Anticonvulsant, Miscellaneous

Adjunct treatment of partial seizures in adults with epilepsy

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Fetal abnormalities and death have been reported in animals, however, there are no studies in pregnant women. It is not known if zonisamide is excreted in human milk. Use during pregnancy/lactation only if the potential benefits outweigh the potential risks.

Hypersensitivity to sulfonamides or zonisamide.

Rare, but potentially fatal sulfonamide reactions have occurred following the use of zonisamide. These reactions include Stevens-Johnson syndrome and toxic epidermal necrolysis, usually appearing within 2-16 weeks of drug initiation. Discontinue zonisamide if rash develops. Decreased sweating and hyperthermia requiring hospitalization have been reported in children. The safety and efficacy in children <16 years of age has not been established. Discontinue zonisamide in patients who develop acute renal failure or a significant sustained increase in creatinine/BUN concentration. Kidney stones have been reported. Use cautiously in patients with renal or hepatic dysfunction. Do not use if estimated Cl_cr <50 mL/minute. Significant CNS effects include psychiatric symptoms, psychomotor slowing, and fatigue or somnolence. Fatigue and somnolence occur within the first month of treatment, most commonly at doses of 300-500 mg/day. Abrupt withdrawal may precipitate seizures; discontinue or reduce doses gradually.

Adjunctive Therapy: Frequencies noted in patients receiving other anticonvulsants:

Central nervous system: Somnolence (17%), dizziness (13%)

Gastrointestinal: Anorexia (13%)

1% to 10%:

Central nervous system: Headache (10%), agitation/irritability (9%), fatigue (8%), tiredness (7%), ataxia (6%), confusion (6%), decreased concentration (6%), memory impairment (6%), depression (6%), insomnia (6%), speech disorders (5%), mental slowing (4%), anxiety (3%), nervousness (2%), schizophrenic/schizophreniform behavior (2%), difficulty in verbal expression (2%), status epilepticus (1%)

Dermatologic: Rash (3%), bruising (2%)

Gastrointestinal: Nausea (9%), abdominal pain (6%), diarrhea (5%), dyspepsia (3%), weight loss (3%), constipation (2%), dry mouth (2%), taste perversion (2%)

Neuromuscular & skeletal: Paresthesia (4%)

Ocular: Diplopia (6%), nystagmus (4%)

Respiratory: Rhinitis (2%)

Miscellaneous: Flu-like syndrome (4%)

Additional adverse effects have been reported as frequent (occur in at least 1:100 patients), infrequent (occur in 1:100 to 1:1000 patients), or rare (occur in less than 1:1000 patients):

Frequent: Tremor, convulsion, hyperesthesia, incoordination, pruritus, vomiting, weakness, abnormal gait, accidental injury, amblyopia, tinnitus, pharyngitis, increased cough

Infrequent: Flank pain, malaise, abnormal dreams, vertigo, movement disorder, hypotonia, euphoria, chest pain, facial edema, palpitations, tachycardia, vascular insufficiency, hypotension, hypertension, syncope, bradycardia, peripheral edema, edema, cerebrovascular accident, maculopapular rash, acne, alopecia, dry skin, eczema, urticaria, hirsutism, pustular rash, vesiculobullous rash, dehydration, decreased libido, amenorrhea, flatulence, gingivitis, gum hyperplasia, gastritis, gastroenteritis, stomatitis, glossitis, melena, ulcerative stomatitis, gastroduodenal ulcer, dysphagia, weight gain, urinary frequency, dysuria, urinary incontinence, impotence, urinary retention, urinary urgency, polyuria, nocturia, rectal hemorrhage, gum hemorrhage, leukopenia, anemia, cholelithiasis, thrombophlebitis, neck rigidity, leg cramps, myalgia, myasthenia, arthralgia, arthritis, hypertonia, neuropathy, twitching, hyperkinesia, dysarthria, peripheral neuritis, parethesia, increased reflexes, allergic reaction, lymphadenopathy, immunodeficiency, thirst, sweating, parosmia, conjunctivitis, visual field defect, glaucoma, deafness, hematuria, dyspnea

Rare: Dystonia, encephalopathy, atrial fibrillation, heart failure, ventricular extrasystoles, petechia, hypoglycemia, hyponatremia, gynecomastia, mastitis, menorrhagia, cholangitis, hematemesis, colitis, duodenitis, esophagitis, fecal incontinence, mouth ulceration, enuresis, bladder pain, bladder calculus, thrombocytopenia, microcytic anemia, cholecystitis, cholestatic jaundice, increased AST (SGOT), increased ALT (SGPT), circumoral paresthesia, dyskinesia, facial paralysis, hypokinesia, myoclonus, lupus erythematosus, increased lactic dehydrogenase, oculogyric crisis, photophobia, iritis, albuminuria, pulmonary embolus, apnea, hemoptysis

Case Reports: Stevens-Johnson syndrome, toxic epidermal necrolysis, aplastic anemia, agranulocytosis, kidney stones, increased BUN, increased serum creatinine, increased serum alkaline phosphatase

No specific antidotes are available; experience with doses >800 mg/day is limited. Emesis or gastric lavage, with airway protection, should be done following a recent overdose. General supportive care and close observation are indicated. Renal dialysis may not be effective due to low protein binding (40%).

CYP3A4 enzyme substrate

Zonisamide did not affect steady state levels of carbamazepine, phenytoin, or valproate.

Cimetidine: Single dose zonisamide levels were not altered by cimetidine.

Store at controlled room temperature 25°C (77°F). Protect from moisture and light.

The exact mechanism of action is not known. May stabilize neuronal membranes and suppress neuronal hypersynchronization through action at sodium and calcium channels. Does not affect GABA activity.

Distribution: V_d: 1.45 L/kg

Protein binding: 40%

Metabolism: Hepatic (CYP3A4), forms N-acetyl zonisamide and 2-sulfamoylacetyl phenol (SMAP)

Half-life: 63 hours

Time to peak: 2-6 hours

Elimination: Urine, 62% (35% as parent drug, 65% as metabolites); feces, 3%

Children >16 years and Adults: Oral: For the adjunctive treatment of partial seizures, initial dose is 100 mg/day. Dose may be increased to 200 mg/day after 2 weeks. Further dosage increases to 300 mg and 400 mg/day can then be made with a minimum of 2 weeks between adjustments, in order to reach steady state at each dosage level. Doses of up to 600 mg/day have been studied, however, there is no evidence of increased response with doses above 400 mg/day.

Dosage adjustment in renal/hepatic impairment: Slower titration and frequent monitoring are indicated in patients with renal or hepatic disease. Do not use if Cl_cr <50 mL/minute.

Elderly: Data from clinical trials is insufficient for patients over 65. Begin dosing at the low end of the dosing range.

May be taken with or without food.

Capsules should be swallowed whole; dose may be given once or twice daily; doses of 300 mg/day and higher are associated with increased side effects; steady state levels are reached in 14 days

Monitor BUN and serum creatinine

May cause drowsiness, especially at higher doses. Do not drive a car or operate other complex machinery until effects on performance can be determined. Avoid alcohol and other CNS depressants. Contact healthcare provider immediately if seizures worsen or for any of the following symptoms: skin rash; sudden back pain, abdominal pain, blood in the urine; fever, sore throat, oral ulcers, or easy bruising. Contact healthcare provider before becoming pregnant or breast-feeding. Swallow capsules whole, do not bite or break. It is important to drink 6-8 glasses of water each day while using this medication. Do not stop taking this or other seizure medications without talking to your healthcare professional first.

See Contraindications and Warning/Precautions for use.

Capsule: 100 mg