Indications
Adults
As monotherapy or in combination with other antiepileptic drugs:
- treatment of generalized epileptic seizures (clonic, tonic, tonic-clonic, absence seizures, myoclonic, atonic);
- Lennox-Gastaut syndrome;
- treatment of partial epileptic seizures (partial seizures with or without secondary generalization).
Treatment and prevention of bipolar affective disorders.
Children
As monotherapy or in combination with other antiepileptic drugs:
- treatment of generalized epileptic seizures (clonic, tonic, tonic-clonic, absence seizures, myoclonic, atonic);
- Lennox-Gastaut syndrome;
- treatment of partial epileptic seizures (partial seizures with or without secondary generalization).
Analogs
If necessary, the antiepileptic drug Depakine can be replaced with an analogue that has similar pharmacological properties.
Effective options include:
- Enkorat – 160 rub.;
- Encorat Chrono – 165 rub.;
- Convulex — 98 rub.;
- Valparin, Valparin XP – 179 rub.
A substitute should be selected exclusively by a qualified specialist who has a complete picture of the patient’s disease.
Contraindications
- hypersensitivity to sodium valproate, valproic acid, semisodium valproate, valpromide or to any of the auxiliary components of the drug;
- acute hepatitis;
- chronic hepatitis;
- severe liver disease (especially drug-induced hepatitis) in the patient’s and his close blood relatives’ history;
- severe liver damage with a fatal outcome when using valproic acid in close blood relatives of the patient;
- severe liver dysfunction;
- severe dysfunction of the pancreas;
- hepatic porphyria;
- established mitochondrial diseases caused by mutations in the nuclear gene encoding the mitochondrial enzyme γ-polymerase (POLG), for example, Alpers-Huttenlocher syndrome, and suspected diseases caused by defects in γ-polymerase in children under 2 years of age (applies to the use of drugs forms of the drug Depakine intended for children);
— patients with established disorders of the carbamide cycle (urea cycle);
- combination with mefloquine;
- combination with St. John's wort preparations;
- children under 6 years of age (risk of tablets entering the respiratory tract when swallowed).
Carefully
- history of liver and pancreas diseases;
- pregnancy;
— congenital enzymopathies;
- inhibition of bone marrow hematopoiesis (leukopenia, thrombocytopenia, anemia);
- renal failure (dose adjustment required);
- hypoproteinemia;
- simultaneous use of several anticonvulsants (due to an increased risk of liver damage);
- simultaneous use of drugs that provoke seizures or lower the seizure threshold, such as tricyclic antidepressants, selective serotonin reuptake inhibitors; phenothiazine derivatives, butyrophenone derivatives, chloroquine, bupropion, tramadol (risk of provoking seizures);
- simultaneous use of antipsychotics, MAO inhibitors, antidepressants, benzodiazepines (possibility of potentiating their effects);
- simultaneous use of phenobarbital, primidone, phenytoin, lamotrigine, zidovudine, felbamate, olanzapine, propofol, aztreonam, acetylsalicylic acid, indirect anticoagulants, cimetidine, erythromycin, carbapenems, rifampicin, nimodipine, rufinamide (especially in children), protease inhibitors (lopinavir a, ritonavir ), cholestyramine (due to pharmacokinetic interactions at the level of metabolism or binding to plasma proteins, changes in plasma concentrations of either these drugs and/or valproic acid are possible);
- simultaneous use with carbamazepine (risk of potentiation of the toxic effects of carbamazepine and a decrease in plasma concentrations of valproic acid);
- simultaneous use with topiramate (risk of developing encephalopathy);
- in patients with existing carnitine palmitoyltransferase (CPT) type II deficiency (higher risk of developing rhabdomyolysis when taking valproic acid).
Dosage
Depakine Chrono is intended only for adults and children over 6 years of age weighing more than 17 kg.
Depakine Chrono is a slow-release dosage form, which avoids sudden increases in the concentration of valproic acid in the blood after taking the drug and maintains a constant concentration of valproic acid in the blood throughout the day for a longer period of time.
Extended-release tablets Depakine Chrono 300 mg or 500 mg can be divided to facilitate the administration of an individually selected dose.
The tablets are taken without crushing or chewing them.
Epilepsy
The doctor selects the daily dose individually.
To prevent the development of epilepsy attacks, the drug should be used in the minimum effective dose (especially during pregnancy).
The daily dose is set in accordance with the age and body weight of the patient. A stepwise (gradual) dose increase is recommended until the minimum effective dose is reached.
No clear relationship has been established between daily dose, plasma concentration and therapeutic effect. Therefore, the optimal dose should be determined primarily by clinical response. Determination of plasma valproic acid levels can serve as an addition to clinical monitoring if epilepsy is uncontrolled or if side effects are suspected. The therapeutic blood concentration range is usually 40-100 mg/L (300-700 µmol/L).
For monotherapy, the initial dose is usually 5-10 mg of valproic acid per kg of body weight, then this dose is gradually increased every 4-7 days at the rate of 5 mg of valproic acid per kg of body weight to the dose necessary to achieve control of epileptic seizures.
Average daily doses (with long-term use):
for children 6-14 years old (body weight 20-30 kg)
- 30 mg valproic acid/kg body weight (600-1200 mg);
for teenagers (body weight 40-60 kg)
- 25 mg valproic acid/kg body weight (1000-1500 mg);
for adults and elderly patients (body weight 60 kg and above)
- on average 20 mg of valproic acid/kg body weight (1200-2100 mg).
Although the daily dose is determined by the age and body weight of the patient, the wide range of individual sensitivity to valproate should be taken into account.
If epilepsy is not controlled at these doses, they can be increased under monitoring of the patient's condition and the concentration of valproic acid in the blood. In some cases, the full therapeutic effect of valproic acid does not appear immediately, but develops within 4-6 weeks. Therefore, the daily dose should not be increased above the recommended average daily dose before this date.
The daily dose can be divided into 1-2 doses, preferably with meals.
One-time use is possible for well-controlled epilepsy.
Most patients who are already taking Depakine in a non-extended-release dosage form can be switched to Depakine chrono immediately or within a few days, while patients must continue to take the previously selected daily dose.
For patients who have previously taken antiepileptic drugs, the transition to taking the drug Depakine Chrono should be carried out gradually, reaching the optimal dose of the drug within approximately 2 weeks. In this case, you should immediately reduce the dose of the antiepileptic drug that the patient was taking previously, especially if it is phenobarbital. The withdrawal of an antiepileptic drug that the patient was previously taking should be done gradually.
Because other antiepileptic drugs can reversibly induce liver microsomal enzymes, the plasma concentration of valproic acid should be monitored for 4-6 weeks after taking the last dose of these antiepileptic drugs and, if necessary (as the metabolism-inducing effect of these drugs decreases), the daily dose of valproic acid should be reduced.
If it is necessary to combine valproic acid with other antiepileptic drugs, they should be added to treatment gradually.
Manic episodes in bipolar disorders
Adults
The doctor selects the daily dose individually.
The recommended initial daily dose is 750 mg. In addition, clinical studies have also shown an acceptable safety profile for a starting dose of 20 mg sodium valproate per kg body weight.
Depakine Chrono can be taken 1 or 2 times a day. The dose should be increased as quickly as possible until the minimum effective therapeutic dose that produces the desired clinical effect is achieved.
The average daily dose is in the range of 1000-2000 mg sodium valproate.
Patients receiving a daily dose of more than 45 mg/kg/day should be under close medical supervision.
When continuing treatment of manic episodes in bipolar disorders, the drug is used in an individually selected minimum effective dose.
Children and teenagers
The effectiveness and safety of the drug in the treatment of manic episodes in bipolar disorder in patients under 18 years of age have not been evaluated.
Special patient groups
Female children and adolescents, women of childbearing potential and pregnant women:
Treatment with Depakine Chrono should be started under the supervision of a specialist with experience in the treatment of epilepsy and bipolar disorders. Treatment should only be started if other treatments are ineffective or not tolerated, and the balance of benefit and risk should be carefully re-evaluated when treatment is regularly reviewed. It is preferable to use Depakine drugs for monotherapy and in the lowest effective doses and, if possible, in extended-release dosage forms. During pregnancy, the daily dose should be divided into at least 2 single doses.
Although in elderly patients
There are changes in the pharmacokinetics of valproic acid, they are of limited clinical significance, and the dose of valproic acid in elderly patients should be adjusted in accordance with achieving control of epileptic seizures.
In patients with
renal failure and/or hypoproteinemia,
the possibility of increasing the concentration of the free (therapeutically active) fraction of valproic acid in the blood serum should be taken into account, and if necessary, reduce the dose of valproic acid, focusing on the dose selection, mainly on the clinical picture, and not on the total content valproic acid in blood serum (free fraction and fraction bound to plasma proteins) to avoid possible errors in dose selection.
Compound
The antiepileptic drug is based on valproic acid.
For better absorption of the substance by the body in the production of tablet form, the following are used:
- sodium saccharin;
- hypromellose;
- talc;
- macrogoal
Other chemical compounds are also used as auxiliary components, depending on the form produced:
- solution for external use (drops);
- granules;
- lyophilisate (for intravenous administration);
- syrup.
Side effects
Determination of the frequency of adverse reactions (WHO classification): very often (≥10%), often (≥1% and <10%), infrequently (≥0.1% and <1%), rarely (≥0.01% and <0.1%), very rare (<0.01%),
frequency unknown (cannot be determined from available data).
Congenital, hereditary and genetic disorders:
teratogenic risk.
From the hematopoietic system:
often - anemia, thrombocytopenia; uncommon - pancytopenia, leukopenia, neutropenia. Leukopenia and pancytopenia can occur with or without depression of bone marrow hematopoiesis. After discontinuation of the drug, the blood picture returns to normal.
From the blood coagulation system:
often - bleeding and hemorrhage; rarely - a decrease in the content of blood coagulation factors (at least one), deviation from the norm of blood coagulation parameters (such as an increase in prothrombin time, an increase in aPTT, an increase in thrombin time, an increase in MHO). The appearance of spontaneous ecchymosis and bleeding requires discontinuation of the drug and clinical and laboratory examination.
From the nervous system:
very often - tremor; often - extrapyramidal disorders, stupor*, drowsiness, convulsions*, memory impairment, headache, nystagmus, dizziness (may occur a few minutes after IV injection and disappear spontaneously within a few minutes); uncommon - coma*, encephalopathy*, lethargy*, reversible parkinsonism, ataxia, paresthesia, increased severity of seizures; rarely - reversible dementia combined with reversible brain atrophy, cognitive disorders; frequency unknown - sedation.
*stupor and lethargy sometimes led to transient coma/encephalopathy and were either isolated or combined with an increase in convulsive attacks during treatment, and also decreased when the drug was discontinued or its dose was reduced. Most of these cases have been described during combination therapy, especially with the simultaneous use of phenobarbital or topiramate, or after a sharp increase in the dose of valproic acid.
From the mental side:
infrequently - a state of confusion, aggressiveness**, agitation**, impaired attention**, depression (when valproic acid is combined with other anticonvulsants); rarely - behavioral disorders**, psychomotor hyperactivity**, learning disabilities**, depression (with monotherapy with valproic acid).
**adverse reactions, mainly observed in pediatric patients.
From the senses:
often - reversible and irreversible deafness; frequency unknown - diplopia.
From the digestive system:
very often - nausea; often - vomiting, gum changes (mainly gingival hyperplasia), stomatitis, epigastric pain, diarrhea (which often occurs in some patients at the beginning of treatment, but usually disappears after a few days and does not require cessation of therapy); uncommon - pancreatitis, sometimes fatal (the development of pancreatitis is possible during the first 6 months of treatment; in case of acute abdominal pain, it is necessary to monitor the activity of serum amylase); frequency unknown - abdominal cramps, anorexia, increased appetite. Frequent reactions from the digestive system can be reduced by taking the drug during or after meals.
From the liver and biliary tract:
often - liver damage, which is accompanied by deviations from the norm in indicators of the functional state of the liver, such as a decrease in the prothrombin index, especially in combination with 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 in the blood; liver failure, in exceptional cases with death. It is necessary to monitor patients for possible liver dysfunction.
From the respiratory system:
infrequently - pleural effusion.
From the urinary system:
uncommon - renal failure; rarely - enuresis, tubulointerstitial nephritis, reversible Fanconi syndrome (a complex of biochemical and clinical manifestations of renal tubular damage with impaired tubular reabsorption of phosphate, glucose, amino acids and bicarbonate), the mechanism of development of which is still unclear.
From the immune system:
often - hypersensitivity reactions, for example, urticaria; uncommon - angioedema; rarely - drug rash syndrome with eosinophilia and systemic symptoms (DRESS syndrome).
For the skin and subcutaneous tissues:
often - transient or dose-dependent alopecia (including androgenic alopecia against the background of developed hyperandrogenism, polycystic ovary syndrome, as well as alopecia against the background of developed hypothyroidism), disorders of the nails and nail bed; uncommon - rash, hair disorders (such as disruption of the normal hair structure, change in hair color, abnormal hair growth [disappearance of wavy and curly hair or, conversely, the appearance of curly hair in persons with initially straight hair]); rarely - toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme).
From the musculoskeletal system and connective tissue:
infrequently - a decrease in bone mineral density, osteopenia, osteoporosis and fractures in patients taking valproic acid for a long time (the mechanism of the effect of valproic acid on bone metabolism has not been established); systemic lupus erythematosus.
From the endocrine system:
uncommon - syndrome of inadequate ADH secretion, hyperandrogenism (hirsutism, virilization, acne, male pattern alopecia and/or increased concentrations of androgens in the blood); rarely - hypothyroidism.
From the side of metabolism:
often - hyponatremia, weight gain (since weight gain is a factor contributing to the development of polycystic ovary syndrome); rarely - hyperammonemia*, obesity.
* cases of isolated and moderate hyperammonemia may occur without changes in liver function tests and the need to discontinue treatment. Hyperammonemia has also been reported, accompanied by the appearance of neurological symptoms, incl. development of encephalopathy, vomiting, ataxia), which required discontinuation of valproic acid and additional examination.
From the side of blood vessels:
infrequently - vasculitis.
From the reproductive system:
often - dysmenorrhea; infrequently - amenorrhea; rarely - male infertility, polycystic ovary syndrome; frequency unknown - dysmenorrhea, breast enlargement, galactorrhea.
Benign, malignant and unspecified tumors (including cysts and polyps):
rarely - myelodysplastic syndrome.
Common disorders:
infrequently - hypothermia, mild peripheral edema.
Laboratory and instrumental data:
rarely - biotin deficiency/biotinidase deficiency.
Precautionary measures
Some problems may arise when using Depakine.
To avoid them, it is recommended to adhere to the following precautions:
- It is important to undergo tests periodically to monitor the activity of liver transaminases, platelets in the blood, bilirubin levels, etc. Studies are carried out every 2-3 months, especially when combining the drug with other pharmacological agents of similar action.
- The daily dosage changes throughout the therapy: at the initial stage, a minimum amount of the drug is supposed to be taken, then the dosage is increased weekly to the maximum determined by the attending physician. A couple of weeks before stopping the medication, the daily dose is reduced to the initial level.
- You cannot combine Depakine with drinking alcohol.
- If surgery is planned during the period of antiepileptic therapy or after its completion, the patient undergoes tests to monitor important indicators.
- If signs of an “acute abdomen” appear, you need to donate blood for testing. This will exclude or confirm the diagnosis of acute pancreatitis (monitoring amylase levels).
- If the patient has diabetes, the results of blood and urine tests may be distorted due to the concentration of keto products.
- You should not abruptly stop taking Depakine due to the high risk of increased frequency of epileptic seizures.
- Taking antiepileptic medications provokes a decrease in concentration and causes inhibition of psychomotor reactions. During the period of use of the medicine, driving motor vehicles and performing high-risk work should be avoided.
- To prevent the manifestation of dyspeptic disorders, it is recommended to include enveloping agents and antispasmodics in therapy.
Overdose
Symptoms:
coma with muscle hypotonia, hyporeflexia, miosis, respiratory depression, metabolic acidosis, excessive decrease in blood pressure, vascular collapse/shock. Cases of intracranial hypertension associated with cerebral edema have been described. The presence of sodium in valproic acid preparations in case of overdose can lead to the development of hypernatremia. Symptoms may vary, and seizures have been reported with very high plasma concentrations of valproic acid. With a significant overdose, death is possible, but the prognosis is usually favorable.
Treatment:
in the hospital - gastric lavage, which is effective within 10-12 hours after taking the drug orally. To reduce the absorption of valproic acid, taking activated carbon, incl. its administration through a nasogastric tube. Monitoring and correction of the functional state of the cardiovascular and respiratory systems and maintenance of effective diuresis are required.
It is necessary to monitor the functions of the liver and pancreas. If respiratory depression occurs, mechanical ventilation may be required.
Naloxone has been used with success in some cases. In very severe cases of significant overdose, hemodialysis and hemoperfusion have been effective.
Drug interactions
Effect of valproic acid on other drugs
Valproic acid may potentiate the effect of other psychotropic drugs, such as antipsychotics, MAO inhibitors, antidepressants, benzodiazepines
(with simultaneous use, careful medical monitoring and, if necessary, dose adjustment are recommended).
Valproic acid does not affect serum lithium
.
Valproic acid increases phenobarbital
in plasma (due to a decrease in its hepatic metabolism), and therefore the development of the sedative effect of the latter is possible, especially in children. Therefore, careful medical monitoring of the patient is recommended during the first 15 days of combination therapy with an immediate reduction in the dose of phenobarbital in case of sedation and, if necessary, determination of the plasma concentration of phenobarbital.
Valproic acid increases primidone
in plasma, which leads to increased side effects (such as sedation); with long-term treatment these symptoms disappear. Careful clinical monitoring of the patient is recommended, especially at the beginning of combination therapy, with dose adjustment of primidone if necessary.
Valproic acid reduces total phenytoin
in plasma. In addition, valproic acid increases the concentration of the free fraction of phenytoin with the possibility of developing symptoms of overdose (valproic acid displaces phenytoin from binding to plasma proteins and slows down its hepatic metabolism). Therefore, careful clinical monitoring of the patient and determination of the concentration of phenytoin and its free fraction in the blood is recommended.
With the simultaneous use of valproic acid and carbamazepine
clinical manifestations of carbamazepine toxicity have been reported because valproic acid may potentiate the toxic effects of carbamazepine. Careful clinical monitoring of such patients is recommended, especially at the beginning of combination therapy, with adjustment, if necessary, of the dose of carbamazepine.
Valproic acid slows the metabolism of lamotrigine
in the liver and increases T1/2 of lamotrigine by almost 2 times. This interaction may result in increased toxicity of lamotrigine, particularly severe skin reactions, including toxic epidermal necrolysis. Therefore, careful clinical monitoring and, if necessary, dose adjustment (reduction) of lamotrigine are recommended.
Valproic acid may increase plasma concentrations of zidovudine,
which leads to an increase in the toxicity of zidovudine, especially hematological effects, by slowing down its metabolism by valproic acid. Continuous clinical observation and monitoring of laboratory parameters is necessary. A blood test should be done to rule out the development of anemia during the first two months of combination therapy.
Valproic acid may reduce the mean clearance of felbamate.
by 16%.
Valproic acid may decrease plasma concentrations of olanzapine.
Valproic acid may lead to increased plasma concentrations of rufinamide
. This increase depends on the concentration of valproic acid in the blood. Caution should be exercised, especially in children, because this effect is more pronounced in this population.
Valproic acid may lead to increased plasma concentrations of propofol.
Consideration should be given to reducing the dose of propofol when used concomitantly with valproic acid.
Strengthening the hypotensive effect of nimodipine
(for oral administration and, by extrapolation, for parenteral administration) due to an increase in its plasma concentration (inhibition of the metabolism of nimodipine by valproic acid).
Co-administration of temozolomide
with valproic acid leads to a mild, but statistically significant, decrease in the clearance of temozolomide.
Effect of other drugs on valproic acid
Antiepileptic drugs that can induce liver microsomal enzymes (including phenytoin, phenobarbital, carbamazepine)
reduce plasma concentrations of valproic acid. In case of combination therapy, the dose of valproic acid should be adjusted depending on the clinical response and the concentration of valproic acid in the blood.
Serum concentrations of valproic acid metabolites may be increased when administered concomitantly with phenytoin or phenobarbital.
. Therefore, patients receiving these combinations should be carefully monitored for signs and symptoms of hyperammonemia, as some metabolites of valproic acid can inhibit enzymes of the carbamide cycle (urea cycle).
When used simultaneously with aztreonam
there is a risk of developing seizures due to a decrease in the concentration of valproic acid in the blood plasma. Clinical observation, determination of plasma concentrations of valproic acid and possible dose adjustment of the anticonvulsant during treatment with aztreonam and after its cessation are necessary.
When combining felbamate
and valproic acid, the clearance of valproic acid decreases by 22-50% and, accordingly, the plasma concentration of valproic acid increases. Plasma concentrations of valproic acid should be monitored.
Mefloquine
accelerates the metabolism of valproic acid and is itself capable of causing convulsions, therefore, with their simultaneous use, the development of an epileptic seizure is possible.
With the simultaneous use of valproic acid and St. John's wort preparations
the anticonvulsant effectiveness of valproic acid may be reduced.
In case of simultaneous use of valproic acid and drugs that have a high and strong connection with blood plasma proteins (acetylsalicylic acid)
it is possible to increase the concentration of the free fraction of valproic acid.
With the simultaneous use of valproic acid and indirect anticoagulants (warfarin and other coumarin derivatives)
careful monitoring of INR and prothrombin index is required.
Plasma concentrations of valproic acid may increase with concomitant use of cimetidine or erythromycin
(as a result of a slowdown in its hepatic metabolism).
Reduced concentrations of valproic acid in the blood when used simultaneously with carbapenems (panipenem, meropenem, imipenem):
within 2 days of joint therapy, a 60-100% decrease in the concentration of valproic acid in the blood plasma was observed, which was sometimes combined with the occurrence of seizures. Concomitant use of carbapenems should be avoided in patients receiving a dose of valproic acid due to their ability to rapidly and intensely reduce plasma concentrations of valproic acid. If treatment with carbapenems cannot be avoided, close monitoring of valproic acid blood concentrations should be performed during carbapenem treatment and after its discontinuation.
Rifampicin
may reduce the concentration of valproic acid in the blood, which leads to loss of the therapeutic effect of valproic acid. Therefore, it may be necessary to increase the dose of valproic acid during simultaneous use of rifampicin and after its discontinuation.
Protease inhibitors such as lopinavir, ritonavir
, reduce the plasma concentration of valproic acid when used simultaneously with it.
Cholestyramine
may lead to a decrease in plasma concentrations of valproic acid when used simultaneously.
Other interaction
Concomitant use of valproic acid and topiramate
or
acetazolamide
was accompanied by encephalopathy and/or hyperammonemia. Patients receiving these combinations should be closely monitored for the development of symptoms of hyperammonemic encephalopathy.
Concomitant use of valproic acid and quetiapine
may increase the risk of developing neutropenia/leukopenia.
Valproic acid does not have the ability to induce liver enzymes and, as a result, valproic acid does not reduce the effectiveness of estrogen-progestogen
drugs in women using hormonal contraception.
When taking ethanol and other potentially hepatotoxic drugs
simultaneously with valproic acid, it is possible to enhance the hepatotoxic effect of valproic acid.
Concomitant use of clonazepam
with valproic acid can lead in isolated cases to increased severity of absence status.
With the simultaneous use of drugs that have myelotoxic effects
, with valproic acid the risk of suppression of bone marrow hematopoiesis increases.
Comparison of the effectiveness of Depakine chron and Depakine chronosphere
Depakine chronosphere is more effective than Depakine chron - this means that the ability of the medicinal substance to provide the maximum possible effect is different.
For example, if the therapeutic effect of Depakine Chronosphere is more pronounced, then it is impossible to achieve this effect with Depakine Chron even in large doses.
Also, the speed of therapy is an indicator of the speed of therapeutic action; Depakine chronosphere and Depakine chron are also different, as is bioavailability - the amount of a medicinal substance reaching the site of its action in the body. The higher the bioavailability, the less it will be lost during absorption and use by the body.
