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Pronunciation
(zoe NIS a mide)
Generic Available (U.S.)
Yes
Medication Guide
An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/UCM152828.pdf, must be dispensed with this medication.
REMS Components
Zonegran®: Released from REMS requirement 5/27/2011
Brand Names: U.S.
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
Bipolar disorder
Pregnancy Risk Factor
C
Pregnancy Considerations
Teratogenic effects were observed in animal reproduction studies; therefore, zonisamide is classified as pregnancy category C. Zonisamide crosses the placenta and can be detected in the newborn following delivery. Although adverse fetal events have been reported, the risk of teratogenic effects following maternal use of zonisamide in not clearly defined. Other agents may be preferred until additional data is available. Newborns should be monitored for transient metabolic acidosis after birth. Zonisamide clearance may increase in the second trimester of pregnancy, requiring dosage adjustment. Women of childbearing potential are advised to use effective contraception during therapy.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 http://www.aedpregnancyregistry.org.
Lactation
Excreted into breast milk /not recommended
Breast-Feeding Considerations
Zonisamide is excreted into breast milk in concentrations similar to those in the maternal plasma and has been detected in the plasma of a nursing infant. According to the manufacturer, the decision to continue or discontinue breast-feeding during therapy should take into account the risk of exposure to the infant and the benefits of treatment to the mother.
Contraindications
Hypersensitivity to zonisamide, sulfonamides, or any component of the formulation
Warnings/Precautions
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
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. May cause sedation, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
• 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. 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. Untreated metabolic acidosis may increase the risk of developing nephrolithiasis, nephrocalcinosis, osteomalacia, or osteoporosis.
• 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, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, 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: Do not use in patients with renal impairment (GFR <50 mL/minute).
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. Pediatric patients may be at an increased risk and may have more severe metabolic acidosis. Untreated metabolic acidosis may increase the risk of developing rickets in children; pediatric patients may also have decreased growth rates.
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
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%), seizure (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%), taste perversion (2%), xerostomia (2%), vomiting (1%)
Neuromuscular & skeletal: Paresthesia (4%), abnormal gait (1%), tremor (1%), weakness (1%)
Ocular: Diplopia (6%), nystagmus (4%), amblyopia (1%)
Otic: Tinnitus (1%)
Renal: Kidney stones (4%, children 3% to 8%)
Respiratory: Rhinitis (2%), cough increased (1%), pharyngitis (1%)
Miscellaneous: Flu-like syndrome (4%), accidental injury (1%)
<1%, postmarketing, and/or case reports: Abnormal dreams, acne, agranulocytosis, albuminuria, allergic reaction, alopecia, ALT increased, amenorrhea, anemia, aplastic anemia, apnea, arthralgia, arthritis, AST increased, atrial fibrillation, bladder calculus, bladder pain, bradycardia, BUN increased, cerebrovascular accident, chest pain, cholangitis, cholecystitis, cholelithiasis, cholestatic jaundice, colitis, conjunctivitis, CPK increased, 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, gastroenteritis, gingival hyperplasia, gingivitis, GI ulcer, glaucoma, glossitis, gum hemorrhage, gynecomastia, heart failure, hematuria, hemoptysis, hirsutism, hyper-/hypokinesia, hyper-/hypotension, hyper-/hypotonia, hyperthermia (children), hypoglycemia, hyponatremia, immunodeficiency, impotence, iritis, lactic dehydrogenase increased, leg cramps, leukopenia, libido decreased, lupus erythematosus, lymphadenopathy, maculopapular rash, malaise, mastitis, melena, menorrhagia, metabolic acidosis, microcytic anemia, mouth ulceration, movement disorder, myalgia, myasthenia, myoclonus, neck rigidity, neuropathy, nocturia, oculogyric crisis, oligohidrosis (children), palpitation, pancreatitis, parosmia, peripheral edema, peripheral neuritis, petechia, photophobia, polyuria, pulmonary embolus, pustular rash, rectal hemorrhage, reflexes increased, rhabdomyolysis, serum alkaline phosphatase increased, serum creatinine increased, Stevens-Johnson syndrome, stomatitis, suicidal behavior/ideation, syncope, tachycardia, thirst, thrombocytopenia, thrombophlebitis, toxic epidermal necrolysis, twitching, ulcerative stomatitis, urinary frequency, urinary incontinence, urinary retention, urinary urgency, urticaria, vascular insufficiency, ventricular extrasystoles, vertigo, vesiculobullous rash, visual field defect, weight gain
Metabolism/Transport Effects
Substrate of CYP2C19 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Drug Interactions
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alpha-/Beta-Agonists: Carbonic Anhydrase Inhibitors may decrease the excretion of Alpha-/Beta-Agonists. Exceptions: Dipivefrin. Risk C: Monitor therapy
Amphetamines: Carbonic Anhydrase Inhibitors may decrease the excretion of Amphetamines. Risk C: Monitor therapy
Anticonvulsants (Barbiturate): Carbonic Anhydrase Inhibitors may enhance the adverse/toxic effect of Anticonvulsants (Barbiturate). Specifically, osteomalacia and rickets. Risk C: Monitor therapy
Anticonvulsants (Hydantoin): Carbonic Anhydrase Inhibitors may enhance the adverse/toxic effect of Anticonvulsants (Hydantoin). Specifically, osteomalacia and rickets. Risk C: Monitor therapy
CarBAMazepine: Carbonic Anhydrase Inhibitors may increase the serum concentration of CarBAMazepine. Risk C: Monitor therapy
Carbonic Anhydrase Inhibitors: May enhance the adverse/toxic effect of other Carbonic Anhydrase Inhibitors. The development of acid-base disorders with concurrent use of ophthalmic and oral carbonic anhydrase inhibitors has been reported. Management: Avoid concurrent use of different carbonic anhydrase inhibitors if possible. Monitor patients closely for the occurrence of kidney stones and with regards to severity of metabolic acidosis. Risk X: Avoid combination
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid combination
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
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Flecainide: Carbonic Anhydrase Inhibitors may increase the serum concentration of Flecainide. Risk C: Monitor therapy
Fosphenytoin: May decrease the serum concentration of Zonisamide. Risk C: Monitor therapy
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Ketorolac: May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy
Ketorolac (Nasal): May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy
Ketorolac (Systemic): May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy
Lithium: Carbonic Anhydrase Inhibitors may decrease the serum concentration of Lithium. 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
Memantine: Carbonic Anhydrase Inhibitors may decrease the excretion of Memantine. Risk C: Monitor therapy
MetFORMIN: Carbonic Anhydrase Inhibitors may enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk of developing lactic acidosis may be increased. Risk C: Monitor therapy
Methenamine: Carbonic Anhydrase Inhibitors may diminish the therapeutic effect of Methenamine. Management: Consider avoiding this combination. Monitor for decreased therapeutic effects of methenamine if used concomitant with a carbonic anhydrase inhibitor. 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 decrease the serum concentration of Zonisamide. Risk C: Monitor therapy
Primidone: Carbonic Anhydrase Inhibitors may enhance the adverse/toxic effect of Primidone. Specifically, osteomalacia and rickets. Carbonic Anhydrase Inhibitors may decrease the serum concentration of Primidone. Risk C: Monitor therapy
QuiNIDine: Carbonic Anhydrase Inhibitors may decrease the excretion of QuiNIDine. Risk C: Monitor therapy
Salicylates: May enhance the adverse/toxic effect of Carbonic Anhydrase Inhibitors. Salicylate toxicity might be enhanced by this same combination. Risk D: Consider therapy modification
Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Risk C: Monitor therapy
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: May increase CNS depression; monitor for increased effects with coadministration. Caution patients about effects.
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: Plasma: ~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. Use is not recommended in patients with 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
Metabolic profile, specifically 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 at the same time each day, with or without food. Do not chew, crush, or open capsules; swallow whole. Maintain adequate hydration unless instructed to restrict fluid intake. While using this medication, avoid alcohol. Wear/carry identification of epileptic status and medications. You may experience drowsiness, dizziness, blurred vision, nausea, vomiting, constipation, dry mouth, or loss of appetite. Report CNS changes (changes in speech patterns, mentation changes, suicide 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 change in seizure type or frequency.
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
Observe and teach seizure precautions.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, oral: 25 mg, 50 mg, 100 mg
Zonegran®: 25 mg, 100 mg
Pricing: U.S. (www.drugstore.com)
Capsules (Zonegran)
25 mg (30): $39.99
100 mg (30): $131.99
Capsules (Zonisamide)
25 mg (100): $50.99
50 mg (100): $91.99
100 mg (30): $59.99
Extemporaneously Prepared
Hazardous agent; use appropriate precautions during preparation and disposal.
A 10 mg/mL suspension may be made using capsules and either simple syrup or methylcellulose 0.5%. Empty contents of ten 100 mg capsules into glass mortar. Reduce to a fine powder and add a small amount of Simple Syrup, NF and mix to a uniform paste; mix while adding the chosen vehicle in incremental proportions to almost 100 mL; transfer to an amber calibrated plastic bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 100 mL. Label "shake well" and "refrigerate". When using simple syrup vehicle, stable 28 days at room temperature or refrigerated (preferred). When using methylcellulose vehicle, stable 7 days at room temperature or 28 days refrigerated. Note: Although no visual evidence of microbial growth was observed, storage under refrigeration would be recommended to minimize microbial contamination.
Abobo CV, Wei B, and Liang D, "Stability of Zonisamide in Extemporaneously Compounded Oral Suspensions," Am J Health Syst Pharm, 2009, 66(12):1105-9.
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.
Kimura S, “Zonisamide-Induced Behavior Disorder in Two Children,” Epilepsia, 1994, 35(2):403-5.
International Brand Names
Lexi-Comp.com
Last full review/revision March 2012
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