RYTHMOL SR (Page 5 of 8)

11 DESCRIPTION

RYTHMOL SR (propafenone hydrochloride) is an antiarrhythmic drug supplied in extended-release capsules of 225, 325, and 425 mg for oral administration.

Chemically, propafenone hydrochloride is 2’-[2-hydroxy-3-(propylamino)-propoxy]-3-phenylpropiophenone hydrochloride, with a molecular weight of 377.92. The molecular formula is C21 H27 NO3 •HCl.

Propafenone HCl has some structural similarities to beta-blocking agents. The structural formula of propafenone HCl is given below:

propafenone hydrochloride chemical structure

Propafenone HCl occurs as colorless crystals or white crystalline powder with a very bitter taste. It is slightly soluble in water (20°C), chloroform, and ethanol. RYTHMOL SR capsules are filled with cylindrical-shaped 2 x 2 mm microtablets containing propafenone and the following inactive ingredients: antifoam, gelatin, hypromellose, magnesium stearate, red iron oxide, shellac, sodium dodecyl sulfate, sodium lauryl sulfate, soy lecithin, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Propafenone is a Class 1C antiarrhythmic drug with local anesthetic effects and a direct stabilizing action on myocardial membranes. The electrophysiological effect of propafenone manifests itself in a reduction of upstroke velocity (Phase 0) of the monophasic action potential. In Purkinje fibers, and, to a lesser extent, myocardial fibers, propafenone reduces the fast inward current carried by sodium ions. Diastolic excitability threshold is increased and effective refractory period prolonged. Propafenone reduces spontaneous automaticity and depresses triggered activity.

Studies in anesthetized dogs and isolated organ preparations show that propafenone has beta-sympatholytic activity at about 1/50 the potency of propranolol. Clinical studies employing isoproterenol challenge and exercise testing after single doses of propafenone indicate a beta-adrenergic blocking potency (per mg) about 1/40 that of propranolol in man. In clinical trials with the immediate-release formulation, resting heart rate decreases of about 8% were noted at the higher end of the therapeutic plasma concentration range. At very high concentrations in vitro, propafenone can inhibit the slow inward current carried by calcium, but this calcium antagonist effect probably does not contribute to antiarrhythmic efficacy. Moreover, propafenone inhibits a variety of cardiac potassium currents in in vitro studies (i.e., the transient outward, the delayed rectifier, and the inward rectifier current). Propafenone has local anesthetic activity approximately equal to procaine. Compared with propafenone, the main metabolite, 5-hydroxypropafenone, has similar sodium and calcium channel activity, but about 10 times less beta-blocking activity. (N-depropylpropafenone has weaker sodium channel activity but equivalent affinity for beta-receptors.)

12.2 Pharmacodynamics

Cardiac Electrophysiology

Electrophysiology trials in patients with ventricular tachycardia have shown that propafenone prolongs atrioventricular conduction while having little or no effect on sinus node function. Both atrioventricular nodal conduction time (AH interval) and His-Purkinje conduction time (HV interval) are prolonged. Propafenone has little or no effect on the atrial functional refractory period, but AV nodal functional and effective refractory periods are prolonged. In patients with Wolff-Parkinson-White syndrome, RYTHMOL immediate-release tablets reduce conduction and increase the effective 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)
a Calculated using Bazett’s correction factor.

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

In RAFT [see Clinical Studies (14)] , the distribution of the maximum changes in QTc compared with baseline over the trial in each patient was similar in the groups receiving RYTHMOL SR 225 mg twice daily, 325 mg twice daily, and 425 mg twice daily, and placebo. Similar results were seen in the ERAFT trial.

Table 2. Number of Patients According to the Range of Maximum QTc Change Compared with Baseline over the Trial in Each Dose Group (RAFT Trial).

Range

Maximum

QTc Change

RYTHMOL SR

Placebo

N = 100

n (%)

225 mg

Twice Daily

325 mg

Twice Daily

425 mg

Twice Daily

N = 119

N = 129

N = 123

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)

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