A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Rythmol Side Effects, and Drug Interactions - Propafenone
Rythmol Side Effects, and Drug Interactions - Propafenone
SIDE EFFECTS
Adverse reactions associated with RYTHMOL occur most frequently
in the gastrointestinal, cardiovascular,
and central nervous
systems. About 20% of patients treated with RYTHMOL have discontinued
treatment because
of adverse reactions.
Adverse reactions reported for > 1.5% of 474 SVT patients who
received propafenone in U. S. clinical
trials are presented in the following table by incidence
and percent discontinuation,
reported to the nearest percent.
Adverse Reactions Reported for > 1.5% of SVT Patients
| |
Incidence
(N= 480)
|
% of Pts. who
Discontinued
|
| unusual taste
|
14%
|
1.3%
|
| Nausea and
or Vomiting |
11%
|
2.9%
|
| Dizziness |
9%
|
1.7%
|
| Constipation |
8%
|
0.2%
|
| Headache |
6%
|
0.8%
|
| Fatigue |
6%
|
1.5%
|
| Blurred Vision |
3%
|
0.6%
|
| Weakness |
3%
|
1.3%
|
| Dyspnea |
2%
|
1.0%
|
| Wide Complex Tachycardia
|
2%
|
1.9%
|
| CHF |
2%
|
0.6%
|
| Bradycardia |
2%
|
0.2%
|
| Palpitations |
2%
|
0.2%
|
| Tremor |
2%
|
0.4%
|
| Anorexia |
2%
|
0.2%
|
| Diarrhea |
2%
|
0.4%
|
| Ataxia |
2%
|
0.0%
|
Results of controlled trials in ventricular
arrhythmia patients
comparing adverse reaction
rates on propafenone and placebo,
and on propafenone and quinidine are shown in the following table.
Adverse reactions reported in ³1%
of the patients receiving propafenone are shown, unless they were
more frequent on placebo
than propafenone. The most common events were unusual taste, dizziness,
first degree AV block,
intraventricular conduction
delay, nausea and/or
vomiting, and constipation.
Headache was relatively common also, but was not increased compared
to placebo.
Adverse Reactions Reported for ³1%
of Ventricular Arrhythmia Patients
|
|
Prop/ Placebo Trials
|
Prop/ Quinidine Trials
|
|
Propafenone
|
Placebo
|
Propafenone
|
Quinidine
|
|
(N= 247)
|
(N= 111)
|
(N= 53)
|
(N= 52)
|
| Unusual Taste |
7%
|
1%
|
23%
|
0%
|
| Dizziness |
7%
|
5%
|
15%
|
10%
|
| First Degree AV Block
|
5%
|
1%
|
2%
|
0%
|
| Headache(s) |
5%
|
5%
|
2%
|
8%
|
| Constipation |
4%
|
0%
|
6%
|
2%
|
| Intraventricular
Conduction Delay |
4%
|
0%
|
-
|
-
|
| Nausea
and or Vomiting
|
-
|
1%
|
6%
|
15%
|
| Fatigue |
-
|
-
|
4%
|
2%
|
| Palpitations |
2%
|
1%
|
-
|
-
|
| Blurred Vision |
2%
|
1%
|
6%
|
2%
|
| Dry Mouth |
2%
|
1%
|
6%
|
6%
|
| Dyspnea |
2%
|
3%
|
4%
|
0%
|
| Abdominal Pain/ Cramps
|
-
|
-
|
2%
|
8%
|
| Dyspepsia |
-
|
-
|
2%
|
8%
|
| CHF |
-
|
-
|
2%
|
0%
|
| Fever |
-
|
-
|
2%
|
10%
|
| Tinnitus |
-
|
-
|
2%
|
2%
|
| Vision, Abnormal
|
-
|
-
|
2%
|
2%
|
| Esophagitis |
-
|
-
|
2%
|
0%
|
| Gastroenteritis |
-
|
-
|
2%
|
0%
|
| Anxiety |
2%
|
2%
|
-
|
-
|
| Anorexia |
2%
|
1%
|
-
|
2%
|
| Proarrhythmia |
1%
|
0%
|
2%
|
0%
|
| Flatulence |
1%
|
0%
|
2%
|
0%
|
| Angina |
1%
|
0%
|
2%
|
4%
|
| Second Degree AV
Block |
1%
|
0%
|
-
|
-
|
| Bundle Branch Block
|
1%
|
0%
|
2%
|
2%
|
| Loss of Balance |
1%
|
0%
|
-
|
-
|
| Diarrhea |
1%
|
1%
|
6%
|
39%
|
Adverse reactions reported for ³1%
of 2,127 ventricular arrhythmia
patients who received propafenone in U. S. clinical trials are presented
in the following table
by propafenone daily dose. The most common adverse reactions in
controlled clinical
trials appeared dose related (but note
that most patients spent more time
at the larger doses), especially dizziness,
nausea and/or vomiting,
unusual taste, constipation, and blurred vision. Some less common
reactions may also have been dose related such
as first degree AV block,
congestive heart failure,
dyspepsia, and weakness. The principal
causes of discontinuation were the most common events and are shown
in the table.
Adverse Reactions Reported for ³1%
of Ventricular Arrhythmia Patients N =2127
|
|
Incidence by Total Daily Dose
|
Total Incidence
|
% of
Patients Who Discontinued
|
|
450 mg
|
600 mg
|
900 mg
|
|
(N= 1430)
|
(N= 1337)
|
(N= 1333)
|
(N =2127)
|
|
| Dizziness |
4%
|
7%
|
11%
|
13%
|
2.4%
|
| Nausea
and or
Vomiting
|
2%
|
6%
|
9%
|
11%
|
3.4%
|
| Unusual Taste |
3%
|
5%
|
6%
|
9%
|
0.7%
|
| Constipation |
2%
|
4%
|
5%
|
7%
|
0.5%
|
| Fatigue |
2%
|
3%
|
4%
|
6%
|
1.0%
|
| Dyspnea |
2%
|
2%
|
4%
|
5%
|
1.6%
|
| Proarrhythmia |
2%
|
2%
|
3%
|
5%
|
4.7%
|
| Angina |
2%
|
2%
|
3%
|
5%
|
0.5%
|
| Headache(s) |
2%
|
3%
|
3%
|
5%
|
1.0%
|
| Blurred Vision |
1%
|
2%
|
3%
|
4%
|
0.8%
|
| CHF |
1%
|
2%
|
3%
|
4%
|
1.4%
|
| Ventricular
Tachycardia |
1%
|
2%
|
3%
|
3%
|
1.2%
|
| Dyspepsia |
1%
|
2%
|
3%
|
3%
|
0.9%
|
| Palpitations |
1%
|
2%
|
3%
|
3%
|
0.5%
|
| Rash |
1%
|
1%
|
2%
|
3%
|
0.8%
|
| AV Block,
First Degree |
1%
|
1%
|
2%
|
3%
|
0.3%
|
| Diarrhea |
1%
|
2%
|
2%
|
3%
|
0.6%
|
| Weakness |
1%
|
2%
|
2%
|
2%
|
0.7%
|
| Dry Mouth |
1%
|
1%
|
1%
|
2%
|
0.2%
|
| Syncope/
Near Syncope |
1%
|
1%
|
1%
|
2%
|
0.7%
|
| ORS Duration,
Increased |
1%
|
1%
|
2%
|
2%
|
0.5%
|
| Chest Pain |
1%
|
1%
|
1%
|
2%
|
0.2%
|
| Anorexia |
1%
|
1%
|
2%
|
2%
|
0.4%
|
| Abdominal Pain,
Cramps |
1%
|
1%
|
1%
|
2%
|
0.4%
|
| Ataxia |
0%
|
1%
|
2%
|
2%
|
0.2%
|
| Insomnia |
0%
|
1%
|
1%
|
2%
|
0.3%
|
| Premature
Ventricular Contraction(s) |
1 %
|
1 %
|
1 %
|
2%
|
0.1 %
|
| Bradycardia |
1%
|
1%
|
1%
|
2%
|
0.5%
|
| Anxiety |
1%
|
1%
|
1%
|
2%
|
0.6%
|
| Edema |
1%
|
0%
|
1%
|
1%
|
0.2%
|
| Tremor(s) |
0%
|
1%
|
1%
|
1%
|
0.3%
|
| Diaphoresis |
1%
|
0%
|
1%
|
1%
|
0.3%
|
| Bundle
Branch Block |
0%
|
1%
|
1%
|
1%
|
0.5%
|
| Drowsiness |
1%
|
1%
|
1%
|
1%
|
0.2%
|
| Atrial Fibrillation
|
1%
|
1%
|
1%
|
1%
|
0.4%
|
| Flatulence |
0%
|
1%
|
1%
|
1%
|
0.1%
|
| Hypotension |
0%
|
1%
|
1%
|
1%
|
0.4%
|
| Intraventricular
Conduction Delay |
0%
|
1%
|
1%
|
1%
|
0.1%
|
| Pain, Joints |
0%
|
0%
|
1%
|
1%
|
0.1%
|
In addition, the following adverse reactions were reported less
frequently than 1% either in clinical
trials or in marketing experience
(adverse events for marketing experience
are given in italics). Causality and relationship to propafenone
therapy cannot necessarily
be judged from these events.
Cardiovascular System: Atrial flutter, AV dissociation,
cardiac arrest, flushing, hot
flashes, such sinus
syndrome, sinus
pause or arrest, supraventricular
tachycardia.
Nervous System: Abnormal dreams, abnormal
speech, abnormal vision,
apnea, coma, confusion,
depression, memory
loss, numbness, paresthesias, psychosis/mania, seizures (0.3%),
tinnitus, unusual smell
sensation, vertigo.
Gastrointestinal: A number
of patients with liver
abnormalities associated with propafenone therapy
have been reported in foreign post- marketing experience. Some appeared
due to hepatocellular
injury, some were cholestatic
and some showed a mixed
picture. Some of these reports were simply discovered through clinical
chemistries, others because of clinical symptoms including fulminant
hepatitis and death.
One case was rechallenged
with a positive outcome.
Cholestasis (0.1 %), elevated liver
enzymes (alkaline phosphatase, serum transaminases) (0.2%), gastroenteritis,
hepatitis (0.03%).
Hematologic: Agranulocytosis, anemia,
bruising, granulocytopenia, increased bleeding
time, leukopenia,
purpura, thrombocytopenia.
Other: Alopecia, eye
irritation, hyponatremia/ inappropriate ADH secretion,
impotence, increased
glucose, kidney
failure, positive ANA
(0.7%), lupus erythematosis,
muscle cramps, muscle
weakness, nephrotic syndrome, pain,
pruritus.
DRUG INTERACTIONS
Quinidine: Small doses of quinidine completely inhibit the
hydroxylation metabolic pathway, making all patients, in effect,
slow metabolizers (see
CLINICAL PHARMACOLOGY).
There is, as yet, too little information to recommend concomitant
use of propafenone and quinidine.
Local Anesthetics: Concomitant use of local
anesthetics (i.e., during pacemaker
implantations, surgery,
or dental use) may increase
the risks of central
nervous system
side effects.
Digitalis: RYTHMOL (propafenone hydrochloride) produces
dose-related increases in serum
digoxin levels ranging
from about 35% at 450 mg/day to 85% at 900 mg/day of propafenone
without affecting digoxin
renal clearance. These
elevations of digoxin
levels were maintained for up to 16 months during concomitant
administration. Plasma digoxin
levels of patients on concomitant therapy
should be measured, and digoxin
dosage should ordinarily
be reduced when propafenone is started, especially if a relatively
large digoxin dose is used
or if plasma concentrations
are relatively high.
Beta-Antagonists: In
a study involving healthy
subjects, concomitant administration of propafenone and propranolol
has resulted in substantial increases in propranolol plasma
concentration
and elimination
half-life with no change
in propafenone plasma
levels from control
values. Similar observations have been reported with metoprolol.
Propafenone appears to inhibit the hydroxylation pathway
for the two beta-antagonists (just as quinidine inhibits propafenone
metabolism). Increased plasma
concentrations of metoprolol could overcome its relative cardioselectivity.
In propafenone clinical trials,
patients who were receiving beta-blockers concurrently did not experience
an increased incidence
of side effects. While
the therapeutic range for beta-blockers is wide, a reduction
in dosage may be necessary
during concomitant
administration
with propafenone.
Warfarin: In a study
of eight healthy subjects
receiving propafenone and warfarin concomitantly, mean
steady-state warfarin plasma
concentrations increased 39% with a corresponding
increase in prothrombin
times of approximately 25%. It is therefore recommended that prothrombin
times be routinely monitored and the dose
of warfarin be adjusted if necessary.
Cimetidine: Concomitant administration
of propafenone and cimetidine in 12 healthy
subjects resulted in a 20% increase in steady-state plasma concentrations
of propafenone with no detectable
changes in electrocardiographic parameters beyond that measured
on propafenone alone.
Desipramine: Concomitant administration
of propafenone and desipramine may result in elevated serum
desipramine levels. Both desipramine, a tricyclic antidepressant,
and propafenone are cleared by oxidative pathways of demethylation
and hydroxylation carried out by the hepatic
P-450 cytochrome.
Cyclosporin: Propafenone therapy
may increase levels of cyclosporin.
Theophylline: Propafenone may increase theophylline
concentration during concomitant
therapy with the development
of theophylline
toxicity.
Rifampin: Rifampin may accelerate the metabolism
and decrease the plasma
levels and antiarrhythmic
efficacy of propafenone.
Other: Limited experience
with propafenone combined with calcium antagonists and diuretics
has been reported without evidence
of clinically significant adverse reactions.
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