View source for RYTHMOL warnings and precautions

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{{Propafenone}}
{{CMG}}; {{AE}} {{SS}}

==Warnings and Precautions==

===5.1 Proarrhythmic Effects===

Propafenone has caused new or worsened [[arrhythmias]]. Such proarrhythmic effects include sudden death and life-threatening [[ventricular fibrillation]] such as [[ventricular fibrillation]]  [[ventricular tachycardia]]  [[asystole]]  and torsade de pointes. It may also worsen premature ventricular contractions or supra[[ventricular fibrillation]], and it may prolong the QT interval. 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. Because propafenone prolongs the QRS interval in the electrocardiogram, changes in the QT interval are difficult to interpret [see Clinical Pharmacology (12.2)].

In a US uncontrolled, open-label, multicenter trial in subjects with symptomatic supraventricular [[tachycardia ]](SVT), 1.9% (9/474) of these subjects experienced ventricular [[tachycardia ]](VT) or [[ventricular fibrillation]] (VF) during the trial. However, in 4 of the 9 subjects, the ventricular [[tachycardia ]]was of atrial origin. Six of the 9 subjects that developed [[ventricular fibrillation]] did so within 14 days of onset of therapy. About 2.3% (11/474) of all subjects had a recurrence of SVT during the trial which could have been a change in the subjects’ arrhythmia behavior or could represent a proarrhythmic event. 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.

Overall in clinical trials with RYTHMOL (which included subjects treated for [[ventricular fibrillation]], atrial fibrillation/flutter, and PSVT), 4.7% of all subjects 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). Of the subjects 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 subjects with less serious or benign [[arrhythmias]], which include subjects with an increase in frequency of PVCs, was 1.6%. Although most proarrhythmic events occurred during the first week of therapy, late events also were seen and the CAST trial [see Boxed Warning: Mortality] suggests that an increased risk of proarrythmia is present throughout treatment.

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

===5.2 Unmasking Brugada Syndrome===

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]] [see Contraindications (4)].

5.3 Use With Drugs That Prolong the QT Interval and Antiarrhythmic Agents

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. Avoid the use of propafenone with Class IA and III antiarrhythmic agents (including quinidine and amiodarone). There is only limited experience with the concomitant use of Class IB or IC antiarrhythmics.

5.4 Drug Interactions: Simultaneous Use With Inhibitors of Cytochrome P450 Isoenzymes 2D6 and 3A4

Propafenone is metabolized by CYP2D6, CYP3A4, and CYP1A2 isoenzymes. Approximately 6% of Caucasians in the US 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.

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

5.5 Use in Patients With a History of Heart Failure

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

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

In a US trial of RYTHMOL SR in subjects with symptomatic AF, heart failure was reported in 4 (1.0%) subjects receiving RYTHMOL SR (all doses), compared with 1 (0.8%) subject receiving placebo.

5.6 Conduction Disturbances

Propafenone slows atrioventricular conduction and may also cause dose-related first-degree AV block. 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 [see Contraindications (4), Clinical Pharmacology (12.2)].

The incidence of first-degree, second-degree, and third-degree AV block observed in 2,127 subjects with [[ventricular arrhythmia]] 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. Bundle branch block (1.2%) and intraventricular conduction delay (1.1%) have been reported in subjects receiving propafenone. Bradycardia has also been reported (1.5%). Experience in patients with sick sinus node syndrome is limited and these patients should not be treated with propafenone.

In a US trial in 523 subjects 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.

5.7 Effects on Pacemaker Threshold

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

5.8 Agranulocytosis

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. Unexplained fever or decrease in white cell count, particularly during the initial 3 months of therapy, warrant consideration of possible agranulocytosis or granulocytopenia. Instruct patients to report promptly any signs of infection such as fever, sore throat, or chills.

5.9 Use in Patients With Hepatic Dysfunction

Propafenone is highly metabolized by the liver. Severe liver dysfunction increases the bioavailability of propafenone to approximately 70% compared with 3% to 40% in patients with normal liver function. In 8 subjects with moderate to severe liver disease, the mean half-life was approximately 9 hours. Increased bioavailability of propafenone in these patients may result in excessive accumulation. Carefully monitor patients with impaired hepatic function for excessive pharmacological effects [see Overdosage (10)].

5.10 Use in Patients With Renal Dysfunction

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

In patients with impaired renal function, monitor for signs of overdosage [see Overdosage (10)].

5.11 Use in Patients With Myasthenia Gravis

Exacerbation of myasthenia gravis has been reported during propafenone therapy.

5.12 Elevated ANA Titers

Positive ANA titers have been reported in patients receiving propafenone. They have been reversible upon cessation of treatment and may disappear even in the face of continued propafenone therapy. These laboratory findings were usually not associated with clinical symptoms, but there is one published case of drug-induced lupus erythematosis (positive rechallenge); it resolved completely upon discontinuation of therapy. Carefully evaluate patients who develop an abnormal ANA test and, if persistent or worsening elevation of ANA titers is detected, consider discontinuing therapy.

5.13 Impaired Spermatogenesis

Reversible disorders of spermatogenesis have been demonstrated in monkeys, dogs, and rabbits after high-dose intravenous administration of propafenone. Evaluation of the effects of short-term administration of RYTHMOL on spermatogenesis in 11 normal subjects suggested that propafenone produced a reversible, short-term drop (within normal range) in sperm count.<ref>{{Cite web  | last =  | first =  | title = DailyMed: Search | url = http://dailymed.nlm.nih.gov/dailymed/search.cfm?startswith=RYTHMOL&x=12&y=3 | publisher =  | date =  | accessdate = 12 March 2014 }}</ref></div>
==References==
{{Reflist}}

[[Category:Antiarrhythmic agents]]
[[Category:Ketones]]
[[Category:Phenol ethers]]
[[Category:Alcohols]]
[[Category:Amines]]
[[Category:Sodium channel blockers]]
[[Category:Cardiovascular Drugs]]
[[Category:Drugs]]