Binge eating disorder (off-label use):
Oral: Initial: 100 mg/day for 7 days; may increase dose based on response and tolerability in increments of 100 mg/day every week to a maximum dose of 600 mg/day in 1 or 2 divided doses (Ref). Alternatively, 25 mg/day for 7 days has been studied; may increase dose based on response and tolerability in increments of 50 mg/day every week to a maximum daily dose of 100 mg in patients with a BMI <35 kg/m2 or 150 mg for a BMI ≥35 kg/m2 (Ref).
Focal (partial) onset seizures:
Note: FDA approved for adjunctive treatment of focal (partial) onset seizures; may be used off label as monotherapy for focal (partial) onset seizures (Ref).
Oral: Initial: 100 mg/day in 1 to 2 divided doses. May increase in increments of 100 mg/day every 2 weeks based on response and tolerability up to 400 mg/day. Doses of up to 600 mg/day have been studied; however, there is no evidence of increased response with doses >400 mg/day, and doses ≥300 mg/day are associated with increased side effects.
Discontinuation of therapy: In chronic therapy, withdraw gradually to minimize the potential of increased seizure frequency and status epilepticus (in patients with epilepsy) and withdrawal symptoms (eg, dysphoria, hallucinations, headache, insomnia, tremor), unless safety concerns require more rapid withdrawal. For seizure disorders, some experts suggest withdrawing antiseizure drugs over a few to several (eg, 2 to 6) months (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Kidney impairment prior to treatment initiation:
GFR ≥50 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling. However, slower titration and frequent monitoring are indicated in patients with kidney disease; use with caution.
GFR <50 mL/minute: Use is not recommended. Marked renal impairment may be associated with increased exposure.
Nephrotoxicity or acute kidney injury during treatment:
Discontinue use in patients who develop acute kidney injury or significant, sustained increase in serum creatinine or BUN.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). However, slower titration and frequent monitoring are indicated in patients with hepatic impairment; use with caution.
Dermatologic reactions: Discontinue at the first sign of rash, unless the rash is clearly not drug-related. If Stevens-Johnson syndrome or toxic epidermal necrolysis is suspected, do not resume zonisamide and consider alternative therapy.
Drug reaction with eosinophilia and systemic symptoms: Discontinue therapy if another cause for signs/symptoms of DRESS cannot be established.
Hypersensitivity or other serious reactions: Discontinue immediately if signs of hypersensitivity or other serious reactions (eg, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, other blood dyscrasias) occur.
Metabolic acidosis: If metabolic acidosis develops and persists, consider decreasing dose or tapering dose to discontinue. If continuing zonisamide despite persistent acidosis, consider alkali treatment.
Ophthalmic effects: Discontinue in patients with acute onset of decreased visual acuity and/or ocular pain.
Refer to adult dosing. Use with caution; initiate therapy at the low end of the dosing range.
(For additional information see "Zonisamide: Pediatric drug information")
Partial-onset seizures; adjunct therapy: Note: Zonisamide is approved as adjunct therapy, and trials have also shown efficacy as monotherapy; however, based on results of the SANAD II trial, zonisamide should not be used as first-line therapy in patients ≥5 years, as other agents have shown greater efficacy with a more positive adverse effect profile (Ref).
Children <5 years: Limited data available: Oral: Initial: 1 to 2 mg/kg/day in 2 divided doses; increase dose in increments of 0.5 to 1 mg/kg/day once or twice daily every 2 weeks; usual dose: 5 to 8 mg/kg/day (Ref).
Children ≥5 years and Adolescents <16 years: Limited data available: Oral: Initial: 0.5 to 1 mg/kg/day in 1 to 2 divided doses; increase dose in increments of 0.5 to 1 mg/kg/day in 2 divided doses every 2 weeks; if patients require more rapid titration, dose may be increased in 1.5 mg/kg/day increments; if concomitant CYP3A4 inducing agent, may increase at weekly intervals. Reported usual dose: 5 to 8 mg/kg/day in 1 or 2 divided doses, although some patients may require up to 12 mg/kg/day or a maximum daily dose of 500 mg/day once daily or in 2 divided doses, whichever is less (Ref).
Adolescents ≥16 years: Oral: Initial: 100 mg once daily; dose may be increased to 200 mg/day after 2 weeks; further increases in dose should be made in increments of 100 mg/day and only after a minimum of 2 weeks between adjustments; usual effective dose: 100 to 600 mg/day (Ref). Note: There is no evidence of increased benefit with doses >400 mg/day. Steady-state serum concentrations fluctuate 27% with once-daily dosing, and 14% with twice-daily dosing; patients may benefit from divided doses given twice daily (Ref).
Discontinuation of therapy: Limited data available: Children ≥6 years and Adolescents: There is currently no standard method for the withdrawal of antiseizure medications in pediatric patients. Successful discontinuation of an antiseizure medication is dependent on several factors, including but not limited to: Time of seizure freedom, underlying reason for the seizures, neuroimaging abnormalities, underlying neurodevelopmental status, and medication to be withdrawn (including dose, duration of therapy, and other pharmacokinetic/dynamic considerations) (Ref). To minimize the potential of increased seizure frequency, chronic zonisamide therapy should be withdrawn gradually. In pediatric patients, it has been suggested to decrease dose in ~2 mg/kg increments at weekly intervals (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Slower dosage titration and more frequent monitoring are recommended. Do not use if GFR <50 mL/minute. Marked renal impairment (CrCl <20 mL/minute) was associated with a 35% increase in AUC.
Slower titration and frequent monitoring are indicated.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Frequency not always defined. Frequencies noted in patients receiving other antiseizure medications:
>10%:
Gastrointestinal: Anorexia (13%)
Nervous system: Dizziness (13%), drowsiness (17%)
1% to 10%:
Cardiovascular: Facial edema (≤1%)
Dermatologic: Ecchymoses (2%), hypohidrosis (children), pruritus (≥1%), skin rash (3%), Stevens-Johnson syndrome, toxic epidermal necrolysis
Endocrine & metabolic: Metabolic acidosis
Gastrointestinal: Abdominal pain (6%), constipation (2%), diarrhea (5%), dysgeusia (2%), dyspepsia (3%), nausea (9%), vomiting (≥1%), weight loss (3%), xerostomia (2%)
Hematologic & oncologic: Agranulocytosis, aplastic anemia
Nervous system: Agitation (≤9%), anxiety (3%), ataxia (≥1% to 6%), confusion (6%), decreased mental acuity (4%), depression (6%), dysphasia (2%), fatigue (8%), headache (10%), hyperesthesia (≥1%), hyperthermia, hypotonia (≤1%), insomnia (6%), irritability (≤9%), lack of concentration (6%), memory impairment (6%), nervousness (2%), schizophreniform disorder (2%), seizure (≥1%), speech disturbance (5%), status epilepticus (1%), tiredness (7%)
Neuromuscular & skeletal: Abnormal gait (≥1%), asthenia (≥1%), paresthesia (4%), tremor (≥1%)
Ophthalmic: Amblyopia (≥1%), diplopia (6%), nystagmus disorder (4%)
Otic: Tinnitus (≥1%)
Renal: Nephrolithiasis (4%; children: 3% to 8%)
Respiratory: Increased cough (≥1%), pharyngitis (≥1%), rhinitis (2%)
Miscellaneous: Accidental injury (≥1%), flu-like syndrome (4%)
<1%, postmarketing, and/or case reports: Abnormal dreams, acne vulgaris, acute myopia, acute pancreatitis, albuminuria, alopecia, amenorrhea, anemia, angle-closure glaucoma, aphthous stomatitis, apnea, arthralgia, arthritis, atrial fibrillation, bladder calculus, bladder pain, bradycardia, cardiac failure, cerebrovascular accident, chest pain, cholangitis, cholecystitis, cholelithiasis, cholestatic jaundice, colitis, conjunctivitis, deafness, decreased libido, decreased serum albumin, decreased serum bicarbonate, decreased serum calcium, dehydration, diaphoresis, drug reaction with eosinophilia and systemic symptoms, duodenitis, dysarthria, dyskinesia, dysphagia, dyspnea, dystonia, dysuria, eczema, edema, encephalopathy, esophagitis, euphoria, facial nerve paralysis, fecal incontinence, flank pain, flatulence, gastritis, gastroenteritis, gastrointestinal ulcer, gingival hemorrhage, gingival hyperplasia, gingivitis, glaucoma, glossitis, gynecomastia, heavy menstrual bleeding, hematemesis, hematuria, hemoptysis, hirsutism, hyperammonemia, hyperchloremia, hyperkinetic muscle activity, hyperreflexia, hypersensitivity reaction, hypertension, hypertonia, hypoglycemia, hypokinesia, hyponatremia, hypophosphatemia, hypotension, immunodeficiency, impotence, increased blood urea nitrogen, increased creatine phosphokinase in blood specimen, increased lactic dehydrogenase, increased serum alanine aminotransferase, increased serum alkaline phosphatase, increased serum aspartate aminotransferase, increased serum creatinine, increased thirst, iritis, leukopenia, lower limb cramp, lupus erythematosus, lymphadenopathy, maculopapular rash, malaise, mastitis, melena, microcytic anemia, movement disorder, myalgia, myasthenia, myoclonus, neck stiffness, neuropathy, nocturia, oculogyric crisis, oral mucosa ulcer, palpitation, peripheral edema, peripheral neuritis, petechia, photophobia, polyuria, psychomotor disturbance, psychosis, pulmonary embolism, pustular rash, rectal hemorrhage, rhabdomyolysis, stomatitis, suicidal behavior, suicidal ideation, syncope, tachycardia, thrombocytopenia, thrombophlebitis, twitching, urinary frequency, urinary incontinence, urinary retention, urinary urgency, urticaria, vascular insufficiency, ventricular premature contractions, vertigo, vesiculobullous dermatitis, visual field defect, weight gain, xeroderma
Hypersensitivity to zonisamide, sulfonamides, or any component of the formulation
Note: Although the FDA-approved product labeling states this medication is contraindicated in patients with hypersensitivity to sulfonamide-containing drugs, the scientific basis of this cross-sensitivity has been challenged. See “Warnings/Precautions” for more detail.
Concerns related to adverse effects:
• CNS effects: Significant CNS effects include psychiatric symptoms (eg, depression, psychosis), psychomotor slowing (eg, difficulty with concentration, speech or language problems), and fatigue or somnolence; may occur within the first month of treatment, most commonly at doses of ≥300 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).
• Dermatologic reactions: Severe reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with an onset typically early in therapy.
• Hyperammonemia/encephalopathy: Hyperammonemia, with or without encephalopathy, may occur with monotherapy or in combination with other medications (eg, valproic acid, topiramate); incidence and severity may be dose related. Risk may be increased in patients with inborn errors of metabolism or decreased hepatic mitochondrial activity. May be asymptomatic; monitor for lethargy, vomiting, or unexplained changes in mental status. Hyperammonemia should resolve with a decreased dose or discontinuation of therapy.
• Metabolic acidosis: Use may be associated with the development of metabolic acidosis in certain patients; predisposing conditions/therapies include renal disease, severe respiratory disease, diarrhea, status epilepticus, ketogenic diet, and other medications. Onset typically occurs early in treatment but may develop at any time. Metabolic acidosis is generally dose-dependent but can occur at doses as low as 25 mg daily. Monitor serum bicarbonate. If metabolic acidosis occurs and treatment is continued, alkali treatment should be considered. Untreated metabolic acidosis may increase the risk of developing nephrolithiasis, nephrocalcinosis, osteomalacia, or osteoporosis.
• Multiorgan hypersensitivity reactions: Potentially serious, sometimes fatal drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity reactions, have been reported. Monitor for signs and symptoms (eg, fever, rash, lymphadenopathy, facial swelling, eosinophilia) in association with other organ system involvement (eg, hepatitis, nephritis, hematological abnormalities, myocarditis, myositis). Evaluate immediately if signs or symptoms are present.
• Ophthalmic effects: Has been associated with acute myopia and secondary angle-closure glaucoma in adults and children, typically within 1 month of initiation.
• Renal effects: Creatinine and BUN elevations have been reported; monitor renal function. Kidney stones have also been reported.
• Suicidal ideation: Pooled analysis of trials involving various antiseizure medications (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 (“sulfa”) allergy: The FDA-approved product labeling for many medications containing a sulfonamide chemical group includes a broad contraindication in patients with a prior allergic reaction to sulfonamides. There is a potential for cross-reactivity between members of a specific class (eg, two antibiotic sulfonamides). However, concerns for cross-reactivity have previously extended to all compounds containing the sulfonamide structure (SO2NH2). An expanded understanding of allergic mechanisms indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur or at the very least this potential is extremely low (Brackett 2004; Johnson 2005; Slatore 2004; Tornero 2004). In particular, mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur with nonantibiotic sulfonamides. T-cell-mediated (type IV) reactions (eg, maculopapular rash) are less well understood and it is not possible to completely exclude this potential based on current insights. In cases where prior reactions were severe (Stevens-Johnson syndrome/TEN), some clinicians choose to avoid exposure to these classes.
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).
Other warnings/precautions:
• Withdrawal: Antiseizure medications 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.
Pediatric patients may also be at an increased risk and may have more severe metabolic acidosis. Untreated metabolic acidosis may increase the risk of developing nephrolithiasis, nephrocalcinosis, osteomalacia (or rickets in children), or osteoporosis; pediatric patients may also have decreased growth rates. Oligohydrosis (decreased sweating) and hyperthermia have been reported in 40 pediatric patients; many cases occurred after exposure to elevated environmental temperatures; some cases resulted in heat stroke requiring hospitalization; pediatric patients may be at an increased risk; monitor patients, especially pediatric patients, for decreased sweating and hyperthermia, especially in warm or hot weather; use zonisamide with caution in patients receiving drugs that predispose to heat-related disorders (eg, anticholinergic agents, carbonic anhydrase inhibitors). In children, agitation, anxiety, ataxia, and behavior disorders have been reported (Kimura 1994).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Zonegran: 25 mg
Zonegran: 100 mg [contains fd&c red #40 (allura red ac dye), fd&c yellow #6 (sunset yellow)]
Generic: 25 mg, 50 mg, 100 mg
Suspension, Oral:
Zonisade: 100 mg/5 mL (150 mL) [contains sodium benzoate; strawberry flavor]
May be product dependent
Capsules (Zonegran Oral)
25 mg (per each): $19.66
100 mg (per each): $25.45
Capsules (Zonisamide Oral)
25 mg (per each): $0.17 - $0.55
50 mg (per each): $0.19 - $1.10
100 mg (per each): $0.66 - $2.19
Suspension (Zonisade Oral)
100 mg/5 mL (per mL): $2.97
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Oral:
Capsules: Swallow whole; administer with or without food.
Oral suspension: Shake well before use. Measure dose using provided oral syringe. A household teaspoon or tablespoon is not an adequate measuring device and should not be used. Administer with or without food.
Oral: May be administered without regard to meals.
Capsule: Swallow capsule whole; do not crush, chew, or break capsule.
Oral suspension: Shake well before use. Measure dose using provided oral syringe. A household teaspoon or tablespoon is not an adequate measuring device and should not be used.
Hazardous agent (NIOSH 2016 [group 3]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020789s036lbl.pdf#page=25, must be dispensed with this medication.
Focal (partial) onset seizures: Adjunctive therapy in the treatment of focal (partial) onset seizures in adolescents >16 years of age and adults.
Binge eating disorder
Zonegran may be confused with SINEquan
Zonisamide may be confused with lacosamide
Substrate of CYP2C19 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Alpha-/Beta-Agonists (Indirect-Acting): Carbonic Anhydrase Inhibitors may increase the serum concentration of Alpha-/Beta-Agonists (Indirect-Acting). Risk C: Monitor therapy
Amantadine: Carbonic Anhydrase Inhibitors may increase the serum concentration of Amantadine. Risk C: Monitor therapy
Amphetamines: Carbonic Anhydrase Inhibitors may decrease the excretion of Amphetamines. Risk C: Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification
Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. 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
Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Zonisamide. Risk C: Monitor therapy
Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy
DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Doxylamine: CNS Depressants may enhance the CNS depressant effect of Doxylamine. 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 (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Flecainide: Carbonic Anhydrase Inhibitors may decrease the excretion of Flecainide. Risk C: Monitor therapy
Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification
Ixabepilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Lacosamide: Antiseizure Agents (Sodium Channel Blockers) may enhance the adverse/toxic effect of Lacosamide. Specifically the risk for bradycardia, ventricular tachyarrhythmias, or a prolonged PR interval may be increased. Risk C: Monitor therapy
LamoTRIgine: Zonisamide may enhance the arrhythmogenic effect of LamoTRIgine. LamoTRIgine may enhance the CNS depressant effect of Zonisamide. Management: Consider the risk of serious arrhythmias or death versus any expected benefit of lamotrigine in patients receiving concomitant sodium channel blockers. Additionally, if combined, caution patients that CNS depressant effects may be increased. Risk D: Consider therapy modification
Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lithium: Carbonic Anhydrase Inhibitors may decrease the serum concentration of Lithium. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Mefloquine: May diminish the therapeutic effect of Antiseizure Agents. Mefloquine may decrease the serum concentration of Antiseizure Agents. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of seizures. If antiseizure drugs are being used for another indication, monitor antiseizure drug concentrations and treatment response closely with concurrent use. Risk D: Consider therapy modification
Memantine: Carbonic Anhydrase Inhibitors may increase the serum concentration 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 the concomitant use of medications that alkalinize the urine, such as carbonic anhydrase inhibitors, and methenamine. 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 the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
MetyraPONE: Antiseizure Agents may diminish the diagnostic effect of MetyraPONE. Management: Consider alternatives to the use of the metyrapone test in patients taking antiseizure agents. Risk D: Consider therapy modification
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
Mianserin: May diminish the therapeutic effect of Antiseizure Agents. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Nabilone: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Orlistat: May decrease the serum concentration of Antiseizure Agents. Risk C: Monitor therapy
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
PHENobarbital: Zonisamide may enhance the CNS depressant effect of PHENobarbital. PHENobarbital may decrease the serum concentration of Zonisamide. Risk C: Monitor therapy
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
Primidone: Zonisamide may enhance the CNS depressant effect of Primidone. Primidone may decrease the serum concentration of Zonisamide. Risk C: Monitor therapy
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
Salicylates: May enhance the adverse/toxic effect of Carbonic Anhydrase Inhibitors. Salicylate toxicity might be enhanced by this same combination. Management: Avoid these combinations when possible.Dichlorphenamide use with high-dose aspirin as contraindicated. If another combination is used, monitor patients closely for adverse effects. Tachypnea, anorexia, lethargy, and coma have been reported. Risk D: Consider therapy modification
Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification
Zuranolone: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider therapy modification
Food delays time to maximum concentration, but does not affect bioavailability. Management: Administer without regard to meals.
Women of childbearing potential are advised to use effective contraception during therapy and for 1 month after discontinuation.
Zonisamide crosses the placenta and can be detected in the newborn following delivery (Kawada 2002; Shimoyama 1999). Information related to pregnancy outcomes following maternal use of zonisamide is limited (Hernández-Díaz 2014; Kanemoto 2007; Kondo 1996; Ohtahara 2007). Metabolic acidosis is an adverse effect of zonisamide therapy; newborns exposed to zonisamide in utero should be monitored for transient metabolic acidosis after birth and pregnant women taking zonisamide should be monitored and treated as nonpregnant patients. In general, maternal polytherapy with antiseizure drugs may increase the risk of congenital malformations; monotherapy with the lowest effective dose is recommended. Newborns of women taking antiseizure medications may be at an increased risk of adverse events (Harden and Meader 2009).
Zonisamide clearance may increase during pregnancy, requiring dosage adjustment (Oles 2008; Reisinger 2013). Until additional data is available, other agents may be preferred for the treatment of epilepsy in pregnant women (Ohtahara 2007).
Patients exposed to zonisamide during pregnancy are encouraged to enroll themselves into the NAAED Pregnancy Registry by calling 1-888-233-2334. Additional information is available at http://www.aedpregnancyregistry.org.
Zonisamide is present in breast milk in concentrations similar to those in the maternal plasma and can be detected in the plasma of a nursing infant (Ando 2013; Kawada 2002; Shimoyama 1999). Due to the potential for serious adverse reactions in the nursing infant, the manufacturer recommends a decision be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of treatment to the mother.
BUN, serum creatinine (periodically as clinically indicated); serum bicarbonate (prior to initiation and periodically during therapy); ammonia level (if signs/symptoms of encephalopathy occur); suicidality (eg, suicidal thoughts, depression, behavioral changes); decreased sweating, elevated body temperature especially in warm or hot weather (particularly in pediatric patients).
Timing of serum samples: Draw trough just before next dose.
Laboratory alert level: 40 mcg/mL (SI: 188.4 micromol/L).
Epilepsy: 10 to 40 mcg/mL (SI: 47.1 to 188.4 micromole/L) (AGNP [Hiemke 2018]).
Stabilizes neuronal membranes and suppresses neuronal hypersynchronization through action at sodium and calcium channels; does not affect GABA activity.
Absorption: Rapid (Patsalos 2018); food may delay time to peak.
Distribution: Vd: 1.45 L/kg; highly concentrated in erythrocytes.
Protein binding: 40%.
Metabolism: Hepatic via CYP3A4; undergoes acetylation to form N-acetyl zonisamide and reduction via cytochrome P450 isoenzyme CYP3A4 to 2-sulfamoylacetylphenol (SMAP); SMAP then undergoes conjugation with glucuronide.
Bioavailability: Capsule: >90% (Patsalos 2018).
Half-life elimination: Plasma: ~63 hours (range: 50 to 68 hours).
Time to peak: Capsule: 2 to 6 hours; Oral suspension: 0.5 to 5 hours.
Excretion: Urine (62%, 35% as unchanged drug, 65% as metabolites); feces (3%).
Altered kidney function: Renal clearance decreases with decreased renal function. Marked renal impairment (CrCl less than 20 mL/minute) was associated with an increase in AUC of 35%.
Pediatric: Renal clearance is significantly faster (1.7-fold) in children <5 years of age than children ≥5 years and adolescents. Clearance was more pronounced in pediatric patients receiving concurrent enzyme-inducing antiseizure medications (Wallander 2014).
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