PROCAINAMIDE HCL
DESCRIPTION:
WARNINGS:
Positive ANA Titer: 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.
Pronestyl (Procainamide Hydrochloride Extended- Release Tablets), a Group 1A
cardiac antiarrhythmic drug, is p-amino- N(2-(diethylamino) ethyl)benzamide
monohydrochloride, molecular weight 271.79.
Procainamide hydrochloride differs from procaine which is the p-aminobenzoyl
ester of 2-(diethylamino)-ethanol. Procainamide as the free base has a pKa of
9.24; the monohydrochloride is very soluble in water.
Pronestyl (Procainamide Hydrochloride Extended- Release Tablets) contains 500 mg
or 1000 mg of procainamide hydrochloride for oral administration. The release of
procainamide hydrochloride is controlled by 2 mechanisms using T-Kote(TM)
technology. The core of the tablet consists of a wax matrix which is then coated
with a polymeric, control-release layer. Both strengths of Pronestyl contain
black iron oxide; candelilla wax, FCC; carnauba wax, NF; colloidal silicon
dioxide, NF; hydroxypropyl cellulose, NF; hydroxypropylmethyl cellulose;
magnesium stearate, NF; polyacrylate dispersion; polyethylene glycol 3350, NF;
polyethylene glycol 8000, NF; propylene glycol; simethicone emulsion, USP; talc,
USP; and titanium dioxide.
ACTIONS/CLINICAL PHARMACOLOGY:
MECHANISM OF ACTION: 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 that 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 automatically 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.
PHARMACOKINETICS AND DRUG METABOLISM
ABSORPTION/BIOAVAILABILITY: PA is well absorbed following oral administration.
The absolute bioavailability from immediate-release PA HCl capsules is
approximately 85% in patients and healthy subjects. Bioavailability of Pronestyl
is similar to that of PA HCl extended-release tablets, USP (Procan(R)SR) which
have been shown to be similar to that of immediate-release PA.
The Pronestyl T-Kote(TM) delivery system is designed to control the rate of PA
release such that absorption is sustained throughout a 12-hour dosing interval.
After administration of Pronestyl with a high-fat meal, the extent of PA
absorption was increased by about 20%. Peak, trough, and average plasma PA
concentrations following twice daily administration of Pronestyl to healthy
subjects are similar to those achieved when Procan SR is administered 4 times
daily (Figure 1). In patients with frequent ventricular premature
depolarizations (VPDs), peak and steady-state average PA concentrations
following administration of Pronestyl every 12 hours are bioequivalent to those
following administration of an equivalent daily dose of Procan SR. While
corresponding minimum concentrations are slightly lower than those for Procan
SR, they remain within the acceptable therapeutic range of 3 to 10 mcg/mL.
Figure 1. Mean Steady-State Plasma Concentrations Following Administration of
Two 1000-mg Pronestyl Tablets Every 12 Hours or One 1000-mg Procan SR Tablet
Every 6 Hours to Patients with VPDs.
Twice-daily administration of two 1000-mg Pronestyl tablets to patients with
frequent VPDs produced a mean plasma PA concentration of 4.6 mcg/mL. Average
peak and trough levels are within the generally accepted therapeutic range of 3
to 10 mcg/mL. Relative proportions of PA and N- acetylprocainamide (NAPA) during
administration of Pronestyl are similar to those following administration of
immediate-release PA or Procan SR.
DISTRIBUTION: Plasma protein binding of PA is insignificant, approximately 20%.
The apparent volume of distribution is approximately 2 L/kg. It is not known if
PA crosses the placenta.
METABOLISM/EXCRETION: The elimination half-life of PA is 3 to 4 hours in
patients with normal renal function, but reduced renal function prolongs the
half-life (see Special Populations). PA is mainly eliminated intact by the
kidneys. The only metabolite of any significance is N- acetylprocainamide
(NAPA). Renal excretion accounts for >80% of the elimination of NAPA.
Approximately 16 to 21% of PA is metabolized to NAPA in "slow acetylators"; in
"rapid acetylators" the range is 24 to 33%. In white and black populations the
numbers of rapid and slow acetylators are about 50%. The plasma concentration of
NAPA is lower than the PA concentration in most individuals. The reverse may
occur in individuals forming more of the metabolite while also having reduced
kidney function. NAPA has significant antiarrhythmic activity.
An average of 65% of the dose was recovered as intact drug in the urine after
intravenous administration of PA. The renal clearance of PA ranged from 400 to
600 mL/min. Active renal secretion ranged from 300 to 500 mL/min, and is thus
the major elimination pathway for PA. The tubular secretion utilizes the base-
secreting system also responsible for secretion of metformin, cimetidine,
ranitidine, triamterene, and flecainide. Thus there is a potential for drug-drug
interactions at this level.
SPECIAL POPULATIONS: Patients With Renal Disease: Decline in renal function,
such as that occurring with advancing age or renal disease, increases the PA
elimination half-life which can result in relatively high plasma concentrations
of PA (see WARNINGS). Accumulation of NAPA due to impaired renal function can be
more extensive than accumulation of PA.
Patients With Congestive Heart Failure: PA clearance is reduced in patients
with severe heart failure, in part due to decreased renal perfusion (see
WARNINGS).
Age, Gender, And Race: PA clearance decreases with increasing patient age, in
part due to concurrent decreases in renal function. However, the
pharmacokinetics of PA and NAPA are similar in young healthy subjects (mean age
32 yr) and patients with frequent VPDs (mean age 60 yr) following administration
of Pronestyl every 12 hours. Steady state plasma procainamide concentrations in
women receiving Pronestyl are 30 percent higher than those seen in men receiving
the same dosing regimen. When corrected for body surface area this difference is
only 16 percent. Concentrations of N-acetylprocainamide are not significantly
different among men and women whether corrected for body surface area or not.
Pronestyl tablets produce similar PA and NAPA concentrations in black and
caucasian individuals.
PHARMACODYNAMICS: While therapeutic plasma PA concentrations have been reported
to be 3 to 10 mcg/mL, patients such as those with sustained ventricular
tachycardia may need higher concentrations for adequate control. This may
justify an increased risk of toxicity (see OVERDOSAGE). Where programmed
ventricular stimulation has been used to evaluate efficacy of PA in preventing
recurring ventricular tachyarrhythmias, an average plasma PA concentration of
13.6 mcg/mL was necessary for adequate control. Action of PA on the central
nervous system is not prominent, but high concentrations may cause tremors.
A double-blind, placebo-controlled, dose- response, formulation-crossover study
was conducted, comparing the suppression of VPDs by Pronestyl administered every
12 hours and Procan SR administered every 6 hours. Similar VPD suppression was
observed following administration of both formulations for 1 week each.
Pronestyl demonstrated significant pharmacologic activity (mean percent change
from base line in VPDs) compared with placebo, and a significant linear dose-
response relationship was observed. VPD suppression was maintained throughout
the dosing interval.
In this study, VPD rate tended to decrease with increasing concentration of PA
and NAPA; however, PA concentration alone was a poor predictor of antiarrhythmic
effect. The concentration-effect relationship for administration of Pronestyl
every 12 hours was indistinguishable from that for administration of Procan SR
every 6 hours.
INDICATIONS AND USAGE:
Pronestyl tablets are 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
procainamide, its use with lesser arrhythmias is generally not recommended.
Treatment of patients with asymptomatic ventricular premature depolarizations
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 hematologic disorders
(0.5%), 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" (twisting of the points), characterized by alternation of 1 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:
MORTALITY: IN THE NATIONAL HEART, LUNG,
AND BLOOD INSTITUTE'S CARDIAC ARRHYTHMIA
SUPPRESSION TRIAL (CAST), A LONG-TERM,
MULTI-CENTERED, RANDOMIZED, DOUBLE-BLIND
STUDY IN PATIENTS WITH ASYMPTOMATIC NON-
LIFE-THREATENING VENTRICULAR ARRHYTHMIAS
WHO HAD A MYOCARDIAL INFARCTION MORE THAN 6
DAYS BUT LESS THAN 2 YEARS PREVIOUSLY, AN
EXCESSIVE MORTALITY OR NON-FATAL CARDIAC
ARREST RATE (7.7%) WAS SEEN IN PATIENTS
TREATED WITH ENCAINIDE OR FLECAINIDE
COMPARED WITH THAT SEEN IN PATIENTS
ASSIGNED TO CAREFULLY MATCHED PLACEBO-
TREATED GROUPS (3.0%). THE AVERAGE DURATION
OF TREATMENT WITH ENCAINIDE OR FLECAINIDE
IN THIS STUDY WAS 10 MONTHS.
THE APPLICABILITY OF THE CAST RESULTS TO
OTHER POPULATIONS (EG, THOSE WITHOUT RECENT
MYOCARDIAL INFARCTION) IS UNCERTAIN.
CONSIDERING THE KNOWN PROARRHYTHMIC
PROPERTIES OF PROCAINAMIDE AND THE LACK OF
EVIDENCE OF IMPROVED SURVIVAL FOR ANY
ANTIARRHYTHMIC DRUG IN PATIENTS WITHOUT
LIFE-THREATENING ARRHYTHMIAS, THE USE OF
PRONESTYL AS WELL AS OTHER ANTIARRHYTHMIC
AGENTS SHOULD BE RESERVED FOR PATIENTS WITH
LIFE-THREATENING VENTRICULAR ARRHYTHMIAS.
BLOOD DYSCRASIAS: Agranulocytosis, bone
marrow depression, neutropenia, hypoplastic
anemia, and thrombocytopenia have been
reported in patients receiving procainamide
hydrochloride at a rate of approximately
0.5%. Most of these patients received
procainamide hydrochloride within the
recommended dosage range. Fatalities have
occurred (with approximately 20%-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 hydrochloride 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
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 the 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 concentrations of PA and/or NAPA 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,
dislodgment of mural thrombi may lead to embolization, which should be kept in
mind.
Based upon the approximate half-life of 3 hours for PA, pharmacokinetic steady
state would be reached within 1 day. 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% or
marked prolongation of the Q-T interval occurs, concern for overdosage is
appropriate, and reduction in dosage is advisable if a 50% 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 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 concentrations 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
homeostatis; 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 Warning 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 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 than the benefit of PA
in controlling arrhythmias. Patients with rapid acetylation capability are less
likely to develop the lupoid syndrome after prolonged PA therapy.
INFORMATION FOR PATIENTS: 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, and to
report any history of kidney disease, congestive heart failure, myasthenia
gravis, liver disease, or lupus erythematosus.
The patient should be advised not to break or chew the tablet as this would
interfere with designed dissolution characteristics. The tablet matrix of
Pronestyl may be seen in the stool since it does not disintegrate following
release of procainamide.
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.
Coadministration of cimetidine decreases renal clearance of PA, potentially
leading to clinically significant increases in plasma concentrations. Large
(>300 mg/day) doses of ranitidine possibly have this effect also. Plasma PA
concentrations higher than those for administration of PA alone have been
reported for coadministration with either amiodarone or trimethoprim. Alcohol
(ethanol) consumption tends to decrease the half-life of PA in the blood through
induction of its acetylation to NAPA.
Patients taking PA who require neuromuscular blocking agents such as
succinylcholine may require less than usual doses of the latter, due to PA
effects of 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.
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 pediatric patients have not been
established.
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.
Coadministration of cimetidine decreases renal clearance of PA, potentially
leading to clinically significant increases in plasma concentrations. Large
(>300 mg/day) doses of ranitidine possibly have this effect also. Plasma PA
concentrations higher than those for administration of PA alone have been
reported for coadministration with either amiodarone or trimethoprim. Alcohol
(ethanol) consumption tends to decrease the half-life of PA in the blood through
induction of its acetylation to NAPA.
Patients taking PA who require neuromuscular blocking agents such as
succinylcholine may require less than usual doses of the latter, due to PA
effects of reducing acetylcholine release.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
CARDIOVASCULAR SYSTEM: Hypotension following oral PA administration is rare.
Hypotension and serious disturbances of cardiac rhythm such as ventricular
asystole or fibrillation are more common after intravenous administration (see
OVERDOSAGE, WARNINGS). Second degree heart block has been reported in 2 of
almost 500 patients taking PA orally.
MULTISYSTEM EFFECTS: A lupus erythematosus-like syndrome of arthralgia, pleural
or abdominal pain, and sometimes 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 Warning and PRECAUTIONS). While
some studies have reported less than 1 in 500, others have reported the syndrome
in up to 30% of patients on long-term oral PA therapy. If discontinuation of PA
does not reverse the lupoid symptoms, corticosteroid treatment may be effective.
HEMATOLOGIC SYSTEM: Neutropenia, thrombocytopenia, or hemolytic anemia may
rarely be encountered. Agranulocytosis has occurred after repeated use of PA,
and deaths have been reported (see WARNINGS and Boxed Warning).
SKIN: Angioneurotic edema, urticaria, pruritus, flushing, and maculopapular
rash have also occurred occasionally.
GASTROINTESTINAL SYSTEM: Anorexia, nausea, vomiting, abdominal pain, bitter
taste, or diarrhea may occur in 3 to 4 percent of patients taking oral
procainamide. Hepatomegaly with increased serum aminotransferase activity has
been reported after a single oral dose.
ELEVATED LIVER ENZYMES: Elevations of transaminase with and without elevations
of alkaline phosphatase and bilirubin have been reported in patients taking oral
procainamide. Some patients have had clinical symptoms (eg, 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.
OVERDOSAGE:
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
concentrations 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 mcg/mL are increasingly associated with toxic findings,
which are seen occasionally in the 10 to 12 mcg/mL range, more often in the 12
to 15 mcg/mL range, and commonly in patients with plasma levels greater than 15
mcg/mL. A single oral dose of IR PA 2000 mg may produce overdosage symptoms,
while 3000 mg of IR PA 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.
DOSAGE AND ADMINISTRATION:
The dose should be adjusted for the individual patient, based on clinical
assessment of the degree of underlying myocardial disease, the patient's age,
and renal function. For patients who have been receiving another formulation of
procainamide, the dose of the other formulation can function as a general guide,
but re-titration with Pronestyl is recommended.
As a general guide, for younger patients with normal renal function, an initial
total daily oral dose of up to 50 mg/kg of body weight of Pronestyl tablets may
be used, given in 2 divided doses, every 12 hours, to maintain therapeutic blood
concentrations. 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 concentrations, and decrease the
probability of occurrence of dose- related adverse reactions.
CARE SHOULD BE TAKEN WHEN DISPENSING PRONESTYL TO ASSURE THE BID DOSAGE FORM HAS
BEEN PRESCRIBED AND DISPENSED. Pronestyl tablets should be swallowed whole and
should not be bitten or cut.
To provide up to 50 mg/kg of body weight per day*
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PATIENTS WEIGHING DOSE
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88-110 lb (40-50 kg) 1000 mg q12 hrs
132-154 lb (60-70 kg) 1500 mg q12 hrs
176-198 lb (80-90 kg) 2000 mg q12 hrs
>220 lb (>100 kg) 2500 mg q12 hrs
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* Initial dosage schedule guide only, to be adjusted for each patient
individually, based on age, cardiorenal function, blood concentration (if
available), and clinical response.
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