ective refractory period of the accessory pathway in both directions.
Electrocardiograms
Propafenone prolongs the PR and QRS intervals. Prolongation of the QRS interval makes it difficult to interpret the effect of propafenone on the QT interval.
Table 1. Mean Change ± SD in 12-Lead Electrocardiogram Results (RAFT) RYTHMOL SR Twice Daily Dosing Placebo
225 mg 325 mg 425 mg
n=126 n=135 n=136 n=126
PR (ms) 9±22 12±23 21±24 1±16
QRS (ms) 4±14 6±15 6±15 -2±12
Heart rate 5±24 7±23 2±22 8±27
QTca (ms) 2±30 5±36 6±37 5±35
a Calculated using Bazett’s correction factor
In RAFT [see Clinical Studies (14)], the distribution of the maximum changes in QTc compared to baseline over the study in each patient was similar in the RYTHMOL SR 225 mg twice daily, 325 mg twice daily, and 425 mg twice daily and placebo dose groups. Similar results were seen in the ERAFT study.
Table 2. Number of Patients According to the Range of Maximum QTc Change Compared to Baseline Over the Study in Each Dose Group (RAFT study). Range maximum QTc change RYTHMOL SR Placebo
225 mg
twice daily 325 mg
twice daily 425 mg
twice daily
N=119 N=129 N=123 N=100
n (%) n (%) n (%) n (%)
>20% 1 (1) 6 (5) 3 (2) 5 (4)
10-20% 19 (16) 28 (22) 32 (26) 24 (20)
0 ≤10% 99 (83) 95 (74) 88 (72) 91 (76)
Hemodynamics
Studies in humans have shown that propafenone exerts a negative inotropic effect on the myocardium. Cardiac catherterization studies in patients with moderately impaired ventricular function (mean C.I.=2.61 L/min/m2), utilizing intravenous propafenone infusions (loading dose of 2 mg/kg over 10 min+ followed by 2 mg/min for 30 min) that gave mean plasma concentrations of 3.0 µg/mL (a dose that produces plasma levels of propafenone greater than does recommended oral dosing), showed significant increases in pulmonary capillary wedge pressure, systemic and pulmonary vascular resistances and depression of cardiac output and cardiac index.
12.3 Pharmacokinetics
Absorption/Bioavailability
Maximal plasma levels of propafenone are reached between 3 to 8 hours following the administration of RYTHMOL SR. Propafenone is known to undergo extensive and saturable presystemic biotransformation which results in a dose 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 RYTHMOL SR capsules and RYTHMOL immediate release tablets. In extensive metabolizers, the bioavailability of propafenone from the SR 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 SR formulation relative to the immediate release formulation, to obtain si
