DRUG EVALUATION

Drugs 43 (5): 734-759. 1992 00 12-666 7/92/0005-0734/$13.00/0 © Adis International Limited. All rights reserved. ORE' 99

Cibenzoline

A Review of its Pharmacological Properties and Therapeutic Potential in Arrhythmias Dean w.G. Harron, Rex N. Brogden, Diana Faulds and Andrew Fitton Department of Therapeutics and Pharmacology, The Queen's University of Belfast, Belfast, Northern Ireland, and Adis International Limited, Auckland, New Zealand

Various sections of the manuscript reviewed by: M. Andrejak, Centre Hospitalier Regional et Universitaire D'Amiens, Amiens, France; H. Atarashi, First Department of Internal Medicine, Nippon Medical School, Tokyo, Japan; F. Burkart, Departement Innere Medizin, Universitiitskliniken, Kantonsspital Basel, Basel, Switzerland; M. Cooper, Department of Cardiology, Westmead Hospital, Westmead, New South Wales, Australia; B. Flouvat, Laboratoire de Toxicologie, Hopital Ambroise-Pare, Boulogne, France; H. Hayakawa, First Department of Internal Medicine, Nippon Medical School, Tokyo, Japan; 1.1. Heger, Krannert Institute of Cardiology, Indianapolis, Indiana, USA; D.E. Hilleman, The Cardiac Center of Creighton University, Omaha, Nebraska, USA; K. Kato, The Cardiovascular Institute, Tokyo, Japan; R. Kato, Department of Cardiology, Nagoya National Hospital, Nagoya, Japan; T. Katoh, First Department of Internal Medicine, Nippon Medical School, Tokyo, Japan; R.C. Klein, Veterans Administration Medical Center, Albuquerque, New Mexico, USA; V. Kuhlkamp, Medizinische K1inik Abteilung III, Eberhard-Karls-Universitat, Tiibingen, Germany; S.M. Mohiuddin, The Cardiac Center of Creighton University, Omaha, Nebraska, USA; I. Morganroth, Center of Excellence for Cardiovascular Studies, Philadelphia, Pennsylvania, USA; T. Ozawa, Department of Biomedical Chemistry, University of Nagoya, Nagoya, Japan; A.C. Rankin, Department of Medical Cardiology, Royal Infirm~ry, University of Glasgow, Glasgow, Scotland; S. Saksena, Arrhythmia and Pacemaker Service, Eastern Heart Institute, New Jersey Medical School, Newark, New Jersey, USA; G. Schmidt, First Department of Medicine, Technische Universitat Miinchen, Miinchen, Federal Republic of Germany; R.G. Shanks, Department of Therapeutics and Pharmacology, The Queen's University of Belfast, Belfast, Northern Ireland.

Contents 735 737 737 737 737 740 740 741 741 742 742 745 745 746 747 749

Summary I. Pharmacodynamic Properties 1.I Electrophysiological Properties 1.1.I Effects in Isolated Animal Preparations 1.1.2 Effects in Intact Animals 1.1.3 Effects in Humans 1.2 Antiarrhythmic Activity in Animal Models 1.3 Haemodynamic Effects 1.3.1 Effects in Animal Models 1.3.2 Effects in Patients with Cardiovascular Disease 2. Pharmacokinetic Properties 2.1 Absorption and Distribution 2.2 Metabolism and Excretion 2.3 Effects of Age and Disease 2.4 Plasma Concentration and Clinical Effect 3. Therapeutic Use

735

Cibenzoline: A Review

749 749 751 752 753 754 755 755 756

4. 5. 6. 7.

3.1 Ventricular Arrhythmias 3. I.I Comparisons with Other Antiarrhythmic Agents 3.2 Supraventricular Arrhythmias 3.2.1 Comparisons with Other Antiarrhythmic Agents 3.3 Use in Patients with Cardiovascular Disease Tolerability Drug Interactions Dosage and Administration Place of Cibenzoline in Therapy

Summary Synopsis

Cibenzoline is a class I antiarrhythmic drug with limited class III and IV activity which can be administered orally or intravenously. An elimination half-life of about 8 to 12 hours permits twice daily administration. although age and renal function must be considered when determining dosage. Cibenzoline has some activity in ventricular and supraventricular arrhythmias. including drug-refractory ventricular tachycardia or ventricular arrhythmias following recent acute myocardial infarction. although results in patients with sustained ventricular tachycardia are less promising. In comparative trials. cibenzoline has demonstrated efficacy similar to or better than that of a variety of other class I antiarrhythmic drugs and was at least as well tolerated. with a more convenient dosage schedule. However. further studies to clarify the proarrhythmic effects of cibenzoline and its use in patients with impaired left ventricular function are required. and the use of cibenzoline (and other class I antiarrhythmic agents) in patients with other than potentially lethal ventricular arrhythmias should be avoided following the results of the CAST studies. Thus. cibenzoline is an effective antiarrhythmic agent with afavourable pharmacokinetic profile that may be considered with other class I drugs in patients requiring therapy for high risk arrhythmias. Pharmacodynamic Properties In isolated tissues cibenzoline exhibits class I and to a lesser extent, class III and IV antiarrhythmic activity. In intact animals intravenous cibenzoline increases atrial refractory periods, atrioventricular nodal, intraventricular and His-Purkinje (HV) conduction times, and ventricular refractory periods. Stroke volume decreases as a result of the direct negative inotropic action of cibenzoline combined with an increase in systemic vascular resistance. In patients with arrhythmia cibenzoline produces dose-proportional increases in QRS (~ 33%), QTc (~ 12%), AH (~ 14%), and HV (~ 47%) intervals, and ventricular effective refractory period (~9%). In conjunction with the pronounced decrease in maximum upstroke velocity of the action potential (Vmax ), this indicates a predominantly class Ie profile. Contrary to the bradycardic effect seen in isolated tissues and intact animals, cibenzoline either increases or has no effect on heart rate in man. This may be due to vagolytic activity or to a baroreflex-mediated increase in heart rate due to reported decreases in blood pressure. Cibenzoline also exerts a negative inotropic effect following single-dose intravenous administration, with significant transient decreases in the rate of change of left ventricular pressure, ejection fraction and stroke volume index, accompanied by an increase in vascular resistance, occurring within the therapeutic range of plasma concentrations. Afterload reduction in compensation for the negative inotropic effect appears to occur with longer term oral administration, but these effects require that cibenzoline be used with caution in patients with depressed left ventricular function. Pharmacokinetic Properties Cibenzoline can be administered both intravenously and orally; bioavailability after oral administration is about 85%, with peak plasma concentrations occurring I to 3 hours post dose. The plasma concentration-time profile is best described by a 3-compartment model in healthy

Drugs 43 (5) 1992

736

subjects and a 2-compartment model in patients with acute myocardial infarction. The volume of distribution is large at 4.1 to 7.3 L/kg, and protein binding is 50 to 60%. In humans, 30 to 65% of cibenzoline is excreted unchanged in the urine; total clearance ranges from 30 to 50 L/h and renal clearance from 17 to 30 L/h. In patients with renal impairment and in the elderly, renal clearance of cibenzoline decreases and elimination half-life increases from about 7.5 to more than 20 hours. Plasma concentrations of cibenzoline associated with the abolition of arrhythmias ranged from 293 to 569 ILg/L. In general, a trough plasma concentration greater than 300 ILg/L was associated with antiarrhythmic activity.

Therapeutic Use Cibenzoline has been evaluated in both ventricular and supraventricular tachyarrhythmias. Noncomparative and placebo-controlled trials have demonstrated the efficacy of cibenzoline in patients with arrhythmias, including patients with ventricular arrhythmias refractory to established antiarrhythmic agents. In small comparative studies, cibenzoline was at least as effective as quinidine, disopyramide, mexiletine, aprindine, lidocaine (lignocaine) and nadoxolol in patients with ventricular arrhythmias (cibenzoline response rate 38 to 78%), and as effective as flecainide, quinidine and disopyramide in patients with supraventricular arrhythmias (cibenzoline response rate 36 to 76%). However, results in patients with sustained ventricular tachycardia are less promising (cibenzoline response rate 28 to 54%). Few studies have evaluated the effects of underlying organic cardiovascular disease on the response to cibenzoline therapy. While beneficial effects on haemodynamic functional parameters have been observed with short term cibenzoline administration in this patient group, the effects in patients with a reduced ejection fraction have been variable and considerable caution is recommended in these patients.

Tolerability Cibenzoline has been relatively well tolerated in clinical trials and was usually at least as well tolerated as other antiarrhythmic agents in comparative studies. Gastrointestinal adverse effects, nervousness and tremulousness, and to a lesser extent blurred vision, dry mouth, urinary retention, hypotension/syncope, and asymptomatic increa-ses in liver transaminases and decreases in white blood cell counts have been observed. Prolongation of PR and QRS intervals may also occur and occasional cases of bundle branch block and exacerbation of congestive heart failure have been noted. Limited studies suggest cibenzoline has proarrhythmic effects comparable to other antiarrhythmic agents. As cibenzoline influences the ECG and has a negative inotropic effect, care must be taken when administering other cardioactive agents concomitantly.

Dosage and Administration Cibenzoline dosage should be individually titrated although in clinical trials most patients responded to 130 to 160mg twice daily orally. Cibenzoline is available as the 130mg formulation. In Japan 50 or IOOmg 3 times daily of the cibenzoline succinate has been used. Dosage requirements are reduced in the elderly and it has been recommended that patients with renal dysfunction receive two-thirds the normal dosage once daily, while those with renal failure receive one-third the normal dose 12-hourly or the normal dose 36- to 48-hourly. Plasma concentrations should be monitored initially in patients with compromised renal function, and left ventricular function should be monitored in patients with a severely reduced ejection fraction. Cibenzoline I to 1.75 mg/kg intravenously has been administered in patients with supraventricular arrhythmias and 1 to 3 mg/kg in patients with ventricular arrhythmias, but the use of intravenous cibenzoline has not been well characterised.

737

Cibenzoline: A Review

1. Pharmacodynamic Properties Cibenzoline (cifenline) [fig. 1] is a class I (sodium channel blockers) antiarrhythmic drug which also exhibits some class III (potassium channel blockers) and IV (calcium channel blockers) antiarrhythmic activity.

> 75% ~ VPC frequency

45% (9/20)

PO x '" 18m Palakurthy et al. (1987)

r, co

VTns (14) VC (3) VPC (3)

C 130 or bid PO x Q 300 or qid PO x

160mg 2-3w 400mg 2-3w

C~D

t VPC (2); other (5) t VPC (5); other (11) t VPC (3); other (8)

29% (5/17)

PO

C 2.5 mg/kg then 0.2-0.4 mg/kg/h IV L 1.5 mg/kg then 2-4 mg/min IV

C> PI

~

PO PO

C> PI

20% (4/20)

P~C

Withdrew (3); sudden death (1)

C==Q

C~Q

C~Q

Cibenzoline: A Review

751

Table VII. Contd Reference

Study design

Diagnosis (no. of patients

Treatment regimen

Response criteria

Response rate Adverse effects (no. of patients)

Wasty et al. (1985)a

r, co

VTns (10) VC (2) VPC (1)

C 130-160mg bid PO x 7d

~ 70% l VPC frequency

54% (6/11)

a 300-400mg qid

38% (5/13)

PO x 7d Aprindine (A), disopyramide (0), or mexiletine (M) Tanabe et pi VT (67) C 50-100mg tid VPC (39) PO x 1-3w al. (1988) A 20mg bid PO x 1-3w D 100mg tid PO x 1-3w M 100-150md tid PO x 1-3w

~ 90% l VPC frequency

Death (1); proarrhythmia (1); other (3) Withdrew (2); proarrhythmia (4); other (11)

Relative efficacy

C

~

a

28% (5/18) 31% (9/29)

Withdrew (1)

26% (11/43)

Withdrew (1)

30% (13/44)

Withdrew (4)

a Predominantly or exclusively patients with drug-refractory arrhythmias. b Patients previously responding to cibenzoline in a short term noncomparative study. Abbreviations: db = double-blind; sb = single-blind; r = randomised; pi = parallel; co = crossover; VPC = ventricular premature complexes; VC = ventricular couplets; MI = myocardial infarction; VA = ventricular arrhythmia; VT = ventricular tachycardia; s = sustained; ns = nonsustained; PES = programmed electrical stimulation; d = days; w = weeks; m = months; PO = oral; IV = intravenous; bid = twice daily; tid = 3 times daily; qid = 4 times daily; t = increased; l = decreased; == indicates similar overall efficacy; ~ indicates tendency toward greater overall efficacy; > indicates significantly greater overall efficacy.

(table VII). However, cibenzoline tended to be better tolerated than the other drugs and its dosage schedule was usually more convenient. In other studies, cibenzoline prevented induction of ventricular tachycardia in 16 of 33 patients, compared with 18 of 26 on disopyramide and 6 of 20 on lidocaine (lignocaine) [Miura et al. 1984, 1985], and cibenzoline 260 mg/day produced a degree of VPC suppression similar to that achieved with disopyramide 400 mg/day but considerably better than that seen with nadoxolol 1000 mg/day (Baligadoo & Chiche 1978). Tanabe et al. (1988) found cibenzoline, aprindine, disopyramide and mexiletine were of similar antiarrhythmic efficacy in Japanese patients with ventricular arrhythmias [table VII] but that mean therapeutic plasma drug concentrations (0.27,0.85, 1.76 and 1.08 mg/L, respectively) were lower than those observed in studies involving Western patients reflecting the lower dosage used. A more

recent Japanese study reported cibenzoline 450 mg! day was of superior antiarrhythmic efficacy to disopyramide 300 mg/day in patients with VPCs (Kato et al. 1989b). Comparative studies including patients with sustained ventricular tachycardia are very limited (see table VII), and the role of cibenzoline in this indication cannot be clearly defined as yet. 3.2 Supraventricular Arrhythmias Oral cibenzoline 260 to 450 mg/day has demonstrated antiarrhythmic efficacy in noncom parative trials in patients with paroxysmal supraventricular tachycardia (PSVT), atrial fibrillation, atrial flutter and atrial premature complexes (table VIII), and a dose proportional effect has been reported (Atarashi et al. 1988b). Efficacy observed with short term oral cibenzoline treatment has been maintained during continued treatment in studies of up

752

Drugs 43 (5) 1992

to 2.6 years' duration (Atarashi et al. 1988a; Kiihlkamp et al. 1990a; Sugai et al. 1988; Yokoyama et al. 1988). 3.2.1 Comparisons with Other Antiarrhythmic Agents Oral cibenzoline 260 or 360 mgjday and oral flecainide 200 or 300 mgjday were of similar efficacy in patients with atrial tachycardias, including atrial flutter or fibrillation (table IX). Oral cibenzoline restored sinus rhythm in 7 of 19 patients with atrial fibrillation and in none ofthe 9 patients

Table VIII.

who were previously unresponsive to flecainide; flecainide restored sinus rhythm in 7 of 23 patients including 4 of II previously unresponsive to cibenzoline. During subsequent long term therapy atrial fibrillation recurred in 2 patients in each treatment group (Kiihlkamp et al. 1991). Intravenous administration produced similar rates of conversion to sinus rhythm in patients with atrial fibrillation, but cibenzoline was significantly more effective in atrial flutter and flecainide was more effective in other atrial tachycardias (Metz et al. 1990).

Noncomparative trials of cibenzoline in the treatment of supraventricular tachyarrhythmias (SVT)

Reference

Diagnosis (no. of patients)

Cibenzoline

Response criteria

Response rate

Comment (no. of patients)

Atarashi et al. (1988b)

APC (42); PSVT (25); PAF/PAFI (36)

50-200mg tid PO ~ 7m

~ 75% ~ SVT frequency

51% (13/29 APC + 14/18 PSVT + 13/26 PAF/PAFI)a

Withdrew (5); other adverse effects (9)

Atarashi et al. (1988c)

WPW (4); AVNRT (2)

1.4 mg/kg IV

33% (2/4 WPW AVNRT)

Kato et al. (1989d)

AVRT (10)

1.4 mg/kg IV

Kato et al. (1990)

APC (7)

1.4 mg/kg IV

Unable to induce arrhythmia with PES Unable to induce arrhythmia with PES ~ 75% ~ APC frequency Arrhythmia suppression Unable to induce AF with PES Arrhythmia suppression ~ 75% ~ SVT frequency Accessory pathway block Arrhythmia termination

Arrhythmia termination

60% (7/12)

Kuhlkamp et al. (1990a)

PSVT (2); AF (1); AFI (1); PAF (1) PAF (25) PAF (8)

Sugai et al. (1988) Thebaut et al. (1980) Waleffe et al. (1985)

Yokoyama et al. (1988)

1.5 mg/kg IV 160mg bid PO x 7m

APC (5), PAF/PAFI (8) 300-600 mg/day POx~20m

WPW(8)

1 mg/kg IV

AVNRT (5), WPW (6) IART (1)

1-1.75 mg/kg IV

PSVT, PAF, PAFI (12)

100-150mg tid PO x ~ 6m

+ 0/2

60% (6/10)

Other adverse effects (4)

86% (6/7) 80% (4/5)

AF/AFI persisted (7) or induced (8)

40% (10/25) 50% (4/8) 77% (4/5 APC PAF/PAFI) 43% (5/8) 75% (9/12)

+ 6/8 Partial block (2) Arrhythmia induced on PES (8 [2/5 AVNRT + 6/6 WPWj) Withdrew (2)

a Results for patients receiving cibenzoline 300 mg/day are reported. Abbreviations: AF = atrial fibrillation; AFI = atrial flutter; AVNRT = AV nodal re-entry tachycardia; AVRT = atrioventricular re-entry tachycardia; IART = intra-atrial re-entry tachycardia; PAF = paroxysmal atrial fibrillation; PAFI = paroxysmal atrial flutter; PSVT = paroxysmal supraventricular tachycardia; APC = supraventricular premature complexes; WPW = Wolff-Parkinson-White syndrome; PES = programmed electrical stimulation; m = months; bid = twice daily; tid = 3 times daily; PO = oral; IV = intravenous.

Cibenzoline: A Reyiew

753

Table IX. Comparison of the effects of cibenzoline (C) with other antiarrhythmic agents in patients with supraventricular arrhythmias Reference

Study design

Oisopyramide (D) Kato et al. r, db, pi (1989a)

Diagnosis (no. of patients

Treatment regimen

Response criteria

Response rate

Adverse effects (no. of patients)

APC (52)

C 450 mg/day PO

~ 75% ~ APC frequency

43% (12/28)

t APC (4); other (6) t APC (4); other (3)

D 300 mg/day PO Flecainide (F) KGhlkamp et al. (1991)

Metz et al. (1990)

(0) Frances et al. (1985)

r, co/pi

pi

AF (31)

AF (31) AFI (18) AT (11)

33% (8/24)

C 260 or 360 mg/d PO x 5d then 9m F 200 or 300 mg/d PO x 5d then 9m C 1 mg/kg then 8 mg/kg/d IV x 1d F 1.5 mg/kg then 4.3 mg/kg/d IV x 1d

RestOl'ation of sinus rhythm

C 260 mg/day PO x 6m Q 824 mg/day PO 6m

Maintenance of sinus rhythm

81% (34/42)

Maintenance of sinus rhythm

36% (4/11) 23% (3/13)

Restoration of sinus rhythm

25% (7/28) [67% (4/6) long term] 30% (7/23) [67% (4/6) long term] 53% (16/30)

Other (2) Asystole (1); other (2) Proarrhythmia (2)

Relative efficacy

C==D

C==F

C==F

53% (16/30)

~uinidine

Keefe et al. (1985)

r, db, pi

r, sb, pi

AF/AFI (89)

AF (23) AFI (1)

C 65mg qid PO Q 200mg qid PO

x

60% (28/47)

Withdrew (4); other (9) Withdrew (2); AV block (1); other (11) Withdrew (1) Withdrew (2)

C>Q

C~Q

Abbreviations: db = double-blind; sb = single-blind; r = randomised; pi = parallel; co = crossover; APC = atrial premature complexes; AF = atrial fibrillation; AFI = atrial flutter; AT = atrial tachycardia; d = days; m = months; PO = oral; IV = intravenous; qid = 4 times daily; = increased; ~ = decreased; == indicates similar overall efficacy; ~ indicates tendency toward greater overall efficacy; > indicates significantly greater overall efficacy.

t

Cibenzoline 260 mg/day prevented the recurrence of atrial fibrillation in a larger number of patients than quinidine 824 mg/day during the first 2 weeks (p < 0.04) and after 6 months (p < 0.03) of therapy (Frances et al. 1985). Keefe et al. (1985) reported cibenzoline 260 mg/day was at least as effective as quinidine 800 mg/day in maintaining sinus rhythm in patients with atrial fibrillation or flutter who had been electrically converted (table IX). A recent Japanese study in patients with atrial premature complexes reported cibenzoline 450 mg! day and disopyramide 300 mg/day were of similar efficacy (Kato et al. I 989a).

3.3 Use in Patients with Cardiovascular Disease Patients with arrhythmias and underlying cardiovascular disease are an at-risk group, with a higher incidence of sudden death than patients with idiopathic arrhythmia (Brugada et al. 1991; Meinertz et al. 1991). Several studies evaluating the use of cibenzoline have included patients with myocardial infarction, cardiomyopathy, hypertension, coronary artery disease, angina pectoris, and/ or valvular disease (for example, Atarashi et al. 1988a; Frances et al. 1985; Kostis et al. 1989; Kuhlkamp et al. 1991; Mohiuddin et al. 1987, 1989; Palakurthy et al. 1987), but few have evaluated the

Drugs 43 (5) 1992

754

effects of underlying disease on the response to treatment. Desoutter et al. (1983) studied 10 patients with suspected recent myocardial infarction and either 50 VPCs or dangerous (repeated, polymorphous or early, with R/T phenomenon) VPCs in the hour preceding drug administration. Two bolus doses of cibenzoline 0.5 mg/kg administered intravenously 5 minutes apart, followed 30 minutes later by a continuous infusion of 0.2 to 0.4 mg/kg/h for 22 (mean) hours, significantly reduced VPCs and more dangerous arrhythmias in 8 of 10 patients, but I patient with an anterior myocardial infarction developed transient bifascicular block at the end of infusion. A comparative study evaluating cibenzoline, aprindine, disopyramide and mexiletine in patients with ventricular arrhythmias found that disopyramide was more effective in patients with organic heart disease than in those patients with idiopathic arrhythmia, but this effect was not observed for the other 3 drugs (Tanabe et al. 1988). However, the small number of patients receiving each treatment make conclusions difficult to draw from this study. In a comparison of cibenzoline and flecainide in patients with atrial tachycardia, cibenzoline was more effective in patients with ischaemic heart disease whereas flecainide was more effective in patients with valvular disease (Metz et al. 1990). Cocco et al. (1984) reported that all 5 of 28 patients with ventricular tachycardia who responded to cibenzoline therapy had ischaemic heart disease; nonresponders had ischaemic heart disease (n = 15) or primary cardiomyopathy (n = 8). Thus, evaluation of the use of cibenzoline in patients with arrhythmias and underlying cardiovascular disease is largely incomplete and it remains to be established whether there are subgroups of these patients who may respond particularly well to cibenzoline therapy.

4. Tolerability Cibenzoline has been relatively well tolerated by patients in clinical trials and in comparative studies was usually at least as well tolerated as other

antiarrhythmic agents (tables VII and IX). Adverse events associated with cibenzoline include gastrointestinal upsets (nausea, vomiting, abdominal pain and constipation), nervousness and tremulousness and to a lesser extent, blurred vision, dry mouth, urinary retention, hypotension/syncope, asymptomatic increases in liver transaminases, and decreases in white blood cell count (for example Atarashi et al. 1988c; Brazzell et al. 1984b; Humen et al. 1987; Kato et al. 1988; Klein et al. 1986). There have also been several reports of hypoglycaemia in patients receiving cibenzoline, both in overdose and at therapeutic plasma concentrations, occasionally associated with excessive insulin secretion (Gachot et al. 1988; Gross et al. 1990; Hilleman et al. 1987; Houdent et al. 1991; leandel et al. 1988; Moriya et al. 1990; Noury & Delvaux 1989). Hyperkalaemia has also been observed (Bauer et al. 1989; Hilleman et al. 1987; Wyss et al. 1990) and has been successfully treated with lactate in 1 case (Bauer et al. 1989) but not in another (Wyss et al. 1990). Proteinuria has been reported in some patients, but evidence suggests that bromphenol reagent strips produce a false-positive proteinuria test in cibenzoline recipients (Kovacs et al. 1984). An analysis of patients with an adverse haemodynamic response (cardiogenic shock and intraventricular block) to cibenzoline in a placebo-controlled study found that they had a significantly higher resting heart rate (97 vs 77 beats/min) and pulmonary capillary wedge pressure during exercise (45 vs 31 mm Hg), and a significantly lower cardiac index during exercise (2.2 vs 3.7 L/min/ m 2) and stroke volume index both at rest (17 vs 33 ml/m2) and during exercise (18 vs 33 ml/m2) than did patients without an adverse haemodynamic response (Aymard Dufour & Spriet Pourra 1988; Seals et al. 1987). Assessment of the haemodynamic effects of cibenzoline in patients with cardiac disease revealed beneficial effects on functional parameters with short term oral cibenzoline administration (Seals et al. 1987). However, the effects of cibenzoline on LVEF appear unpredictable and caution is advisable in patients in whom left ventricular function is reduced (section 1.2.2).

755

Cibenzoline: A Review

Assessment of the arrhythmogenicity of antiarrhythmic agents has become increasingly important as almost all antiarrhythmic agents have the potential to produce proarrhythmic effects. Proarrhythmia may be associated with prolongation of the QT interval, but whether this initiates arrhythmia is also determined by the presence of electrolyte disturbances, bradycardia, polymorphic VPCs, a long QT interval at baseline and concomitant therapy with other agents with the potential to prolong QT interval. Patients with pre-existing myocardial abnormalities have the greatest risk of developing proarrhythmias (Zehender at al. 1991). Cibenzoline has been associated with a doseproportional prolongation of the QT interval in electrophysiological studies, predominantly as a result of an increase in QRS duration, although this is not as marked as that seen with some other antiarrhythmic agents (table III; section 1.1). PR interval is also increased during cibenzoline therapy and bundle branch block has been observed in several studies (for example Kostis et al. 1989). A study of 181 patients with drug-refractory ventricular arrhythmias (mean 2 previous unsuccessful trials), investigated the arrhythmogenicity of antiarrhythmic drugs following programmed electrical stimulation (Torres et al. 1985). Drugs causing worsening of arrhythmias in 15% or more of cases included lidocaine, flecainide, verapamil, cibenzoline, and moricizine. However, the small number of tests with each drug meant there were no significant differences in proarrhythmic effects detected between drugs. Cibenzoline produced a reduction in the number of stimuli required to provoke ventricular tachycardia in 4 of 34 cases and conversion of nonsustained tachycardia to sustained tachycardia in 3 of 34 cases. In comparative trials cibenzoline exhibited arrhythmogenicity similar to other antiarrhythmic agents, although the relatively small numbers of patients in these trials, most of whom did not have concurrent left ventricular dysfunction, precludes definite conclusions (tables VII and IX).

5. Drug Interactions Cibenzoline through necessity has been given in combination with other cardioactive drugs in nu-

merous clinical trials, and no significant pharmacodynamic interactions have been identified. However, as cibenzoline influences the ECG and may have a negative inotropic effect, care must be taken when it is administered in conjunction with other drugs having a similar effect. Kushner et al. (1984) reported that 2 of 5 patients with high serum cibenzoline concentrations had a history of congestive heart failure and were concomitantly taking digitalis. However, a study in healthy subjects found no evidence of a pharmacokinetic interaction between the drugs when coadministered (Khoo et al. 1988).

6. Dosage and Administration The dosage of cibenzoline should be individually titrated according to each patient's needs and clinical state, taking into account age, renal function and concomitant administration of other cardioactive drugs. Oral cibenzoline 130 to 160mg twice daily, the dosage frequently used in clinical trials has shown antiarrhythmic activity in both ventricular .and supraventricular tachyarrhythmias, although much higher doses (up to 700 mg/ day) have been required in some patients, particularly those with drug-refractory ventricular arrhythmias. However, only the 130mg formulation is currently available. In Japan, dosages of 50 or IOOmg 3 times daily are recommended (data on file, Fujisawa Pharmaceutical Company). Patients responding to treatment usually had plasma concentrations of cibenzoline greater than 300 ~g/L. Dosage requirements are reduced in the elderly and in patients with renal dysfunction, and plasma cibenzoline concentrations should be monitored initially in these patients. It has been recommended that patients with renal insufficiency receive twothirds ofthe normal dosage once daily, and patients with renal failure should receive one-third the normal dose 12-hourly or the normal dose every 36 to 48 hours (Aronoff et al. 1991). Haemodialysis does not remove cibenzoline to an appreciable degree (Aronoff et al. 1991). Patients with a severely reduced LVEF should be monitored for any worsening of left ventricular function. The use of intravenous cibenzoline has not been

Drugs 43 (5) 1992

756

as well characterised. However, doses of 1 to 1.75 mg/kg have been used effectively in supraventricular arrhythmias and 1 to 3 mg/kg has been effective in patients with ventricular arrhythmias. Dahl et al. (1987) found the intravenous formulation of cibenzoline was compatible with other drugs commonly given intravenously in the acute care setting.

7. Place of Cibenzoline in Therapy The ideal antiarrhythmic drug, as well as being effective against lethal arrhythmias, should also possess several other properties including pharmacokinetic properties unaltered by disease state, renal function, etc., an acceptable dosage regimen, no negative inotropic effect, a wide therapeutic range, no active metabolites and good tolerability. Cibenzoline has dose-proportional pharmacokinetic properties, and a reasonably long elimination half-life permitting a twice daily dosage regimen in most patients, thus facilitating patient compliance. As with most other antiarrhythmic agents, dosage must be adjusted according to patient age and factors influencing the major route of elimination; that is, in patients with renal dysfunction receiving cibenzoline. The negative inotropic effect of cibenzoline is comparable to that of disopyramide and warrants considerable caution in patients with depressed left ventricular function. This may limit the therapeutic usefulness of cibenzoline in patients with sustained ventricular tachycardia, many of whom have depressed left ventricular function, although there is some evidence that with continued oral administration, reduction of afterload may compensate for the negative inotropic effect. In comparative studies cibenzoline was of equivalent or superior efficacy compared with a variety of class I or II antiarrhythmic agents. Although cibenzoline provided effective suppression of supraventricular and ventricular tachycardias in a majority of patients, including those with drugrefractory arrhythmias, it was less effective against sustained ventricular tachycardia. As with most other antiarrhythmic agents the relevance of this

endpoint versus its effectiveness in preventing 'sudden death' remains to be evaluated, and long term studies including evaluation of mortality rates are required. However, in view of the findings of the CAST studies (Investigators of the Cardiac Arrhythmia Suppression Trial 1989: Steinbeck 1991), it seems prudent that the use of class I agents, including cibenzoline, is limited to patients with lethal (sustained) ventricular arrhythmias. Thus, cibenzoline is a moderately effective class I antiarrhythmic agent with a favourable pharmacokinetic profile. It also appears to have an equivalent or lower incidence of adverse events than several other class I antiarrhythmic drugs, although the incidence of proarrhythmic events and its effects in patients with depressed left ventricular function require clarification. Nonetheless, if further comparative studies in larger numbers of patients confirm the present findings, cibenzoline could offer an attractive alternative in high risk patients where class I antiarrhythmic agents are indicated.

References Arena JP, McArdle JJ, Laxminarayan S. Characterization of the class I antiarrhythmic activity of cibenzoline succinate in guinea pig papillary muscle. Journal of Pharmacology and Experimental Therapeutics 240: 441-450, 1987 Aronoff G, Brier M, Mayer ML, Barbalas M, Aogaichi K, et al. Bioavailability and kinetics of cibenzoline in patients with normal and impaired renal function. Journal of Clinical Pharmacology 31: 3844,1991 Atarashi H, Hayakawa H, Kato K, Iinuma H, Hosoda S, et al. Clinical experience of cibenzoline on various arrhythmias in long-term therapy. In Japanese. Rinsho Iyaku 4: 2331-2342, 1988a Atarashi H, Hayakawa H, Kato K, Iinuma H, Hosoda S, et al. Study of clinical effect and safety of cibenzoline on supraventricular arrhythmia. In Japanese. Rinsho Iyaku 4: 1851-1867, 1988b Atarashi H, Iida K, Kou M, Hirayama Y, Gotoh M, et al. Electrophysiologic effects of intravenous cibenzoline succinate, a new class I antiarrhythmic agent. In Japanese Kokyu to Junkan 36: 11191124, 1988c Aymard Dufour MF, Spriet Pourra C. Choc Cardiogenique et bloc intra-ventriculaire majeur au cours d'un traitment par la cibenzoline. Therapie 43: 243-244, 1988 Baligadoo S, Chiche P. Beneficial effects of U.P. 339.01 a new antiarrhythmic agent against ventricular premature beats. Abstract 692. Circulation 58: 11-179, 1978 Bauer Ph, Bollaert PE, Sadoul N, Lambert H, Larcan A. Emploi du Ringer lactate dans I'intoxication a la cibenzoline. Presse Medicale 18: 588, 1989 Bommer W, Seher R, Reffeira p, Tam K, Rebeck K, et ai. Safety and efficacy of cibenzoline versus quinidine for ventricular arrhythmias. Abstract. Clinical Research 33: 4A. 1985 Boucher M, Dubray C. Kantelip JP, Talmant JM. Dufour a, et al. Cardiac electrophysiological effects of cibenzoline in the conscious dog: plasma concentration-response relationships. Journal of Cardiovascular Pharmacology 14: 616-621. 1989

Cibenzoline: A Review

Brazzell RK, Aogaichi K, Heger Jr JJ, Somberg JC, Carliner NH, et al. Cibenzoline plasma concentration and antiarrhythmic effect. Clinical Pharmacology and Therapeutics 35: 307-316, 1984a Brazzell RK, Colburn WA, Aogaichi K, Szuna AJ, Somberg JC, et al. Pharmacokinetics of oral cibenzoline in arrhythmia patients. Clinical Pharmacokinetics 10: 178-186, 1985a Brazzell RK, Khoo K-C, Szuna AJ, Sandor D, Aogaichi K, et al. Pharmacokinetics and pharmacodynamics of intravenous cibenzoline in normal volunteers. Journal of Clinical Pharmacology 25: 418- 423, 1985b Brazzell RK, Rees MMC Khoo K-C Szuna AJ, Sandor D, et al. Age and cibenzoline disposition. Clinical Pharmacology and Therapeutics 36: 613-619, 1984b Browne KF, Prystowsky EN, Zipes DP, Chilson DA, Heger JJ. Clinical efficacy and electrophysiologic effects of cibenzoline therapy in patients with ventricular arrhythmias. Journal of the American College of Cardiology 3: 857-864, 1984 Brugada P, Andries EW, Mont L, Gursoy S, Willems H, et al. Mechanisms of sudden cardiac death. Drugs 41 (SuppI.2): 16-23, 1991 Canal M, Flouvat B, Aubert P, Guedon J, Prinseau J, et al. Pharmacokinetics of cibenzoline in patients with renal impairment. Journal of Clinical Pharmacology 25: 197-203, 1985 Canal M, Flouvat B, Tremblay D, Dufour A. Pharmacokinetics in man of a new antiarrhythmic drug, cibenzoline. European Journal of Clinical Pharmacology 24: 509-515, 1983 Cazes M, Chassaing C Martinet M, Cloaree A, Provost, D, et al. Comparison of anticholinergic effects of cibenzoline, disopyramide, and atropine. Journal of Cardiovascular Pharmacology 15: 308-316,1990 Clementy J, Aymard M-F, Coste P, Bonnet J. Etude comparative en double aveugle de refficacite et de la tolerance de la cibenzoline et du disopyramide dans Ie traitement des extrasystoles ventriculaires stables. Medecine et Hygiene 44:3377-3381 , 1986 Cocco G, Strozzi C, Pansini R, Rochat N, Bulgarelli R. et al. Antiarrhythmic use of cibenzoline, a new class I antiarrhythmic agent with class 3 and 4 properties, in patients with recurrent ventricular tachycardia. European Heart Journal 5: 108-114, 1984 Dahl JM, Roche VF, Hilleman DE. Visual compatability of cibenzoline succinate with commonly used acute-care medications. American Journal of Hospital Pharmacy 44: 1123-1125, 1987 Dangman KH. Cardiac effects of cibenzoline. Journal of Cardiovascular Pharmacology 6: 300-311, 1984 Desoutter P, Dufour A, Aymard MF, Haiat R. Pharmacokinetic study of a new anti-arrhythmic drug, cibenzoline, during the acute phase of myocardial infarction: therapeutic correlations. In Levy S, et al. (Eds) Recent advances in cardiac arrhythmias, Vol 1. pp. 288-293, John Libbey, London, 1983 Dixon R, Carbone J, Tilley J, Liu Y-Y. Radioimmunoassay for the new antiarrhythmic agent cibenzoline in human plasma. Journal of Pharmaceutical Sciences 72: 100-101, 1983 Doorley BM, Hutcheon DE, Dapson Sc. The antifibrilatory effects of cibenzoline on Langendorff-perfused rabbit hearts. Abstract 3956. Federation Proceedings 43: 961. 1984 Frances Y, Luccioni R, Delaage M, Donnarel G, Medvedowsky JL, et al. Prevention au long cours des recidives de fibrillation auriculaire par la cibenzoline. Etude multicentrique a propos de 89 observations. Archives des Maladies du Coeur et des Vaisseaux 78: 99-103, 1985 Furuta T , Toyama J, Yamada K. Comparative study of cibenzoline and disopyramide on fast channel blocking and anticholinergic action in isolated guinea pig cardiac muscle. Environmental Medicine 27: 99-104, 1983 Gachot BA, Bezier M, Cherrier J-F, Daubezc J. Cibenzoline and hypoglycaemia . Correspondence. Lancet 2: 280, 1988 Gross A, Guerci B, Grulet H, Taupin JM, Durlach V. et al. HypogIycemies dues a la cibenzoline. Abstract 44. Diabete et Metabolisme 16: 12, 1990 Hackman MR, Lee TL. Brooks MA. Detcrmination of cibenzoline in plasma and urine by high-performance liquid chromatography. Journal of Chromatography 273: 347-356, 1983 Haruno A, Matsuzaki T, Hashimoto K. Antiarrhythmic effects of optical isomers of cibenzoline on canine ventricular arrhythmias. Journal of Cardiovascular Pharmacology 16: 376-382, 1990 Herpin D, Gaudeau B, Boutaud P, Amiel A, Tourdias, et al. Clinical

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trial of a new anti-arrhythmic drug: cibenzoline (cipralanTM). Current Therapeutic Research 30: 742-752, 1981 Hilleman DE, Mohiuddin SM, Ahmed IS, Dahl JM. Cibenzoline-induced hypoglycemia. Drug Intelligence and Clinical Pharmacy 21: 38-40, 1987 Hinsch E, Dahlen P, Pace D, Klevans L, Cohen M. Antiarrhythmic and hemodynamic profile of cibenzoline. Abstract 5846. Federation Proceedings 42: 1289, 1983 Holazo AA, Brazzell RK, Colburn WA. Pharmacokinetic and pharmacodynamic modeling of cibenzoline prasma concentrations and antiarrhythmic effeet. Journal of Clinical Pharmacology 26: 336345, 1986 Holck M, Osterrieder W. Inhibition of the myocardial Ca 2+ inward current by the class I antiarrhythmicagent, cibenzoline. British Journal of Pharmacology 87: 705-711, 1986 Houdent Ch, Noblet C, Vandoren C, Levesque H, Morin C, et al. Hypoglycemie induite par la cibenzoline chez Ie sujet age. Revue de Medecine Interne 12: 143-145, 1991 Humen DP, Lesoway R, Kostuk WJ. Acute, single, intravenous doses of cibenzoline: an evaluation of safety, tolerance, and hemodynamic effects. Clinical Pharmacology and Therapeutics 41: 537-545, 1987 Humen DP, Lesoway R, Kostuk WJ. Cibenzoline, a new anti-arrhythmic: hemodynamic effects. Abstract II-B. Clinical pharmacology and Therapeutics 35: 248, 1984 Ikeda N, Singh BN. Electrophysiologic profile of a new antiarrhythmic drug, cibenzoline, in isolated cardiac tissues. Abstract 2008. Federation Proceedings 42: 635, 1983 Investigators of the Cardiac Arrhythmia Suppression Trial. Special Report. Preliminary Report. Effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. New England Journal of Medicine 32: 406412, 1989 Jeandel C, Preiss MA, Pierson H, Penin F, Cuny G, et al. Hypoglycaemia induced by cibenzoline. Correspondence. Lancet I: 12321233, 1988 Karagueuzian HS, Sugi K, Ohta M, Meesmann M, Ino T , et al. The efficacy of cibenzolinc and propafenone against inducible sustained and nonsustained ventricular tachycardias in conscious dogs with isolated chronic right ventricular infarction: a comparative study with procainamide. American Heart Journal 112: 1173-1183,1986 Kato K, linuma H, Hosoda S, Sugimoto T, Hayakawa K, et al. Clinical efficacy and safety of cibenzoline in patients with supraventricular premature contraction. A double-blind group comparative trial in comparison with disopyramide in a multi-center cooperation. In Japanese. Rinsho Hyoka 17: 35-55, 1989a Kato K, linuma H, Hosoda S, Sugimoto T, Hayakawa K, et al. Clinical efficacy and safety of cibenzoline in patients with ventricular premature contraction. A double-blind group comparative trial in comparison with disopyramide in a multi-center cooperation. In Japanese. Rinsho Hyoka 17: 11-34, 1989b Kato K, linuma H, Hosoda S, Sugimoto T, Hayakawa K, et al. Dose finding trial of cibenzoline in patients with ventricular premature contraction using double-blind technique in a multi-center cooperation. In Japanese. Rinsho Hyoka 16: 643-660, 1988 Kato R, Sotobata I. Yokota M. Miyagaki H, Ito A, et al. The pharmacokinetics and antiarrhythmic effect of oral cibenzoline. In Japanese. Rinsho Yakuri 20: 363-372, 1989c Kato R, Suzuki M, Goto T, Fukumitsu T, Terasawa T, et al. Suppressive effects of cibenzoline on atrioventricular reentrant tachycardia. Japanese Journal of Electrocardiography 9: 806-815, 1989d Kato T, Hayakawa K. Kato K, Hosoda S, Sugimoto T , et al. Pilot study of intravenou> cibenzoline in patients with ventricular and supraventricular arrhythmias by a multi-center cooperation. In Japanese. Rinsho Iyaku 6: 1179-1192, 1990 Katoh T, Ishihara S. Tanaka T, Kobayashi y, Takada K, et al. Hemodynamic effects of intravenous cibenzoline, a new antiarrhythmic agent. In Japanese. Rinsho Yakuri 19: 707-716, 1988 Keefe D, Williams S, Miura D, Terribile S, Somberg J. A randomized parallel trial of cibenzoline and quinidine for prevention of recurrence of atrial fibrillation or flutter. Abstract. Journal of Clinical Pharmacology 25: 470, 1.985 Keren G, Tepper D, Butler B. Miura D, Aogaichi K, et al. The efficacy

758

of cibenzoline in preventing PES induction of ventricular tachycardia in the dog. Journal of Clinical Pharmacology 24: 466-472, 1984 Khoo K-C, Givens SV, Parson net M, Massarella JW. Effect of oral cibenzoline on steady-state digoxin concentrations in healthy volunteers. Journal of Clinical Pharmacology 28: 29-35, 1988 Khoo K-C, Szuna AJ, Colburn WA, Aogaichi K, Morganroth J, et al. Single-dose pharmacokinetics and dose proportionality of oral cibenzoline. Journal of Clinical Pharmacology 24: 283-288, 1984 Klein RC, Horwitz LD, Rushforth N. Efficacy and safety of oral cibenzoline for ventricular arrhythmias. American Journal of Cardiology 57: 592-597, 1986 Kostis JB, Davis D, Kluger J, Aogaichi K, Smith M. Cifenline in the short-term treatment of patients with ventricular premature complexes: a double-blind placebo-controlled study. Journal ofCardiovascular Pharmacology 14: 88-95, 1989 Kostis JB, Davis D, Kluger J, Williams CB, Krieger SD, et al. Longterm efficacy of cibenzoline in the treatment of ventricular ectopic activity .. Abstract. Clinical Pharmacology and Therapeutics 41: 233, 1987 Kostis JB, Krieger S, Moreyra A, Cosgrove N. Cibenzoline for treatment of ventricular arrhythmias: a double-blind placebo-controlled study. Journal of the American College of Cardiology 4: 372-377, 1984 Kotake H, Matsuoka S, Ogino K, Takami T, Hasegawa J, et al. Electrophysiological study of cibenzoline in voltage-clamped rabbit sinoatrial preparations. Journal of Pharmacology and Experimental Therapeutics 241: 982-986, 1987 Kovacs JL, Tuzel I, Aogaichi K, Heger JJ, Richmond L, et al. Falsepositive urine protein reaction with cibenzoline, a new antiarrhythmic agent. Journal of Clinical Pharmacology 24: 127-128, 1984 Kuhlkamp V, Meerhof J, Schmidt F, Mayer F, Ickrath 0, et al. Electrophysiologic effects and efficacy of cibenzoline on stimulationinduced atrial fibrillation and flutter and implications for treatment of paroxysmal atrial fibrillation. American Journal of Cardiology 65: 628-632, 1990a Kuhlkamp V, Schmid F, Mayer F, Ickrath 0, Haasis R, et al. Effects of intravenous cibenzoline on ventricular vulnerability and electrophysiology in patients with sustained ventricular tachycardia in comparison to a control group. Journal of Cardiovascular Pharmacology 15: 472-475, 1990b Kuhlkamp V, Schmid F, Ress KM, Kramer BK, Mayer F, et al. Quantification of cibenzoline and its imidazole metabolite by high-performance liquid chromatography in human serum. Journal of Chromatography 528: 267-273, 1990c Kuhlkamp V, Schmid F, Risler T, Seipel L. Randomized comparison offlecainide and cibenzoline in the conversion of atrial fibrillation. International Journal of Cardiology 31: 65-69, 1991 Kushner M, Magiros E, Peters R, Carliner N, Plotnick G, et al. The electrophysiologic effects of oral cibenzoline. Journal of Electrocardiology 17: 15-24, 1984 Lang J, Timour Q, Aupetit JF, Lancon JP, Lakhal M, et al. Frequencyand time-dependent depression of ventricular distal conduction by two novel antiarrhythmic drugs, cibenzoline and flecainide. Archives Internationales de Pharmacodynamie et de Therapie 293: 97-108, 1988 Lee MA, Fenster PE, Garcia ZM, Kipps JE, Huang SKS. Cibenzoline for symptomatic ventricular arrhythmias: a prospective, randomized, double-blind, placebo controlled trial and a long term open label study. Canadian Journal of Cardiology 5: 295-298, 1989 Leinweber F-J, Loh AC, Szuna AJ, Carbone JJ, Williams TH, et al. Biotransformation of cibenzoline to 2-(2,2-