Valproic acid (Depakine chrono, Encorate chrono, Convulex, Valparin)


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).

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).

Instructions for use

Adult patients

The antiepileptic drug should be taken orally, combined with food.

The tablet should be swallowed whole with a glass of purified water. The syrup is mixed with a small amount of water or added directly to food.

The treatment regimen recommended by the manufacturer involves two or three times .

The daily dosage is calculated taking into account the patient’s body weight - for each kg of weight there are 15 mg of the drug at the initial stage of therapy (for body weight over 25 kg).

Subsequently, the dosage is increased every 1-2 weeks by 5-10 mg. The resulting figure is daily, so it is divided into 2-3 doses in equal portions. The maximum allowable amount of the drug is 30 mg/kg (in rare cases - up to 60 mg).

It is prohibited to increase a single dose on your own due to the high risk of side effects.

Before adjusting the treatment regimen and dosage, the specialist monitors the concentration of the active substance of the drug in the blood plasma.

When prescribed in combination with other pharmacological products, the daily dose of Depakine per 1 kg of weight is 10-30 mg. Weekly the amount of the drug can be increased by 5-10 mg with proper blood test results.

Children

Patients whose weight does not exceed 25 kg are provided with the following daily allowance:

  • for newborns – up to 30 mg/kg;
  • at the age of 3 to 10 years – up to 40 mg/kg.

When using only Depakine, the dosage is set from 15 to 45 mg/kg, in combination with other pharmacological products - 30-100 mg/kg.

For children under one year of age, the daily dose is divided into 2 doses; others are recommended to take the medicine three times a day.

Recommendations for intravenous use of the drug

The daily norm is 25 mg/kg. The injection is given at intervals of 1; 1.5; 2 days.

The diluted powder is administered intravenously using the jet method (400-800 mg). The use of a dropper is also allowed.

When switching from oral to injection use, it is important to maintain a 4-6 hour interval between the last pill and the first injection.

The initial injection dose should be 0.5-1 mg per kg of patient weight.

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.

The place of valproate (Depakine) in the pharmacotherapy of epilepsy of the 21st century

About the article

6899

0

Regular issues of "RMZh" No. 11 dated May 12, 2009 p. 726

Category: Neurology

Author: Zenkov L.R.

For quotation:

Zenkov L.R. The place of valproates (Depakine) in the pharmacotherapy of epilepsy of the 21st century. RMJ. 2009;11:726.

Epilepsy is the most common serious brain disorder (population prevalence 0.3–2%). The end of the 20th – the beginning of the 21st century. marked unprecedented progress in the pharmacotherapy of epilepsy. About 50 fundamentally new antiepileptic drugs (AEDs) were created and entered the pharmaceutical market, of which the most effective and reliably proven ones are registered in Russia (Table 1).

Epilepsy is the most common serious brain disorder (population prevalence 0.3–2%). The end of the 20th – the beginning of the 21st century. marked unprecedented progress in the pharmacotherapy of epilepsy. About 50 fundamentally new antiepileptic drugs (AEDs) were created and entered the pharmaceutical market, of which the most effective and reliably proven ones are registered in Russia (Table 1). It would seem that a wide range of antiepileptic drugs should significantly improve the treatment of epilepsy, but the real state of affairs does not confirm these expectations. Epidemiological demographic studies in populations where the number of patients taking AEDs is 0–15% show spontaneous remission rates of 30–46% [25,32,36]. And, for example, in the UK, in a typical population of patients receiving antiepileptic drugs observed for 11–14 years, the remission rate is 47%, i.e., it does not differ significantly from that observed in underdeveloped countries, where epilepsy is practically not treated [26,28 ]. What’s worse is that in Russia, where 85% of patients receive antiepileptic therapy, the average percentage of remissions across populations ranges from 3–10% [1], that is, 4–5 times worse than in populations where patients do not receive AEDs . Meanwhile, the remission rate with proper treatment is 60–90%. Obviously, the above disappointing statistics are due to the wrong choice of antiepileptic drug, which leads not only to the ineffectiveness of treatment, but also to aggravation of the course of the disease [7]. Until the 90s of the last century, all drugs were divided into drugs of the first, second and further choices. In modern conditions of the abundance of new drugs in addition to traditional ones, most of the existing standards and recommendations for the treatment of epilepsy have abandoned the above gradation and use the neutral term: “drugs of choice,” avoiding an unambiguous definition of the sequence of their use. The 2006 International League Against Epilepsy recommendations for initial monotherapy for epileptic seizures and syndromes conclude with a less-than-encouraging conclusion about the alarming paucity of well-conducted randomized controlled trials of drugs for the treatment of epileptic seizures, which precludes drawing conclusions about their effectiveness and tolerability. The only practical treatment recommendation is formulated by the general statement: “The final choice of drug for an individual patient should include knowledge of the effectiveness of the drug, taking into account other variables such as safety and tolerability, pharmacokinetics, available dosage forms and cost” [20]. This report is devoted to the consideration from this point of view of one of the most successful antiepileptic AEDs of our time - valproic acid (VPA). The inclusion of the name Depakine in the title is determined by the fact that under this brand, original military-industrial complex preparations have been produced for more than half a century, right up to its most modern and most advanced pharmaceutical forms. The choice of an antiepileptic drug as initial therapy determines the future fate of the patient; therefore, national recommendations, based on an analysis of world practice and expert consensus, determine the list of drugs recommended for the treatment of epilepsy. Most of these recommendations, which include “old,” “traditional,” and “new” antiepileptic drugs, do not specify how they should be used. Having analyzed the recommendations of leading national and international organizations for the period 2000–2005, N. Payakachat et al. [32] came to the conclusion that the recommendations of the UK National Institute for Clinical Excellence (NICE National Institute for Clinical Excellence) are the most adequate for clinical practice. . They recommend starting the treatment of epilepsy with traditional drugs (valproate or carbamazepine), if there are no individual contraindications. Similar recommendations are contained in the standards for the treatment of epilepsy in the Russian Federation, and in them VPA is the first in order of choice [10,37]. This choice is confirmed by a number of international and national expert consensuses [8,11,39–41]. The identification of valproates as the main AEDs in the treatment of epilepsy is not only a consequence of scientific research, but also, mainly, of historically established world medical practice. VPA was synthesized 127 years ago and has been used as a solvent for organic substances for 80 years. In 1962, it was used for this in France by H. Maunier et al., who were studying the anticonvulsant properties of a series of organic substances, and largely accidentally discovered that the ability to suppress epileptic activity did not belong to the new compounds being tested, but to the long-known solvent - VPA. Further studies showed almost unlimited possibilities for using VPA and its derivatives in the treatment of all forms of epilepsy [2,3,5,8–21,24,34,36,39–41]. VPA is the most widely used antiepileptic drug, accounting for, for example, up to 60% in Japan, and on average in the world - about 25% [5]. It is interesting to note the relationship between the effectiveness of treatment in populations where appropriate statistics are available and the percentage of patients receiving valproate, according to published and our own data (Table 2). The correlation coefficient between the data presented in Table 2 is r=0.98 (p=0.004), which indicates a very close direct relationship between the success of treatment and the use of valproic acid drugs. That is why the use of valproate is actively expanding throughout the world. Below, based on our own experience and world practice (mainly over the last 10 years), we analyze the features of the military-industrial complex that determine its place in the treatment of epilepsy. Factors for the clinical effectiveness of valproate An ideal antiepileptic drug should have four main properties: 1) prevent seizures; 2) eliminate interictal neurological, mental and behavioral disorders; 3) give a neuroprotective effect, preventing the progression and promoting recovery from epilepsy (actually an antiepileptic effect). To one degree or another, all these properties are inherent in the military-industrial complex. The success of VPA in suppressing epileptic neuronal activity and, accordingly, seizures is determined by a combination of mechanisms of action. VPA suppresses seizures by activating the GABA system and blocking Ca2+ channels. VPA also affects Ca2+-dependent K+ channels and inhibits the propagation of the discharge from the primary focus. VPA in therapeutic doses, by inhibiting GABA transaminase, delays the decomposition of GABA, and by increasing the activity of the enzyme glutamic acid decarboxylase, it increases the synthesis of GABA, which leads to an increase in the content of the main inhibitory neurotransmitter, GABA, by 30–40%. VPA stabilizes the membrane by participating in the blockade of sodium channels [2, 5, 38]. The clinical success of VPC is determined by the objective factors of high efficiency (70–90% remission in monotherapy), the breadth of the therapeutic spectrum (effective for all forms of epilepsy and types of seizures), good tolerability, the ability to quickly increase the dose, favorable interaction with other drugs [5,8, 11.21]. The long-acting form - Depakine chrono (pharmaceutical) provides a stable therapeutic concentration in the blood, minimal risk of side effects and minimizes the patient's dependence on the drug, since the daily dose can be taken in two or even one evening dose [2,3,5,8]. This year in Russia, in accordance with UK standards [37] and the standards for the treatment of childhood epilepsy by European experts [41], a new form of valproate with prolonged action was registered - Depakine Chronosphere. Its development was stimulated by one of the main problems in the treatment of epilepsy - insufficient compliance with the drug regimen, which is the main reason for the failure of remission and ineffective control of seizures. A large number of patients (mainly children and people with impaired self-control) have difficulty swallowing tablets or capsules with the active substance. The new drug Depakine Chronosphere is tasteless spherical granules with a diameter

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.

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.

Depakine Enteric tablets 300 mg 100 pcs. in Sergiev Posad

Suction

The bioavailability of sodium valproate and valproic acid when taken orally is close to 100%.

When taking Depakine® Chrono 500 mg tablets at a dose of 1000 mg/day, Cmin in plasma is 44.7±9.8 mcg/ml, and Cmax in plasma is 81.6±15.8 mcg/ml. Tmax in plasma is 6.58±2.23 hours. Css in plasma is achieved within 3-4 days of regular use of the drug.

The average therapeutic range for serum concentrations of valproic acid is 50-100 mg/L. If there is a justified need to achieve higher concentrations of valproic acid in the blood plasma, the ratio of the expected benefit and the risk of side effects, especially dose-dependent ones, should be carefully weighed. When the concentration of valproic acid is more than 100 mg/l, an increase in side effects is expected, including the development of intoxication. When the plasma concentration of valproic acid is more than 150 mg/l, a reduction in the dose of the drug is required.

Compared with the enteric-coated dosage form, the drug in the form of a sustained-release tablet in equivalent doses is characterized by the absence of absorption latency, prolonged absorption, identical bioavailability, lower Cmax (approximately 25% decrease in Cmax), but with a more stable phase plateau from 4 to 14 hours after dosing, with a more linear correlation between dose and plasma drug concentration.

Distribution

Binding to plasma proteins (mainly albumin) is high (90-95%), dose-dependent and saturable.

Vd depends on age and is usually 0.13-0.23 l/kg body weight or in young people 0.13-0.19 l/kg body weight.

Valproic acid penetrates the cerebrospinal fluid and the brain. The concentration of valproic acid in the cerebrospinal fluid is 10% of the corresponding concentration in plasma.

Valproic acid passes into breast milk in nursing mothers. At steady state, the concentration of valproic acid in breast milk is 1-10% of its concentration in plasma.

Metabolism

Metabolized by beta-, omega- and omega-1-oxidation and conjugation with glucuronic acid. More than 20 metabolites have been isolated; metabolites after omega-oxidation have a hepatotoxic effect.

Valproic acid does not have an inducing effect on isoenzymes of the cytochrome P450 system: unlike most other antiepileptic drugs, valproic acid does not affect the degree of both its own metabolism and the degree of metabolism of other drugs, such as estrogens, progestogens and indirect anticoagulants.

Removal

It is excreted mainly in the urine after beta-oxidation and conjugation. T1/2 is 15-17 hours. Plasma clearance of valproic acid in patients with epilepsy is 12.7 ml/min.

Pharmacokinetics in special clinical situations

In elderly patients, patients with renal and hepatic insufficiency

binding to plasma proteins is reduced. In severe renal failure, the concentration of the free (therapeutically active) fraction of valproic acid can increase to 8.5-20%.

For hypoproteinemia

the total concentration of valproic acid (free + fraction bound to plasma proteins) may not change, but may decrease due to an increase in the metabolism of the free (not bound to plasma proteins) fraction of valproic acid.

When combined with antiepileptic drugs that induce microsomal liver enzymes,

plasma clearance of valproic acid increases and T1/2 decreases, the degree of their change depends on the degree of induction of microsomal liver enzymes by other antiepileptic drugs.

T1/2 values ​​in children over 2 months of age are close to those in adults.

In patients with liver disease

T1/2 of valproic acid increases.

In case of overdose

an increase in T1/2 up to 30 hours was observed.

Only the free fraction of valproic acid in the blood (10%) is subject to hemodialysis

Features of pharmacokinetics during pregnancy

With an increase in Vd of valproic acid in the third trimester of pregnancy, its renal and hepatic clearance increases. In this case, despite taking the drug in a constant dose, a decrease in the concentration of valproic acid in plasma is possible. In addition, during pregnancy, it is possible to change the degree of binding of valproic acid to plasma proteins, which can lead to an increase in the content of the free (therapeutically active) fraction of valproic acid in the blood serum.

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