Depakine®
Before starting to use the drug and periodically during the first 6 months of treatment, especially in patients at risk of developing liver damage, liver function tests should be performed.
As with the use of most antiepileptic drugs, when using valproic acid, a slight increase in the activity of “liver” transaminases is possible, especially at the beginning of treatment, which occurs without clinical manifestations and is transient. In such patients, it is necessary to conduct a more thorough study of biological parameters, including the prothrombin index. It may be necessary to adjust the dose of the drug, and, if necessary, repeat clinical and laboratory examination.
Before starting therapy or before surgery, as well as in the event of spontaneous occurrence of subcutaneous hematomas or bleeding, it is recommended to determine the bleeding time and the number of formed elements in the peripheral blood, including platelets.
Severe liver damage
Predisposing factors
Isolated cases of severe liver damage, sometimes fatal, have been described. Clinical experience shows that those at risk include patients taking multiple antiepileptic drugs at the same time, children under 3 years of age with severe seizures, especially against the background of brain damage, mental retardation and/or congenital metabolic or degenerative diseases; patients concomitantly taking salicylates (since salicylates are metabolized through the same metabolic pathway as valproic acid).
After 3 years, the risk of liver damage decreases significantly and decreases progressively as the patient ages. In most cases, such liver damage occurred during the first 6 months of treatment, most often between 2 and 12 weeks of treatment and usually when valproic acid was used as part of combination antiepileptic therapy.
Suspicion of liver damage
For early diagnosis of liver damage, clinical observation of patients is mandatory. In particular, you should pay attention to the following symptoms that may precede the onset of jaundice, especially in patients at risk:
- nonspecific symptoms, especially those that began suddenly, such as asthenia, anorexia, lethargy, drowsiness, which are sometimes accompanied by repeated vomiting and abdominal pain;
- resumption of seizures in patients with epilepsy.
Patients or their family members (when using the drug in pediatric patients) should be warned that they should immediately report the occurrence of any of these symptoms to their doctor. Patients should immediately undergo clinical examination and laboratory testing of liver function tests.
Revealing
Liver function tests should be performed before starting treatment and then periodically during the first 6 months of treatment. Among conventional studies, the most informative are studies reflecting the state of the protein-synthetic function of the liver, especially the determination of the prothrombin index. Confirmation of deviation from the norm of the prothrombin index in the direction of its decrease, especially in combination with deviations from the norm of other laboratory parameters (a significant decrease in the content of fibrinogen and blood clotting factors, an increase in the concentration of bilirubin and an increase in the activity of “liver” transaminases), as well as the appearance of other symptoms indicating for liver damage, requires discontinuation of the drug. As a precaution, if patients were taking salicylates concomitantly, their use should also be discontinued.
Pancreatitis
There are rare reported cases of severe forms of pancreatitis in children and adults, which developed regardless of age and duration of treatment. Several cases of hemorrhagic pancreatitis have been observed with rapid progression of the disease from the first symptoms to death.
Children are at increased risk of developing pancreatitis, and this risk decreases with increasing age of the child. Risk factors for developing pancreatitis may include severe seizures, neurological disorders, or anticonvulsant therapy. Liver failure combined with pancreatitis increases the risk of death.
If severe abdominal pain, nausea, vomiting and/or anorexia occur, patients should be evaluated immediately. If pancreatitis is confirmed, in particular, with increased activity of pancreatic enzymes in the blood, the use of valproic acid should be discontinued and appropriate treatment should be started.
Suicidal thoughts and attempts
Suicidal thoughts and attempts have been reported in patients taking antiepileptic drugs for some indications. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs also showed a 0.19% increase in the risk of suicidal thoughts and attempts in all patients taking antiepileptic drugs (including a 0.24% increase in this risk in patients taking antiepileptic drugs for for epilepsy), compared with their frequency in patients taking placebo. The mechanism of this effect is unknown.
Therefore, patients taking the drug should be constantly monitored for suicidal thoughts and attempts. if they occur, appropriate treatment must be carried out. Patients and caregivers are advised to seek immediate medical attention if a patient experiences suicidal thoughts or attempts.
Carbapenems
The simultaneous use of carbapenems is not recommended (see section “Interaction with other drugs”, “With caution”).
Patients with known or suspected mitochondrial diseases
Valproic acid can initiate or aggravate the manifestations of mitochondrial diseases in the patient, caused by mutations in mitochondrial DNA, as well as in the nuclear gene encoding the mitochondrial enzyme γ-polymerase (POLG). In particular, in patients with congenital neurometabolic syndromes caused by mutations in the gene encoding γ-polymerase (POLG), such as patients with Alpers-Huttenlocher syndrome, a higher incidence of acute liver failure and liver-related deaths was associated with the use of valproic acid. outcomes. Diseases due to γ-polymerase defects may be suspected in patients with a family history of such diseases or symptoms suggestive of their presence, including unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus, mental and physical retardation, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia or complicated migraine with visual (occipital) aura and others. In accordance with current clinical practice, testing for mutations in the polymerase γ gene (POLG) should be performed to diagnose such diseases (see section "Contraindications").
Paradoxical increase in the frequency and severity of seizures (including the development of status epilepticus) or the emergence of new types of seizures
As with other antiepileptic drugs, when taking valproic acid, instead of improvement, some patients experienced a reversible increase in the frequency and severity of seizures (including the development of status epilepticus) or the appearance of new types of seizures. If seizures worsen, patients should immediately consult their doctor (see section "Side effects").
Female children and adolescents, women of childbearing potential and pregnant women
Pregnancy Prevention Program
Valproic acid has a high teratogenic effect; the use of valproic acid leads to a high risk of congenital malformations and developmental disorders of the central nervous system in the fetus.
The use of valproic acid is contraindicated:
- during pregnancy for epilepsy, except in cases of absence of alternative treatment methods (see sections “Special instructions”, “Use during pregnancy and breastfeeding”);
— during pregnancy in the treatment and prevention of bipolar affective disorders;
- in women of childbearing potential, unless all the conditions of the Pregnancy Prevention Program are met (see sections “Special Instructions”, “Use during Pregnancy and Breastfeeding”).
When prescribing drugs containing valproic acid, you must:
— conduct an individual assessment of the circumstances of prescribing the drug in each individual case, discuss possible methods of therapy and make sure that the patient understands the potential risks and the need for measures taken to minimize them;
— make sure that the patient has childbearing potential;
— make sure that the patient understands the nature and magnitude of the risks of using valproic acid during pregnancy, in particular, the risks of teratogenic effects, as well as the risks of disorders of the mental and physical development of the child;
— make sure that the patient understands the need to conduct a pregnancy test before starting and during treatment;
- explain the necessary methods of contraception, make sure that the patient uses reliable methods of contraception continuously during treatment with drugs containing valproic acid;
— make sure that the patient understands the need to regularly contact a specialist in the treatment of epilepsy and bipolar affective disorders (at least once a year) to re-analyze the prescribed therapy;
- make sure that the patient understands the need to contact her doctor if she is planning a pregnancy in order to promptly assess the possibility of switching to alternative therapy before stopping the use of contraception;
- inform about the need for immediate consultation with your doctor if you suspect pregnancy;
— ensure that the patient has received all the necessary explanations about the risks and necessary precautions.
The above information is also relevant for women who are not currently sexually active, unless the attending physician is satisfied that there is no childbearing potential.
Female pediatric patients
When prescribing drugs containing valproic acid, you must:
— make sure that female pediatric patients/their legal representatives understand the need to consult with their doctor upon the onset of menarche;
— ensure that female pediatric patients who have reached menarche, or their legal representatives, receive detailed information about the risks of congenital malformations and disorders of the central nervous system in the fetus.
The treating physician should re-evaluate the prescribed valproic acid therapy annually and evaluate the possibility of prescribing alternative therapy. If medications containing valproic acid are the treatment of choice, ensure that reliable methods of contraception are used and that the Pregnancy Prevention Program is followed. Before puberty, the possibility of switching patients to alternative treatment methods should be constantly considered.
Pregnancy test
Before starting treatment with drugs containing valproic acid, it is necessary to exclude pregnancy. Therapy with drugs containing valproic acid cannot be prescribed to women of childbearing potential unless a negative pregnancy test (pregnancy blood test) has been confirmed by a health care professional, in order to exclude the use of the drug during pregnancy.
Contraception methods
Female patients of childbearing potential who are prescribed therapy with drugs containing valproic acid should use reliable methods of contraception continuously throughout the entire treatment period.
Female patients of childbearing potential should be provided with detailed information about methods of preventing pregnancy, and such patients may also seek advice from their physician if they are not using a reliable method of contraception.
You must use at least one reliable method of contraception (preferably simultaneously with methods such as an intrauterine system or implant) or two complementary methods of contraception, including barrier methods. When prescribing a contraceptive method to a patient, it is necessary to take an individualized approach and discuss all possible contraceptive options with the patient to ensure that the patient adheres to and adheres to the regimen. In case of amenorrhea, the patient should also be warned about the use of effective methods of contraception.
Annual analysis of prescribed therapy
At least once a year, the treating physician should evaluate whether medications containing valproic acid are the treatment of choice. The risks associated with therapy should be discussed when prescribing the drug and at each annual review of the prescribed therapy, and ensure that the patient understands all risks.
Planning a pregnancy
If a patient is planning to become pregnant, a specialist in the treatment of epilepsy and bipolar affective disorder should evaluate therapy with drugs containing valproic acid and consider alternative therapy. Every effort should be made to switch the patient from therapy with drugs containing valproic acid before conception and until contraception is discontinued (see section “Use during pregnancy and breastfeeding”). If alternative therapy is not available, the patient should be advised of the risks associated with the use of drugs containing valproic acid for the unborn child to help make an informed decision about family planning.
What to do if you become pregnant?
If you become pregnant, you should contact your healthcare provider immediately to evaluate your treatment and consider alternative therapy.
The health worker must ensure that:
— patients understand all the risks described above;
— patients received recommendations not to stop therapy with valproic acid and to immediately contact their doctor when planning pregnancy.
Concomitant use with estrogen-containing drugs
Valproic acid does not reduce the therapeutic effectiveness of hormonal contraceptives. However, drugs containing estrogen, including estrogen-containing hormonal contraceptives, may increase the clearance of valproic acid, which may lead to a decrease in its serum concentration and, consequently, a decrease in its effectiveness. It is necessary to monitor the concentration of valproic acid in the blood serum and clinical effectiveness (seizure control and mood control) when prescribing or discontinuing estrogen-containing drugs (see section "Interaction with other drugs").
Children (information refers to dosage forms of the drug that can be taken by children under 3 years of age)
In children under 3 years of age, if it is necessary to use the drug, it is recommended to use it in monotherapy and in the dosage form recommended for children. In this case, before starting treatment, the ratio of the potential benefit from the use of valproic acid and the risk of liver damage and the development of pancreatitis when using it should be assessed.
In children under 3 years of age, the simultaneous use of valproic acid and salicylates should be avoided due to the risk of liver toxicity.
Kidney failure
It may be necessary to reduce the dose of valproic acid due to an increase in the concentration of its free fraction in the blood serum. If it is impossible to monitor plasma concentrations of valproic acid, the dose of the drug should be adjusted based on clinical observation of the patient.
Enzyme deficiency of the carbamide cycle (urea cycle)
If an enzymatic deficiency of the carbamide cycle is suspected, the use of valproic acid is contraindicated. Several cases of hyperammonemia with stupor or coma have been described in such patients. In these cases, metabolic studies should be carried out before starting treatment with valproic acid (see section "Contraindications").
In children with unexplained gastrointestinal symptoms (anorexia, vomiting, episodes of cytolysis), a history of lethargy or coma, mental retardation, or a family history of death of a newborn or child, metabolic studies should be performed before initiating treatment with valproic acid, in particular, determination of ammonemia (presence of ammonia and its compounds in the blood) on an empty stomach and after meals (see section “Contraindications”).
Patients with systemic lupus erythematosus
Despite the fact that during treatment with the drug, dysfunction of the immune system is extremely rare, the potential benefits of its use must be compared with the potential risks when using the drug in patients with systemic lupus erythematosus.
Weight gain
Patients should be warned about the risk of weight gain at the start of treatment and measures, mainly diet, should be taken to minimize this phenomenon.
Patients with diabetes mellitus
Given the possibility of adverse effects of valproic acid on the pancreas, when using the drug in patients with diabetes mellitus, blood glucose concentrations should be carefully monitored. When testing urine for the presence of ketone bodies in patients with diabetes, it is possible to obtain false-positive results, since valproic acid is excreted by the kidneys, partly in the form of ketone bodies.
Patients infected with human immunodeficiency virus (HIV)
In vitro studies have shown that valproic acid stimulates HIV replication under certain experimental conditions. The clinical significance of this fact is unknown. In addition, the significance of data obtained from in vitro studies for patients receiving maximally suppressive antiretroviral therapy has not been established. However, these data should be taken into account when interpreting the results of continuous viral load monitoring in HIV-infected patients taking valproic acid.
Patients with existing carnitine palmitoyltransferase (CPT) type II deficiency
Patients with existing CPT type II deficiency should be warned of the increased risk of rhabdomyolysis when taking valproic acid.
Ethanol
During treatment with valproic acid, ethanol consumption is not recommended.
Other special instructions
The inert matrix of the drug (extended release drug), due to the nature of its excipients, is not absorbed in the gastrointestinal tract; after the release of the active substances, the inert matrix is excreted by the intestines.
Instructions for use DEPAKINE CHRONO
The use of antiepileptic drugs may in rare cases be accompanied by the recurrence and development of more severe seizures or the episodic appearance of a new type of seizure in patients, these seizures are not dependent on the spontaneous fluctuations established in these patients. This primarily concerns simultaneously administered antiepileptic therapy, pharmacokinetic interactions with other drugs, toxicity, and overdose.
To avoid overdose, you should not use simultaneously other drugs whose metabolism produces valproic acid (including divalproate, valpromide).
There are extremely rare reports of severe and fatal cases of liver disease. In the vast majority of cases, such liver damage occurs within the first 6 months of treatment, usually between 2 and 12 weeks, and most often with combination therapy with antiepileptic drugs. At increased risk are infants and children under 3 years of age with severe epilepsy, especially those associated with brain damage, mental retardation, and/or congenital metabolic or degenerative diseases. Over the age of 3 years, the frequency of such complications decreases significantly and gradually decreases with age.
Early diagnosis of liver lesions is based primarily on clinical examination. In particular, you should take into account 2 types of symptoms that may precede jaundice, especially in patients at risk:
- on the one hand, nonspecific general symptoms, usually appearing suddenly, such as asthenia, anorexia, extreme fatigue, drowsiness, sometimes accompanied by repeated vomiting and abdominal pain;
- on the other hand, relapse of epileptic seizures, despite adequate treatment.
It is recommended to inform the patient, and if it is a child, then his family, that if these clinical symptoms develop, you should immediately consult a doctor. In such cases, in addition to clinical examination, a liver function test should be immediately performed.
In order to timely detect liver dysfunction, it is necessary to periodically monitor liver function during the first 6 months of treatment, especially in patients at risk. Among the standard parameters, the most important are tests reflecting the protein-synthetic function of the liver and especially the prothrombin index. If a pathologically low level of prothrombin is detected, especially in combination with other laboratory test results (significant decrease in the level of fibrinogen and blood coagulation factors, increase in the level of bilirubin and transaminases), treatment with Depakin Chrono should be suspended. If the patient has been prescribed salicylates (concomitant therapy), as a precautionary measure, their use should also be discontinued, since they are metabolized along the same route.
In extremely rare cases, severe forms of pancreatitis were observed, which in some cases led to death. These cases were observed regardless of the patient's age or duration of treatment, although younger children appear to be at increased risk.
Pancreatitis with an unfavorable outcome was usually observed in young children, in patients with severe epilepsy, brain damage, or when using complex anticonvulsant therapy. Insufficiency of liver function in pancreatitis increases the risk of death.
When treating with Depakine Chrono, as with other antiepileptic drugs, a slight, isolated and temporary increase in transaminase levels may be observed, especially at the beginning of treatment in the absence of any clinical symptoms. In this case, it is recommended to do a more complete laboratory examination (including determination of the prothrombin index), if necessary, adjust the dose and repeat the tests depending on changes in parameters.
For asymptomatic thrombocytopenia, reducing the dose of sodium valproate usually achieves regression of thrombocytopenia if the platelet count and epilepsy control allow.
The condition of patients who experience an increase in body weight during therapy with Depakine Chrono should be monitored, because this is a risk factor for the development of polycystic ovary syndrome.
Patients should be warned about the risk of weight gain early in treatment and the need to follow an appropriate diet.
Before starting therapy or surgery in the case of hematomas or spontaneous bleeding, it is recommended to conduct a hematological blood test (determine the blood count, including platelet count, bleeding time and coagulation tests).
In patients with renal failure, it is recommended to take into account the increased concentration of free form of valproic acid in the serum and reduce the dose.
In case of acute abdominal pain and gastrointestinal symptoms (nausea, vomiting and/or anorexia), it is necessary to conduct diagnostic tests for the presence of pancreatitis and, in case of elevated levels of pancreatic enzymes, discontinue the drug and prescribe alternative therapy.
Sodium valproate is not recommended for use in patients with carbamide cycle enzyme deficiency. In such patients, several cases of hyperammonemia accompanied by stupor and/or coma have been described.
Although it has been shown that during treatment with Depakine Chrono, dysfunction of the immune system is extremely rare, the potential benefits of therapy and the risks should be assessed if it is necessary to use the drug in patients suffering from SLE.
Patients should be warned about the risk of weight gain early in treatment; To minimize this effect, the patient should follow an appropriate diet.
Use in pediatrics
In children with unexplained gastrointestinal symptoms (anorexia, vomiting, episodes of cytolysis), a history of lethargy or coma, mental retardation, or a family history of death of a newborn or young child, metabolic studies, especially ammonemia, should be performed before initiating treatment with sodium valproate. on an empty stomach and after meals.
The simultaneous administration of salicylate derivatives to children should be avoided due to possible hepatotoxicity.
Impact on the ability to drive vehicles and operate machinery
During treatment, patients should be warned about the possible occurrence of temporary drowsiness and the need to be careful when driving vehicles and other activities that require high concentration and speed of psychomotor reactions (especially when using combined anticonvulsant therapy).
Depakin
Liver dysfunction : There have been rare reports of severe and fatal liver disease. At increased risk are infants and children under 3 years of age with severe epilepsy, especially epilepsy associated with brain damage, mental retardation, and/or congenital metabolic or degenerative diseases. Over the age of 3 years, the frequency of such complications decreases significantly and gradually decreases with age. In most cases, liver dysfunction was observed during the first 6 months of treatment, usually between 2 and 12 weeks, and most often with combined antiepileptic treatment. Early diagnosis is based primarily on clinical examination. In particular, two factors that may precede jaundice should be taken into account, especially in patients at risk. On the one hand, nonspecific general symptoms, usually appearing suddenly, such as asthenia, anorexia, extreme fatigue, drowsiness, sometimes accompanied by repeated vomiting and abdominal pain. On the other hand, recurrence of epileptic seizures during antiepileptic therapy It is recommended to inform the patient, and if it is a child, then his family, that if such clinical symptoms develop, one should immediately consult a doctor. In addition to a clinical examination, an immediate liver function test should be performed. Liver function should be checked periodically during the first 6 months of treatment. Among the classical tests, the most important are those reflecting liver protein synthesis, and especially the prothrombin index. If an abnormally low level of prothrombin is detected, a significant decrease in the level of fibrinogen and coagulation factors, an increase in the level of bilirubin and liver transaminases, treatment with Depakin® Chrono should be suspended. It is also necessary to interrupt treatment with salicylates if they were included in the treatment regimen, since they share metabolic pathways with valproate.
Pancreatitis In rare cases, severe forms of pancreatitis, sometimes fatal, have been reported. These cases were observed regardless of the patient's age and duration of treatment, although the risk of developing pancreatitis decreased with increasing age of the patients. Insufficiency of liver function in pancreatitis increases the risk of death. It is necessary to measure liver function before starting treatment and periodically during the first 6 months of treatment, especially in patients at risk. It should be emphasized that when treating both Depakin® Chrono and other antiepileptic drugs, a slight, isolated and temporary increase in transaminase levels may be observed, especially at the beginning of treatment, in the absence of any clinical symptoms. In this case, it is recommended to conduct a more complete laboratory examination (including, in particular, determination of the prothrombin index) in order to revise the dosage, if necessary, and repeat the tests depending on changes in parameters. For children under 3 years of age, the use of valproate (in the recommended dosage form) as monotherapy is recommended, but before starting treatment, the potential benefits of treatment with the drug should be assessed in relation to the risk of developing liver disease or pancreatitis. Before starting therapy or surgery, in the case of hematomas or spontaneous bleeding, it is recommended to conduct a hematological blood test (determine the blood count, including platelet count, bleeding time and coagulation tests). Combined use with salicylates should be avoided in children under 3 years of age due to the risk of hepatotoxicity. In patients with renal failure, it is recommended to take into account the increased concentration of free form of valproic acid in the serum and reduce the dose. In case of acute abdominal pain and gastrointestinal symptoms such as nausea, vomiting and/or anorexia, it is necessary to be able to recognize pancreatitis and, if the level of pancreatic enzymes is elevated, discontinue the drug, taking alternative therapeutic measures. Sodium valproate is not recommended for patients with carbamide cycle enzyme deficiency. In such patients, several cases of hyperammonemia accompanied by stupor and/or coma have been described. In children with unexplained gastrointestinal symptoms (anorexia, vomiting, cases of cytolysis), a history of lethargy or coma, with mental retardation, or a family history of death of a newborn or child, metabolic studies, especially ammonemia with fasting and after eating. Although it has been shown that during treatment with Depakin® Chrono, dysfunction of the immune system is extremely rare, the potential benefits of its use must be compared with the potential risks when prescribing the drug to patients suffering from systemic lupus erythematosus. Patients should be warned about the risk of weight gain at the beginning of treatment, and measures, mainly dietary, should be taken to minimize this phenomenon.
Impact on the ability to drive vehicles or other machinery . During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.
Depakine in the treatment of epilepsy in children
• a wide range of therapeutic activity (impact on a variety of types of attacks); • possibility of use in various age groups; • linear and predictable pharmacokinetics; • lack of autoinduction of liver enzymes; • the ability to quickly and easily increase the dose; • absence of life-threatening side effects; minimal number of serious side effects; • absence of negative impact on cognitive functions; • absence of the phenomenon of tolerance (“habituation”) and low risk of aggravation of epileptic seizures; • a wide selection of dosage forms (syrup, tablets, extended-release tablets, solution for intravenous administration); • affordable price. Unfortunately, there is not yet an “ideal” antiepileptic drug for all forms of epilepsy and for all patients with epilepsy. It is possible that each form of epilepsy requires its own special AED, since epilepsies are heterogeneous conditions, presumably with different mechanisms of epileptogenesis. Therefore, the number of drugs used to treat epilepsy has increased significantly over the past 10 years and continues to increase at a rapid pace. Currently, there is a fairly wide selection of AEDs with a variety of mechanisms of action. The World Health Organization (WHO) considers the following 6 antiepileptic drugs to be “essential”: carbamazepine, sodium valproate, phenytoin, phenobarbital, diazepam and ethosuximide. According to WHO, drugs that meet the requirements for improving health in the majority of patients in a particular population (in this case, the population of patients with epilepsy) are necessary. Despite the large number of AEDs, a neurologist usually uses 3–4 drugs in daily practice. The first two belong to traditional AEDs and are called the “gold standard” for the treatment of epilepsy. These are carbamazepine and valproate (valproic acid salt). In the European literature on epileptology, these drugs are called “first-line antiepileptic drugs.” In the American tradition, phenytoin is added to carbamazepine and valproate. Of course, the definition of the term “first-line AED” depends on national preferences and the availability of the drug in a particular country. In addition, the choice of priority drugs may change due to the introduction of new AEDs into practice. Sodium valproate (original drug - Depakine, pharmaceutical, France) has been used in the treatment of epilepsy for 37 years. During this time, various aspects of its pharmacokinetics, efficacy and tolerability have been carefully studied. Next, we consider how Depakine corresponds to the “ideal” drug that we would like to have at our disposal for the treatment of epilepsy. Efficacy in different types of seizures and different epileptic syndromes It is possible that sodium valproate demonstrates the widest spectrum of antiepileptic activity of all known AEDs, since it is essentially effective in all types of seizures, regardless of the form of epilepsy. Its effectiveness has been proven for a variety of types of generalized epileptic seizures - tonic-clonic, myoclonus, absence seizures, epileptic spasms, generalized tonic and atonic seizures. It is the first-line drug of choice in the treatment of most idiopathic and symptomatic generalized epilepsies [1]. The effectiveness of valproate is considered unsurpassed in the treatment of idiopathic generalized epilepsies [2]. The drug allows you to get rid of different types of seizures observed in juvenile myoclonic epilepsy (myoclonus, generalized tonic-clonic seizures and absence seizures) for the vast majority of patients. A recently published study by Nikolson A. et al. (2004), which included a large population of patients with idiopathic generalized epilepsy, showed the superior effectiveness of valproate compared to topiramate and lamotrigine [3]. In patients with childhood absence epilepsy, the use of valproate can achieve remission in 80% of all cases [4]. Valproate is widely used in the treatment of atypical absence seizures, tonic, atonic and myoclonic seizures associated with cryptogenic and symptomatic generalized epilepsies. It is used for Lennox-Gastaut syndrome and in the treatment of West syndrome, progressive myoclonus-epilepsy [1]. Sodium valproate is effective in the treatment of focal seizures of various localizations, perhaps slightly inferior in effectiveness to carbamazepine [2]. It is known that in the treatment of partial epilepsy, as a rule, carbamazepine is the first-line drug of choice. At the same time, there are a number of randomized studies showing that sodium valproate is also effective in partial epilepsy, its effectiveness is comparable to that of carbamazepine [5]. For example, a study on the comparative effectiveness and tolerability of various AEDs in the treatment of partial epilepsy demonstrated similar effectiveness of valproate and carbamazepine and slightly better tolerability of valproate [6]. Similar results were obtained by M. de Silva et al. (1996) in a pediatric population with partial epilepsy [7]. A recent study conducted by Kuncikova M. and the VIPe Study Group, as close as possible to daily clinical practice, showed that sodium valproate is effective and well tolerated in the treatment of partial epilepsy in children and adults [8]. The remission rate reached 84% in children and 73% in adults and was similar for different types of epileptic seizures, different etiologies of epilepsy and localization of the epileptic focus. In addition, there was a high level of retention on the drug (% of patients continuing treatment after some time); it reached 90% after 6 months of treatment. Only 2% of patients discontinued participation in the study due to side effects. Based on the results obtained, the researchers conclude that sodium valproate may be the first-line drug of choice in the treatment of partial epilepsy in children and adults. It should be mentioned that there is no clear boundary between focal and generalized epilepsies. Facts such as the presence of focal seizures in the structure of generalized epilepsies, the detection of focal EEG changes in generalized epilepsies in 30–35% of all cases, the presence of focal structural abnormalities in idiopathic generalized epilepsies, as well as the leading role of the frontal lobes in the pathogenesis of this form of epilepsy are well known. like juvenile myoclonic. On the other hand, focal epileptic seizures can be accompanied by secondary generalized epileptic discharges on the EEG. This phenomenon is called secondary bilateral synchronization. Secondary bilateral synchronization is an encephalographic pattern consisting of a sequence of focal spikes, polyspikes or spike-wave complexes (less commonly slow waves), followed by a burst of bilateral, synchronous and symmetrical spike-wave activity, distributed over both hemispheres. The development of secondary bilateral synchronization leads to aggravation of the course of epilepsy with an increase in the total number of attacks and the appearance of new, previously uncharacteristic for the patient, types of attack. Seizures associated with secondary bilateral synchrony are potentially disabling, as many of them result in patients falling. E. Perrucca et al. and other researchers advise not to prescribe or prescribe with great caution carbamazepine in the presence of secondary bilateral synchronization on the EEG, despite the fact that the exact mechanisms of aggravation of epilepsy in this case are not known [9]. If secondary bilateral synchronization occurs during the administration of carbamazepine and leads to aggravation of the course of epilepsy, carbamazepine should be discontinued. In a patient with focal epilepsy with secondary bilateral synchronization, the drugs of choice are valproate, ethosuximide, lamotrigine, topiramate in monotherapy or in various combinations. Relatively speaking, we treat these focal epilepsies in the same way as generalized ones (with the same drugs). In children of the first three years of life, without video-EEG monitoring, it is difficult to distinguish focal seizures from generalized ones (clinically they are very similar). In a significant number of children, accurate diagnosis of the form of epilepsy is impossible in the early stages of examination, and sometimes later, even despite the use of the most complex diagnostic methods. In addition, childhood is characterized by an extraordinary variety of epileptic syndromes; the boundaries between them are sometimes blurred, some syndromes can evolve into others, etc. In such clinical situations, it is recommended to prescribe AEDs that are effective in a wide range of conditions and have a low potential risk of attack aggravation, that is, valproate. A separate indication for the use of valproate is the presence of status epilepticus in a child. Our country does not have most of the drugs that are used throughout the world to relieve status epilepticus (there are no dosage forms for intravenous administration of drugs such as phenobarbital and phenytoin). In fact, the only drug that domestic neurologists and resuscitators have at their disposal is a benzodiazepine for intravenous injection. The appearance and distribution of the injectable form of Depakine in our country has significantly facilitated the fight against status epilepticus, including in children. Injectable Depakine is believed to be effective in approximately 70–80% of all cases of status epilepticus not sensitive to benzodiazepine [1]. It is possible that the breadth of the therapeutic spectrum of sodium valproate is due to the multiple mechanisms of action of valproic acid. According to E. Perucca, “evaproic acid should be considered not only a GABAergic drug, but a substance with different and complex mechanisms of action” [1]. E. Perucca lists the following mechanisms of action of valproic acid: • increases the synthesis and release of GABA, thereby potentiating GABAergic transmission in certain areas of the brain; • reduces the release of excitatory amino acids, b-hydroxybutyric acid and weakens the excitation of neurons caused by the activation of N-methylD-aspartate (NMDA) glutamate receptors; • has a direct effect on membrane excitation, including blockade of voltage-dependent sodium channels; • modulates dopaminergic and serotonergic transmission (this mechanism is used to ensure the effectiveness of the drug in psychiatric disorders and other neurological disorders in addition to epilepsy). Use of the drug in various age groups Valproate is effective in all age groups: from young children to elderly patients with epilepsy. Children have their own peculiarities in the metabolism of drugs, including AEDs. The metabolic rate in young children is higher than in adults due to higher activity of liver enzymes. Therefore, in childhood, it is possible to use higher dosages of AEDs (in particular, it is possible to use valproate dosages of more than 30–40 mg per kg of body weight per day). Features of the pharmacokinetics and pharmacodynamics of sodium valproate The drug has linear and predictable pharmacokinetics (therapeutic concentration in the blood increases in direct proportion to increasing doses of the drug). Well and quickly absorbed after oral administration. The maximum concentration of the drug in the blood when using capsules, tablets without a special coating and syrup is achieved after 1–3 hours. If the tablets are surrounded by a special coating that dissolves in the intestines, then the maximum concentration is reached after 3–5 hours. Sodium valproate is an AED widely used in the polytherapy of epilepsy. Based on data from experimental and clinical studies, it is assumed that valproate has a synergistic effect with lamotrigine [10]. The combination of valproate and lamotrigine is often used in the treatment of both generalized and focal epilepsies in children. The predominant effectiveness of the combination of sodium valproate with ethosuximide in the treatment of absence epilepsy has been proven [10]. In general, sodium valproate does not accelerate its own metabolism and the metabolism of other antiepileptic drugs, thereby not leading to the development of toxic effects or a decrease in the therapeutic effect. However, when using combinations of drugs, you should always be aware of their interactions. Although valproate does not induce liver enzymes, it may affect the concentrations of other drugs in the blood of patients. In general, valproate slightly increases the concentrations of carbamazepine, ethosuximide, lamotrigine, topiramate, phenytoin and phenobarbital. In turn, enzyme-inducing drugs (phenytoin, carbamazepine, phenobarbital) reduce the concentration of valproate when used together. The ability to quickly achieve a therapeutic dose is a significant advantage of sodium valproate compared to a number of other AEDs. The starting dose of valproate (10 mg per kg of body weight per day), in fact, is the minimum effective dose at which it is already possible to reduce the number of epileptic seizures. The maintenance daily dose can be achieved after 5–10 days. As a rule, it will be equal to 20–30 mg per kg of body weight per day; in some children, higher doses are used, but this already requires monitoring the concentration of the drug in the patient’s blood serum. Tolerability of the drug. Valproate is considered to have a favorable tolerability profile [1,9,11]. Its side effects are well studied and documented. The two most important idiosyncrasies associated with valproate have been described: pancreatitis and liver failure. Acute pancreatitis rarely leads to death, and a severe clinical situation can be avoided if the drug is discontinued if symptoms of pancreatitis develop (acute abdominal pain, vomiting, increased activity of urinary diastase and blood amylase). As for liver failure, it develops in one in 20,000 patients taking valproate. Fatal outcomes when hepatotoxicity occurs can be avoided if the risk factors for its development are known and the drug is promptly discontinued if symptoms occur. Parents of a patient being prescribed valproate for the first time should consult a doctor immediately if the child experiences apathy, drowsiness, anorexia, vomiting, and an increase in the number of seizures. In addition to prompt drug withdrawal, intravenous administration of L-carnitine is recommended. The risk group includes children under two years of age, especially those receiving AED polytherapy, suffering from mental retardation and the presence of certain inborn errors of metabolism (mitochondrial encephalomyopathies, in which carnitine metabolism is impaired). This same risk group includes children who already have liver disease or have elevated liver enzymes. The most common chronic side effects are gastrointestinal (nausea, vomiting, dyspepsia). The use of tablets with a special enteric coating or with controlled release of the active substance can significantly reduce the frequency of these side effects. Side effects such as weight gain, tremor, dysmenorrhea and transient hair loss are relatively common. The incidence of weight gain is about 15% [1]. As a rule, dietary restrictions do not lead to weight normalization. Since the effect of weight gain is dose-dependent, it is advisable to use the minimum effective dose to prevent its development. Alopecia may occur in up to 12% of all patients receiving the drug, is dose-dependent (disappears with dose reduction) or may resolve spontaneously despite continued treatment. Data on the possibility of developing polycystic ovary syndrome while taking valproate and the incidence of this complication are extremely contradictory, since there are studies demonstrating a high frequency of this pathology in the population of girls and women with epilepsy, regardless of the AEDs used [1]. Thrombocytopenia is a dose-dependent side effect, often reversible by reducing the dose of the drug, and rarely serves as a reason for discontinuation of the drug. As a rule, it does not lead to any clinical manifestations if the platelet count is not lower than 100,000/μl. Careful monitoring of the platelet count is indicated when the platelet count is less than 80,000/µL. According to expert epileptologists, the question of discontinuing the drug arises if thrombocytopenia leads to the appearance of other symptoms - disorders of the coagulation system or the formation of hemorrhages on the skin and mucous membranes [10]. A separate problem in studying the side effects of AEP is their influence on cognitive functions (the speed of psychomotor reactions, memory and attention). This problem is especially relevant in the treatment of epilepsy in children. It is believed that if the negative impact of AEP on cognitive functions is observed in a child, then this can significantly violate his learning, that is, reduce the quality of life. It is possible that the prolonged existence of the negative impact of AEP in children can lead to summation and increase in cognitive violations. Most researchers admit that in children the least negative effects on cognitive functions have valproate and lamotridine (recently, levetiracetes are added to these two drugs). The risk of aggravation of epileptic attacks. Recently, it has become obvious that the AEP could potentially aggravate (worsen) the course of epilepsy (Table 1). It is well known that sodium valproate is an Aer with a low risk of aggravation of epileptic attacks. Given the importance of the safe use of AEP, E. Hirsh and P. Genton studied all the affordable literature on the aggravation of attacks by Walproat [12]. They analyzed 20 publications dedicated to 99 clinical cases. The authors conclude that, given the total number of patients in the world receiving valproates, the aggravating potential of this drug can be considered low. All conditions and conditions under which Walproat can cause a deterioration in the course of epilepsy are well known and can be avoided (for example, the situation of an overdose of the drug). Long -term clinical experience in the use of valproates confirms the conclusions based on the study of publications. The low risk of aggravation emphasizes the feasibility of using valproat in a wide range of children with epilepsy. Another problem that occurs with prolonged use of AEP is the development of addiction to the drug (tolerance), as a result of which the initially high effectiveness of the drug decreases. In clinical practice, the phenomenon of tolerance leads to the fact that a patient in remission, at some time, against the background of an unchanged dose of the drug, a relapse of epileptic attacks arise. Relapse inevitably entails an increase in the dose of the drug, and after some time as a result of addictive the effect of increasing the dose disappears again. But an endless increase in the dose of AEP is impossible, so patients are often transferred to another drug. The most pronounced phenomenon of addiction for such an AEP group as benzodiazepines. Partly for this reason, benzodiazepines are rarely used in chronic treatment of epilepsy. Admission to varying degrees is also characteristic of other AEP. In the experimental models of epilepsy, it is shown that of all AEP the smallest addiction develops precisely to Valproata [13]. The high level of retention of patients with epilepsy on the valproat is also associated with this (see above). The variety of dosage forms in Russia precisely Valproat is the Aer with the widest selection of dosage forms. It is produced in the form of a syrup, tablets with an intestinal shell (Depakin Enterik), prolonged tablets (chrono depakin), a solution for iv administration. Children of an early age, as well as to those children who have disorders of swallowing, may be prescribed anticonvulsants in the form of syrup. However, prolonged use of liquid forms implies multiple intake of the drug during the day. It should be taken into account that multiple methods of the drug complicate the process of therapy for the patient. This should be avoided if our patient can swallow pills without much difficulty. One of the most rational and effective approaches is the use of prolonged drugs or so -called drugs with controlled release. In trading names, these drugs are designated as “retard” or “chrono” (depakin chrono). The use of prolonged drugs allows: • Avoid pronounced fluctuations in blood concentrations; • reduce the number of techniques per day; • reduce the likelihood of dose -dependent side effects; • Apply higher doses of the drug. The higher therapeutic efficiency of the sodium of sodium prolonged action in comparison with conventional forms of release was demonstrated in a number of studies [11]. Sometimes the transfer of the patient from the usual form of the drug to a prolonged form and without increasing the dose gives a distinct positive clinical effect. While the usual drug should be taken 3 times a day, the drug of prolonged action can be used once or twice a day. Of course, a decrease in the frequency of taking the drug simplifies the drug for the patient and improves the quality of his life. Therefore, from the very beginning of therapy, preference should be given to dosage forms with controlled release. The above has already been said about how important it was to provide emergency assistance to the appearance of the injection form of the valproat. In the near future, another dosage form of sodium valproata - chronosphere (Chronosphere®) will become available in Russia. This is a smell powder and with a neutral taste (unlike syrup), consisting of microparticles (microspheres), which, like Depakin Chrono, guarantees the controlled release of the drug, that is, it can be used 1-2 times a day. The chronicle is intended for children under 6 years of age. The powder can be dissolved in cold drinks and non -combustible food, while dividing the powder can provide a more thorough selection of dose of the drug. Thus, the sodium valproate is one of the main AEPs used in children with epilepsy. Walproat can help a child of any age and with any epileptic syndrome if the doctor knows the side effects of the drug well and can avoid their occurrence. The key to the successful use of Walproat is its low price compared to the price of newer AEPs (especially taking into account the fact that price increase does not always guarantee an increase in efficiency). Thus, despite many years of experience in using the drug, and most likely, thanks to this experience, Valproat continues to be a “gold standard” in the treatment of epilepsy in children.
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