Mexiletine Other names: Mexiletine hydrochloride

The organic cation transporter 2 (OCT2) provides an important pathway for the uptake of cationic compounds in the kidney. Mexiletine may interact with drugs transported by OCT2 (such as metformin and dofetilide).

If mexiletine and other OCT2 substrates are to be used concurrently, the OCT2 substrate blood levels should be monitored, particularly when the mexiletine dose is changed. An appropriate adjustment in the dose of the OCT2 substrate should be considered.

Co-administration of mexiletine with a hepatic enzyme inducer (CYP1A2 inducer: omeprazole; CYP2D6 inducer: phenytoin, rifampicin) may increase the clearance and elimination rate of mexiletine due to an increased hepatic metabolism, resulting in decreased plasmatic concentrations and half-life of mexiletine.

In a clinical study, co-administration of mexiletine with phenytoin resulted in a significant decrease in exposure to mexiletine (p<0.003) due to enhanced clearance as reflected in significantly decreased elimination half-life (17.2 to 8.4 hours, p<0.02).

Therefore, based on the clinical response, the mexiletine dosage should be adapted during and after treatment with the enzyme inducer.

After the oral administration of single (167 mg) and multiple (83 mg twice a day during 8 days) doses of mexiletine, total clearance of mexiletine is significantly increased in smokers (1.3 to 1.7-fold) due to induction of CYP1A2, resulting in a correspondingly decreased elimination half-life and drug exposure. Mexiletine dose may need to be increased if a patient starts to smoke during mexiletine treatment and decreased if a patient stops smoking.

Co-administration of mexiletine with a hepatic enzyme inhibitor (CYP1A2 inhibitor: ciprofloxacin, fluvoxamine, propafenone; CYP2D6 inhibitor: propafenone, quinidine) significantly increases mexiletine exposure and thus the associated risk of adverse reactions to mexiletine. In a single-dose interaction study, the clearance of mexiletine was decreased by 38% following the co-administration of fluvoxamine, an inhibitor of CYP1A2. Therefore, clinical and ECG monitoring, as well as adaptation of mexiletine dosage may be indicated throughout and after treatment with a CYP1A2 or CYP2D6 inhibitor.

Mexiletine is a potent inhibitor of CYP1A2; therefore, co-administration of mexiletine with medicinal products metabolised by CYP1A2 (such as theophylline, caffeine, lidocaine or tizanidine) may be associated with elevations in plasma concentrations of the concomitant medicine that could increase or prolong the therapeutic efficacy and/or the adverse reactions, especially if mexiletine is co-administered with CYP1A2 substrates with narrow therapeutic window, e.g. theophylline and tizanidine.

The CYP1A2 substrate blood levels should be monitored, particularly when the mexiletine dose is changed. An appropriate adjustment in the dose of the CYP1A2 substrate should be considered.

The experience with mexiletine in patients with severe renal impairment is limited. Therefore, the use of mexiletine is not recommended in this patient population.

Mexiletine should be used with caution in patients with mild or moderate hepatic impairment. In these patients, it is recommended that the dose should only be increased after at least 2 weeks of treatment.

Mexiletine should not be used in patients with severe hepatic impairment.

Co-administration of mexiletine and other classes of antiarrhythmics (class Ib: lidocaine, phenytoin, tocainide; class II: propranolol, esmolol, timolol, metoprolol, atenolol, carvedilol, bisoprolol, nebivolol; class IV: verapamil, diltiazem) is not recommended, unless exceptionally, because of the increased risk of adverse cardiac reactions.

In a clinical study in 12 subjects (5 healthy subjects and 7 patients with cardiac arrhythmias), the clearance of caffeine was decreased by 50% following the administration of mexiletine. Increased concentrations of caffeine occurring with the co-administration of mexiletine may be of concern in patients with cardiac arrhythmia. It is, therefore, recommended to reduce caffeine intake during treatment with mexiletine.

Mexiletine may induce an arrhythmia or accentuate a pre-existing arrhythmia, either diagnosed or undiagnosed.

Before starting mexiletine treatment, detailed and careful cardiac evaluation (ECG, 24-48-hour Holter-monitoring and echocardiography) should be carried out in all patients in order to determine the cardiac tolerability of mexiletine. A cardiac evaluation is recommended shortly after treatment start (e.g. within 48 hours).

Throughout treatment with mexiletine, and in relation with dose changes, cardiac monitoring of patients needs to be adapted as a function of the heart condition of the patient:

• In patients without cardiac abnormalities, periodic ECG monitoring is recommended (every 2 years or more frequently if considered necessary).
• In patients with cardiac abnormalities, and in patients prone to such abnormalities, detailed cardiac evaluation, including ECG, should be carried out before and after any dose increase. During maintenance treatment, detailed cardiac evaluation, including ECG, 24-48 hour Holter-monitoring and echocardiography, is recommended at least annually, or more frequently if considered necessary as part of routine cardiac assessment.

Patients should be informed about the presenting symptoms of arrhythmias (fainting, palpitation, chest pain, shortness of breath, light-headedness, lipothymia, and syncope) and should be advised to immediately contact an emergency centre if there are any symptoms of arrhythmias.

For some cardiac disorders, the benefit of the antimyotonic effects of mexiletine needs to be balanced against the risk of cardiac complications on a case by case basis. Mexiletine should be stopped immediately in case any cardiac conduction abnormalities.

Electrolytic imbalance such as hypokalaemia, hyperkalaemia or hypomagnesaemia may increase the proarrhythmic effects of mexiletine. Therefore, electrolytic evaluation should be done prior to initiating therapy with mexiletine in every patient. Electrolyte imbalance needs to be corrected before administering mexiletine and to be monitored throughout treatment (with a periodicity to be adapted patient by patient).

DRESS refers to a syndrome which includes in its complete form severe cutaneous eruptions, fever, lymphadenopathy, hepatitis, haematological abnormalities with eosinophilia and atypical lymphocytes, and can involve other organs. Symptoms typically occur 1-8 weeks after exposure to the medicinal product. Severe systemic manifestations are responsible for a 10% mortality rate. Incidence of DRESS has been reported between 1:100 and 1:10.000 patients treated.

Several medicinal products including anticonvulsants, antibiotics and also mexiletine have been identified as possible causes. Patients with known hypersensitivity to mexiletine or any other ingredients of this product or to any local anaesthetic are at high risk of developing DRESS and should not receive mexiletine.

Smoking affects mexiletine pharmacokinetics. Mexiletine dose may need to be increased if a patient starts to smoke and decreased if a patient stops to smoke.

Epileptic patients need to be monitored because mexiletine can increase the frequency of seizure episodes.

There are no or limited amount of data from the use of mexiletine in pregnant women. Limited clinical data of the use of mexiletine in pregnant women shows that mexiletine crosses the placenta and reaches the foetus. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

As a precautionary measure, it is preferable to avoid the use of mexiletine during pregnancy.

Mexiletine is excreted in human milk. There is insufficient information on the effects of mexiletine in newborns/infants. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from mexiletine therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

The effects of mexiletine on fertility in humans have not been studied. Animal studies with mexiletine do not indicate harmful effects with respect to fertility.

Mexiletine may have minor influence on the ability to drive and use machines. Fatigue, confusion, blurred vision may occur following administration of mexiletine.