"SILVER SPRING, MD â€” The US Food and Drug Administration (FDA) is warning of several treatment-related serious adverse events in association with implantable left ventricular assist devices (LVADs) in heart-failure patients.
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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 MEXITIL (mexiletine hcl) and the lack of evidence of improved survival for any antiarrhythmic drug in patients without life-threatening arrhythmias, the use of MEXITIL (mexiletine hcl) as well as other antiarrhythmic agents should be reserved for patients with life-threatening ventricular arrhythmia.
Acute Liver Injury
In post-marketing experience abnormal liver function tests have been reported, some in the first few weeks of therapy with MEXITIL (mexiletine hydrochloride, USP). Most of these have been observed in the setting of congestive heart failure or ischemia and their relationship to MEXITIL (mexiletine hcl) has not been established.
If a ventricular pacemaker is operative, patients with second or third degree heart block may be treated with MEXITIL (mexiletine hydrochloride, USP) 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 MEXITIL (mexiletine hcl) ; 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 MEXITIL (mexiletine hydrochloride, USP) can cause worsening of arrhythmias. This has been uncommon in patients with less serious arrhythmias (frequent premature beats or non-sustained ventricular tachycardia: see ADVERSE REACTIONS), 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, 10-15% of patients had exacerbation of the arrhythmia, a rate not greater than that of other agents.
MEXITIL (mexiletine hcl) should be used with caution in patients with hypotension and severe congestive heart failure because of the potential for aggravating these conditions.
Since MEXITIL (mexiletine hcl) is metabolized in the liver, and hepatic impairment has been reported to prolong the elimination half-life of MEXITIL (mexiletine hcl) , patients with liver disease should be followed carefully while receiving MEXITIL (mexiletine hcl) . 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 MEXITIL (mexiletine hcl) therapy. The minor fluctuations in urinary pH associated with normal diet do not affect the excretion of MEXITIL (mexiletine hcl) .
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 MEXITIL (mexiletine hcl) treatment. It is recommended that patients in whom an abnormal liver test has occurred, or who have signs or symptoms suggesting liver dysfunction, be carefully evaluated. If persistent or worsening elevation of hepatic enzymes is detected, consideration should be given to discontinuing therapy.
Among 10,867 patients treated with mexiletine in the compassionate use program, marked leukopenia (neutrophils less than 1000/mm3) 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 MEXITIL (mexiletine hcl) 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, MEXITIL (mexiletine hcl) should be discontinued. Blood counts usually return to normal within one month of discontinuation. (See ADVERSE REACTIONS).
Convulsions (seizures) did not occur in MEXITIL (mexiletine hcl) 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.
Carcinogenesis, Mutagenesis and Impairment of Fertility
Studies of carcinogenesis in rats (24 months) and mice (18 months) did not demonstrate any tumorigenic potential. MEXITIL (mexiletine hcl) was found to be non-mutagenic in the Ames test. MEXITIL (mexiletine hcl) did not impair fertility in the rat.
Pregnancy Category C
Reproduction studies performed with MEXITIL (mexiletine hydrochloride, USP) in rats, mice and rabbits at doses up to four times the maximum human oral dose (24 mg/kg in a 50 kg patient) revealed no evidence of teratogenicity or impaired fertility but did show an increase in fetal resorption. There are no adequate and well-controlled studies in pregnant women; this drug should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
MEXITIL (mexiletine hcl) appears in human milk in concentrations similar to those observed in plasma. Therefore, if the use of MEXITIL (mexiletine hcl) is deemed essential, an alternative method of infant feeding should be considered.
Safety and effectiveness in the pediatric population have not been established.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 4/8/2009
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