Zonisamide (Systemic)


VA CLASSIFICATION
Primary: CN400

Commonly used brand name(s): Zonegran.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Anticonvulsant—

Indications

Accepted

Epilepsy, partial (treatment)—Zonisamide is indicated for adjunctive therapeutic use in the treatment of partial seizures in adults{01}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Sulfonamide {01}.
Molecular weight—
    212.23 {01}

pKa—
    10.2{01}

Solubility
    Zonisamide is moderately soluble in water and in 0.1N hydrochloric acid{01}.

Mechanism of action/Effect:

The exact method by which zonisamide exerts its anticonvulsant effect is unknown. Some in vitro studies suggest a blockade of sodium channels, with consequent stabilization of neuronal membranes and suppression of neuronal hypersynchronization, whereas other in vitro studies have shown zonisamide to suppress synaptically-driven electrical activity without affecting postsynaptic GABA or glutamate responses. It appears then, that zonisamide does not potentiate the synaptic activity of GABA. Zonisamide also serves as a weak inhibitor of carbonic anhydrase{01}

Absorption:

Variable, yet relatively rapid rate of absorption, with delays in time to maximum concentration when administered with food{01}{04}.

Distribution:

The apparent volume of distribution (Vd) of zonisamide is 1.45 L/kg{01}.

Zonisamide is distributed to breast milk, cerebrospinal fluid, and erythrocytes. Concentration in erythrocytes is approximately 8 times higher than in plasma{01} and the milk-to-plasma ratio is 0.93{02}.

The concentration of zonisamide in cerebrospinal fluid is approximately 76% of the concentration found in plasma{03}.

Protein binding:

Moderate (40%) {01}

Biotransformation:

Hepatic , does not induce own metabolism. Zonisamide undergoes acetylation and reduction, forming N-acetyl zonisamide, and the open-ring metabolite 2–sulfamoylacetyl phenol, respectively{01}. Reduction of zonisamide is mediated by cytochrome P450 isoenzyme 3A4 (CYP3A4){01}.


Half-life:

Elimination, in plasma—63 hours{01}

Elimination, in erythrocytes—105 hours{01}

Note: Concurrent administration of CYP3A4–inducing or inhibiting medications with zonisamide has altered serum concentrations and half-life values. Zonisamide serum half-life values are decreased to 27 hours in the presence of phenytoin, to 38 hours in the presence of either carbamazepine or phenobarbital, and to 46 hours when administered concomitantly with valproate{01}.


Time to peak concentration:

2 to 6 hours{01}
Note: In the presence of food, delayed to between 4 and 6 hours{01}. However, food does not alter the absolute bioavailability of zonisamide{01}.



Peak plasma concentration:

2 to 5 mcg/mL, following a 200 to 400 mg zonisamide oral dose{01}

Note: In patients with significant renal function impairment, where the creatinine clearance is <20 mL/min, the area under the concentration-time curve (AUC) for zonisamide is increased by 35%{01}.


Elimination:
    Renal— 62%{01}
    Fecal—3%{01}

Note: Plasma clearance of zonisamide is approximately 0.30 to 0.35 mL/min/kg in patients not receiving concomitant therapy with enzyme-inducing anticonvulsants. Zonisamide clearance is increased to 0.5 mL/min/kg in patients concurrently receiving enzyme-inducing anticonvulsant medications{01}.



Precautions to Consider

Cross-sensitivity and/or related problems

Patients with hypersensitivity reactions to sulfonamide antibiotics may also be allergic to zonisamide{01}.

Carcinogenicity

No evidence of carcinogenicity was found in mice or rats receiving zonisamide in their diet at doses of up to 80 mg per kg of body weight (mg/kg) a day (equivalent to the maximum recommended human dose [MRHD] of 400 mg a day on a mg per square meter of body surface area [mg/m2] basis in mice and 1 to 2 times the MRHD on a mg/m2 basis in rats) for two years{01}.

Mutagenicity

Zonisamide increased mutation frequency in Chinese hamster lung cells in the absence of metabolic activation. Zonisamide was neither mutagenic nor clastogenic in the Ames test, the in vitro mouse lymphoma assay, sister chromatid exchange test, and human lymphocyte cytogenetics assay, and the in vivo rat bone cytogenetics assay {01}.

Pregnancy/Reproduction
Fertility—
Studies in female rats receiving zonisamide at doses of 20, 60, and 200 mg per kg of body weight (mg/kg) (the low end of the dosing range corresponds to approximately one half the MRHD on a mg per m2 basis), before mating and during the initial phase of gestation, exhibited signs of reproductive toxicity as indicated by decreases in corpora lutea, implantations, and live fetuses. These effects were observed at all doses {01}.

The effect of zonisamide on human fertility is unknown.

Pregnancy—
Zonisamide crosses the placenta. Adequate and well-controlled studies in humans have not been done. Zonisamide should be used during pregnancy only if the benefit justifies the potential risk to the fetus. Effective contraception should be used in women of child-bearing potential who are taking zonisamide.{01}

Zonisamide has been shown to be embryolethal in pregnant cynomolgus monkeys and teratogenic in pregnant mice, rats, and dogs when administered during the gestational phase of organogenesis. Cardiovascular and skeletal malformations predominated in the offspring of pregnant dogs receiving up to 60 mg/kg/day, while increased frequencies of skeletal and craniofacial defects were observed in the offspring of pregnant mice administered up to 500 mg/kg/day. These fetal abnormalities were observed at zonisamide doses and maternal plasma concentration levels that were similar to or lower than therapeutic levels in humans{01}.

FDA Pregnancy Category C{01}


Labor and delivery—

The effect of zonisamide on labor and delivery in humans is not known.

Breast-feeding

Zonisamide is distributed into human breast milk, at a milk-to-plasma ratio of 0.93{02}. Zonisamide should be used by nursing mothers only if the potential benefit outweighs the potential risk to the nursing infant{01}.

Pediatrics

Appropriate studies have not been performed on the relationship of age to the effects of zonisamide in pediatric patients. Oligohydrosis and hyperthermia have been reported in pediatric and adolescent patients after receiving zonisamide{01}.


Geriatrics


Single-dose pharmacokinetic study of zonisamide in healthy elderly adults (mean age 69 years) was similar to that in healthy young adults (mean age 28 years). Although appropriate studies on the relationship of age to the effects of zonisamide have not been performed in the geriatric population, no geriatrics-specific problems have been reported to date. However, elderly patients are more likely to have age-related impairments in cardiac, hepatic, or renal function, which may require adjustments in dosing for patients receiving zonisamide. It is recommended that elderly patients receive dosages at the low end of the normal range{01}.


Pharmacogenetics

Oligohydrosis and hyperthermia were reported in Japanese children and adolescents during zonisamide therapy. This phenomenon has not been observed in studies of Caucasian patients receiving zonisamide{01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Other anticonvulsants that induce cytochrome P450 isoenzymes (particularly CYP3A4) will increase metabolism and plasma clearance of zonisamide, resulting in lower plasma concentrations. Conversely, other medications that inhibit CYP3A4 will likewise inhibit zonisamide metabolism and plasma clearance. Zonisamide neither induces nor inhibits cytochrome P450 isoenzymes and is not expected to interfere with other medications that are metabolized by the P450 isoenzyme group{01}{03}.


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» CNS depression-producing medications, other (see Appendix II)    (additive sedation effects may occur)


Anticonvulsants, including
» Carbamazepine
» Phenobarbital
» Phenytoin
» Valproate    (Antiepileptic agents that are cytochrome P450 inducers have caused decreased serum concentrations of zonisamide{01}{04})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alkaline phosphatase, serum    (Mean increases of 7% have been observed in patients receiving zonisamide{01})


Blood urea nitrogen, serum    (Elevations of approximately 8% over baseline levels were observed in patients receiving zonisamide{01})


Creatinine, serum    (Elevations of approximately 8% over baseline levels have been observed during administration of zonisamide{01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Previous hypersensitivity reaction to zonisamide or any other sulfonamide{01}
» Renal failure (glomerular filtration rate < 50 mL/min){01}
Risk-benefit should be considered when the following medical problems exist
Hepatic dysfunction    (Zonisamide is metabolized by the liver; plasma clearance may be impaired{01})


Renal dysfunction    (Zonisamide excretion may be reduced in the presence of impaired renal function{01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):


Impaired renal function{01}
Creatinine, serum
Blood Urea Nitrogen, serum


Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Ataxia (shakiness and unsteady walk)
{01}
Incidence less frequent
    
Confusion (mood or mental changes)
    
depression
    
ecchymosis (bruising; large, flat, blue or purplish patches on the skin)
    
rash
    
schizophrenic or schizophreniform behavior (agitation; delusions; hallucinations)
{01}
{01}

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Anorexia (loss of appetite)
    
agitation or irritability (anxiety; restlessness)
    
dizziness
    
somnolence (sleepiness; unusual drowsiness)
{01}
Incidence less frequent
    
Constipation
    
diarrhea
    
difficulty in concentrating
    
difficulty in verbal expression (problems with speech or speaking)
    
difficulty with memory
    
diplopia (double vision)
    
dry mouth
    
dyspepsia (acid or sour stomach; belching; heartburn; indigestion)
    
fatigue (unusual tiredness or weakness)
    
flu syndrome (aching muscles and joints; chills; headache; fever; general feeling of discomfort )
    
insomnia (sleeplessness; trouble sleeping)
    
mental slowing
    
nausea
    
nervousness
    
nystagmus (uncontrolled back and forth and/or rolling eye movements)
    
paresthesia (tingling, burning, or prickly sensations)
    
rhinitis (runny nose; sneezing; stuffy nose )
    
speech abnormalities (difficulty in speaking)
    
taste perversion (bad, unusual, or unpleasant taste; change in taste )
    
tiredness
    
weight loss
{01}




Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Bradycardia (slow or irregular heartbeat)
    
coma (loss of consciousness)
    
hypotension ( confusion; dizziness, faintness or light-headedness when getting up from a lying down or sitting position; unusual tiredness or weakness)
    
respiratory depression (blue fingernails, lips, or skin; difficult or troubled breathing)

{01}
Treatment of overdose


To decrease absorption:
Emesis should be induced or gastric lavage applied, employing appropriate airway protection techniques.{01}



To enhance elimination :
Renal dialysis may not be effective, due to the low protein binding profile (40%) of zonisamide{01}



Specific treatment:
There are no specific treatments or antidotes for zonisamide toxicity. Treatment is generally symptomatic and supportive{01}



Monitoring:
Monitoring of electrocardiographic rhythm, blood pressure, and respiratory function{01}



Supportive care:
Maintaining respiratory and cardiac function{01}

Usual and customary measures of managing circulatory collapse{01}

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Zonisamide (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to zonisamide or other sulfonamides

Pregnancy—Risk-benefit should be considered because of selective developmental toxicity including teratogenicity demonstrated in animal studies.





Breast-feeding—Distributed into breast milk. Risk-benefit should be considered.




Use in children——Appropriate studies have not been performed regarding the relationship of age to the effects of zonisamide in pediatric patients younger than 16 years of age. Oligohydrosis and hyperthermia have been reported in pediatric and adolescent patients after receiving zonisamide. Safety and efficacy have not been established.

Other medications, especially CNS depression-producing agents, carbamazepine, phenobarbital, phenytoin, or valproate.
Other medical problems, especially renal failure (glomerular filtration rate < 50 mL/min)

Proper use of this medication
» Swallowing whole, not chewing or breaking capsule

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next scheduled dose; not doubling doses

Proper storage

Precautions while using this medication
» Importance of regular visits to physician to check progress of therapy

» Discussing alcohol use or use of other CNS depressants with physician

» Possible blurred or double vision, dizziness, drowsiness, or light-headedness; caution when driving, using machinery, or doing other jobs that require alertness

Checking with physician if condition does not improve within a few weeks or if it becomes worse

» Contacting physician immediately if skin rash develops, if experiencing fever, sore throat, oral ulcers, easy bruising, or worsening of seizures

» Checking with physician immediately if a child taking zonisamide is not sweating as usual

» Using effective contraception (in woman of childbearing age)

» Not discontinuing zonisamide abruptly; checking with physician about gradually reducing dosage before stopping completely

» Importance of adequate fluid intake during therapy to help prevent kidney stone formation


Side/adverse effects
Signs of potential side effects, especially agitation, ataxia, confusion, diplopia, dizziness, depression, ecchymosis, nystagmus, paresthesia, rash, schizophrenic or schizophreniform behavior, somnolence, or speech abnormalities


For oral dosing forms:
Abrupt discontinuation in a responsive epileptic patient may result in convulsions and possibly status epilepticus; gradual withdrawal is recommended{01}.

Many of the side effects of zonisamide are dose-related. Side effects may be minimized by initiating therapy with low doses, which should be increased gradually at weekly intervals until an adequate response is obtained{01}.

Diet/Nutrition
Drinking plenty of water (6–8 glasses per day) may be useful to help prevent kidney stones{01}.

Zonisamide may be taken with or without food. Capsules should be swallowed whole{01}.


Oral Dosage Forms

ZONISAMIDE CAPSULES

Usual Adult Dose
Anticonvulsant

Patients 16 years of age and older
Initial—Oral, 100 mg a day, the dosage being increased by 100 mg a day increments at intervals of at least two weeks to allow for attainment of steady state plasma levels, up to 400 mg a day. Since many side effects are more frequent at doses of 300 mg and above, it is suggested that treatment may be prolonged at lower dosing levels in order to more accurately assess all effects of zonisamide at steady state.
Note: The long half-life of zonisamide may require a waiting period of up to two weeks after dosing adjustment, for the achievement of steady state plasma concentrations{01}.

Maintenance—Oral, 200 to 400 mg a day, in one single, or two equally-divided doses{01}


Usual adult prescribing limits
Dosage should generally not exceed 400 mg/day; little information is available regarding doses greater than 600 mg/day{01}.

Usual Pediatric Dose
Anticonvulsant{01}
Safety and efficacy have not been established for children younger than 16 years of age


Usual Geriatric Dose
Geriatric patients should start at the low end of the dosing range. {01}See Usual adult dose.

Usual geriatric prescribing limit
See Usual adult prescribing limits.

Strength(s) usually available
U.S.—


100 mg (Rx) [Zonegran (2–piece capsule) (microcrystalline cellulose) (hydrogenated vegetable oil) (sodium laurel sulfate) (gelatin)]

Packaging and storage:
Store below 25°C (77° F), preferably between 15 and 30° C (59 and 86°F). Protect from light and moisture.{01}

Auxiliary labeling:
   • May cause dizziness, light-headedness, or drowsiness.
   • Swallow capsule whole. Do not break or chew.
   • Drink plenty of fluids.
   • Protect from light and moisture.



Developed: 06/13/2000



References
  1. Product Information: Zonegran™, zonisamide. Elan Pharmaceuticals, South San Fransisco, California (PI revised 3/2000) reviewed 5/2000.
  1. Shimoyama R, Ohkubo T & Sugawara K: Monitoring of zonisamide in human breast milk and maternal plasma by solid-phase extraction HPLC method. Biomed Chromatogr 1999; 13:370–372.
  1. Hammond EJ, Perchalski RJ & Wilder BJ: Neuropharmacology of zonisamide, a new antiepileptic drug. Gen Pharmacol 1987; 18(3):303–307.
  1. Perucca E & Bialer M: The clinical pharmacokinetics of the newer antiepileptic drugs. Clin Pharmacokinet 1996; 31(1):29–46.
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