Valopicsim (Tablets) Instructions for Use

Marketing Authorization Holder

Sandoz, d.d. (Slovenia)

Manufactured By

Dragenopharm Apotheker Pueschl, GmbH (Germany)

Or

Salutas Pharma, GmbH (Germany)

ATC Code

N03AG01 (Valproic acid)

Active Substance

Valproic acid (Rec.INN registered by WHO)

Dosage Form

Valopicsim

Extended-release film-coated tablets, 300 mg: 5, 10 or 50 pcs.

Dosage Form, Packaging, and Composition

Extended-release film-coated tablets white, oblong, with a score on both sides.

Excipients: ethylcellulose – 7.2 mg, hypromellose (high molecular weight) – 105.6 mg, colloidal hydrated silicon dioxide – 30 mg, sodium saccharin (E954) – 6 mg, colloidal anhydrous silicon dioxide – 2.4 mg.

Film coating composition 1: macrogol 6000 – 1.3 mg, hypromellose (low molecular weight) – 4.2 mg, titanium dioxide (E171) – 0.6 mg.
Film coating composition 2: methacrylic acid – ethyl acrylate copolymer (1:1)* – 4.8 mg, macrogol 6000 – 0.6 mg, talc – 0.6 mg.

10 pcs. – Al/Al blisters (5) – cardboard packs.
10 pcs. – Al/Al blisters (10) – cardboard packs.
10 pcs. – Al/Al blisters (20) – cardboard packs.

* contains small amounts of surfactants such as sodium lauryl sulfate and polysorbate 80. Their content may vary depending on the manufacturer.

Clinical-Pharmacological Group

Anticonvulsant drug

Pharmacotherapeutic Group

Anticonvulsant agent

Pharmacological Action

Antiepileptic agent.

The mechanism of action is believed to be 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 in 1-3 hours. The therapeutic concentration of valproic acid in blood plasma is 50-100 mg/l.

C_ss is reached on the 2nd-4th day of treatment depending on the intervals between doses. Plasma protein binding is 80-95%. Concentration levels in the cerebrospinal fluid correlate with the magnitude of the protein-unbound fraction.

Valproic acid crosses 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 during 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 symptomatology, 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 tic.

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 3-4 day intervals 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 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 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, 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 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 agents with hepatotoxic action, hepatotoxic effects may be enhanced.

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

With simultaneous use, the plasma concentration of zidovudine increases, leading to increased toxicity.

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

With simultaneous use with felbamate, the plasma concentration of valproic acid 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 plasma concentration of phenytoin 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 plasma concentration of phenytoin. Phenytoin reduces the plasma concentration of valproate, 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 plasma concentration. Phenobarbital increases the rate of metabolism of valproic acid, which leads to a decrease in its plasma concentration.

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 plasma concentration of valproic acid.

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