Precautions
Hepatic Dysfunction:
Propafenone is highly metabolized by the liver and should, therefore, be administered cautiously to patients with impaired hepatic function. Severe liver dysfunction increases the bioavailability of propafenone to approximately 70% compared to 3-40% for patients with normal liver function. In eight patients with moderate to severe liver disease, the mean half-life was approximately 9 hours. As a result, the dose of propafenone given to patients with impaired hepatic function should be approximately 20-30% of the dose given to patients with normal hepatic function (see DOSAGE AND ADMINISTRATION). Careful monitoring for excessive pharmacological effects (see OVERDOSAGE) should be carried out.
Renal Dysfunction:
A considerable percentage of propafenone metabolites (18.5%-38% of the dose/48 hours) are excreted in the urine.
Until further data are available, propafenone HCl should be administered cautiously to patients with impaired renal function. These patients should be carefully monitored for signs of overdosage (see OVERDOSAGE).
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. Patients who develop an abnormal ANA test should be carefully evaluated and, if persistent or worsening elevation of ANA titers is detected, consideration should be given to discontinuing therapy.
Impaired Spermatogenesis:
Reversible disorders of spermatogenesis have been demonstrated in monkeys, dogs and rabbits after high dose intravenous administration of propafenone HCl. Evaluation of the effects of short-term RYTHMOL administration on spermatogenesis in 11 normal subjects had suggested that propafenone HCl produced a reversible, short-term drop (within normal range) in sperm count. Subsequent evaluations in 11 patients receiving RYTHMOL chronically have suggested no effect of propafenone HCl on sperm count.
Neuromuscular Dysfunction:
Exacerbation of myasthenia gravis has been reported during propafenone therapy.
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 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 50Hpropafenone 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 :
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 HCI 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 HCI 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).
Carcinogenesis, mutagenesis, impairment of fertility
Lifetime maximally tolerated oral dose studies in mice (up to 360 mg/kg/day, about twice the maximum recommended human oral daily dose [MRHD] on a mg/m2 basis) and rats (up to 270 mg/kg/day, about 3 times the MRHD on a mg/m2 basis) provided no evidence of a carcinogenic potential for propafenone HCI.
Propafenone HCI tested negative for mutagenicity in the Ames (salmonella) test and the mouse dominant lethal test, and tested negative for clastogenicity in the Chinese hamster micronucleus test, and other in vivo tests for chromosomal aberrations in rat bone marrow and Chinese hamster bone marrow and spermatogonia.
Propafenone HCI, administered intravenously to rabbits, dogs, and monkeys, has been shown to decrease spermatogenesis. These effects were reversible, were not found following oral dosing of propafenone HCI, were seen a lethal or near lethal dose levels and were not seen in rats treated either orally or intravenously (see PRECAUTIONS, Impaired Spermatogenesis). Treatment of male rabbits for 10 weeks prior to mating at an oral dose of 120 mg/kg/day (about 2.4 times the MRHD on a mg/m2 basis) or an intravenous dose of 3.5 mg/kg/day (a spermatogenesis-impairing dose) did not result in evidence of impaired fertility. Nor was there evidence of impaired fertility when propafenone HCI was administered orally to male and female rats at dose levels up to 270 mg/kg/day (about 3 times the MRHD on mg/m2 basis).
Pregnancy
Teratogenic effects Pregnancy Category C.
Propafenone HCI has been shown to be embryotoxic (decreased survival) in rabbits and rats when given in oral maternally toxic doses of 150 mg/kg day (about 3 times the maximum recommended human dose [MRHD] on a mg/m2 basis) and 600 mg/kg/day (about 6 times the MRHD on a mg/m2 basis), respectively. Although maternally tolerated doses (up to 270 mg/kg/day, about 3 times the MRHD on a mg/m2 basis) produced no evidence of embryotoxicity in rats, post-implantation loss was elevated in all rabbit treatment groups (doses as low as 15 mg/kg/day, about 1/3 the MRHD on a mg/m2 basis). There are no adequate and well-controlled studies in pregnant women. RYTYMOL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic effects
In a study in which female rats received daily oral doses of propafenone HCI from mid-gestation through weaning of their offspring, doses as low as 90 mg/kg/day (equivalent to the MRHD on a mg/m2 basis) produced increases in maternal deaths. Doses of 360 or more mg/kg/day (4 or more times the MRHD on a mg/m2 basis) resulted in reductions in neonatal survival, body weight gain and physiological development.
Labor and delivery
It is not known whether the use of propafenone during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetrical intervention.
Nursing mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serous adverse reactions in nursing infants from propafenone HCI, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric use
The safety and effectiveness of propafenone HCI in pediatric patients have not been established.
Geriatric use
Clinical studies of RYTHMOL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
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