ZONEGRAN® (zonisamide) capsules
`
`DESCRIPTION
`
`ZONEGRAN® (zonisamide) is an antiseizure drug chemically classified as a sulfonamide
`and unrelated to other antiseizure agents. The active ingredient is zonisamide, 1,2­
`benzisoxazole-3-methanesulfonamide. The empirical formula is C8H8N2O3S with a
`molecular weight of 212.23. Zonisamide is a white powder, pKa = 10.2, and is moderately
`soluble in water (0.80 mg/mL) and 0.1 N HCl (0.50 mg/mL).
`
`
`
`The chemical structure is:
`
`Rx Only
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`
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`ZONEGRAN is supplied for oral administration as capsules containing 25 mg or 100 mg
`zonisamide. Each capsule contains the labeled amount of zonisamide plus the following
`inactive ingredients: microcrystalline cellulose, hydrogenated vegetable oil, sodium lauryl
`sulfate, gelatin, and colorants.
`
`
`
`CLINICAL PHARMACOLOGY
`
`
`
`Mechanism of Action: The precise mechanism(s) by which zonisamide exerts its antiseizure
`effect is unknown. Zonisamide demonstrated anticonvulsant activity in several experimental
`models. In animals, zonisamide was effective against tonic extension seizures induced by
`maximal electroshock but ineffective against clonic seizures induced by subcutaneous
`pentylenetetrazol. Zonisamide raised the threshold for generalized seizures in the kindled rat
`model and reduced the duration of cortical focal seizures induced by electrical stimulation of
`the visual cortex in cats. Furthermore, zonisamide suppressed both interictal spikes and the
`secondarily generalized seizures produced by cortical application of tungstic acid gel in rats
`or by cortical freezing in cats. The relevance of these models to human epilepsy is unknown.
`
`Zonisamide may produce these effects through action at sodium and calcium channels. In
`vitro pharmacological studies suggest that zonisamide blocks sodium channels and reduces
`voltage-dependent, transient inward currents (T-type Ca2+ currents), consequently stabilizing
`neuronal membranes and suppressing neuronal hypersynchronization. In vitro binding
`studies have demonstrated that zonisamide binds to the GABA/benzodiazepine receptor
`ionophore complex in an allosteric fashion which does not produce changes in chloride flux.
`Other in vitro studies have demonstrated that zonisamide (10–30 µg/mL) suppresses
`synaptically-driven electrical activity without affecting postsynaptic GABA or glutamate
`responses (cultured mouse spinal cord neurons) or neuronal or glial uptake of [3H]-GABA
`(rat hippocampal slices). Thus, zonisamide does not appear to potentiate the synaptic activity
`of GABA. In vivo microdialysis studies demonstrated that zonisamide facilitates both
`dopaminergic and serotonergic neurotransmission. Zonisamide also has weak carbonic
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`ARGENTUM Exhibit 1207
`Argentum Pharmaceuticals LLC v. Research Corporation Technologies, inc.
`IPR2016-00204
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`anhydrase inhibiting activity, but this pharmacologic effect is not thought to be a major
`contributing factor in the antiseizure activity of zonisamide.
`
` Pharmacokinetics: Following a 200–400 mg oral zonisamide dose, peak plasma
`
`concentrations (range: 2–5 µg/mL) in normal volunteers occur within 2–6 hours. In the
`presence of food, the time to maximum concentration is delayed, occurring at 4–6 hours, but
`food has no effect on the bioavailability of zonisamide. Zonisamide extensively binds to
`erythrocytes, resulting in an eight-fold higher concentration of zonisamide in red blood cells
`(RBC) than in plasma. The pharmacokinetics of zonisamide are dose proportional in the
`range of 200–400 mg, but the Cmax and AUC increase disproportionately at 800 mg, perhaps
`due to saturable binding of zonisamide to RBC. Once a stable dose is reached, steady state is
`achieved within 14 days. The elimination half-life of zonisamide in plasma is about 63 hours.
`The elimination half-life of zonisamide in RBC is approximately 105 hours.
`
`The apparent volume of distribution (V/F) of zonisamide is about 1.45 L/kg following a
`400 mg oral dose. Zonisamide, at concentrations of 1.0–7.0 µg/mL, is approximately 40%
`bound to human plasma proteins. Protein binding of zonisamide is unaffected in the presence
`of therapeutic concentrations of phenytoin, phenobarbital or carbamazepine.
`
`Metabolism and Excretion: Following oral administration of 14C-zonisamide to healthy
`volunteers, only zonisamide was detected in plasma. Zonisamide is excreted primarily in
`urine as parent drug and as the glucuronide of a metabolite. Following multiple dosing, 62%
`of the 14C dose was recovered in the urine, with 3% in the feces by day 10. Zonisamide
`undergoes acetylation to form N-acetyl zonisamide and reduction to form the open ring
`metabolite, 2–sulfamoylacetyl phenol (SMAP). Of the excreted dose, 35% was recovered as
`zonisamide, 15% as N-acetyl zonisamide, and 50% as the glucuronide of SMAP. Reduction
`of zonisamide to SMAP is mediated by cytochrome P450 isozyme 3A4 (CYP3A4).
`Zonisamide does not induce its own metabolism. Plasma clearance of zonisamide is
`approximately 0.30–0.35 mL/min/kg in patients not receiving enzyme-inducing antiepilepsy
`drugs (AEDs). The clearance of zonisamide is increased to 0.5 mL/min/kg in patients
`concurrently on enzyme-inducing AEDs.
`
`Renal clearance is about 3.5 mL/min. The clearance of an oral dose of zonisamide from RBC
`is 2 mL/min.
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`
`
`Special Populations:
`
`Renal Insufficiency: Single 300 mg zonisamide doses were administered to three
`groups of volunteers. Group 1 was a healthy group with a creatinine clearance ranging
`
`from 70–152 mL/min. Group 2 and Group 3 had creatinine clearances ranging from
`14.5–59 mL/min and 10–20 mL/min, respectively. Zonisamide renal clearance
`decreased with decreasing renal function (3.42, 2.50, 2.23 mL/min, respectively).
`Marked renal impairment (creatinine clearance < 20 mL/min) was associated with an
`increase in zonisamide AUC of 35% (see DOSAGE AND ADMINISTRATION
`
`section).
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`Interactions of Zonisamide with Other Antiepilepsy Drugs (AEDs):
`Concurrent medication with drugs that either induce or inhibit CYP3A4 may alter
`serum concentrations of zonisamide. Concomitant administration of phenytoin and
`carbamazepine increases zonisamide plasma clearance from 0.30-0.35 mL/min/kg to
`0.35–0.5 mL/min/kg. The half-life of zonisamide is decreased to 27 hours by
`phenytoin, to 38 hours by phenobarbital and carbamazepine, and to 46 hours by
`valproate. Plasma protein binding of phenytoin and carbamazepine was not affected by
`zonisamide administration (see PRECAUTIONS, Drug Interactions subsection).
`
`
`Clinical Studies: The effectiveness of ZONEGRAN as adjunctive therapy (added to other
`antiepilepsy drugs) has been established in three multicenter, placebo-controlled, double
`blind, 3-month clinical trials (two domestic, one European) in 499 patients with refractory
`partial onset seizures with or without secondary generalization. Each patient had a history of
`at least four partial onset seizures per month in spite of receiving one or two antiepilepsy
`drugs at therapeutic concentrations. The 499 patients (209 women, 290 men) ranged in age
`from 13–68 years with a mean age of about 35 years. In the two US studies, over 80% of
`patients were Caucasian; 100% of patients in the European study were Caucasian.
`ZONEGRAN or placebo was added to the existing therapy. The primary measure of
`effectiveness was median percent reduction from baseline in partial seizure frequency. The
`secondary measure was proportion of patients achieving a 50% or greater seizure reduction
`from baseline (responders). The results described below are for all partial seizures in the
`intent-to-treat populations.
`
`In the first study (n = 203), all patients had a 1-month baseline observation period, then
`received placebo or ZONEGRAN in one of two dose escalation regimens; either 1)
`100 mg/day for five weeks, 200 mg/day for one week, 300 mg/day for one week, and then
`400 mg/day for five weeks; or 2) 100 mg/day for one week, followed by 200 mg/day for five
`weeks, then 300 mg/day for one week, then 400 mg/day for five weeks. This design allowed
`a 100 mg vs. placebo comparison over weeks 1–5, and a 200 mg vs. placebo comparison
`over weeks 2–6; the primary comparison was 400 mg (both escalation groups combined) vs.
`placebo over weeks 8–12. The total daily dose was given as twice a day dosing. Statistically
`significant treatment differences favoring ZONEGRAN were seen for doses of 100, 200, and
`400 mg/day.
`
`In the second (n = 152) and third (n = 138) studies, patients had a 2–3 month baseline, then
`were randomly assigned to placebo or ZONEGRAN for three months. ZONEGRAN was
`introduced by administering 100 mg/day for the first week, 200 mg/day the second week,
`then 400 mg/day for two weeks, after which the dose (ZONEGRAN or placebo) could be
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`Hepatic Disease: The pharmacokinetics of zonisamide in patients with impaired liver
`function have not been studied (see DOSAGE AND ADMINISTRATION section).
`
`Age: The pharmacokinetics of a 300 mg single dose of zonisamide was similar in
`young (mean age 28 years) and elderly subjects (mean age 69 years).
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`Gender and Race: Information on the effect of gender and race on the
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`pharmacokinetics of zonisamide is not available.
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`Table 1.
`
`Study
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`adjusted as necessary to a maximum dose of 20 mg/kg/day or a maximum plasma level of 40
`µg/mL. In the second study, the total daily dose was given as twice a day dosing; in the third
`study, it was given as a single daily dose. The average final maintenance doses received in
`the studies were 530 and 430 mg/day in the second and third studies, respectively. Both
`studies demonstrated statistically significant differences favoring ZONEGRAN for doses of
`400–600 mg/day, and there was no apparent difference between once daily and twice daily
`dosing (in different studies). Analysis of the data (first 4 weeks) during titration
`demonstrated statistically significant differences favoring ZONEGRAN at doses between
`100 and 400 mg/day. The primary comparison in both trials was for any dose over Weeks 5–
`12.
`
`Median % Reduction in All Partial Seizures and % Responders in
`Primary Efficacy Analyses: Intent-To-Treat Analysis
`
`Median % reduction
`in partial seizures
`
`
`% Responders
`
`
`
`
`ZONEGRAN
`Study 1:
`n=98
`Weeks 8-12:
`40.5%*
`
`
`Study 2:
`n=69
`Weeks 5-12:
`29.6%*
`
`
`Study 3:
`n=67
`Weeks 5-12:
`27.2%*
`* p<0.05 compared to placebo
`
`
`Placebo
`n=72
`9.0%
`
`n=72
`-3.2%
`
`n=66
`-1.1%
`
`ZONEGRAN
`n=98
`41.8%*
`
`n=69
`29.0%
`
`n=67
`28.0%*
`
`Placebo
`n=72
`22.2%
`
`n=72
`15.0%
`
`n=66
`12.0%
`
`
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`Table 2.
`
`Median % Reduction in All Partial Seizures and % Responders for
`Dose Analyses in Study 1: Intent-To-Treat Analysis
`
`Dose Group
`
`Median % reduction
`in partial seizures
`
`
`
`ZONEGRAN
`Placebo
`100-400 mg/day:
`n=112
`n=83
`Weeks 1-12:
`32.3%*
`5.6%
`
`
`
`100 mg/day:
`n=56
`n=80
`Weeks 1-5:
`24.7%*
`8.3%
`
`
`
`200 mg/day:
`n=55
`n=82
`Weeks 2-6:
`20.4%*
`4.0%
`* p<0.05 compared to placebo
`
`
`% Responders
`
`
`
`ZONEGRAN
`n=112
`32.1%*
`
`n=56
`25.0%*
`
`n=55
`25.5%*
`
`
`Placebo
`n=83
`9.6%
`
`n=80
`11.3%
`
`n=82
`9.8%
`
`
`Figure 1 presents the proportion of patients (X-axis) whose percentage reduction from
`
`baseline in the all partial seizure rate was at least as great as that indicated on the Y-axis in
`the second and third placebo-controlled trials. A positive value on the Y-axis indicates an
`improvement from baseline (i.e., a decrease in seizure rate), while a negative value indicates
`a worsening from baseline (i.e., an increase in seizure rate). Thus, in a display of this type,
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`Figure 1
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`the curve for an effective treatment is shifted to the left of the curve for placebo. The
`proportion of patients achieving any particular level of reduction in seizure rate was
`consistently higher for the ZONEGRAN groups compared to the placebo groups. For
`example, Figure 1 indicates that approximately 27% of patients treated with ZONEGRAN
`experienced a 75% or greater reduction, compared to approximately 12% in the placebo
`groups.
`
`Proportion of Patients Achieving Differing Levels of Seizure
`Reduction in ZONEGRAN and Placebo Groups in Studies 2 and 3
`
`
`
`
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`No differences in efficacy based on age, sex or race, as measured by a change in seizure
`frequency from baseline, were detected.
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`INDICATIONS AND USAGE
`
`ZONEGRAN is indicated as adjunctive therapy in the treatment of partial seizures in adults
`with epilepsy.
`
`CONTRAINDICATIONS
`
`ZONEGRAN is contraindicated in patients who have demonstrated hypersensitivity to
`sulfonamides or zonisamide.
`
`WARNINGS
`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.
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`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.
`
`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 oligohidrosis 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 underestimates 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
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`temperatures. Heat stroke, requiring hospitalization, was diagnosed in some cases.
`There have been no reported deaths.
`
`Pediatric patients appear to be at an increased risk for zonisamide-associated
`oligohidrosis 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 should be aware that the safety and effectiveness of zonisamide in
`pediatric patients have not been established, and that zonisamide is not approved for
`use in pediatric patients.
`
`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.
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`Table 3 shows absolute and relative risk by indication for all evaluated AEDs.
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`Table 3: Risk by indication for antiepileptic drugs in the pooled analysis
`Indication
`Placebo Patients
`Drug Patients
`Relative Risk:
`Risk Difference:
`with Events
`with Events Per
`Incidence of
`Additional Drug
`Per 1000 Patients
`1000 Patients
`Events in Drug
`Patients with
`Patients/Incidence Events Per 1000
`in Placebo Patients
`Patients
`
` Epilepsy
`
`Psychiatric
`
`Other
`
`Total
`
`
`1.0
`5.7
`1.0
`2.4
`
`3.4
`8.5
`1.8
`4.3
`
`3.5
`1.5
`1.9
`1.8
`
`2.4
`2.9
`0.9
`1.9
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`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).
`
`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.
`
`Teratogenicity: 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). It
`
`cannot be said with any confidence, however, that even mild seizures do not pose some
`hazards to the developing fetus. Zonisamide should be used during pregnancy only if the
`potential benefit justifies the potential risk to the fetus.
`
`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
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`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 should be cautioned
`about this possibility and special care should be taken by patients if they drive, operate
`machinery, or perform any hazardous task.
`
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`PRECAUTIONS
`
`General: Somnolence is commonly reported, especially at higher doses of ZONEGRAN (see
`WARNINGS: Cognitive/ Neuropsychiatric Adverse Events subsection). Zonisamide is
`metabolized by the liver and eliminated by the kidneys; caution should therefore be exercised
`when administering ZONEGRAN to patients with hepatic and renal dysfunction (see
`CLINICAL PHARMACOLOGY, Special Populations subsection).
`
`Kidney Stones: Among 991 patients treated during the development of ZONEGRAN, 40
`patients (4.0%) with epilepsy receiving ZONEGRAN developed clinically possible or
`confirmed kidney stones (e.g. clinical symptomatology, sonography, etc.), a rate of 34 per
`1000 patient-years of exposure (40 patients with 1168 years of exposure). Of these, 12 were
`symptomatic, and 28 were described as possible kidney stones based on sonographic
`detection. In nine patients, the diagnosis was confirmed by a passage of a stone or by a
`definitive sonographic finding. The rate of occurrence of kidney stones was 28.7 per 1000
`patient-years of exposure in the first six months, 62.6 per 1000 patient-years of exposure
`between 6 and 12 months, and 24.3 per 1000 patient-years of exposure after 12 months of
`use. There are no normative sonographic data available for either the general population or
`patients with epilepsy. The clinical significance of the sonographic finding is unknown. The
`analyzed stones were composed of calcium or urate salts. In general, increasing fluid intake
`and urine output can help reduce the risk of stone formation, particularly in those with
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`predisposing risk factors. It is unknown, however, whether these measures will reduce the
`risk of stone formation in patients treated with ZONEGRAN.
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`Effect on Renal Function: In several clinical studies, zonisamide was associated with a
`statistically significant 8% mean increase from baseline of serum creatinine and blood urea
`nitrogen (BUN) compared to essentially no change in the placebo patients. The increase
`appeared to persist over time but was not progressive; this has been interpreted as an effect
`on glomerular filtration rate (GFR). There were no episodes of unexplained acute renal
`failure in clinical development in the US, Europe, or Japan. The decrease in GFR appeared
`within the first 4 weeks of treatment. In a 30-day study, the GFR returned to baseline within
`2–3 weeks of drug discontinuation. There is no information about reversibility, after drug
`discontinuation, of the effects on GFR after long-term use. ZONEGRAN should be
`discontinued in patients who develop acute renal failure or a clinically significant sustained
`increase in the creatinine/BUN concentration. ZONEGRAN should not be used in patients
`with renal failure (estimated GFR < 50 mL/min) as there has been insufficient experience
`concerning drug dosing and toxicity.
`
`Sudden Unexplained Death in Epilepsy: During the development of ZONEGRAN, nine
`sudden unexplained deaths occurred among 991 patients with epilepsy receiving
`ZONEGRAN for whom accurate exposure data are available. This represents an incidence of
`7.7 deaths per 1000 patient years. Although this rate exceeds that expected in a healthy
`population, it is within the range of estimates for the incidence of sudden unexplained deaths
`in patients with refractory epilepsy not receiving ZONEGRAN (ranging from 0.5 per 1000
`patient-years for the general population of patients with epilepsy, to 2–5 per 1000 patient-
`years for patients with refractory epilepsy; higher incidences range from 9–15 per 1000
`patient-years among surgical candidates and surgical failures). Some of the deaths could
`represent seizure-related deaths in which the seizure was not observed.
`
`Status Epilepticus: Estimates of the incidence of treatment emergent status epilepticus in
`ZONEGRAN-treated patients are difficult because a standard definition was not employed.
`Nonetheless, in controlled trials, 1.1% of patients treated with ZONEGRAN had an event
`labeled as status epilepticus compared to none of the patients treated with placebo. Among
`patients treated with ZONEGRAN across all epilepsy studies (controlled and uncontrolled),
`1.0% of patients had an event reported as status epilepticus.
`
`Information for Patients: Patients should be informed of the availability of a Medication
`Guide, and they should be instructed to read the Medication Guide prior to taking Zonegran.
`Patients should be instructed to take Zonegran only as prescribed.
`
`Patients should be advised as follows: (See Medication Guide)
`
`
`
`
`
`
`1. ZONEGRAN may produce drowsiness, especially at higher doses. Patients should be
`advised not to drive a car or operate other complex machinery until they have
`gained experience on ZONEGRAN sufficient to determine whether it affects their
`performance.
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`2. Patients should contact their physician immediately if a skin rash develops or seizures
`worsen.
`
`
`3. Patients should contact their physician immediately if they develop signs or symptoms,
`such as sudden back pain, abdominal pain, and/or blood in the urine, that could indicate a
`kidney stone. Increasing fluid intake and urine output may reduce the risk of stone
`formation, particularly in those with predisposing risk factors for stones.
`
`4. Patients should contact their physician immediately if a child has been taking
`ZONEGRAN and is not sweating as usual with or without a fever.
`
`5. Because zonisamide can cause hematological complications, patients should contact their
`physician immediately if they develop a fever, sore throat, oral ulcers, or easy bruising.
`
`
`
`6. Suicidal Thinking and Behavior - Patients, their caregivers, and families should be
`counseled that AEDs, including Zonegran, may increase the risk of suicidal thoughts and
`behavior and should be advised of the need to be alert for the emergence or worsening of
`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.
`
`
`7. As with other AEDs, patients should contact their physician if they intend to become
`pregnant or are pregnant during ZONEGRAN therapy. Patients should notify their
`physician if they intend to breast-feed or are breast-feeding an infant.
`
`Patients should be encouraged to enroll in the North American Antiepileptic Drug
`(NAAED) Pregnancy Registry if they become pregnant. This registry is collecting
`information about the safety of antiepileptic drugs during pregnancy. To enroll, patients
`can call the toll free number 1-888-233-2334 (see PRECAUTIONS, Pregnancy
`subsection).
`
`
`8. Patients should contact their physician immediately if they develop severe muscle pain
`and/or weakness.
`
`
`Laboratory Tests: In several clinical studies, zonisamide was associated with a mean
`increase in the concentration of serum creatinine and blood urea nitrogen (BUN) of
`approximately 8% over the baseline measurement. Consideration should be given to
`monitoring renal function periodically (see PRECAUTIONS, Effect on Renal Function
`
`subsection).
`
`Zonisamide was associated with an increase in serum alkaline phosphatase. In the
`randomized, controlled trials, a mean increase of approximately 7% over baseline was
`associated with zonisamide compared to a 3% mean increase in placebo-treated patients.
`These changes were not statistically significant. The clinical relevance of these changes is
`unknown.
`
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`Revised April 2009
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