Zoresan

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZORESAN® (ZORESAN®)

Composition:

Active substance: zonisamide;

1 hard capsule contains zonisamide 25 mg or 50 mg or 100 mg;

Excipients:

microcrystalline cellulose, sodium lauryl sulfate, colloidal anhydrous silicon dioxide, hydrogenated castor oil;

Capsule shell:

for 25 mg or 50 mg hard capsule: gelatin, purified water, iron oxide yellow (E 172), iron oxide black (E 172), titanium dioxide (E 171), sodium lauryl sulfate;

for 100 mg hard capsule: gelatin, purified water, iron oxide red (E 172), titanium dioxide (E 171), sodium lauryl sulfate.

Pharmaceutical form. Hard capsules.

Main physicochemical properties:

25 mg hard capsules: hard gelatin capsule of size № 4 with an opaque grey cap and an opaque white body containing a white to almost white powder;

50 mg hard capsules: hard gelatin capsule of size № 3 with an opaque grey cap and an opaque white body containing a white to almost white powder;

100 mg hard capsules: hard gelatin capsule of size № 1 with an opaque red cap and an opaque white body containing a white to almost white powder.

Pharmacotherapeutic group. Antiepileptic drugs. Other antiepileptic drugs. Zonisamide. ATC code N03AX15.

Pharmacological Properties.

Pharmacodynamics.

Zonisamide is an antiepileptic agent, a benzisoxazole derivative. In vitro, it weakly inhibits carbonic anhydrase and is chemically unrelated to other antiepileptic drugs.

Mechanism of Action.

The mechanism of action of zonisamide is not fully understood. It is believed to block voltage-sensitive sodium and calcium channels, thereby disrupting synchronized neuronal firing, suppressing seizure development, and preventing further spread of epileptic activity. Zonisamide also exerts a modulating effect on GABA-mediated neuronal inhibition.

Pharmacodynamic Effects.

The antiseizure activity of zonisamide has been evaluated in various epilepsy models, primarily in groups with induced or inherited seizures, demonstrating zonisamide as a broad-spectrum antiepileptic agent. Zonisamide prevents seizures induced by maximal electroshock, limits seizure spread—including propagation of excitation from the cerebral cortex to subcortical structures—and suppresses activity of the epileptogenic focus. Unlike phenytoin and carbamazepine, zonisamide exhibits selective action against seizures originating in the cerebral cortex.

Pharmacokinetics.

Absorption.

Zonisamide is almost completely absorbed after oral administration. The maximum plasma or serum concentration (Cmax) is reached within 2–5 hours after intake. Presystemic metabolism is considered negligible. Absolute bioavailability is estimated at approximately 100%. The bioavailability of zonisamide after oral administration is not affected by food intake, although food may delay the time to reach Cmax in plasma or serum.

AUC and Cmax values of zonisamide increased almost linearly after single doses (in the dose range of 100–800 mg) and after multiple dosing (in the dose range of 100–400 mg once daily). Increases in these parameters at steady state slightly exceed predictions based on administered dose, possibly due to saturable binding of zonisamide to erythrocytes. Steady state is achieved within 13 days. There is slightly greater accumulation than expected compared to single-dose administration.

Distribution.

Zonisamide is 40–50% bound to plasma proteins. In vitro studies have shown that the presence of various antiepileptic drugs (e.g., phenytoin, phenobarbital, carbamazepine, and sodium valproate) does not affect the extent of zonisamide binding to plasma proteins. The apparent volume of distribution in adults is approximately 1.1–1.7 L/kg, indicating extensive tissue distribution. The erythrocyte-to-plasma ratio is about 15 at low concentrations and about 3 at higher concentrations.

Biotransformation.

Zonisamide is metabolized via the CYP3A4 isoenzyme. The primary metabolic pathway involves cleavage of the benzisoxazole ring, forming 2-sulfamoyl acetylphenol (SMAP), as well as N-acetylation. Both zonisamide and SMAP may undergo conjugation with glucuronic acid. Metabolites not detectable in plasma are devoid of antiseizure activity. There is no evidence that zonisamide induces its own metabolism.

Elimination.

The observed oral clearance of zonisamide at steady state is approximately 0.7 L/h, and the terminal half-life is about 60 hours (in the absence of concomitant administration of CYP3A4 inducers). The elimination half-life is independent of dose and repeated administration. Fluctuations in zonisamide plasma or serum concentrations over the dosing interval are low (<30%). The primary route of elimination of metabolites and unchanged zonisamide is via urine. Renal clearance of unchanged zonisamide is relatively low (approximately 3.5 mL/min); about 15–30% of the administered dose is excreted unchanged.

Linearity/Non-linearity.

Exposure to zonisamide increases over time until steady state is reached, which occurs after approximately 8 weeks. In patients with higher body weight, steady-state serum concentrations of zonisamide are lower, but these differences are minor. Age (≥12 years) and sex do not have a significant effect on zonisamide concentrations in patients with epilepsy during the steady-state period. Dose adjustment of zonisamide is not required when used concomitantly with other antiepileptic drugs, including CYP3A4 inducers.

Pharmacokinetic/Pharmacodynamic Relationship.

Zonisamide reduces the average seizure frequency over a 28-day period, and this reduction is proportional to the (log-linear relationship) average concentration of zonisamide.

Special Patient Populations.

Renal Impairment.

In patients with renal impairment, renal clearance of single doses of zonisamide positively correlates with creatinine clearance. AUC of zonisamide in plasma was increased by 35% in patients with creatinine clearance <20 mL/min.

Patients with Hepatic Impairment.

The pharmacokinetics of zonisamide in patients with hepatic impairment has not been well studied.

Elderly Patients.

No clinically significant differences in the pharmacokinetics of zonisamide have been observed between young (21–40 years) and elderly (65–75 years) patients.

Children (5–18 years).

Limited data suggest that the pharmacokinetics of zonisamide in children are similar to those observed in adults.

Clinical characteristics.

Indications.

Zoresan**®** is indicated as:

• monotherapy in adult patients with partial epileptic seizures with or without secondary generalization, with newly diagnosed epilepsy;
• adjunctive therapy in adults and children aged 6 years and older with partial epileptic seizures with or without secondary generalization.

Contraindications.

Hypersensitivity to the active substance, to any of the excipients, or to sulfonamides.

Interaction with other medicinal products and other forms of interactions.

Effect of zonisamide on cytochrome P450 enzyme system

An in vitro study of the effect of zonisamide on hepatic microsomal oxidation in human hepatocytes showed no significant effect (<25%) of the drug on the activity of cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 at plasma concentrations of zonisamide that are 2 times or more above therapeutic levels. Therefore, an effect of zonisamide on the pharmacokinetics of other medicinal products via mechanisms related to cytochrome P450 is not expected, as demonstrated in vivo for carbamazepine, phenytoin, ethinylestradiol, and desipramine.

Potential effect of zonisamide on other medicinal products.

Antiepileptic drugs.

In patients with epilepsy, long-term administration of zonisamide at therapeutic doses has no clinically significant effect on the pharmacokinetics of carbamazepine, lamotrigine, phenytoin, and sodium valproate.

Oral contraceptives.

In clinical studies involving healthy volunteers, administration of zonisamide at therapeutic doses did not affect serum concentrations of ethinylestradiol or norethisterone contained in combined oral contraceptives.

Carbonic anhydrase inhibitors.

Zonisamide should be used with caution in combination with carbonic anhydrase inhibitors such as topiramate and acetazolamide in adult patients, due to insufficient data to exclude a possible pharmacodynamic interaction between them (see section "Special precautions"). Zonisamide should not be prescribed to children concurrently with carbonic anhydrase inhibitors such as topiramate and acetazolamide, due to insufficient data to exclude a possible pharmacodynamic interaction between them (see section "Special precautions").

P-gp substrates.

Results of in vitro studies indicate that zonisamide is a weak inhibitor of P-gp (MDR1) protein with an IC50 of 267 µmol/L, thus there is a theoretical possibility that zonisamide may affect the pharmacokinetics of medicinal products that are P-gp substrates. Caution is recommended when initiating or discontinuing zonisamide treatment or changing its dose in patients who are also taking medicinal products that are P-gp substrates (e.g., digoxin, quinidine).

Potentially possible effect of other medicinal products on the action of zonisamide.

Clinical studies have shown that concomitant administration of lamotrigine with zonisamide has no significant effect on the pharmacokinetics of the latter. Concomitant use of zonisamide with medicinal products that may cause urolithiasis increases the risk of kidney stone formation; therefore, their simultaneous use should be avoided.

Zonisamide is metabolized via CYP3A4 (reductive cleavage),
N-acetyl-transferases, and glucuronic acid conjugation. Therefore, substances that induce or inhibit these enzymes may affect the pharmacokinetics of zonisamide.

• Enzyme inducers. The effect of zonisamide is reduced when administered concomitantly with medicinal products that increase the activity of cytochrome CYP3A4, such as phenytoin, carbamazepine, and phenobarbital, in patients receiving antiepileptic therapy. These effects are not clinically significant when zonisamide is added to an already established treatment regimen; however, clinically significant changes in zonisamide concentration may occur when discontinuing, changing the dosage regimen, or adding other CYP3A4-inducing agents. In such cases, dose adjustment of zonisamide may be required. Rifampicin is a potent CYP3A4 inducer. If concomitant administration with zonisamide is necessary, the patient's condition should be closely monitored, and the dose of zonisamide and other CYP3A4 substrates should be adjusted as needed.
• Inhibitors of CYP3A4 enzymes. Clinical study data have not shown a significant effect of specific and non-specific CYP3A4 inhibitors on the pharmacokinetic parameters of zonisamide. Administration of ketoconazole (400 mg/day) or cimetidine (1200 mg/day) did not have a clinically significant effect on the pharmacokinetics of a single dose of zonisamide in healthy volunteers. Therefore, dose adjustment of zonisamide when administered concomitantly with CYP3A4 inhibitors is not required.

Children.

Drug interaction studies have not been conducted in children.

Special precautions for use.

Skin rash of unknown origin.

Serious rashes, including cases of Stevens-Johnson syndrome, have been reported with zonisamide use.

Zonisamide should be discontinued if patients develop rashes that cannot be explained by other causes. All patients who develop rashes while taking zonisamide should be closely monitored, especially if they are also receiving other antiepileptic drugs known to cause rashes.

Seizures upon discontinuation of therapy.

According to current clinical practice, discontinuation of zonisamide in patients with epilepsy should be performed gradually by tapering the dose to reduce the likelihood of seizure occurrence. There is insufficient evidence supporting the discontinuation of concomitant antiepileptic drugs when seizure control is achieved with adjunctive zonisamide therapy to switch to zonisamide monotherapy. Therefore, withdrawal of concomitant antiepileptic drugs should be done cautiously.

Reactions related to sulfonamide group.

Zonisamide is a benzisoxazole derivative containing a sulfonamide group. Serious immune-related adverse reactions associated with sulfonamide-containing drugs include skin rashes, allergic reactions, and severe hematological disorders, including aplastic anemia, which in very rare cases may lead to fatal outcomes.

Cases of agranulocytosis, thrombocytopenia, leukopenia, aplastic anemia, pancytopenia, and leukocytosis have been reported. Insufficient data are available to assess a possible relationship between these events and the dose or duration of zonisamide treatment.

Acute myopia and secondary angle-closure glaucoma.

A syndrome consisting of acute myopia associated with secondary angle-closure glaucoma has been reported in adult and pediatric patients receiving zonisamide. Symptoms include sudden onset of decreased visual acuity and/or eye pain. Ophthalmologic examination may reveal myopia, reduced anterior chamber depth, hyperemia (redness) of the eye, and elevated intraocular pressure. This syndrome may be related to suprachoroidal effusion leading to anterior displacement of the lens and iris, resulting in secondary angle-closure glaucoma. Symptoms may occur within hours or weeks after initiating therapy. Management includes prompt discontinuation of zonisamide as advised by a physician and appropriate measures to reduce intraocular pressure. Untreated elevated intraocular pressure of any etiology may lead to serious consequences, including permanent vision loss. Caution should be exercised when treating patients with a history of eye disorders.

Suicidal thoughts and behavior.

Suicidal thoughts and behavior have been reported in patients treated with antiepileptic drugs for various indications. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs also showed an increased risk of suicidal ideation and behavior. The mechanism of this risk is unknown, and available data do not exclude the possibility of increased risk with zonisamide. Therefore, patients should be monitored for the emergence of suicidal thoughts and behavior, and appropriate treatment should be considered. Patients (and caregivers) should be advised to contact their physician immediately if suicidal thoughts or behaviors occur.

Nephrolithiasis.

In some patients, particularly those predisposed to nephrolithiasis, there may be an increased risk of kidney stone formation and associated signs and symptoms such as renal colic, kidney pain, or flank pain. Nephrolithiasis may lead to chronic kidney damage. Risk factors for nephrolithiasis include prior kidney stone formation, family history of nephrolithiasis, and hypercalciuria. None of these risk factors reliably predict kidney stone formation during zonisamide treatment. Additionally, patients taking other medications associated with nephrolithiasis may also have an increased risk.

Increased fluid intake and enhanced diuresis may help reduce the risk of kidney stone formation, especially in individuals with risk factors.

Metabolic acidosis.

Hyperchloremic metabolic acidosis without an anion gap (i.e., decreased bicarbonate levels below the reference range in the absence of chronic respiratory alkalosis) has been associated with zonisamide therapy. The development of metabolic acidosis is due to renal bicarbonate loss caused by the inhibitory effect of zonisamide on carbonic anhydrase. This electrolyte imbalance has been observed in placebo-controlled clinical trials and during the post-marketing period. Metabolic acidosis induced by zonisamide typically occurs early in treatment but may occur at any stage. Bicarbonate reduction is usually mild (mean decrease approximately 3.5 mEq/L at a daily dose of 300 mg in adults); however, more significant reductions may occur rarely. Conditions or treatments that predispose to acidosis (e.g., kidney disease, severe respiratory disorders, status epilepticus, diarrhea, surgery, ketogenic diet, or medications) may exacerbate the suppressive effect of zonisamide on bicarbonate levels.

The risk of zonisamide-induced metabolic acidosis is higher in younger patients, and the condition tends to be more severe in this population. Appropriate assessment and monitoring of serum bicarbonate levels are necessary in patients receiving zonisamide who have conditions that may increase the risk of acidosis; in patients at increased risk of adverse effects from metabolic acidosis; and in patients with symptoms suggestive of metabolic acidosis. If persistent metabolic acidosis develops, consideration should be given to reducing the dose or discontinuing zonisamide (with gradual tapering or dose reduction), as osteopenia may develop.

If a decision is made to continue zonisamide therapy in the presence of persistent acidosis, correction of acid-base balance should be considered.

Metabolic acidosis during zonisamide treatment may lead to hyperammonemia (with or without encephalopathy). The risk of hyperammonemia may be increased in patients concurrently taking other medications that can cause hyperammonemia (e.g., valproate) or in individuals with urea cycle disorders or reduced hepatocyte mitochondrial activity. Patients who develop unexplained lethargy or changes in mental status during zonisamide treatment should be evaluated for hyperammonemic encephalopathy, and blood ammonia levels should be assessed.

Zonisamide should be used cautiously in adult patients who are also receiving carbonic anhydrase inhibitors such as topiramate or acetazolamide, as insufficient data are available to exclude pharmacodynamic interactions.

Heat stroke.

Cases of decreased sweating and elevated body temperature have been reported, primarily in children. Caution should be exercised when prescribing zonisamide to adults concurrently receiving medications that may promote overheating, including carbonic anhydrase inhibitors and drugs with anticholinergic activity.

Pancreatitis.

Patients who develop clinical signs of pancreatitis while taking zonisamide should be monitored for pancreatic lipase and amylase levels. In confirmed cases of pancreatitis without other obvious causes, discontinuation of zonisamide and appropriate treatment are recommended.

Rhabdomyolysis.

Patients taking zonisamide who develop severe muscle pain and/or weakness, with or without fever, should be evaluated for markers of muscle injury, including creatine phosphokinase and aldolase levels. If these are elevated and no other obvious causes (e.g., trauma or major epileptic seizure) are present, discontinuation of zonisamide and appropriate treatment are recommended.

Women of childbearing potential.

Women of childbearing potential must use effective contraception during zonisamide therapy and for 1 month after discontinuation (see section "Use during pregnancy or breastfeeding"). Zonisamide must not be used in women of childbearing potential who are not using effective contraception, except in cases of extreme necessity and only if the potential benefit is considered to outweigh the risks to the fetus. Women of childbearing potential receiving zonisamide therapy should consult a specialist. They must be fully informed about the risks and benefits of zonisamide use and understand the potential impact of therapy on the fetus before treatment initiation. Before starting zonisamide therapy, women of childbearing potential should consider undergoing a pregnancy test. In case of planned pregnancy, conception, or discontinuation of contraception, women must consult their physician regarding review of zonisamide therapy, including the possibility of alternative treatment regimens. If a woman receiving zonisamide becomes pregnant or suspects she may be pregnant, she should immediately seek medical advice.

Physicians prescribing zonisamide must ensure that patients are fully informed about the necessity of using appropriate effective contraceptive methods. They must also ensure that oral contraceptives or their component doses are adequate based on individual clinical assessment.

Body weight.

Zonisamide therapy may cause weight loss. Nutritional supplements and increased caloric intake are necessary during treatment of patients with low body weight or weight loss due to zonisamide therapy. Significant weight loss warrants consideration of zonisamide discontinuation. Weight reduction may be more pronounced in children.

Children.

The above safety measures also apply to children.

The following precautions in pediatric patients require special attention.

Heat stroke and dehydration.

Prevention of overheating and dehydration in children.

Zonisamide may cause decreased sweating and hyperthermia in children, which, if untreated, may lead to brain injury and fatal outcomes. Children are at high risk, especially in hot weather conditions.

If a child is taking zonisamide, the following measures should be observed:

• Avoid overheating, especially in hot weather;
• Avoid strenuous physical activity, especially in hot weather;
• Drink large amounts of cool water;
• Do not use the following medications: carbonic anhydrase inhibitors (such as topiramate and acetazolamide) and anticholinergic drugs (such as clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine, and oxybutynin).

If any of the following symptoms occur in a child, immediate emergency medical assistance must be sought, and immediate first-aid measures must be taken.

Symptoms:

• Hot, dry skin;
• Minimal or absent sweating;
• Confusion;
• Muscle spasms;
• Rapid heartbeat and/or breathing.

Emergency first-aid measures:

• Move the child to a cool, shaded area;
• Moisten the child’s skin with water to cool it;
• Give the child cool water to drink.

Cases of decreased sweating and elevated body temperature have been reported mainly in children. In some cases, heat stroke was diagnosed requiring hospitalization. Some cases of heat stroke required hospitalization and resulted in fatal outcomes. Most cases occurred during warm weather. Patients and caregivers should be warned about the potential seriousness of heat stroke, situations in which it may occur, and measures to take if any signs or symptoms appear. Patients or caregivers must be advised to consume adequate fluids, avoid excessive heat, and avoid strenuous physical exertion. Physicians must inform children and their parents/guardians about the recommendations for preventing heat stroke and overheating in children as stated in the instructions for use. If signs or symptoms of dehydration, oligohidrosis, or elevated body temperature occur, discontinuation of zonisamide should be considered.

Zonisamide must not be used in children who are concurrently receiving other drugs that may provoke thermoregulatory disturbances, such as carbonic anhydrase inhibitors and anticholinergic medications.

Body weight.

Worsening clinical condition and discontinuation of antiepileptic drugs have been associated with weight loss and led to fatal outcomes. Zonisamide is not recommended for children with low body weight or poor appetite. Weight reduction occurs with similar frequency across different pediatric age groups. Due to the potentially serious consequences of weight loss in children, body weight must be monitored throughout therapy.

If a child shows failure to gain weight according to growth charts, nutritional supplements or increased food intake should be implemented. Otherwise, zonisamide should be discontinued.

Data on zonisamide use in patients weighing less than 20 kg are limited. Therefore, caution is advised when treating children aged 6 years and older weighing less than 20 kg. The impact of prolonged low body weight on a child’s growth and development is unknown.

Metabolic acidosis.

The risk of metabolic acidosis due to zonisamide therapy is higher in children, and the condition tends to be more severe clinically in this age group. Appropriate monitoring of serum bicarbonate levels is required in these patients. The long-term impact of low bicarbonate levels on growth and development is unknown.

Zonisamide must not be used in children concurrently receiving other carbonic anhydrase inhibitors, such as topiramate or acetazolamide.

Nephrolithiasis.

Kidney stone formation (nephrolithiasis) has been observed in pediatric patients. In some patients, particularly those predisposed to nephrolithiasis, there may be an increased risk of kidney stone formation and associated signs and symptoms such as renal colic, kidney pain, or flank pain. Nephrolithiasis may lead to chronic kidney damage. Risk factors for nephrolithiasis include prior kidney stone formation, family history of nephrolithiasis, and hypercalciuria. None of these risk factors reliably predict kidney stone formation during zonisamide treatment.

Increased fluid intake and diuresis may help reduce the risk of kidney stone formation, especially in individuals with risk factors. Renal ultrasound may be performed at the physician’s discretion. If kidney stones are detected, zonisamide should be discontinued.

Hepatic function impairment.

Elevations in certain liver function parameters, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and bilirubin, have been observed in pediatric patients during zonisamide therapy. If adverse hepatic events are suspected, liver function should be evaluated and a decision made regarding zonisamide discontinuation.

Cognitive function.

Cognitive impairment in patients with epilepsy may be related to the underlying disease and/or antiepileptic drug use. In a placebo-controlled study of zonisamide in children and adolescents, the proportion of patients with cognitive impairment was quantitatively higher in the zonisamide group compared to the placebo group.

Excipients.

Zoresan**®** contains hydrogenated castor oil, which may cause gastrointestinal discomfort and diarrhea.

Use during pregnancy or breastfeeding.

Women of childbearing potential.

Women of childbearing potential must use effective contraception during zonisamide therapy and for 1 month after discontinuation (see section "Special precautions for use").

Zonisamide must not be used in women of childbearing potential who are not using effective contraception, except in cases of extreme necessity and only if the potential benefit outweighs the possible risk to the fetus. Women of childbearing potential receiving zonisamide therapy should consult a specialist. They must be fully informed about the risks and benefits of zonisamide use and understand the potential impact of therapy on the fetus before treatment initiation. Before starting zonisamide therapy, women of childbearing potential should consider undergoing a pregnancy test. In case of planned pregnancy, conception, or discontinuation of contraception, women must consult their physician regarding review of zonisamide therapy, including the possibility of alternative treatment regimens.

As with other antiepileptic drugs, abrupt discontinuation of zonisamide in pregnant women should be avoided due to the risk of seizures, which may have serious consequences for both mother and fetus. The risk of congenital malformations in children whose mothers take antiepileptic drugs increases 2–3 times. Most commonly observed malformations include cleft lip, cardiovascular system abnormalities, and neural tube defects. Combination antiepileptic therapy is associated with a higher risk of congenital malformations compared to monotherapy.

Pregnancy.

Data on zonisamide use in pregnant women are limited. Animal studies have shown reproductive toxicity. The potential risk in humans is unknown.

Reports indicate increased incidence of low birth weight infants, preterm births, or infants small for gestational age. Registry data have shown that zonisamide use was associated with approximately a 5%–8% increase in low birth weight infants, 8%–10% in preterm births, and 7%–12% in infants small for gestational age (compared to women receiving lamotrigine monotherapy).

Zonisamide should not be used during pregnancy except when, in the physician’s opinion, the potential benefit outweighs the possible risk to the fetus. If zonisamide is prescribed to pregnant women, they must be fully informed about the potential harm of such treatment to the fetus and receive the minimum effective dose under close clinical monitoring.

Breastfeeding period.

Zonisamide passes into breast milk at concentrations similar to those in plasma. Breastfeeding women may use the drug only if, in the physician’s opinion, the benefit to the mother outweighs the potential risk of discontinuing breastfeeding for the infant. Breastfeeding should be discontinued during treatment. Due to the long elimination half-life of zonisamide, breastfeeding may be resumed no earlier than 1 month after discontinuation of the drug.

Fertility.

There are no available clinical data on the effect of zonisamide on human fertility. Animal studies have demonstrated changes in fertility parameters.

Ability to affect reaction speed when driving or operating machinery.

No studies have been conducted on the effect of zonisamide on the ability to drive or operate machinery. However, given that some patients may experience drowsiness or difficulty concentrating, especially at the beginning of therapy or after dose increases, patients should refrain from activities requiring heightened attention, such as driving or operating machinery.

Method of administration and dosage.

Zoresan® should be administered orally, independent of food intake.

Adults.

Dose escalation and maintenance dose.

Zonisamide can be used as monotherapy or as adjunctive therapy. The dose of the drug should be titrated according to clinical response. The recommended dose titration regimen and maintenance dose levels are presented in Table 1. For some patients, particularly those not taking drugs that induce the CYP3A4 isoenzyme, a clinical response may be achieved with lower doses.

Table 1.

Recommended dose escalation regimen and maintenance dose levels in adults

Treatment regimen	Dose titration phase			Maintenance dose
	Weeks 1–2	Weeks 3–4	Weeks 5–6
Monotherapy Adults with newly diagnosed epilepsy	100 mg/day (once daily)	200 mg/day (once daily)	300 mg/day (once daily)	300 mg/day (once daily) If higher doses are needed: increase by 100 mg every two weeks up to the maximum recommended dose of 500 mg/day
Adjunctive therapy with medicinal products that induce CYP3A4 isoenzyme	Week 1	Week 2	Weeks 3–5
	50 mg/day (in two divided doses)	100 mg/day (in two divided doses)	Increase by 100 mg weekly	300–500 mg/day (in one or two doses).
Adjunctive therapy without medicinal products that induce CYP3A4 isoenzyme or in patients with renal or hepatic impairment	Weeks 1–2	Weeks 3–4	Weeks 5–10
	50 mg/day (in two divided doses)	100 mg/day (in two divided doses)	Increase by 100 mg every two weeks	300–500 mg/day (in one or two doses). Some patients may respond to lower doses.

Discontinuation of the drug.

If zonisamide therapy needs to be discontinued, the drug should be withdrawn gradually. The dose should be reduced by 100 mg per week, with simultaneous adjustment of doses of other antiepileptic drugs (if necessary).

Children (aged 6 years and older).

Dose escalation and maintenance dose levels.

Zonisamide should be added to previously prescribed therapy in children aged 6 years and older. The dose should be titrated according to clinical response. The recommended dose titration regimen and maintenance dose levels are presented in Table 2. In some patients, particularly those not taking drugs that induce the CYP3A4 isoenzyme, a clinical response may be achieved with lower doses.

Children, their parents, or caregivers should be advised about the special instructions for patients regarding measures to prevent heat stroke (see section "Special precautions for use").

Table 2.

Recommended dose escalation regimen and maintenance dose levels in children aged
6 years and older.

Treatment regimen	Dose titration phase		Maintenance dose
Concomitant therapy with medicinal products that induce CYP3A4 isoenzyme	1st week	2–8th weeks	Patients with body weight from 20 to 55 kg*	Patients with body weight > 55 kg
	1 mg/kg/day (once daily)	Increase by 1 mg/kg with weekly intervals	6–8 mg/kg/day (once daily)	300–500 mg/day (once daily)
Concomitant therapy without medicinal products that induce CYP3A4 isoenzyme	1–2nd weeks	≥ 3 weeks	Patients with body weight from 20 to 55 kg*	Patients with body weight > 55 kg
	1 mg/kg/day (once daily)	Increase by 1 mg/kg with two-week intervals	6–8 mg/kg/day (once daily)	300–500 mg/day (once daily)

*To maintain the therapeutic dose, the child's body weight should be monitored and the dose adjusted accordingly in case of weight changes (until a body weight of 55 kg is reached). The dosing regimen is 6–8 mg/kg/day up to a maximum dose of 500 mg/day.

The safety and efficacy of zonisamide in children under 6 years of age or in children with body weight less than 20 kg have not been established. There are limited data on the use of zonisamide in patients with body weight less than 20 kg. Therefore, children aged 6 years and older with body weight less than 20 kg should be treated with caution.

It is not always possible to achieve the calculated dose precisely using the available Zoresan**®** dosage strengths. In such cases, the calculated dose should be rounded up or down to the nearest available Zoresan**®** dosage strength (25, 50, and 100 mg).

Discontinuation of the drug.

If discontinuation of zonisamide therapy is required, the drug should be withdrawn gradually by reducing the dose by 2 mg/kg once weekly (Table 3).

Table 3.

Recommended dose reduction regimen for zonisamide in children aged 6 years and older.

Body weight	Dose reduction with weekly intervals:
20–28 kg	From 25 to 50 mg/day*
29–41 kg	From 50 to 75 mg/day*
42–55 kg	100 mg/day*
> 55 kg	100 mg/day*

*All daily doses are single doses.

Geriatric patients.

Caution should be exercised when prescribing zonisamide to elderly patients due to insufficient data on its use in this patient population. The safety profile of zonisamide should also be taken into account (see section "Adverse Reactions").

Patients with renal impairment.

Caution is required when treating patients with renal impairment, as data on the use of zonisamide in this patient group are limited. A slower dose titration of zonisamide may be necessary. Since zonisamide and its metabolites are eliminated by the kidneys, the drug should be discontinued in patients who develop acute renal failure or exhibit a clinically significant persistent increase in serum creatinine.

In patients with renal impairment, renal clearance of single doses of zonisamide positively correlates with creatinine clearance. Plasma AUC of zonisamide increased by 35% in individuals with creatinine clearance < 20 mL/min.

Patients with hepatic impairment.

The use of zonisamide in patients with hepatic impairment has not been studied. Therefore, the use of the drug in patients with severe hepatic impairment is not recommended. Caution should be exercised when treating patients with mild to moderate hepatic impairment; a slower dose titration may be required.

Children.

The drug should be administered to children aged 6 years and older and with body weight above 20 kg.

Overdose.

Symptoms.

Cases of accidental and intentional overdose have been reported in adults and children. In some cases, overdose was asymptomatic, especially when gastric lavage and induced vomiting were performed promptly.

In other cases, overdose was accompanied by the following symptoms: somnolence, nausea, gastritis, nystagmus, myoclonus, coma, bradycardia, renal dysfunction, arterial hypotension, and respiratory depression.

A very high plasma concentration of zonisamide (100.1 µg/mL) was observed approximately 31 hours after overdose with zonisamide and clonazepam. The patient who overdosed on these drugs developed coma and respiratory depression. However, after 5 days, he regained consciousness and did not experience any complications.

Treatment.

There is no specific antidote for the treatment of zonisamide overdose. In cases of confirmed or suspected overdose, gastric lavage or induced vomiting should be performed along with standard supportive measures aimed at maintaining airway patency. Supportive therapy should also be provided, including regular monitoring of vital signs and careful observation of the patient's condition. Since zonisamide has a long elimination half-life, symptoms of overdose may be prolonged. As hemodialysis reduces plasma zonisamide concentrations in patients with renal impairment, it may be considered as a treatment option for drug overdose.

Adverse reactions.

Summary of safety profile

Zonisamide has been administered to over 1200 patients in clinical trials, more than 400 of whom received the drug for at least 1 year. In addition, extensive post-marketing experience with zonisamide has been accumulated in Japan since 1989 and in the United States since 2000.

It should be noted that zonisamide is a benzisoxazole derivative containing a sulfonamide group. Serious immune system-related adverse reactions associated with sulfonamide-containing medicinal products include skin rashes, allergic reactions, and severe hematological disorders, including aplastic anemia, which in very rare cases may lead to fatal outcomes (see section "Special precautions and warnings").

The most commonly reported adverse reactions in controlled adjunctive therapy trials were somnolence, dizziness, and anorexia. The most commonly reported adverse reactions in a randomized, controlled monotherapy trial of zonisamide compared to extended-release carbamazepine in patients receiving zonisamide were decreased bicarbonate levels, loss of appetite, and weight loss. The incidence of substantial decrease in serum bicarbonate levels (decrease to less than 17 mEq/L and by more than 5 mEq/L) was 3.8%. The incidence of significant weight loss of 20% or more was 0.7%.

Adverse reactions associated with the use of zonisamide, reported during clinical trials and post-marketing surveillance, are listed below. Frequencies are classified according to the following categories:

Very common ≥1/10
Common ≥1/100 to <1/10
Uncommon ≥1/1,000 to <1/100
Rare ≥1/10,000 to <1/1,000
Very rare <1/10,000
Not known Cannot be estimated from available data

Table 4.
Adverse reactions associated with zonisamide, reported during adjunctive therapy clinical trials and post-marketing surveillance.

System Organ Class	Very common	Common	Uncommon	Rare
Infections and infestations			Pneumonia, urinary tract infections
Blood and lymphatic system disorders		Ecchymosis		Agranulocytosis, aplastic anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, thrombocytopenia
Immune system disorders		Hypersensitivity		Drug-induced hypersensitivity syndrome, DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms)
Metabolism and nutrition disorders	Anorexia		Hypokalemia	Metabolic acidosis, renal tubular acidosis
Psychiatric disorders	Agitation, irritability, confusion, depression	Emotional lability, anxiety, insomnia, psychotic disorders	Anger, aggression, suicidal thoughts and suicide attempts	Hallucinations
Nervous system disorders	Ataxia, dizziness, memory impairment, somnolence	Bradypsychia, attention disturbance, nystagmus, paresthesia, speech disorder, tremor	Seizures	Amnesia, coma, grand mal convulsions, myasthenic syndrome, neuroleptic malignant syndrome, epileptic status
Eye disorders	Diplopia			Angle-closure glaucoma, eye pain, myopia, blurred vision, decreased visual acuity
Respiratory, thoracic and mediastinal disorders				Dyspnea, aspiration pneumonia, respiratory distress, pneumonitis associated with hypersensitivity
Gastrointestinal disorders		Abdominal pain, constipation, diarrhea, dyspepsia, nausea	Vomiting	Pancreatitis
Hepatobiliary disorders			Cholecystitis, cholelithiasis	Hepatocellular injury
Skin and subcutaneous tissue disorders		Rash, pruritus, alopecia		Anhidrosis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis
Musculoskeletal and connective tissue disorders				Rhabdomyolysis
Renal and urinary disorders		Nephrolithiasis	Urolithiasis	Hydronephrosis, renal failure, abnormal urine composition
General disorders and administration site conditions		Increased fatigue, influenza-like illness, increased body temperature, peripheral edema
Investigations	Decreased bicarbonate levels	Decreased body weight		Increased creatine phosphokinase levels, increased creatinine levels, increased urea levels, abnormal liver function biochemical tests
Injury, poisoning and procedural complications				Heat stroke

In addition, there have been isolated cases of sudden unexpected death in patients with epilepsy receiving zonisamide.

Table 5.

Adverse reactions in a randomized controlled monotherapy study comparing zonisamide with extended-release carbamazepine.

System organ class	Very common	Common	Uncommon
Infections and infestations			Urinary tract infections, pneumonia
Blood and lymphatic system disorders			Leukopenia, thrombocytopenia
Musculoskeletal and connective tissue disorders		Decreased appetite	Hypokalemia
Psychiatric disorders		Agitation, depression, insomnia, mood swings, anxiety	Confusion, acute psychosis, aggression, suicidal thoughts, hallucinations
Nervous system disorders		Ataxia, dizziness, memory impairment, somnolence, bradypsychia, attention disturbances, paresthesia	Nystagmus, speech disorder, tremor, seizures
Eye disorders		Diplopia
Respiratory, thoracic and mediastinal disorders			Respiratory disturbances
Gastrointestinal disorders		Constipation, diarrhea, dyspepsia, nausea, vomiting	Abdominal pain
Hepatobiliary disorders			Acute cholecystitis
Skin and subcutaneous tissue disorders		Rash	Pruritus, ecchymosis
General disorders and administration site conditions		Malaise, fever, irritability
Investigations	Decreased bicarbonate levels	Weight loss, increased blood creatine phosphokinase, increased alanine aminotransferase, increased aspartate aminotransferase	Urinalysis abnormalities

Additional information regarding special patient groups

Elderly patients

A pooled analysis of safety data from 95 elderly patients showed a relatively higher incidence of peripheral edema and pruritus compared to younger patients.

A review of post-marketing data in patients over 65 years of age indicates a higher frequency, compared to the general population, of the following events: Stevens-Johnson syndrome and drug-induced hypersensitivity syndrome, and sudden unexpected death in patients with epilepsy.

Pediatric patients

The safety profile of zonisamide in children who participated in placebo-controlled clinical trials (aged 6 to 17 years) is consistent with the safety profile of the drug in adults. Among 465 patients included in the pediatric safety database (including 67 patients who continued in the open-label extension phase of the controlled clinical trial), 7 deaths (1.5%; 14.6/1000 patient-years) occurred: 2 due to status epilepticus, one of which was associated with significant weight loss (10% over 3 months) in a patient with low body weight, followed by discontinuation of the drug; 1 due to head trauma/hematoma; and 4 deaths occurred in patients with pre-existing neurological functional deficits of various etiologies (2 cases of sepsis associated with pneumonia/multiorgan failure, 1 case of sudden unexpected death in epilepsy patients, and 1 case of head trauma). Overall, in 70.4% of patients who received zonisamide in the controlled study or in the open-label extension phase, serum bicarbonate levels below 22 mmol/L were observed at least once during treatment. Low bicarbonate levels persisted for a prolonged period (median 188 days).

In a pooled safety analysis of data from 420 children (183 aged 6 to 11 years and 237 aged 12 to 16 years, with a mean treatment duration of approximately 12 months), relatively more frequent reports were received for pneumonia, dehydration, decreased sweating, liver function biochemical abnormalities, otitis media, pharyngitis, sinusitis, upper respiratory tract infections, cough, epistaxis, and rhinitis, abdominal pain, vomiting, rash and eczema, and fever (particularly in those under 12 years of age), compared to data from adult patients. Amnesia, increased creatinine levels, lymphadenopathy, and thrombocytopenia were reported less frequently. The incidence of weight loss of 10% or more was 10.7% (see section "Special precautions"). In some cases, weight loss was associated with delayed progression to the next Tanner stage and delayed bone maturation.

Reporting of adverse reactions

Reporting of adverse reactions after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25°C.

Keep out of reach of children.

Packaging.

10 capsules per blister; 3 or 6 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

GLF PHARM LTD LLC.

Manufacturer's location and address of business operations.

54 Davydovskoho Hryhorii Street, Sumy, Sumy region, 40020, Ukraine.

INSTRUCTION

for medical use of the medicinal product

ZORESAN®

(ZORESAN®)

Composition:

Active ingredient: zonisamide;

1 hard capsule contains zonisamide 25 mg, or 50 mg, or 100 mg;

Excipients:

microcrystalline cellulose, sodium lauryl sulfate, colloidal anhydrous silicon dioxide, hydrogenated castor oil;

Capsule shell:

for 25 mg or 50 mg hard capsules: gelatin, purified water, yellow iron oxide (E 172), black iron oxide (E 172), titanium dioxide (E 171), sodium lauryl sulfate;

for 100 mg hard capsules: gelatin, purified water, red iron oxide (E 172), titanium dioxide (E 171), sodium lauryl sulfate.

Pharmaceutical form. Hard capsules.

Main physico-chemical properties:

25 mg hard capsules: size № 4 hard gelatin capsule with an opaque grey cap and an opaque white body, containing white to almost white powder;

50 mg hard capsules: size № 3 hard gelatin capsule with an opaque grey cap and an opaque white body, containing white to almost white powder;

100 mg hard capsules: size № 1 hard gelatin capsule with an opaque red cap and an opaque white body, containing white to almost white powder.

Pharmacotherapeutic group. Antiepileptic drugs. Other antiepileptic drugs. Zonisamide. ATC code N03AX15.

Pharmacological Properties.

Pharmacodynamics.

Zonisamide is an antiepileptic agent, a derivative of benzisoxazole. In vitro, it weakly inhibits carbonic anhydrase and is chemically unrelated to other antiepileptic drugs.

Mechanism of action.

The mechanism of action of zonisamide is not fully understood. It is believed to block voltage-sensitive sodium and calcium channels, thereby disrupting synchronized neuronal excitation, inhibiting seizure development, and preventing further spread of epileptic activity. Zonisamide also has a modulating effect on GABA-mediated neuronal inhibition.

Pharmacodynamic effects.

The anticonvulsant activity of zonisamide has been evaluated in various models of epilepsy, primarily in groups with induced or inherited seizures, demonstrating zonisamide as a broad-spectrum antiepileptic agent. Zonisamide prevents convulsions induced by maximal electroshock, limits the spread of seizures, including the propagation of excitation from the cerebral cortex to subcortical structures, and also suppresses the activity of the epileptogenic focus. Unlike phenytoin and carbamazepine, zonisamide has a selective action against seizures originating in the cerebral cortex.

Pharmacokinetics.

Absorption.

Zonisamide is almost completely absorbed after oral administration; Cmax in serum or plasma is reached within 2–5 hours after intake. Presystemic metabolism is considered negligible. Absolute bioavailability is estimated at approximately 100%. The bioavailability of zonisamide after oral administration is not affected by food intake, although food may delay the time to reach Cmax in plasma or serum.

AUC and Cmax values of zonisamide increased almost linearly after single-dose administration (in the dose range of 100–800 mg) and after multiple dosing (in the dose range of 100–400 mg once daily). The increase in these parameters at steady state slightly exceeds that predicted from the administered dose, possibly due to saturable binding of zonisamide to erythrocytes. Steady state is achieved within 13 days. There is slightly greater accumulation than expected compared to single-dose administration.

Distribution.

Zonisamide is bound to plasma proteins by 40–50%. In vitro studies have shown that the presence of various antiepileptic drugs (e.g., phenytoin, phenobarbital, carbamazepine, and sodium valproate) does not affect the degree of plasma protein binding of zonisamide. The apparent volume of distribution in adults is approximately 1.1–1.7 L/kg, indicating extensive tissue distribution of zonisamide. The erythrocyte/plasma ratio is about 15 at low concentrations and about 3 at higher concentrations.

Biological transformation.

Zonisamide is metabolized via the CYP3A4 isoenzyme. The main metabolic pathway is cleavage of the benzisoxazole ring, resulting in the formation of 2-sulfamoyl acetylphenol (SMAP), as well as N-acetylation. Zonisamide and SMAP may undergo conjugation with glucuronic acid. Metabolites not detectable in plasma are devoid of anticonvulsant activity. There is no evidence that zonisamide is capable of inducing its own metabolism.

Elimination.

The observed clearance of zonisamide at steady state after oral administration is approximately 0.7 L/h, and the terminal half-life is about 60 hours (in the absence of concomitant administration of inducers of CYP3A4 isoenzyme activity). The half-life is independent of dose and repeated administration. Fluctuations in zonisamide concentrations in serum or plasma over the dosing interval are low (<30%). The primary route of elimination of metabolites and unchanged zonisamide is via urine. Renal clearance of unchanged zonisamide is relatively low (approximately 3.5 mL/min); about 15–30% of the administered dose is excreted unchanged.

Linearity/Non-linearity.

Exposure to zonisamide increases over time until steady state is reached, which occurs approximately after 8 weeks. In patients with higher body weight, steady-state serum concentrations of zonisamide are lower, but these differences are minor. Age (≥12 years) and sex do not have a significant effect on zonisamide concentrations in patients with epilepsy during the steady-state period. Dose adjustment of zonisamide when used concomitantly with other antiepileptic drugs, including CYP3A4 isoenzyme inducers, is not required.

Pharmacokinetic/pharmacodynamic relationship.

Zonisamide reduces the average seizure frequency over a 28-day period, and this reduction is proportional to (log-linear relationship) the average concentration of zonisamide.

Special patient groups.

Renal impairment.

In patients with renal impairment, renal clearance of single doses of zonisamide positively correlates with creatinine clearance. AUC of zonisamide in plasma was increased by 35% in patients with creatinine clearance <20 mL/min.

Patients with hepatic impairment.

The pharmacokinetics of zonisamide in patients with hepatic impairment has not been sufficiently studied.

Elderly patients.

No clinically significant differences in the pharmacokinetics of zonisamide have been observed between young (21–40 years) and elderly (65–75 years) patients.

Children (5–18 years).

Limited data indicate that the pharmacokinetics of zonisamide in children is similar to that observed in adults.

Clinical characteristics.

Indications.

Zoresan**®** is indicated as:

• monotherapy in adult patients with partial epileptic seizures with or without secondary generalization, with newly diagnosed epilepsy;
• adjunctive therapy in adults and children aged 6 years and older with partial epileptic seizures with or without secondary generalization.

Contraindications.

Hypersensitivity to the active substance, to any of the excipients, or to sulfonamides.

Interaction with other medicinal products and other forms of interactions.

Effect of zonisamide on cytochrome P450 enzyme system

In vitro studies investigating the effect of zonisamide on hepatic microsomal oxidation in human hepatocytes showed no significant effect (<25%) of the drug on the activity of cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 at plasma concentrations of zonisamide that are two times or more above therapeutic levels. Therefore, an effect of zonisamide on the pharmacokinetics of other drugs via mechanisms related to cytochrome P450 is not expected, as demonstrated in vivo for carbamazepine, phenytoin, ethinylestradiol, and desipramine.

Potential effect of zonisamide on other medicinal products.

Antiepileptic drugs.

In patients with epilepsy, long-term administration of zonisamide at therapeutic doses has no clinically significant effect on the pharmacokinetics of carbamazepine, lamotrigine, phenytoin, and sodium valproate.

Oral contraceptives.

In clinical studies involving healthy volunteers, administration of zonisamide at therapeutic doses did not affect serum concentrations of ethinylestradiol or norethisterone components of combined oral contraceptives.

Carbonic anhydrase inhibitors.

Zonisamide should be used with caution in combination with carbonic anhydrase inhibitors such as topiramate and acetazolamide in adult patients, as there are insufficient data to exclude a pharmacodynamic interaction between them (see section "Special precautions"). Zonisamide should not be administered concomitantly with carbonic anhydrase inhibitors such as topiramate and acetazolamide in children, due to insufficient data to exclude a possible pharmacodynamic interaction between them (see section "Special precautions").

P-gp substrates.

In vitro study results indicate that zonisamide is a weak inhibitor of P-glycoprotein (P-gp, MDR1) with an IC50 of 267 µmol/L, thus creating a theoretical possibility of zonisamide affecting the pharmacokinetics of medicinal products that are P-gp substrates. Caution is recommended when initiating or discontinuing zonisamide treatment or adjusting its dose in patients who are also taking medicinal products that are P-gp substrates (e.g., digoxin, quinidine).

Potentially possible effect of other medicinal products on zonisamide efficacy.

Clinical studies have shown that concomitant administration of lamotrigine with zonisamide has no significant effect on the pharmacokinetics of the latter. Concomitant use of zonisamide with medicinal products that may cause urolithiasis increases the risk of kidney stone formation; therefore, simultaneous use of such products should be avoided.

Zonisamide is metabolized via cytochrome CYP3A4 (reductive cleavage), N-acetyl-transferases, and glucuronic acid conjugation. Therefore, substances that induce or inhibit these enzymes may affect the pharmacokinetics of zonisamide.

• Enzyme inducers. The effect of zonisamide is reduced when administered concomitantly with medicinal products that increase the activity of cytochrome CYP3A4, such as phenytoin, carbamazepine, and phenobarbital, in patients receiving antiepileptic therapy. These effects are not clinically significant when zonisamide is added to ongoing therapy; however, clinically significant changes in zonisamide concentration may occur when discontinuing, changing the dosing regimen of, or adding other CYP3A4-inducing agents. In such cases, dose adjustment of zonisamide may be required. Rifampicin is a potent inducer of CYP3A4. If concomitant administration with zonisamide is necessary, the patient should be closely monitored, and the dose of zonisamide and other CYP3A4 substrate drugs should be adjusted as needed.
• Inhibitors of CYP3A4 enzymes. Clinical study data have not shown a significant effect of specific or non-specific CYP3A4 inhibitors on the pharmacokinetic parameters of zonisamide. Administration of ketoconazole (400 mg/day) or cimetidine (1200 mg/day) did not have a clinically significant effect on the pharmacokinetics of single-dose zonisamide in healthy volunteers. Therefore, dose adjustment of zonisamide is not required when administered concomitantly with CYP3A4 inhibitors.

Children.

Drug interaction studies have not been conducted in children.

Special precautions for use.

Skin rash of unknown origin.

Serious rashes, including cases of Stevens–Johnson syndrome, have been reported with the use of zonisamide.

Zonisamide should be discontinued in patients who develop rashes that cannot be explained by other causes. All patients who develop rashes while taking zonisamide should be closely monitored, especially if they are also receiving other antiepileptic drugs known to cause rashes.

Seizures due to treatment withdrawal.

According to current clinical practice, discontinuation of zonisamide in patients with epilepsy should be performed gradually by tapering the dose to reduce the likelihood of seizure occurrence. There is insufficient evidence to support the discontinuation of concomitant antiepileptic drugs when seizure control is achieved with zonisamide as adjunctive therapy, with the aim of switching to zonisamide monotherapy. Therefore, withdrawal of concomitant antiepileptic drugs should be performed cautiously.

Reactions related to sulfonamide group.

Zonisamide is a benzisoxazole derivative containing a sulfonamide group. Serious immune-related adverse reactions associated with drugs containing a sulfonamide group include skin rashes, allergic reactions, and severe hematological disorders, including aplastic anemia, which in very rare cases may lead to fatal outcomes.

Cases of agranulocytosis, thrombocytopenia, leukopenia, aplastic anemia, pancytopenia, and leukocytosis have been reported. There is insufficient information to assess a possible relationship between these events and the dose or duration of zonisamide treatment.

Acute myopia and secondary angle-closure glaucoma.

A syndrome consisting of acute myopia associated with secondary angle-closure glaucoma has been reported in adult and pediatric patients receiving zonisamide. Symptoms include acute onset of decreased visual acuity and/or eye pain. Ophthalmologic examination may reveal myopia, reduced anterior chamber depth, ocular hyperemia (redness), and elevated intraocular pressure. This syndrome may be related to suprachoroidal effusion, leading to anterior displacement of the lens and iris, resulting in secondary angle-closure glaucoma. Symptoms may occur within hours or weeks after initiating therapy. Management includes prompt discontinuation of zonisamide as recommended by a physician and appropriate measures to reduce intraocular pressure. Untreated elevated intraocular pressure of any etiology may lead to serious consequences, including permanent vision loss. Caution should be exercised when treating patients with a history of eye disorders.

Suicidal thoughts and behavior.

Suicidal thoughts and behavior have been reported in patients treated with antiepileptic drugs for various indications. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs also showed an increased risk of suicidal thoughts and behavior. The mechanism of this risk is unknown, and available data do not exclude a potential increased risk with zonisamide use. Patients should be monitored for the emergence of suicidal thoughts and behavior, and appropriate treatment should be considered. Patients (and caregivers) should be advised to seek medical advice if suicidal thoughts or behavior occur.

Nephrolithiasis.

In some patients, particularly those predisposed to nephrolithiasis, there may be an increased risk of kidney stone formation and associated signs and symptoms such as renal colic, kidney pain, or flank pain. Nephrolithiasis may lead to chronic kidney damage. Risk factors for nephrolithiasis include prior kidney stone formation, family history of nephrolithiasis, and hypercalciuria. None of these risk factors reliably predict kidney stone formation during zonisamide treatment. Additionally, patients taking other medications associated with nephrolithiasis may also have an increased risk.

Increased fluid intake and enhanced diuresis may help reduce the risk of kidney stone formation, especially in individuals with risk factors.

Metabolic acidosis.

Hyperchloremic metabolic acidosis without an anion gap (i.e., decreased bicarbonate levels below the reference range in the absence of chronic respiratory alkalosis) has been associated with zonisamide therapy. The development of metabolic acidosis is due to renal bicarbonate loss caused by the inhibitory effect of zonisamide on carbonic anhydrase. This electrolyte imbalance has been observed in placebo-controlled clinical trials and during the post-marketing period. Metabolic acidosis induced by zonisamide typically occurs early in treatment but may develop at any stage. Bicarbonate reduction is usually mild (mean decrease approximately 3.5 mEq/L at a daily dose of 300 mg in adults); however, more pronounced reductions may occur in rare cases. Conditions or treatments that lead to acidosis (e.g., kidney disease, severe respiratory disorders, status epilepticus, diarrhea, surgery, ketogenic diet, or medications) may exacerbate the bicarbonate-lowering effect of zonisamide.

The risk of zonisamide-induced metabolic acidosis is higher in younger patients, and the condition may have a more severe course. Appropriate assessment and monitoring of serum bicarbonate levels are necessary in patients receiving zonisamide who have conditions that may increase the risk of acidosis, in those at increased risk of adverse effects from metabolic acidosis, and in those with symptoms suggestive of metabolic acidosis. If persistent acidosis develops, consideration should be given to reducing the dose or discontinuing zonisamide (with gradual tapering or dose reduction), as osteopenia may develop.

If a decision is made to continue zonisamide therapy in the presence of persistent acidosis, correction of acid-base balance should be considered.

Metabolic acidosis during zonisamide treatment may lead to hyperammonemia (with or without encephalopathy). The risk of hyperammonemia may be increased in patients concurrently taking other medications that can cause hyperammonemia (e.g., valproate) or in individuals with urea cycle disorders or reduced hepatocyte mitochondrial activity. Patients who develop unexplained lethargy or changes in mental status during zonisamide treatment should be evaluated for the risk of hyperammonemic encephalopathy, and blood ammonia levels should be measured.

Zonisamide should be used with caution in adult patients who are concurrently receiving carbonic anhydrase inhibitors such as topiramate or acetazolamide, as there is insufficient data to exclude a pharmacodynamic interaction.

Heat stroke.

Cases of decreased sweating and elevated body temperature have been reported, primarily in children. Caution should be exercised when prescribing zonisamide to adults who are concurrently taking medications that may promote overheating, including carbonic anhydrase inhibitors and drugs with anticholinergic activity.

Pancreatitis.

Patients who develop clinical signs of pancreatitis while taking zonisamide should be monitored for pancreatic lipase and amylase levels. In confirmed cases of pancreatitis without other obvious causes, discontinuation of zonisamide and initiation of appropriate treatment are recommended.

Rhabdomyolysis.

Patients taking zonisamide who develop severe muscle pain and/or weakness, with or without fever, should be evaluated for markers of muscle injury, including creatine phosphokinase and aldolase levels. If these markers are elevated and no other obvious causes (e.g., trauma or major epileptic seizure) are present, discontinuation of zonisamide and initiation of appropriate treatment are recommended.

Women of childbearing potential.

Women of childbearing potential must use effective contraception during zonisamide therapy and for 1 month after discontinuation (see section "Use during pregnancy or breastfeeding"). Zonisamide should not be used in women of childbearing potential who are not using effective contraception, except in cases of extreme necessity and only if the potential benefit is considered to outweigh the risks to the fetus. Women of childbearing potential receiving zonisamide therapy should consult a specialist. They must be fully informed about the risks and benefits of zonisamide use and understand the potential impact of therapy on the fetus before treatment initiation. Before starting zonisamide therapy, women of childbearing potential should consider undergoing a pregnancy test. If pregnancy is planned, prior to conception and discontinuation of contraception, women should consult their physician regarding a review of zonisamide therapy, including the possibility of alternative treatment regimens. If a woman receiving zonisamide therapy becomes pregnant or suspects she may be pregnant, she should immediately seek medical advice.

Physicians prescribing zonisamide must ensure that female patients are fully informed about the necessity of using appropriate effective contraceptive methods. They must also ensure that oral contraceptives or their component doses are adequate based on individual clinical assessment.

Body weight.

Zonisamide therapy may lead to weight reduction. Nutritional supplements and increased caloric intake are necessary when treating patients with low body weight or experiencing weight loss during zonisamide therapy. If significant weight loss occurs, discontinuation of zonisamide should be considered. Weight reduction in children may be more pronounced.

Children.

The safety measures listed above also apply to children.

The following precautions specific to pediatric patients require particular attention.

Heat stroke and dehydration.

Prevention of overheating and dehydration in children.

Zonisamide may cause decreased sweating and overheating in children, which, if not promptly addressed, may lead to brain damage and fatal outcomes. Children are at high risk, especially in hot weather conditions.

If a child is taking zonisamide, the following measures should be followed:

• Avoid overheating, especially in hot weather;
• Avoid strenuous physical activity, especially in hot weather;
• Drink large amounts of cool water;
• Do not use the following medications: carbonic anhydrase inhibitors (such as topiramate and acetazolamide) and anticholinergic drugs (such as clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine, and oxybutynin).

If any of the following symptoms occur in a child, immediate emergency medical attention should be sought, and immediate first-aid measures should be taken.

Symptoms:

• Hot, dry skin;
• Little or no sweating;
• Confusion;
• Muscle spasms;
• Rapid heartbeat and/or breathing.

Emergency first-aid measures:

• Move the child to a cool, shaded place;
• Moisten the child's skin with water to cool them down;
• Give the child cool water to drink.

Cases of decreased sweating and elevated body temperature have been reported primarily in children. In some cases, heat stroke was diagnosed, requiring hospitalization. In several cases, heat stroke required hospitalization and led to fatal outcomes. Most cases occurred during warm weather. Patients and caregivers should be warned about the potential seriousness of heat stroke, situations in which it may occur, and measures to take if any signs or symptoms appear. Patients or caregivers should be advised to consume adequate fluids, avoid excessive heat, and avoid strenuous physical exertion. Physicians should inform children and their parents/guardians about the recommendations for preventing heat stroke and overheating in children as stated in the instructions for use. If signs or symptoms of dehydration, oligohidrosis, or elevated body temperature occur, discontinuation of zonisamide should be considered.

Zonisamide should not be used in children who are concurrently receiving other medications that may provoke thermoregulatory disturbances, such as carbonic anhydrase inhibitors and anticholinergic drugs.

Body weight.

Worsening general condition and discontinuation of antiepileptic drugs have been associated with weight loss and led to fatal outcomes. Zonisamide use is not recommended in children with low body weight or in children with poor appetite. Weight reduction occurs with similar frequency across different pediatric age groups. Due to the potential seriousness of weight loss consequences in children, body weight must be monitored throughout therapy.

If a child shows delayed weight gain according to growth charts, nutritional supplements or increased food intake should be implemented. Otherwise, zonisamide should be discontinued.

Data on the use of zonisamide in patients weighing less than 20 kg are limited. Therefore, caution should be exercised when treating children aged 6 years and older who weigh less than 20 kg. The long-term impact of low body weight on a child's growth and development is unknown.

Metabolic acidosis.

The risk of metabolic acidosis due to zonisamide therapy is higher in children, and the clinical presentation in this age group may be more severe. Appropriate monitoring of serum bicarbonate levels is necessary in this patient group. The long-term impact of low bicarbonate levels on growth and development is unknown.

Zonisamide should not be used in children concurrently receiving other carbonic anhydrase inhibitors, such as topiramate or acetazolamide.

Nephrolithiasis.

Kidney stone formation (nephrolithiasis) has been observed in pediatric patients. In some patients, particularly those predisposed to nephrolithiasis, there may be an increased risk of kidney stone formation and associated signs and symptoms such as renal colic, kidney pain, or flank pain. Nephrolithiasis may lead to chronic kidney damage. Risk factors for nephrolithiasis include prior kidney stone formation, family history of nephrolithiasis, and hypercalciuria. None of these risk factors reliably predict kidney stone formation during zonisamide treatment.

Increased fluid intake and diuresis may help reduce the risk of kidney stone formation, especially in individuals with risk factors. Ultrasound examination of the kidneys may be performed at the physician's discretion. If kidney stones are detected, zonisamide should be discontinued.

Liver function impairment.

Elevations in certain liver function parameters, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and bilirubin, have been observed in pediatric patients during zonisamide therapy. If adverse liver effects are suspected, liver function should be evaluated and a decision on zonisamide discontinuation should be made.

Cognitive function.

Cognitive impairment in patients with epilepsy may be related to the underlying disease and/or the use of antiepileptic drugs. In a placebo-controlled study using zonisamide in children and adolescents, the proportion of patients with cognitive impairment was quantitatively higher in the zonisamide group compared to the placebo group.

Excipients.

Zoresan**®** contains hydrogenated castor oil, which may cause gastrointestinal discomfort and diarrhea.

Use during pregnancy or breastfeeding.

Women of childbearing potential.

Women of childbearing potential must use effective contraception during zonisamide therapy and for 1 month after discontinuation (see section "Special precautions for use").

Zonisamide should not be used in women of childbearing potential who are not using effective contraception, except in cases of extreme necessity and only if the potential benefit is considered to outweigh the risks to the fetus. Women of childbearing potential receiving zonisamide therapy should consult a specialist. They must be fully informed about the risks and benefits of zonisamide use and understand the potential impact of therapy on the fetus before treatment initiation. Before starting zonisamide therapy, women of childbearing potential should consider undergoing a pregnancy test. If pregnancy is planned, prior to conception and discontinuation of contraception, women should consult their physician regarding a review of zonisamide therapy, including the possibility of alternative treatment regimens.

As with therapy using other antiepileptic drugs, abrupt discontinuation of zonisamide in pregnant women should be avoided due to the risk of seizure occurrence, which may lead to serious consequences for both the mother and the fetus. The risk of congenital malformations in children whose mothers take antiepileptic drugs increases 2–3 times. The most commonly observed malformations include cleft lip, cardiovascular system abnormalities, and neural tube defects. Combination therapy with anticonvulsant drugs is associated with a higher risk of congenital malformations compared to monotherapy.

Pregnancy.

There are limited data on the use of zonisamide in pregnant women. Animal studies have shown reproductive toxicity. The potential risk in humans is unknown.

Reports have indicated an increased incidence of infants with low birth weight, preterm birth, or small-for-gestational-age infants. Registry data from pregnant women have shown that zonisamide use led to an increase of approximately 5%–8% in the proportion of infants with low birth weight, 8%–10% in preterm births, and 7%–12% in infants small-for-gestational-age (compared to data from women receiving lamotrigine monotherapy).

Zonisamide should not be used during pregnancy except when, in the physician's opinion, the potential benefit outweighs the possible risk to the fetus. If zonisamide is prescribed to pregnant women, they must be fully informed about the potential harm of such treatment to the fetus and receive the minimum effective dose under close clinical monitoring.

Breastfeeding period.

Zonisamide passes into breast milk at concentrations similar to those in plasma. The drug may be used during breastfeeding only if, in the physician's opinion, the benefit of zonisamide to the mother outweighs the potential risk of discontinuing breastfeeding for the infant. Breastfeeding should be discontinued during drug administration. Due to the long elimination half-life of zonisamide, breastfeeding may be resumed no earlier than 1 month after discontinuation.

Fertility.

There are no available clinical data on the effect of zonisamide on human fertility. Animal studies have demonstrated changes in fertility parameters.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of zonisamide on the ability to drive or operate machinery have not been conducted. However, given that some patients may experience drowsiness or difficulty concentrating, especially at the beginning of therapy or after dose increases, patients should refrain from activities requiring high concentration, such as driving or operating machinery.

Method of administration and dosage.

Zoresan® should be administered orally, independent of food intake.

Adults.

Dosage escalation and maintenance dose.

Zonisamide can be used as monotherapy or as adjunctive therapy. The dose should be titrated according to clinical response. The recommended dosage titration regimen and maintenance dose levels are provided in Table 1. For some patients, particularly those not taking drugs that induce the CYP3A4 isoenzyme, a clinical response may be achieved with lower doses.

Table 1.

Recommended dosage titration regimen and maintenance dose levels in adults

Treatment regimen	Dose titration phase			Maintenance dose
	Weeks 1–2	Weeks 3–4	Weeks 5–6
Monotherapy Adults with newly diagnosed epilepsy	100 mg/day (once daily)	200 mg/day (once daily)	300 mg/day (once daily)	300 mg/day (once daily) If higher doses are required: increase by 100 mg every two weeks up to the maximum recommended dose of 500 mg/day
Adjunctive therapy with medicinal products that induce CYP3A4 isoenzyme	Week 1	Week 2	Weeks 3–5
	50 mg/day (in two divided doses)	100 mg/day (in two divided doses)	Increments of 100 mg weekly	300–500 mg/day (in one or two doses).
Adjunctive therapy without medicinal products that induce CYP3A4 isoenzyme or in patients with renal or hepatic impairment	Weeks 1–2	Weeks 3–4	Weeks 5–10
	50 mg/day (in two divided doses)	100 mg/day (in two divided doses)	Increments of 100 mg every two weeks	300–500 mg/day (in one or two doses). Some patients may respond to lower doses.

Discontinuation of the drug.

If discontinuation of zonisamide therapy is necessary, the drug should be withdrawn gradually. The dose should be reduced by 100 mg per week, with simultaneous adjustment of the doses of other antiepileptic drugs (if required).

Children (aged 6 years and older).

Dose escalation and maintenance dose levels.

In children aged 6 years and older, zonisamide should be added to previously prescribed therapy. The dose of the drug should be titrated according to clinical response. The recommended dose escalation regimen and maintenance dose levels are presented in Table 2. In some patients, particularly those not taking drugs that induce the CYP3A4 isoenzyme, a clinical response may be achieved with lower doses.

Children, their parents, or caregivers should be advised about specific patient instructions regarding measures to prevent heat stroke (see section "Special precautions").

Table 2.

Recommended dose escalation regimen and maintenance dose levels in children aged
6 years and older.

Treatment regimen	Dose titration phase		Maintenance dose
Concomitant therapy with medicinal products that induce CYP3A4 isoenzyme	1st week	2–8th weeks	Patients with body weight from 20 to 55 kg*	Patients with body weight > 55 kg
	1 mg/kg/day (once daily)	Increase by 1 mg/kg with weekly intervals	6–8 mg/kg/day (once daily)	300–500 mg/day (once daily)
Concomitant therapy without medicinal products that induce CYP3A4 isoenzyme	1–2nd weeks	≥ 3 weeks	Patients with body weight from 20 to 55 kg*	Patients with body weight > 55 kg
	1 mg/kg/day (once daily)	Increase by 1 mg/kg with two-week intervals	6–8 mg/kg/day (once daily)	300–500 mg/day (once daily)

*To maintain the therapeutic dose, the child's body weight should be monitored and the dose adjusted accordingly if body weight changes (until the body weight reaches 55 kg). The dosing regimen is 6–8 mg/kg/day up to a maximum dose of 500 mg/day.

The safety and efficacy of zonisamide in children under 6 years of age or in children with body weight less than 20 kg have not been established. There are limited data on the use of zonisamide in patients with body weight less than 20 kg. Therefore, children aged 6 years and older with body weight less than 20 kg should be treated with caution.

It is not always possible to achieve the calculated dose precisely using the available doses of Zoresan**®. In such cases, the calculated dose should be rounded up or down to the nearest available Zoresan®** dose (25, 50, and 100 mg).

Discontinuation of the drug.

If zonisamide therapy needs to be discontinued, the drug should be withdrawn gradually by reducing the dose by 2 mg/kg once weekly (Table 3).

Table 3.

Recommended dose reduction regimen of zonisamide in children aged 6 years and older.

Body weight	Reduce dose in weekly intervals:
20–28 kg	From 25 to 50 mg/day*
29–41 kg	From 50 to 75 mg/day*
42–55 kg	100 mg/day*
> 55 kg	100 mg/day*

*All daily doses are single doses.

Elderly patients.

Caution should be exercised when prescribing zonisamide to elderly patients due to insufficient data on its use in this patient group. The safety profile of zonisamide should also be taken into account (see section "Side effects").

Patients with renal impairment.

Caution is required when treating patients with renal impairment, as data on the use of zonisamide in this patient population are limited. A slower dose titration may be necessary. Since zonisamide and its metabolites are excreted by the kidneys, the drug should be discontinued in patients who develop acute renal failure or exhibit clinically significant persistent increases in serum creatinine.

In patients with renal impairment, renal clearance of single doses of zonisamide positively correlates with creatinine clearance. Plasma AUC of zonisamide increased by 35% in individuals with creatinine clearance < 20 mL/min.

Patients with hepatic impairment.

The use of zonisamide in patients with hepatic impairment has not been studied. Therefore, the use of the drug is not recommended in patients with severe hepatic impairment. Caution should be exercised when treating patients with mild to moderate hepatic impairment, and a slower dose titration may be required.

Children.

The drug should be administered to children aged 6 years and older and weighing more than 20 kg.

Overdose.

Symptoms.

Cases of accidental and intentional overdose have been reported in adults and children. In some cases, overdose was asymptomatic, especially when gastric lavage and induced emesis were performed promptly.

In other cases, overdose was accompanied by the following symptoms: somnolence, nausea, gastritis, nystagmus, myoclonus, coma, bradycardia, renal dysfunction, arterial hypotension, and respiratory depression.

A very high plasma concentration of zonisamide (100.1 µg/mL) was observed approximately 31 hours after overdose with zonisamide and clonazepam. The patient developed coma and respiratory depression. However, after 5 days, the patient regained consciousness and experienced no complications.

Treatment.

There is no specific antidote for the treatment of zonisamide overdose. If overdose is confirmed or suspected, gastric lav游戏副本

Adverse reactions.

Summary of safety profile

Zonisamide has been studied in over 1200 patients during clinical trials, more than 400 of whom received the drug for at least 1 year. In addition, extensive post-marketing experience with zonisamide has been accumulated in Japan since 1989 and in the United States since 2000.

It should be noted that zonisamide is a benzisoxazole derivative containing a sulfonamide group. Serious immune system-related adverse reactions associated with sulfonamide-containing medicinal products include skin rashes, allergic reactions, and severe hematological disorders, including aplastic anemia, which in very rare cases may lead to fatal outcomes (see section "Special precautions").

The most commonly reported adverse reactions in controlled adjunctive therapy trials were somnolence, dizziness, and anorexia. The most commonly reported adverse reactions in a randomized, controlled monotherapy trial of zonisamide compared to extended-release carbamazepine in patients receiving zonisamide were decreased bicarbonate levels, loss of appetite, and weight loss. The incidence of marked decrease in serum bicarbonate levels (decrease to less than 17 mEq/L and by more than 5 mEq/L) was 3.8%. The incidence of marked weight loss of 20% or more was 0.7%.

Adverse reactions associated with the use of zonisamide, reported during clinical trials and post-marketing surveillance, are listed below. The frequencies are classified according to the following scheme:

Very common ≥1/10
Common from ≥1/100 to <1/10
Uncommon from ≥1/1000 to <1/100
Rare from ≥1/10000 to <1/1000
Very rare <1/10000
Not known Cannot be estimated from available data

Table 4.
Adverse reactions associated with zonisamide, reported during clinical trials of adjunctive therapy and post-marketing surveillance.

System Organ Class	Very common	Common	Uncommon	Very rare
Infections and infestations			Pneumonia, urinary tract infections
Blood and lymphatic system disorders		Ecchymosis		Agranulocytosis, aplastic anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, thrombocytopenia
Immune system disorders		Hypersensitivity		Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), drug-induced hypersensitivity syndrome
Metabolism and nutrition disorders	Anorexia		Hypokalemia	Metabolic acidosis, renal tubular acidosis
Psychiatric disorders	Agitation, irritability, confusion, depression	Emotional lability, anxiety, insomnia, psychotic disorders	Anger, aggression, suicidal thoughts and suicide attempts	Hallucinations
Nervous system disorders	Ataxia, dizziness, memory impairment, somnolence	Bradypsychia, attention disturbance, nystagmus, paresthesia, speech disorder, tremor	Seizures	Amnesia, coma, grand mal convulsions, myasthenic syndrome, neuroleptic malignant syndrome, epileptic status
Eye disorders	Diplopia			Angle-closure glaucoma, eye pain, myopia, blurred vision, decreased visual acuity
Respiratory, thoracic and mediastinal disorders				Dyspnea, aspiration pneumonia, respiratory disorder, hypersensitivity-related pneumonitis
Gastrointestinal disorders		Abdominal pain, constipation, diarrhea, dyspepsia, nausea	Vomiting	Pancreatitis
Hepatobiliary disorders			Cholecystitis, cholelithiasis	Hepatocellular damage
Skin and subcutaneous tissue disorders		Rash, pruritus, alopecia		Anhidrosis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis
Musculoskeletal and connective tissue disorders				Rhabdomyolysis
Renal and urinary disorders		Nephrolithiasis	Urolithiasis	Hydronephrosis, renal failure, abnormal urine composition
General disorders and administration site conditions		Increased fatigue, influenza-like illness, increased body temperature, peripheral edema
Investigations	Decreased bicarbonate levels	Weight decreased		Increased creatine phosphokinase level, increased creatinine level, increased urea level, liver function test abnormalities
Injury, poisoning and procedural complications				Heat stroke

In addition, there have been isolated cases of sudden unexpected death in patients with epilepsy receiving zonisamide.

Table 5.

Adverse reactions in a randomized controlled monotherapy study comparing zonisamide with carbamazepine extended-release.

System organ class	Very common	Common	Uncommon
Infections and infestations			Urinary tract infections, pneumonia
Blood and lymphatic system disorders			Leukopenia, thrombocytopenia
Metabolism and nutrition disorders		Decreased appetite	Hypokalemia
Psychiatric disorders		Agitation, depression, insomnia, mood swings, anxiety	Confusion, acute psychosis, aggression, suicidal thoughts, hallucinations
Nervous system disorders		Ataxia, dizziness, memory impairment, somnolence, bradypsychia, attention disturbance, paresthesia	Nystagmus, speech disorder, tremor, seizures
Eye disorders		Diplopia
Respiratory, thoracic and mediastinal disorders			Respiratory disorder
Gastrointestinal disorders		Constipation, diarrhea, dyspepsia, nausea, vomiting	Abdominal pain
Hepatobiliary disorders			Acute cholecystitis
Skin and subcutaneous tissue disorders		Rash	Pruritus, ecchymosis
General disorders and administration site conditions		Fatigue, fever, irritability
Investigations	Decreased bicarbonate levels	Weight loss, increased blood creatine phosphokinase, increased alanine aminotransferase, increased aspartate aminotransferase	Abnormal urine composition

Additional information regarding special patient groups

Elderly patients

A pooled analysis of safety data from 95 elderly patients showed a relatively higher incidence of peripheral edema and pruritus compared to younger patients.

A review of post-marketing data in patients over 65 years of age indicates a higher frequency, compared to the general population, of the following events: Stevens-Johnson syndrome and drug hypersensitivity syndrome, and sudden unexpected death in patients with epilepsy.

Paediatric patients

The safety profile of zonisamide in children who participated in placebo-controlled clinical trials (aged 6 to 17 years) corresponds to the safety profile of the drug in adults. Among 465 patients included in the paediatric safety database (including 67 patients who continued in the open-label phase of the extended controlled clinical trial), 7 children died (1.5%; 14.6/1000 patient-years): 2 cases due to status epilepticus, one of which was associated with significant weight loss (10% over 3 months) in a patient with low body weight, followed by discontinuation of the drug; 1 case due to head trauma/hematoma; and 4 cases in patients with pre-existing neurological functional deficits of various etiologies (2 cases of sepsis associated with pneumonia/multi-organ failure, 1 case of sudden unexpected death in epilepsy patients, and 1 case of head trauma). Overall, in 70.4% of patients who received zonisamide in the controlled study or in the open-label extension phase, serum bicarbonate levels below 22 mmol/L were observed at least once during treatment. Low bicarbonate levels persisted for a prolonged period (median 188 days).

In a pooled analysis of safety data from 420 children (183 aged 6 to 11 years and 237 aged 12 to 16 years, with a mean duration of treatment of approximately 12 months), relatively more frequent reports were observed for pneumonia, dehydration, decreased sweating, hepatic biochemical abnormalities, otitis media, pharyngitis, sinusitis, upper respiratory tract infections, cough, epistaxis and rhinitis, abdominal pain, vomiting, rash and eczema, and fever (especially in those under 12 years of age), compared to data from adult patients. Reports of amnesia, increased creatinine levels, lymphadenopathy, and thrombocytopenia occurred less frequently. The incidence of weight loss of 10% or more was 10.7% (see section "Special precautions"). In some cases, weight loss was associated with delayed progression to the next Tanner stage and delayed bone maturation.

Reporting of adverse reactions

Reporting of adverse reactions after medicinal product authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25°C.

Keep out of reach of children.

Packaging.

10 capsules per blister; 3 or 6 blisters per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Kusum Healthcare Pvt Ltd.

Manufacturer's address and site of operations.

SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.

Date of last review.