Monograph: |
Propafenone Hydrochloride
A white powder. Soluble in hot water and in methyl
Alcohol; slightly soluble in alcohol and in chloroform: very
alightly soluble in acetone: practically insoluble in ether and
in toluene. A 0.5% solution has a pH of 5.0 lo 6.2. Store in
airtight containers. Protect from light.
Adverse Effects
Propafenone can cause disturbances in cardiac con-
duction which can result in bradycardia, heart block
and sinus arrest. It may aggravate heart failure
and may cause hypotension. In common with other
antiarrhythmics, propafenone may induce or worsen arrhythmias in some patients.
Among the most common adverse effects are gastro-
intestinal intolerance, dry mouth, a bitter or metallic
taste, dizziness, blurred vision, headache, and fa-
tigue. Convulsions, blood dyscrasias, liver disor-
ders. lupus erythematosus, skin rashes, and
impotence have also been reported. Increased
breathlessness and worsening of asthma have been
reported.
Effects on the heart. Fatal exacerbation of ventricular
tachycardia was associated with propafenone therapy in a 63-
year-old man.
Effects on the liver. A review of liver injury secondary to
propafenone therapy has concluded it is a rare occurrence and
appears to be due to hepatocellular injury, cholestasis, or a
combination.
Effects on mental state. Delusions, hallucinations, and
paranoia have been reported in an elderly patient following
two (loses of propafenone. The manufacturer had received re-
ports of mania and psychosis.' Amnesia developed in a 61-
year-old man six days after starting treatment with propaf-
enone Symptoms resolved 6 to 7 hours after discontinuing
the drug.
Effects on the nervous system. Myoclonus has been re-
ported in one patient receiving propafenone.' Peripheral neu-
ropathy developed in a patient 10 months after starting
treatment with propafenone.' Symptoms had resolved 6
months after stopping the drug.
Lupus erythematosus. Symptoms of lupus erythematosus
and raised antinuclear antibody titres were associated with
propafenone therapy on 2 occasions in a 63-year-old woman.'
Precautions
Propafenone is contra-indicated in patients with un-
controlled heart failure, conduction disturbances in-
cluding heart block unless controlled by artificial
pacing, cardiogenic shock not arrhythmia-induced.
severe bradycardia. or pronounced hypotension. It
may alter the endocardial pacing threshold and ad-
justment nay be necessary in patients with pace-
makers.
Propafenone's beta-blocking activity can exacerbate
obstructive airways disease: it should be used with
great caution in patients with this disease and if the
disease is severe then propafenone is contra-indicat
ed. Propafenone may aggravate myasthenia gravis
and should be avoided in patients with this condi
tion. Electrolyte disturbances should be corrected
before initiating propafenone treatment. Propaf
enone should be used with caution in patients will
hepatic or renal impairment.
Pregnancy and breast feeding. Experience in one patient
given propafenone throughout the last trimester of pregnancy
indicated that despite transplacental diffusion propafenone
could safely be used at this time without harm to the fetus
Propafenone and its metabolite were excreted in breast milk
although it was considered that the amount would have repre
sented a markedly sub therapeutic dose to the infant who in
any case was not breast fed.
Interactions
Propafenone is extensively metabolised by the he
patic mixed function oxidase system and plasma
propafenone concentrations may be reduced by in
ducers of this system such as Rifampicin; enzyme in
hibitors, such as Cimetidine and guanidine, ma
increase plasma-propafenone concentrations (see
below). Propafenone itself may alter the plasm
concentrations of other drugs given concomitantly
affected include beta blockers, cyclosporine.
desipramine, digoxin, theophylline. and warfarin.
Details are given under the individual drug mono-
graphs.
Rifampicin has lowered steady-state plasma concentrations of
propafenone with the reappearance of arrhythmia. Quinidine
inhibits the hepatic metabolism of propafenone and has raised
plasma-propafenone concentrations in extensive metabolis-
ers; the plasma concentration of the active 5-hydroxy metab-
olite was reduced and that of the N-depropyl metabolite
increased but there was no change in the clinical response.
Cimetidine has also been reported to raise plasma-propaf-
enone concentrations. The mean steady-state concentration
increased by 22% but the wide interindividual variability
meant this change was not significant.
Pharmacokinetics
Propafenone is readily and almost completely ab-
sorbed from the gastro-intestinal tract. It is metabo-
lised in the liver and the extent of metabolism is
genetically determined. In subjects with the exten-
sive metaboliser phenotype there is extensive first-
pass metabolism to two active metabolites, 5-hy-
droxypropafenone and N-depropylpropafenone, and
6 to other minor inactive metabolites. In the small pro-
portion of subjects with the slow metaboliser pheno-
type little or no 5-hydroxypropafenone is formed.
The bioavailability of propafenone is dependent
upon metaboliser phenotype but more importantly
on dosage as the first-pass metabolism is saturable.
In practice doses are high enough to compensate for
differences in phenotype. Propafenone and its me-
tabolites also undergo glucuronidation.
Propafenone is extensively (more than 95%) protein
bound.
Propafenone is excreted in the urine and faeces
mainly in the form of conjugated metabolites. The
elimination half-life is reported to be 2 to 10 hours
in extensive metabolisers and 10 to 32 hours in slow
metabolisers.
Propafenone crosses the placenta and is distributed
into breast milk.
Uses and Administration
Propafenone hydrochloride is a class lc antiarrhythmic
with some negative inotropic and beta
adrenoceptor blocking activity. It is used in the man
agement of supraventricular and ventricular arrhythmias.
The usual initial dose by mouth is 150 mg three
times daily and this may be increased, if necessary
at intervals of 3 to 4 days up to a maximum of
300 mg three times daily. Patients of less than 70 kg
body-weight should be given reduced doses: the eld
erly may also respond to reduced doses. Doses may
need to be reduced if hepatic function is impaired.
Propafenone hydrochloride has also been given by
slow intravenous injection or by infusion.
Administration in renal impairment. Propafenone is ex-
tensively metabolised and the metabolites formed are excret
ed in the urine and faeces. A study of the effect of renal
function on disposition of propafenone found that renal im
pairment did not alter the pharmacokinetics of propafenone or
5-hvdroxypropafenone.' Nevertheless, the manufacturers ad
vise that caution is necessary if propafenone is administered
to patients with impaired renal function.
Cardiac arrhythmias. Harly reviews' showed propaf-
enone, a class lc antiarrhythmic. to be effective in a large va-
riety of cardiac arrhythmias including ventricular
arrhythmias and supraventricular arrhythmias .such as atrial
flutter and atrial fibrillation. It has been used successfully to
treat arrhythmias in children. However, the results of the
Cardiac Arrhythmia Suppression Trial (known as CAST),
demonstrating that other class I antiarrhythmics (encainide,
Hecainide. and moracizine) were associated with an increased
mortality rate when used for asymptomatic ventricular ar-
rhythmias in post-infarction patients, led to many drugs of
this class being restricted lo severe or life-threatening ven-
tricular arrhythmias: this restriction has also applied to
propatenone in many countries although, in some use in su-
praventncular arrhythmias is permitted. As well as having an
tiarrhythmic aclions propafenone also has some beta-
adrenoceplor blocking activity and this theoretically may be
beneficial in post-infarction patients, hut in the absence of
data showing safety and efficacy of propafenone in this situa-
tion such use is not considered warranted. A more recent
review acknowledges a general trend against the use of class
lc antiarrhythrnics. including propafenone. in patients with
nonsustained ventricular arrhythmias. Another supports its
use in supravemricular arrhythmias.
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