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home > drugs a-z list > rythmol (propafenone) drug center > rythmol (propafenone) drug - side effects and drug interactions
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What is atrial fibrillation?
Atrial fibrillation (AF) is the most common, abnormal rhythm of the heart.
The heart contracts (beats) and pumps blood with a regular rhythm, for example,
at a rate of 60 beats per minute there is a beat every second. The heart may
beat faster or slower with a shorter or longer interval between beats, but at
any one rate the interval between beats is constant. This regular rhythm occurs
as a result of regular electrical discharges (currents) that travel through the
heart and cause the muscle of the heart to contract. In atrial fibrillation, the electrical
discharges are irregular and rapid and, as a result, the heart beats irregularly
and, usually, rapidly.
Atrial fibrillation is common; half a million new cases are diagnosed yearly
in the U.S., and billions of dollars are spent annually on its diagnosis and
treatment.
What causes atrial fibrillation?
Normal function of the he...
Rythmol
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SIDE EFFECTS
Adverse reactions associated with propafenone HCl occur most frequently in the gastrointestinal, cardiovascular, and central nervous systems. About 20% of patients treated with propafenone HCl 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 for ≥ 1% of the patients receiving propafenone as 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 ≥ 1% of Ventricular Arrhythmia
Patients
| Prop./Placebo Trials | Prop./Quinidine Trials | |||
| Prop. | Placebo | Prop. | 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 | 3% | 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 | - | - | 2% | 8% |
| Pain/Cramps | ||||
| 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% | 0% | 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 ≥ 1% 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 ≥ 1% of Ventricular Arrhythmia
Patients
N=2127
| Incidence by Total Daily Dose |
Total Incidence |
% of Pts. Who Discont. |
|||
| 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% |
| QRS 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, sick 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 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
Propafenone is metabolized by CYP2D6 (major pathway) and CYP1A2 and CYP3A4. Drugs that inhibit CYP2D6 (such as desipramine, paroxetine, ritonavir, sertraline), CYP1A2 (such as amiodarone), and CYP3A4 (such as ketaconazole, ritonavir, saquinavir, erythromycin, and grapefruit juice) can be expected to cause increased plasma levels of propafenone. Appropriate monitoring is recommended when RYTHMOL (propafenone) SR is used together with such drugs. In addition, propafenone is an inhibitor of CYP2D6. Coadministration of propafenone with drugs metabolized by CYP2D6 (such as desipramine, imipramine, haloperidol, venlafaxine) might lead to increased plasma concentrations of these drugs. The effect of propafenone on the P-Glycoprotein transporter has not been studied.
Quinidine: Small doses of quinidine completely inhibit the CYP2D6 hydroxylation metabolic pathway, making all patients, in effect, slow metabolizers (see CLINICAL PHARMACOLOGY). Concomitant administration of quinidine (50 mg TID) with 150 mg immediate release propafenone TID decreased the clearance of propafenone by 60% in EM, making them PM. Steady-state plasma concentrations increased by more that 2-fold for propafenone, and decreased 50% for 5-OH-propafenone A 100 mg dose of quinidine increased steady state concentrations of propafenone 3-fold. Concomitant use of propafenone and quinidine is not recommended.
Digoxin: Concomitant use of propafenone and digoxin increased steady-state serum digoxin exposure (AUC) in patients by 60 to 270%, and decreased the clearance of digoxin by 31 to 67%. Plasma digoxin levels of patients receiving propafenone should be monitored and digoxin dosage adjusted as needed.
Lidocaine: No significant effects on the pharmacokinetics of propafenone or lidocaine have been seen following their concomitant use in patients. However, concomitant use of propafenone and lidocaine have been reported to increase the risks of central nervous system side effects of lidocaine.
Beta-Antagonists: Concomitant use of propafenone and propranolol in healthy subjects increased propranolol plasma concentrations at steady state by 113%. In 4 patients, administration of metoprolol with propafenone increased the metoprolol plasma concentrations at steady state by 100-400%. The pharmacokinetics of propafenone was not affected by the coadministration of either propranolol or metoprolol. In clinical trials using propafenone immediate release tablets, patients who were receiving beta-blockers concurrently did not experience an increased incidence of side effects.
Warfarin: The concomitant administration of propafenone and warfarin increased warfarin plasma concentrations at steady state by 39% in healthy volunteers and prolonged the prothrombin time in patients taking warfarin. Adjustment of the warfarin dose should be guided by monitoring of the prothrombin time.
Cimetidine: Concomitant administration of propafenone immediate release tablets and cimetidine in 12 healthy subjects resulted in a 20% increase in steady-state plasma concentrations of propafenone.
Rifampin: Concomitant administration of rifampin and propafenone in extensive metabolizers decreased the plasma concentrations of propafenone by 67% with a corresponding decrease of 50H-propafenone by 65%. The concentrations of norpropafenone increased by 30%. In poor metabolizers, there was a 50% decrease in propafenone plasma concentrations and increased the AUC and Cmax of norpropafenone by 74 and 20%, respectively. Urinary excretion of propafenone and its metabolites decreased significantly. Similar results were noted in elderly patients: Both the AUC and Cmax propafenone decreased by 84%, with a corresponding decrease in AUC and Cmax of 50H-propafenone by 69 and 57%.
Fluoxetine: Concomitant administration of propafenone and fluoxetine in extensive metabolizers increased the S propafenone Cmax and AUC by 39 and 50% and the R propafenone Cmax and AUC by 71 and 50%.
Amiodarone: Concomitant administration of propafenone and amiodarone can affect conduction and repolarization and is not recommended.
Post Marketing Reports: Orlistat may limit the fraction of propafenone available for absorption. In post marketing reports, abrupt cessation of orlistat in patients stabilized on propafenone has resulted in severe adverse events including convulsions, atrioventricular block and acute circulatory failure.
Renal and Hepatic Toxicity in Animals
Renal changes have been observed in the rat following 6 months of oral administration of propafenone HCl at doses of 180 and 360 mg/kg/day (about 2 and 4 times, respectively, the maximum recommended human daily dose [MRHD] on a mg/m² basis). Both inflammatory and non-inflammatory changes in the renal tubules, with accompanying interstitial nephritis, were observed. These changes were reversible, as they were not found in rats allowed to recover for 6 weeks. Fatty degenerative changes of the liver were found in rats following longer durations of administration of propafenone HCl at a dose of 270 mg/kg/day (about 3 times the MRHD on a mg/m² basis). There were no renal or hepatic changes at 90 mg/kg/day (equivalent to the MRHD on a mg/m² basis).
Last reviewed on RxList: 8/14/2008
This monograph has been modified to include the generic and brand name in many instances.
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