INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo PRONESTYL CAPSULES
PRONESTYL INJECTION

SCHEDULING STATUS
S4

PROPRIETARY NAME
(and dosage form)

PRONESTYL CAPSULES
PRONESTYL INJECTION

COMPOSITION
PRONESTYL CAPSULES: Each capsule contains 250 mg
procainamide hydrochloride.

PRONESTYL INJECTION: Procainamide hydrochloride 100 mg/mL with benzyl alcohol 0,9% m/v and sodium bisulphite 0,09 % m/v as preservatives.

PHARMACOLOGICAL CLASSIFICATION
Category A 6.2 Cardiac Depressants.

PHARMACOLOGICAL ACTION
Procainamide depresses the excitability of cardiac muscle to electrical stimulation and slows conduction in the atrium, the bundle of His, and the ventricle. The refractory period of the atrium is considerably more prolonged than that of the ventricle. Contractility of the heart is usually not affected, nor is cardiac output decreased to any extent unless myocardial damage exists. In the absence of any arrhythmia, the heart rate may occasionally be accelerated by conventional doses, suggesting that the drug possesses anticholinergic properties.

Larger doses can induce atrioventricular block and ventricular extrasystoles which may proceed to ventricular fibrillation. These effects on the myocardium are reflected in the electrocardiogram; a widening of the QRS complex occurs most consistently; less regularly the P-R and Q-T intervals are prolonged, and the QRS and T waves show some decrease in voltage.

The action of procainamide begins almost immediately after intramuscular or intravenous administration. Plasma levels after intramuscular injection are at their peak in 15 to 60 minutes. Following oral administration, plasma levels of the drug are comparable to those obtained parenterally, and are maximal within an hour; therapeutic levels are usually attained in half that time.

Therapeutic plasma levels have been reported to be 3 to 10 µg/mL, with those for the majority of the patients in the range of 4 to 8 µg/mL.

Procainamide is less readily hydrolyzed than procaine, and plasma levels decline slowly - about 10 % to 20 % per hour. The drug is excreted primarily in the urine about 10 % as free and conjugated p-aminobenzoic acid and about 60 % in the unchanged form. The fate of the remainder is unknown.

INDICATIONS
PRONESTYL Capsules are indicated in the treatment of premature ventricular contractions and ventricular tachycardia, atrial fibrillation, and paroxysmal atrial tachycardia.

PRONESTYL Injection is indicated in the treatment of ventricular extrasystoles and tachycardia, atrial fibrillation, paroxysmal atrial tachycardia, and cardiac arrhythmias associated with anaesthesia and surgery.

CONTRA-INDICATIONS
It has been suggested that procainamide be contra-indicated in patients with myasthenia gravis. Hypersensitivity to the drug is an absolute contra-indication; 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. Procainamide is also contra-indicated in cases of second and third degree A-V block unless an electrical pacemaker is operative.

PRONESTYL Injection is not recommended for use in children.

DOSAGE AND DIRECTIONS FOR USE
Oral administration is preferred. When parenteral therapy is necessary, intramuscular administration is the method of choice. Intravenous use should be limited to extreme emergencies.

If procainamide therapy is continued for appreciable periods, electrocardiograms should be made occasionally to determine the need for the drug.

Oral dose: For ventricular tachycardia, an initial dose of 1 gram orally followed thereafter by a total daily dose of 50 mg/kg of body weight given at 3 hour intervals. The suggested oral dosage for premature ventricular contractions is 50 mg/kg of body weight daily given in divided doses at 3 hour intervals.

To provide 50 mg/kg day: Give patients weighing less than 55 kg 250 mg every 3 hours; give patients between 55 kg and 91 kg one to two 250 mg capsules every 3 hours; and give patients over 91 kg 500 mg every 3 hours. This dosage schedule is for use as a guide for treating the average patient but all patients must be considered on an individual basis.

In atrial fibrillation and paroxysmal atrial tachycardia, an initial dose of 1,25 g may be followed in one hour by 0,75 g if there have been no electrocardiographic changes. A dose of 0,5 to 1 g may then be given every 2 hours until arrhythmia is interrupted or the limit of tolerance is reached. Suggested maintenance dosage is 0,5 to 1 g every 4 to 6 hours.

Intramuscular dose: If the oral route is not feasible, 0,5 to 1 g may be given intramuscularly, repeated every 6 hours until oral therapy is possible.

Intravenous dose: The usual intravenous dose for ventricular extrasystoles and tachycardia ranges from 0,2 to 1 g; for atrial fibrillation and paroxysmal atrial tachycardia, the intravenous dose averages 0,5 g although up to 1 g may be required.

Caution: Intravenous use of procainamide may be accompanied by a hypotensive response, sometimes precipitous. For this reason the intravenous dose should not exceed 1 g, and should be diluted to permit greater control of infusion rate. It should be administered at a rate not exceeding 25 to 50 mg per minute.

Direct Intravenous Administration: To reduce the possibility of a hypotensive response, 100 mg doses may be administered every five minutes by direct slow intravenous injection, at a rate not exceeding 50 mg in any one minute, until the arrhythmia is suppressed or the maximum dosage of 1 g has been administered. Blood pressure must be taken and the electrocardiogram read before each dose.

Some effects may be seen after the first 100 or 200 mg, and it is unusual to require more than 500 to 600 mg to achieve satisfactory antiarrhythmic effects.

To maintain therapeutic levels, an infusion may then be started at a rate of 2 to 6 mg procainamide per minute (see Table: Dilutions and Rates for Intravenous Infusions) depending on the patient’s body mass, circulatory condition and renal function.

Intravenous Infusion: An alternative method of achieving and then maintaining a therapeutic plasma concentration is to infuse 500 to 600 mg of procainamide at a constant rate over a period of 25 to 30 minutes and then changing to another infusion for maintenance at a rate of 2 to 6 mg/min (see Dilutions and Rates for Intravenous Infusions).

Intravenous therapy should be terminated as soon as the patient’s basic cardiac rhythm appears to be stabilized and, if indicated, the patient should be placed on oral antiarrhythmic maintenance therapy. A period of about 3 to 4 hours (one half-life) should elapse after the last intravenous dose of procainamide before administering the first oral dose of procainamide.

Intravenous administration should be monitored electrocardiographically so that the infusion may be stopped when the arrhythmia is interrupted or when excessive widening of the ORS complex or prolongation of the P-R interval suggests the occurrence of myocardial toxicity. Patients should be kept in a supine position and blood pressure should be measured almost continuously during administration. If the fall in blood pressure exceeds 15 mm Hg, administration should be temporarily discontinued. Phenylephrine Hydrochloride Injection USP or Levarterenol Bitartrate Injection USP should be available to counteract severe hypotensive responses.

Surgical Use:
For cardiac arrhythmias associated with anaesthesia and surgery, the suggested parenteral dose is 0,1 to 0,5 g, preferably given intramuscularly.

DILUTIONS AND RATES FOR INTRAVENOUS INFUSIONS *
Approximate Infusion mL of Infusion
Final Bottle Size Pronestyl Rate
Concentration (mL) (100 mg/mL) 
    be added 
0,25 (2 mg/mL) 500 10 1-3
  250 5 mL/min
0,4 % (4 mg/mL) 500 20 0,5 -1,5
  250 10 mL/min

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
During administration of the drug 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 tachysystole is particularly hazardous. Correction of atrial fibrillation with resultant forceful contractions of the atrium, may cause a dislodgement 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 second and third degree A-V 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.

Since 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 procamamide. If the ventricular rate is significantly slowed by procainamide without attainment of regular atrio-ventricular conduction, the drug should be stopped and the patient re-evaluated as asytole may result under these circumstances.

In patients receiving normal dosage, but who have both liver and kidney disease, symptoms of overdosage (principally ventricular tachycardia and severe hypotension) may occur due to drug accumulation.

Instances of a syndrome resembling lupus erythematosus have been reported in connection with maintenance procainamide therapy. The mechanism of this syndrome is uncertain. Polyarthralgia arthritis and pleuritic pain are common symptoms; to a lesser extent fever myalgia skin lesions, pleural effusion and pericarditis may occur. Rare cases of thrombocytopenia or Coombs positive haemolytic anaemia have been reported which may be related to this syndrome.

Patients receiving procainamide for extended periods of time or in whom symptoms suggestive of a lupus-like reaction appear should have antinuclear antibody titers measured at regular intervals. If there is a rising titer or if clinical symptoms of LE appear, the benefit/risk ratio related to continued procainamide therapy should be assessed. The LE syndrome may be reversible upon discontinuance of the drug. If discontinuation of the drug does not cause remission of the symptoms, steroid therapy may be effective. If the syndrome develops in a patient with recurrent life-threatening arrhythmias not controllable by other antiarrhythmic agents steroid suppressive therapy may be used concomitantly with procainamide.

Hypotension following oral administration is rare. Serious disturbances of cardiac rhythm such as ventricular asystole or fibrillation are more common with intravenous administration.

Reactions consisting of fever and chills have also been reported, including a case with fever and chills plus nausea, vomiting, abdominal pain acute hepatomegaly and a rise in serum glutamic oxaloacetic transaminase following single doses of the drug. Bitter taste, diarrhoea weakness mental depression, giddiness, and psychosis with hallucinations have been reported. The possibility of such untoward effects should be borne in mind.

Hypersensitivity reactions such as angioneurotic oedema and maculopapular rash have also occurred.

Agranulocytosis has occasionally followed the repeated use of the drug, and deaths have occurred. Therefore, routine blood counts are advisable during maintenance procainamide therapy. The patients should be instructed to report any soreness of the mouth, throat, or gums, unexplained fever or any symptoms of upper respiratory tract infection. If any of these should occur, and leukocyte counts indicate cellular depression, procainamide therapy should be discontinued and appropriate treatment should be instituted immediately.

Because procainamide is a peripheral vasodilator, intravenous administration may produce transient but at times severe lowering of blood pressure, particularly in conscious patients. Intramuscular injection is less likely to be accompanied by serious falls in blood pressure. Serious disturbances of cardiac rhythm such as ventricular asystole or fibrillation are also more common with intravenous administration. Precautionary measures to be followed during intravenous injection are given in the section on “DOSAGE AND DIRECTIONS FOR USE”.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Oral:
Large oral doses of procainamide may sometimes produce anorexia, nausea, urticaria, and/or pruritus. Specific cardiac adverse reactions as described for intravenous overdose may occur as well. The therapy is the same.

Intravenously: Intravenously overdosage is manifested by ventricular tachycardia which can evolve into ventricular fibrillation and asystole.

Antidote: Antidote is recommended to be alpha-adrenergic stimulation such as administration of adrenaline or isoprenaline.

Defibrillation and treatment for cardiac arrest may be required as well.

IDENTIFICATION
PRONESTYL CAPSULES: Size No. 2 yellow hard gelatin capsules printed ‘SQUIBB’in black on both halves of the capsule.

PRONESTYL INJECTION: Colourless or very pale yellow clear solution in clear glass vaccine vial.

PRESENTATION
PRONESTYL CAPSULES: Bottles of 100.
PRONESTYL INJECTION: 10 mL vials.

STORAGE INSTRUCTIONS
PRONESTYL CAPSULES: Store at room temperature not exceeding 25°C. Avoid excessive heat. Hygroscopic, keep and dispense in tightly closed container.

PRONESTYL INJECTION: Store at room temperature not exceeding 25°C. Avoid excessive heat.

The solution which is colourless initially, may develop a slightly yellow colour in time. This does not indicate a change which would prevent its use, but a solution any darker than light amber or discoloured in any other way should not be used.

KEEP OUT OF REACH OF CHILDREN.

REFERENCE NUMBER
PRONESTYL CAPSULES - G2895 (Act 101 of 1965)
PRONESTYL INJECTION - G2894 (Act 101 of 1965)

NAME AND BUSINESS ADDRESS OF APPLICANT
BRISTOL-MYERS SQUIBB (PTY) LTD *
AMR Park, 1 Concorde Road East, Bedfordview 2008

DATE OF PUBLICATION OF THIS PACKAGE INSERT
29/3/88

*Authorised user of the TM PRONESTYL

290084         12/92

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