Absorption/Bioavailability

Maximal plasma levels of propafenone are reached between 3 to 8 hours following the administration of propafenone hydrochloride extended-release capsules. Propafenone is known to undergo extensive and saturable presystemic biotransformation which results in a dose-dependent and dosage-form-dependent absolute bioavailability; e.g., a 150-mg immediate-release tablet had an absolute bioavailability of 3.4%, while a 300-mg immediate-release tablet had an absolute bioavailability of 10.6%.

Absorption from a 300-mg solution dose was rapid, with an absolute bioavailability of 21.4%. At still larger doses, above those recommended, bioavailability of propafenone from immediate- release tablets increased still further.

Relative bioavailability assessments have been performed between propafenone hydrochloride extended-release capsules and propafenone hydrochloride immediate-release tablets. In extensive metabolizers, the bioavailability of propafenone from the ER formulation was less than that of the immediate-release formulation as the more gradual release of propafenone from the prolonged-release preparations resulted in an increase of overall first-pass metabolism (see Metabolism). As a result of the increased first-pass effect, higher daily doses of propafenone were required from the ER formulation relative to the immediate-release formulation to obtain similar exposure to propafenone. The relative bioavailability of propafenone from the 325-mg twice-daily regimens of propafenone hydrochloride extended-release capsules approximates that of propafenone hydrochloride immediate-release 150-mg 3-times-daily regimen. Mean exposure to 5-hydroxypropafenone was about 20% to 25% higher after ER capsule administration than after immediate-release tablet administration.

Food increased the exposure to propafenone 4-fold after single-dose administration of 425 mg of propafenone hydrochloride extended-release capsules. However, in the multiple-dose trial (425-mg dose twice daily), the difference between the fed and fasted state was not significant.

Distribution

Following intravenous administration of propafenone, plasma levels decline in a bi-phasic manner consistent with a 2-compartment pharmacokinetic model. The average distribution half- life corresponding to the first phase was about 5 minutes. The volume of the central compartment was about 88 liters (1.1 L/kg) and the total volume of distribution about 252 liters.

In serum, propafenone is greater than 95% bound to proteins within the concentration range of 0.5 to 2 mcg/mL.

Metabolism

There are 2 genetically determined patterns of propafenone metabolism. In over 90% of patients, the drug is rapidly and extensively metabolized with an elimination half-life from 2 to 10 hours. These patients metabolize propafenone into 2 active metabolites: 5-hydroxypropafenone, which is formed by CYP2D6, and N-depropylpropafenone (norpropafenone), which is formed by both CYP3A4 and CYP1A2.

In less than 10% of patients, metabolism of propafenone is slower because the 5-hydroxy metabolite is not formed or is minimally formed. In these patients, the estimated propafenone elimination half-life ranges from 10 to 32 hours. Decreased ability to form the 5-hydroxy metabolite of propafenone is associated with a diminished ability to metabolize debrisoquine and a variety of other drugs, such as encainide, metoprolol, and dextromethorphan, whose metabolism is mediated by the CYP2D6 isozyme. In these patients, the N-depropylpropafenone metabolite occurs in quantities comparable to the levels occurring in extensive metabolizers.

As a consequence of the observed differences in metabolism, administration of propafenone hydrochloride extended-release capsules to slow and extensive metabolizers results in significant differences in plasma concentrations of propafenone, with slow metabolizers achieving concentrations about twice those of the extensive metabolizers at daily doses of 850 mg/day. At low doses the differences are greater, with slow metabolizers attaining concentrations about 3 to 4 times higher than extensive metabolizers. In extensive metabolizers, saturation of the hydroxylation pathway (CYP2D6) results in greater- than-linear increases in plasma levels following administration of propafenone hydrochloride extended-release capsules. In slow metabolizers, propafenone pharmacokinetics is linear. Because the difference decreases at high doses and is mitigated by the lack of the active 5-hydroxymetabolite in the slow metabolizers, and because steady-state conditions are achieved after 4 to 5 days of dosing in all patients, the recommended dosing regimen of propafenone hydrochloride extended-release capsules is the same for all patients. The larger inter-subject variability in blood levels requires that the dose of the drug be titrated carefully in patients with close attention paid to clinical and ECG evidence of toxicity [see Dosage and Administration (2)].

The 5-hydroxypropafenone and norpropafenone metabolites have electrophysiologic properties similar to propafenone in vitro. In man after administration of propafenone hydrochloride extended-release capsules, the 5- hydroxypropafenone metabolite is usually present in concentrations less than 40% of propafenone. The norpropafenone metabolite is usually present in concentrations less than 10% of propafenone.

Inter-Subject Variability: With propafenone, there is a considerable degree of inter-subject variability in pharmacokinetics which is due in large part to the first-pass hepatic effect and non- linear pharmacokinetics in extensive metabolizers. A higher degree of inter-subject variability in pharmacokinetic parameters of propafenone was observed following both single- and multiple- dose administration of propafenone hydrochloride extended-release capsules. Inter-subject variability appears to be substantially less in the poor-metabolizer group than in the extensive-metabolizer group, suggesting that a large portion of the variability is intrinsic to CYP2D6 polymorphism rather than to the formulation.

Stereochemistry: Propafenone hydrochloride is a racemic mixture. The R- and S-enantiomers of propafenone display stereoselective disposition characteristics. In vitro and in vivo studies have shown that the R-isomer of propafenone is cleared faster than the S-isomer via the 5-hydroxylation pathway (CYP2D6). This results in a higher ratio of S-propafenone to R-propafenone at steady state. Both enantiomers have equivalent potency to block sodium channels; however, the S-enantiomer is a more potent beta-antagonist than the R-enantiomer. Following administration of propafenone hydrochloride immediate-release tablets or propafenone hydrochloride extended-release capsules, the S/R ratio for the area under the plasma concentration-time curve was about 1.7. The S/R ratios of propafenone obtained after administration of 225-mg, 325-mg, and 425-mg propafenone hydrochloride extended-release capsules are independent of dose. In addition, no difference in the average values of the S/R ratios is evident between genotypes or over time.

Specific Populations

Patients with Hepatic Impairment: Decreased liver function increases the bioavailability of propafenone. Absolute bioavailability assessments have not been determined for the capsule formulation of propafenone hydrochloride extended-release capsules. Absolute bioavailability of propafenone hydrochloride immediate-release tablets is inversely related to indocyanine green clearance, reaching 60% to 70% at clearances of 7 mL/min and below. Protein binding decreases to about 88% in patients with severe hepatic dysfunction. The clearance of propafenone is reduced and the elimination half-life increased in patients with significant hepatic dysfunction [see Warnings and Precautions (5.9)].