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Medication Safety Issues
Sound-alike/look-alike issues:
Zonegran® may be confused with Sinequan®
Zonisamide may be confused with lacosamide
Pronunciation
(zoe NIS a mide)
U.S. Brand Names
Generic Available
Yes
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Adjunct treatment of partial seizures in children >16 years of age and adults with epilepsy
Use: Unlabeled/Investigational
Bipolar disorder
Pregnancy Risk Factor
C
Pregnancy Considerations
Fetal abnormalities and death have been reported in animals, however, there are no studies in pregnant women. Based on limited case reports, it appears zonisamide crosses the placenta. Use during pregnancy only if the potential benefits outweigh the potential risks.Patients exposed to zonisamide during pregnancy are encouraged to enroll themselves into the AED Pregnancy Registry by calling 1-888-233-2334. Additional information is available at www.aedpregnancyregistry.org.
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
Based on limited case reports, it appears zonisamide is excreted in breast milk. Use during lactation only if the potential benefits outweigh the potential risks.
Contraindications
Hypersensitivity to zonisamide, sulfonamides, or any component of the formulation
Warnings/Precautions
Concerns related to adverse effects:
• CNS effects: 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.
• Metabolic acidosis: Use may be associated with the development of metabolic acidosis (generally dose-dependent) in certain patients; predisposing conditions/therapies include renal disease, severe respiratory disease, diarrhea, surgery, ketogenic diet, and other medications. Pediatric patients may also be at an increased risk and may have more severe metabolic acidosis. Serum bicarbonate should be monitored prior to initiation and during therapy; if metabolic acidosis occurs, consider decreasing the dose or tapering the dose to discontinue. If use continued despite acidosis, alkali treatment should be considered.
• Renal calculus: Discontinue therapy in patients who develop acute renal failure or a significant sustained increase in creatinine/BUN concentration; kidney stones have been reported.
• Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ?24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify healthcare provider immediately if symptoms occur.
• Sulfonamide reactions: Rare, but potentially fatal sulfonamide reactions have occurred following use. These reactions include Stevens-Johnson syndrome and toxic epidermal necrolysis, usually appearing within 2-16 weeks of drug initiation; discontinue if rash develops. Chemical similarities are present among sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides, and loop diuretics (except ethacrynic acid). Use in patients with sulfonamide allergy is specifically contraindicated in product labeling, however, a risk of cross-reaction exists in patients with allergy to any of these compounds; avoid use when previous reaction has been severe.
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Renal impairment: Use with caution in patients with renal impairment.
Concurrent drug therapy issues:
• Sedatives: Effects with other sedative drugs or ethanol may be potentiated.
Special populations:
• Pediatrics: Safety and efficacy have not been established in children <16 years of age. Decreased sweating (oligohydrosis) and hyperthermia requiring hospitalization have been reported in children.
Other warnings/precautions:
• Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.
Adverse Reactions
Adjunctive therapy: Frequencies noted in patients receiving other anticonvulsants:
>10%:
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%), concentration decreased (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%), convulsion (1%), hyperesthesia (1%), incoordination (1%)
Dermatologic: Rash (3%), bruising (2%), pruritus (1%)
Gastrointestinal: Nausea (9%), abdominal pain (6%), diarrhea (5%), dyspepsia (3%), weight loss (3%), constipation (2%), dry mouth (2%), taste perversion (2%), vomiting (1%)
Neuromuscular & skeletal: Paresthesia (4%), abnormal gait (1%), tremor (1%), weakness (1%)
Ocular: Diplopia (6%), nystagmus (4%), amblyopia (1%)
Otic: Tinnitus (1%)
Respiratory: Rhinitis (2%), cough increased (1%), pharyngitis (1%)
Miscellaneous: Flu-like syndrome (4%), accidental injury (1%)
<1%: Abnormal dreams, acne, albuminuria, allergic reaction, alopecia, ALT increased, amenorrhea, anemia, apnea, arthralgia, arthritis, AST increased, atrial fibrillation, bladder calculus, bladder pain, bradycardia, cerebrovascular accident, chest pain, cholangitis, cholecystitis, cholelithiasis, cholestatic jaundice, circumoral paresthesia, colitis, conjunctivitis, deafness, dehydration, diaphoresis, dry skin, duodenitis, dysarthria, dyskinesia, dysphagia, dyspnea, dystonia, dysuria, eczema, edema, encephalopathy, enuresis, esophagitis, euphoria, facial edema, facial paralysis, fecal incontinence, flank pain, flatulence, gastritis, gastroduodenal ulcer, gastroenteritis, gingivitis, glaucoma, glossitis, gum hemorrhage, gum hyperplasia, gynecomastia, heart failure, hematemesis, hematuria, hemoptysis, hirsutism, hyper-/hypokinesia, hyper-/hypotension, hyper-/hypotonia, hypoglycemia, hyponatremia, immunodeficiency, impotence, iritis, lactic dehydrogenase increased, leg cramps, leukopenia, libido decreased, lupus erythematosus, lymphadenopathy, maculopapular rash, malaise, mastitis, melena, menorrhagia, microcytic anemia, mouth ulceration, movement disorder, myalgia, myasthenia, myoclonus, neck rigidity, neuropathy, nocturia, oculogyric crisis, palpitation, parosmia, peripheral edema, peripheral neuritis, petechia, photophobia, polyuria, pulmonary embolus, pustular rash, rectal hemorrhage, reflexes increased, stomatitis, syncope, tachycardia, thirst, thrombocytopenia, thrombophlebitis, twitching, ulcerative stomatitis, urinary frequency, urinary incontinence, urinary retention, urinary urgency, urticaria, vascular insufficiency, ventricular extrasystoles, vertigo, vesiculobullous rash, visual field defect, weight gain
Postmarketing and/or case reports: Agranulocytosis, aplastic anemia, BUN increased, hyperthermia, kidney stones, metabolic acidosis, oligohydrosis, serum creatinine increased, serum alkaline phosphatase increased, Stevens-Johnson syndrome, suicidal behavior/ideation, toxic epidermal necrolysis
Metabolism/Transport Effects
Substrate of CYP2C19 (minor), 3A4 (major)
Drug Interactions
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Ketorolac: May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy
Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Risk D: Consider therapy modification
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification
PHENobarbital: May decrease the serum concentration of Zonisamide. Risk C: Monitor therapy
Phenytoin: May increase the metabolism of Zonisamide. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (may increase CNS depression).
Food: Food delays time to maximum concentration, but does not affect bioavailability.
Storage
Store at controlled room temperature 25°C (77°F). Protect from moisture and light.
Mechanism of Action
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.
Pharmacodynamics/Kinetics
Distribution: Vd: 1.45 L/kg
Protein binding: 40%
Metabolism: Hepatic via CYP3A4; forms N-acetyl zonisamide and 2-sulfamoylacetyl phenol (SMAP)
Half-life elimination: 63 hours
Time to peak: 2-6 hours
Excretion: Urine (62%, 35% as unchanged drug, 65% as metabolites); feces (3%)
Dosage
Oral:
Children >16 years and Adults:
Adjunctive treatment of partial seizures: Initial: 100 mg/day; dose may be increased to 200 mg/day after 2 weeks. Further dosage increases to 300 mg/day 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.
Mania (unlabeled use): Initial: 100-200 mg/day; maximum: 600 mg/day (Kanba, 1994)
Elderly: Data from clinical trials is insufficient for patients >65 years; begin dosing at the low end of the dosing range.
Dosage adjustment in renal/hepatic impairment: Slower titration and frequent monitoring are indicated in patients with renal or hepatic disease. There is insufficient experience regarding dosing/toxicity in patients with estimated GFR <50 mL/minute. Marked renal impairment (Clcr <20 mL/minute) was associated with a 35% increase in AUC.
Administration: Oral
Capsules should be swallowed whole. Dose may be administered 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.
Monitoring Parameters
BUN, serum creatinine; serum bicarbonate (prior to initiation and periodically during therapy); suicidality (eg, suicidal thoughts, depression, behavioral changes)
Dietary Considerations
May be taken without regard to meals.
Patient Education
Take exactly as directed, as the same time each day, with or without food. Do not increase frequency, alter dose, or discontinue without consulting prescriber. If you miss a dose, take as soon as possible. If it is almost time for your next dose, skip the missed dose. Do not chew, crush, or open capsules; swallow whole. Maintain adequate hydration unless instructed to restrict fluid intake. Avoid grapefruit juice while on this medication. While using this medication, avoid alcohol, herbal remedies, OTC or prescriptions drugs (especially pain medication, antihistamines, psychiatric medications, sedatives, or hypnotics) unless approved by your prescriber. Wear/carry identification of epileptic status and medications. You may experience drowsiness, dizziness, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); or nausea, vomiting, constipation, dry mouth, or loss of appetite (small frequent meals, frequent mouth care, chewing gum, or sucking hard candy may help). Report CNS changes (changes in speech patterns, mentation changes, suicidal ideation, depression, changes in cognition or memory, unusual thought patterns, coordination difficulties, or excessive drowsiness); extreme fatigue, loss of appetite, or hyperventilation; respiratory difficulty or tightening of the throat; swelling of mouth, lips, or tongue; muscle cramping, weakness, or pain; rash or skin irritations; unusual bruising or bleeding (mouth, urine, stool); fever, sore throat, or sores in your mouth; swelling of extremities; sudden back pain, pain on urination, or dark/bloody urine (signs of kidney stones); or other adverse responses, including change in seizure type or frequency. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed.
Geriatric Considerations
Consider the CNS effects commonly experienced in the first month of therapy.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation) and abnormal taste.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Nursing: Physical Assessment/Monitoring
Assess other medications patient may be taking for increased risk of drug/drug interactions. Monitor therapeutic effectiveness, laboratory results, and adverse reactions at beginning of therapy and periodically with long-term use. Observe and teach seizure precautions. Assess knowledge/teach patient appropriate use, interventions to reduce side effects, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule: 25 mg, 50 mg, 100 mg
Zonegran®: 25 mg, 100 mg
Pricing: U.S. (www.drugstore.com)
Capsules (Zonegran)
25 mg (30): $34.00
100 mg (30): $97.47
Capsules (Zonisamide)
25 mg (100): $49.99
50 mg (100): $91.99
100 mg (30): $59.99
References
Kanba S, Yagi G, Kamijima K, et al, “The First Open Study of Zonisamide, A Novel Anticonvulsant, Shows Efficacy in Mania,” Prog Neuropsychopharmacol Biol Psychiatry, 1994, 18(4):707-15.
Kawada K, Itoh S, Kusaka T, et al, “Pharmacokinetics of Zonisamide in Perinatal Period,” Brain Dev, 2002, 24(2):95-7.
International Brand Names
Lexi-Comp.com
Last full review/revision November 2009
Content last modified November 2009
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