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 medicinal products 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 plasma 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 dose 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 dose 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 medicinal product 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 (5-6 Child-Pugh score) or moderate (7-9 Child-Pugh score) hepatic impairment. In these patients, it is recommended that the dose should only be increased after at least 2 weeks of treatment.

The experience with mexiletine in patients with severe hepatic impairment is limited. Therefore, mexiletine should not be used in this patient population.

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 cross-react in various amphetamine screening assays, which can lead to a false-positive urine test for amphetamines when mexiletine is taken.

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).

Increased concentrations of caffeine occurring with the co-administration of mexiletine may be of concern in patients with cardiac arrhythmia.

CYP2D6 polymorphism may affect mexiletine pharmacokinetics. Higher systemic exposure is expected in patients who are CYP2D6 poor metabolisers or who take medicinal products that inhibit CYP2D6. A period of at least 7 days before dose increase must be respected to ensure that steady-state levels are reached and that mexiletine is well tolerated in all patients, irrespective of CYP450 polymorphism.

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

Summary of the safety profile

The most commonly reported adverse reactions in patients treated with mexiletine are abdominal pain (12%), insomnia (12%) and vertigo (8%).

The most serious reported adverse reactions in patients treated with mexiletine are DRESS and arrhythmia (atrioventricular block, arrhythmia, ventricular fibrillation).

Tabulated list of adverse reactions

The adverse reactions are tabulated in the table below by MedDRA SOC (system organ class) and by frequency, most frequent reactions first, according to the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000), not known (cannot be estimated from the available data). Very common and common adverse reactions are derived from data from the MYOMEX study; less common adverse reactions are derived from post-marketing data. Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Tabulated list of adverse reaction:

Paediatric population

The safety assessment in children and adolescents was studied in the MEX-NM-301 study in which 12 paediatric patients aged from 6 to 17 years and weighing at least 20 kg received mexiletine. Two (2) of these patients reported adverse drug reactions. Adverse drug reactions established for adults are considered applicable to children and adolescents.