Zonegran
Skin rashes
Severe skin reactions, including Stevens-Johnson syndrome, have been reported during therapy with Zonegran.
It is recommended to discontinue the drug in patients who develop skin rashes that cannot be explained by other reasons. All patients who develop skin rashes while taking the drug should be closely monitored, especially patients concomitantly prescribed other antiepileptic drugs that themselves can cause skin rashes.
Withdrawal syndrome
The drug is discontinued by gradually reducing the dose to avoid the occurrence of epileptic seizures. There is insufficient data on the discontinuation of concomitantly used antiepileptic drugs after achieving control of seizures when using the drug as part of adjuvant therapy for the transition to monotherapy with Zonegran. Therefore, withdrawal of concomitant antiepileptic treatment should be carried out with caution.
Reactions associated with the presence of a sulfonamide group
Zonisamide contains a sulfonamide group. Serious adverse reactions from the immune system associated with taking drugs that contain a sulfonamide group include the appearance of skin rashes and other allergic reactions, as well as the development of severe hematological disorders, including aplastic anemia, which in very rare cases can be fatal.
Cases of agranulocytosis, thrombocytopenia, leukopenia, aplastic anemia, pancytopenia and leukocytosis have been reported. There is insufficient information to assess the possible relationship of these phenomena with the size of the drug dose taken and the duration of treatment.
Suicidal thinking and behavior
The development of suicidal thinking and behavior is possible in patients taking antiepileptic drugs for a number of 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 phenomenon is unknown; the available data do not exclude the possibility of an increased risk of suicidal behavior while taking zonisamide. Patients should be monitored for suicidal thoughts and behavior and appropriate treatment provided. Patients (and their caregivers) should be advised to seek medical help if suicidal thoughts and behavior occur.
Nephrolithiasis
Some patients, especially those with a predisposition to nephrolithiasis, may have an increased risk of developing kidney stones and developing signs and symptoms such as renal colic, kidney pain, or flank pain. Nephrolithiasis can lead to chronic kidney damage. Risk factors for nephrolithiasis include previous kidney stone formation, as well as a family history of nephrolithiasis and hypercalciuria. None of these risk factors are reliable predictors of kidney stone formation during zonisamide treatment. In addition, the risk may be increased in patients taking other drugs known to cause urolithiasis. Increasing fluid intake and forced diuresis helps reduce the risk of stone formation, including in patients with a predisposition to this.
Metabolic acidosis
The formation of hyperchloremic metabolic acidosis without anion gap (decrease in bicarbonate levels in the absence of chronic gas alkalosis) is associated with therapy with Zonegran. The development of metabolic acidosis is due to the loss of bicarbonate in the kidneys due to the inhibitory effect of zonisamide on carbonic anhydrase, and is possible at any stage of treatment, although it is more often observed in the early stages of treatment. Similar violations were observed both during placebo-controlled clinical trials and in the post-marketing period. The decrease in bicarbonate levels is usually insignificant; in rare cases, patients may experience a more significant decrease. Conditions or treatments that predispose to the development of acidosis (eg, kidney disease, severe respiratory distress, status epilepticus, diarrhea, surgery, diet that promotes the formation of ketone bodies, certain medications) may enhance the effect of zonisamide on bicarbonate levels.
The risk and severity of metabolic acidosis increases in younger patients. If signs or symptoms of metabolic acidosis occur, it is recommended to evaluate serum bicarbonate concentrations. If the developed metabolic acidosis does not go away, you should consider reducing the dose or completely stopping the drug (with a gradual dose reduction), as osteopenia may develop. If the decision is made to continue therapy in the presence of persistent acidosis, the use of alkaloids should be considered.
Caution should be exercised when administered concomitantly with carbonic anhydrase inhibitors (eg, topiramate and acetazolamide), as there is insufficient data to exclude a pharmacodynamic interaction.
Heatstroke
Cases of decreased sweating and increased body temperature were recorded mainly in patients under 18 years of age. In some cases, heat stroke occurred, requiring hospital treatment. Most cases occurred in high ambient temperatures. Patients and/or caregivers should be warned to maintain adequate hydration and avoid exposure to elevated temperatures. Caution should be exercised when prescribing zonisamide concomitantly with drugs that promote overheating, including carbonic anhydrase inhibitors and anticholinergics.
Pancreatitis
If patients develop signs of pancreatitis while taking zonisamide, monitoring the level of pancreatic lipases and amylase is necessary. In case of confirmed pancreatitis in the absence of other obvious causes, it is recommended to discontinue the drug and prescribe appropriate treatment.
Rhabdomyolysis
If patients taking zonisamide develop severe muscle pain and/or weakness, especially when accompanied by fever, assessment of markers of muscle damage, including creatine phosphokinase and aldolase levels, is required. If they increase, in the absence of other obvious causes, such as trauma or grand mal seizure, it is recommended to discontinue the drug and prescribe appropriate treatment.
Women with preserved childbearing potential
Women with preserved childbearing potential should use reliable methods of contraception during treatment with Zonegran and for 1 month after its discontinuation.
Weight loss
The drug Zonegran can cause weight loss, therefore, during the treatment of patients with low body weight or when reducing it, it is necessary to prescribe nutritional supplements and enhanced nutrition. If there is a significant decrease in body weight, the possibility of discontinuing the drug should be considered. Weight loss in children may be more pronounced.
Pediatric patients
The above precautions apply to children and adolescents. The following are precautions that you should pay particular attention to.
Heat stroke and dehydration
Prevention of overheating and dehydration in children. The drug Zonegran can cause a decrease in sweating and lead to overheating, and in the absence of appropriate help, the child may experience brain damage and death. Children are at high risk, especially in hot weather.
If your child is taking Zonegran:
- Avoid overheating, especially in hot weather
— Significant physical activity should be avoided, especially in hot weather
- Water consumption should be increased
- The following drugs should not be used: carbonic anhydrase inhibitors (such as topiramate and acetazolamide) and anticholinergic drugs (such as clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine and oxybutynin).
SEEK IMMEDIATE MEDICAL CARE IF ANY OF THE FOLLOWING SYMPTOMS OCCUR: Feeling very hot on the skin with little or no sweating, or if the child experiences confusion, muscle spasms, or the child's heart rate or breathing increases.
- it is necessary to place the child in a cool, shaded place;
- moisten the baby's skin with water to cool it;
- Give the child cool water to drink.
Cases of decreased sweating and increased body temperature have been reported, mainly in children. In some cases, heat stroke has occurred, requiring hospitalization. In some cases, fatal heat stroke has been reported. In most cases, the phenomenon occurred during warm weather. The patient and their caregivers should be warned about the possible severity of heat stroke, the situations in which it may occur, and the steps to take if any signs or symptoms occur. Patients or caregivers should be advised to drink sufficient fluids and avoid excessive exercise, depending on the patient's condition. If signs and symptoms of dehydration, oligohidrosis or increased body temperature appear, discontinuation of the drug should be considered.
Zonegran should not be used in children concomitantly receiving other medications that may predispose patients to heat-related disorders; This includes carbonic anhydrase inhibitors and drugs with anticholinergic effects.
Weight loss
Cases of weight loss have been described, which led to a deterioration in the general condition and cessation of the use of antiepileptic drugs, leading to death. The use of Zonegran is not recommended in children with low body weight or in children with poor appetite.
The incidence of weight loss is similar in different age groups, however, given the possible severity of weight loss in children, weight control should be monitored in this group of patients. If the patient’s weight gain is delayed, based on physical development charts, it is recommended to review the diet or increase the amount of food taken, otherwise the drug should be discontinued.
Clinical studies have limited data in patients weighing less than 20 kg. In this regard, when treating children aged 6 years and older with a body weight of less than 20 kg, caution should be exercised. The effects of long-term low body weight on growth and development in children are unknown.
Metabolic acidosis
The risk of acidosis associated with zonisamide use in children and adolescents may be higher and more severe. In this group of patients, appropriate monitoring and monitoring of serum bicarbonate levels is necessary. The long-term effects of low bicarbonate levels on growth and development are unknown.
Zonegran should not be used in children concomitantly with other carbonic anhydrase inhibitors, such as topiramate or acetazolamide.
Nephrolithiasis
Kidney stones have been reported in children. Some patients, especially those with a predisposition to nephrolithiasis, may have an increased risk of developing kidney stones and associated signs and symptoms such as renal colic, kidney pain, or flank pain. Urolithiasis can lead to chronic kidney damage. Risk factors for urolithiasis include previous kidney stone formation and a family history of nephrolithiasis and hypercalciuria. None of these risk factors are reliable predictors of kidney stone formation during zonisamide treatment. Increasing fluid intake and increasing diuresis may reduce the risk of kidney stones, especially in people with risk factors. At the discretion of the doctor, an ultrasound examination of the kidneys may be performed. If kidney stones are detected, the drug should be discontinued.
Liver dysfunction
Increases in liver and biliary function tests such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), gammaglutamyltransferase (GGT) and bilirubin were observed in children and adolescents, but no clear pattern was found for values above the upper limit of normal. However, if adverse events from the liver are suspected, liver function should be assessed and the issue of discontinuing the drug should be decided.
Cognitive functions
Cognitive impairment in patients with epilepsy is associated with the underlying disease and/or the use of antiepileptic drugs. 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 with the placebo group.
Excipients
The composition of the drug with a dosage of 100 mg includes the dyes “sunset yellow” (E110) and “charming red” (E129), which can cause allergic reactions.
Impact on the ability to drive vehicles and machinery:
Special studies of the effect of the drug on the ability to drive vehicles and operate machinery have not been conducted. The drug Zonegran can cause (especially at the beginning of therapy or when increasing the dose) drowsiness and difficulty concentrating, and therefore, during the treatment period, care must be taken when engaging in activities that require increased concentration and speed of psychomotor reactions.
Zonegran®
Skin rashes
Severe skin reactions, including Stevens-Johnson syndrome, have been reported during therapy with Zonegran®.
It is recommended to discontinue the drug Zonegran® in patients who develop skin rashes that cannot be explained by other reasons. All patients who develop skin rashes while taking Zonegran® should be closely monitored, especially patients who are concomitantly prescribed other antiepileptic drugs that themselves can cause skin rashes.
Withdrawal syndrome
Discontinuation of the drug Zonegran® is carried out by gradually reducing the dose to avoid the occurrence of epileptic seizures. There is insufficient data on the discontinuation of concomitantly used antiepileptic drugs after achieving control of seizures when using the drug Zonegran® as part of adjuvant therapy for the transition to monotherapy with the drug Zonegran®. Therefore, withdrawal of concomitant antiepileptic treatment should be carried out with caution.
Reactions associated with the presence of a sulfonamide group
Zonegran® contains a sulfonamide group. Serious adverse reactions from the immune system associated with taking drugs that contain a sulfonamide group include the appearance of skin rashes and other allergic reactions, as well as the development of severe hematological disorders, including aplastic anemia, which in very rare cases leads to death outcome.
Cases of agranulocytosis, thrombocytopenia, leukopenia, aplastic anemia, pancytopenia and leukocytosis have been reported. There is insufficient information to assess the possible relationship of these phenomena with the dose of Zonegran® taken and the duration of treatment.
Suicidal thinking and behavior
The development of suicidal thinking and behavior is possible in patients taking antiepileptic drugs for a number of 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 phenomenon is unknown; available data do not exclude the possibility of an increased risk of suicidal behavior while taking the drug Zonegran®. Patients should be monitored for suicidal thoughts and behavior and appropriate treatment provided. Patients (and their caregivers) should be advised to seek medical help if suicidal thoughts and behavior occur.
Nephrolithiasis
Some patients, especially those with a predisposition to nephrolithiasis, may have an increased risk of developing kidney stones and developing signs and symptoms such as renal colic, kidney pain, or flank pain. Nephrolithiasis can lead to chronic kidney damage. Risk factors for nephrolithiasis include previous kidney stone formation, as well as a family history of nephrolithiasis and hypercalciuria. None of these risk factors are reliable predictors of kidney stone formation during zonisamide treatment. In addition, the risk may be increased in patients taking other drugs known to cause urolithiasis. Increasing fluid intake and forced diuresis helps reduce the risk of stone formation, including in patients with a predisposition to this.
Metabolic acidosis
The formation of hyperchloremic metabolic acidosis without an anion gap (decrease in bicarbonate levels in the absence of chronic gas alkalosis) is associated with therapy with Zonegran® The development of metabolic acidosis is caused by the loss of bicarbonates in the kidneys due to the inhibitory effect of zonisamide on carbonic anhydrase, and is possible at any stage of treatment, although it is more often noted in the early stages of treatment. Similar violations were observed both during placebo-controlled clinical trials and in the post-marketing period. The decrease in bicarbonate levels is usually insignificant (the average value is approximately 3.5 mEq/L at a daily dose of 300 mg in adults); in rare cases, patients may experience a more significant decrease. Conditions or treatments that predispose to the development of acidosis (eg, kidney disease, severe respiratory distress, status epilepticus, diarrhea, surgery, diet that promotes the formation of ketone bodies, certain medications) may enhance the effect of zonisamide on bicarbonate levels.
The risk and severity of metabolic acidosis increases in younger patients. If signs or symptoms of metabolic acidosis occur, it is recommended to evaluate serum bicarbonate concentrations. If the developed metabolic acidosis does not go away, you should consider reducing the dose or completely stopping taking Zonegran® (with a gradual dose reduction), as osteopenia may develop. If the decision is made to continue therapy in the presence of persistent acidosis, the use of alkaloids should be considered.
Caution should be exercised when administered concomitantly with carbonic anhydrase inhibitors (for example, topiramate and acetazolamide), as there is insufficient data to exclude a pharmacodynamic interaction (see section "Interaction with other drugs").
Heatstroke
Cases of decreased sweating and increased body temperature were recorded mainly in patients under 18 years of age. In some cases, heat stroke occurred, requiring hospital treatment. Most cases occurred in high ambient temperatures. Patients and/or caregivers should be warned to maintain adequate hydration and avoid exposure to elevated temperatures. Caution must be exercised when prescribing Zonegran® simultaneously with drugs that cause overheating of the body, including carbonic anhydrase inhibitors and anticholinergics.
Pancreatitis
If patients develop signs of pancreatitis while taking Zonegran®, monitoring the level of pancreatic lipases and amylase is necessary. In case of confirmed pancreatitis in the absence of other obvious causes, it is recommended to discontinue the drug Zonegran® and prescribe appropriate treatment.
Rhabdomyolysis
If patients taking Zonegran develop severe muscle pain and/or weakness, especially accompanied by fever, an assessment of markers of muscle damage, including creatine phosphokinase and aldolase levels, is required. If they increase, in the absence of other obvious causes, such as trauma or grand mal seizure, it is recommended to discontinue the drug Zonegran® and prescribe appropriate treatment.
Women with preserved childbearing potential
Women with preserved childbearing potential should use reliable methods of contraception during treatment with Zonegran® and for 1 month after its discontinuation (see section “Use during pregnancy and breastfeeding”).
Weight loss
Zonegran® can cause weight loss, therefore, during the treatment of patients with low body weight or when reducing it, it is necessary to prescribe nutritional supplements and enhanced nutrition. If there is a significant decrease in body weight, you should consider discontinuing the drug Zonegran®. Weight loss in children may be more pronounced.
Pediatric patients
The above precautions apply to children and adolescents. The following are precautions that you should pay particular attention to.
Heat stroke and dehydration
Prevention of overheating and dehydration in children Zonegran® can cause decreased sweating and lead to overheating, and in the absence of appropriate help, the child may experience brain damage and death. Children are at high risk, especially in hot weather.
If the child is taking Zonegran®:
-Overheating should be avoided, especially in hot weather
-Strong physical activity should be avoided, especially in hot weather
-Water consumption should be increased
-The following drugs should not be used: 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, SEEK MEDICAL CARE IMMEDIATELY:
A feeling of intense heat from the skin with little or no sweating, or when the child experiences confusion, muscle spasms, or the child's heart rate or breathing increases.
- it is necessary to place the child in a cool, shaded place;
-moisten the baby's skin with water to cool it;
-give the child cool water to drink.
Cases of decreased sweating and increased body temperature have been reported, mainly in children. In some cases, heat stroke has occurred, requiring hospitalization. In some cases, fatal heat stroke has been reported. In most cases, the phenomenon occurred during warm weather. The patient and their caregivers should be warned about the possible severity of heat stroke, the situations in which it may occur, and the steps to take if any signs or symptoms occur. Patients or caregivers should be advised to drink sufficient fluids and avoid excessive exercise, depending on the patient's condition. If signs and symptoms of dehydration, oligohidrosis or increased body temperature appear, discontinuation of Zonegran® should be considered.
The drug Zonegran® should not be used in children who are simultaneously receiving other medications, the use of which may predispose patients to the development of disorders associated with exposure to excess heat; This includes carbonic anhydrase inhibitors and drugs with anticholinergic effects.
Weight loss
Cases of weight loss have been described, which led to a deterioration in the general condition and cessation of the use of antiepileptic drugs, leading to death. The use of Zonegran® is not recommended in children with low body weight or in children with poor appetite.
The incidence of weight loss is similar in different age groups, however, given the possible severity of weight loss in children, weight control should be monitored in this group of patients. If the patient’s weight gain is delayed, based on physical development charts, it is recommended to review the diet or increase the amount of food taken, otherwise the use of Zonegran® should be discontinued.
Clinical studies have limited data in patients weighing less than 20 kg. In this regard, when treating children aged 6 years and older with a body weight of less than 20 kg, caution should be exercised. The effects of long-term low body weight on growth and development in children are unknown.
Metabolic acidosis
The risk of acidosis associated with zonisamide use in children and adolescents may be higher and more severe. In this group of patients, appropriate monitoring and monitoring of serum bicarbonate levels is necessary. The long-term effects of low bicarbonate levels on growth and development are unknown.
Zonegran® should not be used in children concomitantly with other carbonic anhydrase inhibitors, such as topiramate or acetazolamide.
Nephrolithiasis
Kidney stones have been reported in children. Some patients, especially those with a predisposition to nephrolithiasis, may have an increased risk of developing kidney stones and associated signs and symptoms such as renal colic, kidney pain, or flank pain. Urolithiasis can lead to chronic kidney damage. Risk factors for urolithiasis include previous kidney stone formation and a family history of nephrolithiasis and hypercalciuria. None of these risk factors are reliable predictors of kidney stone formation during zonisamide treatment. Increasing fluid intake and increasing diuresis may reduce the risk of kidney stones, especially in people with risk factors. At the discretion of the doctor, an ultrasound examination of the kidneys may be performed. If kidney stones are detected, Zonegran® should be discontinued.
Liver dysfunction
Increases in liver and biliary function tests such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), gammaglutamyltransferase (GGT) and bilirubin were observed in children and adolescents, but no clear pattern was found for values above the upper limit of normal. However, if adverse events from the liver are suspected, liver function should be assessed and the issue of discontinuing the drug Zonegran® should be decided.
Cognitive functions
Cognitive impairment in patients with epilepsy is associated with the underlying disease and/or the use of antiepileptic drugs. 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 with the placebo group.
Excipients
The composition of the drug Zonegran® with a dosage of 100 mg contains the dyes “sunset yellow” (E110) and “charming red” (E129), which can cause allergic reactions.
