Mexiletine dosing

Since the achievement of steady-state mexiletine levels depends on the extent of absorption, not on its rate, it seems very unlikely that these drugs will affect the antiarrhythmic effects of mexiletine during chronic dosing. However, these drugs may cause variations in the antiarrhythmic effects of initial oral mexiletine doses, which may be a problem if rapid control ofthe arrhythmia is essential. In general, no special precautions would appear necessary. 

Control can be achieved in most patients with 200 to 300 mg given every 8 hours. If satisfactory response is not achieved at 300 mg every 8 hours, and the patient tolerates mexiletine well, try 400 mg every 8 hours. The severity of CNS side effects increases with total daily dose do not exceed 1200 mg/day. 

Renal/hepatic function impairment In general, patients with renal failure will require the usual doses of mexiletine. Patients with severe liver disease, however, may require lower doses and must be monitored closely. Similarly, marked right-sided CHF can reduce hepatic metabolism and reduce the dose needed. 

Transferring to mexiletine When transferring from other Class I oral antiarrhythmics to mexiletine, based on theoretical considerations, initiate with a 200 mg dose, and titrate to response as described above, 6 to 12 hours after the last dose of quinidine sulfate, 3 to 6 hours after the last dose of procainamide, 6 to 12 hours after the last disopyramide dose or 8 to 12 hours after the last tocainide dose. 

An upward adjustment in dose may be required when mexiletine is administered with phenytoin or rifampin, since these drugs stimulate the hepatic metabolism of mexiletine, reducing its plasma concentration. 

Mexiletine is metabolized by CYP2D6, CYP1A2, and CYP3A4 fluvoxamine inhibits CYP1A2. It is not surprising therefore that fluvoxamine 50 mg bd for 7 days increased the Cmax and AUC of a single oral dose of mexiletine 200 mg in six healthy Japanese men (43). 

MEXILETINE ANTIMUSCARINICS -ATROPINE Delayed absorption of mexiletine Anticholinergic effects delay gastric emptying and absorption May slow the onset of action of the first dose of mexiletine, but this is not of clinical significance for regular dosing (atropine does not l the total dose absorbed)... 

MEXILETINE BRONCHODILATORS -THEOPHYLLINE Theophylline levels may be t by mexiletine cases of theophylline toxicity have been reported Mexiletine inhibits CYP1A2-mediated metabolism of theophylline 1 the theophylline dose (by up to 50%). Monitor theophylline levels and watch for toxicity... 

Mexiletine is similar to lignocaine (lidocaine) but is effective by the oral route (t) 10 h). It has been used for ventricular arrhythmias especially those complicating myocardial infarction. The drug is usually poorly tolerated. Adverse reactions are almost universal and dose-related and include nausea. 

Liver damage due to lidocaine has rarely been reported. However, severe liver damage has been reported shortly after the withdrawal of mexiletine 300 mg/day and the introduction of lidocaine 1000 mg/day, although lidocaine in the same dose had been used during the previous week (40). The lidocaine was withdrawn and the liver enzymes normalized after treatment with prednisolone. 

In an open study of the antidystonic effect of mexiletine (200 mg/day increasing to a maximum of 800 mg/day) in spasmodic torticollis in six patients, mexiletine produced significant improvement and there were no adverse effects in five of the six patients in the other patient dizziness occurred at the highest dose and required a reduction in dosage (11). 

In a double-blind, placebo-controlled, crossover study of the use of mexiletine in 20 patients with neuropathic pain with prominent allodynia the dosage was titrated to maximum of 900 mg/day or until dose-limiting adverse effects occurred. Mexiletine produced little beu-eficial effect and the two most common adverse effects were nausea aud sedatiou (12). Other adverse effects that occurred iu oue or two patients each included insomnia, trismus, headache, agitation, nightmares, and tremor. 

Mexiletine is metabolized mainly by CYP2D6 and CYP1A2. Omeprazole is an inducer of CYP1A2 and might therefore be expected to interact with mexiletine. However, in a study in nine healthy men there was no evidence of an effect of steady-state omeprazole 40 mg/ day on the single-dose kinetics of mexiletine 200 mg (50). 

The interaction of rifampicin with mexiletine has been reviewed (105). The mean half-life of a single dose of mexiletine 400 mg fell from 8.5 to 5 hours in eight healthy subjects who took rifampicin 600 mg/day for 10 days (119). 

Absorption Lidocaine is ineffective orally 60% to 70% of an oral dose is metabolized by the liver before reaching the systemic circulation. It is only administered IVfor arrhythmias. Both mexiletine and tocainide are well absorbed orally. 

Mexiletine hydrochloride is u.sed fur long-term oral prophylaxis of ventricular tachycardia. The drug is given in 200-tu 400-mg doses every 8 hours. 

Glynn-Bamhart, A. M. et al., Effect of low-dose methotrexate on the disposition of glucocorticoids and theophylline, J. Allergy Clin. Immunol., 88(2) 180-186, 1991. Ueno, K. et al., Mechanism of interaction between theophylline and mexiletine. Drug Intell. Clin. Pharm., 25(7-8) 727-730, 1991. 

The fact that the metabolism of mexiletine cosegregates with debrisoquine hydroxylation was not known until recently [112]. Initial studies [129,130] on the stereoselective pharmacokinetics of mexiletine did not distinguish between poor and extensive metabolizers of debrisoquine in their study subjects (Table 13). These studies showed modest or no stereoselectivity in the systemic clearance, the renal clearance, and the terminal plasma half-life of the drug [129,130]. In 1993, Turgeon and colleagues [112] reported the kinetics of the individual enantiomers of mexiletine after a single dose of the racemate in 10 EMs and 4 PMs in the absence and presence of steady-state... 

The antacid almasilate (Gelusil), given one hour before a single 400-mg dose of mexiletine, resulted in a slight delay in absorption (time to maximum concentration prolonged from 1.7 to 2.9 hours), but had no effect on the extent of absorption in healthy subjects. ... 

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