Tonocard (Tocainide HCl)

TONOCARD® AstraZeneca Tocainide HCl Antiarrhythmic Agent

Action and Clinical

Tocainide is a primary amine analog of lidocaine. Its electrophysiologic properties are similar to those of lidocaine. It possesses class IB properties in the modified electrophysiological classification of antiarrhythmic drugs proposed by Vaughan-Williams. In studies of isolated dog Purkinje fibres, tocainide in concentrations of 1 to 50 g/mL had no significant effect on resting membrane potential, but reduced the amplitude and rate of depolarization (dv/dt) of the action potential. Tocainide decreased the effective refractory period (ERP) to a lesser extent than the action potential duration (APD) resulting in an increase in the ERP/APD ratio. In patients with cardiac disease, tocainide produced no clinically significant changes in sinus nodal function, effective refractory periods, or intracardiac conduction times when studied under electrophysiologic testing procedures. Tocainide does not prolong ventricular depolarization (QRS duration) or repolarization (QT intervals) as measured by electrocardiography.

Pharmacokinetics: The absorption of tocainide from the gastrointestinal tract is almost complete and peak plasma levels occur within 1 to 2 hours after an oral dose. Tocainide shows insignificant first-pass elimination and its bioavailability is exceeding 95%. The extent of bioavailability is unaffected by food.

The half-life is 15.6±3.8 hours. This is increased to about 27 hours in patients with end stage renal failure. At antiarrhythmic concentrations, tocainide is approximately 10% bound to plasma proteins. The optimal plasma range for tocainide is approximately 4 to 10 g/mL (18 to 45 µmol/L). Elimination occurs by both renal excretion and metabolic degradation and is not dose dependent. The principal metabolite of tocainide in urine was found to be N-carboxytocainide glucuronide (25% of dose after repeated oral administration).

The amount of tocainide excreted unchanged in urine is about 40% of the given dose and is independent of the route of administration. Alkalinization of the urine significantly reduces the amount of tocainide excreted.

Hemodynamics: Cardiac catheterization studies in man utilizing i.v. tocainide infusions (0.5 to 0.75 mg/kg/min over 15 min) have shown that tocainide usually produces a small degree of depression of parameters of left ventricular function, such as left ventricular dP/dt, and left ventricular end diastolic pressure. There were usually no changes in cardiac output or clinical evidence of increasing congestive heart failure in the well compensated patients studied. Small but statistically significant increases in aortic and pulmonary arterial pressures have been consistently observed and are probably related to small increases in vascular resistance. When used concomitantly with a beta-blocking drug, tocainide further reduced cardiac index and left ventricular dP/dt and further increased pulmonary wedge pressure.

No clinically significant changes in heart rate, blood pressure, or signs of myocardial depression were observed in a study of 72 post-myocardial infarction patients receiving long-term therapy with oral tocainide at usual doses (400 mg every 8 hours). Tocainide has been used safely in patients with acute myocardial infarction and various degrees of congestive heart failure. It has, however, a small negative inotropic effect and can increase peripheral resistance slightly. It therefore should be used cautiously in patients with known heart failure, particularly if a beta-blocker is given as well (see Precautions).

Indications Indications and Clinical Uses:

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.

For the treatment of documented life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia. Tocainide may also be used for the treatment of patients with documented symptomatic ventricular arrhythmias when the symptoms are of sufficient severity to require treatment. Due to its adverse reaction profile (blood dyscrasias, pulmonary fibrosis, proarrhythmic effects), tocainide should be used only in patients not responding to other therapy, or when other therapy is not tolerated. Tocainide 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, tocainide 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 tocainide in patients with recent myocardial infarction have not been adequately studied and, therefore, its use in this condition cannot be recommended.

Contra-Indications:

In patients with known hypersensitivity to local anesthetics of the amide type and in patients with second or third degree AV block in the absence of a pacemaker.

Warnings in Clinical States:

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 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.

Proarrhythmic Effects: Tocainide has been reported to aggravate or induce arrhythmias in some patients (see Adverse Effects).

Blood Dyscrasias: Tocainide therapy should only be instituted when facilities are available for regular monitoring of blood counts. Agranulocytosis, bone marrow depression, leukopenia, neutropenia, aplastic/hypoplastic anemia and thrombocytopenia have been reported in patients receiving tocainide; concomitant septicemia and/or fatalities have occurred. A complete hemogram (hematocrit, hemoglobin, RBC count, and morphology if appropriate, complete WBC with differential and platelet count) should be performed before the patient is started on tocainide. Patients should be instructed to promptly report the development of bruising, bleeding, unusual tiredness or any signs of infection such as fever, sore throat or chills. Since most of these events have been noted during the first 12 weeks of therapy, it is recommended that blood counts be performed weekly during this period, and frequently thereafter. If any of these hematological disorders is identified, tocainide should be discontinued, and appropriate treatment instituted.

Pulmonary Toxicity: Pulmonary fibrosis, interstitial pneumonitis, fibrosing alveolitis, pulmonary edema, and pneumonia, possibly drug related, have been reported in patients receiving tocainide.

Many of these events occurred in patients who were seriously ill. The experiences are usually characterized by bilateral infiltrates on x-ray and are frequently associated with dyspnea and cough. Fever may or may not be present. Patients should be instructed to promptly report the development of any pulmonary symptoms such as exertional dyspnea, cough or wheezing. Chest x-rays are advisable at that time. If these pulmonary disorders develop, tocainide should be discontinued.

Ventricular Rate: Acceleration of ventricular rate occurs infrequently when antiarrhythmic agents are administered to patients with atrial flutter or fibrillation (see Adverse Effects).

Pregnancy: Fetal abnormalities were reported in all test groups in a rabbit teratogenicity study. At the highest dose level (100 mg/kg) the incidence differed significantly from the control group. Although maternal toxicity was observed at these doses, a drug effect on the fetus cannot be excluded. The safety of tocainide in pregnancy has not been established and therefore tocainide should not be administered unless the expected benefits outweigh the potential risks.

Precautions:

Tocainide should be used with caution in patients with heart failure or with minimal cardiac reserve because of the potential for aggravating the degree of heart failure. It should also be used with caution in patients who are receiving beta-blockers and/or other antiarrhythmic drugs.:

Tocainide has been reported to aggravate or induce arrhythmias in some patients (see Adverse Effects).

Since antiarrhythmic drugs may be ineffective in patients with hypokalemia, any potassium deficit should be corrected.

Caution should be used in the institution or continuation of antiarrhythmic therapy in the presence of signs of increasing depression of cardiac conductivity.

Occupational Hazards: Because tocainide can cause CNS effects such as lightheadedness/dizziness/vertigo/giddiness, tremor/quivering/tremulousness, confusion/disorientation, patients should be cautioned about engaging in activities requiring mental alertness, judgment and physical coordination (such as driving an automobile or operating dangerous machinery) when these effects occur.

Tocainide should be used with caution in patients with severe renal disease because of the risk of accumulation (see Dosage).

Patients receiving tocainide should have periodic testing of liver function, as hepatitis and abnormal liver tests have been reported. Because of risk of accumulation, patients with pre-existing severe hepatic disease should be treated with caution (see Dosage).

A lupus-erythematous-like syndrome has been reported in a few patients receiving tocainide. While a causal relationship has not been established, it is recommended that patients on long-term treatment be monitored for this possibility.

In epilepsy, tocainide should be used with caution because of the risk of precipitating convulsions.

Lactation: It is not known whether tocainide is secreted into breast milk. Therefore the drug is not recommended for use in lactating mothers unless the expected benefits outweigh the potential risks.

Children: The use of tocainide in children is not recommended since the safety and efficacy in children have not been established.

Geriatrics: Because of the possible risk of impaired elimination or increased sensitivity in the elderly, tocainide should be used with caution (see Dosage).

Drug Interactions:

Caution should be exercised in the use of multiple drug therapy. Specific interaction studies with a beta-blocker have been carried out and showed no clinically significant interactions. However, in patients with sick sinus syndrome and patients with impaired atrioventricular conduction, the small depression of myocardial contractility resulting from the administration of tocainide may become significant when a beta-blocker and tocainide are administered concomitantly.

Tocainide has been used clinically with digitalis and other antiarrhythmic agents (quinidine, disopyramide, procainamide), anticoagulants and diuretics without evidence of untoward effects. Concurrent use of tocainide and lidocaine leads to potentiation of adverse effects involving the CNS.

There is no evidence of pharmacokinetic interaction between tocainide and phenobarbital, clofibrate or salicylamide.

Because of the limited plasma protein binding and the relatively large apparent volume of distribution of tocainide, significant interactions involving plasma protein binding displacement are unlikely.

Adverse Reactions:

Tocainide has been evaluated in both short-term (n=1 358) and long-term (n=262) controlled studies as well as an emergency use program. Dosages were lower in most of the controlled studies (1 200 mg/day) and higher in the emergency use program (1 800 mg/day and more). In long-term (2 to 6 months) controlled studies, the most frequent adverse reactions were lightheadedness/dizziness (15.3%), nausea (14.5%), paresthesia/numbness (9.2%), and tremor (8.5%). These reactions were generally mild, transient, dose-related and reversible with a reduction in dosage, by taking the drug with food, or by therapy discontinuation. Tremor, when present, may be useful as a clinical indicator that the maximum dose is being approached. Adverse reactions leading to therapy discontinuation occurred in 21% of patients in long-term controlled trials and were usually related to the CNS or gastrointestinal system.

Adverse reactions occurring in greater than 1% of patients from the short-term and long-term controlled studies.

Adverse Reactions Occurring in Greater than 1% of Patients

Percentage of Patients Controlled Studies

Short-term (n=1 358) Long-term (n=262)

CNS

Lightheadedness/dizziness/ vertigo/giddiness 8.0 15.3

Paresthesia/numbness 3.5 9.2

Tremor/quivering/ tremulousness 2.9 8.4

Confusion/disorientation/ hallucinations 2.1 2.7

Altered mood/awareness 1.5 3.4

Restlessness/shakiness/ nervousness 1.5 0.4

Blurred vision/visual disturbances 1.3 1.5

Discoordination/unsteadiness/ walking disturbances 1.2 0.0

Anxiety 1.1 1.5

Tinnitus/hearing loss 0.4 1.5

Ataxia 0.2 3.0

Nystagmus 0.0 1.1

Gastrointestinal

Nausea 15.2 14.5

Vomiting 8.3 4.6

Anorexia 1.2 1.9

Diarrhea/loose stools 0.0 3.8

Cardiovascular

Hypotension 3.4 2.7

Bradycardia 1.8 0.4

Palpitations 1.8 0.4

Chest pain 1.6 0.4

Conduction disturbances 1.5 0.0

Left ventricular failure 1.4 0.0

Other

Sweating/cold sweat/night sweats/clammy 5.1 2.3

Headache 2.1 4.6

Tiredness/drowsiness/fatigue/ lethargy/lassitude/ sleepiness 1.6 0.8

Hot/cold feelings 0.5 1.5

Rash/skin lesions 0.4 8.4

An additional group of about 2 000 patients has been treated in a program allowing for the use of tocainide under emergency use circumstances. These patients were seriously ill with the large majority on multiple drug therapy, and comparatively high doses of tocainide were used. Fifty-four percent of the patients continued in the program for 1 year or longer, and 12% were treated for longer than 3 years, with the longest duration of therapy being 9 years. Adverse reactions leading to therapy discontinuation occurred in 12% of patients (usually CNS effects or rash).

A tabulation of adverse reactions occurr in 1% or more of patients.

CPS:TABLE_C06800$$36_t2

Adverse Reactions Occurring in 1% or More of Patients

Percentage of Patients Emergency Use (n=1 927)

CNS

Lightheadedness/dizziness/ vertigo/giddiness 25.3

Tremor/quivering/ tremulousness 21.6

Restlessness/shakiness/ nervousness 11.5

Confusion/disorientation/ hallucinations 11.2

Altered mood/awareness 11.0

Ataxia 10.8

Blurred vision/visual disturbances 10.0

Paresthesia/numbness 9.2

Nystagmus 1.1

Gastrointestinal

Nausea 24.6

Anorexia 11.3

Vomiting 9.0

Diarrhea/loose stools 6.8

Cardiovascular

Increased ventricular arrhythmias/PVCs 10.9

CHF/progression of CHF 4.0

Tachycardia 3.2

Hypotension 1.8

Conduction disturbances 1.3

Bradycardia 1.0

Other

Rash/skin lesion 12.2

Sweating/cold sweat/night sweats/clammy 8.3

Arthritis/arthralgia 4.7

Myalgia 1.7

Lupus 1.6

Adverse reactions occurring in less than 1% of patients in either the controlled studies or the emergency use program or those reported from marketed use are as follows:

Hematopoietic: agranulocytosis, hypoplastic anemia, leukopenia, thrombocytopenia, anemia. These have been reported in 0.18% of patients and continue to be reported in countries where the drug is on the market. These hematologic disorders usually occurred after 2 to 12 weeks of therapy (see Warnings).

CNS: coma, convulsions/seizures, depression, psychosis, mental change, agitation, altered taste/smell, difficulty concentrating, diplopia, dysarthria, impaired memory, increased stuttering/slurred speech, insomnia/sleeping disturbance, local anesthesia, nightmares, thirst, weakness, myasthenia gravis.

Gastrointestinal: abdominal pain/discomfort, constipation, dysphagia, gastrointestinal symptoms (including dyspepsia), abnormal liver function tests, hepatitis, jaundice.

Cardiovascular: ventricular fibrillation, extension of acute myocardial infarction, cardiogenic shock, angina, AV block, hypertension, increased QRS duration, pleurisy/pericarditis, prolonged QT interval, right bundle branch block, syncope, vaso-vagal episodes, cardiomegaly, sinus arrest.

Pulmonary: respiratory arrest, pulmonary edema, pulmonary embolism, pulmonary fibrosis, alveolitis, pneumonia, pneumonitis, dyspnea.

Other: increased ANA, urinary retention, polyuria/increased diuresis, alopecia, cinchonism, claudication, cold extremities, dry mouth, earache, edema, fever, hiccups, itching, leg cramps, malaise, metallic/menthol taste, muscle twitching/ spasm, neck pain, pain radiating from neck, pallor/flushed face, pressure on shoulder, yawning, vasculitis.

Pulmonary fibrosis, pneumonitis, alveolitis, pulmonary edema, and pneumonia, possibly drug related, have been reported in patients receiving tocainide. The incidence of pulmonary fibrosis was 0.03% in controlled trials and the emergency use program. These events usually occurred in seriously ill patients. Symptoms of these pulmonary disorders and/or x-ray changes usually occurred following 3 to 18 weeks of therapy and 2 patients died (see Warnings).

Symptoms And Treatment Of Overdose:

Symptoms: Overdosage of tocainide can result in signs of CNS toxicity, including convulsions and respiratory depression.

Treatment: Should convulsions, signs of respiratory depression or respiratory arrest develop, the patency of the airway and adequacy of ventilation must be assured immediately. Should convulsions persist despite ventilation with oxygen, small increments of anticonvulsive agents may be given i.v.

Examples of such agents include a benzodiazepine (e.g., diazepam), an ultrashort-acting barbiturate (e.g., thiopental or thioamylal), or a short-acting barbiturate (e.g., pentobarbital or secobarbital).

Studies to date indicate that tocainide has a hemodialysis clearance approximately equivalent to its renal clearance in normal individuals.

Dosage And Administration:

The dosage of tocainide should be adjusted individually, based on therapeutic response and tolerance.

Initiation of treatment, as with other antiarrhythmic agents used to treat life-threatening ventricular arrhythmias, should be carried out in hospital.

The following dose regimens can be used as guidelines: The recommended initial dosage is 1 200 mg daily (400 mg every 8 hours).

Adults: The usual adult dosage of tocainide is between 1 200 to 1 800 mg/day, given in divided doses every 6 to 8 hours. Higher doses up to 2 400 mg/day divided into 4 doses every 6 hours should be used only in patients with refractory ventricular arrhythmias who failed to respond to other available therapy.

Six-hour dosing intervals generally are better tolerated than 8 hour intervals.

Geriatrics: The initial dosage for elderly patients should be reduced to 800 mg/day (400 mg every 12 hours). Because of the possible risk of impaired elimination or increased sensitivity in the elderly, any dose increase should be monitored. A 6- to 8-hour dosing regimen should be employed for higher dosage.

In patients with severe hepatic or renal insufficiency (creatinine clearance less than 30 mL/min) the initial dose should be reduced to 800 mg/day (400 mg every 12 hours).

With total renal failure the initial dose should be reduced to 400 mg daily. Monitoring of plasma concentrations is recommended in renal or hepatic diseases.

Conversion from Lidocaine: Adequate information on the most appropriate regimen for conversion from i.v. lidocaine to oral tocainide is lacking. Based on pharmacokinetic considerations, at present the following regimen can be used as a guideline: Initiate oral therapy with a 400 mg dose of tocainide upon cessation of the lidocaine infusion.

Follow with a 400 mg dose of tocainide every 4 hours during the first 8 hours.

Continue therapy with a regimen of 400 mg every 8 hours. During the first 24 hours of conversion, ECG and blood pressure monitoring is mandatory.

Availability And Storage:

Each yellow, biconvex, circular, film-coated tablet, engraved A/TT, contains: tocainide HCl 400 mg. Nonmedicinal ingredients: hydroxypropyl methylcellulose, iron oxide, magnesium stearate, methylcellulose, paraffin, polyethylene glycol and titanium dioxide. Gluten-, lactose-, sodium- and tartrazine-free. Bottles of 100. Store at room temperature 15 to 30°C.

TONOCARD® AstraZeneca Tocainide HCl Antiarrhythmic Agent

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