Safety evaluation of tocainide in the American emergency use program

Safety evaluation of tocainide Emergency 1Jse Program

in the

American

Howard R. Horn, M.D., Zareh Hadidian, Ph.D., Jeanne L. Johnson, A.B., Helen G. Vassallo, Ph.D., John H. Williams, M.D., and Michael D. Young, M.D., Ph.D. Framingham, Mass. This is a report of the safety evaluation of tocainide Tocainide Emergency Use Program. This humanitarian emergency use were unresponsive experiences lightheadedness,

reported

discontinuation conclusive

were tremors,

on therapy. laboratory of chronic

of new conduction

of life-threatening, to take the approved

neurologic nausea,

of to’cainide in evidence of permanent

safety assessment arrhythmias and

and vomiting,

16%

intractable antiarrhythmic

gastrointestinal and anorexia.

patients entered made ,tocainide

ventricular

into available

arrhythmias The most

drugs.

in nature Adverse

and included experiences

the

antiarrhythmic disturbances,

agents are convulsions,,

discussed, lupus

including erythematosus-like

dizziness, resulted

congestive

American for

in patients who frequent adverse in the

of these patients and were transient and reversible with organ injury. Adverse experiences having special relevance

but with

demonstrated life-threatening

a statistically ventricular

significant arrhythmia

decrease 8, tocainide

in Q-T duration. is a safe agent

heart illness,

and

no to the failure, deaths

while

It is concluded with a favorable

that

in risk-

ratio.

Tocainide, a new lidocaine-like oral antiarrhythmic agent, has been studied extensively in planned protocols.‘-4 In addition, this membraneactive, agent ham been available since 1974 for emergency use in patients with intractable ventricular arrhythmias. Consequently, the American Tocainide Emergency Use Program has provided a unique opportunity to evaluate the safety of tocainide in seriously ill patients treated with the drug for periods up to 41.5 months. The first 369 patients adlmitted to the program between November 30, 1974, and September 30, 1978, are the subject of tlhis report. These patients entered the protocol in response to requests by their physicians who1 had reached an impasse in the management of their life-threatening refractory ventricular arrhythmias. Over 200 practicing phyFrom

369 has

No significant abnormal trends were observed in routine hematologic and biochemical screening tests or in ophthalmologic or chest x-ray examinations. An evaluation of the effects tocainide administration on EGG intervals showed no significant change in P-K or OR.9

intervals patients benefit

in the treatment to or unable

in the first protocol

Astra

Reprint Products,

Pharmaceutical

Products,

Inc.,

Framingham,

+ 04$00.40/O

0 1980

The

C. V. Mosby

Clinical Most

Mass.

parameters frequetnt

in safety adverse

assessment

experiences

reported.

In a long-term, open-label, open-endled study of patients with severe underlying heart disease

requests: H
OOOZ-8703/80/131037

sicians participated in the program as investigators during this 4-year period. The criteria for entering the program were that the ventricular arrhythmias were consildered to be life threatening and the patients were unresponsive to or were unable to take (intolerance or contraindication) the approved antiarrhythmic drugs, quinidine, procainamide, propranolol, and subsequently disopyramide. Upon entry into the protocol, 60% of these patients were in New York Heart Association Class III or IV, demonstrating, respectively, moderate or severe compromise of cardiac status. Seventy-one (19%) patients were treated with tocainide for over 1 year, 51 (14%) for 6 to 12 months, and 107 (29%) for 1 to 6 months.

Co.

American

Heart

Journal

1037

le 1. Percentage adverse experiences

occurrence off most frequent in 369 patients treated with

tocainide

GCXt$-Oint~Stinal

34 16 15

Nausea

Vomiting Anorexia Central

nwuous

systwn

Dizziness Lightheadedness Tremoss Paresthesias Confusion Nervousness Other Palpitations Shortness of breath Rash

31 24 22 16 15 13 17 13 12

associated with life-threatening refractory ventricular arrhythmias, one should anticipate the reporting of a number of adverse experiences because of tbe long duration of exposure to a variety of factors. This was the case an the Emergency Use Program, as most patients reported one or more adverse experiences at some point during the entire period of treatment. Table percentage occurrence of the most I shows erse experiences in the 369 patients frequent in this study. The sources of data for this table include not only documented information from the conventional investigator’s data form but also all other available information, some of which may be considered undocumented. The latter sources include hospital and office charts, physician’s and nurse’s notes, physician’s correspondence, and reports of the sponsor’s site telephone contacts. Patients were inelu table if an adverse experience occurred oniy once during the entire period of treatment. The majority of reported adverse experiences were neuroc or gastrointestinaP in nature. The neurologic experiences appeared to be related to dosing, indicating a possible relation to peak blood Bevels and penetration of the blood-brain barrier, such as occurs with hdocaine. Although these mostly subjective experiences were sometimes distressful for the patients, they were usually transient in nature and reversible with no evidence of permanent organ injury.

~~~~5~~~~~~~~~~~~~ resanltin in ~~~~~~~~~~~~~ tion off nidm The adverse experiences of rtance were tltnose severe enough to greatest result in the discontinuation of tocamide therapy. This occurred in 60 (16%) of the patients in the program. The frequency distribution dtf these adverse experiences is provided in Table II. Chdy rarely was a causal relationship between toNcainicle and the adverse experience tested by a rechallenge with tocamide. In deahng with severely ill patients it is difficult to establish cause-and-effect relatiornships f~or any drug and particularly diEcult for an antiarrhythmic agent. Newrologie and gastromtestinal adverse experiences were a primary cause of discontinuation in 48 of the 60

arOpouesp3095;). Rash as the only adverse experience accounted for four patient discontinuations. In two patients recurrence sf the rash was observed- following rechallenge with tocainide. While fever was reported as an adverse experience, in only one subject did it subside with discontinuation of tocainide and return with rechallenge. One patient was discontinued because of hepatitis? csnfirmed by a liver biopsy that could not distinguish between infection and a drug reaction. Cytomegalovirus was suggested as a possible etiologic agent by the investigator. Another patient was discontinued because of elevated liver enzymes. This patient ha aortk vahe replacement just prior to starting tocainide and the bihty of a serum hepatitis must be considOne patient was discontinued (after receiv408 mg of tocainide over 24 hours) because of the development of acute pulmonary edema 5 hours after the last dose. The patient had a previous left ventricular aneurysmectomy ana was in New York Association Functional Class H&T. Underst y this patient was not rechallenged and other possible inciting factors coda not be completely ruled out. One patient was discontinued because of the development of polyasthritis and an elevated antinuclear antibody (ANA) titer. The investigator stated that other explanations could not be as the concurrent treatment wit and the recently discontinued proeainamide. One patient was discontinued because of recurrent periearditis associated with an elevated ANA titer, both of which antedated the onset of tocaine therapy. One patient d@ve~Qped what appeared on chest x-ray films LQ be an interstitial

Safety evaluation

pulmonary edema that persisted despite diuretic therapy. A lung biopsy was interpreted as showing interstitial pneumonitis. This patient was afebrile with no rash or joint symptoms and had a normal white cell count and ANA titer. Tocainide was stopped and treatment with corticosteroids begun, after which pulmonary function and chest x-ray findings improved. She was not rechallenged with tocainide, and other possible causes were not ruled out. Special therapy.

adverse

experiences

in antiarrhythmic

In the safety evaluation of a new antiarrhythmic agent there are several adverse of particular importance. These experiences include increased1 congestive heart failure, increased ventricular arrhythmia, aggravation of preexisting cardiac conduction disturbances, convulsions, and a lupus erythematosus-like syndrome. In the Emergency Program no causal relationship with tocainide to these experiences could be definitely established. Even if a causal relationship were established between tocainide and such effects, the comparison with conventional antiarrhythmic agents would be most favorable. Table III exhibits these special adverse effects for the 369 Tocainide Emergency Program patients. There were five patients in whom the initiation of tocainide therapy was reported to have possibly aggravated severe preexisting heart failure. All five patients were in New York Heart Association Functional Class IV before tocainide treatment. Three had a diagnosis of cardiomyopathy and two had coronary disease with old myocardial infarction. Only one of the patients was discontinued because of this experience and four of the patients were known to subsequently die of heart failure. It is of interest that a number of patients who were unable to tolerate disopyramide or propranlolol because of heart failure were subsequently able to tolerate tocainide. Only four patients who received an adequate trial of tocainide therapy were stopped because of an alleged increase in ventricular arrhythmia occurring during initiation of therapy. Of interest, at least eight long-term tocainide responders, with abolition or substantial reduction of lifethreatening arrhythmic events while on tocainide, had been uncontrolled and had manifested a prolonged Q-T interval during prior treatment with quinidine, procainamide, and disopyramide. There were two patients with preexisting car-

American Heart Journal

of tocainide

in Emergency

Use Program

II. Adverse experiences resulting in discontinuation among 369 patients

Table

No. of patients

Adverse experience Neurologic Gastrointestinal Neurologic/gastrointesinal Neurologic/sun sensitivity Neurologic/supraventricular Rash, fever, neurologic Rash Rash, fever, hepatitis Elevated liver enzymes Increased congestive heart Arthritis Recurrent pericarditis Interstitial pneumonitis

tachycardia

failure

Total

24

(6.5%)

12 11

(3.2%) (3.0%)

1

(0.27%)

1

(0.27%)

1

(0.27%)

4 1

(1.1%) (0.27%)

1 1

(0.27%) (0.27%)

1

(0.27%)

1 1

(0.27%) (0.27%)

60 (16.3%)

III. Adverse experiences of particular relevance in antiarrhythmic drug therapy Table

Adverse experiences Increased congestive heart failure during initiation of tocainide therapy Increase of ventricular arrhythmia during initiation of tocainide Possible aggravation of preexisting cardiac conduction disturbances Convulsions Lupus erythematosus-like illness

No. of possible occurrences in 369 patients

5 (1.4%)

4 (1.1%)

2 (0.5%) 2 (0.5%) 3 (0.8%)

disc conduction disturbances that may possibly have been aggravated by tocainide, although other explanations exist for the observed conduction changes. One patient who exhibited transient second-degree A-V block was concurrently receiving digoxin and a beta blocker and was continued on tocainide for 36 months without any subsequent conduction problem. The other patient had advanced degrees of A-V block but had recently undergone mitral valve replacement, which may be associated with transient or permanent changes in A-V conduction. Convulsions were reported to occur in two patients while on tocainide; no other obvious explanation for these convulsions exists. Both patients were women over 80 years of age; one

1039

previous brain damage from multiple cardiopulmonary resuscitations and the other had a toicanniae bhod level Qf 20 pg/ml. There were three patients in whom a lupus erythematosus-like illness was reported while on tocaaniae. Tw0 of these were aiscQntinued and had CQnfQunaing faactors preventing the aetermination d a causal relationship to tocainide. The third patient had a prior history 5f a procamamade-induced lupus-like illness, A myocardial biopsy done before tocainide was started revealed ““myocarditis,” and the possibihty of a preexisting collagen disease was raised. WbiPe on tocainide he bad intermittent arthralgias, rash, fever, light sensitivity, and proteinuria. The ANA titer Auctuated between negative and positive for 38 months of continuous tocamsde treatment, during wbieh the drug was never stopped. y. Thirty-three patients died while on tocainide therapy. Of these patients, 28 had a diagnosis of c5ronary artery disease and five had car~iom~o~at~y, Prior to tocainide therapy 58% of the 33 patients were in New York Heart Association Functional Class IV and 85% were in Class III or IV, which pIaced them in a high-risk category for death. Thirteen d the deaths (39%) were characterized as arrhythmic or sudden. Seven patients died of acute myocardial infarction, eight patients of progressive heart failure, one of a cerebrovascular accident, one of a pulmonary embolus, one of pneumonia, and in two patients the causes were unclear. Eleven of the thirteen arrhythmic deaths occurred in patients with a documented history of resuscitation for ventricular fibrillation prior to tocainide therapy. In no case did either the patient’s physician or the sponsor find conclusive or even strongly suggestive evidence that tocainide caused the death. had

No significant abnormal trends were detected in the laboratory safety screening data. This assessment included periodic measurements of hemoglobm, hematocrit, red blood cell counts, reticulocyte counts, white blood cell and differential counts, platelet counts, blood urea natrogen, creatinine, liver function, electrolytes, Coombs’ tests, ANA titers, urinalyses, ana chest x-ray films. Routine ophthalmologic examinations detected no specific toxic effect on the eye.

Electrocardiography as a parameter of drug saffety was the subject of special study. The 7bcainiae Emergency Use Program atiorded a unique opportunity to evaluate the effects of long-term oral antiarrhythmic therapy on EGG mtervals in contrast to protocol5 in which tocainide was admmistered orally for only brief perj0a5+2or intravenously.~~ 6 Accordin ation of P-R interval, QRS durati corrected Q-T interval was perfmmed retrospectively on a gr0up of 43 emergency patients wb.0 had received the drug for at l’east 6 months, with a mean of 16 months. Chronic to~cainide therapy rodueed no significant change in P-R interval or lted in a statistically sigT, duration. This latter observation may have been due to a tocainide effect or alternatively to the discontinuation of quinidine-like drugs just before or durmg tocainide therapy.

Based on this analysis of the first 369 patients in the Tocainide Emergency Program, our conclusi~ns are as follow: (I) Adverse experiences with tscainide were primarily neurologic and gastr5~~testi~a~ in nature. (2) Adverse experiences were transient and reversibPe, with no conclusive evidence of permanent organ injury. (3) Adverse experiences resulted in discontinuation of tocainide in 16% of patients. (4) In patients with Bife-threatening ventricular arrhythmias, tocainide is a safe agent with a favorable riskbenefit ratio.

~~~~~E~~~~ 1. Winkle RA,

2.

3.

4.

5.

6.

Me& PJ, Fitzgerald JW, Harrison DC: Clinical efficacy and pharmacokinetics of a new orally effective antiarrhythmic, tocainide. Circulation 54884, 1976. McDevitt DG, Nies AS, Wilkinson GR, Smith RF, Woosley RL, Qates JA: Antiarrhythmic effects of a lidocaine congener, tocainide, Z-amino-2’,6’-propionoxyh&de, in man. Clin Pharmacol Ther I Winkle RA, Meffin PJ, Harrison DC: Long-term tocainide therapy for ventricular arrhythmias. Circulation 57:1008, 1978. LeWinter MM, Engler RL, Karliner JS: Tocainide therapy for treatment of ventricular arrhythmias: Assessment with ambulatory electrocardiographic monitoring and treadmill exercise. Am J Cardiol 45:1045, 1980. Anderson JL, Mason JW, Winkle IRA, Mefhn PJ, Fowles RE, Peters F, Harrison DC: Clinical eiectrophysiologic effects of tocainide. Circulation 57685, 1978. Horowitz EN, Josephson ME, Farshidi F: Human electropharmacology of tocainide, a hdocaine congener. Am J Cardiol 42:276, 1978.