Potentially Fatal Reactions to Sulfonamides: Fatalities have occurred, although rarely, as a result of severe
reactions to sulfonamides (zonisamide is a sulfonamide) including Stevens-Johnson syndrome, toxic
epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood
dyscrasias. Such reactions may occur when a sulfonamide is readministered irrespective of the route of
administration. If signs of hypersensitivity or other serious reactions occur, discontinue zonisamide
immediately. Specific experience with sulfonamide-type adverse reaction to zonisamide is described below.
Serious Skin Reactions: Consideration should be given to discontinuing ZONEGRAN in patients
who develop an otherwise unexplained rash. If the drug is not discontinued, patients should be
observed frequently. Seven deaths from severe rash [i.e. Stevens-Johnson syndrome (SJS) and toxic
epidermal necrolysis (TEN)] were reported in the first 11 years of marketing in Japan. All of the
patients were receiving other drugs in addition to zonisamide. In post-marketing experience from Japan,
a total of 49 cases of SJS or TEN have been reported, a reporting rate of 46 per million patient-years
of exposure. Although this rate is greater than background, it is probably an underestimate of the true
incidence because of under-reporting. There were no confirmed cases of SJS or TEN in the US,
European, or Japanese development programs.
In the US and European randomized controlled trials, 6 of 269 (2.2%) zonisamide patients discontinued
treatment because of rash compared to none on placebo. Across all trials during the US and European
development, rash that led to discontinuation of zonisamide was reported in 1.4% of patients (12.0
events per 1000 patient-years of exposure). During Japanese development, serious rash or rash that led
to study drug discontinuation was reported in 2.0% of patients (27.8 events per 1000 patient-years).
Rash usually occurred early in treatment, with 85% reported within 16 weeks in the US and European
studies and 90% reported within two weeks in the Japanese studies. There was no apparent relationship
of dose to the occurrence of rash.
Serious Hematologic Events
Two confirmed cases of aplastic anemia and one confirmed case of
agranulocytosis were reported in the first 11 years of marketing in Japan, rates greater than generally
accepted background rates. There were no cases of aplastic anemia and two confirmed cases of
agranulocytosis in the US, European, or Japanese development programs. There is inadequate
information to assess the relationship, if any, between dose and duration of treatment and these events.
Drug Reaction With Eosinophilia And Systemic Symptoms (DRESS)/Multi-Organ
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as
multi-organ hypersensitivity, has occurred with ZONEGRAN. Some of these events have been fatal or
life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy
and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis,
hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection.
Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not
noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g.,
fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are
present, the patient should be evaluated immediately. ZONEGRAN should be discontinued if an
alternative etiology for the signs or symptoms cannot be established.
Oligohidrosis And Hyperthermia In Pediatric Patients
Oligohidrosis, sometimes resulting in heat stroke and hospitalization, is seen in association with
zonisamide in pediatric patients .
During the pre-approval development program in Japan, one case of oligohidros is was reported
in 403 pediatric patients, an incidence of 1 case per 285 patient-years of exposure. While there
were no cases reported in the US or European development programs, fewer than 100 pediatric
patients participated in these trials.
In the first 11 years of marketing in Japan, 38 cases were reported, an estimated reporting rate of
about 1 case per 10,000 patient-years of exposure. In the first year of marketing in the US, 2
cases were reported, an estimated reporting rate of about 12 cases per 10,000 patient-years of
exposure. These rates are underes timates of the true incidence because of under-reporting.
There has also been one report of heat stroke in an 18-year-old patient in the US.
Decreased sweating and an elevation in body temperature above normal characterized these
cases. Many cases were reported after exposure to elevated environmental temperatures. Heat
stroke, requiring hos pitalization, was diagnosed in some cases. There have been no reported
Pediatric patients appear to be at an increased risk for zonisamide-associated oligohidros is and
hyperthermia. Patients, especially pediatric patients, treated with ZONEGRAN should be
monitored closely for evidence of decreased sweating and increased body temperature,
especially in warm or hot weather. Caution should be used when zonisamide is prescribed with
other drugs that predispose patients to heat-related disorders; these drugs include, but are not
limited to, carbonic anhydrase inhibitors and drugs with anticholinergic activity.
The practitioner s hould be aware that the s afety and effectivenes s of zonisamide in pediatric
patients have not been es tablis hed, and that zonisamide is not approved for us e in pediatric
Suicidal Behavior And Ideation
Antiepileptic drugs (AEDs), including ZONEGRAN, increase the risk of suicidal thoughts or behavior
in patients taking these drugs for any indication. Patients treated with any AED for any indication should
be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any
unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different
AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted
Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to
placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate
of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24%
among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal
thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in
the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about
drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week
after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because
most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or
behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.
The finding of increased risk with AEDs of varying mechanisms of action and across a range of
indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary
substantially by age (5-100 years) in the clinical trials analyzed.
Table 3 shows absolute and relative risk by indication for all evaluated AEDs.
Table 3. Risk by Indication for Antiepileptic Drugs in the Pooled
Events in Drug
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the
epilepsy and psychiatric indications.
Anyone considering prescribing ZONEGRAN or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which
AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of
suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the
prescriber needs to consider whether the emergence of these symptoms in any given patient may be
related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of
the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of
suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported
immediately to healthcare providers (see WARNINGS, Cognitive/Neuropsychiatric Adverse Events subsection below).
Zonisamide causes hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum
bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) (see PRECAUTIONS, Laboratory Tests subsection). This metabolic acidosis is caused by renal
bicarbonate loss due to the inhibitory effect of zonisamide on carbonic anhydrase. Generally,
zonisamide-induced metabolic acidosis occurs early in treatment, but it can develop at any time during
treatment. Metabolic acidosis generally appears to be dose-dependent and can occur at doses as low as
25 mg daily.
Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders,
status epilepticus, diarrhea, ketogenic diet, or specific drugs) may be additive to the bicarbonate
lowering effects of zonisamide.
Some manifestations of acute or chronic metabolic acidosis include hyperventilation, nonspecific
symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or
stupor. Chronic, untreated, metabolic acidosis may increase the risk for nephrolithiasis or
nephrocalcinosis. Nephrolithiasis has been observed in the clinical development program in 4% of
adults treated with ZONEGRAN, has also been detected by renal ultrasound in 8% of pediatric treated
patients who had at least one ultrasound prospectively collected, and was reported as an adverse event
in 3% (4/133) of pediatric patients (see PRECAUTIONS, Kidney Stones subsection).
Chronic, untreated metabolic acidosis may result in osteomalacia (referred to as rickets in pediatric
patients) and/or osteoporosis with an increased risk for fracture. Of potential relevance, zonisamide
treatment was associated with reductions in serum phosphorus and increases in serum alkaline
phosphatase, changes that may be related to metabolic acidosis and osteomalacia (see PRECAUTIONS, Laboratory Tests subsection).
Chronic, untreated metabolic acidosis in pediatric patients may reduce growth rates. A reduction in
growth rate may eventually decrease the maximal height achieved. The effect of zonisamide on growth
and bone-related sequelae has not been systematically investigated.
Measurement of baseline and periodic serum bicarbonate during treatment is recommended. If metabolic
acidosis develops and persists, consideration should be given to reducing the dose or discontinuing
zonisamide (using dose tapering). If the decision is made to continue patients on zonisamide in the face
of persistent acidosis, alkali treatment should be considered.
Serum bicarbonate was not measured in the adjunctive controlled trials of adults with epilepsy.
However, serum bicarbonate was studied in three clinical trials for indications which have not been
approved: a placebo-controlled trial for migraine prophylaxis in adults, a controlled trial for
monotherapy in epilepsy in adults, and an open label trial for adjunctive treatment of epilepsy in pediatric
patients (3-16 years). In adults, mean serum bicarbonate reductions ranged from approximately 2 mEq/L
at daily doses of 100 mg to nearly 4 mEq/L at daily doses of 300 mg. In pediatric patients, mean serum
bicarbonate reductions ranged from approximately 2 mEq/L at daily doses from above 100 mg up to 300
mg, to nearly 4 mEq/L at daily doses from above 400 mg up to 600 mg.
In two controlled studies in adults, the incidence of a persistent treatment-emergent decrease in serum
bicarbonate to less than 20 mEq/L (observed at 2 or more consecutive visits or the final visit) was doserelated
at relatively low zonisamide doses. In the monotherapy trial of epilepsy, the incidence of a
persistent treatment-emergent decrease in serum bicarbonate was 21% for daily zonisamide doses of 25
mg or 100 mg, and was 43% at a daily dose of 300 mg. In a placebo-controlled trial for prophylaxis of
migraine, the incidence of a persistent treatment-emergent decrease in serum bicarbonate was 7% for
placebo, 29% for 150 mg daily, and 34% for 300 mg daily. The incidence of persistent markedly
abnormally low serum bicarbonate (decrease to less than 17 mEq/L and more than 5 mEq/L from a
pretreatment value of at least 20 mEq/L) in these controlled trials was 2% or less.
In the pediatric study, the incidence of persistent, treatment-emergent decreases in serum bicarbonate to
levels less than 20 mEq/L was 52% at doses up to 100 mg daily, was 90% for a wide range of doses up
to 600 mg daily, and generally appeared to increase with higher doses. The incidence of a persistent
markedly abnormally low serum bicarbonate value was 4% at doses up to 100 mg daily, was 18% for a
wide range of doses up to 600 mg daily, and generally appeared to increase with higher doses. Some
patients experienced moderately severe serum bicarbonate decrements down to a level as low as 10
The relatively high frequencies of varying severities of metabolic acidosis observed in this study of
pediatric patients (compared to the frequency and severity observed in various clinical trial
development programs in adults) suggest that pediatric patients may be more likely to develop metabolic
acidosis than adults.
Seizures On Withdrawal
As with other AEDs, abrupt withdrawal of ZONEGRAN in patients with epilepsy may precipitate
increased seizure frequency or status epilepticus. Dose reduction or discontinuation of zonisamide
should be done gradually.
Women of child bearing potential who are given zonisamide should be advised to use effective
contraception. Zonisamide was teratogenic in mice, rats, and dogs and embryolethal in monkeys when
administered during the period of organogenesis. A variety of fetal abnormalities, including
cardiovascular defects, and embryo-fetal deaths occurred at maternal plasma levels similar to or lower
than therapeutic levels in humans. These findings suggest that the use of ZONEGRAN during pregnancy
in humans may present a significant risk to the fetus (see PRECAUTIONS, Pregnancy subsection).
Zonisamide should be used during pregnancy only if the potential benefit justifies the potential risk to
Cognitive/Neuropsychiatric Adverse Events:
Use of ZONEGRAN was frequently associated with central nervous system-related adverse events.
The most significant of these can be classified into three general categories: 1) psychiatric symptoms,
including depression and psychosis, 2) psychomotor slowing, difficulty with concentration, and speech
or language problems, in particular, word-finding difficulties, and 3) somnolence or fatigue.
In placebo-controlled trials, 2.2% of patients discontinued ZONEGRAN or were hospitalized for
depression compared to 0.4% of placebo patients. Among all epilepsy patients treated with
ZONEGRAN, 1.4% were discontinued and 1.0% were hospitalized because of reported depression or
suicide attempts. In placebo-controlled trials, 2.2% of patients discontinued ZONEGRAN or were
hospitalized due to psychosis or psychosis-related symptoms compared to none of the placebo patients.
Among all epilepsy patients treated with ZONEGRAN, 0.9% were discontinued and 1.4% were
hospitalized because of reported psychosis or related symptoms.
Psychomotor slowing and difficulty with concentration occurred in the first month of treatment and were
associated with doses above 300 mg/day. Speech and language problems tended to occur after 6–10
weeks of treatment and at doses above 300 mg/day. Although in most cases these events were of mild to
moderate severity, they at times led to withdrawal from treatment.
Somnolence and fatigue were frequently reported CNS adverse events during clinical trials with
ZONEGRAN. Although in most cases these events were of mild to moderate severity, they led to
withdrawal from treatment in 0.2% of the patients enrolled in controlled trials. Somnolence and fatigue
tended to occur within the first month of treatment. Somnolence and fatigue occurred most frequently at
doses of 300–500 mg/day. Patients s hould be cautioned about this pos s ibility and s pecial care
s hould be taken by patients if they drive, operate machinery, or perform any hazardous tas k.