Propafenone Hydrochloride (Page 4 of 8)

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 extended-release capsules 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

Of the total number of subjects in Phase 3 clinical trials of propafenone hydrochloride extended-release 46% were 65 and older, while 16% were 75 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals at higher doses cannot be ruled out. The effect of age on the pharmacokinetics and pharmacodynamics of propafenone has not been studied.

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 Extended Release Capsules, USP are an antiarrhythmic drug supplied in extended-release capsules of 225 mg, 325 mg and 425 mg for oral administration.

Chemically, propafenone hydrochloride, USP is 2’-[2-hydroxy-3-(propylamino)-propoxy]-3-phenylpropiophenone hydrochloride, with a molecular weight of 377.9. The molecular formula is C₂₁ H₂₇ NO₃ •HCl.

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

Propafenone hydrochloride, USP occurs as a white to almost white powder or crystals. It is soluble in methanol and in hot water; slightly soluble in alcohol and in chloroform; very slightly soluble in acetone; insoluble in diethyl ether and in toluene.

Propafenone Hydrochloride Extended-Release Capsules, USP are filled with white to off white colored, round shaped flat mini tablets, containing propafenone hydrochloride, USP and the following inactive ingredients: black iron oxide, gelatin, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, potassium hydroxide, shellac, sodium lauryl sulfate and titanium dioxide.

USP dissolution test is pending.

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 to 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, propafenone hydrochloride 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)

	Propafenone Hydrochloride Extended-release Capsules 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
QTc* (ms)	2±30	5±36	6±37	5±35

*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 propafenone hydrochloride extended-release capsules 225 mg twice daily, 325 mg twice daily, and 425 mg twice daily and placebo dose groups. Similar results were seen in the ERAFT trial.

Table 2. Number of Patients According to the Range of Maximum QTc change compared to baseline over the Trial in each dose group (RAFT Trial).

Range maximum QTc change	Propafenone Hydrochloride Extended-release Capsules			Placebo
	225 mgTwice Daily	325 mgTwice Daily	425 mgTwice 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 Trials in humans have shown that propafenone exerts a negative inotropic effect on the myocardium. Cardiac catheterization trials 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 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.