Mexiletine Hcl

Drug overview for MEXILETINE HCL (mexiletine hcl):

Generic name: MEXILETINE HCL (mex-IL-e-teen)
Drug class: Antiarrhythmic - Class IB (Systemic)
Therapeutic class: Cardiovascular Therapy Agents

Mexiletine hydrochloride is a local anesthetic-type, class 1B antiarrhythmic agent.

No enhanced Uses information available for this drug.

DRUG IMAGES

MEXILETINE 150 MG CAPSULE
MEXILETINE 200 MG CAPSULE
MEXILETINE 250 MG CAPSULE

The following indications for MEXILETINE HCL (mexiletine hcl) have been approved by the FDA:

Indications:
Ventricular arrhythmias

Professional Synonyms:
Ventricular arrhythmia

Dosing information for MEXILETINE HCL
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
MEXILETINE 150 MG CAPSULE	Maintenance	Adults take 2 capsules (300 mg) by oral route every 8 hours with food
MEXILETINE 200 MG CAPSULE	Maintenance	Adults take 1 capsule (200 mg) by oral route every 8 hours with food
MEXILETINE 250 MG CAPSULE	Maintenance	Adults take 1 capsule (250 mg) by oral route every 8 hours with food

Generic dosing information for MEXILETINE HCL
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
MEXILETINE 150 MG CAPSULE	Maintenance	Adults take 2 capsules (300 mg) by oral route every 8 hours with food
MEXILETINE 200 MG CAPSULE	Maintenance	Adults take 1 capsule (200 mg) by oral route every 8 hours with food
MEXILETINE 250 MG CAPSULE	Maintenance	Adults take 1 capsule (250 mg) by oral route every 8 hours with food

The following drug interaction information is available for MEXILETINE HCL (mexiletine hcl):

Contraindicated
Severe
Moderate

There are 4 contraindications. These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.

Drug Interaction	Drug Names
Rasagiline (Greater Than 0.5 mg)/Selected CYP1A2 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Inhibitors of CYP1A2 may inhibit the metabolism of rasagiline.(1) CLINICAL EFFECTS: Concurrent use of a CYP1A2 inhibitor may increase levels of and adverse effects from rasagiline.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of rasagiline states that patients receiving concurrent therapy with an inhibitor of CYP1A2 should receive no more than 0.5 mg of rasagiline daily.(1) Concurrent therapy with vemurafenib may require extended monitoring for interaction onset and severity because steady-state levels of vemurafenib are not attained for approximately 15 days.(2) DISCUSSION: In a study in 12 healthy subjects, ciprofloxacin (500 mg twice daily) increased the area-under-curve (AUC) of rasagiline (2 mg twice daily) by 83%.(1) Strong CYP1A2 inhibitors linked to this monograph include angelica root, ciprofloxacin, enasidenib, enoxacin, and rofecoxib. Moderate CYP1A2 inhibitors linked to this monograph include capmatinib, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, and vemurafenib.(3-5)	AZILECT, RASAGILINE MESYLATE
Disopyramide/Class IB, II, and IV Antiarrhythmics SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Disopyramide has been shown to prolong the QTc interval. Concurrent use with other agents that affect the heart rate and rhythm may result in unpredictable effect on heart rhythm.(1-2) CLINICAL EFFECTS: The concurrent use of disopyramide with other agents that affect the heart rate and rhythm may result in in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1-2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of disopyramide states that concurrent use of disopyramide with antiarrhythmic agents should be reserved for patients with life-threatening arrhythmias who are demonstrably unresponsive to single-agent antiarrhythmic therapy. The Australian manufacturer of disopyramide states that the concurrent use of other antiarrhythmics, such as Class I, II, III, or IV is contraindicated.(1) The US manufacturer of verapamil states that disopyramide should not be administered within 48 hours before or 24 hours after verapamil.(2) If concurrent therapy is deemed medically necessary, obtain serum calcium, magnesium, and potassium levels and monitor ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: Because combinations of antiarrhythmics are not well researched and concurrent use may result in unpredictable effects, the Australian manufacturer of disopyramide states that the concurrent use of other antiarrhythmics, such as Class I, II, III, or IV is contraindicated.(1)	DISOPYRAMIDE PHOSPHATE, NORPACE, NORPACE CR
Fezolinetant/CYP1A2 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Inhibitors of CYP1A2 may inhibit the metabolism of fezolinetant.(1) CLINICAL EFFECTS: Concurrent use of a CYP1A2 inhibitor may increase levels of and adverse effects from fezolinetant.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of fezolinetant states that concurrent use with CYP1A2 inhibitors is contraindicated.(1) DISCUSSION: In a study, fluvoxamine, a strong CYP1A2 inhibitor, increased fezolinetant maximum concentration (Cmax) and area-under-curve (AUC) by 80% and 840%, respectively. Mexiletine (400 mg every 8 hours), a moderate CYP1A2 inhibitor, increased fezolinetant Cmax and AUC by 40% and 360%, respectively. Cimetidine (300 mg every 6 hours), a weak CYP1A2 inhibitor, increased fezolinetant Cmax and AUC by 30% and 100%, respectively.(1) Strong CYP1A2 inhibitors linked to this monograph include angelica root, ciprofloxacin, enasidenib, enoxacin, fluvoxamine, and rofecoxib. Moderate CYP1A2 inhibitors linked to this monograph include capmatinib, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, vemurafenib, and viloxazine. Weak CYP1A2 inhibitors linked to this monograph include allopurinol, artemisinin, caffeine, cannabidiol, cimetidine, curcumin, dan-shen, deferasirox, disulfiram, Echinacea, famotidine, ginseng, norfloxacin, obeticholic acid, parsley, piperine, propafenone, propranolol, ribociclib, simeprevir, thiabendazole, ticlopidine, triclabendazole, verapamil, zileuton.(2-4)	VEOZAH
Selected CYP2D6 Substrates/Mavorixafor SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Mavorixafor is a strong inhibitor of CYP2D6 and is expected to inhibit the metabolism of agents through this pathway.(1) CLINICAL EFFECTS: Concurrent use of mavorixafor may result in elevated levels of and toxicity from agents metabolized by CYP2D6.(1) PREDISPOSING FACTORS: With tricyclic antidepressants, the risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). With anticholinergic agents, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(2) PATIENT MANAGEMENT: The US manufacturer of mavorixafor states concurrent use with CYP2D6 substrate that are highly dependent on CYP2D6 metabolism is contraindicated.(1) DISCUSSION: Mavorixafor (400 mg) increased dextromethorphan (CYP2D6 substrate) maximum concentration (Cmax) and area-under-curve (AUC) by 6-fold and 9-fold, respectively.(1) Selected CYP2D6 substrates linked to this monograph include: aripiprazole, brexpiprazole, desipramine, deutetrabenazine, dextromethorphan, doxepin, encainide, fenfluramine, metoclopramide, methoxyphenamine, metoprolol, mexiletine, nebivolol, paroxetine, perphenazine, risperidone, tetrabenazine, trimipramine, venlafaxine, and yohimbine.	XOLREMDI

There are 2 severe interactions. These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.

Drug Interaction	Drug Names
Tizanidine/Selected Antiarrhythmics SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Amiodarone, mexiletine, propafenone, and verapamil may inhibit the metabolism of tizanidine by CYP1A2.(1) CLINICAL EFFECTS: Concurrent use of amiodarone, mexiletine, propafenone, or verapamil may result in elevated levels of and effects from tizanidine, including hypotension, bradycardia, drowsiness, sedation, and decreased psychomotor function. PREDISPOSING FACTORS: The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(2) PATIENT MANAGEMENT: The US manufacturer of tizanidine states that concurrent use of tizanidine with inhibitors of CYP1A2, such as zileuton, should be avoided. If concurrent use is warranted, tizanidine should be initiated with a 2 mg dose and increased in 2-4 mg steps daily based on patient response to therapy. If adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue tizanidine therapy.(1) DISCUSSION: In a study in 10 healthy subjects, concurrent fluvoxamine, another inhibitor of CYP1A2, increased tizanidine maximum concentration (Cmax), area-under-curve (AUC), and half-life (T1/2) by 12-fold, 33-fold, and 3-fold, respectively. Significant decreases in blood pressure and increases in drowsiness and psychomotor impairment occurred.(1) In a study in 10 healthy subjects, concurrent ciprofloxacin, another inhibitor of CYP1A2, increased tizanidine Cmax and AUC by 7-fold and 10-fold, respectively. Significant decreases in blood pressure and and increases in drowsiness and psychomotor impairment occurred.(1) In an open label study in 12 healthy subjects, concurrent tizanidine (single 2 mg dose) with mexiletine (50 mg, 3 times a day for one day and then 2 times for one day), increased tizanidine Cmax and AUC by 3.1-fold and 3.6-fold, respectively. Subjects were found to have significantly lower systolic and diastolic blood pressure after concurrent administration as well as drowsiness, dry mouth, or dizziness.(3) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.	TIZANIDINE HCL, ZANAFLEX
Vorasidenib/Moderate CYP1A2 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Moderate CYP1A2 inhibitors may inhibit the metabolism of vorasidenib.(1) CLINICAL EFFECTS: Concurrent use of moderate CYP1A2 inhibitors may result in elevated levels of and effects from vorasidenib, including hepatotoxicity.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer for vorasidenib states concurrent use with moderate CYP1A2 inhibitors should be avoided.(1) If concurrent use of moderate CYP1A2 inhibitors cannot be avoided, monitor for increased risk of adverse reactions and modify the dose of vorasidenib as recommended in the prescribing information.(1) DISCUSSION: Vorasidenib is primarily metabolized by CYP1A2.(1) Concurrent use of vorasidenib and fluvoxamine (a strong CYP1A2 inhibitor) is predicted to increase vorasidenib maximum concentration (Cmax) and area-under-curve (AUC) by greater than 5-fold.(1) In a study, concurrent use of vorasidenib and ciprofloxacin (a moderate CYP1A2 inhibitor) increased vorasidenib Cmax 1.3-fold and AUC 2.5-fold.(1) Moderate CYP1A2 inhibitors linked to this monograph include: capmatinib, ciprofloxacin, dipyrone, fexinidazole, genistein, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, vemurafenib, and viloxazine.(2)	VORANIGO

Drug Interaction

Drug Names

Tizanidine/Selected Antiarrhythmics

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Amiodarone, mexiletine, propafenone, and verapamil may inhibit the metabolism of tizanidine by CYP1A2.(1)

CLINICAL EFFECTS: Concurrent use of amiodarone, mexiletine, propafenone, or verapamil may result in elevated levels of and effects from tizanidine, including hypotension, bradycardia, drowsiness, sedation, and decreased psychomotor function.

PREDISPOSING FACTORS: The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(2)

PATIENT MANAGEMENT: The US manufacturer of tizanidine states that concurrent use of tizanidine with inhibitors of CYP1A2, such as zileuton, should be avoided. If concurrent use is warranted, tizanidine should be initiated with a 2 mg dose and increased in 2-4 mg steps daily based on patient response to therapy. If adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue tizanidine therapy.(1)

DISCUSSION: In a study in 10 healthy subjects, concurrent fluvoxamine, another inhibitor of CYP1A2, increased tizanidine maximum concentration (Cmax), area-under-curve (AUC), and half-life (T1/2) by 12-fold, 33-fold, and 3-fold, respectively. Significant decreases in blood pressure and increases in drowsiness and psychomotor impairment occurred.(1) In a study in 10 healthy subjects, concurrent ciprofloxacin, another inhibitor of CYP1A2, increased tizanidine Cmax and AUC by 7-fold and 10-fold, respectively.

Significant decreases in blood pressure and and increases in drowsiness and psychomotor impairment occurred.(1) In an open label study in 12 healthy subjects, concurrent tizanidine (single 2 mg dose) with mexiletine (50 mg, 3 times a day for one day and then 2 times for one day), increased tizanidine Cmax and AUC by 3.1-fold and 3.6-fold,

respectively. Subjects were found to have significantly lower systolic and diastolic blood pressure after concurrent administration as well as drowsiness, dry mouth, or dizziness.(3) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems.

This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

TIZANIDINE HCL, ZANAFLEX

Vorasidenib/Moderate CYP1A2 Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Moderate CYP1A2 inhibitors may inhibit the metabolism of vorasidenib.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP1A2 inhibitors may result in elevated levels of and effects from vorasidenib, including hepatotoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer for vorasidenib states concurrent use with moderate CYP1A2 inhibitors should be avoided.(1) If concurrent use of moderate CYP1A2 inhibitors cannot be avoided, monitor for increased risk of adverse reactions and modify the dose of vorasidenib as recommended in the prescribing information.(1)

DISCUSSION: Vorasidenib is primarily metabolized by CYP1A2.(1) Concurrent use of vorasidenib and fluvoxamine (a strong CYP1A2 inhibitor) is predicted to increase vorasidenib maximum concentration (Cmax) and area-under-curve (AUC) by greater than 5-fold.(1) In a study, concurrent use of vorasidenib and ciprofloxacin (a moderate CYP1A2 inhibitor) increased vorasidenib Cmax 1.3-fold

and AUC 2.5-fold.(1) Moderate CYP1A2 inhibitors linked to this monograph include: capmatinib, ciprofloxacin, dipyrone, fexinidazole, genistein, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, vemurafenib, and viloxazine.(2)

VORANIGO

There are 8 moderate interactions. The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.

Drug Interaction	Drug Names
Disopyramide; Mexiletine; Propafenone/Rifamycins SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Rifampin and other rifamycins may increase the hepatic metabolism of disopyramide,(1-2) mexiletine(3) and propafenone(4-6). CLINICAL EFFECTS: Concurrent use of rifampin may result in decreased levels and effectiveness of disopyramide,(2) mexiletine(3) and propafenone(4-6). PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor patient's cardiac function and serum disopyramide, mexiletine or propafenone levels. Adjust the dosage accordingly. DISCUSSION: Coadministration of mexiletine and rifampin have been reported to decrease the elimination half-life and increase the nonrenal clearance of mexiletine.(3) In a study in six elderly subjects, pretreatment with rifampin (600 mg daily for 9 days) decreased the bioavailability of a single dose of oral propafenone (300 mg) by 86%. Maximum QRS prolongation after oral propafenone was decreased by 50%. There were no significant effects on intravenous propafenone.(5) In a study in six extensive CYP2D6 metabolizers and six poor CYP2D6 metabolizers, pretreatment with rifampin (600 mg daily for 9 days) decreased the bioavailability of a single dose of oral propafenone by 67% and by 41% in extensive and poor metabolizers, respectively. Maximum QRS prolongation after oral propafenone decreased by 38% and by 40% in extensive and poor metabolizers, respectively. There were no effects on intravenous propafenone.(6) During concomitant administration of disopyramide and rifampin to patients with tuberculosis, serum disopyramide concentrations decreased by approximately 50% while the concentration of an active metabolite of disopyramide increased.(1) Concurrent administration of disopyramide and rifampin to a 62-year-old patient produced subtherapeutic disopyramide levels and a failure in correcting the patient's arrhythmia. Five days after stopping rifampin, disopyramide levels increased and the arrhythmia was abolished.(2) Rifamycins linked to this monograph are rifabutin, rifampin and rifapentine.	PRIFTIN, RIFABUTIN, RIFADIN, RIFAMPIN, TALICIA
Rasagiline (Less Than or Equal To 0.5 mg)/Selected CYP1A2 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Inhibitors of CYP1A2 may inhibit the metabolism of rasagiline.(1) CLINICAL EFFECTS: Concurrent use of a CYP1A2 inhibitor may increase levels of and adverse effects from rasagiline.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of rasagiline states that patients receiving concurrent therapy with an inhibitor of CYP1A2 should receive no more than 0.5 mg of rasagiline daily.(1) Concurrent therapy with vemurafenib may require extended monitoring for interaction onset and severity because steady-state levels of vemurafenib are not attained for approximately 15 days.(2) DISCUSSION: In a study in 12 healthy subjects, ciprofloxacin (500 mg twice daily) increased the area-under-curve (AUC) of rasagiline (2 mg twice daily) by 83%.(1) Strong CYP1A2 inhibitors linked to this monograph include: angelica root, ciprofloxacin, enasidenib, enoxacin, and rofecoxib. Moderate CYP1A2 inhibitors linked to this monograph include: capmatinib, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, and vemurafenib.(3-5)	AZILECT, RASAGILINE MESYLATE
Theophylline Derivatives/Selected CYP1A2 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: CYP1A2 inhibitors may reduce the elimination rate of theophylline derivatives. CLINICAL EFFECTS: The concurrent administration of selected CYP1A2 inhibitors and theophylline or their derivatives may result in increased levels and toxicity of theophylline.(1-19) PREDISPOSING FACTORS: Concomitant therapy with inhibitors of CYP3A4 (e.g. clarithromycin, itraconazole, ritonavir) which block a secondary metabolic pathway for theophylline, may increase the magnitude of this interaction. PATIENT MANAGEMENT: Theophylline levels should be closely monitored in patients receiving concurrent therapy. The dosage of theophylline may need to be decreased after a CYP1A2 inhibitor is initiated. If the CYP1A2 inhibitor is discontinued in a patient stabilized on the combination, the theophylline level may fall. Monitor theophylline levels and adjust dose accordingly. DISCUSSION: A study in 5 patients with active hepatitis B and 4 healthy subjects examined the effects of a single dose of interferon alpha (9 million units in 8 subjects, 18 million units in 1 subject). There was no effect on theophylline in 1 subject. In the other 8 subjects, interferon increased theophylline half-life by 70% and decreased theophylline clearance by 49% (range 33% to 81%).(1) A study in 11 healthy subjects examined the effects of interferon alpha (3 million International Units daily for 3 days) on a single aminophylline (4 mg/kg) infusion. Interferon increased the half-life, area-under-curve (AUC), and mean residence time by 13.7%, 17.9%, and 16.3%, respectively. Theophylline clearance decreased by 9.1%.(2) In a study in healthy males, peginterferon alfa-2a (180 mcg once weekly for 4 weeks) increased theophylline AUC by 25%.(3,4) Concurrent interferon alfa has been shown to increase theophylline levels by 100%.(5) A study in 7 patients with chronic hepatitis C examined the effects of interferon beta (3 million to 9 million International Units daily for 8 weeks) on theophylline ethylenediamine (single 250 mg infusion). Interferon decreased theophylline clearance by 26.3% and increased theophylline half-life by 39.3%. There was no correlation between interferon dose and effect. The greatest effect was seen in a patient who received 3 million International Units daily, while no effect was seen in a patient who received 9 million International Units daily.(6) Increased serum theophylline levels with signs and symptoms of theophylline toxicity have been reported in patients following the addition of mexiletine to their treatment.(7-15) In a study evaluated the combination of disulfiram and theophylline in 20 recovering alcoholics. Patients received a single IV dose of theophylline while being given either 250 mg or 500 mg of disulfiram daily. Both dosages of disulfiram decreased the clearance of theophylline. However, the effect was greatest in patients receiving disulfiram 500 mg daily.(16) Increases in serum theophylline concentration and half-life have been reported during concurrent administration of theophylline and ticlopidine.(17) In healthy subjects, rofecoxib (12.5 mg/day, 25 mg/day, or 50 mg/day for seven days) increased the area-under-curve (AUC) of a single dose of theophylline (300 mg) by 38% to 60%. Therefore, the manufacturer of rofecoxib recommends that theophylline levels be monitored if rofecoxib is initiated or changed in patients receiving theophylline.(18) Selected CYP1A2 inhibitors linked to this monograph include: Angelica dahurica, artemisinin, cannabidiol, curcumin, danshen, dipyrone, disulfiram, echinacea, enasidenib, fexinidazole, genistein, ginseng, interferons, methoxsalen, mexiletine, parsley, phenylpropanolamine, pipemidic acid, piperine, propafenone, ribociclib, rofecoxib, rucaparib, simeprevir, ticlopidine, triclabendazole, verapamil.(19)	AMINOPHYLLINE, DYPHYLLINE, ELIXOPHYLLIN, THEO-24, THEOPHYLLINE, THEOPHYLLINE ANHYDROUS, THEOPHYLLINE ER, THEOPHYLLINE ETHYLENEDIAMINE
Pirfenidone/Moderate CYP1A2 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Pirfenidone is primarily metabolized by CYP1A2 which is responsible for about 50% of its conversion to inactive drug. CYP2C9, 2C19, 2D6 and 2E1 are additional minor contributors to pirfenidone metabolism.(1) Inhibitors of CYP1A2 may inhibit the metabolism of pirfenidone.(1) CLINICAL EFFECTS: Concurrent pirfenidone use with moderate inhibitors of CYP1A2 may lead to increased systemic concentrations and toxicity from pirfenidone, including serious liver injury.(1) PREDISPOSING FACTORS: A greater risk of adverse events may result from concomitant treatment with strong or moderate inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), CYP2C19 (e.g. fluconazole, fluoxetine, ticlopidine) and CYP2D6 (e.g. fluoxetine, paroxetine).(1) The magnitude of this interaction may be reduced in cigarette smokers. Cigarette smoking induces production of CYP1A2 and, in the absence of a CYP1A2 inhibitor, leads to decreased systemic concentrations of pirfenidone.(1) PATIENT MANAGEMENT: The manufacturer of pirfenidone states that for concurrent use with moderate inhibitors of CYP1A2, dose reduction is recommended. Reduce the dose of pirfenidone to two-267 mg capsules three times a day (total daily dose of 1602 mg/day).(1) Combinations of strong or moderate CYP1A2 inhibitors with strong or moderate CYP2C9, CYP2C19, and/or CYP2D6 inhibitors should be discontinued prior to and avoided during pirfenidone treatment.(1) DISCUSSION: Pirfenidone is converted to inactive metabolites prior to elimination. CYP1A2 is responsible for approximately half of this metabolism. In an interaction study conducted in non-smokers and smokers, coadministration of pirfenidone with fluvoxamine (a strong CYP1A2 inhibitor), an agent which inhibits multiple pirfenidone elimination pathways (CYP1A2, CYP2C9, CYP2C19), led to an approximately 4-fold and 7-fold, respectively, increase in pirfenidone exposure.(1) In a single-dose study in 27 healthy subjects, coadministration of 801 mg of pirfenidone and 750 mg of ciprofloxacin on Day 6 (ciprofloxacin was dosed at 750 mg twice daily from Day 2 to Day 7) increased the exposure to pirfenidone by 81%.(1) Moderate CYP1A2 inhibitors linked to this monograph include: capmatinib, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, vemurafenib, and viloxazine.(2)	ESBRIET, PIRFENIDONE
Lacosamide/Sodium Channel Blockers; Potassium Channel Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Lacosamide may enhance the slow inactivation of voltage-gated sodium channels and may cause dose-dependent bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1) CLINICAL EFFECTS: Concurrent use of lacosamide and agents that affect cardiac conduction (sodium channel blockers and potassium channel blockers) may increase the risk of bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Lacosamide should be used with caution in patients on concomitant medications that affect cardiac conduction, including sodium channel blockers and potassium channel blockers.(1) If concurrent use is needed, obtain an ECG before lacosamide therapy and after lacosamide dose is titrated to steady-state.(1) Patients should be monitored closely when lacosamide is given intravenously.(1) DISCUSSION: In a clinical trial in patients with partial-onset seizures, asymptomatic first-degree atrioventricular (AV) block occurred in 4/944 (0.4%) of patient who received lacosamide compared to 0/364 (0%) with placebo.(1) In a clinical trial in patients with diabetic neuropathy, asymptomatic first-degree AV block occurred in 5/1023 (0.5%) of patients who received lacosamide compared to 0/291 (0%) with placebo.(1) Second-degree and complete AV block have been reported in patients with seizures.(1) One case of profound bradycardia was observed in a patient during a 15-minute infusion of 150 mg of lacosamide.(1) A case report of a 49 year old male with refractory complex partial and generalized seizures described the development of ventricular tachycardia four months after addition of lacosamide 400 mg/day to the existing regimen of carbamazepine, lamotrigine, clonazepam, and valproate. The patient's ECG showed first-degree AV block, posterior left fascicular block, and severe widening of the QRS complex, all of which resolved upon discontinuation of lacosamide.(2)	LACOSAMIDE, MOTPOLY XR, VIMPAT
Mexiletine/Cobicistat; Tipranavir SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Cobicistat and tipranavir may inhibit the metabolism of mexiletine by CYP2D6.(1-3) CLINICAL EFFECTS: Concurrent use of cobicistat or tipranavir with mexiletine may result in elevated levels of mexiletine, which may lead to serious and/or life-threatening effects.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The combination of cobicistat or tipranavir with mexiletine should be used with caution. Clinical monitoring is recommended with concomitant use.(1-3) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: Cobicistat is a weak CYP2D6 inhibitor,(1) and tipranavir is a moderate CYP2D6 inhibitor.(2) They may inhibit the metabolism and increase levels of mexiletine.(3)	APTIVUS, EVOTAZ, GENVOYA, PREZCOBIX, STRIBILD, SYMTUZA, TYBOST
Mexiletine/Strong CYP2D6 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Bupropion, dacomitinib, fluoxetine, paroxetine, and quinidine may inhibit the metabolism of mexiletine at CYP2D6.(1-7) CLINICAL EFFECTS: Concurrent use of CYP2D6 inhibitors may result in elevated levels of and toxicity from mexiletine, including vertigo, insomnia, and abdominal pain.(1-5) PREDISPOSING FACTORS: The interaction may be more severe in patients who are ultrarapid metabolizers of CYP2D6.(1-5) PATIENT MANAGEMENT: The UK manufacturer states coadministration of mexiletine with a strong CYP2D6 inhibitor may lead to increased levels and toxicity from mexiletine. Clinical monitoring is recommended during and after concurrent therapy for changes in mexiletine levels.(1) The US manufacturer states if concurrent use is warranted, mexiletine should be slowly titrated to response and closely monitored.(2) DISCUSSION: Mexiletine is 90% metabolized in the liver, with CYP2D6 as the primary pathway. CYP2D6 phenotypes significantly affect drug levels of mexiletine.(3-5) In an interaction study (8 extensive and 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable.(2) In a pharmacokinetic study in CYP2D6 phenotypes, patients with CYP2D6 extensive metabolizers had a decreased extent of the formation of both metabolites by more than 50% and 85% for the microsomes from CYP2D61/10 and 10/*10 livers, respectively.(3) Strong CYP2D6 inhibitors linked to this monograph include: bupropion, dacomitinib, fluoxetine, paroxetine, and quinidine.(6-7)	APLENZIN, AUVELITY, BUPROPION HCL, BUPROPION HCL SR, BUPROPION XL, CONTRAVE, FLUOXETINE DR, FLUOXETINE HCL, FORFIVO XL, NUEDEXTA, OLANZAPINE-FLUOXETINE HCL, PAROXETINE CR, PAROXETINE ER, PAROXETINE HCL, PAROXETINE MESYLATE, PAXIL, PAXIL CR, PROZAC, QUINIDINE GLUCONATE, QUINIDINE SULFATE, VIZIMPRO, WELLBUTRIN SR, WELLBUTRIN XL
Mexiletine/Phenytoin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Phenytoin, a moderate CYP1A2 inducer, may induce the metabolism of mexiletine.(1) CLINICAL EFFECTS: Concurrent use may result in decreased levels and effectiveness of mexiletine.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitoring of mexiletine plasma levels is recommended during concurrent use to avoid ineffective therapy.(1) The dose of mexiletine may need to be adjusted when phenytoin therapy is started or discontinued. DISCUSSION: Coadministration of mexiletine and rifampin (a moderate CYP1A2 inducer) have been reported to decrease the elimination half-life and increase the nonrenal clearance of mexiletine.(2) A pharmacokinetic study in 6 healthy volunteers found a decrease in the mean area-under-curve (AUC) of a single dose of mexiletine 400 mg when given with a seven day course of phenytoin 300 mg. The mean AUC of a single dose of mexiletine 400 mg alone was 17.2 ng/ml compared to 8.01 ng/ml when given with phenytoin 300 mg.(3)	CEREBYX, DILANTIN, DILANTIN-125, FOSPHENYTOIN SODIUM, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED

The following contraindication information is available for MEXILETINE HCL (mexiletine hcl):

Overview
Contraindicated
Severe
Moderate

Drug contraindication overview.

Mexiletine hydrochloride is contraindicated in patients with second- or third-degree AV block (unless a cardiac pacemaker is in place) or cardiogenic shock.

There are 3 contraindications. Absolute contraindication.

Contraindication List
Cardiogenic shock
Complete atrioventricular block
Second degree atrioventricular heart block

There are 0 severe contraindications.

There are 7 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Acute myocardial infarction
Disease of liver
Hypotension
Seizure disorder
Severe chronic heart failure
Sick sinus syndrome
Tobacco smoker

The following adverse reaction information is available for MEXILETINE HCL (mexiletine hcl):

Overview
Severe
Less Severe

Adverse reaction overview.

Adverse effects occurring in 1% or more of patients receiving mexiletine include nausea, vomiting, heartburn, diarrhea, constipation, changes in appetite, abdominal pain/discomfort, abdominal cramps, dry mouth, dizziness, lightheadedness, tremor, nervousness, weakness, fatigue, confusion/clouded sensorium, coordination difficulties, changes in sleep pattern, paresthesia or numbness, depression, headache, arthralgia, fever, blurred vision/visual disturbances, tinnitus, dyspnea, chest pain, palpitations, increased ventricular arrhythmia/ventricular premature contractions, angina or angina-like symptoms, rash, and non-specific edema. In controlled clinical trials, 40% of patients have discontinued the drug because of adverse effects. During postmarketing surveillance, exacerbation of congestive heart failure (in patients with impaired ventricular function), pancreatitis, and pulmonary changes including pulmonary infiltration and pulmonary fibrosis (some patients had preexisting comorbidities and/or were receiving drugs with a potential for pulmonary toxicity), drowsiness, nystagmus, ataxia, dyspepsia, and hypersensitivity reaction have been reported in patients receiving mexiletine.

There are 17 severe adverse reactions.

More Frequent	Less Frequent
None.	Abnormal hepatic function tests Chest pain Dyspnea Increased aspartate transaminase Ventricular premature beats

Rare/Very Rare
Acute hepatic failure Acute pancreatitis Agranulocytosis DRESS syndrome Hepatic necrosis Leukopenia Neutropenic disorder Pulmonary fibrosis Pulmonary infiltrates Seizure disorder Thrombocytopenic disorder Ventricular arrhythmias

There are 27 less severe adverse reactions.

More Frequent	Less Frequent
Dizziness Dyskinesia Gastrointestinal irritation Heartburn Nausea Nervousness Tremor Vomiting	Acute cognitive impairment Blurred vision Constipation Diarrhea Fatigue General weakness Headache disorder Insomnia Paresthesia Skin rash Slurred speech Tinnitus

Rare/Very Rare
Abdominal pain with cramps Accidental fall Arthralgia Fever Hypotension Syncope Xerostomia

The following precautions are available for MEXILETINE HCL (mexiletine hcl):

Pediatric
Pregnant
Lactation
Geriatric

Safety and efficacy of mexiletine in children have not been established.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

Category C. (See Users Guide)

Mexiletine is distributed into milk at concentrations similar to those achieved in plasma. Discontinue nursing or drug, taking into account the importance of the drug to the woman.

No enhanced Geriatric Use information available for this drug.

Ventricular arrhythmias
I49.01	Ventricular fibrillation
I49.02	Ventricular flutter
I49.9	Cardiac arrhythmia, unspecified