Convulsofin^®-Retard (Tablets) Instructions for Use

ATC Code

N03AG01 (Valproic acid)

Active Substance

Valproic acid (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Anticonvulsant drug

Pharmacotherapeutic Group

Anticonvulsant agent

Pharmacological Action

Antiepileptic agent. It is believed that the mechanism of action is associated with an increase in the GABA content in the CNS, which is due to the inhibition of GABA-transaminase, as well as a decrease in the reuptake of GABA in the brain tissues.

This apparently leads to a decrease in the excitability and convulsive readiness of the motor zones of the brain. It helps to improve the mental state and mood of patients.

Pharmacokinetics

Valproic acid is rapidly and almost completely absorbed from the gastrointestinal tract, oral bioavailability is about 93%. Food intake does not affect the degree of absorption. C_max in blood plasma is reached in 1-3 hours. The therapeutic concentration of valproic acid in blood plasma is 50-100 mg/l.

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

It is metabolized by glucuronidation and oxidation in the liver.

Valproic acid (1-3%) and its metabolites are excreted by the kidneys. T_1/2 in monotherapy and in healthy volunteers is 8-20 hours.

When combined with other drugs, T_1/2 can be 6-8 hours due to the induction of metabolic enzymes.

Indications

Epileptic seizures: generalized, focal (partial) with simple and complex symptoms, minor. Convulsive syndrome in organic brain diseases. Behavioral disorders associated with epilepsy. Manic-depressive psychosis with bipolar course, not amenable to treatment with lithium preparations or other drugs. Febrile seizures in children, childhood tics.

ICD codes

Dosage Regimen

Tablets

Individual. For oral administration in adults and children weighing more than 25 kg, the initial dose is 10-15 mg/kg/day. Then the dose is gradually increased by 200 mg/day at intervals of 3-4 days until a clinical effect is achieved. The average daily dose is 20-30 mg/kg. For children weighing less than 25 kg and newborns, the average daily dose is 20-30 mg/kg.

Frequency of administration – 2-3 times/day with meals.

IV (in the form of sodium valproate) is administered at a dose of 400-800 mg or by drip at the rate of 25 mg/kg over 24, 36 and 48 hours. If simultaneous oral and IV administration is necessary, the first administration is carried out by IV infusion at a dose of 0.5-1 mg/kg/h 4-6 hours after the last oral intake.

Maximum doses for oral administration for adults and children weighing more than 25 kg – 50 mg/kg/day. Use in a dose of more than 50 mg/kg/day is possible provided that the concentration of valproate in the blood plasma is monitored. If the plasma concentration is more than 200 mg/l, the dose of valproic acid should be reduced.

Adverse Reactions

From the CNS tremor of the hands or arms is possible; rarely – changes in behavior, mood or mental state, diplopia, nystagmus, spots before the eyes, impaired coordination of movements, dizziness, drowsiness, headache, unusual excitement, motor restlessness or irritability.

From the digestive system mild cramps in the abdomen or stomach area, loss of appetite, diarrhea, indigestion, nausea, vomiting are possible; rarely – constipation, pancreatitis.

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

From the metabolism unusual decrease or increase in body weight.

From the gynecological status menstrual cycle disorders.

Dermatological reactions alopecia.

Allergic reactions skin rash.

Contraindications

Severe liver dysfunction; severe pancreatic dysfunction; porphyria; hemorrhagic diathesis; severe thrombocytopenia; first trimester of pregnancy; lactation (breastfeeding); hypersensitivity to valproic acid.

Use in Pregnancy and Lactation

Use during pregnancy is not recommended, especially in the first trimester. It should be borne in mind that Valproic acid can cause various congenital anomalies, especially spina bifida.

Valproic acid is excreted in breast milk. There are reports that valproate concentrations in breast milk were 1-10% of the concentration in maternal plasma. Use during breastfeeding is contraindicated.

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

Use in Hepatic Impairment

Contraindicated in liver dysfunction, acute and chronic hepatitis. Use with caution in patients with a history of liver disease.

It should be borne in mind that the risk of developing liver side effects is increased when conducting combined anticonvulsant therapy. Liver function should be regularly monitored during treatment.

Use in Renal Impairment

Use with caution in renal impairment.

Pediatric Use

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

Special Precautions

Use with caution in patients with pathological blood changes, with organic brain diseases, a history of liver disease, hypoproteinemia, and renal dysfunction.

In patients receiving other anticonvulsants, treatment with valproic acid should be started gradually, reaching a clinically effective dose after 2 weeks. Then a gradual withdrawal of other anticonvulsants is carried out. In patients not treated with other anticonvulsants, the clinically effective dose should be reached after 1 week.

It should be borne in mind that the risk of developing liver side effects is increased when conducting combined anticonvulsant therapy.

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

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

Effect on ability to drive vehicles and mechanisms

During treatment, caution should be exercised when driving vehicles and other activities that require high concentration and rapid psychomotor reactions.

Drug Interactions

With simultaneous use of neuroleptics, antidepressants, MAO inhibitors, benzodiazepine derivatives, ethanol, the inhibitory effect on the CNS is enhanced.

With simultaneous use of drugs that have a hepatotoxic effect, the hepatotoxic effect may be enhanced.

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 liver microsomal enzymes under the influence of carbamazepine. Valproic acid potentiates the toxic effect of carbamazepine.

With simultaneous use, the metabolism of lamotrigine slows down and its T_1/2 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 primidone – an increase in the concentration of primidone in the 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.

With simultaneous use with felbamate, the concentration of valproic acid in the blood plasma increases, which is accompanied by manifestations of toxic action (nausea, drowsiness, headache, decrease in platelet count, cognitive impairment).

With simultaneous use with phenytoin during the first few weeks, the total concentration of phenytoin in the blood plasma may decrease due to its displacement from protein binding sites by sodium valproate, induction of liver microsomal enzymes and acceleration of phenytoin metabolism. Further, inhibition of phenytoin metabolism by valproate occurs 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 liver enzymes, possibly also increases the formation of a secondary, but hepatotoxic, metabolite of valproic acid.

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

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

With simultaneous use of cimetidine, erythromycin, an increase in the concentration of valproic acid in the plasma is possible due to a decrease in its metabolism in the liver.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.