Propafenone Hydrochloride (Page 4 of 7)

8.2 Lactation

Risk Summary
Propafenone and its active metabolite, 5-OH-propafenone, are present in human milk, but the levels are likely to be low. There are no data on the effects of propafenone on the breastfed infant or the effects on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for propafenone and any potential adverse effects on the breastfed infant from propafenone or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Infertility
Males: Based on human and animal studies, propafenone hydrochloride tablets may transiently impair spermatogenesis in males. Evaluation of the effects on spermatogenesis was performed in 11 healthy males given oral propafenone 300 mg b.i.d. for 4 days, which was then increased to 300 mg t.i.d. for an additional 4 days. Study findings included a 28% reduction in semen sample volume on Treatment Day 8 and a 27% reduction in sperm count 64 days after treatment (both values remained within the laboratories normal reference range). These effects were not seen in follow-up visits up to 120 days after treatment. Reversible decreases in spermatogenesis have been demonstrated in monkeys, dogs, and rabbits after lethal or near-lethal intravenous doses of propafenone [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of propafenone in pediatric patients have not been established.

8.5 Geriatric Use

Clinical trials of propafenone hydrochloride tablets did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. 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.

10 OVERDOSAGE

The symptoms of overdosage may include hypotension, somnolence, bradycardia, intra-atrial and intraventricular conduction disturbances, and rarely, convulsions and high-grade ventricular arrhythmias. Defibrillation, as well as infusion of dopamine and isoproterenol, has been effective in controlling abnormal rhythm and blood pressure. Convulsions have been alleviated with intravenous diazepam. General supportive measures such as mechanical respiratory assistance and external cardiac massage may be necessary.

The hemodialysis of propafenone in patients with an overdose is expected to be of limited value in the removal of propafenone as a result of both its high protein binding (greater than 95%) and large volume of distribution.

11 DESCRIPTION

Propafenone Hydrochloride Tablets USP are an antiarrhythmic drug supplied in scored, film-coated tablets of 150 mg, 225 mg and 300 mg for oral administration. Propafenone has some structural similarities to beta-blocking agents.

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. The structural formula of propafenone hydrochloride is given below:

Propafenone hydrochloride occurs as colorless crystals or white crystalline powder with a very bitter taste. It is slightly soluble in water (20°C), chloroform, and ethanol. The following inactive ingredients are contained in the tablet: corn starch, croscarmellose sodium, hypromellose, maltodextrin, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, povidone, silicon dioxide colloidal, titanium dioxide, and triacetin.

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, 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 ElectrophysiologyElectrophysiology trials in subjects 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, propafenone hydrochloride 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 2. Mean Changes in Electrocardiogram Intervals^a

Interval	Total Daily Dose (mg)
	337.5 mg		450 mg		675 mg		900 mg
	msec	%	msec	%	msec	%	msec	%
RR	-14.5	-1.8	30.6	3.8	31.5	3.9	41.7	5.1
PR	3.6	2.1	19.1	11.6	28.9	17.8	35.6	21.9
QRS	5.6	6.4	5.5	6.1	7.7	8.4	15.6	17.3
QTc	2.7	0.7	-7.5	-1.8	5.0	1.2	14.7	3.7

^a Change and percent change based on mean baseline values for each treatment group.

In any individual patient, the above ECG changes cannot be readily used to predict either efficacy or plasma concentration.

Propafenone hydrochloride tablets cause a dose-related and concentration-related decrease in the rate of single and multiple PVCs and can suppress recurrence of ventricular tachycardia. Based on the percent of patients attaining substantial (80% to 90%) suppression of ventricular ectopic activity, it appears that trough plasma levels of 0.2 to 1.5 mcg/mL can provide good suppression, with higher concentrations giving a greater rate of good response.

When 600 mg/day propafenone was administered to subjects with paroxysmal atrial tachyarrhythmias, mean heart rate during arrhythmia decreased 14 beats per min and 37 beats per min for subjects with PAF and subjects with PSVT, respectively.

Hemodynamics
Trials in humans have shown that propafenone hydrochloride exerts a negative inotropic effect on the myocardium. Cardiac catheterization trials in subjects with moderately impaired ventricular function (mean CI = 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 mcg/mL (a dose that produces plasma levels of propafenone greater than recommended oral dosing) showed significant increases in pulmonary capillary wedge pressure, systemic and pulmonary vascular resistances, and depression of cardiac output and cardiac index.