Tonocard

General

In patients with known heart failure or minimal cardiac reserve, TONOCARD (tocainide hcl) should be used with caution because of the potential for aggravating the degree of heart failure.

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

In patients with severe liver or kidney disease, the rate of drug elimination may be significantly decreased (see DOSAGE AND ADMINISTRATION).

Since antiarrhythmic drugs may be ineffective in patients with hypokalemia, the possibility of a potassium deficit should be explored and, if present, the deficit should be corrected.

Like all other oral antiarrhythmics, TONOCARD (tocainide hcl) has been reported to increase arrhythmias in some patients (see ADVERSE REACTIONS).

Information for Patients

See PATIENT INFORMATION section.

Laboratory Tests

As with other antiarrhythmics, abnormal liver function tests, particularly in the early stages of therapy, have been reported. Periodic monitoring of liver function should be considered. Hepatitis and jaundice have been reported in some patients.

Drug Interactions

See DRUG INTERACTIONS section.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of tocainide was studied in mice using oral doses up to 300 mg/kg/day (about 6 times the maximum recommended human dose) for up to 94 weeks in males and 102 weeks in females and in rats at doses up to 200 mg/kg/day for 24 months. Tocainide did not affect the type or incidence of neoplasia in the two studies.

Tocainide did not show any mutagenic potential when evaluated in vivo in the micronucleus test using mice at oral doses up to 187.5 mg/kg/day (about 7 times the usual human dose). Also, no mutagenic activity was seen in vitro in the Ames microbial mutagen test or in the mouse lymphoma forward mutation assay.

Reproduction and fertility studies in rats showed no adverse effects on male or female fertility at oral doses up to 200 mg/kg/day (about 8 times the usual human dose).

Pregnancy

Pregnancy Category C. In a teratogenicity study in rabbits, tocainide was administered orally at doses of 25, 50, and 100 mg/kg/day (about 1 to 4 times the usual human dose). No evidence of a drug-related teratogenic effect was noted; however, these doses were maternotoxic and produced a dose-related increase in abortions and stillbirths. In a teratogenicity study in rats, an oral dose of 300 mg/kg/day (about 12 times the usual human dose) showed no evidence of treatment-related fetal malformations, but maternotoxicity and an increase in fetal resorptions were noted. An oral dose of 30 mg/kg/day (about twice the usual human dose) did not produce any adverse effects.

In reproduction studies in rats at maternotoxic oral doses of 200 and 300 mg/kg/day (about 8 and 12 times the usual human dose, respectively), dystocia, and delayed parturition occurred which was accompanied by an increase in stillbirths and decreased survival in offspring during the first week postpartum. Growth and viability of surviving offspring were not affected for the remainder of the lactation period.

There are no adequate and well-controlled studies in pregnant women. TONOCARD (tocainide hcl) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether tocainide is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from TONOCARD, (tocainide hcl) a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in children have not been established.

Action

Tocainide, like lidocaine, produces dose dependent decreases in sodium and potassium conductance, thereby decreasing the excitability of myocardial cells. In experimental animal models, the dose-related depression of sodium current is more pronounced in ischemic tissue than in normal tissue.

Electrophysiology

Tocainide is a Class I antiarrhythmic compound with electrophysiologic properties in man similar to those of lidocaine, but dissimilar from quinidine, procainamide, and disopyramide.

In studies of isolated dog Purkinje fibers, tocainide in concentrations of 1-50 mcg/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, TONOCARD (tocainide hcl) produced no clinically significant changes in sinus nodal function, effective refractory periods, or intracardiac conduction times when studied under electrophysiologic testing procedures.

Tocainide, like lidocaine, characteristically does not prolong ventricular depolarization (QRS duration) or repolarization (QT intervals) as measured by electrocardiography. Theoretically, therefore, TONOCARD (tocainide hcl) may be useful in the treatment of ventricular arrhythmias associated with a prolonged QT interval.

Patients who respond to lidocaine also respond to TONOCARD (tocainide hcl) in a majority of cases. Failure to respond to lidocaine usually predicts failure to respond to TONOCARD, (tocainide hcl) but there are exceptions to this.

In a controlled comparison with quinidine, 600 mg b.i.d. of TONOCARD (tocainide hcl) produced a mean reduction of 42 percent in PVC count, compared to a 54 percent reduction by quinidine 300 mg every 6 hours. Among all patients entered into the study, about one-fifth of tocainide recipients and one-third of quinidine recipients had 75 percent or greater reductions in PVC count or had elimination of ventricular tachycardia.

Pharmacokinetics

Following oral administration of tocainide, peak plasma concentrations occur within 0.5 to 2 hours. The average plasma half-life in patients is approximately 15 hours. Although the effective plasma concentration may vary from patient to patient, the usual therapeutic plasma range (as defined by 50-80 percent PVC suppression) is 4-10 mcg/mL (18-45 micromole/L), expressed as tocainide hydrochloride. Tocainide is approximately 10 percent bound to plasma protein.

In contrast to lidocaine, tocainide undergoes negligible first pass hepatic degradation. Following oral administration, the bioavailability of TONOCARD (tocainide hcl) approaches 100 percent. The extent of its bioavailability is unaffected by food. Tocainide has no cardioactive metabolites. Approximately 40 percent of the administered dose of tocainide is excreted unchanged in the urine. Acidification of the urine has not been shown to significantly alter tocainide excretion in the urine, but alkalinization of the urine results in a significant decrease in the percent of tocainide excreted unchanged in the urine. Animal data indicate that tocainide crosses the blood-brain barrier; however, it has less lipid solubility than lidocaine.

Hemodynamics

Cardiac catheterization studies in man utilizing intravenous tocainide infusions (0.5-0.75 mg/kg/mm 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 TONOCARD (tocainide hcl) at usual doses (400 mg q8h). When tocainide was administered orally at a dose of 120 mg/kg to anesthetized dogs (14 times the initial maximum dose recommended for humans), a negative inotropic effect was observed: the rate of change of left ventricular pressure decreased by up to 29 percent of control at 3 hours after administration. This effect was not observed at lower doses (60 mg/kg). 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.)

Dizziness or lightheadedness may be more likely to occur in the elderly, who are usually more sensitive to the effects of tocainide.

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

In the U.S.

• Tonocard

Available Dosage Forms:

• Tablet

Therapeutic Class: Antiarrhythmic, Group IB

Chemical Class: Amino Amide

Tocainide belongs to the group of medicines known as antiarrhythmics. It is used to correct irregular heartbeats to a normal rhythm.

Tocainide produces its helpful effects by slowing nerve impulses in the heart and making the heart tissue less sensitive.

Tocainide is available only with your doctor's prescription.

Applies to tocainide: oral tablet

Along with its needed effects, tocainide (the active ingredient contained in Tonocard) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor as soon as possible if any of the following side effects occur while taking tocainide:

• Trembling or shaking

• Blisters on skin
• cough or shortness of breath
• fever or chills
• irregular heartbeats
• peeling or scaling of skin
• skin rash (severe)
• sores in mouth
• unusual bleeding or bruising

Some side effects of tocainide may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Dizziness or lightheadedness
• loss of appetite
• nausea

• Blurred vision
• confusion
• headache
• nervousness
• numbness or tingling of fingers and toes
• skin rash
• sweating
• vomiting

Applies to tocainide: oral tablet

General

Tocainide is generally well tolerated. Minor, transient, dose-dependent side effects have occurred frequently (up to 80%) and usually involved nervous system or gastrointestinal symptoms. Approximately 21% of patients discontinued tocainide (the active ingredient contained in Tonocard) because of adverse effects. The incidence of side effects increased when plasma tocainide concentrations exceeded 10 mcg/mL. Tremor may indicate that the maximum dosage is being approached.

General adverse reactions affecting the body as a whole included fatigue (0.8% to 1.6%) and hot or cold sensations (0.5% to 1.5%). Cinchonism, asthenia, and malaise have been reported in less than 1% of patients.[Ref]

Gastrointestinal

Gastrointestinal side effects are the most frequently observed. Nausea, vomiting, and anorexia have occurred in 15% to 35% of patients. Dosage reductions or administration with food, which will not affect tocainide (the active ingredient contained in Tonocard) plasma concentrations, helps minimize these side effects. Diarrhea has been reported in 6.8% of patients. Pancreatitis, abdominal discomfort, constipation, dysphagia, stomatitis, taste alteration, dry mouth and thirst were reported in less than 1% of patients.[Ref]

Nervous system

Nervous system side effects have occurred in 15% to 25% of patients on chronic therapy. Lightheadedness/dizziness/vertigo (8% to 25.3%), tremors (2.9% to 21.6%), paresthesia (3.5% to 9.2%), coordination difficulties (1.2%), and headache (2.1% to 4.6%) have been reported. Neurologic side effects are usually dose-related and resolve with dosage reductions. Adverse effects such as coma, seizures, myasthenia gravis, dysarthria, decreased mental acuity/impaired memory, increased stuttering/slurred speech, and local anesthesia have been reported in less than 1% of patients.[Ref]

Tocainide, like lidocaine, crosses the blood-brain barrier and may produce neurotoxicity, including seizures. Tremor and paresthesias indicate a maximum tolerable dosage.[Ref]

Cardiovascular

Cardiovascular side effects such as exacerbation of old or induction of new arrhythmias, including ventricular tachycardia or fibrillation, have occurred in 16% of patients. Although tocainide (the active ingredient contained in Tonocard) has a minimal effect on the sinus node, cases of sinus arrest and SA block have been reported, particularly in patients with sick sinus syndrome. Exacerbation of congestive heart failure occurred in 1% to 5% of patients. Bradycardia (1.8%), hypotension (3.4%), and chest pain (1.6%) have been reported. Angina, hypertension, claudication, increased QRS duration, extension of acute myocardial infarction, vaso-vagal episodes, syncope, and edema have occurred.[Ref]

Hematologic

Tocainide-associated blood dyscrasias have been reported most often during the first 2 to 12 weeks of therapy.[Ref]

Hematologic side effects of tocainide have been rare (0.2% of patients), but serious reactions and death have occurred. Aplastic anemia and agranulocytosis have been associated with tocainide, some were irreversible and resulted in death. Weekly complete blood count analysis is recommended during the first three months of therapy and monthly, thereafter. Bone marrow depression and granuloma, hemolytic anemia, anemia, leukopenia, neutropenia, thrombocytopenia, and eosinophilia have been associated with tocainide therapy in less in 1% of patients. Septicemia and septic shock have been reported.[Ref]

Hypersensitivity

Hypersensitivity reactions manifesting as rash, fever, joint pain, eosinophilia, or abnormal liver function tests have been reported in up to 25% of patients. Stevens-Johnson syndrome has been associated with tocainide (the active ingredient contained in Tonocard) Interstitial pneumonitis is a rare side effect of tocainide and may be initiated by a hypersensitivity mechanism.[Ref]

Dermatologic

Data from 21 reports of severe skin reactions between 1985 to 1986, indicated 67% of the reactions occurred during the first 3 weeks of therapy.[Ref]

Dermatologic side effects occurred in 12% to 28% of patients. Serious reactions have included Stevens-Johnson syndrome, erythema multiforme, rash with stomatitis, or rash requiring or prolonging hospitalization. Overall, the incidence of serious skin reactions is 0.5 to 3.8 per 100,000 prescriptions of tocainide, with fatalities in 0.9 per 100,000 prescriptions. Diaphoresis has been reported in up to 8.3% of patients.[Ref]

Psychiatric

Psychiatric side effects have included confusion/disorientation/hallucinations (2.1% to 11.2%), altered mood/awareness (1.5% to 11%), nervousness (11.5%), and anxiety (1.1% to 1.5%). Psychosis/disturbances, depression, agitation, insomnia/sleep disturbances, and dream abnormalities have been reported in less than 1% of patients.[Ref]

Respiratory

Respiratory side effects, although rare, have resulted in death. Tocainide-associated pulmonary fibrosis has occurred, most often in seriously ill patients. Symptoms of dyspnea and cough usually presented within 3 to 18 weeks of initiation of therapy. Interstitial infiltrates were seen on radiologic examination. Respiratory arrest, pulmonary edema, fibrosing alveolitis, pneumonia, interstitial pneumonitis (0.03%), dyspnea, hiccough, yawning, and smell alterations have been reported in less than 1% of patients.[Ref]

Evidence of a hypersensitivity mechanism has been reported for tocainide-associated pulmonary fibrosis.[Ref]

Hepatic

Hepatic side effects usually have been mild and transient, manifesting as slightly elevated liver function tests. Hepatitis and jaundice have been reported in less than 1% of patients.[Ref]

Immunologic

A 75-year-old man with a history of coronary artery bypass grafting and short runs of ventricular tachycardia was given tocainide (the active ingredient contained in Tonocard) 400 mg every 8 hours. Three weeks after initiation of therapy he developed unexplained malaise, chills, sweats, and fever and was given oral antibiotics. His physical exam was noncontributory; laboratory tests revealed a white blood cell count of 4,400/mm3. An evaluation of typical and atypical infectious pathogens was negative. A CT scan noted a right pleural effusion and hepatosplenomegaly. Bone marrow aspiration revealed numerous noncaseating granuloma, decreased iron stores, and 30% cellularity. A serum ANA was positive at 1:640 (speckled pattern). Resolution of all symptoms occurred within one week of discontinuing tocainide. Rechallenge was not attempted.[Ref]

Immunologic and clinical changes consistent with a lupus-like syndrome have been reported.[Ref]

Musculoskeletal

Musculoskeletal side effects such as arthritis/arthralgia (4.7%) and myalgia (1.7%), and ataxia (02.% to 10.8%) have been reported. Side effects occurring in less than 1% of patients included muscle cramps/twitches/spasms, neck pain or pain radiating from the neck, and shoulder pressure.[Ref]

Ocular

Ocular disturbances have included blurred vision in up to 10% of patients. Nystagmus occurred less frequently (1.1%).[Ref]

Other

Ototoxicity characterized by vertigo and tinnitus/hearing loss has occurred in 25.3% and 1.1% of patients, respectively. Rare incidences of earache have been reported.[Ref]

Genitourinary

Genitourinary side effects including urinary retention, polyuria, and increased diuresis have occurred in less than 1% of patients.[Ref]

Some side effects of Tonocard may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.