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
Zonegran Side Effects, and Drug Interactions - Zonisamide
Zonegran Side Effects, and Drug Interactions - Zonisamide
SIDE EFFECTS
The most commonly observed adverse events associated
with the use of ZONEGRAN in controlled clinical trials that were not seen
at an equivalent frequency among placebo-treated patients were somnolence,
anorexia, dizziness, headache, nausea, and agitation/irritability.
In controlled clinical trials, 12% of patients receiving
ZONEGRAN as adjunctive therapy discontinued due to an adverse event compared
to 6% receiving placebo. Approximately 21% of the 1,336 patients with
epilepsy who received ZONEGRAN in clinical studies discontinued treatment
because of an adverse event. The adverse events most commonly associated
with discontinuation were somnolence, fatigue and/or ataxia (6%), anorexia
(3%), difficulty concentrating (2%), difficulty with memory, mental slowing,
nausea/vomiting (2%), and weight loss (1%). Many of these adverse events
were dose-related (see WARNINGS
and PRECAUTIONS).
Adverse Event Incidence in Controlled Clinical Trials:
Table 3 lists treatment-emergent adverse events that
occurred in at least 2% of patients treated with ZONEGRAN in controlled
clinical trials that were numerically more common in the ZONEGRAN group.
In these studies, either ZONEGRAN or placebo was added to the patient’s
current AED therapy. Adverse events were usually mild or moderate in intensity.
The prescriber should be aware that these figures, obtained
when ZONEGRAN was added to concurrent AED therapy, cannot be used to predict
the frequency of adverse events in the course of usual medical practice
when patient characteristics and other factors may differ from those prevailing
during clinical studies. Similarly, the cited frequencies cannot be directly
compared with figures obtained from other clinical investigations involving
different treatments, uses, or investigators. An inspection of these frequencies,
however, does provide the prescriber with one basis by which to estimate
the relative contribution of drug and non-drug factors to the adverse
event incidences in the population studied.
TABLE 3: Incidence (%) of Treatment-Emergent Adverse Events
in Placebo-Controlled, Add-On Trials (Events that occurred in at least
2% of ZONEGRAN-treated patients and occurred more frequently in ZONEGRAN-treated
than placebo-treated patients)
|
BODY SYSTEM/ PREFERRED TERM
|
ZONEGRAN (n=269) %< /p>
|
Placebo (n=230) %< /p>
|
|
BODYAS AWHOLE
|
|
Headache
|
10
|
8
|
|
Abdominal Pain
|
6
|
3
|
|
Flu Syndrome
|
4
|
3
|
|
DIGESTIVE
|
|
Anorexia
|
13
|
6
|
|
Nausea
|
9
|
6
|
|
Diarrhea
|
5
|
2
|
|
Dyspepsia
|
3
|
1
|
|
Constipation
|
2
|
1
|
|
Dry Mouth
|
2
|
1
|
|
HEMATOLOGIC AND LYMPHATIC
|
|
Ecchymosis
|
2
|
1
|
|
METABOLIC AND NUTRITIONAL
|
|
Weight Loss
|
3
|
2
|
|
NERVOUS SYSTEM
|
|
Dizziness
|
13
|
7
|
|
Ataxia
|
6
|
1
|
|
Nystagmus
|
4
|
2
|
|
Paresthesia
|
4
|
1
|
|
NEUROPSYCHIATRIC AND COGNITIVE DYSFUNCTION- ALTERED COGNITIVE FUNCTION
|
|
Confusion
|
6
|
3
|
|
Difficulty Concentrating
|
6
|
2
|
|
Difficulty with Memory
|
6
|
2
|
| Mental Slowing |
4 |
2 |
| NEUROPSYCHIATRIC AND COGNITIVE DYSFUNCTION-EHAVIORALABNORMALITIES
(NON-PSYCHOSIS- RELATED) |
| Agitation/Irritability |
9
|
4
|
| Depression |
6
|
3
|
| Insomnia |
6
|
3
|
| Anxiety |
3
|
2
|
| Nervousness |
2
|
1
|
| NEUROPSYCHIATRIC AND COGNITIVE
DYSFUNCTION BEHAVIORALABNOR-MALITIES (PSYCHOSIS-RELATED) |
| Schizophrenic/Schizophreniform
Behavior |
2 |
0 |
| NEUROPSYCHIATRIC AND COGNITIVE
DYSFUNCTION- CNS DEPRESSION |
| Somnolence |
17 |
7 |
| Fatigue |
8 |
6 |
| Tiredness |
7 |
5 |
| NEUROPSYCHIATRIC AND COGNITIVE
DYSFUNCTION- SPEECH AND LANGUAGE ABNORMALITIES |
| Speech Abnormalities |
5
|
|
| Difficulties in Verbal |
2
|
2<1
|
| Expression |
|
|
| RESPIRATORY |
| Rhinitis |
2
|
1
|
| SKIN AND APPENDAGES |
| Rash |
3
|
2
|
| SPECIAL SENSES |
| Diplopia |
6
|
3
|
|
Taste Perversion
|
2
|
0
|
Other Adverse Events Observed During Clinical Trials:
ZONEGRAN has been administered to 1,598 individuals during
all clinical trials, only some of which were placebo-controlled. During
these trials, all events were recorded by the investigators using their
own terms. To provide a useful estimate of the proportion of individuals
having adverse events, similar events have been grouped into a smaller
number of standardized categories using a modified COSTARTdictionary.
The frequencies represent the proportion of the 1,598 individuals exposed
to ZONEGRAN who experienced an event on at least one occasion. All events
are included except those already listed in the previous table or discussed
in WARNINGS or PRECAUTIONS,
trivial events, those too general to be informative, and those not reasonably
associated with ZONEGRAN.
Events further classified within each category and listed
in order of decreasing frequency as follows: frequent occurring in at
least 1:100 patient; infrequent occurring in 1:100 to 1:1000 patients;
rare occurring in fewer than 1:1000 patients.
Body as a Whole: Frequent: Accidental injury,
asthenia. Infrequent: Chest pain, flank pain, malaise, allergic reaction,
face edema, neck rigidity. Rare: Lupus erythematosus.
Cardiovascular: Infrequent: Palpitation,
tachycardia, vascular insufficiency, hypotension, hypertension, thrombophlebitis,
syncope, bradycardia. Rare: Atrial fibrillation, heart failure, pulmonary
embolus, ventricular extrasystoles.
Digestive: Frequent: Vomiting. Infrequent:
Flatulence, gingivitis, gum hyperplasia, gastritis, gastroenteritis, stomatitis,
cholelithiasis, glossitis, melena, rectal hemorrhage, ulcerative stomatitis,
gastro-duodenal ulcer, dysphagia, gum hemorrhage. Rare: Cholangitis, hematemesis,
cholecystitis, cholestatic jaundice, colitis, duodenitis, esophagitis,
fecal incontinence, mouth ulceration.
Hematologic and Lymphatic: Infrequent:
Leukopenia, anemia, immunodeficiency, lymphadenopathy. Rare: Thrombocytopenia,
microcytic anemia, petechia.
Metabolic and Nutritional: Infrequent:
Peripheral edema, weight gain, edema, thirst, dehydration. Rare: Hypoglycemia,
hyponatremia, lactic dehydrogenase increased, SGOT increased, SGPT increased.
Musculoskeletal: Infrequent: Leg cramps,
myalgia, myasthenia, arthralgia, arthritis.
Nervous System: Frequent: Tremor, convulsion,
abnormal gait, hyperesthesia, incoordination. Infrequent: Hypertonia,
twitching, abnormal dreams, vertigo, libido decreased, neuropathy, hyperkinesia,
movement disorder, dysarthria, cerebrovascular accident, hypotonia, peripheral
neuritis, parathesia, reflexes increased. Rare: Circumoral paresthesia,
dyskinesia, dystonia, encephalopathy, facial paralysis, hypokinesia, hyperesthesia,
myoclonus, oculogyric crisis.
Behavioral Abnormalities - Non-Psychosis-Related:
Infrequent: Euphoria.
Respiratory: Frequent: Pharyngitis, cough
increased. Infrequent: Dyspnea. Rare: Apnea, hemoptysis.
Skin and Appendages: Frequent: Pruritus.
Infrequent:
Maculopapular rash, acne, alopecia, dry skin, sweating,
eczema, urticaria, hirsutism, pustular rash, vesiculobullous rash.
Special Senses: Frequent: Amblyopia, tinnitus.
Infrequent: Conjuctivitis, parosmia, deafness, visual field defect, glaucoma.
Rare: Photophobia, iritis.
Urogenital: Infrequent: Urinary frequency,
dysuria, urinary incontinence, hematura, impotence, urinary retention,
urinary urgency, amenorrhea, polyuria, nocturia. Rare: Albuninuria, enuresis,
bladder pain, bladder calculus, gynocomastia, mastitis, menorrhagia.
DRUG ABUSE AND DEPENDENCE
The abuse and dependence potential of ZONEGRAN has not
been evaluated in human studies (see WARNINGS,
Cognitive/Neuropsychiatric Adverse Events subsection). In a series
of animal studies, zonisamide did not demonstrate abuse liability and
dependence potential. Monkeys did not self-administer zonisamide in a
standard reinforcing paradigm. Rats exposed to zonisamide did not exhibit
signs of physical dependence of the CNS-depressant type. Rats did not
generalize the effects of diazepam to zonisamide in a standard discrimination
paradigm after training, suggesting that zonisamide does not have abuse
potential of the benzodiazepine-CNS depressant type.
DRUG INTERACTIONS
Effects of ZONEGRAN on the pharmacokinetics of other
antiepilepsy drugs (AEDs): Zonisamide had no appreciable effect on the
steady state plasma concentrations of phenytoin, carbamazepine, or valproate
during clinical trials. Zonisamide did not inhibit mixed-function liver
oxidase enzymes (cytochrome P450), as measured in human liver microsomal
preparations, in vitro. Zonisamide is not expected to interfere with the
metabolism of other drugs that are metabolized by cytochrome P450 isozymes.
Effects of other drugs on ZONEGRAN pharmacokinetics:
Drugs that induce liver enzymes increase the metabolism
and clearance of zonisamide and decrease its half-life. The half-life
of zonisamide following a 400 mg dose in patients concurrently on enzyme-inducing
AEDs such as phenytoin, carbamazepine, or phenobarbital was between 27-38
hours; the half-life of zonisamide in patients concurrently on the non-enzyme
inducing AED, valproate, was 46 hours. Concurrent medication with drugs
that either induce or inhibit CYP3A4 would be expected to alter serum
concentrations of zonisamide.
Interaction with cimetidine: Zonisamide single dose pharmacokinetic
parameters were not affected by cimetidine (300 mg four times a day for
12 days).
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