NDC 70518-3180 Zonisamide

Zonisamide

NDC Product Code 70518-3180

NDC CODE: 70518-3180

Proprietary Name: Zonisamide What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Zonisamide What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • Zonisamide is used with other medications to prevent and control seizures (epilepsy). Zonisamide is a sulfonamide anticonvulsant and a carbonic anhydrase inhibitor. It is unknown how zonisamide works to prevent seizures.

Product Characteristics

Color(s):
BROWN (C48332 - BROWN OPAQUE CAP AND WHITE OPAQUE BODY)
Shape: CAPSULE (C48336)
Size(s):
18 MM
Imprint(s):
IG;228
Score: 1

NDC Code Structure

  • 70518 - Remedyrepack Inc.

NDC 70518-3180-0

Package Description: 100 POUCH in 1 BOX > 1 CAPSULE in 1 POUCH (70518-3180-1)

NDC Product Information

Zonisamide with NDC 70518-3180 is a a human prescription drug product labeled by Remedyrepack Inc.. The generic name of Zonisamide is zonisamide. The product's dosage form is capsule and is administered via oral form. The RxNorm Crosswalk for this NDC code indicates a single RxCUI concept is associated to this product: 314285.

Dosage Form: Capsule - A solid oral dosage form consisting of a shell and a filling. The shell is composed of a single sealed enclosure, or two halves that fit together and which are sometimes sealed with a band. Capsule shells may be made from gelatin, starch, or cellulose, or other suitable materials, may be soft or hard, and are filled with solid or liquid ingredients that can be poured or squeezed.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Zonisamide Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.


Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)
  • HYDROGENATED CASTOR OIL (UNII: ZF94AP8MEY)
  • GELATIN, UNSPECIFIED (UNII: 2G86QN327L)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • FERRIC OXIDE RED (UNII: 1K09F3G675)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Decreased Central Nervous System Disorganized Electrical Activity - [PE] (Physiologic Effect)
  • Anti-epileptic Agent - [EPC] (Established Pharmacologic Class)
  • Sulfonamides - [CS]
  • Carbonic Anhydrase Inhibitors - [MoA] (Mechanism of Action)
  • P-Glycoprotein Inhibitors - [MoA] (Mechanism of Action)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Remedyrepack Inc.
Labeler Code: 70518
FDA Application Number: ANDA077869 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 08-04-2021 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2022 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Zonisamide Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Description

Zonisamide, USP is an antiseizure drug chemically classified as a sulfonamide and unrelated to other antiseizure agents. The active ingredient is zonisamide USP, 1,2-benzisoxazole-3-methanesulfonamide. The empirical formula is C


8H


8N


2O


3S with a molecular weight of 212.23. Zonisamide USP 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 is supplied for oral administration as capsules containing 100 mg zonisamide.Each 100 mg capsule contains the labeled amount of zonisamide plus the following inactive ingredients: microcrystalline cellulose, hydrogenated vegetable oil, gelatin and colorants. Components of gelatin capsules (For 100 mg: titanium dioxide, gelatin and FDA/E172 red iron oxide). Imprint ink dye (Black SW- 9008/SW-9009).

Pharmacokinetics:

AbsorptionFollowing a 200 to 400 mg oral zonisamide dose, peak plasma concentrations (range: 2 to 5 mcg/mL) in normal volunteers occur within 2 to 6 hours. In the presence of food, the time to maximum concentration is delayed; occurring at 4 to 6 hours, but food has no effect on the bioavailability of zonisamide. Zonisamide absorption is dose-proportional in the range of 200 to 400 mg. C


max 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.


DistributionThe 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 to 7.0 mcg/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 EliminationFollowing 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 to 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 to 152 mL/min. Group 2 and Group 3 had creatinine clearances ranging from 14.5 to 59 mL/min and 10 to 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 Zonisamide 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, Zonisamide is not expected to affect the pharmacokinetics of other drugs via cytochrome P450-mediated mechanisms.Potential for Zonisamide to affect other drugsAnti-epileptic drugsIn epileptic patients, steady state dosing with Zonisamide resulted in no clinically relevant pharmacokinetic effects on carbamazepine, lamotrigine, phenytoin, or sodium valproate.Oral contraceptivesIn healthy subjects, steady state dosing with Zonisamide did not affect serum concentrations of ethinylestradiol or norethisterone in a combined oral contraceptive.CYP2D6 substratesCoadministration 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 substrateAn in vitro study showed that zonisamide is a weak inhibitor of P-gp (MDR1) with an IC


50 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 Zonisamide or changing the Zonisamide dose in patients who are also receiving drugs which are P-gp substrates (e.g., digoxin, quinidine).


Potential for Medicinal Products to Affect ZonisamideConcomitant 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 to 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 Zonisamide 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 Zonisamide 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 Zonisamide 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 Zonisamide dosing is not necessary when co-administered with known CYP3A4 inhibitors.

Indications And Usage

Zonisamide capsules are indicated as adjunctive therapy in the treatment of partial seizures in adults with epilepsy.

Contraindications

Zonisamide capsules are 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.Serious Skin Reactions: Consideration should be given to discontinuing zonisamide 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 Hypersensitivity: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ hypersensitivity, has occurred with zonisamide. 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. Zonisamide 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 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 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.
Acute Myopia and Secondary Angle Closure Glaucoma:
Acute myopia and secondary angle closure glaucoma have been reported in patients receiving zonisamide capsules. Elevated intraocular pressure can lead to serious sequelae, including permanent vision loss, if left untreated.

Symptoms in reported cases have included acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia (redness), and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated with ciliochoroidal effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. symptoms typically occur within one month after initiating zonisamide capsules therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with zonisamide capsules has been reported both in pediatric patients and in adults. The primary treatment to reverse symptoms is discontinuation of zonisamide capsules as rapidly as possible, according to the judgment of the treating physician. Other therapeutic measures, in conjunction with discontinuation of zonisamide capsules, may be helpful. Myopia and secondary angle closure glaucoma usually resolve or improve after discontinuation of zonisamide capsules.
Suicidal Behavior and Ideation:Antiepileptic drugs (AEDs), including zonisamide, 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 to 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 analysisIndication


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: 


Additional 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


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 zonisamide 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).

Metabolic Acidosis:

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 zonisamide, 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).


Metabolic acidosis can also increase the risk for hyperammonemia, particularly in the presence of drugs which can cause hyperammonemia.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 to 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 dose-related 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 mEq/L.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.

Adverse Reactions

The most common adverse reactions with zonisamide (an incidence at least 4% greater than placebo) in controlled clinical trials and shown in descending order of frequency were somnolence, anorexia, dizziness, ataxia, agitation/irritability, and difficulty with memory and/or concentration.In controlled clinical trials, 12% of patients receiving zonisamide as adjunctive therapy discontinued due to an adverse reaction compared to 6% receiving placebo. Approximately 21% of the 1,336 patients with epilepsy who received zonisamide in clinical studies discontinued treatment because of an adverse reaction. The most common adverse reactions leading to discontinuation were somnolence, fatigue and/or ataxia (6%), anorexia (3%), difficulty concentrating (2%), difficulty with memory, mental slowing, nausea/vomiting (2%), and weight loss (1%). Many of these adverse reactions were dose-related (see


WARNINGS and


PRECAUTIONS).


Adverse Reaction Incidence in Controlled Clinical Trials: Table 4 lists adverse reactions that occurred in at least 2% of patients treated with zonisamide in controlled clinical trials that were numerically more common in the zonisamide group. In these studies, either zonisamide or placebo was added to the patient’s current AED therapy.


Table 4. Adverse Reactions in Placebo-Controlled, Add-On Trials (Events that occurred in at least 2% of Zonisamide-treated patients and occurred more frequently in Zonisamide-treated than placebo-treated patients)BODY SYSTEM/PREFERRED TERMZONISAMIDE


(n=269)


%


PLACEBO


(n=230)


%


BODY AS A WHOLEHeadache


10


8


Abdominal Pain


6


3


Flu Syndrome


4


3


DIGESTIVEAnorexia


13


6


Nausea


9


6


Diarrhea


5


2


Dyspepsia


3


1


Constipation


2


1


Dry Mouth


2


1


HEMATOLOGIC AND LYMPHATICEcchymosis


2


1


METABOLIC AND NUTRITIONAL Weight Loss


3


2


NERVOUS SYSTEM    Dizziness


13


7


    Ataxia


6


1


    Nystagmus


4


2


    Paresthesia


4


1


    NEUROPSYCHIATRIC AND COGNITIVE DYSFUNCTION-ALTERED COGNITIVE FUNCTION    Confusion


6


3


    Difficulty Concentrating


6


2


    Difficulty with Memory


6


2


    Mental Slowing


4


2


    NEUROPSYCHIATRIC AND COGNITIVE DYSFUNCTION-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


RESPIRATORYRhinitis


2


1


SKIN AND APPENDAGESRash


3


2


SPECIAL SENSESDiplopia


6


3


Taste Perversion


2


0


Other Adverse Reactions in Clinical Trials: zonisamide has been administered to 1,598 individuals during all clinical trials, only some of which were placebo-controlled. The frequencies represent the proportion of the 1,598 individuals exposed to zonisamide who experienced an event on at least one occasion. All events are included except those already listed in the previous table or discussed in


WARNINGS or


PRECAUTIONS, trivial events, those too general to be informative, and those not reasonably associated with zonisamide.


Events are further classified within each category and listed in order of decreasing frequency as follows:


frequent occurring in at least 1:100 patients;


infrequent occurring in 1:100 to 1:1000 patients;


rare occurring in fewer than 1:1000 patients.


Body as a Whole: Frequent: Accidental injury, asthenia.


Infrequent: Chest pain, flank pain, malaise, allergic reaction, face edema, neck rigidity.


Rare: Lupus erythematosus.


Cardiovascular: Infrequent: Palpitation, tachycardia, vascular insufficiency, hypotension, hypertension, thrombophlebitis, syncope, bradycardia.


Rare: Atrial fibrillation, heart failure, pulmonary embolus, ventricular extrasystoles.


Digestive: Frequent: Vomiting.


Infrequent: Flatulence, gingivitis, gum hyperplasia, gastritis, gastroenteritis, stomatitis, cholelithiasis, glossitis, melena, rectal hemorrhage, ulcerative stomatitis, gastro-duodenal ulcer, dysphagia, gum hemorrhage.


Rare: Cholangitis, hematemesis, cholecystitis, cholestatic jaundice, colitis, duodenitis, esophagitis, fecal incontinence, mouth ulceration.


Hematologic and Lymphatic: Infrequent: Leukopenia, anemia, immunodeficiency, lymphadenopathy.


Rare: Thrombocytopenia, microcytic anemia, petechia.


Metabolic and Nutritional: Infrequent: Peripheral edema, weight gain, edema, thirst, dehydration.


Rare: Hypoglycemia, hyponatremia, lactic dehydrogenase increased, SGOT increased, SGPT increased.


Musculoskeletal: Infrequent: Leg cramps, myalgia, myasthenia, arthralgia, arthritis.


Nervous System: Frequent: Tremor, convulsion, abnormal gait, hyperesthesia, incoordination.


Infrequent: Hypertonia, twitching, abnormal dreams, vertigo, libido decreased, neuropathy, hyperkinesia, movement disorder, dysarthria, cerebrovascular accident, hypotonia, peripheral neuritis, reflexes increased.


Rare: Dyskinesia, dystonia, encephalopathy, facial paralysis, hypokinesia, hyperesthesia, myoclonus, oculogyric crisis.


Behavioral Abnormalities –Non-Psychosis-Related: Infrequent: Euphoria.


Respiratory: Frequent: Pharyngitis, cough increased.


Infrequent: Dyspnea.


Rare: Apnea, hemoptysis.


Skin and Appendages: Frequent: Pruritus.


Infrequent: Maculopapular rash, acne, alopecia, dry skin, sweating, eczema, urticaria, hirsutism, pustular rash, vesiculobullous rash.


Special Senses: Frequent: Amblyopia, tinnitus.


Infrequent: Conjunctivitis, parosmia, deafness, visual field defect, glaucoma.


Rare: Photophobia, iritis.


Urogenital: Infrequent: Urinary frequency, dysuria, urinary incontinence, hematuria, impotence, urinary retention, urinary urgency, amenorrhea, polyuria, nocturia.


Rare: Albuminuria, enuresis, bladder pain, bladder calculus, gynecomastia, mastitis, menorrhagia.

Post Marketing Experience

The following serious adverse reactions have been reported since approval and use of zonisamide 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, drug reaction with eosinophilia and systemic symptoms (DRESS), acute myopia and secondary angle closure glaucoma, and hyperammonemia and encephalopathy (see


WARNINGS).


To report SUSPECTED ADVERSE REACTIONS, contact Cipla Ltd. at 1-866-604-3268 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Abuse And Dependence

The abuse and dependence potential of zonisamide has not been evaluated in human studies (see


WARNINGS,


Cognitive/Neuropsychiatric Adverse Events subsection). In a series of animal studies, zonisamide did not demonstrate abuse liability and dependence potential. Monkeys did not self-administer zonisamide in a standard reinforcing paradigm.


Rats exposed to zonisamide did not exhibit signs of physical dependence of the CNS-depressant type. Rats did not generalize the effects of diazepam to zonisamide in a standard discrimination paradigm after training, suggesting that zonisamide does not have abuse potential of the benzodiazepine-CNS depressant type.

Overdosage

Human Experience: Experience with zonisamide daily doses over 800 mg/day is limited. During zonisamide clinical development, three patients ingested unknown amounts of zonisamide as suicide attempts, and all three were hospitalized with CNS symptoms. One patient became comatose and developed bradycardia, hypotension, and respiratory depression; the zonisamide plasma level was 100.1 mcg/mL measured 31 hours post-ingestion. Zonisamide plasma levels fell with a half-life of 57 hours, and the patient became alert five days later.


Management: No specific antidotes for zonisamide overdosage are available. Following a suspected recent overdose, emesis should be induced or gastric lavage performed with the usual precautions to protect the airway. General supportive care is indicated, including frequent monitoring of vital signs and close observation.


Zonisamide has a long half-life (see


CLINICAL PHARMACOLOGY section). Due to the low protein binding of zonisamide (40%), renal dialysis may be effective. The effectiveness of renal dialysis as a treatment of overdose has not been formally studied. A poison control center should be contacted for information on the management of zonisamide overdosage.

Dosage And Administration

Zonisamide, USP is recommended as adjunctive therapy for the treatment of partial seizures in adults. Safety and efficacy in pediatric patients below the age of 16 have not been established. Zonisamide should be administered once or twice daily, using 25 mg or 100 mg capsules. Zonisamide is given orally and can be taken with or without food. Capsules should be swallowed whole.Adults over Age 16: The prescriber should be aware that, because of the long half-life of zonisamide, up to two weeks may be required to achieve steady state levels upon reaching a stable dose or following dosage adjustment. Although the regimen described below is one that has been shown to be tolerated, the prescriber may wish to prolong the duration of treatment at the lower doses in order to fully assess the effects of zonisamide at steady state, noting that many of the side effects of zonisamide are more frequent at doses of 300 mg per day and above. Although there is some evidence of greater response at doses above 100 to 200 mg/day, the increase appears small and formal dose-response studies have not been conducted.


The initial dose of zonisamide should be 100 mg daily. After two weeks, the dose may be increased to 200 mg/day for at least two weeks. It can be increased to 300 mg/day and 400 mg/day, with the dose stable for at least two weeks to achieve steady state at each level. Evidence from controlled trials suggests that zonisamide doses of 100 to 600 mg/day are effective, but there is no suggestion of increasing response above 400 mg/day (see


CLINICAL PHARMACOLOGY,


Clinical Studies subsection). There is little experience with doses greater than 600 mg/day.


Patients with Renal or Hepatic Disease: Because zonisamide is metabolized in the liver and excreted by the kidneys, patients with renal or hepatic disease should be treated with caution, and might require slower titration and more frequent monitoring (see


CLINICAL PHARMACOLOGY and


PRECAUTIONS).

How Supplied

Zonisamide, USP is available as 100 mg two-piece hard gelatin capsules. The capsules imprinted with codes are printed in black ink. Zonisamide, USP is available in bottles with strengths and capsule description as follows:Size "1" Brown Opaque Cap and White Opaque Body imprinted with 100 mg on the cap and IG228 on the body in black ink, filled with White to Off-white powder.NDC: 70518-3180-00NDC: 70518-3180-01PACKAGING: 100 in 1 BOXPACKAGING: 1 in 1 POUCHStore at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature], in a dry place and protected from light.Revised: 07/2020Repackaged and Distributed By:Remedy Repack, Inc.625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

Spl Medguide

  • What is the most important information I should know about zonisamide capsules? Zonisamide capsules may cause serious side effects, including:Serious skin rash that can cause death.Serious allergic reactions that may affect different parts of the body.Less sweating and increase in your body temperature (fever).Serious eye problems.Suicidal thoughts or actions in some people.Increased level of acid in your blood (metabolic acidosis).Problems with your concentration, attention, memory, thinking, speech, or language.Blood cell changes such as reduced red and white blood cell counts.These serious side effects are described below.1. Zonisamide capsules may cause a serious skin rash that can cause death. These serious skin reactions are more likely to happen when you begin taking zonisamide capsules within the first 4 months of treatment but may occur at later times.2. Zonisamide can cause other types of allergic reactions or serious problems that may affect different parts of the body such as your liver, kidneys, heart, or blood cells. You may or may not have a rash with these types of reactions. These reactions can be very serious and can cause death. Call your health care provider right away if you have:feversevere muscle painrashswollen lymph glandsswelling of your faceunusual bruising or bleedingweakness, fatigueyellowing of your skin or the white part of your eyes3. Zonisamide may cause you to sweat less and to increase your body temperature (fever). You may need to be hospitalized for this. You should watch for decreased sweating and fever, especially when it is hot and especially in children taking Zonisamide.Call your health care provider right away if you have:high fever, recurring fever, or long lasting feverless sweat than normal4. Zonisamide may cause eye problems. Serious eye problems include:sudden decrease in vision with or without eye pain and rednessa blockage of fluid in the eye causing increased pressure in the eye (secondary angle closure glaucoma)These eye problems can lead to permanent loss of vision if not treated.Call your healthcare provider right away if you have any new eye symptoms, including any eye pain or redness or any new problems with your vision.5. Like other antiepileptic drugs, zonisamide may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.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 dyingattempt to commit suicidenew or worse depressionnew or worse anxietyfeeling agitated or restlesspanic attackstrouble sleeping (insomnia)new or worse irritabilityacting aggressive, being angry, or violentacting on dangerous impulsesan extreme increase in activity and talking (mania)other unusual changes in behavior or moodSuicidal 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.How can I watch for early symptoms of suicidal thoughts and actions?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.Call your healthcare provider between visits as needed, especially if you are worried about symptoms.Do not stop zonisamide without first talking to a healthcare provider.Stopping zonisamide 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).6. Zonisamide can increase the level of acid in your blood (metabolic acidosis). If left untreated, metabolic acidosis can cause brittle or soft bones (osteoporosis, osteomalacia, osteopenia), kidney stones and can slow the rate of growth in children. Metabolic acidosis can happen with or without symptoms.Sometimes people with metabolic acidosis will:feel tirednot feel hungry (loss of appetite)feel changes in heartbeathave trouble thinking clearlyYour healthcare provider should do a blood test to measure the level of acid in your blood before and during your treatment with zonisamide.7. Zonisamide may cause problems with your concentration, attention, memory, thinking, speech, or language.8. Zonisamide can cause blood cell changes such as reduced red and white blood cell counts. call your healthcare provider if you develop fever, sore throat, sores in your mouth or unusual bruising.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? Zonisamide is a prescription medicine that is used with other medicines to treat partial seizures in adults.It is not known if zonisamide is safe or effective in children under 16 years of age.Do not take zonisamide capsules: Do not take zonisamide capsules if you are allergic to medicines that contain sulfa.Before taking zonisamide capsules, tell your healthcare provider about all your medical conditions, including if you:have or have had depression, mood problems or suicidal thoughts or behaviorhave kidney problemshave liver problemshave 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 problemare on a diet high in fat called a ketogenic diethave diarrheahave high blood levels of ammoniaTell your healthcare provider if you: 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.
  • You and your healthcare provider should decide if you should take zonisamide capsules while you are pregnant.
  • If you become pregnant while taking zonisamide, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.
  • Are breastfeeding or plan to breastfeed. Zonisamide can pass into your breast milk. It is not known if zonisamide 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.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins or herbal supplements.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 to take.Take zonisamide capsules with or without food.Swallow the capsules whole.If you take too much zonisamide, call your local Poison Control Center or go to the nearest emergency room right away.Do not stop taking zonisamide without talking to your healthcare provider. Stopping zonisamide capsules suddenly can cause serious problems, including seizures that will not stop (status epilepticus).What should I avoid while taking zonisamide capsules? 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 affects you. Zonisamide can slow your thinking and motor skills.What are the possible side effects of zonisamide capsules? Zonisamide capsules can cause serious side effects. See “What is the most important information I should know about zonisamide capsules ?”Other serious side effects include: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 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.
  • High blood ammonia levels. High ammonia in the blood can affect your mental activities, slow your alertness, make you feel tired, or cause vomiting.
  • The most common side effects of zonisamide capsules include:drowsinessloss of appetitedizzinessproblems with concentration or memorytrouble with walking and coordinationagitation or irritabilitySide effects can happen at any time, but are more likely to happen during the first several weeks after starting zonisamide capsules.These are not all of the possible side effects of zonisamide capsules.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should I store zonisamide capsules?Store zonisamide capsules at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]Keep zonisamide capsules dry and away from lightKeep zonisamide capsules and all medicines out of the reach of children. General Information about the safe and effective use of zonisamide capsules Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use zonisamide for a condition for which it was not prescribed. Do not give zonisamide capsules to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about zonisamide capsules that is written for health professionals.For more information, call Cipla Ltd. at 1-866-604-3268.What are the ingredients in zonisamide capsules?Active ingredient: zonisamide USP
  • Inactive ingredients: microcrystalline cellulose, hydrogenated vegetable oil, gelatin and colorants. Components of gelatin capsules (For 100 mg: titanium dioxide, gelatin and FDA/E172 red iron oxide). Imprint ink dye (Black SW- 9008/SW-9009)
  • This Medication Guide has been approved by the U.S. Food and Drug Administration.Repackaged By / Distributed By: RemedyRepack Inc.625 Kolter Drive, Indiana, PA 15701(724) 465-8762Medication Guide
  • Zonisamide Capsules, USP
  • (zoe nis’ a mide)

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