Plasma concentrations of procainamide and NAPA should be monitored
in patients with renal disease, hepatic disease, cardiac failure,
or low cardiac output states.
In patients with cardiac failure or shock or in patients with low
cardiac output and extrarenal azotemia, the apparent volume of distribution
and/or the elimination rate of procainamide can decrease considerably
for a given dose, thereby resulting in increased plasma concentrations.
Such patients should therefore be carefully monitored and the dose
or frequency of administration reduced if warranted.
Antinuclear antibodies (ANA) are often found in patients receiving
long-term procainamide therapy. The induction of ANA appears to
be independent of dosage. Patients with procainamide-induced increases
in ANA titers may develop a syndrome resembling systemic lupus erythematosus
(SLE). The mechanism of this syndrome is uncertain. Polyarthralgia,
arthritic symptoms, fever, skin lesions and pleuritic pain are common
symptoms; to a lesser extent, myalgia, pleural effusion, pericarditis,
headache, fatigue, weakness, nausea, and abdominal pain may occur.
Rare cases of thrombocytopenia, Coombs’ positive hemolytic
anemia, increased AST, ALT, and serum amylase have been reported
which may be related to this SLE-like syndrome.
It is recommended that tests for SLE be carried out at regular intervals
in patients receiving maintenance procainamide therapy. The drug
should be discontinued if there is rising ANA titer or clinical
symptoms of SLE appear. The SLE-like syndrome may be reversible
upon discontinuation of the drug. If discontinuation does not cause
remission of the symptoms, corticosteroid therapy may be effective.
If the SLE-like syndrome develops in a patient with recurrent life-threatening
arrhythmias not controllable by other antiarrhythmic agents, corticosteroid
suppressive
therapy may be used concomitantly with procainamide.
Pregnancy: Animal reproduction studies have not been conducted
with procainamide. It is also not known whether procainamide can
cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity.
There has been some evidence of the diffusion of procainamide across
the placental membrane. Therefore, due to the potential accumulation
and slow rate of elimination of procainamide and N-acetylprocainamide
in the fetus, the potential benefit of the use of procainamide during
pregnancy should be weighed against the possible hazard to the fetus.
Lactation: Both procainamide and N-acetylprocainamide are
secreted 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.
Children: Safety and effectiveness in children have not been
established.
Drug Interactions: Antiarrhythmics: Concurrent use with procainamide
may result in additive cardiac effects and/or additive toxic effects.
In acute myocardial infarctions procainamide may potentiate the
cardiac depressant action of beta blocking agents such as propranolol.
Anticholinergics: Procainamide enhances the anticholinergic
effects. Extreme caution must be exercised with such a combination.
Anticholinesterases: Procainamide antagonizes the effect of anticholinesterases
in myasthenia gravis, and paralysis returns.
Antihypertensives: Procainamide may potentiate the hypotensive
effects of thiazide diuretics and other antihypertensive agents.
Adjustment of dosage may be required.
Cimetidine: It has been reported that the histamine H2-antagonist
cimetidine reduces renal clearance of procainamide and NAPA resulting
in higher plasma concentrations for longer durations. Caution should
be exercised when administering these drugs concurrently especially
in the elderly who have a reduced ability to clear all three. Dosage
modification may be required.
Neuromuscular Blocking Agents: Procainamide potentiates the
effects of skeletal muscle relaxants such as succinylcholine.
It also may enhance or prolong the neuromuscular blocking activity
of bacitracin, colistimethate, dihydrostreptomycin, gentamicin,
gramicidin, kanamycin, neomycin, polymyxin B, streptomycin and viomycin,
producing respiratory depression.
Antibiotics: Procainamide has also been reported to interact
with kanamycin, neomycin and streptomycin to cause apnea and muscle
weakness, due to an additive neuromuscular blocking effect.
ADVERSE
EFFECTS
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The
overall incidence of adverse effects with procainamide is about
9.2%. The most commonly occurring are gastrointestinal upset 3.9%,
cardiovascular effects (ventricular dysrhythmias, bradycardia, hypotension
and shock) 3.3% and drug fever 1.6%.
The most serious adverse reactions reported are granulocytopenia
and the development of antinuclear antibodies (ANA). Granulocytopenia
is most likely to occur within the first 3 months of therapy. Prolonged
administration of procainamide often leads to the development of
a positive ANA test with or without symptoms of lupus erythematosus
like syndrome (see Warnings).
Incidence greater than 1%: elevated ANA, sometimes associated
with drug-induced lupus syndrome.
Gastrointestinal symptoms, especially with large oral doses: anorexia,
nausea, vomiting, diarrhea.
Cardiovascular Effects: bradycardia, arrhythmias, cardiac failure,
shock.
Hypersensitivity reactions, which may be manifested by one or more
of the following: pruritus, urticaria, angioneurotic edema, maculopapular
rash, fever, eosinophilia, hypergammaglobulinemia.
Incidence less than 1%: granulocytopenia (incidence about 0.5%),
sometimes resulting in death, thrombocytopenia, immune hemolytic
anemia, convulsions, psychosis with hallucinations, confusion, mental
depression, giddiness, light-headedness, weakness, bitter taste.
Rare: hypotension. A case was reported with fever and chills,
plus nausea, vomiting, abdominal pain, acute hepatomegaly
and a rise in serum glutamic oxaloacetic transaminase following
a single dose of the drug. Vasculitis (hypersensitivity-type).
OVERDOSAGE
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Symptoms:
Signs and symptoms of overdosage of procainamide include severe
hypotension, ventricular fibrillation, widening of the QRS complex,
junctional tachycardia, intraventricular conduction delay, oliguria,
lethargy, confusion, nausea and vomiting.
Treatment: If ingestion is recent, gastric lavage or emesis
may reduce absorption. Dopamine, phenylephrine or norepinephrine
may be helpful in reversing severe hypotensive responses. Management
of overdosage includes symptomatic treatment with ECG and blood
pressure monitoring. Procainamide toxicity can usually be treated,
if necessary, by administering vasopressors after adequate fluid
volume replacement. I.V. infusion of 1/6 molar sodium lactate injection
reportedly reduces the cardiotoxic effects of procainamide.
The urinary elimination of procainamide is proportional to the glomerular
filtration rate but is also affected by changes in urinary pH. Procainamide
is relatively lipid-soluble as a free base but the ionized form
is not. Acid urine, therefore, leads to ion trapping of procainamide
which enters the urine by passive diffusion from the plasma.
Accordingly, renal clearance of procainamide can be considerably
increased by maintaining a low urinary pH and high flow rates.
If procainamide toxicity causes severe hypotension and renal insufficiency,
urinary elimination of procainamide and NAPA is decreased and hemodialysis
may be required. Hemodialysis significantly reduces the serum half-life
of procainamide and effectively removes procainamide and NAPA. Peritoneal
dialysis is not effective.
Overdosage symptoms may result following a single 2 g dose of conventional
immediate-release procainamide; 3 g may be dangerous, especially
if patient is a slow acetylator, has decreased renal function or
underlying organic heart disease.
It has been reported that 1 patient who ingested approximately 7
g of procainamide recovered after treatment consisting of i.v. norepinephrine,
i.v. furosemide, attempted volume expansion with albumin, and hemodialysis.
Also reported, is the case of an elderly patient who recovered after
ingestion of approximately 19 g of procainamide.
The patient was treated with i.v. isoproterenol and i.v. epinephrine.
The latter report suggested that insertion of a ventricular pacing
electrode is a reasonable precautionary measure in case high grade
SV block develops.
DOSAGE
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Procan
SR is a sustained release dosage form not intended for initial therapy.
For initial therapy by oral administration, conventional oral formulations
of procainamide are recommended. Patients stabilized to an appropriate
dosage level can be transferred to an equivalent daily dosage regimen
of Procan SR tablets.
Procan SR tablets should not be crushed or chewed as this would
interfere with the designed dissolution characteristics.
The tablet matrix of Procan SR may be seen in the stool since it
does not disintegrate following release of procainamide.
The duration of action of procainamide supplied in this sustained-release
dosage form allows dosing at intervals
of every 6 hours, which may encourage patient compliance.
In elderly patients and in patients with impaired renal function
(decreased creatinine clearance) excretion is delayed and reduced
frequency of administration is required (see Precautions).
Atrial Fibrillation and Paroxysmal Atrial Tachycardia: Suggested
Titration Dosage: (Standard tablets should be used.) Initial dose
of 1.25 g of standard oral procainamide preparation, followed in
1 hour by 0.75 g if there have been no ECG changes, and then given
at a dose of 0.5 to 1 g every 2 hours until arrhythmia is interrupted
or the limit of tolerance is reached.
Ventricular Tachycardia: Suggested Titration Dosage: (Standard
tablets should be used.) Initial dose of 1 g of standard oral procainamide
preparation, followed by total daily dose of 50 mg/kg of body weight,
given in divided doses at 3-hour intervals, to be increased until
arrhythmia is interrupted or the limit of tolerance is reached.
Suggested Maintenance Dosage of Procan SR: 50 mg/kg of body
weight daily given in divided doses at 6-hour intervals starting
2 to 3 hours after the last dose of standard oral procainamide.
Although the dosage for each patient must be determined on an individual
basis, Table 1 may be used as a guide for providing the total daily
dosage using Procan SR.
Table 1: Procan SR
Suggested Maintenance Dosage
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Patient’s
Weight
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Approximate
Total Daily Dosage
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Dosage with
Procan SR
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<55 kg
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2 000 mg
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Two 250 mg tablets or one 500
mg tablet q6h |
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55 to 91 kg
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3 000 mg
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One 750 mg tablet q6h |
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>91 kg
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4 000 mg
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Two 500 mg tablets q6h |
SUPPLIED
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250 mg: Each elliptical, green,
film-coated, sustained-release tablet, imprinted PROCAN SR 250 mg,
contains: procainamide HCl 250 mg. Nonmedicinal ingredients: carnauba
wax, hydrogenated soybean oil, lactose, magnesium stearate and silicon
dioxide colloidal; coating: candelilla wax, hydroxypropyl methylcellulose,
methylparaben, opaspray green, polyethylene glycol, propylparaben
and vanillin. Energy: 2.67 kJ (0.64 kcal). Sodium: <1 mmol (0.04
mg). Gluten-, sulfite- and tartrazine-free. Bottles of 100.
500 mg: Each elliptical, yellow, scored, film-coated, sustained-release
tablet, imprinted PROCAN SR 500 mg, contains: procainamide HCl 500
mg. Nonmedicinal ingredients: carnauba wax, magnesium stearate,
polyethylene glycol, silicon dioxide colloidal and sugar; coating:
candelilla wax, hydroxypropyl methylcellulose, methylparaben, opaspray
yellow, polyethylene glycol, propylparaben and vanillin. Energy:
2.31 kJ (0.55 kcal). Sodium: <1 mmol (0.06 mg). Gluten-, lactose-,
sulfite- and tartrazine-free. Bottles of 100.
750 mg: Each elliptical, orange, scored, film-coated, sustained-release
tablet, imprinted PROCAN SR 750 mg, contains: procainamide HCl 750
mg. Nonmedicinal ingredients: carnauba wax, magnesium stearate,
polyethylene glycol and silicon dioxide colloidal; coating: alcohol,
candelilla wax, hydroxypropyl methylcellulose, opaspray medium orange,
polyethylene glycol, propylene glycol and vanillin. Energy: 0 kcal.
Sodium: <1 mmol (0.07 mg). Gluten-, lactose-, paraben, sulfite-
and tartrazine-free. Bottles of 100.
Protect from moisture. Store at controlled room temperature, 15
to 30°C.
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