Zonegran

Before taking zonisamide,

• tell your doctor and pharmacist if you are allergic to zonisamide, diuretics ('water pills'), oral medications for diabetes, sulfa drugs, or any other medications.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, and nutritional supplements you are taking or plan to take. Be sure to mention any of the following: amiodarone (Cordarone, Pacerone);antifungals such as itraconazole (Sporanox) and ketoconazole (Nizoral); carbonic anhydrase inhibitors such as acetazolamide (Diamox) and methazolamide; clarithromycin (Biaxin, in Prevpac); diltiazem (Cardizem, Dilacor, Tiazac); erythromycin (E.E.S., E-Mycin, Erythrocin); fluvoxamine (Luvox); HIV protease inhibitors such as indinavir (Crixivan), nelfinavir (Viracept), and ritonavir (Norvir, in Kaletra); medications for irritable bowel disease, motion sickness, Parkinson's disease, ulcers, or urinary problems; other medications for seizures including carbamazepine (Carbatrol, Epitol, Tegretol),phenobarbital (Luminal, Solfoton), phenytoin (Dilantin, Phenytek),and valproic acid (Depakene, Depakote); nefazodone (Serzone); hormonal contraceptives (birth control pills, patches, rings, and injections); pioglitazone (Actos, in Actoplus, in Duetact); rifabutin (Mycobutin); rifampin (Rifadin, Rimactane); troleandomycin (TAO) (not available in the U.S.); and verapamil (Calan, Covera, Isoptin, Verelan). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor what herbal products you are taking, especially St. John's wort.
• tell your doctor if you are following a ketogenic diet (a high fat, low carbohydrate diet used to control seizures) or if you have or have ever had breathing problems, kidney liver, or lung disease. Also tell your doctor if you have diarrhea now, or if you develop diarrhea at any time during your treatment.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. You should use birth control to prevent pregnancy during your treatment. Talk to your doctor about birth control methods that will work for you. If you become pregnant while taking zonisamide, call your doctor.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking zonisamide.
• you should know that zonisamide may make you drowsy. Do not drive a car, operate machinery, or perform dangerous tasks until you know how this medication affects you.
• you should know that zonisamide can decrease the body's ability to sweat and make it harder for your body to cool down when it gets very hot. This happens most often in warm weather and to children who take zonisamide. (Children should not normally take zonisamide, but in some cases, it may be prescribed by a doctor.) You should avoid exposure to heat and call your doctor right away if you have a fever and/or are not sweating as usual.
• you should know that your mental health may change in unexpected ways and you may become suicidal (thinking about harming or killing yourself or planning or trying to do so) while you are taking zonisamide for the treatment of epilepsy, mental illness, or other conditions. A small number of adults and children 5 years of age and older (about 1 in 500 people) who took anticonvulsants such as zonisamide to treat various conditions during clinical studies became suicidal during their treatment. Some of these people developed suicidal thoughts and behavior as early as 1 week after they started taking the medication. There is a risk that you may experience changes in your mental health if you take an anticonvulsants medication such as zonisamide, but there may also be a risk that you will experience changes in your mental health if your condition is not treated. You and your doctor will decide whether the risks of taking an anticonvulsant medication are greater than the risks of not taking the medication. You, your family, or your caregiver should call your doctor right away if you experience any of the following symptoms: panic attacks; agitation or restlessness; new or worsening irritability, anxiety, or depression; acting on dangerous impulses; difficulty falling or staying asleep; aggressive, angry, or violent behavior; mania (frenzied, abnormally excited mood); talking or thinking about wanting to hurt yourself or end your life; withdrawing from friends and family; preoccupation with death and dying; giving away prized possessions; or any other unusual changes in behavior or mood. Be sure that your family or caregiver knows which symptoms may be serious so they can call the doctor if you are unable to seek treatment on your own.

Talk to your doctor about eating grapefruit and drinking grapefruit juice while taking this medicine.

Drink 6-8 glasses of water every day during your treatment with zonisamide.

Keep all appointments with your doctor and the laboratory. Your doctor may order certain lab tests to check your body's response to zonisamide.

Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

Dosage Forms & Strengths

capsule

• 25mg
• 50mg
• 100mg

Partial Seizures

Initial: 100 mg PO qDay

Titrate up by 100 mg increments q2Week to no more than 600 mg PO qDay (may divide q12hr after 1st week)

Weight Loss (Off-label)

100 mg increments q2Week to no more than 600 mg PO qDay (may divide q12hr after first week); use 600 mg/day in patients who have not lost at least 5% of their initial body weight

Dosing Modifications

Renal impairment: Slower titration and more frequent monitoring advised; not recommended if patient's glomerular filtration rate is less than 50 mL/min

Hepatic impairment: Slower titration and more frequent monitoring advised

Dosage Forms & Strengths

capsule

• 25mg
• 50mg
• 100mg

<16 years

Not recommended

>16 years

Partial seizures

• Same as in adults

Administer as in adults; initiate dosing at the lower end of the dosing range

Zonisamide is a sulfa drug with anti-convulsant effects.

Zonisamide is used together with other anti-convulsant medications to treat partial seizures in adults with epilepsy.

Zonisamide may also be used for purposes not listed in this medication guide.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include slow heart rate, feeling light-headed, fainting, and slow or shallow breathing.

This medication may impair your thinking or reactions. Avoid driving or operating machinery until you know how zonisamide will affect you.

Avoid drinking alcohol. It can increase some of the side effects of zonisamide.

Taking this medicine with other drugs that make you sleepy can worsen this effect. Ask your doctor before taking zonisamide with a sleeping pill, narcotic pain medicine, muscle relaxer, or medicine for anxiety or depression.

Other drugs may interact with zonisamide, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

• Importance of providing copy of written patient information (medication guide) each time zonisamide is dispensed.1 21

• Risk of serious skin rash that can cause death; these skin reactions are more likely to happen within the first 4 months of starting therapy, but may occur later.1 Importance of immediately contacting clinician if skin rash occurs.1

• Importance of patients being aware that zonisamide can prevent sweating, which makes it harder for the body to cool down when it gets very hot; this is more likely to occur in warmer weather, in children, and during physical exercise.1 13 26 Importance of avoiding exposure to heat, maintaining adequate hydration, and informing clinicians immediately if fever or increased body temperature and/or decreased sweating occurs, particularly in children or in hot weather.1 13 26

• Risk of blood cell abnormalities such as reduced RBC and WBC counts.1 Importance of contacting clinician if fever, sore throat, sores in the mouth, or unusual bruising occurs.1

• Risk of suicidality (anticonvulsants, including zonisamide, may increase risk of suicidal thoughts or actions in about 1 in 500 people).1 15 21 Importance of patients, family, and caregivers being alert to day-to-day changes in mood, behavior, and actions and immediately informing clinician of any new or worrisome behaviors (e.g., talking or thinking about wanting to hurt oneself or end one’s life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).1 15

• Importance of patients being aware that zonisamide may cause metabolic acidosis.19 Importance of patients being aware that blood tests to measure serum bicarbonate levels may be performed.19 Symptoms of metabolic acidosis include breathing fast (hyperventilation), fatigue, and loss of appetite; more severe symptoms include an irregular heart beat or unconsciousness.19

• May cause drowsiness, especially at higher dosages.1 Avoid driving or operating machinery while taking zonisamide until experience with the drug’s effects has been established.1

• Risk of kidney stones.1 Importance of informing patients that increasing fluid intake (i.e., by drinking 6–8 glasses of water a day) and urine output may reduce the risk of stone formation, particularly in those with predisposing factors.1 Importance of immediately reporting symptoms of kidney stones (e.g., sudden back pain, abdominal pain, and/or blood in urine) to clinician.1

• Importance of immediately reporting worsening of seizures and severe muscle pain and/or weakness to clinician.1

• Importance of women informing clinicians if they are or plan to become pregnant.1 19 Importance of informing women who are or plan to become pregnant that zonisamide may cause metabolic acidosis, which may negatively affect fetal development during pregnancy.19 Importance of clinicians informing women about the existence of and encouraging enrollment in pregnancy registries (see Pregnancy under Warnings/Precautions: Specific Populations, in Cautions).1

• Importance of informing nursing women and those who plan to breast-feed that zonisamide can appear in the breast milk, and that the effects of this exposure on the infant are unknown.19 Importance of women informing clinicians if they plan to breast-feed.1 19

• Importance of swallowing zonisamide capsules whole and not biting into or breaking into the capsules; zonisamide may be taken with or without food.1

• Importance of informing patients not to stop taking zonisamide without talking to their clinician since stopping the drug suddenly can cause serious problems, including seizures.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription drugs, OTC drugs, and special diets (e.g., ketogenic diet), as well as any concomitant illnesses (e.g., liver disease, kidney disease, severe lung disorders, diarrhea, surgery, depression, bipolar disorder) or family history of suicidality or bipolar disorder.1 13 19

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Discouragement
• feeling sad or empty
• irritability
• lack of appetite
• loss of interest or pleasure
• mood or mental changes
• shakiness or unsteady walking
• tiredness
• trouble with concentrating
• trouble with sleeping

• Agitation
• bruising
• delusions
• hallucinations
• large, flat blue or purplish patches on the skin
• rash

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Abdominal or stomach pain
• anxiety
• difficulty with memory
• dizziness
• double vision
• headache
• loss of appetite
• nausea
• restlessness
• sleepiness
• unusual drowsiness
• unusual tiredness or weakness

• Aching muscles or joints
• acid or sour stomach
• bad, unusual, or unpleasant taste in the mouth
• belching
• change in taste
• chills
• constipation
• diarrhea
• difficulty with speaking
• difficulty with thinking
• dry mouth
• fever
• general ill feeling
• headache
• heartburn
• indigestion
• mental slowness
• nervousness
• runny or stuffy nose
• sneezing
• tingling, burning, or prickly feelings on the skin
• uncontrolled, back and forth, or rolling eye movements
• weight loss

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of too much acid in the blood (acidosis) like confusion; fast breathing; fast heartbeat; a heartbeat the does not feel normal; very bad stomach pain, upset stomach, or throwing up; feeling very sleepy; shortness of breath; or feeling very tired or weak.
• Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
• Very bad dizziness or passing out.
• Change in balance.
• Feeling confused.
• Not sweating during activities or in warm temperatures.
• High fever, fever that goes away and comes back, or long-lasting fever.
• Back pain, belly pain, or blood in the urine. May be signs of a kidney stone.
• If seizures are worse or not the same after starting this medicine.
• Not able to focus.
• Trouble speaking.
• A burning, numbness, or tingling feeling that is not normal.
• Not able to control eye movements.
• Change in eyesight.
• Memory problems or loss.
• Bone pain.
• Very bad muscle pain or weakness.
• Swelling in the arms or legs.
• Shakiness, trouble moving around, or stiffness.
• Patients who take Zonegran (zonisamide) may be at a greater risk of having thoughts or actions of suicide. The risk may be greater in people who have had these thoughts or actions in the past. Call the doctor right away if signs like low mood (depression), nervousness, restlessness, grouchiness, panic attacks, or changes in mood or actions are new or worse. Call the doctor right away if any thoughts or actions of suicide occur.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Feeling sleepy.
• Feeling tired or weak.
• Dizziness.
• Headache.
• Upset stomach.
• Not hungry.
• Loose stools (diarrhea).
• Not able to sleep.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

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 is a carbonic anhydrase inhibitor. The contribution of this pharmacological action to the therapeutic effects of zonisamide is unknown. However, as a carbonic anhydrase inhibitor, zonisamide may cause metabolic acidosis (see WARNINGS, Metabolic Acidosis subsection).

Pharmacokinetics:

Absorption

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 absorption is dose-proportional in the range of 200-400 mg. Cmax and AUC, however, increase disproportionately at 800 mg, possibly due to saturable binding of zonisamide to red blood cells. Once a stable dose is reached, steady state is achieved within 14 days.

Distribution

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. Zonisamide extensively binds to erythrocytes, resulting in an eight-fold higher concentration of zonisamide in red blood cells than in plasma. Protein binding of zonisamide is unaffected in the presence of therapeutic concentrations of phenytoin, phenobarbital or carbamazepine.

Metabolism and Elimination

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 radiolabeled dose was recovered in the urine, with 3% in the feces by day 10. Zonisamide undergoes acetylation by N-acetyl-transferases 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. The plasma clearance of oral 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.

After a single-dose administration, renal clearance of zonisamide is approximately 3.5 mL/min. The clearance of an oral dose of zonisamide from red blood cells is 2 mL/min. The elimination half-life of zonisamide in plasma is approximately 63 hours. The elimination half-life of zonisamide in red blood cells is approximately 105 hours.

Specific Populations:

Renal Impairment: 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).

Hepatic Impairment: 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).

Gender and Race: Information on the effect of gender and race on the pharmacokinetics of zonisamide is not available.

Effects of Zonegran on cytochrome P450 enzymes

In vitro studies using human liver microsomes show insignificant (<25%) inhibition of cytochrome P450 isozymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4, 2B6 or 2C8 at zonisamide levels approximately two-fold or greater than clinically relevant unbound serum concentrations. Therefore Zonegran is not expected to affect the pharmacokinetics of other drugs via cytochrome P450-mediated mechanisms.

Potential for Zonegran to affect other drugs

Anti-epileptic drugs

In epileptic patients, steady state dosing with Zonegran resulted in no clinically relevant pharmacokinetic effects on carbamazepine, lamotrigine, phenytoin, or sodium valproate.

Oral contraceptives

In healthy subjects, steady state dosing with Zonegran did not affect serum concentrations of ethinylestradiol or norethisterone in a combined oral contraceptive.

CYP2D6 substrates

Coadministration of multiple dosing of zonisamide up to 400 mg/day with single 50-mg doses of desipramine did not significantly affect the pharmacokinetic parameters of desipramine, a probe drug for CYP2D6 activity.

P-gp substrate
An in vitro study showed that zonisamide is a weak inhibitor of P-gp (MDR1) with an IC50 of 267 µmol/L. There is a theoretical potential for zonisamide to affect the pharmacokinetics of drugs which are P-gp substrates.

Caution is advised when starting or stopping Zonegran or changing the Zonegran dose in patients who are also receiving drugs which are P-gp substrates (e.g., digoxin, quinidine)

Potential for Medicinal Product to Affect Zonegran

Concomitant medications that can induce or inhibit CYP3A4 or N-acetyl-transferases may affect the pharmacokinetics of zonisamide. Drugs which inhibit or induce glucuronide conjugation are not expected to influence the pharmacokinetics of zonisamide.

The absence of a clinically significant pharmacokinetic interaction between zonisamide and lamotrigine indicates a low potential for zonisamide to interact with substances which are metabolized by UDP-GT.

CYP3A4 Induction: 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.

These effects are unlikely to be of clinical significance when Zonegran is added to existing therapy; however, changes in zonisamide concentrations may occur if concomitant CYP3A4 inducing anti-epileptic or other drugs are withdrawn, dose adjusted or introduced, an adjustment of the Zonegran dose may be required. If co-administration with a potent CYP3A4 inducer (e.g., rifampicin) is necessary, the patient should be closely monitored and the dose of Zonegran and other drugs that are CYP3A4 substrate may need to be adjusted.

CYP3A4 Inhibition: Steady-state dosing of either ketoconazole (400 mg/day) or cimetidine (1200 mg/day) had no clinically relevant effects on the single dose pharmacokinetics of zonisamide given to healthy subjects. Therefore, modification of Zonegran dosing is not necessary when co-administered with known CYP3A4 inhibitors.

Interactions of Zonisamide with Other Carbonic Anhydrase Inhibitors: 

Concomitant use of Zonegran, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., topiramate, acetazolamide or dichlorphenamide), may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Therefore, if Zonegran is given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic acidosis (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 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.

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, 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.

Figure 1 Proportion of Patients Achieving Differing Levels of Seizure Reduction in Zonegran and Placebo Groups in Studies 2 and 3

No differences in efficacy based on age, sex or race, as measured by a change in seizure frequency from baseline, were detected.

Zonegran is contraindicated in patients who have demonstrated hypersensitivity to sulfonamides or zonisamide.

The following serious adverse reactions have been reported since approval and use of Zonegran worldwide. These reactions are reported voluntarily from a population of uncertain size; therefore, it is not possible to estimate their frequency or establish a causal relationship to drug exposure.

Acute pancreatitis, rhabdomyolysis, increased creatine phosphokinase, and drug reaction with eosinophilia and systemic symptoms (DRESS) (see WARNINGS).

To report SUSPECTED ADVERSE REACTIONS, contact Concordia Pharmaceuticals Inc. at 1-877-370-1142 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

You should not use Zonegran if you are allergic to zonisamide. You may not be able to take Zonegran if you have ever had a severe allergic to a sulfa drug such as sulfamethoxazole, sulfisoxazole, or sulfamethoxazole-trimethoprim (Bactrim, Septra, Sulfatrim, SMX-TMP or SMZ-TMP, and others). A sulfa drug allergic reaction can be fatal.

To make sure Zonegran is safe for you, tell your doctor if you have:

• liver disease;

• kidney disease;

• stomach flu or illness causing diarrhea;

• a growth disorder;

• a bone disorder that causes soft or weak bones or low bone mineral density;

• a history of depression, or suicidal thoughts or actions;

• if you have ever had metabolic acidosis (too much acid in your blood); or

• if you have been on a ketogenic diet (high-fat, high-protein, low-carb).

You may have thoughts about suicide while taking this medicine. Your doctor should check your progress at regular visits. Your family or other caregivers should also be alert to changes in your mood or symptoms.

In animal studies, Zonegran caused birth defects and infant death. It is not known whether these effects would occur in people taking doses recommended for humans. Ask your doctor about your personal risk. Use effective birth control to prevent pregnancy while you are taking Zonegran.

If you are already pregnant, do not start or stop taking Zonegran during pregnancy without your doctor's advice. Zonegran can cause metabolic acidosis, which could harm an unborn baby. However, having a seizure during pregnancy could harm both the mother and the baby. Tell your doctor right away if you become pregnant while taking zonisamide.

Zonisamide can pass into breast milk and may harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Zonegran is not approved for use by anyone younger than 18 years old.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include slow heart rate, feeling light-headed, fainting, and slow or shallow breathing.

Taking this medicine with other drugs that make you sleepy can worsen this effect. Ask your doctor before taking Zonegran with a sleeping pill, narcotic pain medicine, muscle relaxer, or medicine for anxiety or depression.

Other drugs may interact with zonisamide, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.