RYTMONORM Film-coated tablet Ref.[50652] Active ingredients: Propafenone

Propafenone is a racemic mixture of S- and R-propafenone.

Absorption

Rytmonorm is nearly completely absorbed after oral administration with peak plasma levels occurring approximately two to three hours after administration in most individuals. Although food increased the maximal plasma concentration and bioavailability in a single dose study, during multiple dose administration of propafenone to healthy subjects, food did not change bioavailability significantly.

Distribution

Propafenone distributes rapidly. The steady-state volume of distribution is 1.9 to 3.0 L/kg. The degree of plasma protein binding of propafenone is concentration dependent and decreased from 97.3% at 0.25 microg/mL to 81.3% at 100 microg/mL.

Biotransformation

Propafenone is known to undergo extensive and saturable presystemic biotransformation (CYP2D6 hepatic first pass effect) which results in a dose- and dosage form dependent absolute bioavailability e.g., a 150 mg tablet had absolute bioavailability of 3.4%, while a 300 mg tablet had absolute bioavailability of 10.6%. A 300 mg solution which was rapidly absorbed, had absolute bioavailability of 21.4%. At still larger doses, above those recommended, bioavailability increased still further. Decreased liver function also increased bioavailability; bioavailability is inversely related to indocyanine green clearance reaching 60 to 70% at clearances of 7 mL/min and below.

There are two genetically determined patterns of propafenone metabolism. In over 90% of patients, the drug is rapidly and extensively metabolised with an elimination half-life from two to ten hours (extensive metabilizers). These patients metabolise propafenone into two active metabolites: 5-hydroxypropafenone, which is formed by CYP2D6, and N-depropyl-propafenone (norpropafenone), which is formed by both CYP3A4 and CYP1A2. In vitro preparations have shown these two metabolites to have antiarrhythmic activity comparable to propafenone, but in man they both are usually present in concentrations less than 20% of propafenone. Nine additional metabolites have been identified, most in only trace amounts. It is the saturable hydroxylation pathway that is responsible for the nonlinear pharmacokinetic disposition.

In less than 10% of patients (and in any patient also receiving quinidine, see section 4.4), metabolism of propafenone is slower because the 5-hydroxy metabolite is not formed or is minimally formed (i.e. poor metabolizers). Decreased ability to form the 5-hydroxy metabolite of propafenone is associated with a diminished ability to metabolise debrisoquine and a variety of other drugs (encainide, metoprolol, dextromethorphan). In these patients, the N-depropyl-propafenone occurs in quantities comparable to the levels occurring in extensive metabolisers. In slow metabolisers propafenone pharmacokinetics are linear.

There are significant differences in plasma concentrations of propafenone in slow and extensive metabolisers, the former achieving concentrations 1.5 to 2.0 times those of the extensive metabolisers at daily doses of 675-900 mg/day. At low doses the differences are greater, with slow metabolisers attaining concentrations more than five times that of extensive metabolisers. Because the difference decreases at high doses and is mitigated by the lack of the active 5-hydroxy metabolite in the slow metabolisers, and because steady-state conditions are achieved after 3 to 4 days of dosing, the recommended dosing regimen is the same regardless of the metabolic status for all patients (poor versus extensive metabolisers). The greater variability in blood levels require that the drug be titrated carefully in all patients with close attention to clinical and ECG evidence of toxicity (see section 4.2).

Elimination

The estimated propafenone elimination half-life ranges from 2 to 10 hours for extensive metabolizers and from 10 to 32 hours for poor metabolizers. Clearance of propafenone is 0.67 to 0.81 L/h/kg.

The clearance of propafenone is reduced and the oral bioavailability and the elimination half-life are increased in patients with hepatic dysfunction (see sections 4.2 and 4.4).

Linearity/non-linearity

In slow metabolizers, propafenone pharmacokinetics are linear.

In extensive metabolizers, Rytmonorm follows a nonlinear pharmacokinetic disposition presumably due to saturation of first pass hepatic metabolism (hydroxylation pathway, CYP2D6) as the liver is exposed to higher concentrations of propafenone. For example, for a three-fold increase in daily dose from 300 to 900 mg/day there is a ten-fold increase in steady-state plasma concentration. The top 25% of patients given 375 mg/day, however, had, a mean concentration of propafenone larger than the bottom 25%, and about equal to the second 25%, of patients given a dose of 900 mg.

Inter / intra individual variability

With propafenone hydrochloride, there is a considerable degree of individual variability in pharmacokinetics which is due in large part to the first pass hepatic effect and non-linear pharmacokinetics in extensive metabolizers. The large variability in blood levels requires that the dose be titrated carefully in patients, paying close attention to clinical and electrocardiographic evidence of toxicity.

Elderly population

Propafenone exposure in elderly subjects with normal renal function was highly variable, and not significantly different from healthy young subjects. Exposure to 5-hydroxypropafenone was similar, but exposure to propafenone glucuronides was doubled.

Renal impairment

In patients with renal impairment, exposure to propafenone and 5-hydroxypropafenone was similar to that in healthy controls, while accumulation of glucuronide metabolites was observed. Propafenone hydrochloride should be administered cautiously in patients with renal disease.

Hepatic impairment

Propafenone shows an increased oral bioavailability and half-life in patients with liver impairment. The dosage must be adjusted in patients with liver disease.

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential or toxicity to reproduction.

Studies in anaesthetised dogs and isolated organ preparations show that Rytmonorm has beta-sympatholytic activity at about 1/50 of potency of propranolol.

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. Propafenone has local anaesthetic activity approximately equal to procaine.

Carcinogenesis, mutagenesis and impairment on fertility

Lifetime maximally tolerated oral dose studies in mice (up to 80 mg/kg/day) and rats (up to 270 mg/kg/day) provided no evidence of a carcinogenic potential for propafenone.

Propafenone was not mutagenic when assayed for genotoxicity in:

1. Mouse dominant lethal test;
2. Rat bone marrow chromosome analysis;
3. Chinese hamster bone marrow and spermatogonia chromosome analysis;
4. Chinese hamster micronucleus test; and
5. Ames bacterial test.

Propafenone administered intravenously to rabbits, dogs and monkeys has been shown to decrease spermatogenesis. These effects were reversible, were not found following oral dosing of propafenone, were seen only at lethal or sublethal dose levels and were not seen in rats treated either orally or intravenously (see section 4.4). Propafenone did not affect either male or female fertility rates when administered intravenously to rats and rabbits at dose levels up to 18 times the maximum recommended daily human dose of 900 mg (based on 60 kg human body weight).