Mexiletine Hydrochloride

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Overview

What is Mexiletine Hydrochloride?

Mexiletine hydrochloride is an orally active antiarrhythmic agent. It is a white to off-white crystalline powder with slightly bitter taste, freely soluble in water and in alcohol. Mexiletine hydrochloride has a pKa of 9.2. The chemical name of mexiletine hydrochloride is 1-methyl-2-(2,6-xylyloxy)ethylamine hydrochloride and its structural formula is:

C H NO HCl M.W. 215.72

Each capsule for oral administration, contains 150 mg, 200 mg, or 250 mg of mexiletine hydrochloride. 100 mg of mexiletine hydrochloride is equivalent to 83.31 mg of mexiletine base. In addition, each capsule contains the following excipients: colloidal silicon dioxide, magnesium stearate and pregelatinized starch. The capsule shell contains: FD&C Yellow #6, gelatin and titanium dioxide. The 150 mg capsule also contains: D&C Red #28 and FD&C Blue #1 and the 250 mg capsule also contains: D&C Yellow #10 and FD&C Blue #1. The imprinting ink contains: ammonium hydroxide, black iron oxide, D&C Yellow #10, ethyl alcohol, FD&C Blue #1, FD&C Blue #2, FD&C Red #40, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac.

What does Mexiletine Hydrochloride look like?

What are the available doses of Mexiletine Hydrochloride?

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What should I talk to my health care provider before I take Mexiletine Hydrochloride?

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How should I use Mexiletine Hydrochloride?

Mexiletine hydrochloride capsules are indicated for the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia, that, in the judgment of the physician, are life-threatening. Because of the proarrhythmic effects of mexiletine, its use with lesser arrhythmias is generally not recommended. Treatment of patients with asymptomatic ventricular premature contractions should be avoided.

Initiation of mexiletine treatment, as with other antiarrhythmic agents used to treat life-threatening arrhythmias, should be carried out in the hospital.

Antiarrhythmic drugs have not been shown to enhance survival in patients with ventricular arrhythmias.

The dosage of mexiletine hydrochloride must be individualized on the basis of response and tolerance, both of which are dose-related. Administration with food or antacid is recommended. Initiate mexiletine therapy with 200 mg every eight hours when rapid control of arrhythmia is not essential. A minimum of two to three days between dose adjustments is recommended. Dose may be adjusted in 50 or 100 mg increments up or down.

As with any antiarrhythmic drug, clinical and electrocardiographic evaluation (including Holter monitoring if necessary for evaluation) are needed to determine whether the desired antiarrhythmic effect has been obtained and to guide titration and dose adjustment.

Satisfactory control can be achieved in most patients by 200 to 300 mg given every eight hours with food or antacid. If satisfactory response has not been achieved at 300 mg q8h, and the patient tolerates mexiletine well, a dose of 400 mg q8h may be tried. As the severity of CNS side effects increases with total daily dose, the dose should not exceed 1200 mg/day.

In general, patients with renal failure will require the usual doses of mexiletine hydrochloride. Patients with severe liver disease, however, may require lower doses and must be monitored closely. Similarly, marked right-sided congestive heart failure can reduce hepatic metabolism and reduce the needed dose. Plasma level may also be affected by certain concomitant drugs (see , ).

What interacts with Mexiletine Hydrochloride?

Mexiletine hydrochloride capsules are contraindicated in the presence of cardiogenic shock or pre-existing second-or third-degree AV block (if no pacemaker is present).

What are the warnings of Mexiletine Hydrochloride?

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What are the precautions of Mexiletine Hydrochloride?

General

If a ventricular pacemaker is operative, patients with second or third degree heart block may be treated with mexiletine hydrochloride if continuously monitored. A limited number of patients (45 of 475 in controlled clinical trials) with pre-existing first degree AV block were treated with mexiletine; none of these patients developed second or third degree AV block. Caution should be exercised when it is used in such patients or in patients with pre-existing sinus node dysfunction or intraventricular conduction abnormalities.

Like other antiarrhythmics mexiletine hydrochloride can cause worsening of arrhythmias. This has been uncommon in patients with less serious arrhythmias (frequent premature beats or nonsustained ventricular tachycardia: see ), but is of greater concern in patients with life-threatening arrhythmias such as sustained ventricular tachycardia. In patients with such arrhythmias subjected to programmed electrical stimulation or to exercise provocation, 10 to 15% of patients had exacerbation of the arrhythmia, a rate not greater than that of other agents.

Mexiletine should be used with caution in patients with hypotension and severe congestive heart failure because of the potential for aggravating these conditions.

Since mexiletine is metabolized in the liver, and hepatic impairment has been reported to prolong the elimination half-life of mexiletine, patients with liver disease should be followed carefully while receiving mexiletine. The same caution should be observed in patients with hepatic dysfunction secondary to congestive heart failure.

Concurrent drug therapy or dietary regimens which may markedly alter urinary pH should be avoided during mexiletine hydrochloride therapy. The minor fluctuations in urinary pH associated with normal diet do not affect the excretion of mexiletine.

SGOT Elevation and Liver Injury

In three month controlled trials, elevations of SGOT greater than three times the upper limit of normal occurred in about 1% of both mexiletine-treated and control patients. Approximately 2% of patients in the mexiletine compassionate use program had elevations of SGOT greater than or equal to three times the upper limit of normal. These elevations frequently occurred in association with identifiable clinical events and therapeutic measures such as congestive heart failure, acute myocardial infarction, blood transfusions and other medications. These elevations were often asymptomatic and transient, usually not associated with elevated bilirubin levels and usually did not require discontinuation of therapy. Marked elevations of SGOT (> 1000 U/L) were seen before death in four patients with end-stage cardiac disease (severe congestive heart failure, cardiogenic shock).

Rare instances of severe liver injury, including hepatic necrosis, have been reported in association with mexiletine treatment. It is recommended that patients in whom an abnormal liver test has occurred, or who have signs of symptoms suggesting liver dysfunction, be carefully evaluated. If persistent or worsening elevation of hepatic enzymes is detected, consideration should be given to discontinuing therapy.

Blood Dyscrasias

Among 10,867 patients treated with mexiletine in the compassionate use program, marked leukopenia (neutrophils less than 1000/mm ) or agranulocytosis were seen in 0.06% and milder depressions of leukocytes were seen in 0.08%, and thrombocytopenia was observed in 0.16%. Many of these patients were seriously ill and receiving concomitant medications with known hematologic adverse effects. Rechallenge with mexiletine in several cases was negative. Marked leukopenia or agranulocytosis did not occur in any patient receiving mexiletine alone; five of the six cases of agranulocytosis were associated with procainamide (sustained release preparations in four) and one with vinblastine. If significant hematologic changes are observed, the patient should be carefully evaluated, and, if warranted, mexiletine should be discontinued. Blood counts usually return to normal within a month of discontinuation (see ).

Convulsions (seizures) did not occur in mexiletine controlled clinical trials. In the compassionate use program, convulsions were reported in about 2 of 1000 patients. Twenty-eight percent of these patients discontinued therapy. Convulsions were reported in patients with and without a prior history of seizures. Mexiletine should be used with caution in patients with known seizure disorder.

Drug Interactions

Since mexiletine hydrochloride is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 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. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs is initiated, the dose of mexiletine should be slowly titrated to desired effect.

In a large compassionate use program mexiletine has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with mexiletine, lowered mexiletine plasma levels have been reported. Monitoring of mexiletine plasma levels is recommended during such concurrent use to avoid ineffective therapy.

In a formal study, benzodiazepines were shown not to affect mexiletine plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent mexiletine and digoxin, diuretics, or propranolol.

Concurrent administration of cimetidine and mexiletine has been reported to increase, decrease, or leave unchanged mexiletine plasma levels; therefore patients should be followed carefully during concurrent therapy.

Mexiletine does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to mexiletine, has been reported to lower serum digoxin levels.

Concurrent use of mexiletine and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range

35 to 136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting mexiletine. Theophylline plasma levels returned to pre-mexiletine values within 48 hours after discontinuing mexiletine. If mexiletine and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the mexiletine dose is changed. An appropriate adjustment in theophylline dose should be considered.

Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of mexiletine.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies of carcinogenesis in rats (24 months) and mice (18 months) did not demonstrate any tumorigenic potential. Mexiletine was found to be non-mutagenic in the Ames test. Mexiletine did not impair fertility in the rat.

Pregnancy

Nursing Mothers

Mexiletine appears in human milk in concentrations similar to those observed in plasma. Therefore, if the use of mexiletine hydrochloride is deemed essential, an alternative method of infant feeding should be considered.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

What are the side effects of Mexiletine Hydrochloride?

Mexiletine hydrochloride commonly produces reversible gastrointestinal and nervous system adverse reactions but is otherwise well tolerated. Mexiletine has been evaluated in 483 patients in one month and three month controlled studies and in over 10,000 patients in a large compassionate use program. Dosages in the controlled studies ranged from 600 to 1200 mg/day; some patients (8%) in the compassionate use program were treated with higher daily doses (1600 to 3200 mg/day). In the three month controlled trials comparing mexiletine to quinidine, procainamide and disopyramide, the most frequent adverse reactions were upper gastrointestinal distress (41%), lightheadedness (10.5%), tremor (12.6%) and coordination difficulties (10.2%). Similar frequency and incidence were observed in the one month placebo-controlled trial. Although these reactions were generally not serious, and were dose-related and reversible with a reduction in dosage, by taking the drug with food or antacid or by therapy discontinuation, they led to therapy discontinuation in 40% of patients in the controlled trials. presents the adverse events reported in the one-month placebo-controlled trial.

Table 1: Comparative Incidence (%) of Adverse Events Among Patients Treated with Mexiletine and Placebo in the 4 Week, Double-blind Crossover Trial

Table 2

Table 2: Comparative Incidence (%) of Adverse Events Among Patients Treated with Mexiletine or Control Drugs in the 12 Week Double-blind Trials

Less than 1%: Syncope, edema, hot flashes, hypertension, short-term memory loss, loss of consciousness, other psychological changes, diaphoresis, urinary hesitancy/retention, malaise, impotence/decreased libido, pharyngitis, congestive heart failure.

An additional group of over 10,000 patients has been treated in a program allowing administration of mexiletine hydrochloride under compassionate use circumstances. These patients were seriously ill with the large majority on multiple drug therapy. Twenty-four percent of the patients continued in the program for one year or longer. Adverse reactions leading to therapy discontinuation occurred in 15 percent of patients (usually upper gastrointestinal system or nervous system effects). In general, the more common adverse reactions were similar to those in the controlled trials. Less common adverse events possibly related to mexiletine use include:

	MexiletineN = 53	PlaceboN = 49
Cardiovascular
Palpitations	7.5	10.2
Chest Pain	7.5	4.1
Increased Ventricular Arrythmia/PVCs	1.9	-
Digestive
Nausea/Vomiting/Heartburn	39.6	6.1
Central Nervous System
Dizziness/Lightheadedness	26.4	14.3
Tremor	13.2	-
Nervousness	11.3	6.1
Coordination Difficulties	9.4	-
Changes in Sleep Habits	7.5	16.3
Paresthesias/Numbness	3.8	2.0
Weakness	1.9	4.1
Fatigue	1.9	2.0
Tinnitus	1.9	4.1
Confusion/Clouded Sensorium	1.9	2.0
Other
Headache	7.5	6.1
Blurred Vision/Visual Disturbances	7.5	2.0
Dyspnea/Respiratory	5.7	10.2
Rash	3.8	2.0
Non-specific Edema	3.8	-
	Mexiletine N = 430	Quinidine N = 262	Procainamide N = 78	Disopyramide N = 69
Cardiovascular
Palpitations	4.3	4.6	1.3	5.8
Chest Pain	2.6	3.4	1.3	2.9
Angina/Angina-like Pain	1.7	1.9	2.6	2.9
Increased Ventricular Arrhythmias/PVCs	1.0	2.7	2.6	-
Digestive
Nausea/Vomiting/ Heartburn	39.3	21.4	33.3	14.5
Diarrhea	5.2	33.2	2.6	8.7
Constipation	4.0	-	6.4	11.6
Changes in Appetite	2.6	1.9	-	-
Abdominal Pain/Cramps/ Discomfort	1.2	1.5	-	1.4
Central Nervous System
Dizziness/Lightheadedness	18.9	14.1	14.1	2.9
Tremor	13.2	2.3	3.8	1.4
Coordination Difficulties	9.7	1.1	1.3	-
Changes in Sleep Habits	7.1	2.7	11.5	8.7
Weakness	5.0	5.3	7.7	2.9
Nervousness	5.0	1.9	6.4	5.8
Fatigue	3.8	5.7	5.1	1.4
Speech Difficulties	2.6	0.4	-	-
Confusion/Clouded Sensorium	2.6	-	3.8	-
Paresthesias/Numbness	2.4	2.3	2.6	-
Tinnitus	2.4	1.5	-	-
Depression	2.4	1.1	1.3	1.4
Other
Blurred Vision/Visual Disturbances	5.7	3.1	5.1	7.2
Headache	5.7	6.9	7.7	4.3
Rash	4.2	3.8	10.3	1.4
Dyspnea/Respiratory	3.3	3.1	5.1	2.9
Dry Mouth	2.8	1.9	5.1	14.5
Arthralgia	1.7	2.3	5.1	1.4
Fever	1.2	3.1	2.6	-

Cardiovascular System

Syncope and hypotension, each about 6 in 1000; bradycardia, about 4 in 1000; angina/angina-like pain, about 3 in 1000; edema, atrioventricular block/conduction disturbances and hot flashes, each about 2 in 1000; atrial arrhythmias, hypertension and cardiogenic shock, each about 1 in 1000.

Central Nervous System

Short-term memory loss, about 9 in 1000 patients; hallucinations and other psychological changes, each about 3 in 1000; psychosis and convulsions/seizures, each about 2 in 1000; loss of consciousness, about 6 in 10,000.

Digestive

Dysphagia, about 2 in 1000; peptic ulcer, about 8 in 10,000; upper gastrointestinal bleeding, about 7 in 10,000; esophageal ulceration, about 1 in 10,000. Rare cases of severe hepatitis/acute hepatic necrosis.

Skin

Rare cases of exfoliative dermatitis and Stevens-Johnson syndrome with mexiletine treatment have been reported.

Laboratory

Abnormal liver function tests, about 5 in 1000; positive ANA and thrombocytopenia, each about 2 in 1000; leukopenia (including neutropenia and agranulocytosis), about 1 in 1000; myelofibrosis, about 2 in 10,000 patients.

Other

Diaphoresis, about 6 in 1000; altered taste, about 5 in 1000; salivary changes, hair loss and impotence/decreased libido, each about 4 in 1000; malaise, about 3 in 1000; urinary hesitancy/retention, each about 2 in 1000; hiccups, dry skin, laryngeal and pharyngeal changes and changes in oral mucous membranes, each about 1 in 1000; SLE syndrome, about 4 in 10,000.

Hematology

Blood dyscrasias were not seen in the controlled trials but did occur among 10,867 patients treated with mexiletine in the compassionate use program (see ).

Myelofibrosis was reported in two patients in the compassionate use program; one was receiving long-term thiotepa therapy and the other had pretreatment myeloid abnormalities.

In postmarketing experience, there have been isolated, spontaneous reports of pulmonary changes including pulmonary infiltration and pulmonary fibrosis during mexiletine therapy with or without other drugs or diseases that are known to produce pulmonary toxicity. A causal relationship to mexiletine therapy has not been established. In addition, there have been isolated reports of drowsiness, nystagmus, ataxia, dyspepsia, hypersensitivity reaction, and exacerbation of congestive heart failure in patients with pre-existing compromised ventricular function. There have been rare reports of pancreatitis associated with mexiletine treatment.

What should I look out for while using Mexiletine Hydrochloride?

Mexiletine hydrochloride capsules are contraindicated in the presence of cardiogenic shock or pre-existing second-or third-degree AV block (if no pacemaker is present).

WARNINGS

Mortality

In the National Heart, Lung and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multicentered, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had a myocardial infarction more than six days but less than two years previously, an excessive mortality or non-fatal cardiac arrest rate (7.7%) was seen in patients treated with encainide or flecainide compared with that seen in patients assigned to carefully matched placebo-treated groups (3.0%). The average duration of treatment with encainide or flecainide in this study was ten months.

The applicability of the CAST results to other populations (e.g., those without recent myocardial infarction) is uncertain. Considering the known proarrhythmic properties of mexiletine and the lack of evidence of improved survival for any antiarrhythmic drug in patients without life-threatening arrhythmias, the use of mexiletine as well as other antiarrhythmic agents should be reserved for patients with life-threatening ventricular arrhythmia.

Acute Liver Injury

In postmarketing experience abnormal liver function tests have been reported, some in the first few weeks of therapy with mexiletine hydrochloride. Most of these have been observed in the setting of congestive heart failure or ischemia and their relationship to mexiletine hydrochloride has not been established.

What might happen if I take too much Mexiletine Hydrochloride?

Clinical findings associated with mexiletine overdosage have included drowsiness, confusion, nausea, hypotension, sinus bradycardia, paresthesia, seizures, bundle branch block, AV heart block, asystole, ventricular tachyarrythmia, including ventricular fibrillation, cardiovascular collapse and coma. The lowest known dose in a fatality case was 4.4 g with postmortem serum mexiletine level of 34 to 37 mcg/mL (Jequier P. et. al., Lancet 1976: 1 (7956): 429). Patients have recovered from ingestion of 4 g to 18 g of mexiletine (Frank S. E. et. al., Am J Emerg Med 1991: 9:43-48).

There is no specific antidote for mexiletine. Management of mexiletine overdosage includes general supportive measures, close observation and monitoring of vital signs. In addition, the use of pharmacologic interventions (e.g., pressor agents, atropine or anticonvulsants) or transvenous cardiac pacing is suggested, depending on the patient’s clinical condition.

How should I store and handle Mexiletine Hydrochloride?

As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions prepared from oxaliplatin. The use of gloves is recommended. If a solution of oxaliplatin contacts the skin, wash the skin immediately and thoroughly with soap and water. If oxaliplatin contacts the mucous membranes, flush thoroughly with water.Procedures for the handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published . There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions prepared from oxaliplatin. The use of gloves is recommended. If a solution of oxaliplatin contacts the skin, wash the skin immediately and thoroughly with soap and water. If oxaliplatin contacts the mucous membranes, flush thoroughly with water.Procedures for the handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published . There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.Mexiletine hydrochloride capsules USP, 150 mg are white granular powder in a hard gelatin capsule with an opaque tan cap and an opaque orange body, imprinted with N on one side and 739 and 150 on the other in black ink. They are supplied as follows: 42291-624-01 bottles of 100. Mexiletine hydrochloride capsules USP, 200 mg are white granular powder in a hard gelatin capsule with an opaque orange cap and an opaque orange body, imprinted with N on& one side and 740 and 200 on the other in black ink. They are supplied as follows: 42291-625-01 bottles of 100. Mexiletine hydrochloride capsules USP, 250 mg are white granular powder in a hard gelatin capsule with an opaque green cap and an opaque orange body, imprinted with N on one side and 741 and 250 on the other in black ink. They are supplied as follows: 42291-626-01 bottles of 100. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured For:AvKARE, Inc.Pulaski, TN 38478Mfg. Rev. B 08/04 AV 02/13 (P) Mexiletine hydrochloride capsules USP, 150 mg are white granular powder in a hard gelatin capsule with an opaque tan cap and an opaque orange body, imprinted with N on one side and 739 and 150 on the other in black ink. They are supplied as follows: 42291-624-01 bottles of 100. Mexiletine hydrochloride capsules USP, 200 mg are white granular powder in a hard gelatin capsule with an opaque orange cap and an opaque orange body, imprinted with N on& one side and 740 and 200 on the other in black ink. They are supplied as follows: 42291-625-01 bottles of 100. Mexiletine hydrochloride capsules USP, 250 mg are white granular powder in a hard gelatin capsule with an opaque green cap and an opaque orange body, imprinted with N on one side and 741 and 250 on the other in black ink. They are supplied as follows: 42291-626-01 bottles of 100. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured For:AvKARE, Inc.Pulaski, TN 38478Mfg. Rev. B 08/04 AV 02/13 (P) Mexiletine hydrochloride capsules USP, 150 mg are white granular powder in a hard gelatin capsule with an opaque tan cap and an opaque orange body, imprinted with N on one side and 739 and 150 on the other in black ink. They are supplied as follows: 42291-624-01 bottles of 100. Mexiletine hydrochloride capsules USP, 200 mg are white granular powder in a hard gelatin capsule with an opaque orange cap and an opaque orange body, imprinted with N on& one side and 740 and 200 on the other in black ink. They are supplied as follows: 42291-625-01 bottles of 100. Mexiletine hydrochloride capsules USP, 250 mg are white granular powder in a hard gelatin capsule with an opaque green cap and an opaque orange body, imprinted with N on one side and 741 and 250 on the other in black ink. They are supplied as follows: 42291-626-01 bottles of 100. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured For:AvKARE, Inc.Pulaski, TN 38478Mfg. Rev. B 08/04 AV 02/13 (P) Mexiletine hydrochloride capsules USP, 150 mg are white granular powder in a hard gelatin capsule with an opaque tan cap and an opaque orange body, imprinted with N on one side and 739 and 150 on the other in black ink. They are supplied as follows: 42291-624-01 bottles of 100. Mexiletine hydrochloride capsules USP, 200 mg are white granular powder in a hard gelatin capsule with an opaque orange cap and an opaque orange body, imprinted with N on& one side and 740 and 200 on the other in black ink. They are supplied as follows: 42291-625-01 bottles of 100. Mexiletine hydrochloride capsules USP, 250 mg are white granular powder in a hard gelatin capsule with an opaque green cap and an opaque orange body, imprinted with N on one side and 741 and 250 on the other in black ink. They are supplied as follows: 42291-626-01 bottles of 100. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured For:AvKARE, Inc.Pulaski, TN 38478Mfg. Rev. B 08/04 AV 02/13 (P) Mexiletine hydrochloride capsules USP, 150 mg are white granular powder in a hard gelatin capsule with an opaque tan cap and an opaque orange body, imprinted with N on one side and 739 and 150 on the other in black ink. They are supplied as follows: 42291-624-01 bottles of 100. Mexiletine hydrochloride capsules USP, 200 mg are white granular powder in a hard gelatin capsule with an opaque orange cap and an opaque orange body, imprinted with N on& one side and 740 and 200 on the other in black ink. They are supplied as follows: 42291-625-01 bottles of 100. Mexiletine hydrochloride capsules USP, 250 mg are white granular powder in a hard gelatin capsule with an opaque green cap and an opaque orange body, imprinted with N on one side and 741 and 250 on the other in black ink. They are supplied as follows: 42291-626-01 bottles of 100. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured For:AvKARE, Inc.Pulaski, TN 38478Mfg. Rev. B 08/04 AV 02/13 (P) Mexiletine hydrochloride capsules USP, 150 mg are white granular powder in a hard gelatin capsule with an opaque tan cap and an opaque orange body, imprinted with N on one side and 739 and 150 on the other in black ink. They are supplied as follows: 42291-624-01 bottles of 100. Mexiletine hydrochloride capsules USP, 200 mg are white granular powder in a hard gelatin capsule with an opaque orange cap and an opaque orange body, imprinted with N on& one side and 740 and 200 on the other in black ink. They are supplied as follows: 42291-625-01 bottles of 100. Mexiletine hydrochloride capsules USP, 250 mg are white granular powder in a hard gelatin capsule with an opaque green cap and an opaque orange body, imprinted with N on one side and 741 and 250 on the other in black ink. They are supplied as follows: 42291-626-01 bottles of 100. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured For:AvKARE, Inc.Pulaski, TN 38478Mfg. Rev. B 08/04 AV 02/13 (P) Mexiletine hydrochloride capsules USP, 150 mg are white granular powder in a hard gelatin capsule with an opaque tan cap and an opaque orange body, imprinted with N on one side and 739 and 150 on the other in black ink. They are supplied as follows: 42291-624-01 bottles of 100. Mexiletine hydrochloride capsules USP, 200 mg are white granular powder in a hard gelatin capsule with an opaque orange cap and an opaque orange body, imprinted with N on& one side and 740 and 200 on the other in black ink. They are supplied as follows: 42291-625-01 bottles of 100. Mexiletine hydrochloride capsules USP, 250 mg are white granular powder in a hard gelatin capsule with an opaque green cap and an opaque orange body, imprinted with N on one side and 741 and 250 on the other in black ink. They are supplied as follows: 42291-626-01 bottles of 100. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured For:AvKARE, Inc.Pulaski, TN 38478Mfg. Rev. B 08/04 AV 02/13 (P) Mexiletine hydrochloride capsules USP, 150 mg are white granular powder in a hard gelatin capsule with an opaque tan cap and an opaque orange body, imprinted with N on one side and 739 and 150 on the other in black ink. They are supplied as follows: 42291-624-01 bottles of 100. Mexiletine hydrochloride capsules USP, 200 mg are white granular powder in a hard gelatin capsule with an opaque orange cap and an opaque orange body, imprinted with N on& one side and 740 and 200 on the other in black ink. They are supplied as follows: 42291-625-01 bottles of 100. Mexiletine hydrochloride capsules USP, 250 mg are white granular powder in a hard gelatin capsule with an opaque green cap and an opaque orange body, imprinted with N on one side and 741 and 250 on the other in black ink. They are supplied as follows: 42291-626-01 bottles of 100. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured For:AvKARE, Inc.Pulaski, TN 38478Mfg. Rev. B 08/04 AV 02/13 (P) Mexiletine hydrochloride capsules USP, 150 mg are white granular powder in a hard gelatin capsule with an opaque tan cap and an opaque orange body, imprinted with N on one side and 739 and 150 on the other in black ink. They are supplied as follows: 42291-624-01 bottles of 100. Mexiletine hydrochloride capsules USP, 200 mg are white granular powder in a hard gelatin capsule with an opaque orange cap and an opaque orange body, imprinted with N on& one side and 740 and 200 on the other in black ink. They are supplied as follows: 42291-625-01 bottles of 100. Mexiletine hydrochloride capsules USP, 250 mg are white granular powder in a hard gelatin capsule with an opaque green cap and an opaque orange body, imprinted with N on one side and 741 and 250 on the other in black ink. They are supplied as follows: 42291-626-01 bottles of 100. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured For:AvKARE, Inc.Pulaski, TN 38478Mfg. Rev. B 08/04 AV 02/13 (P)

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Clinical Information

Chemical Structure

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Clinical Pharmacology

Mexiletine hydrochloride is a local anesthetic, antiarrhythmic agent, structurally similar to lidocaine, but orally active. In animal studies, mexiletine has been shown to be effective in the suppression of induced ventricular arrhythmias, including those induced by glycoside toxicity and coronary artery ligation. Mexiletine, like lidocaine, inhibits the inward sodium current, thus reducing the rate of rise of the action potential, Phase 0. Mexiletine decreased the effective refractory period (ERP) in Purkinje fibers. The decrease in ERP was of lesser magnitude than the decrease in action potential duration (APD), with a resulting increase in the ERP/APD ratio.

Non-Clinical Toxicology

Mexiletine hydrochloride capsules are contraindicated in the presence of cardiogenic shock or pre-existing second-or third-degree AV block (if no pacemaker is present).

WARNINGS

Mortality

In the National Heart, Lung and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multicentered, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had a myocardial infarction more than six days but less than two years previously, an excessive mortality or non-fatal cardiac arrest rate (7.7%) was seen in patients treated with encainide or flecainide compared with that seen in patients assigned to carefully matched placebo-treated groups (3.0%). The average duration of treatment with encainide or flecainide in this study was ten months.

The applicability of the CAST results to other populations (e.g., those without recent myocardial infarction) is uncertain. Considering the known proarrhythmic properties of mexiletine and the lack of evidence of improved survival for any antiarrhythmic drug in patients without life-threatening arrhythmias, the use of mexiletine as well as other antiarrhythmic agents should be reserved for patients with life-threatening ventricular arrhythmia.

Acute Liver Injury

In postmarketing experience abnormal liver function tests have been reported, some in the first few weeks of therapy with mexiletine hydrochloride. Most of these have been observed in the setting of congestive heart failure or ischemia and their relationship to mexiletine hydrochloride has not been established.

Since mexiletine hydrochloride is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 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. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs is initiated, the dose of mexiletine should be slowly titrated to desired effect.

In a large compassionate use program mexiletine has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with mexiletine, lowered mexiletine plasma levels have been reported. Monitoring of mexiletine plasma levels is recommended during such concurrent use to avoid ineffective therapy.

In a formal study, benzodiazepines were shown not to affect mexiletine plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent mexiletine and digoxin, diuretics, or propranolol.

Concurrent administration of cimetidine and mexiletine has been reported to increase, decrease, or leave unchanged mexiletine plasma levels; therefore patients should be followed carefully during concurrent therapy.

Mexiletine does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to mexiletine, has been reported to lower serum digoxin levels.

Concurrent use of mexiletine and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range

35 to 136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting mexiletine. Theophylline plasma levels returned to pre-mexiletine values within 48 hours after discontinuing mexiletine. If mexiletine and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the mexiletine dose is changed. An appropriate adjustment in theophylline dose should be considered.

Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of mexiletine.

If a ventricular pacemaker is operative, patients with second or third degree heart block may be treated with mexiletine hydrochloride if continuously monitored. A limited number of patients (45 of 475 in controlled clinical trials) with pre-existing first degree AV block were treated with mexiletine; none of these patients developed second or third degree AV block. Caution should be exercised when it is used in such patients or in patients with pre-existing sinus node dysfunction or intraventricular conduction abnormalities.

Like other antiarrhythmics mexiletine hydrochloride can cause worsening of arrhythmias. This has been uncommon in patients with less serious arrhythmias (frequent premature beats or nonsustained ventricular tachycardia: see ), but is of greater concern in patients with life-threatening arrhythmias such as sustained ventricular tachycardia. In patients with such arrhythmias subjected to programmed electrical stimulation or to exercise provocation, 10 to 15% of patients had exacerbation of the arrhythmia, a rate not greater than that of other agents.

Mexiletine should be used with caution in patients with hypotension and severe congestive heart failure because of the potential for aggravating these conditions.

Since mexiletine is metabolized in the liver, and hepatic impairment has been reported to prolong the elimination half-life of mexiletine, patients with liver disease should be followed carefully while receiving mexiletine. The same caution should be observed in patients with hepatic dysfunction secondary to congestive heart failure.

Concurrent drug therapy or dietary regimens which may markedly alter urinary pH should be avoided during mexiletine hydrochloride therapy. The minor fluctuations in urinary pH associated with normal diet do not affect the excretion of mexiletine.

Mexiletine hydrochloride commonly produces reversible gastrointestinal and nervous system adverse reactions but is otherwise well tolerated. Mexiletine has been evaluated in 483 patients in one month and three month controlled studies and in over 10,000 patients in a large compassionate use program. Dosages in the controlled studies ranged from 600 to 1200 mg/day; some patients (8%) in the compassionate use program were treated with higher daily doses (1600 to 3200 mg/day). In the three month controlled trials comparing mexiletine to quinidine, procainamide and disopyramide, the most frequent adverse reactions were upper gastrointestinal distress (41%), lightheadedness (10.5%), tremor (12.6%) and coordination difficulties (10.2%). Similar frequency and incidence were observed in the one month placebo-controlled trial. Although these reactions were generally not serious, and were dose-related and reversible with a reduction in dosage, by taking the drug with food or antacid or by therapy discontinuation, they led to therapy discontinuation in 40% of patients in the controlled trials. presents the adverse events reported in the one-month placebo-controlled trial.

Table 1: Comparative Incidence (%) of Adverse Events Among Patients Treated with Mexiletine and Placebo in the 4 Week, Double-blind Crossover Trial

Table 2

Table 2: Comparative Incidence (%) of Adverse Events Among Patients Treated with Mexiletine or Control Drugs in the 12 Week Double-blind Trials

Less than 1%: Syncope, edema, hot flashes, hypertension, short-term memory loss, loss of consciousness, other psychological changes, diaphoresis, urinary hesitancy/retention, malaise, impotence/decreased libido, pharyngitis, congestive heart failure.

An additional group of over 10,000 patients has been treated in a program allowing administration of mexiletine hydrochloride under compassionate use circumstances. These patients were seriously ill with the large majority on multiple drug therapy. Twenty-four percent of the patients continued in the program for one year or longer. Adverse reactions leading to therapy discontinuation occurred in 15 percent of patients (usually upper gastrointestinal system or nervous system effects). In general, the more common adverse reactions were similar to those in the controlled trials. Less common adverse events possibly related to mexiletine use include:

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72

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Interactions

A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).

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