Moricizine

Christopher A. Clyne, M.D., N.A. Mark Estes, III, M.D., and Paul J. Wang, M.D.
N Engl J Med 1992; 327:255-260July 23, 1992DOI: 10.1056/NEJM199207233270407
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MORICIZINE hydrochloride was first synthesized in the Soviet Union in 1964,1 2 3 and
after pharmacologic and clinical evaluation in the United States4 5 6 7 8 9 10 11 12 13 14
15 16 17 18 19 it was approved by the Food and Drug Administration in June 1990 to
treat documented life-threatening ventricular arrhythmias. The drug (molecular weight,
464) is a phenothiazine derivative, with a carbamic ethol ester side chain attached to the
second position of the phenothiazine ring (10-(3-morpholinopropionyl) phenothiazine-2-

carbamic acid ethol ester hydrochloride) (Fig. 1Figure 1

The Chemical
Structure of Moricizine.). It is chemically unrelated to any currently approved
antiarrhythmic drug,20 21 22 23 24 25 and despite having a phenothiazine structure, it
lacks dopamine-antagonist activity and the behavioral and autonomic actions of
neuroleptic phenothiazines.1 , 24 Like other Class I antiarrhythmic drugs, moricizine
reduces the fast inward sodium current of the action potential.22 23 24 25 26 27
Although moricizine has been approved for the treatment of patients with life-threatening
ventricular arrhythmias, the doses required to produce antiarrhythmic effects in these
patients are variable and side effects are common, as described below. Moricizine,
encainide, and flecainide were evaluated in patients with asymptomatic ventricular
ectopic beats in the Cardiac Arrhythmia Suppression Trial (CAST).28 Although these
beats could be suppressed, mortality was not significantly improved in the patients
treated with moricizine, and the use of encainide and flecainide resulted in excess
mortality. The second CAST study (CAST-II) compared moricizine with placebo to test
the hypothesis that the suppression of asymptomatic or mildly symptomatic ventricular
arrhythmias in patients after a myocardial infarction would improve survival.29 This trial
was terminated because of excess mortality in the patients given moricizine, who were
not screened for suppression of ventricular arrhythmias during the first two weeks of drug
treatment, and also because of a low probability of a long-term survival benefit. Thus, as
in the case of other antiarrhythmic drugs, the decision to treat a patient with moricizine
assumes that the benefits of treatment are greater than the risks.

Electrophysiologic Effects
Effects on Cardiac Action Potentials
Moricizine blocks the fast inward sodium channels of cardiac muscle, as reflected in a
reduced maximal upstroke of phase zero of the transmembrane action potential recorded
in frog atria, guinea pig papillary muscle, and canine Purkinje fibers.24 , 25 , 30 31 32 As
with other sodium-channel blockers, the effect is greatest at faster rates in partially
depolarized tissue and can result in the slowing of conduction.22 , 32 , 33
It has proved difficult to subclassify moricizine within the group of Class I
antiarrhythmic agents. The clinical differentiation of these drugs relies on their effect on
the effective refractory period and on the QRS, HV, and JT intervals, whereas the cellular
electrophysiologic effects depend on the kinetics of binding to sodium channels and
dissociation from them.34 The classification of a drug according to the one set of criteria
often conflicts with its classification according to the other.34 On the basis of available
data, moricizine does not fit readily into any of the subclasses of sodium-channel
blocking drugs already described.
In isolated canine Purkinje fibers, moricizine decreases the duration of the action
potential and the effective refractory period.24 , 32 , 35 These effects on repolarization are
similar in some respects to those of lidocaine.24 , 32 , 35 , 36 Flecainide also reduces the
duration of the action potential in canine cardiac Purkinje fibers, but unlike moricizine, it
prolongs the effective refractory period.37 , 38 Moricizine also decreases automaticity32 ,
35 , 39 and triggered activity.40

Electrophysiologic Effects in Vivo

In humans moricizine slows atrioventricular nodal and intraventricular conduction,
resulting in significant dose-related increases in the PR, QRS, and corrected QT
intervals,20 , 23 , 41 , 42 and it increases the AH and HV intervals, as detected by
intracardiac recording.14 Moricizine does not substantially affect the sinus-node recovery
time in patients with normal sinus-node function,42 but its action in patients with
abnormal sinus-node function is unknown, mandating its use only with caution in such
patients. Moricizine does not have substantial effects on intraatrial conduction or atrial
effective refractory periods.23 Its effects on pacing threshold and sensing have not been
fully evaluated. Reevaluation of pacing threshold and sensing is therefore recommended
after the drug is started, particularly in patients who depend on pacemakers. Furthermore,
because there are no data on the effect of the drug on defibrillation thresholds, the
thresholds should be reevaluated after a steady-state plasma drug concentration has been
reached in patients with implantable defibrillators.

Hemodynamic Effects
As is true with other antiarrhythmic agents, congestive heart failure may occur during
moricizine therapy, most commonly in patients with reduced left ventricular ejection

fractions and a history of congestive heart failure.19 , 43 , 44 In the Cardiac Arrhythmia

Pilot Study, a 10-center clinical trial investigating the safety and long-term (one year)
antiarrhythmic effects of encainide, flecainide, imipramine, and moricizine in 502
patients after myocardial infarction, the overall incidence of heart failure in patients
treated with moricizine (26 percent), encainide (19 percent), or flecainide (35 percent) did
not differ significantly from that in the patients given placebo (21 percent).19 , 44 Of the
1072 patients in whom moricizine was used in uncontrolled trials in the United States,43
467 (44 percent) had a clinical history of congestive heart failure, and 71 of these 467
patients (15 percent) had exacerbations of their heart failure. In the remaining 605
patients (56 percent) without previous heart failure, symptoms or signs of heart failure
developed in 5 (1 percent). In comparison, treatment with oral disopyramide exacerbated
heart failure in 12 of 22 patients with a history of heart failure (55 percent) and induced
heart failure in 4 of 78 patients with no such history (5 percent).45 The development or
exacerbation of congestive heart failure is rare in patients receiving long-term therapy
with quinidine and procainamide, even patients with a history of congestive heart
failure.46 , 47

Clinical Pharmacokinetics
Orally administered moricizine is almost completely absorbed from the gastrointestinal
tract.48 Its bioavailability is approximately 30 to 40 percent, resulting primarily from a
first-pass effect.48 The hepatic biotransformation of the drug involves sulfur oxidation,
ring hydroxylation, N-dealkylation, acetylation, amide hydrolysis, N-oxidation, and
glucuronide or sulfate conjugation.48 Approximately 40 metabolites have been isolated,
and their antiarrhythmic potencies are unknown.
Peak plasma concentrations of moricizine after a single oral dose of the drug are reached
in 0.8 to 2.0 hours.49 There is evidence of substantial protein binding in both peripheral
tissue and serum.48 One study has suggested that plasma moricizine concentrations fall
during long-term treatment,48 but the mechanism and importance of this decrease are not
known. The mean terminal elimination half-life after a single oral dose of moricizine is 3
to 4 hours in normal subjects50 and 6 to 13 hours in patients with arrhythmias.51
Less than 1 percent of the drug is excreted unchanged in the urine after a single 500-mg
dose of moricizine labeled with carbon-14.48 The half-life of intact [14C]moricizine was
23 hours, as compared with 84 hours for the half-life of radioactivity for any form of the
drug a finding consistent with the extensive metabolism of moricizine to compounds
that persist in the plasma longer than the parent drug.4 , 48 , 52 , 53 Moricizine has been
little studied in patients with renal failure; Pratt and colleagues reported an elimination
half-life of 47 hours in one such patient.8

Dosing Recommendation
Most patients can be treated with a total dose of moricizine of 200 to 300 mg every eight
hours.51 , 53 The administration of the drug within 30 minutes before or after a meal
results in a delay in reaching the peak plasma concentration, but the presence of food in

the stomach does not affect the absolute peak plasma concentration.48 The dose may be
increased at three-day intervals, from the initial oral dose of 200 mg every eight hours to
250 mg every eight hours and then to 300 mg every eight hours.51 , 53 , 54 The dose
response data for moricizine, like those for all other antiarrhythmic drugs, are largely
based on the suppression of ventricular arrhythmias in patients with premature ventricular
complexes and unsustained ventricular tachycardia. In such patients there is a linear
relation between the dose of moricizine and the suppression of spontaneous ventricular
premature complexes.53 The plasma concentrations of moricizine and its metabolites
have not been proved to predict antiarrhythmic efficacy or toxicity.48 Therefore, other
measurements of drug effects, such as programmed electrical stimulation or ambulatory
electrocardiographic monitoring, are used to guide long-term drug therapy.7 , 42 , 48 At
present, there are few data on the use of moricizine in patients with hepatic or renal
insufficiency. If the drug is used in such patients, therapy should be initiated cautiously
and the patients monitored closely for signs of toxicity.

Drug Interactions
The concomitant administration of moricizine and digoxin does not appear to affect
plasma digoxin concentrations.55 , 56 Because of its effect on atrioventricular nodal
conduction, however, moricizine may further prolong the PR interval in patients taking
digoxin or other drugs affecting the function of the atrioventricular node. The
concomitant oral administration of cimetidine (300 mg four times per day) diminishes the
clearance of moricizine by 48 percent, increases its mean plasma elimination half-life by
35 percent,50 , 57 and increases plasma concentrations by 40 percent. In contrast,
ranitidine does not alter moricizine metabolism.21 Moricizine increases the plasma
concentrations of theophylline by 46 to 68 percent and decreases the elimination half-life
of theophylline by 20 to 34 percent.21 Therefore, plasma theophylline concentrations
should be monitored when these drugs are used concomitantly. Although moricizine may
slightly shorten the elimination half-life of warfarin,21 neither the prothrombin time nor
the warfarin dosage requirement changes significantly after moricizine therapy is
begun.21

Clinical Effects
Although ventricular ectopy increases the risk of sudden cardiac death after myocardial
infarction, it is not known whether treatment with antiarrhythmic drugs can prevent lifethreatening arrhythmias in patients with ventricular arrhythmias. The results of the
CAST-II trial comparing the use of moricizine with placebo in the prevention of mortality
after myocardial infarction revealed no benefit from moricizine.29 Furthermore, the
doses of moricizine that are effective in asymptomatic patients with ventricular ectopic
beats often differ from those required to treat other antiarrhythmic end points (the
suppression of inducible arrhythmias and the prevention of sudden death). The potential
for the aggravation of arrhythmias and other adverse effects without a proved benefit may
be an important consideration in the use of moricizine in patients who have had a
myocardial infarction. Thus, the suppression of asymptomatic arrhythmias after

myocardial infarction is not an appropriate indication for the use of moricizine or any
other drug.

Unsustained Ventricular Arrhythmias

A drug's ability to reduce the frequency of premature ventricular complexes and
unsustained ventricular tachycardia (defined as a ventricular rhythm consisting of more
than 2 consecutive beats at a rate of more than 100 beats per minute) during ambulatory
monitoring is often used to assess the drug's ability to suppress spontaneous ventricular
arrhythmias. It is important to note, however, that there is no known relation between the
suppression of ventricular arrhythmias and a reduction in the subsequent incidence of
sudden cardiac death or mortality from any cause. In fact, a dissociation between the
suppression of ventricular premature complexes and sudden cardiac mortality was among
the findings of the CAST study.28
Moricizine is effective in suppressing spontaneous premature ventricular complexes and
unsustained ventricular tachycardia in both short-term7 8 9 and long-term8 , 19 studies in
60 to 80 percent of patients. The safety and effectiveness of moricizine in suppressing
premature ventricular complexes and unsustained ventricular tachycardia have been
compared with those of other antiarrhythmic agents. In the Cardiac Arrhythmia Pilot
Study, 502 patients were randomly assigned to initial therapy with one of four active
drugs (encainide, flecainide, imipramine, and moricizine) or placebo.19 In the initial
phase of drug and dose selection, moricizine suppressed spontaneous ventricular
arrhythmias with intermediate potency (in 60 percent of patients) as compared with
imipramine (in 52 percent), encainide (in 79 percent), and flecainide (in 83 percent). In
the one-year follow-up phase of the trial, moricizine retained this degree of ability to
suppress ventricular arrhythmias (in 61 percent of patients) as compared with the other
antiarrhythmic drugs (suppression in 54 percent with imipramine, in 76 percent with
encainide, and in 77 percent with flecainide).19 In comparative trials moricizine was as
effective for the suppression of ventricular arrhythmias as quinidine10 and more effective
than propranolol6 or disopyramide.11
The effect of the suppression of ventricular ectopic activity by moricizine on subsequent
mortality was examined in the CAST-II study, which involved the randomization of
patients with recent myocardial infarctions, asymptomatic or mildly symptomatic
ventricular premature depolarizations, and ejection fractions of 40 percent or less.29
During the initial 14-day exposure phase, 1325 patients were randomly assigned to
receive placebo or moricizine. In this two-week phase, treatment with moricizine was
associated with an excess mortality; 17 of 665 moricizine-treated patients died or had
cardiac arrests, as compared with 3 of 660 patients given placebo (P<0.01). In the longterm phase of the trial, there were 49 deaths and cardiac arrests due to arrhythmias among
the 581 patients treated with moricizine, as compared with 42 deaths and cardiac arrests
among the 574 patients given placebo (P = 0.46). Although no statistically significant
difference in mortality or cardiac arrest due to arrhythmias was found during the longterm phase, the trial was terminated, since it was highly unlikely that a survival benefit
would be achieved if the trial was completed.

Sustained Ventricular Arrhythmias

At present, moricizine is indicated only for the treatment of patients with life-threatening
ventricular arrhythmias, such as sustained ventricular tachycardia or ventricular
fibrillation. In patients with a history of sustained ventricular tachycardia or fibrillation
resistant to other antiarrhythmic drugs, short-term treatment with moricizine suppresses
the induction of ventricular arrhythmias, as assessed by programmed ventricular
stimulation, in 10 to 30 percent of patients.13 14 15 , 58 This rate of suppression of
ventricular arrhythmias is similar to that found with other antiarrhythmic drugs.59
In small studies of patients with reduced left ventricular ejection fractions, out-of-hospital
cardiac arrests, or symptomatic ventricular tachycardia who were also found to have
inducible sustained ventricular arrhythmias, the arrhythmias could be induced during
follow-up electrophysiologic study in all but 12 to 37 percent after 1 to 37 days of
treatment with oral moricizine at a dose of 10 to 15 mg per kilogram of body weight per
day.14 , 15 , 58 Proarrhythmia requiring the discontinuation of therapy occurred in 20 to
38 percent of the patients. The tachycardia was slowed in one of these studies, with the
length of the tachycardia cycle increasing from 250 to 326 msec (P<0.001).14
Among 117 patients undergoing paired programmed ventricular stimulation, inducible
arrhythmias were suppressed in 34 (29 percent) after six days of therapy with oral
moricizine (mean dose, 936 mg per day).13 Of the patients who responded, 28 (82
percent) continued moricizine therapy for a mean of 203 days (range, 3 to 1530).13 The
remaining 90 patients discontinued therapy (14 of them within the first four months)
because of lack of efficacy, drug-related adverse effects, other adverse effects, or
spontaneous remission.13 Sixteen percent of the patients who did not have follow-up
electrophysiologic evaluation had evidence of a proarrhythmic drug effect on the basis of
noninvasive monitoring.13

Supraventricular Arrhythmias
Moricizine has not been approved for use in patients with supraventricular arrhythmias.
Preliminary reports suggest that it may be effective in pediatric patients with ectopic
atrial tachycardia.60 It has not been studied in patients with paroxysmal supraventricular
tachycardia or atrial fibrillation.

Adverse Effects
The adverse cardiovascular effects of moricizine include the worsening of arrhythmias,
conduction disturbances, and as discussed previously, heart failure. In the Cardiac
Arrhythmia Pilot Study, disqualifying ventricular tachycardia, proarrhythmia, or syncope
occurred in 6 percent of the patients treated with moricizine, as compared with 7 percent,
7 percent, 2 percent, and 9 percent of those treated with encainide, flecainide,
imipramine, and placebo, respectively.19 In the 1072 patients who received moricizine in
U.S. trials, the adverse cardiovascular effects that resulted in the discontinuation of the
drug included conduction defects, sinus pauses, junctional rhythm, and atrioventricular

block (in 2 percent of patients).43 , 61 Hession et al.12 reported a 12 percent incidence of

aggravation of arrhythmia in 102 patients treated with oral moricizine for five to six days.
More recently, two groups reported a high rate of proarrhythmia (27 to 45 percent) in
moricizine-treated patients who had depressed left ventricular ejection fractions (<40
percent) and a history of congestive heart failure.62 , 63
Moricizine also causes nausea and dizziness sufficient to result in the discontinuation of
the drug in 2 to 34 percent of patients in short-term (14 day) and long-term (1 year)
studies.7 , 19 , 61 , 62 In the Cardiac Arrhythmia Pilot Study, the rate of withdrawal after
one year of treatment with moricizine was 34 percent, as compared with 21 percent, 26
percent, and 37 percent for encainide, flecainide, and placebo, respectively. There was a
statistically significant increase in the incidence of dizziness during moricizine treatment
(13 percent) as compared with placebo (none) (P = 0.004).19 In an uncontrolled study by
the drug's manufacturer of 1256 patients receiving short-term treatment (14 days or less),
dizziness and nausea were more frequent in the patients given moricizine (11 percent and
7 percent, respectively) than in the patients given placebo (5 percent and 3 percent,
respectively).61 Three patients had drug-related fever that was confirmed by a
rechallenge. Six patients had elevated concentrations of serum aminotransferase or
bilirubin, and thrombocytopenia developed in two, both of whom were also being treated
with other drugs known to cause thrombocytopenia.64
Moricizine is a new Class I antiarrhythmic drug approved for the treatment of lifethreatening ventricular arrhythmias. Its efficacy for the suppression of ventricular
arrhythmias is similar to that of other Class I antiarrhythmic drugs. Like other
antiarrhythmic drugs, moricizine has the potential for exacerbating ventricular
arrhythmias and congestive heart failure, especially in patients with a history of
congestive heart failure, reduced left ventricular ejection fractions, or sustained
ventricular arrhythmias, and it should be used with caution in such patients.
Although moricizine may add to the clinician's choices of antiarrhythmic agents for the
treatment of patients with life-threatening ventricular arrhythmias, its effectiveness and
safety in treating these or other ventricular arrhythmias have not yet been proved. The
discontinuation of the moricizine phase of the CAST study due to a lack of benefit should
remind clinicians that the decision to use moricizine or any other antiarrhythmic agent
should be based on an assessment of potential benefits and risks and that treatment of
asymptomatic ventricular arrhythmias with any of the currently available antiarrhythmic
drugs is not indicated.