A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Mexitil Side Effects, and Drug Interactions - Mexiletine HCl
Mexitil Side Effects, and Drug Interactions - Mexiletine HCl
SIDE EFFECTS
Mexitil® (mexiletine hydrochloride, USP) commonly produces
reversible gastrointestinal and nervous system adverse reactions but is
otherwise well tolerated. Mexitil® 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 600-1200 mg/day; some patients (8%) in the compassionate
use program were treated with higher daily doses (1600-3200 mg/day). In
the three-month controlled trials comparing Mexitil® 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. A tabulation of the adverse
events reported in the one-month placebo-controlled trial follows:
Comparative Incidence (%) Of Adverse Events Among Patients
Treated With Mexiletine And Placebo In The 4-Week, Double-Blind Crossover
Trial
| |
Mexiletine |
Placebo |
| N=53 |
N=49 |
| Cardiovascular |
| Palpitations |
7.5 |
10.2 |
| Chest Pain |
7.5 |
4.1 |
| Increased Ventricular Arrhythmia/PVC's |
1.9 |
6.1 |
| Digestive |
| Nausea/Vomiting/Heartburn |
39.6 |
6.1 |
| Central Nervous System |
| Dizziness/ Lightheadness |
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 |
- |
A tabulation of adverse reactions occurring in one percent or more of
patients in the three-month controlled studies follows:
Comparative Incidence (%) Of Adverse Events Among Patients
Treated With Mexiletine Or Control Drugs In The 12-Week Double-Blind Trials
| |
Mexiletine |
Placebo |
Procainamide |
Disopyramide |
| N=430 |
N=262 |
N=78 |
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 Arrhythmia/ PVC's |
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/ Lightheadness |
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 |
- |
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 Mexitil® (mexiletine hydrochloride,
USP) 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
Mexitil® use include:
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 Mexitil® (mexiletine hydrochloride, USP)
treatment have been reported.
Laboratory: Abnormal liver function tests, about 5 in 1000 patients;
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 PRECAUTIONS).
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 fibrosis during Mexitil®
therapy with or without other drugs or diseases that are known to produce
pulmonary toxicity. A causal relationship to Mexitil® therapy
has not been established. In addition, there have been isolated reports
of exacerbation of congestive heart failure in patients with pre-existing
compromised ventricular function. There have been rare reports of pancreatitis
associated with Mexitil® treatment.
DRUG INTERACTIONS
In a large compassionate use program Mexitil® 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 Mexitil®, lowered Mexitil® plasma levels
have been reported. Monitoring of Mexitil® plasma levels
is recommended during such concurrent use to avoid ineffective therapy.
In a formal study, benzodiazepines were shown not to affect Mexitil®
plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected
by concurrent Mexitil® and digoxin, diuretics, or propranolol.
Concurrent administration of cimetidine and Mexitil® has
been reported to increase, decrease, or leave unchanged Mexitil®
plasma levels; therefore patients should be followed carefully during
concurrent therapy.
Mexitil® does not alter serum digoxin levels but magnesium-aluminum
hydroxide, when used to treat gastrointestinal symptoms due to Mexitil®,
has been reported to lower serum digoxin levels.
Concurrent use of Mexitil® and theophylline may lead to
increased plasma theophylline levels. One controlled study in eight normal
subjects showed a 72% mean increase (range 35-136%) in plasma theophylline
levels. This increase was observed at the first test point which was the
second day after starting Mexitil®. Theophylline plasma
levels returned to pre-Mexitil® values within 48 hours
after discontinuing Mexitil®. If Mexitil and theophylline
are to be used concurrently, theophylline blood levels should be monitored,
particularly when the Mexitil® 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 Mexitil®.
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