Long-term clinical experience with mexiletine

Long-term

clinical

experience

with mexiletine

Mexiletine was given to 12 patients for different periods of time varying from 4 to 96 months, with a mean of 47.8 months. At the latest follow-up in August 1983, five patients had been taking mexiletine for 74 to 96 months (mean 85 months). Mexiletine was well tolerated and serious side effects were not seen. In particular, there was no rise in antinuclear factor titer. The serum level of mexiletine was easily maintained within the therapeutic range, and most side effects correlated closely with the drug level. It is concluded that mexiletine can be administered for a long time as a safe alternative to other antiarrhythmic drugs. (AM HEART J 107:1099, 1984.)

Bengt W. Johansson, M.D., Lam Stavenow, M.D., and Arne Hanson,

Ph.D.

Malmii, Sweden

There is no ideal antiarrhythmic agent on the market today. The efficacy of available antiarrhythmic agents is often limited and side effects are common. For example, lidocaine can only be given intravenously, procainamide may induce a systemic lupus erythematosus-like syndrome,* quinidine can cause gastrointestinal side effects,2 and B-blockade may unmask latent cardiac failure. To study the side effects of long-term treatment, we administered mexiletine orally to 12 patients for periods ranging from 4 to 96 months. METHODS

Twelve patients with ventricular arrhythmias were given mexiletine for a mean period of 47.8 months (Table I). The initial dosewas209 mg three times daily, but in some casesthe dosagewas modified becauseof side effects or lack of efficacy. The patients were followed according to a strict protocol during the first 18 months (Table II). Side effects were registered and serum levels of the drug were measuredaccording to a technique previously described.3 The samephysician (L. S.) examined the patients on all occasions.Other drugs were prescribed when indicated for other conditions. The later follow-up period, after the first 18 months, included determination of hemoglobin value, sedimentation rate, glucosuria,and proteinuria at irregular intervals. Additional laboratory tests were ordered only when they were warranted by the clinical condition. In August 1983, all surviving patients were seenagain for a full examination (Table II). This included two patients who stopped taking medication in February (No. 10, Table I) and June (No. 4, Table I) 1983after 74 and 84 months, respectively. From tal. Reprint General

the Sections requests: Hospital,

of Cardiology

and

Toxicology,

Bengt W. Johansson, M.D., S-214 01 Malmii, Sweden.

M&no Section

General

Hospi-

of Cardiology,

Three patients (Nos. 5, 8, and 9, Table I) were still on mexiletine; one of these (No. 8) was abroad at follow-up and laboratory data refer to values recorded 1 to 3 years earlier. RESULTS Eighteen-month follow-up. No drug-related laboratory abnormalities were seen during the course of the study. The titer of antinuclear factor (ANF) did not rise. One patient (No. 5, Table I) had two transient rises in liver enzyme values, but they returned to normal despite continuation of mexiletine therapy. Patient 10 experienced positional vertigo, which disappeared during the course of mexiletine therapy. In summary, no toxic effects were noted in the hepatic, renal, or cardiovascular systems during the 18 months the protocol in Table II was followed. Subjective side effects included a fast finger tremor in four patients, vertigo in two, ataxia in one, and nausea in four. Tremor and nausea were most common during the first 3 to 4 weeks of treatment and disappeared later without dosage reduction. In patient 12 (Table I) the tremor was correlated with a high serum mexiletine value of 11.2 pmol/L. The other central nervous system side effects occurred when the serum mexiletine level was at the upper limit of the therapeutic range. Two patients died of nonarrhythmic causes during the study. In neither case was death attributable to mexiletine. Patient 12 died of heart failure after 6 months of treatment and patient 11 died 4 months later of pulmonary embolism. Most patients achieved serum levels of 2.8 and 8.4 clmol/L, which we found to be the therapeutic range.3 Temporary reduction of dosage in some

1099

may, 1984

Johansson,Stavenow, and Hanson

1100

Table Pt.

I. Clinical

treated

1 2 3 4 5 6 I 8 9 10 11 12 AMI within

Sex

(Yr)

M M M F M M M M M M M M

69 59

= acute myocardial parentheses could

76 57 58 70 68 62 75 59 71 65

Heart

Journal

with mexiletine

Age

No.

Abbreviations: *Side effects

data on 12 patients

American

Diagnosis

AMI AM1 IHD Idiopathic AM1 AMI AM1 AMI IHD AM1 AM1 AM1

infarction; IHD = iscbemic not be ascribed to mexiletine.

Side effects

*

Tremor (Ataxia) Tremor

Duration treatment

of

(mo)

24 24 21

VES

84 85 34

Nausea

36

(Dysarthria, nausea) Nausea, tremor Nausea (positional vertigo) Vertigo Tremor, vertigo, nystagmus heart

patients resulted in mexiletine concentrations just below the lower limit. One patient, No. 12 (Table I), had a serum level of 11.2 pmol/L while receiving 1206 mg of mexiletine daily. Foliow-up August 1983. Medication had been discontinued in seven patients after 21 to 84 months (mean 42.4 months). Two of these patients are lost to follow-up after at least 24 months on mexiletine. The drug was discontinued in two patients because the referring physician felt that the original indication for mexiletine was no longer present. The last three patients spontaneously stopped taking medication, not because of side effects but because they felt well despite a dose reduction. Three patients have continued on mexiletine for a mean of 88.7 months (range 85 to 96 months). Each patient has had continued suppression of arrhythmias on mexiletine. One of the three patients has had no side effects, whereas the other two patients experienced nausea and dizziness. The nausea disappeared in one of them after 2 months of therapy. The other experienced dizziness intermittently, always with an increased dosage and concomitantly high serum levels. The laboratory data obtained on the three patients in August 1983 failed to demonstrate any abnormal values. Laboratory tests were also normal in two patients who stopped taking mexiletine in June and February of 1983 after 84 and 74 months of therapy, respectively. One of the first three patients (No. 5, Table I) had a slight increase in liver enzymes in August 1983. As on previous occasions, this increase was attributed to gallbladder disease. DISCUSSION

Mexiletine is almost completely absorbed from the gastrointestinal tract, and when standard doses

disease;

VES

= ventricular

96 85 74 4 6

extrasystoles.

are administered, a stable serum concentration within the therapeutic range is achieved. Absorption is decreased by severe cardiac failure and concomitant administration of narcotic analgesics.* The drug is metabolized in the liver, primarily by oxidation and reduction.5 It is possible that the rate of metabolism may be influenced by cigarette smoking or exposure to enzyme-inducing agents such as phenobarbital. The percentage of unchanged drug in the urine is pH-dependent.“b7 The purpose of the present study was not to evaluate the e5cacy of mexiletine, which has been shown to be comparable to other antiarrhythmic agents.4~8-11Our results from ECGs performed over the long term in three patients show that the drug is as effective as quinidine and disopyramide in decreasing the number of ventricular extrasystoles.3 There is no evidence that either of the two deaths in our series was a result of inadequate control of arrhythmia. The side effects of mexiletine can be classified into three groups: cardiovascular, gastrointestinal, and neurologic. Cardiovascular adverse effects have been described by Roos et all2 who concluded that the drug should not be given to patients with conduction defects within or below the atrioventricular node, or to subjects with known sinus node dysfunction. We did not include patients with these conduction defects in the present study. Hypotension, sinus bradycardia, and sinus arrest are uncommon and usually occur only after intravenous administration, although these side effects have also been reported after oral administration.13 Gastrointestinal side effects, especially nausea, are the most frequently observed and seem to be related to the size of the single dose. These side effects often occur at the beginning of treatment and

Volume Number

107 5, Part 2

tend to disappear in a few weeks. There are exceptions to the rule: In one of our patients nausea persisted for 2 months. In many cases discomfort can be diminished by administering a smaller dose four times a day instead of three times. Central nervous system side effects are related to the total daily dose and the serum concentration. Certain neurologic side effects, especially tremor, occur during the first weeks of treatment and often disappear without reduction of dosage. Therapy should not be discontinued when neurologic side effects occur, since a minor reduction of dosage is often sufficient to eliminate the problem. Mexiletine had negligible effects on the laboratory profile and no toxic effects on the hepatic, renal, or hematopoietic systems. In particular, no rise in ANF was seen. It is of interest that ANF can return to normal in patients with procainamide-induced systemic lupus erythematosus (SLE) after mexiletine has been substituted for procainamide. One of our patients, not included in this series, illustrates this phenomenon: Case report. A diagnosisof sarcoidosisin a 65-year-old woman in 1969 was based on the results of skin biopsy. Ventricular ectopic beats were first noted in 1970 and were presumed to be due to myocardial sarcoidosis.An episode of ventricular tachycardia in 1970 was treated with corticosteroids and procainamide, but the patient developed an SLE syndrome with high ANF values. A change to quinidine resulted in a drug fewer after a few days. Therefore, mexiletine was administered and the antiarrhythmic result was good. The high ANF titer slowly decreaseddespite continuous mexiletine administration. The patient died of myocardial failure in August 1977.Autopsy revealed heavy myocardial fibrosis containing epithelioid granulomas.

Mexiletine was well tolerated in this series of patients and was not discontinued because of side effects in any case. Among the 10 surviving patients five have received continuous mexiletine therapy for 74 to 96 months (at the latest follow-up in August 1983). There have been no subjective side effects in two and no changes in laboratory values that can be ascribed to the drug. Two of the other five patients were lost to follow-up after at least 24 months on mexiletine, and the remaining three patients, who were free of side effects, stopped taking the drug because the original indication for therapy no longer existed. Short-term studies14s l5 show a cardiodepressive effect comparable to that of lidocaine, or no such effect at all. It is not known whether long-term treatment with mexiletine is associated with a cardiodepressive effect. One may speculate on whether mexiletine contributed to cardiac failure in patient 12. However,

Clinical

experience

with

mexiletine

1101

II. Protocol for the follow-up of patients in Table I Table

Time Before

treatment

3 days 1 mo 3 mo 6,12, and 18 mo August 1983

Tests BP, pulse rate, Hb, RBC, L, tbrombocytes, folate, cobalamines, bilirubin, ASAT, ALAT, ALP, GT, LD, Na, K, creatinine, urate, blood glucose, cholesterol, triglyceride, ANF BP, pulse rate, mexiletine serum level Same as at 3 days Same as 3 days + laboratory tests performed before treatment Same as at 3 mo Same as at 3 mo

Abbreviations: BP = blood pressure; Hb = hemoglobin concentration; RBC = red blood cell count; L = leukocytes; ASAT = aspartate aminotransferase; ALAT = alanine aminotransferase; ALP = alkaline phosphatase; GT = glutamyl transpeptidase; LD = lactate dehydrogenase; ANF = antinuclear factor.

this patient had chronic glomerulonephritis with uremia and a history of four myocardial infarctions, conditions that could very well explain the cardiac failure. No clinical symptoms or signs ascribable to mexiletine occurred in the surviving patients. We conclude that mexiletine can be given in the long term and that it is a safe alternative to other antiarrhythmic drugs. It is usually well tolerated and serious side effects are very rare. In this respect our results agree with those of other long-term studies, although those studies had shorter followup periods.16-1s The drug is especially valuable when it is desirable to avoid the gastrointestinal effects of quinidine or the SLE-inducing effects of procainamide. While mexiletine may be given intravenously, it should not be regarded as a first-line drug for this route of administration. However, it can be valuable in lidocaine-resistant arrhythmias and in digitalis toxicity.‘, *O Santinelli et a121 reported a beneficial effect of mexiletine in patients with ventricular arrhythmias in association with hypokalemia occurring after cardiac surgery. However, Gaube and Griend12* found that hypokalemia delays the effect of mexiletine and that a larger dose is required to achieve the same result as during normokalemia. REFERENCES

1. Henningsen NC, Cederberg A, Hanson A, Johansson BW: Effects of long-term treatment with procainamide. Acta Med Stand 198:475, 1975. 2. Eriksson J-E, Hanson A, Horlin R, Johansson BW, Ohlsson 0, Otto U, Syren G: Evaluation of quinidine Lipetteso-a sustained release preparation. Acta Med Stand 205:53, 1979. 3. Stavenow L, Hanson A, Johansson BW: Mexiletine in treatment of ventricular arrhythmias. Acta Med Stand 205:411, 1979.

May,1984 1102

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and Hanson

4. Jewitt

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7.

8.

9.

10.

D, McComish M, Jackson G: Ambulatory monitoring in the controlled assessment of antiarrhythmic drug therapy. Postgrad Med J 7(suppl):67, 1976. Be&et AH, Chidomere EC: The distribution, metabolism, and excretion of mexiletine in man. Postgrad Med J l(suppl):60, 1977. Kiddie MA, Kaye CM: The renal excretion of mexiletine (K6 1173) under controlled conditions of urine pH. Br J Clin Pharmacol 1:86, 1974. Kiddie MA, Kaye CM, Turner P, Shaw TRD: The influence of urinary pH on the elimination of mexiletine. Br J Clin Pharmacol 1:229, 1974. Cambell RWF, Talbot RG, Dolder MA, Murray A, Prescott LF, Julian DG: Comparison of procainamide and mexiletine in prevention of ventricular arrhythmias after myocardial infarction. Lancet 1:1257, 1975. Talbot RG, Clark RA, Nimmo J, Neilson JMM, Julian DG, Prescott LF: Treatment of ventricular arrhythmias with mexiletine (KB 1773). Lancet 2:399, 1973. Talbot RG, Julian DG, Prescott LF: Long-term treatment of ventricular arrhythmias with oral mexiletine. AM HEART J

91x58,

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11. Podrid PJ, Lown B: Mexiletine for ventricular arrhythmias. Am J Cardiol 47:895, 1981. 12. Roos J. Paalman ACA. Dunning AJ: Electrophysiological effects of mexiletine in man. Br Heart J 38:1262, -1976. 13. Sloman JG, Hunt D, Baker G, Ross D: Tolerance and side effects of oral mexiletine. In Sandoe E, Julian DG, Biell JW, editors: Management of ventricular tachycardia-role of mexiletine. In Proceedings of a symposium held in Copenhagen, May 25-27, 1978. Amsterdam, 1979, Excerpta Medica, p 329.

American

Heart

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14. Pozenel H: Klinisch-haemodynamische Untersuchungen mit Mexiletine-einem neuen Antiarrhythmikum. Hem 9:148, 1977. 15. Shaw TRD: The effect of mexiletine on ventricular ejection: A comparison with lignocaine and propranolol. Postgrad Med J l:(suppl):69, 1977. 16. Steen SN, Smith RL, Ginzton L, Criley JM: Mexiletine: Long-term therapy of cardiac dysrhythmias Am Rev Respir Dis (abstr). 121:194, 1980. 17. Uebis R, Kraemer R, Merx W, Effert S, Jacobs U: Mehrjahrige Therapie mit Mexitil: Effektivitat und Vertraglichkeit (abstr). Z Kardiol 71:181, 1982. 18. Podrid PJ, Lown B: Long-term treatment of ventricular arrhythmia with mexiletine (abstr). Circulation 66(suppl 2):11-142, 1982. 19. Henning B, Merx W, Brunner H, Hartel H: Nebenwirkungen bei Langzeitanwendung von Mexiletin. Verh Dtsch Ges Inn Med 84i742, 1978. 20. Campbell NPS, Chaturvedi NC, Shanks RG, Kelly JG, Strong JE, Adgey AAJ: The development of mexiletine in the management of ventricular dysrhythmias. Postgrad Med J l(suppl):114, 1977. 21. Santinelli V, Chiariello M, Stanislao M, Condorelli M: Intravenous mexiletine in management of lidocaine-resistant ventricular tachycardia. AM HEART J 105:680, 1983. 22. Gaube W, Griendl W: Moderne Antiarrhythmika unter besonderer Beriicksichtigung des Kaliumstoffwechsels. In Hitzenberger G, Flener R, editors: Moderne Antiarrhythmika. Munchen, 1977, Urban & Schwarzenberg, p 139.