Zonisamide

Zonisamide is an anticonvulsant / antihypertensive agent belonging to Carbonic Anhydrase Inhibitor.

Zonisamide is a Carbonic Anhydrase Inhibitor used to treat partial seizures.

Following a 200–400 mg oral zonisamide dose, peak plasma concentrations (range: 2–5 µg/mL) in normal volunteers occur within 2–6 hours. Zonisamide absorption is dose-proportional in the range of 200–400 mg. Cmax and AUC, however, increase disproportionately at 800 mg, possibly due to the saturable binding of zonisamide to red blood cells. Once a stable dose is reached, a steady state is achieved within 14 days. The apparent volume of distribution (V/F) of zonisamide is about 1.45 L/kg following a 400 mg oral dose. Zonisamide, at concentrations of 1.0–7.0 µg/mL, is approximately 40% bound to human plasma proteins. Protein binding of zonisamide is unaffected in the presence of therapeutic concentrations of phenytoin, phenobarbital, or carbamazepine. Zonisamide is excreted primarily in urine as a parent drug and as the glucuronide of a metabolite. The clearance of an oral dose of Zonisamide from red blood cells is 2 mL/min. The elimination half-life of zonisamide in plasma is approximately 63 hours. The elimination half-life of zonisamide in red blood cells is approximately 105 hours.

Zonisamide shows common side effects like Nausea, vomiting, weight loss, changes in taste, diarrhea, constipation, heartburn, dry mouth, headache, dizziness, confusion, irritability, difficulty falling asleep or staying asleep, difficulty with memory, pain, burning, numbness, or tingling in the hands or feet, uncontrollable eye movements, double vision, etc.

Zonisamide is available in the form of Oral capsules and Oral suspension.

Zonisamide is available in India, the US, the UK, Canada, Africa, Russia, Korea, Europe, Japan, and Australia.

Zonisamide belonging to the Carbonic Anhydrase Inhibitor acts as an anticonvulsant/antihypertensive agent.

Zonisamide blocks sodium channels and reduces voltage-dependent, transient inward currents (T-type Ca²⁺ currents), consequently stabilizing neuronal membranes and suppressing neuronal hyper synchronization. In vitro binding studies have demonstrated that zonisamide binds to the GABA/benzodiazepine receptor ionophore complex in an allosteric fashion which does not produce changes in chloride flux. Other in vitro studies have demonstrated that zonisamide (10–30 μg/mL) suppresses synaptically-driven electrical activity without affecting postsynaptic GABA or glutamate responses (cultured mouse spinal cord neurons) or neuronal or glial uptake of [³H]-GABA (rat hippocampal slices). Thus, zonisamide does not appear to potentiate the synaptic activity of GABA. In vivo microdialysis studies demonstrated that zonisamide facilitates both dopaminergic and serotonergic neurotransmission.

Zonisamide is a carbonic anhydrase inhibitor. The contribution of this pharmacological action to the therapeutic effects of Zonisamide is unknown.

The onset of action of Zonisamide is not clinically established.

The Duration of Action for Zonisamide in the body is not clinically established.

The Tmax was found within 2-6 hours and Cmax about 2-5mcg/mL following the administration of Zonisamide.

Zonisamide is available in the form of Oral capsules and Oral suspension.

Zonisamide Capsule is taken orally and is usually taken once a day.

Zonisamide is an anticonvulsant medication that is used to treat a certain type of seizure (partial seizures). This medicine is not recommended for use in patients under 16 years of age.

Zonisamide is an anticonvulsant / antihypertensive agent belonging to Carbonic Anhydrase Inhibitor.

Zonisamide stabilizes neuronal membranes and suppresses neuronal hyper synchronization through action at sodium and calcium channels; does not affect GABA activity.

• Zonisamide is approved for use in clinical indications as adjunctive therapy in the treatment of partial seizures in adults with epilepsy.

• Seizures

16 years of age and older:

Initial dose: 100 mg orally once a day

Titration: After 2 weeks at 100 mg/day, the dose may be increased to 200 mg/day as either a single or divided dose (100 mg orally 2 times a day) for at least 2 weeks; it can then be increased to 300 mg/day, then 400 mg/day either as a single daily dose or divided into 2 daily doses, with the dose stable for at least 2 weeks to achieve steady state at each level

Maintenance dose: 400 mg/day

Maximum dose: 600 mg/day

Less than 16 years of age:

Not recommended.

Zonisamide is available in the form of Oral capsules and Oral suspension.

Zonisamide is contraindicated in patients who have demonstrated hypersensitivity to sulfonamides or zonisamide.

• 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. It may cause sedation, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

• Dermatologic reactions

Severe reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with 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. The risk may be increased in patients with inborn errors of metabolism or decreased hepatic mitochondrial activity. It 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 reactions 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 (Blood urea nitrogen) 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 the duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify the 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.

Consumption of alcohol is not recommended with zonisamide as it may cause drowsiness and dizziness.

Zonisamide is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Zonisamide, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pregnancy category C

Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant the use of the drug in pregnant women despite potential risks. This drug should be used during pregnancy only if the benefit outweighs the risk.

• Common Adverse effects

Somnolence, Anorexia, Dizziness, Headache, Nausea, Fatigue, Tiredness, Abdominal pain, Ataxia, Confusion, Depression, Diplopia, Insomnia, Difficulty concentrating, Diarrhea, Speech disorder, Flu-like symptoms, Mental slowing, Nystagmus, Paresthesia, Dyspepsia, Weight loss, Rash, Constipation, Rhinitis, Difficulty with verbal expression, Ecchymosis, Xerostomia, Nervousness, Schizophrenic/schizophreniform behavior, Taste perversion.

• Rare Adverse effects

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.

• CNS Depressants

Concomitant administration of Zonisamide and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. Because of the potential of zonisamide to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse events, zonisamide should be used with caution if used in combination with alcohol or other CNS depressants.

• Other Carbonic Anhydrase Inhibitors

Concomitant use of zonisamide, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., topiramate, acetazolamide, or dichlorphenamide), may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation or the risk of hyperammonemia. Therefore, if zonisamide is given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic.

• Drug Abuse and Dependence

The abuse and dependence potential of zonisamide has not been evaluated in human studies. In a series of animal studies, zonisamide did not demonstrate abuse liability and dependence potential. Monkeys did not self-administer zonisamide in a standard reinforcing paradigm. Rats exposed to zonisamide did not exhibit signs of physical dependence on the CNS depressant type. Rats did not generalize the effects of diazepam to zonisamide in a standard discrimination paradigm after training, suggesting that zonisamide does not have the abuse potential of the benzodiazepine-CNS depressant type.

The common side effects of Zonisamide include the following

• Common

Nausea, vomiting, weight loss, changes in taste, diarrhea, constipation, heartburn, dry mouth, headache, dizziness, confusion, irritability, difficulty falling asleep or staying asleep, difficulty with memory, pain, burning, numbness, or tingling in the hands or feet, uncontrollable eye movements, double vision.

• Rare

Rash, blistering or peeling of the skin, worsening or longer-lasting seizures, sudden back pain, stomach pain, pain when urinating, bloody or dark urine, fever, sore throat, chills, cough, and other signs of infection, sores in the mouth, easy bruising, difficulty thinking of words or trouble speaking, difficulty thinking or concentrating, lack of coordination, difficulty walking, severe weakness, severe muscle pain, extreme tiredness, loss of appetite, fast, shallow breathing, irregular heartbeat, loss of consciousness.

• Pregnancy

Pregnancy Category C

Zonisamide was teratogenic in mice, rats, and dogs, and embryo lethal in monkeys when administered during the period of organogenesis. Fetal abnormalities or embryo-fetal deaths occurred in these species at zonisamide dosage and maternal plasma levels similar to or lower than therapeutic levels in humans, indicating that the use of this drug in pregnancy entails a significant risk to the fetus. A variety of external, visceral, and skeletal malformations was produced in animals by prenatal exposure to zonisamide. Cardiovascular defects were prominent in both rats and dogs.

There are no adequate and well-controlled studies on pregnant women. Zonisamide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

• Nursing Mothers

Zonisamide is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Zonisamide, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

• Pediatric Use

The safety and effectiveness of Zonisamide in children under age 16 have not been established. Acute myopia and secondary angle closure glaucoma has been reported in pediatric patients. Cases of oligohidrosis and hyperpyrexia have been reported. Zonisamide commonly causes metabolic acidosis in pediatric patients. Hyperammonemia with encephalopathy has been reported in pediatric patients. Chronic untreated metabolic acidosis in pediatric patients may cause nephrolithiasis and/or nephrocalcinosis, osteoporosis, and/or osteomalacia (potentially resulting in rickets), and may reduce growth rates. A reduction in growth rate may eventually decrease the maximal height achieved. The effect of zonisamide on growth and bone-related sequelae has not been systematically investigated.

• Geriatric Use

Single dose pharmacokinetic parameters are similar in elderly and young healthy. Clinical studies of zonisamide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

No specific antidotes for Zonisamide overdosage are available. Following a suspected recent overdose, emesis should be induced or gastric lavage performed with the usual precautions to protect the airway. General supportive care is indicated, including frequent monitoring of vital signs and close observation.

Zonisamide has a long half-life. Due to the low protein binding of zonisamide (40%), renal dialysis may be effective. The effectiveness of renal dialysis as a treatment of overdose has not been formally studied. A poison control center should be contacted for information on the management of Zonisamide overdosage.

Pharmacodynamic

By stopping the spread of seizure discharges, zonisamide prevents the extensor component of tonic convulsion, restricts the spread of focal seizures, and prevents the propagation of seizures from the cortex to subcortical structures. In animal models, zonisamide was effective against tonic extension seizures but ineffective against clonic seizures. It also increased the threshold for generalized seizures and reduced the duration of cortical focal seizures. Aside from its antiepileptic effects, zonisamide is capable of activating neuroprotective mechanisms. It inhibits nitric oxide synthase and ​​reduces ischemia-induced memory impairment and lipid peroxidation.

The use of Zonisamide may lead to potentially fatal reactions. Severe reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, and aplastic anemia have been reported in patients treated with sulfonamides such as zonisamide. Zonisamide may also lead to the development of serious hematological events, drug reaction with eosinophilia and systemic symptoms (DRESS) and multi-organ hypersensitivity, acute myopia, and secondary angle closure glaucoma, as well as suicidal behavior and ideation. Zonisamide is a carbonic anhydrase inhibitor, which may lead to metabolic acidosis in patients treated with this drug. Its therapeutic effects due to this pharmacological action are unknown.

Pharmacokinetics

• Absorption

Following a 200–400 mg oral zonisamide dose, peak plasma concentrations (range: 2–5 µg/mL) in normal volunteers occur within 2–6 hours. In the presence of food, the time to maximum concentration is delayed; occurring at 4–6 hours, but food has no effect on the bioavailability of zonisamide. Zonisamide absorption is dose-proportional in the range of 200–400 mg. Cmax and AUC, however, increase disproportionately at 800 mg, possibly due to the saturable binding of zonisamide to red blood cells. Once a stable dose is reached, a steady state is achieved within 14 days.

• Distribution

The apparent volume of distribution (V/F) of zonisamide is about 1.45 L/kg following a 400 mg oral dose. Zonisamide, at concentrations of 1.0–7.0 µg/mL, is approximately 40% bound to human plasma proteins. Zonisamide extensively binds to erythrocytes, resulting in an eight-fold higher concentration of zonisamide in red blood cells than in plasma. Protein binding of zonisamide is unaffected in the presence of therapeutic concentrations of phenytoin, phenobarbital, or carbamazepine.

• Metabolism and Excretion

Following oral administration of 14C-zonisamide to healthy volunteers, only zonisamide was detected in plasma. Zonisamide is excreted primarily in urine as a parent drug and as the glucuronide of a metabolite. Following multiple dosing, 62% of the radiolabeled dose was recovered in the urine, with 3% in the feces by day 10. Zonisamide undergoes acetylation by N-acetyl-transferases to form N-acetyl zonisamide and reduction to form the open ring metabolite, 2–sulfamoylacetyl phenol (SMAP). Of the excreted dose, 35% was recovered as zonisamide, 15% as N-acetyl zonisamide, and 50% as the glucuronide of SMAP. The reduction of zonisamide to SMAP is mediated by cytochrome P450 isozyme 3A4 (CYP3A4). Zonisamide does not induce its own metabolism. The plasma clearance of oral zonisamide is approximately 0.30–0.35 mL/min/kg in patients not receiving enzyme-inducing antiepilepsy drugs (AEDs). The clearance of zonisamide is increased to 0.5 mL/min/kg in patients concurrently on enzyme-inducing AEDs. After a single-dose administration, renal clearance of zonisamide is approximately 3.5 mL/min. The clearance of an oral dose of zonisamide from red blood cells is 2 mL/min. The elimination half-life of zonisamide in plasma is approximately 63 hours. The elimination half-life of zonisamide in red blood cells is approximately 105 hours.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020789s022s025lbl.pdf
• https://www.rxlist.com/zonegran-drug.htm#description
• https://reference.medscape.com/drug/zonegran-zonisade-zonisamide-343025
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• https://www.uptodate.com/contents/zonisamide-drug-information#F236212