MEXITIL

Clinical safety rating: caution

Comprehensive clinical and safety monograph for MEXITIL (MEXITIL).

How it works

Mexiletine is a class IB antiarrhythmic agent that blocks voltage-gated sodium channels, reducing the fast inward sodium current during phase 0 of the action potential. It shortens the action potential duration and decreases excitability in cardiac myocytes.

What the body does with it

Metabolism	Primarily metabolized by CYP2D6 and CYP1A2 via oxidative pathways, with minor contributions from CYP2E1 and CYP3A4. Mexiletine is also a substrate for CYP2D6, and genetic polymorphisms can affect its clearance.
Excretion	Renal: ~80-90% as unchanged drug and metabolites (primarily glucuronide conjugates); fecal: ~10-20% via biliary elimination. Impaired renal function prolongs elimination.
Half-life	Terminal half-life: 10-17 hours (mean ~12 hours) in adults with normal renal function. Context: Requires dosing every 8 hours; half-life prolonged in hepatic impairment and congestive heart failure.
Protein binding	~50-70% bound, primarily to alpha-1-acid glycoprotein (AAG). Binding is saturable and increased in inflammatory states due to elevated AAG.
Volume of Distribution	5-10 L/kg (mean ~7 L/kg). Clinical meaning: Extensive tissue distribution, with high uptake in myocardium, brain, and liver; reflects sequestration and slow redistribution.
Bioavailability	Oral: ~80-90% (consistent absorption; first-pass metabolism minimal). Food delays absorption but does not reduce extent.
Onset of Action	Oral: 30-120 minutes (time to antiarrhythmic effect); IV: 5-15 minutes (when used, though mexiletine is primarily oral therapy).
Duration of Action	Oral: 8-12 hours (dosing interval 8 hours). Clinical notes: Steady-state achieved in 2-3 days due to half-life; therapeutic effect persists throughout dosing interval.

Classification & Brands

Dosing & administration

200-300 mg orally every 8 hours; maximum 1200 mg/day.

Dosage form	CAPSULE
Renal impairment	CrCl 10-50 mL/min: reduce dose by 50-75%; CrCl <10 mL/min: use 25-50% of normal dose.
Liver impairment	Child-Pugh class B: reduce dose by 50%; Child-Pugh class C: avoid use.
Pediatric use	Not established; limited data: 6-15 mg/kg/day divided every 8 hours orally.
Geriatric use	Start at low end of dosing range; monitor for CNS and cardiovascular side effects.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for MEXITIL (MEXITIL).

Breastfeeding	Mexiletine is excreted into human breast milk with a milk-to-plasma ratio (M/P) of approximately 1.4. Limited data suggest infant exposure is low (estimated relative infant dose <10% of maternal weight-adjusted dose). Caution advised; monitor infant for bradycardia, feeding difficulties, and lethargy.
Teratogenic Risk	In the first trimester, mexiletine (MEXITIL) is classified as Pregnancy Category C; animal studies have shown embryotoxicity and teratogenicity at maternally toxic doses, but no adequate human studies exist. Second and third trimester risks include potential fetal bradycardia and hypoglycemia due to placental transfer. Use only if potential benefit outweighs risk.

Warnings & precautions

■ FDA Black Box Warning

None

Side Effect Profile

Serious Effects

Absolute Contraindications

["Pre-existing second- or third-degree AV block (unless a pacemaker is present)","Cardiogenic shock","Hypersensitivity to mexiletine or any component of the formulation","Severe hepatic impairment"]

Clinical Precautions

Precautions

["Proarrhythmic effects: Mexiletine can aggravate existing arrhythmias or induce new arrhythmias, including ventricular fibrillation or torsade de pointes.","Use with caution in patients with hepatic impairment, as elimination may be reduced.","May cause seizures, especially at high doses or with rapid dose escalation.","Hematologic effects: Rare cases of agranulocytosis and thrombocytopenia have been reported.","May exacerbate myasthenia gravis due to neuromuscular blocking effects.","Avoid abrupt discontinuation in patients with ischemic heart disease or ventricular arrhythmias."]

Clinical Tips & Counseling

Drug interactions

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MEXITIL

Clinical safety rating: caution

Comprehensive clinical and safety monograph for MEXITIL (MEXITIL).

How it works

What the body does with it

Metabolism	Primarily metabolized by CYP2D6 and CYP1A2 via oxidative pathways, with minor contributions from CYP2E1 and CYP3A4. Mexiletine is also a substrate for CYP2D6, and genetic polymorphisms can affect its clearance.
Excretion	Renal: ~80-90% as unchanged drug and metabolites (primarily glucuronide conjugates); fecal: ~10-20% via biliary elimination. Impaired renal function prolongs elimination.
Half-life	Terminal half-life: 10-17 hours (mean ~12 hours) in adults with normal renal function. Context: Requires dosing every 8 hours; half-life prolonged in hepatic impairment and congestive heart failure.
Protein binding	~50-70% bound, primarily to alpha-1-acid glycoprotein (AAG). Binding is saturable and increased in inflammatory states due to elevated AAG.
Volume of Distribution	5-10 L/kg (mean ~7 L/kg). Clinical meaning: Extensive tissue distribution, with high uptake in myocardium, brain, and liver; reflects sequestration and slow redistribution.
Bioavailability	Oral: ~80-90% (consistent absorption; first-pass metabolism minimal). Food delays absorption but does not reduce extent.
Onset of Action	Oral: 30-120 minutes (time to antiarrhythmic effect); IV: 5-15 minutes (when used, though mexiletine is primarily oral therapy).
Duration of Action	Oral: 8-12 hours (dosing interval 8 hours). Clinical notes: Steady-state achieved in 2-3 days due to half-life; therapeutic effect persists throughout dosing interval.

Classification & Brands

Dosing & administration

200-300 mg orally every 8 hours; maximum 1200 mg/day.

Dosage form	CAPSULE
Renal impairment	CrCl 10-50 mL/min: reduce dose by 50-75%; CrCl <10 mL/min: use 25-50% of normal dose.
Liver impairment	Child-Pugh class B: reduce dose by 50%; Child-Pugh class C: avoid use.
Pediatric use	Not established; limited data: 6-15 mg/kg/day divided every 8 hours orally.
Geriatric use	Start at low end of dosing range; monitor for CNS and cardiovascular side effects.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for MEXITIL (MEXITIL).

Breastfeeding	Mexiletine is excreted into human breast milk with a milk-to-plasma ratio (M/P) of approximately 1.4. Limited data suggest infant exposure is low (estimated relative infant dose <10% of maternal weight-adjusted dose). Caution advised; monitor infant for bradycardia, feeding difficulties, and lethargy.
Teratogenic Risk	In the first trimester, mexiletine (MEXITIL) is classified as Pregnancy Category C; animal studies have shown embryotoxicity and teratogenicity at maternally toxic doses, but no adequate human studies exist. Second and third trimester risks include potential fetal bradycardia and hypoglycemia due to placental transfer. Use only if potential benefit outweighs risk.

Warnings & precautions

■ FDA Black Box Warning

None

Side Effect Profile

Serious Effects

Absolute Contraindications

["Pre-existing second- or third-degree AV block (unless a pacemaker is present)","Cardiogenic shock","Hypersensitivity to mexiletine or any component of the formulation","Severe hepatic impairment"]