Instructions Depakine syrup bottle 150 ml
Composition
active ingredient: sodium valproate;
1 ml of syrup contains 57.64 mg of sodium valproate;
excipients: methylparaben (E 218), propylparaben (E 216), sucrose, sorbitol crystallizing solution (E 420), glycerin, artificial cherry flavor, concentrated hydrochloric acid or sodium hydroxide, purified water.
Dosage form
Syrup.
Main physicochemical properties: transparent syrupy liquid of pale yellow color with a cherry odor.
Pharmacotherapeutic group
Antiepileptic drugs. ATX code N03A G01.
Pharmacological properties
Pharmacodynamics
The pharmacological activity of valproate is primarily directed at the central nervous system. It has anticonvulsant properties against a wide range of seizures in animals and epilepsy in humans.
Experimental and clinical studies have identified two mechanisms of anticonvulsant action of valproate.
The first is a direct pharmacological effect, which depends on the concentration of valproate in blood plasma and brain tissues.
The second is indirect – possibly related to valproate metabolites that remain in the brain, or to modifications of neurotransmitters, or to a direct effect on the membrane.
The most likely hypothesis is that after valproate administration, the level of gamma-aminobutyric acid (GABA) increases.
Valproate shortens the duration of the intermediate phase of sleep and simultaneously prolongs the slow-wave sleep phase.
Pharmacokinetics
In various pharmacokinetic studies of valproate, it has been shown that the bioavailability in the blood after oral administration is close to 100%. The volume of distribution is mainly limited to the blood and extracellular fluid. Valproate penetrates the cerebrospinal fluid and brain tissue. The half-life is 15-17 hours. The minimum concentration of valproate in the serum, necessary for a therapeutic effect, is usually 40-50 mg/l and varies in a wide range from 40 to 100 mg/l. If it is necessary to achieve a higher concentration, the expected benefit must be weighed against the likelihood of side effects, especially dose-dependent ones. At valproate concentrations above 150 mg/l, the dose of the drug must be reduced. Saturation plasma concentrations are reached after 3-4 days. Valproate is strongly bound to plasma proteins. Plasma protein binding is dose-dependent and saturable. Valproate is excreted mainly in the urine, after metabolism by glucuronide conjugation and beta-oxidation. The valproate molecule is dialyzable, but hemodialysis is effective only against the free fraction of valproate in the blood (approximately 10%). Valproate does not induce enzymes of the cytochrome P450 metabolic system; therefore, unlike most other antiepileptic drugs, it does not accelerate its own degradation or the degradation of other substances such as estrogen-progestogens and oral anticoagulants.
Indication
Adults and children. As monotherapy or in combination with other antiepileptic drugs for
- treatment of generalized epilepsy with the following types of seizures: clonic, tonic, tonic-clonic, absence, myoclonic, atonic and Lennox-Gastaut syndrome;
- treatment of focal epilepsy: focal seizures with or without secondary generalization.
Children: Prevention of recurrent seizures after one or more seizures complicated by febrile seizures when intermittent prophylaxis with benzodiazepines is ineffective.
Contraindication
History of hypersensitivity to valproate, divalproate, valpromide or any component of the drug.
Acute hepatitis and chronic hepatitis. Severe hepatitis in the patient's or his relatives' history, especially caused by drugs.
Hepatic porphyria.
Concomitant use with mefloquine and St. John's wort preparations (see "Interaction with other medicinal products and other types of interactions").
Fructose intolerance, glucose and galactose malabsorption syndrome, sucrose-isomaltase deficiency - due to the presence of sucrose and sorbitol in the composition of the drug.
Valproate is contraindicated in patients with known mitochondrial disorders caused by mutations in the nuclear gene encoding the mitochondrial enzyme polymerase gamma, such as Alpers-Huttenlocher syndrome, in children under two years of age suspected of having a polymerase gamma-related disorder, and in patients with a history of ornithine cycle disorders (see section 4.4).
Interaction with other medicinal products and other types of interactions
Contraindicated combinations.
With mefloquine. In patients with epilepsy, there is a risk of epileptic seizures due to increased metabolism of valproic acid and the convulsant effect of mefloquine.
With St. John's wort. Risk of decreased plasma concentration and reduced efficacy of the drug.
Undesirable combinations.
With penems: Risk of seizures due to rapid decrease in plasma valproic acid concentrations, which may reach levels below the detection threshold.
Combinations that require caution when used.
With aztreonam. Risk of seizures due to decreased plasma valproic acid concentrations. Clinical monitoring of the patient, determination of plasma drug concentrations, and possible dose adjustment of the anticonvulsant during antimicrobial treatment and after its discontinuation is recommended.
With carbamazepine. Increased concentration of the active metabolite of carbamazepine in the blood plasma, the appearance of signs of its overdose. The concentration of valproic acid in the blood plasma decreases due to increased metabolism in the liver under the influence of carbamazepine. With simultaneous use, clinical monitoring of the patient's condition is necessary, determination of the concentrations of valproic acid and carbamazepine in the blood plasma, and revision of the dosage of both drugs.
With felbamate. Increase in serum valproic acid concentration by 22-50% and risk of overdose. Clinical and laboratory monitoring is required, valproate doses may need to be adjusted during felbamate treatment and after its withdrawal. In addition, valproic acid may reduce the mean clearance of felbamate by up to 16%.
With phenobarbital and, by extrapolation, primidone. Increased plasma concentrations of phenobarbital or primidone with signs of overdose due to inhibition of their metabolism in the liver, most often in children. Decreased plasma concentrations of valproic acid due to increased metabolism in the liver by phenobarbital or primidone. Clinical monitoring of the patient is necessary during the first 15 days of combined treatment and immediate reduction of the dose of phenobarbital or primidone with signs of sedation; plasma levels of both anticonvulsants should be monitored.
With phenytoin and, by extrapolation, phosphophenytoin. Change in phenytoin plasma concentration. Threat of decreased valproic acid plasma concentration due to increased hepatic metabolism by phenytoin. Clinical monitoring of the patient, determination of plasma levels of both anticonvulsants and possible dose adjustment are recommended.
With cholestyramine: may reduce the absorption of Depakine®.
With rifampicin. Risk of seizures due to increased hepatic metabolism of valproate by rifampicin. Clinical monitoring, monitoring of laboratory parameters and possible dose adjustment of the anticonvulsant are indicated during and after rifampicin therapy.
With topiramate. Risk of hyperammonemia or encephalopathy under the influence of valproic acid when used simultaneously with topiramate. Careful clinical and laboratory monitoring of the patient's condition is necessary at the beginning of treatment and with the appearance of symptoms indicating the occurrence of this effect.
With zidovudine. There is a risk of increased side effects of zidovudine, particularly hematological, due to increased metabolism under the influence of valproic acid. Constant clinical and laboratory monitoring of the patient is required. During the first two months of combined treatment, blood tests should be performed to detect possible anemia.
Combinations to consider.
With nimodipine (oral and, by extrapolation, parenteral administration). Risk of increased hypotensive effect of nimodipine due to increased plasma concentration (weakening of its metabolism by valproic acid).
Other types of interactions.
With oral contraceptives. Since the drug does not induce enzyme activity, it does not reduce the effectiveness of estrogen-progestogen hormonal contraceptives.
Neuroleptics, monoamine oxidase inhibitors (MAOIs), antidepressants and benzodiazepines. Depakine may potentiate the effects of other neuropsychotropic agents such as neuroleptics, MAOIs, antidepressants and benzodiazepines. In this regard, clinical observation and, possibly, adjustment of therapy is necessary.
Temozolomide: Concomitant use of temozolomide and valproate may result in a small decrease in temozolomide clearance, but there is no evidence of the clinical significance of this interaction.
Quetiapine: Concomitant use of valproate and quetiapine may increase the risk of neutropenia/leukopenia.
The use of Depakine simultaneously with drugs that have a high degree of binding to blood plasma proteins (for example, acetylsalicylic acid) may lead to an increase in the concentration of the free fraction of valproic acid in blood plasma.
Depakine may increase the concentration of the free fraction of warfarin due to competition for albumin binding sites. Therefore, prothrombin time should be monitored more closely in patients receiving vitamin K antagonists.
Application features
Female children/female adolescents/women of reproductive age/pregnant women. Due to the high teratogenic potential and the risk of developmental disorders in infants exposed to valproate in utero, Depakine should not be used in female children, female adolescents, women of reproductive age and pregnant women, except when alternative treatments are ineffective or not tolerated by the patients. The benefits and risks of using this drug should be carefully reviewed at regular treatment evaluations, at puberty and immediately when a woman of reproductive age taking Depakine plans to become pregnant or becomes pregnant.
Women of childbearing potential should use effective contraception during treatment with this medicine and should be informed of the risks associated with the use of Depakine during pregnancy (see section "Use during pregnancy or breastfeeding").
The prescribing physician should ensure that the patient is provided with comprehensive information about the risks in the form of appropriate materials, such as a patient information booklet, to better understand the risks of using the drug.
In particular, the prescribing physician must ensure that the patient understands:
- the nature and importance of the risks associated with exposure to the drug during pregnancy, in particular teratogenic risks and risks of developmental disorders;
- the need to use effective contraception;
- the need for regular evaluation of treatment;
- the need to immediately consult a doctor in case of planning or probable pregnancy.
If possible, all measures should be taken to replace the drug in women planning to become pregnant with a suitable alternative treatment method before conception (see section "Use during pregnancy or lactation").
Treatment with valproate should only be continued after a reassessment by a physician experienced in the treatment of epilepsy of the benefits and risks of such therapy for the patient.
Since this medicinal product is metabolized to valproic acid, it should not be combined with other medicinal products that undergo the same metabolism to prevent valproic acid overdose (e.g. divalproate, valpromide).
Liver disease.
Conditions of occurrence: There have been isolated reports of severe liver disease with this medication, and sometimes fatal cases.
The greatest risk of developing hepatitis is among infants and children under 3 years of age with severe epilepsy, especially those associated with brain damage, mental retardation, and/or metabolic or degenerative diseases of genetic origin. In children over 3 years of age, the incidence of hepatitis is much lower and gradually decreases with age.
In the vast majority of cases, liver function abnormalities are observed in the first 6 months of treatment, usually between 2 and 12 weeks, and more often with complex antiepileptic treatment.
Warning signs. Early diagnosis is based mainly on clinical examination. In particular, two types of symptoms that may precede jaundice should be considered, especially in patients at risk:
- first, nonspecific symptoms that usually occur suddenly: asthenia, anorexia, exhaustion, drowsiness, which are sometimes accompanied by repeated vomiting and abdominal pain;
- secondly, recurrence of epileptic seizures despite proper treatment.
It is recommended to inform the sick child and his/her parents that if such clinical symptoms appear, it is necessary to immediately consult a doctor. In addition to the clinical examination, it is necessary to immediately conduct a liver function test.
Detection. During the first 6 months of treatment, liver function should be checked periodically. The most important tests are those that reflect the protein-synthetic function of the liver, especially the prothrombin time (PT). If an abnormally low prothrombin time is detected, especially if it is accompanied by changes in other laboratory parameters (significant decrease in fibrinogen and blood clotting factors, increase in bilirubin and transaminases), treatment should be discontinued. If salicylates are taken concomitantly, they should also be discontinued as a precaution (since they use the same metabolic pathway).
Pancreatitis: Pancreatitis, sometimes fatal, has been reported in isolated cases. The disease can occur regardless of the age of the patient and the duration of treatment, with young children being at particular risk.
Fatal pancreatitis is most often seen in young children and in patients with severe epilepsy, brain damage, or those receiving complex antiepileptic therapy. If pancreatitis occurs in the setting of renal failure, the risk of fatal outcome increases significantly.
Suicide risk. Suicidal thoughts and behavior may occur in patients treated with antiepileptic drugs in several indications. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs has also shown a small increased risk of suicidal thoughts and behavior. The reasons for this are unclear, and the available data do not allow us to exclude an increased risk with sodium valproate. Therefore, careful monitoring of the patient is necessary to identify any signs of suicidal thoughts and behavior in a timely manner, with the possible appointment of appropriate treatment. Patients (and their caregivers) should be warned that if suicidal thoughts or behavior appear, they should seek medical help.
Warnings regarding use in epilepsy.
Occasionally, the use of an antiepileptic drug may cause more severe seizures or the development of a new type of seizure, independent of the spontaneous fluctuations observed in some types of epilepsy. In the case of valproate, such events may occur in the event of a change in concomitant antiepileptic treatment or pharmacokinetic interaction (see section 5.1), toxicity (liver disease or encephalopathy) (see sections 4.4 and 4.8) or overdose.
Interaction with other drugs.
This medicinal product is not recommended for concomitant use with lamotrigine and penems (see section “Interaction with other medicinal products and other types of interactions”).
Due to the presence of sucrose and sorbitol in the composition of the drug, it is not recommended for patients with fructose intolerance, glucose and galactose malabsorption syndrome, or sucrose-isomaltase deficiency.
This medicinal product contains 13.88 mg sodium per 100 mg sodium valproate. This should be taken into consideration by patients on a strict low-sodium diet.
Precautions during use.
Liver function tests should be performed prior to initiation of treatment (see Contraindications) and periodically during the first 6 months of treatment, especially in patients at risk.
It should be emphasized that, as with most antiepileptic drugs, isolated and transient moderate elevations of transaminases without any clinical symptoms may occur, especially at the beginning of treatment.
In case of increased transaminase levels, it is recommended to perform a more complete laboratory examination (in particular, determine the prothrombin time) in order to revise the dosage if necessary. Depending on the results obtained, the tests should be repeated.
It is recommended to perform a blood test (complete blood count including platelet count, bleeding time, coagulation tests) before starting treatment and before any surgical intervention and in case of hematomas or spontaneous bleeding (see section "Adverse reactions").
When treating children, simultaneous administration of salicylate derivatives should be avoided due to the risk of hepatotoxicity and bleeding.
In patients with renal insufficiency, it is necessary to take into account the increased concentration of valproic acid circulating in the blood and reduce the dose of the drug accordingly.
If acute abdominal pain or gastrointestinal symptoms such as nausea, vomiting and/or anorexia occur, pancreatitis should be excluded, and if pancreatic enzyme levels are elevated, the drug should be discontinued and appropriate alternative therapeutic measures should be taken.
It is not recommended to prescribe the drug to patients with urea cycle enzyme deficiency. Several cases of hyperammonemia with stupor or coma have been observed in such patients.
In children with a history of hepatic and gastrointestinal disorders of unknown etiology (anorexia, vomiting, cases of acute cytolysis), with cases of lethargy or coma, with mental retardation, or in the case of a family history of neonatal or young child death, appropriate biochemical metabolic studies should be performed before starting treatment with the drug, especially for the presence of ammoniumemia on an empty stomach and after eating.
Despite the fact that the drug causes immune system dysfunction very rarely, when prescribing the drug to patients with systemic lupus erythematosus, the benefit/risk ratio should be assessed.
Before starting treatment with the drug, patients should be warned about the possibility of weight gain, and that this effect can be minimized by following a diet.
Patients with concomitant carnitine palmitoyltransferase (CPT) type II deficiency should be warned about the increased risk of rhabdomyolysis when taking valproate.
When prescribing this drug, it is necessary to exclude pregnancy in women of reproductive age and ensure that they use effective contraception before starting treatment.
During treatment with Depakine®, the use of alcohol is not recommended.
Use during pregnancy or breastfeeding
Depakine should not be used in female children, female adolescents, women of reproductive age and pregnant women, except in cases where other methods of treatment are ineffective or not tolerated by the patients. Women of reproductive age should use effective contraception during treatment with this drug. If possible, all measures should be taken to replace the drug in women planning to become pregnant with a suitable alternative treatment method before conception.
Risk associated with valproate exposure during pregnancy.
Both valproate monotherapy and valproate-containing polytherapy are associated with adverse pregnancy outcomes. Available evidence suggests that antiepileptic polytherapy, including valproate, is associated with a higher risk of congenital malformations than valproate monotherapy.
Congenital developmental defects.
A meta-analysis of registries and cohort studies showed that 10.73% of children born to women with epilepsy who received valproate monotherapy during pregnancy had congenital malformations (95% CI: 8.16–13.29). This risk of the most common malformations is higher than in the general population, where the risk is approximately 2–3%. This risk is dose-dependent, but it is not possible to establish a threshold dose below which there is no risk.
Available data indicate an increased incidence of rare and common birth defects. The most common birth defects include neural tube defects, facial dysmorphism, cleft lip and palate, craniostenosis, cardiac, renal, and genitourinary malformations (particularly hypospadias), limb defects (including bilateral radial aplasia), and multiple anomalies of various body systems.
Developmental disorders.
Available data suggest that intrauterine exposure to valproate may cause adverse effects on the mental and physical development of exposed children. This risk is likely to be dose-related, but the available data do not allow a threshold dose below which the risk is absent. The precise period of pregnancy during which the risk of these effects exists has not been determined, and the possibility of a risk throughout the entire pregnancy cannot be excluded.
Studies involving preschool children exposed to valproate during fetal development have shown that approximately 30-40% of cases have developmental delays, such as delayed speech and walking, decreased intellectual function, poor language skills (spoken and understood), and memory impairment.
The intelligence quotient (IQ) of school-aged children (aged 6 years) exposed to valproate in utero was on average 7-10 points lower than that of children exposed to other antiepileptic drugs. Although the role of other factors cannot be excluded, there is evidence that the risk of reduced intellectual function in children exposed to valproate may not depend on maternal IQ.
Data on long-term effects are limited.
Available evidence suggests that children exposed to valproate in utero have an increased risk of autism spectrum disorders (approximately 3-fold) and childhood autism (approximately 5-fold) compared with the general population studied.
Limited data suggest that children exposed to valproate in utero may be more likely to develop symptoms of attention deficit hyperactivity disorder.
Female children, female adolescents and women of reproductive age (see information above and section "Special warnings and precautions for use").
If a woman is planning a pregnancy.
Valproate treatment of women planning to become pregnant or who are pregnant should be re-evaluated.
If possible, all measures should be taken to replace the drug in women planning to become pregnant with an appropriate alternative treatment method before conception.
Valproate treatment should not be discontinued without a reassessment by a physician experienced in the treatment of epilepsy of the benefits and risks of such therapy for the patient. If, based on a careful assessment of the risks and benefits, it is decided to continue valproate treatment during pregnancy, the following is recommended.
The lowest effective dose should be used and the daily dose of valproate should be divided into several doses to be taken throughout the day. The use of a prolonged-release formulation may be more acceptable than other formulations to avoid high peak plasma concentrations.
Taking folate supplements before pregnancy may reduce the risk of neural tube defects in the fetus, which is common in all pregnancies. However, the available evidence does not support the idea that this prevents birth defects or developmental defects due to valproate exposure.
Specialized prenatal monitoring is necessary to detect possible fetal neural tube defects or other malformations.
Very rare cases of hemorrhagic syndrome have been reported in newborns whose mothers took valproate during pregnancy. This hemorrhagic syndrome is associated with thrombocytopenia, hypofibrinogenemia and/or decreased levels of other coagulation factors. Afibrinogenemia, which can be fatal, has also been reported. However, this syndrome must be distinguished from decreased levels of vitamin K caused by phenobarbital and enzyme inducers. In this regard, newborns should be monitored for platelet count, plasma fibrinogen level, coagulation tests and coagulation factors.
Cases of hypoglycemia have been reported in newborns whose mothers took valproate during the third trimester of pregnancy.
Cases of hypothyroidism have been reported in newborns whose mothers took valproate during pregnancy.
Newborns whose mothers took valproate during the last trimester of pregnancy may develop a withdrawal syndrome (in particular, in the form of nervous excitement, irritability, increased excitability, increased neuro-reflex excitability, hyperkinesia, tonic disorders, tremor, convulsions and sucking disorders).
Breast-feeding.
Valproate is excreted in human milk at concentrations ranging from 1 to 10% of its maternal plasma level. Blood disorders have been observed in newborns/infants whose mothers were treated with this drug (see section "Adverse reactions").
A decision on whether to discontinue breast-feeding or to discontinue/abstain from Depakine should be made taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility.
There have been reports of amenorrhea, polycystic ovary syndrome and increased testosterone levels in women taking valproate (see section 4.8). Valproate may also impair male fertility (see section 4.8). In the cases reported, the fertility dysfunction is reversible and resolves after discontinuation of treatment.
Ability to influence reaction speed when driving vehicles or other mechanisms
The patient should be warned about the risk of drowsiness, especially in the case of combined antiepileptic therapy or in the case of a combination of the drug with other drugs that cause drowsiness. During treatment, it is not recommended to drive a car or operate complex mechanisms.
Method of administration and doses
The drug is intended for oral use. To open the bottle, press the cap and turn it. After using the drug, the bottle must be carefully closed.
The dose of syrup should be measured using the dosing device with the adapter plug included in the package. It is advisable to take the drug during meals, dividing the daily dose.
- for 2 doses – for children under 1 year old,
- for 3 doses – for children aged 1 year and over.
The average daily dose is:
- infants and children under 12 years of age: 30 mg/kg body weight (preference should be given to syrup, oral solution or prolonged-release granules);
- children (from 12 years of age) and adults: 20-30 mg/kg of body weight (preference should be given to tablets, prolonged-release tablets or prolonged-release granules).
The dose of the drug should be calculated individually for each patient in mg/kg of body weight. For children under 3 years of age, sodium valproate is recommended exclusively as monotherapy if the expected benefit of treatment outweighs the risk of liver disease and pancreatitis in patients of this age group.
Initiation of treatment. The optimal dose for a patient already using antiepileptic drugs that are being replaced by Depakine should be achieved gradually, over approximately 2 weeks. Then, depending on the effectiveness of the treatment, the dose of the other antiepileptic drug should be reduced.
For a patient not taking other antiepileptic drugs, the dose should be increased gradually every 2-3 days to reach the optimal dose within about a week.
If combination treatment with other antiepileptic drugs is necessary, they should be added gradually (see “Interaction with other medicinal products and other types of interactions”).
Female children, female adolescents, women of reproductive age, and pregnant women
. Treatment with the drug should be initiated and supervised by a specialist experienced in the treatment of epilepsy. Treatment with this drug should only be prescribed when other therapies are ineffective or not tolerated by patients (see sections "Special warnings and precautions for use" and "Use during pregnancy or lactation"); the benefits and risks of using this drug should be carefully reviewed at regular treatment evaluations. As a rule, the drug Depakine.
Ò is prescribed as monotherapy at the lowest dose at which a treatment effect is observed, and, if possible, as a prolonged-release dosage form to avoid high peak plasma concentrations. The daily dose should be divided into at least two doses.
The drug can be used in pediatric practice. It is recommended that sodium valproate be prescribed to children under 3 years of age only as monotherapy after assessing the potential benefit of treatment and the risk of developing liver disease and pancreatitis, which exists in patients of this age group (see also the section "Features of use").
Overdose
The clinical picture of severe acute overdose usually includes a more or less profound coma with muscle hypotension, hyporeflexia, miosis, respiratory depression and metabolic acidosis, arterial hypotension and vascular collapse/shock.
Several cases of intracranial hypertension associated with cerebral edema have been described.
Emergency care in a hospital should include: if necessary, gastric lavage, ensuring effective diuresis, constant monitoring of the cardiovascular and respiratory systems. In very severe cases, extrarenal blood purification should be performed if necessary.
The prognosis for such an overdose is generally favorable. However, several fatal cases have been reported.
The presence of sodium in valproate may lead to hypernatremia in case of overdose.
Adverse reactions
Congenital, familial and genetic disorders (see sections "Special instructions" and "Use during pregnancy or breastfeeding").
Teratogenic risk (see section "Use during pregnancy or breastfeeding").
Blood and lymphatic system disorders.
Cases of dose-related thrombocytopenia have been reported, which usually occurred in a systematic manner and had no clinical consequences.
In patients with asymptomatic thrombocytopenia, simple dose reduction based on platelet levels and disease control usually resolves thrombocytopenia.
Decreased fibrinogen levels or prolonged bleeding time have been reported, usually without clinical consequences, especially at high doses. Valproate has been shown to inhibit the second phase of platelet aggregation. Less commonly, anemia, macrocytosis, leukopenia, and, exceptionally, pancytopenia have been reported.
Red marrow aplasia or pure red cell aplasia.
Agranulocytosis.
Decreased levels of coagulation factors (at least one), abnormal coagulation tests (e.g. prolonged prothrombin time, prolonged activated partial thromboplastin time, prolonged thrombin time, increased international normalized ratio (INR)) (see sections 4.4 and 4.5), biotin deficiency/biotinidase deficiency.
Nervous system disorders.
Transient and/or dose-related adverse events have been reported: small-amplitude postural tremor and sedation.
Uncommon cases of ataxia and paraesthesia have been reported.
Irreversible extrapyramidal disorders have occasionally been observed, which, however, may have included cases of reversible parkinsonian syndrome.
Very rare cases of cognitive impairment with gradual onset and progressive development (which may progress to dementia) have been described, which were reversible within a few weeks or months after discontinuation of the drug.
Confusion or seizures: Several cases of stupor or lethargy, sometimes leading to transient coma (encephalopathy), have been reported with valproate, either isolated or associated with a paradoxical increase in seizures, which resolved after discontinuation of the drug or a reduction in dose. These events most often occurred with polytherapy (especially with phenobarbital or topiramate) or after a sharp increase in the dose of valproate.
Isolated moderate hyperammonemia has been frequently observed in the absence of changes in liver function tests, especially in the context of polytherapy; this side effect should not be a reason for discontinuation of the drug. However, cases of hyperammonemia with neurological symptoms (which may even progress to coma) have also been reported, and this situation therefore requires additional examinations (see section "Special warnings and precautions for use").
