Depakine^® Enteric 300 (Tablets) Instructions for Use

Marketing Authorization Holder

Sanofi Winthrop Industrie (France)

Manufactured By

Sanofi-Aventis, SAU (Spain)

ATC Code

N03AG01 (Valproic acid)

Active Substance

Valproic acid (Rec.INN registered by WHO)

Dosage Form

Depakine® Enteric 300

Enteric-coated tablets, 300 mg: 100 pcs.

Dosage Form, Packaging, and Composition

Enteric-coated tablets white, round, biconvex.

Excipients: povidone K-90 (polyvidone K-90) – 8 mg, calcium silicate hydrate – 15 mg, talc – 9 mg, magnesium stearate – 3 mg.

Coating composition: methacrylic acid and methyl methacrylate copolymer (1:1) – approx. 19.63 mg, talc – approx. 19.63 mg, cellacephate (cellulose acetate phthalate) – approx. 23.22 mg, diethyl phthalate – approx. 9.73 mg, Opaspray white (type K1-7000) – approx. 17.79 mg (titanium dioxide – 17.5 mg, hypromellose – 0.29 mg).

10 pcs. – blisters (10) – cardboard packs.

Clinical-Pharmacological Group

Anticonvulsant drug

Pharmacotherapeutic Group

Antiepileptic agents; fatty acid derivatives

Pharmacological Action

Antiepileptic agent. It is believed that the mechanism of action is associated with an increase in GABA content in the CNS, which is due to inhibition of GABA transaminase, as well as a decrease in GABA reuptake in 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 after 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 convulsions in children, childhood tics.

ICD codes

Dosage Regimen

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 administration.

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 plasma concentration of valproate 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, prolonged 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 during combined anticonvulsant therapy. Liver function should be regularly monitored during treatment.

Use in Renal Impairment

Use with caution in patients with 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 blood pathologies, 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 previously 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 during 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 engaging in other activities that require high concentration and quick 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 with hepatotoxic effects, 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 plasma increases, which leads to an increase in its toxicity.

With simultaneous use with carbamazepine, the concentration of valproic acid in plasma decreases due to an increase in its metabolism rate, 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 is slowed down and its T_1/2 is increased.

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

With simultaneous use with meropenem, a decrease in the concentration of valproic acid in plasma is possible; with primidone – an increase in the concentration of primidone in plasma; with salicylates – a possible enhancement of the effects of valproic acid due to its displacement by salicylates from binding to plasma proteins.

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

With simultaneous use with phenytoin during the first few weeks, the total concentration of phenytoin in plasma may decrease due to its displacement from plasma 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 plasma. Phenytoin reduces the concentration of valproate in plasma, probably due to an increase in its metabolism in the liver. It is believed that phenytoin, as an inducer of liver enzymes, may also increase the formation of a secondary, but hepatotoxic, metabolite of valproic acid.

With simultaneous use, Valproic acid displaces phenobarbital from binding to plasma proteins, resulting in an increase in its concentration in plasma. Phenobarbital increases the rate of metabolism of valproic acid, which leads to a decrease in its concentration in 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 plasma.

With simultaneous use of cimetidine, erythromycin, an increase in the concentration of valproic acid in 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.