ZONISAMIDE
FULL PRESCRIBING INFORMATION: CONTENTS*
- ZONISAMIDE DESCRIPTION
- CLINICAL PHARMACOLOGY
- ZONISAMIDE INDICATIONS AND USAGE
- ZONISAMIDE CONTRAINDICATIONS
- WARNINGS
- PRECAUTIONS
- ZONISAMIDE ADVERSE REACTIONS
- DRUG ABUSE AND DEPENDENCE
- OVERDOSAGE
- ZONISAMIDE DOSAGE AND ADMINISTRATION
- HOW SUPPLIED
- Medication Guide
- PACKAGE LABEL - ZONISAMIDE - 25 MG - CAPSULES
FULL PRESCRIBING INFORMATION
ZONISAMIDE DESCRIPTION
Zonisamide capsule 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:
Zonisamide capsules are supplied for oral administration as capsules containing 25 mg, 50 mg and 100 mg zonisamide. Each capsule contains the labeled amount of zonisamide plus the following inactive ingredients: microcrystalline cellulose, sodium lauryl sulfate, hydrogenated vegetable oil, colloidal silicon dioxide, sodium starch glycolate, talc, gelatin, titanium dioxide. For 100 mg D&C red # 28, D&C yellow # 10, and FD&C # yellow 6 and for 50 mg contains FD&C red # 40, FD&C yellow # 5, and FD&C Blue # 1.
CLINICAL PHARMACOLOGY
Mechanism of Action:
In vitro2+In vitroin vitro3In vivo
WARNINGS, Metabolic Acidosis
Pharmacokinetics:
maxMetabolism and Excretion:
1414Special Populations:
Renal Insufficiency:DOSAGE AND ADMINISTRATION
Hepatic Disease:
Age:
Gender and Race:
Interactions of Zonisamide with Other Antiepilepsy Drugs (AEDs):
PRECAUTIONS, Drug Interactions
Interactions of Zonisamide with Other Carbonic Anhydrase Inhibitors:
PRECAUTIONS, Drug Interactions
Clinical Studies:
| Study | Median % reduction in partial seizures | %Responders | ||
|---|---|---|---|---|
| Zonisamide Capsules | Placebo | Zonisamide Capsules | Placebo | |
| Study 1: | n=98 | n=72 | n=98 | n=72 |
| Weeks 8-12: | 40.5%* | 9.0% | 41.8%* | 22.2% |
| Study 2: | n=69 | n=72 | n=69 | n=72 |
| Weeks 5-12: | 29.6%* | -3.2% | 29.0% | 15.0% |
| Study 3: | n=67 | n=66 | n=67 | n=66 |
| Weeks 5-12: | 27.2%* | -1.1% | 28.0%* | 12.0% |
| Dose Group | Median % reduction in partial seizures | %Responders | ||
|---|---|---|---|---|
| Zonisamide Capsules | Placebo | Zonisamide Capsules | Placebo | |
| 100-400 mg/day: | n=112 | n=83 | n=112 | n=83 |
| Weeks 1-12: | 32.3%* | 5.6% | 32.1%* | 9.6% |
| 100 mg/day: | n=56 | n=80 | n=56 | n=80 |
| Weeks 1-5: | 24.7%* | 8.3% | 25.0%* | 11.3% |
| 200 mg/day: | n=55 | n=82 | n=55 | n=82 |
| Weeks 2-6: | 20.4%* | 4.0% | 25.5%* | 9.8% |
Figure 1 Proportion of Patients Achieving Differing Levels of Seizure Reduction in Zonisamide Capsules and Placebo Groups in Studies 2 and 3
ZONISAMIDE INDICATIONS AND USAGE
ZONISAMIDE CONTRAINDICATIONS
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.Serious Skin Reactions:
Consideration should be given to discontinuing zonisamide capsules in patients who develop an otherwise unexplained rash. If the drug is not discontinued, patients should be observed frequently.Serious Hematologic 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 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 zonisamide capsules 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
| Indication |
Placebo Patients with Events Per 1000 Patients | Drug Patients with Events Per 1000 Patients | Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients |
Risk Difference: Drug Patients with Events Per 1000 Patients |
|---|---|---|---|---|
| Epilepsy | 1.0 |
3.4 |
3.5 | 2.4 |
| Psychiatric |
5.7 |
8.5 |
1.5 | 2.9 |
| Other | 1.0 |
1.8 | 1.9 |
0.9 |
|
Total |
2.4 |
4.3 |
1.8 | 1.9 |
WARNINGS, Cognitive/Neuropsychiatric Adverse Events
Metabolic Acidosis:
PRECAUTIONS, Laboratory TestsPRECAUTIONS, Kidney Stones
PRECAUTIONS, Laboratory Tests
Seizures on Withdrawal:
Teratogenicity:
PRECAUTIONS, PregnancyCognitive/ Neuropsychiatric Adverse Events:
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.
PRECAUTIONS
General:
WARNINGS: Cognitive/ Neuropsychiatric Adverse EventsCLINICAL PHARMACOLOGY, Special PopulationsKidney Stones:
WARNINGS, Metabolic AcidosisWARNINGS, Metabolic Acidosis
Effect on Renal Function:
Sudden Unexplained Death in Epilepsy:
Status Epilepticus:
Information for Patients:
- Zonisamide capsules 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 zonisamide capsules sufficient to determine whether it affects their performance. Because of the potential of zonisamide to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse events, zonisamide should be used with caution if used in combination with alcohol or other CNS depressants.
- Patients should contact their physician immediately if a skin rash develops or seizures worsen.
- 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.
- Patients should contact their physician immediately if a child has been taking zonisamide capsules and is not sweating as usual with or without a fever.
- Because zonisamide can cause hematological complications, patients should contact their physician immediately if they develop a fever, sore throat, oral ulcers, or easy bruising.
- Suicidal Thinking and Behavior - Patients, their caregivers, and families should be counseled that AEDs, including zonisamide capsules, 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.
- Patients should contact their physician immediately if they develop fast breathing, fatigue/tiredness, loss of appetite, or irregular heart beat or palpitations (possible manifestations of metabolic acidosis).
- As with other AEDs, patients should contact their physician if they intend to become pregnant or are pregnant during zonisamide capsules therapy. Patients should notify their physician if they intend to breast-feed or are breast-feeding an infant.
Laboratory Tests:
PRECAUTIONS, Effect on Renal FunctionWARNINGS, Metabolic Acidosis
Drug Interactions:
Effects of zonisamide capsules on the pharmacokinetics of other antiepilepsy drugs (AEDs):in vitroEffects of other drugs on zonisamide capsules pharmacokinetics:
Interaction with cimetidine:
Drug Interactions with CNS Depressants: zonisamide
Other Carbonic Anhydrase Inhibitors: zonisamidezonisamideCLINICAL PHARMACOLOGY, Interactions of Zonisamide with Other Carbonic Anhydrase Inhibitors
Carcinogenicity, Mutagenesis, Impairment of Fertility:
22in vitro in vivo
2
Pregnancy:
Pregnancy Category CWARNINGS, TeratogenicityWARNINGS, Metabolic Acidosis
22
22
Labor and Delivery
Use in Nursing Mothers
Pediatric Use:
WARNINGS, Oligohidrosis and Hyperthermia in Pediatric Patients WARNINGS, Metabolic AcidosisGeriatric Use:
CLINICAL PHARMACOLOGY, Special PopulationsZONISAMIDE ADVERSE REACTIONS
WARNINGS and PRECAUTIONS
Adverse Event Incidence in Controlled Clinical Trials:
| BODY SYSTEM/PREFERRED TERM | Zonisamide Capsules (n=269) % |
Placebo (n=230) % |
|---|---|---|
| BODY AS A WHOLE | ||
| 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 |
| HEMATOLOGIS 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-ALERTED COGNITIVE FUNCTION | ||
| Confusion | 6 | 3 |
| Difficulty Concentrating | 6 | 2 |
| Difficulty with Memory | 6 | 2 |
| Mental Slowing | 4 | 2 |
| NEUROPSYCHIATRIC AND COGNITIVE DYSFUNCTION-BEHAVIORAL ABNORMALITIES (NON-PSYCHOSIS-RELATED) | ||
| Agitation/Irritability | 9 | 4 |
| Depression | 6 | 3 |
| Insomnia | 6 | 3 |
| Anxiety | 3 | 2 |
| Nervousness | 2 | 1 |
| NEUROPSYCHIATRIC AND COGNITIVE DYSFUNCTION-BEHAVIORAL ABNORMALITIES (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 | 2 |
| Difficulties in Verbal Expression | 2 | <1 |
| 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:
WARNINGSPRECAUTIONSfrequentinfrequentrare
Body as a Whole: Frequent:Infrequent:Rare:
Cardiovascular: Infrequent:Rare:
Digestive: Frequent: Infrequent:Rare:
Hematologic and Lymphatic: Infrequent:Rare:
Metabolic and Nutritional: Infrequent:Rare:
Musculoskeletal: Infrequent:
Nervous System: Frequent: Infrequent:
Behavioral Abnormalities - Non-Psychosis-Related: Infrequent:
Respiratory: Frequent:Infrequent:Rare:
Skin and Appendages: Frequent: Infrequent:
Special Senses: Frequent:Infrequent: Rare:
Urogenital: Infrequent:Rare:
DRUG ABUSE AND DEPENDENCE
WARNINGS, Cognitive/Neuropsychiatric Adverse EventsOVERDOSAGE
Human Experience:Management:
CLINICAL PHARMACOLOGY
ZONISAMIDE DOSAGE AND ADMINISTRATION
Adults over Age 16:
CLINICAL PHARMACOLOGY, Clinical Studies
Patients with Renal or Hepatic Disease: CLINICAL PHARMACOLOGYPRECAUTIONS
HOW SUPPLIED
| Strength |
Description |
Pack |
NDC No. |
|---|---|---|---|
| 25 mg |
White opaque body, imprinted with W945 and White opaque cap, containing white powder. |
Bottle of 100 |
64679-945-01 |
| 50 mg |
White opaque body, imprinted with W946 and Grey opaque cap, containing white powder. |
Bottle of 100 |
64679-946-01 |
| 100 mg |
White opaque body, imprinted with W990 and Orange opaque cap, containing white powder. |
Bottle of 100 |
64679-990-01 |
Manufactured by:
Distributed by:
Medication Guide
Zonisamide Capsules
What is the most important information I should know about zonisamide capsules?
Call your health care provider right away if you have:
- a skin rash
- high fever, recurring fever, or long lasting fever
- less sweat than normal
Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:
- thoughts about suicide or dying
- attempt to commit suicide
- new or worse depression
- new or worse anxiety
- feeling agitated or restless
- panic attacks
- trouble sleeping (insomnia)
- new or worse irritability
- acting aggressive, being angry, or violent
- acting on dangerous impulses
- an extreme increase in activity and talking (mania)
- other unusual changes in behavior or mood
- Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.
- Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
- Keep all follow-up visits with your healthcare provider as scheduled.
Do not stop zonisamide capsules without first talking to a healthcare provider.
- Stopping zonisamide capsules suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus).
- feel tired
- not feel hungry (loss of appetite)
- feel changes in heartbeat
- have trouble thinking clearly
Zonisamide capsules can have other serious side effects. For more information ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you. Be sure to read the section titled “What are the possible side effects of zonisamide capsules?”
What is zonisamide capsule?
Who should not take zonisamide capsules ?
What should I tell my healthcare provider before taking zonisamide capsules
- have or have had depression, mood problems or suicidal thoughts or behavior
- have kidney problems
- have liver problems
- have a history of metabolic acidosis (too much acid in your blood)
- have weak, brittle bones or soft bones (osteomalacia, osteopenia or osteoporosis)
- have a growth problem
- are on a diet high in fat called a ketogenic diet
- have diarrhea
- are pregnant or plan to become pregnant. Zonisamide capsules may harm your unborn baby. Women who can become pregnant should use effective birth control. Tell your healthcare provider right away if you become pregnant while taking zonisamide capsules.
- are breastfeeding or plan to breastfeed. Zonisamide capsules can pass into your breast milk. It is not known if zonisamide capsules in your breast milk can harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take zonisamide capsules.
How should I take zonisamide capsules?
- Take zonisamide capsules exactly as prescribed. Your healthcare prescriber may change your dose. Your healthcare provider will tell you how much zonisamide capsules to take.
- Take zonisamide capsules with or without food.
- Swallow the capsules whole.
- If you take too much zonisamide capsules, call your local Poison Control Center or go to the nearest emergency room right away.
- Do not stop taking zonisamide capsules without talking to your healthcare provider. Stopping zonisamide capsules suddenly can cause serious problems, including seizures that will not stop (status epilepticus).
- Do not drink alcohol or take other drugs that make you sleepy or dizzy while taking zonisamide capsules until you talk to your health care provider. Zonisamide capsules taken with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse.
- Do not drive, operate heavy machinery, or do other dangerous activities until you know how zonisamide capsules affects you. Zonisamide capsules can slow your thinking and motor skills.
- The side effects mentioned above (see "What is the most important information I should know about zonisamide capsules ?")
- kidney stones: back pain, stomach pain, or blood in your urine may mean you have kidney stones. Drink plenty of fluids while you take zonisamide capsules to lower your chance of getting kidney stones.
- problems with mood or thinking (new or worse depression; sudden changes in mood, behavior, or loss of contact with reality, sometimes associated with hearing voices or seeing things that are not really there; feeling sleepy or tired; trouble concentrating; speech and language problems). Call your healthcare provider right away if you have any of the symptoms listed above.
- drowsiness
- loss of appetite
- dizziness
- problems with concentration or memory
- trouble with walking and coordination
- agitation or irritability
How should I store zonisamide capsules ?
- Store zonisamide capsules at 20°-25°C (68°-77°F) [See USP Controlled Room Temperature].
- dry and away from light
General Information about the safe and effective use of zonisamide capsules
What are the ingredients in zonisamide capsules ?
Manufactured by:
Distributed by:
PACKAGE LABEL - ZONISAMIDE - 25 MG - CAPSULES
ZONISAMIDEZONISAMIDE CAPSULE
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PLEASE, BE CAREFUL!
Be sure to consult your doctor before taking any medication!
