(mexiletine hydrochloride, USP)
Capsules of 150 mg, 200 mg and 250 mg
MEXITIL® (mexiletine hydrochloride, USP) is an orally active antiarrhythmic agent available as 150 mg, 200 mg and 250 mg capsules. 100 mg of mexiletine hydrochloride is equivalent to 83.31 mg of mexiletine base. It is a white to off-white crystalline powder with slightly bitter taste, freely soluble in water and in alcohol. MEXITIL has a pKa of 9.2.
Chemically, MEXITIL is 1-methyl-2-(2, 6-xylyloxy) ethylamine hydrochloride and has the following structural formula:
MEXITIL capsules contain the following excipients: colloidal silicon dioxide, corn starch, magnesium stearate, titanium dioxide, gelatin, pharmaceutical glaze, simethicone, FD&C Red No. 40, and FD&C Blue No. 1; the MEXITIL 150 mg and 250 mg capsules also contain FD&C Yellow No. 10 and D&C Red No. 28. MEXITIL capsules may contain one or more of the following components: sodium lauryl sulfate, lecithin, shellac, and FD&C Blue No. 1 Aluminum Lake.
Mechanism of Action
MEXITIL (mexiletine hydrochloride, USP) is a local anesthetic, antiarrhythmic agent, structurally similar to lidocaine, but orally active. In animal studies, MEXITIL has been shown to be effective in the suppression of induced ventricular arrhythmias, including those induced by glycoside toxicity and coronary artery ligation. MEXITIL, like lidocaine, inhibits the inward sodium current, thus reducing the rate of rise of the action potential, Phase 0. MEXITIL decreased the effective refractory period (ERP) in Purkinje fibers. The decrease in ERP was of lesser magnitude than the decrease in action potential duration (APD), with a resulting increase in the ERP/APD ratio.
Electrophysiology in Man
Mexiletine is a Class 1B antiarrhythmic compound with electrophysiologic properties in man similar to lidocaine, but dissimilar from quinidine, procainamide, and disopyramide.
In patients with normal conduction systems, MEXITIL has a minimal effect on cardiac impulse generation and propagation. In clinical trials, no development of second-degree or third-degree AV block was observed. MEXITIL did not prolong ventricular depolarization (QRS duration) or repolarization (QT intervals) as measured by electrocardiography. Theoretically, therefore, MEXITIL may be useful in the treatment of ventricular arrhythmias associated with a prolonged QT interval.
In patients with pre-existing conduction defects, depression of the sinus rate, prolongation of sinus node recovery time, decreased conduction velocity and increased effective refractory period of the intraventricular conduction system have occasionally been observed.
The antiarrhythmic effect of MEXITIL has been established in controlled comparative trials against placebo, quinidine, procainamide and disopyramide. MEXITIL, at doses of 200-400 mg q8h, produced a significant reduction of ventricular premature beats, paired beats, and episodes of non-sustained ventricular tachycardia compared to placebo and was similar in effectiveness to the active agents. Among all patients entered into the studies, about 30% in each treatment group had a 70% or greater reduction in PVC count and about 40% failed to complete the 3 month studies because of adverse effects. Follow-up of patients from the controlled trials has demonstrated continued effectiveness of MEXITIL in long-term use.
Hemodynamic studies in a limited number of patients, with normal or abnormal myocardial function, following oral administration of MEXITIL, have shown small, usually not statistically significant, decreases in cardiac output and increases in systemic vascular resistance, but no significant negative inotropic effect. Blood pressure and pulse rate remain essentially unchanged. Mild depression of myocardial function, similar to that produced by lidocaine, has occasionally been observed following intravenous MEXITIL therapy in patients with cardiac disease.
MEXITIL is well absorbed (~90%) from the gastrointestinal tract. Unlike lidocaine, its first-pass metabolism is low. Peak blood levels are reached in two to three hours. In normal subjects, the plasma elimination half-life of MEXITIL is approximately 10-12 hours. It is 50-60% bound to plasma protein, with a volume of distribution of 5-7 liters/kg. MEXITIL is mainly metabolized in the liver, the primary pathway being CYP2D6 metabolism, although it is also a substrate for CYP1A2. With involvement of CYP2D6, there can be either poor or extensive metabolizer phenotypes. Since approximately 90% of MEXITIL is metabolized in the liver into inactive metabolites, pathological changes in the liver can restrict hepatic clearance of MEXITIL and its metabolites. The metabolic degradation proceeds via various pathways including aromatic and aliphatic hydroxylation, dealkylation, deamination and N-oxidation. Several of the resulting metabolites are submitted to further conjugation with glucuronic acid (phase II metabolism); among these are the major metabolites p-hydroxymexiletine, hydroxy-methylmexiletine and N-hydroxy-mexiletine. Approximately 10% is excreted unchanged by the kidney. While urinary pH does not normally have much influence on elimination, marked changes in urinary pH influence the rate of excretion: acidification accelerates excretion, while alkalinization retards it.
Several metabolites of mexiletine have shown minimal antiarrhythmic activity in animal models. The most active is the minor metabolite N-methylmexiletine, which is less than 20% as potent as mexiletine. The urinary excretion of N-methylmexiletine in man is less than 0.5%. Thus the therapeutic activity of MEXITIL is due to the parent compound.
Hepatic impairment prolongs the elimination half-life of MEXITIL. In eight patients with moderate to severe liver disease, the mean half-life was approximately 25 hours.
Consistent with the limited renal elimination of MEXITIL, little change in the half-life has been detected in patients with reduced renal function. In eight patients with creatinine clearance less than 10 ml/min, the mean plasma elimination half-life was 15.7 hours; in seven patients with creatinine clearance between 11-40 ml/min, the mean half-life was 13.4 hours.
The absorption rate of MEXITIL is reduced in clinical situations such as acute myocardial infarction in which gastric emptying time is increased. Narcotics, atropine and magnesium-aluminum hydroxide have also been reported to slow the absorption of MEXITIL. Metoclopramide has been reported to accelerate absorption.
Mexiletine plasma levels of at least 0.5 mcg/ml are generally required for therapeutic response. An increase in the frequency of central nervous system adverse effects has been observed when plasma levels exceed 2.0 mcg/ml. Thus the therapeutic range is approximately 0.5 to 2.0 mcg/ml. Plasma levels within the therapeutic range can be attained with either three times daily or twice daily dosing but peak to trough differences are greater with the latter regimen, creating the possibility of adverse effects at peak and arrhythmic escape at trough. Nevertheless, some patients may be transferred successfully to the twice daily regimen. (See DOSAGE AND ADMINISTRATION).