Mexiletine Hydrochloride (Page 3 of 5)

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

Teratogenic Effects

Reproduction studies performed with mexiletine 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.

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.

ADVERSE REACTIONS

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. Table 1 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
Mexiletine N = 53 Placebo N = 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

Weakness

1.9

4.1

Fatigue

1.9

2

Tinnitus

1.9

4.1

Confusion/Clouded Sensorium

1.9

2

Other

Headache

7.5

6.1

Blurred Vision/Visual Disturbances

7.5

2

Dyspnea/Respiratory

5.7

10.2

Rash

3.8

2

Non-specific Edema

3.8

Table 2 presents the adverse reactions occurring in one percent or more of patients in the three month controlled studies.

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

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

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

5.3

7.7

2.9

Nervousness

5

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


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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