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Rythmol (Propafenone) Side Effects, Interactions, Warning, Dosage


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9.15.2017 | Jennifer Bargeman
Rythmol
Rythmol (Propafenone) Side Effects, Interactions, Warning, Dosage

There were 5 deaths, 3 in the pooled RYTHMOL SR group (0.8%) and 2 in the placebo group (1.6%). Concurrent use of propafenone with other antiarrhythmic agents has not been well studied. In a study of sustained-release propafenone (RYTHMOL SR), there were too few deaths to assess the long term risk to patients. In the overall RYTHMOL SR and RYTHMOL immediate-release database of 8 studies, the mortality rate was 2.5% per year on propafenone and 4.0% per year on placebo.

It is therefore essential that each patient given RYTHMOL be evaluated electrocardiographically prior to and during therapy to determine whether the response to RYTHMOL supports continued treatment. It may also worsen premature ventricular contractions or supraventricular arrhythmias, and it may prolong the QT interval. Such proarrhythmic effects include sudden death and life-threatening ventricular arrhythmias such as ventricular fibrillation, ventricular tachycardia, asystole and torsade de pointes. Because propafenone prolongs the QRS interval in the electrocardiogram, changes in the QT interval are difficult to interpret. Propafenone has caused new or worsened arrhythmias.

Included as part of the PRECAUTIONS section.

Dispense in a tight, light-resistant container.

Revised: March 2013. Manufactured for GlaxoSmithKline by: Halo Pharmaceutical, Inc., Whippany, NJ 07981. Distributed by: GlaxoSmithKline, Research Triangle Park, NC 27709.

Nervous System: Apnea, coma.

150 mg bottles of 100: NDC 225 mg bottles of 100: NDC.

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. Orlistat may limit the fraction of propafenone available for absorption.

As with other antiarrhythmic agents, in the elderly or in ventricular arrhythmia patients with marked previous myocardial damage, the dose of RYTHMOL should be increased more gradually during the initial phase of treatment.

RYTHMOL (propafenone hydrochloride) Tablets WARNING MORTALITY.

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%. Table 1: Adverse Reactions Reported for > 1.5% of SVT Patients Incidence (N = 480) % of Pts.

About 20% of patients treated with RYTHMOL have discontinued treatment because of adverse reactions. Adverse reactions associated with RYTHMOL occur most frequently in the gastrointestinal, cardiovascular, and central nervous systems.

Some appeared due to hepatocellular injury, some were cholestatic and some showed a mixed picture. Gastrointestinal: A number of patients with liver abnormalities associated with propafenone therapy have been reported in post-marketing experience. 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.

Although most proarrhythmic events occurred during the first week of therapy, late events also were seen and the CAST study suggests that an increased risk of proarrythmia is present throughout treatment. Of the patients who had worsening of VT (4%), 92% had a history of VT and/or VT/VF, 71% had coronary artery disease, and 68% had a prior myocardial infarction. The incidence of proarrhythmia in patients with less serious or benign arrhythmias, which include patients with an increase in frequency of PVCs, was 1.6%. Overall in clinical trials with RYTHMOL (which included patients treated for ventricular arrhythmias, atrial fibrillation/flutter, and PSVT), 4.7% of all patients had new or worsened ventricular arrhythmia possibly representing a proarrhythmic event (0.7% was an increase in PVCs; 4.0% a worsening, or new appearance, of VT or VF).

Increased exposure to propafenone may lead to cardiac arrhythmias and exaggerated beta-adrenergic blocking activity. Therefore, avoid simultaneous use of RYTHMOL with both a CYP2D6 inhibitor and a CYP3A4 inhibitor. Because of its metabolism, the combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition in users of propafenone is potentially hazardous.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during post-approval use of RYTHMOL.

In a U.S. trial of RYTHMOL SR in patients with symptomatic AF, heart failure was reported in 4 (1.0%) patients receiving RYTHMOL SR (all doses), compared to 1 (0.8%) patient receiving placebo.

RYTHMOL is indicated to: Usage Considerations:

However, in 4 of the 9 patients, the ventricular tachycardia was of atrial origin. Case reports in patients treated with propafenone for atrial fibrillation / flutter have included increased premature ventricular contractions (PVCs), VT, VF, torsade de pointes, asystole, and death. uncontrolled, open label, multicenter trial in patients with symptomatic supraventricular tachycardia (SVT), 1.9% (9/474) of these patients experienced ventricular tachycardia (VT) or ventricular fibrillation (VF) during the study. In a U.S. About 2.3% (11/474) of all patients had a recurrence of SVT during the study which could have been a change in the patients' arrhythmia behavior or could represent a proarrhythmic event. Six of the nine patients that developed ventricular arrhythmias did so within 14 days of onset of therapy.

In 8 patients with moderate to severe liver disease, the mean half-life was approximay 9 hours. Carefully monitor patients with impaired hepatic function for excessive pharmacological effects. Severe liver dysfunction increases the bioavailability of propafenone to approximay 70% compared to 3 to 40% in patients with normal liver function. Propafenone is highly metabolized by the liver. Increased bioavailability of propafenone in these patients may result in excessive accumulation.

Cardiovascular System: Atrial flutter, AV dissociation, cardiac arrest, flushing, hot flashes, sick sinus syndrome, sinus pause or arrest, supraventricular tachycardia.

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).

Call your doctor at once if you have a serious side effect such as:

Headache was relatively common also, but was not increased compared to placebo. Other reactions reported more frequently than on placebo or comparator and not already reported elsewhere included anxiety, angina, second degree AV block, bundle branch block, loss of balance, congestive heart failure, and dyspepsia. In controlled trials in patients with ventricular arrhythmia, the most common reactions reported for RYTHMOL and more frequent than on placebo were unusual taste, dizziness, first degree AV block, intraventricular conduction delay, nausea and/or vomiting, and constipation.

Average PR interval prolongation and increases in QRS duration are also dose-related. Do not give propafenone to patients with atrioventricular and intraventricular conduction defects in the absence of a pacemaker. Propafenone slows atrioventricular conduction and may also cause dose-related first degree AV block.

150 mg and 225 mg scored, round, film-coated tablets.

The usefulness and safety of dosages exceeding 900 mg per day have not been established. If additional therapeutic effect is needed, the dose of RYTHMOL may be increased to 300 mg every 8 hours (900 mg/day). Initiate therapy with RYTHMOL 150 mg given every eight hours (450 mg/day). The dose of RYTHMOL must be individually titrated on the basis of response and tolerance. Dosage may be increased at a minimum of 3 to 4 day intervals to 225 mg every 8 hours (675 mg/day).

Blood and Lymphatic System: Increased bleeding time.

Propafenone may alter both pacing and sensing thresholds of implanted pacemakers and defibrillators. During and after therapy, monitor and re-program these devices accordingly.

Nervous System: Abnormal dreams, abnormal speech, abnormal vision, confusion, depression, memory loss, numbness, paresthesias, psychosis / mania, seizures (0.3%), tinnitus, unusual smell sensation, vertigo.

The molecular formula is C 21 H 27 NO 3 •HCl.The structural formula of propafenone HCl is given below:. Chemically, propafenone hydrochloride (HCl) is 2'--3-phenylpropiophenone hydrochloride, with a molecular weight of 377.92.

Visit the FDA MedWatch website or call 1-800-FDA-1088. You are encouraged to report negative side effects of prescription drugs to the FDA.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In 4 patients, administration of metoprolol with propafenone increased the metoprolol plasma concentrations at steady state by 100% to 400%. In clinical trials using propafenone immediate release tablets, patients who were receiving beta-blockers concurrently did not experience an increased incidence of side effects. Concomitant use of propafenone and propranolol in healthy subjects increased propranolol plasma concentrations at steady state by 113%. The pharmacokinetics of propafenone was not affected by the coadministration of either propranolol or metoprolol.

Avoid the use of propafenone with Class IA and III antiarrhythmic agents (including quinidine and amiodarone). The use of RYTHMOL in conjunction with other drugs that prolong the QT interval has not been extensively studied. Such drugs may include many antiarrhythmics, some phenothiazines, tricyclic antidepressants, and oral macrolides. Withhold Class IA and III antiarrhythmic agents for at least 5 half-lives prior to dosing with RYTHMOL. There is only limited experience with the concomitant use of Class IB or IC antiarrhythmics.

Propafenone exerts a negative inotropic activity on the myocardium as well as beta blockade effects and may provoke overt heart failure.

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 has been reported to increase the risks of central nervous system side effects of lidocaine.

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.

Other: Alopecia, eye irritation, impotence, increased glucose, positive ANA (0.7%), muscle cramps, muscle weakness, nephrotic syndrome, pain, pruritus.

Amiodarone : Concomitant administration of propafenone and amiodarone can affect conduction and repolarization and is not recommended.

In patients with hepatic impairment or thosewith significant widening of the QRS complex or second or third degree AV block, consider reducing the dose.

RYTHMOL (propafenone hydrochloride) is an antiarrhythmic drug supplied in scored, film-coated tablets of 150 and 225 mg for oral administration. Propafenone has some structural similarities to beta-blocking agents.

Propafenone is metabolized by CYP2D6, CYP3A4, and CYP1A2 isoenzymes. Approximay 6% of Caucasians in the U.S. population are naturally deficient in CYP2D6 activity and to a somewhat lesser extent in other demographic groups. Drugs that inhibit these CYP pathways (such as desipramine, paroxetine, ritonavir, sertraline for CYP2D6; ketoconazole, erythromycin, saquinavir, and grapefruit juice for CYP3A4; and amiodarone and tobacco smoke for CYP1A2) can be expected to cause increased plasma levels of propafenone.

RYTHMOL tablets are supplied as white, biconvex, scored, round, film-coated tablets containing either 150 mg or 225 mg of propafenone hydrochloride and embossed (on the same side) with GS and TF5 for the 150 mg tablet, and GS and F1X for the 225 mg tablet, in the following package sizes:

Adjust the warfarin dose as needed by monitoring INR (international normalized ratio). The concomitant administration of propafenone and warfarin increased warfarin plasma concentrations at steady state by 39% in healthy volunteers and prolonged the prothrombin time (PT) in patients taking warfarin.

Of the patients with CHF probably related to propafenone, 80% had preexisting heart failure and 85% had coronary artery disease. In clinical trial experience with RYTHMOL, new or worsened congestive heart failure ( CHF ) has been reported in 3.7% of patients with ventricular arrhythmia; of those 0.9% were considered probably or definiy related to propafenone HCl. CHF attributable to propafenone HCl developed rarely ( < 0.2%) in ventricular arrhythmia patients who had no previous history of CHF. CHF occurred in 1.9% of patients studied with PAF or PSVT.

clinical trials are presented in Table 1 by incidence and percent discontinuation, reported to the nearest percent. Adverse reactions reported for > 1.5% of 474 SVT patients who received RYTHMOL in U.S.

It is slightly soluble in water (20°C), chloroform and ethanol. The following inactive ingredients are contained in the tablet: corn starch, hypromellose, magnesium stearate, polyethylene glycol, polysorbate, povidone, propylene glycol, sodium starch glycolate, and titanium dioxide. Propafenone HCl occurs as colorless crystals or white crystalline powder with a very bitter taste.

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%

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Adverse reactions reported for ≥ 1% of 2,127 ventricular arrhythmia patients who received propafenone in U.S. Some less common reactions may also have been dose-related such as first degree AV block, congestive heart failure, dyspepsia, and weakness. The most common adverse reactions 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. clinical trials were evaluated by daily dose. Other adverse reactions included rash, syncope, chest pain, abdominal pain, ataxia, and hypotension.

Renal and Urinary: Hyponatremia /inappropriate ADH secretion, kidney failure.

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%. Monitor plasma digoxin levels of patients receiving propafenone and adjust digoxin dosage as needed.

The combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition with administration of propafenone may increase the risk of adverse reactions, including proarrhythmia. Drugs that inhibit CYP2D6 (such as desipramine, paroxetine, ritonavir, or sertraline) and CYP3A4 (such as ketoconazole, ritonavir, saquinavir, erythromycin, or grapefruit juice) can be expected to cause increased plasma levels of propafenone. Therefore, simultaneous use of RYTHMOL with both a CYP2D6 inhibitor and a CYP3A4 inhibitor should be avoided [see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION ].

In addition, the following adverse reactions were reported less frequently than 1% either in clinical trials or in marketing experience. Causality and relationship to propafenone therapy cannot necessarily be judged from these events.

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Gastrointestinal: Cholestasis, elevated liver enzymes (alkaline phosphatase, serum transaminases), gastroenteritis, hepatitis.

Unexplained fever or decrease in white cell count, particularly during the initial 3 months of therapy, warrant consideration of possible agranulocytosis or granulocytopenia. Agranulocytosis has been reported in patients receiving propafenone. Generally, the agranulocytosis occurred within the first 2 months of propafenone therapy and upon discontinuation of therapy, the white count usually normalized by 14 days. Instruct patients to report promptly any signs of infection such as fever, sore throat, or chills.

Concomitant administration of quinidine (50 mg three times daily) with 150 mg immediate release propafenone three times daily decreased the clearance of propafenone by 60% in extensive metabolizers, making them slow metabolizers. Steady-state plasma concentrations more than doubled for propafenone, and decreased 50% for 5-OH-propafenone. A 100 mg dose of quinidine tripled steady state concentrations of propafenone. Quinidine : Small doses of quinidine compley inhibit the CYP2D6 hydroxylation metabolic pathway, making all patients, in effect, slow metabolizers. Avoid concomitant use of propafenone and quinidine.

Hematologic: Agranulocytosis, anemia, bruising, granulocytopenia, leukopenia, purpura, thrombocytopenia.

Brugada Syndrome may be unmasked after exposure to RYTHMOL. Perform an ECG after initiation of RYTHMOL, and discontinue the drug if changes are suggestive of Brugada Syndrome.

Therefore, avoid simultaneous use of RYTHMOL with both a CYP2D6 inhibitor and a CYP3A4 inhibitor [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS ]. The combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition with the simultaneous administration of propafenone may significantly increase the concentration of propafenone and thereby increase the risk of proarrhythmia and other adverse events.

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Approximay 50% of propafenone metabolites are excreted in the urine following administration of RYTHMOL.

Immune System: lupus erythematosis.

trial in 523 patients with a history of symptomatic AF treated with RYTHMOL SR, sinus bradycardia (rate < 50 beats/min) was reported with the same frequency with RYTHMOL SR and placebo. In a U.S.

In slow 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. The concentrations of norpropafenone increased by 30%. Rifampin : Concomitant administration of rifampin and propafenone in extensive metabolizers decreased the plasma concentrations of propafenone by 67% with a corresponding decrease of 5-OH-propafenone by 65%. 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 5-OH-propafenone by 69% and 57%.

Bradycardia has also been reported (1.5%). The incidence of first degree, second degree, and third degree AV block observed in 2,127 ventricular arrhythmia patients was 2.5%, 0.6%, and 0.2%, respectively. Development of second or third degree AV block requires a reduction in dosage or discontinuation of propafenone HCl. Experience in patients with sick sinus node syndrome is limited and these patients should not be treated with propafenone. Bundle branch block (1.2%) and intraventricular conduction delay (1.1%) have been reported in patients receiving propafenone.

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