Valproic acid - instructions for use, dose, side effects, contraindications

Inhibits GABA-transferase, increases the content in central nervous system gamma-aminobutyric acid, which causes a decrease in the threshold of excitability and the level of convulsive readiness of the motor zones of the brain. When ingested, dissociates to valproate ion, which is absorbed into the blood plasma. Food decreases the absorption rate.

Pharmacokinetics:

Valproic acid is quickly and almost completely absorbed from the gastrointestinal tract, bioavailability when ingested is about 93%. Eating does not affect the degree of absorption. Maximum concentration in blood plasma is achieved in 1-3 hours. The therapeutic concentration of valproic acid in blood plasma is 50-100 mg / l.

C_ss is achieved on the 2nd-4th day of treatment, depending on the intervals between doses. Binding to plasma proteins is 80-95%. The concentration levels in the cerebrospinal fluid correlate with the size of the protein-unbound fraction. Valproic acid penetrates the placental barrier, excreted in breast milk.

Metabolized by glucuronization and oxidation in the liver.

Valproic acid (1-3%) and its metabolites are excreted by the kidneys. Half-life with monotherapy and in healthy volunteers is 8-20 hours.

When combined with other drugsElimination half-life may be 6-8 hours due to the induction of metabolic enzymes.

Indications:

Epileptic seizures: generalized, focal (focal, partial) with simple and complex symptomatology, small. Convulsive syndrome with organic brain diseases. Behavioral disorders associated with epilepsy. Manic-depressive psychosis with a bipolar course, not amenable to treatment with lithium drugs or other drugs. Febrile convulsions in children, children's teak.

ICD-10

V.F30-F39.F31 Bipolar affective disorder

V.F90-F98.F95 Tiki

VI.G40-G47.G40 Epilepsy

XVIII.R25-R29.R25.2 Cramp and spasm

Contraindications:

Hypersensitivity, incl. "family" (death of close relatives against the intake of valproic acid), liver and pancreas diseases (in some patients, a significant decrease in metabolism in the liver), hemorrhagic diathesis. Contraindications for violations of liver function, acute and chronic hepatitis.Use with caution in liver diseases in history.

Carefully:

It should be borne in mind that the risk of side effects from the liver is elevated when combined anticonvulsant therapy is performed. During the treatment it is necessary to regularly monitor the liver function.

Use with caution for violations of kidney function.

Children are at increased risk for developing severe or life-threatening hepatotoxic effects. In patients under 2 years of age and in children receiving combination therapy, the risk is even higher, but with increasing age, it decreases.

They are used with caution in patients with pathological changes in blood, with organic brain diseases, liver diseases in history, hypoproteinemia, renal dysfunction.

Pregnancy and lactation:

Action category for the fetus by Food and Drug Administration (US Food and Drug Administration) - D. ПApplication during pregnancy is not recommended. It should be borne in mind that valproic acid can cause a variety of congenital anomalies, especially spina bifida.

Valproic acid is excreted in breast milk.There are reports that the concentrations of valproate in breast milk were 1-10% of the concentration in the blood plasma of the mother. During lactation, the application is possible in cases of extreme necessity.

Women of childbearing age during the period of treatment are recommended to use reliable methods of contraception.

Dosing and Administration:

Inside, during or immediately after a meal. Daily intake for adults at the beginning treatment is 0.3-0.6 g, for 1-2 weeks it is gradually increased to 0.9-1.5 g, a single dose for adults is 0.3-0.45 g. The daily dose for children is 15-50 mg / kg (in the beginning - 15 mg / kg, then a gradual increase for 5-10 mg / kg per week).

Side effects:

From the side central nervous system: possibly trembling hands or hands; rarely - changes in behavior, mood or mental state, diplopia, nystagmus, spots before the eyes, movement coordination disorders, dizziness, drowsiness, headache, unusual agitation, motor anxiety or irritability.

From the digestive system: Slight spasms in the abdomen or in the stomach region, loss of appetite, diarrhea, digestive disorders, nausea, vomiting; rarely - constipation, pancreatitis.

From the side of the blood coagulation system: thrombocytopenia, prolongation of bleeding time.

From the side of metabolism: unusual decrease or increase in body weight.

From the gynecological status: menstrual cycle disorders.

Dermatological reactions: alopecia.

Allergic reactions: skin rash.

Overdose:

Occurs when the concentration of the drug in the blood exceeds 100-150 μg / ml.

Diarrhea, respiratory failure, muscle hypotension, hyporeflexia, miosis, coma (on the electroencephalogram - intensification of slow waves and background activity).

Treatment is symptomatic; hemodialysis. Specific treatment with severe depression central nervous system spend naloxone. Care must be taken, provocation of cramps is possible!

Interaction:

With the simultaneous use of neuroleptics, antidepressants, monoamine oxidase inhibitors, benzodiazepine derivatives, ethanol, the oppressive effect on central nervous system.

At simultaneous application of the means possessing hepatotoxic action, strengthening of a hepatotoxic action is possible.

With simultaneous use, the effects of antiplatelet agents (including acetylsalicylic acid) and anticoagulants are enhanced.

With simultaneous use, the concentration of zidovudine in the blood plasma increases, which leads to an increase in its toxicity.

With simultaneous use with carbamazepine, the concentration of valproic acid in the blood plasma decreases due to an increase in the rate of its metabolism, caused by the induction of microsomal enzymes of the liver under the influence of carbamazepine. Valproic acid potentiates the toxic effect of carbamazepine.

With simultaneous use, metabolism of lamotrigine is slowed down and its half-life increases.

With simultaneous use with mefloquine, the metabolism of valproic acid in the blood plasma increases and the risk of seizures increases.

With simultaneous use with meropenem, a decrease in the concentration of valproic acid in the blood plasma is possible; with primidon - an increase in the concentration of primidone in blood plasma; with salicylates - it is possible to enhance the effects of valproic acid due to its displacement by salicylates from the connection with plasma proteins.

When used simultaneously with felbamate, the concentration of valproic acid in the blood plasma increases, which is accompanied by manifestations of toxic action (nausea,drowsiness, headache, a decrease in the number of platelets, cognitive impairment).

With simultaneous application with phenytoin for the first few weeks, the total concentration of phenytoin in the blood plasma can decrease due to its displacement from the sites of binding to plasma proteins by sodium valproate, the induction of microsomal liver enzymes and the acceleration of the metabolism of phenytoin. Then there is an inhibition of the metabolism of phenytoin by valproate and, as a result, an increase in the concentration of phenytoin in the blood plasma. Phenytoin reduces the concentration of valproate in the blood plasma, probably due to an increase in its metabolism in the liver. It is believed that phenytoin as an inducer of hepatic enzymes, may also increase the formation of a secondary, but hepatotoxic, valproic acid metabolite.

With simultaneous application valproic acid expels phenobarbital from the connection with plasma proteins, as a result, its concentration in the blood plasma increases. Phenobarbital increases the metabolic rate of valproic acid, which leads to a decrease in its concentration in the blood plasma.

There have been reports of increased effects of fluvoxamine and fluoxetine when used simultaneously withalproic acid. With simultaneous use with fluoxetine, some patients experienced an increase or decrease in the concentration of valproic acid in the blood plasma.

With the simultaneous use of cimetidine, erythromycin, it is possible to increase the concentration of valproic acid in the plasma by reducing its metabolism in the liver.

Special instructions:

Patients who receive other anticonvulsants, treatment with valproic acid should be started gradually, reaching a clinically effective dose in 2 weeks. Then, a gradual cancellation of other anticonvulsants is carried out. In patients who have not been treated with other anticonvulsants, a clinically effective dose should be achieved after 1 week.

It should be borne in mind that the risk of side effects from the liver is elevated when combined anticonvulsant therapy is performed.

During the treatment it is necessary to regularly monitor liver function, the picture of peripheral blood, the state of the blood coagulation system (especially during the first 6 months of treatment).

Impact on the ability to drive vehicles and manage mechanisms

During the treatment period, care should be taken when driving vehicles and other activities requiring high concentration of attention and rapid psychomotor reactions.

Instructions

Valproic acid (Acidum valproicum)