VALPARIN CHRONO 300/500 (Sodium Valproate and Valporic acid)

VALPARIN CHRONO 300/500 (Sodium Valproate and Valporic acid)

VALPARIN CHRONO 300/500 (Sodium Valproate and Valporic acid)

Valproate exerts its effects primarily on the central nervous system. Its anticonvulsant properties are exerted against a wide variety of epilepsies experimental animal models and humans. Its main mechanism of action seems to be related to reinforcement of the gabanergic pathways.


Generalized or partial epilepsy

  • Primarily generalized: petit mal, grand mal, atonic, mixed, myoclonic epilepsies.
  • Partial: with simple or complex seizures.
  • Secondary generalized seizures
  • Specific syndromes (Lennox-Gastaut).


Acute hepatitis; chronic hepatitis; family history of severe hepatitis; notably drug-induced hepatitis; porpyria; hypersensitivity to sodium valproate.


Liver damage resulting in fatalities have been exceptionally reported. Patients most at risk, especially in cases of multiple anti-convulsant therapies, are infants and young children under the age of 3 with severe seizures disorders. After the age 3 the incidence reduces significantly and progressively decreases with age. Monotherapy is recommended in children under 3 years of age, but the potential benefit of Valparin chrono should be weighed against the risk of liver damage. Liver function test are required before beginning treatment as is periodic monitoring during the first 6 months, especially in at-risk patients.

It should be underlined that like most epileptics, there may be an isolated and transient increase in liver enzymes, in the absence of any clinical signs especially at the beginning of treatment. In such cases complete laboratory workup should be performed (including prothrombin time), dosage may be reconsidered and workup should be repeated on the basis of the changes in the parameters.

In children under 3 years of age salicylates should not be prescribed concurrently due to the risk of liver toxicity.

In patients with renal insufficiency, increased serum concentrations of free valproic acid should be taken into account and dosage should be consequently be adjusted.

In case of acute abdominal pain, serum amylase level should be determined before deciding on surgery, as exceptional cases of pancreatitis have been reported.

Blood tests including cell count, platelet count, bleeding time and coagulation test are recommended prior to initiation of therapy and surgery and in case of spontaneous bruising or bleeding

Immune disorders have been noted only exceptionally and hence benefit valparin chrono should be weighed against potential risk in patients with SLE.

In pregnancy

The global risk of malformations in women receiving valproate during the first trimester of pregnancy is not higher than the risk described with other antiepletics. Facial dysmorphia, neural tube defects, like myelomeningocele, spinabifida have been reported. the frequency of these is estimated to be 1 to 2%.

In lactation

Excretion of valproate in breast milk is low, with a concentration between 1% and 10% of maternal serum levels, up to now children breast fed that have been monitored during the neonatal period have not experienced clinical effects.

Adverse reactions

  • Rare cases of liver dysfunction
  • Confusion or convulsions: a few cases of stupor either isolated or associated with an upsurge in convulsion with sodium valproate have been observed, and they regress on discontinuation of treatment or dosage reduction. These states usually occur in a multiple drug treatment context (especially Phenobarbital) or on abrupt increase of sodium valproate doses.
  • Certain subjects may present, at the beginning of treatment, gastrointestinal disturbances (nausea, gastric pain), which generally stop after a few days, without discontinuation of treatment.
  • Transient dose dependent adverse effects have been reported: hair loss, fine postural tremor.
  • Weight gain has been observed, as have amenorrhea and menstrual disturbances.
  • Dose related rise in bleeding time, decrease in fibrinogen have been reported
  • Hematologic side effects: thrombocytopenia, rarely anaemia, leucopenia or pancytopenia.
  • Isolated hyperammonaemia without change in liver function test may occur. This should not cause treatment discontinuation.
  • Rarely pancreatitis, vasculitis, hearing loss.
Drug interactions

Imipramine antidepressants: Imipramine antidepressants may promote generalized convulsions. Clinical monitoring and possibly dosage increase of antiepileptics may be necessary.

Phenobarbital: Increase in plasma Phenobarbital concentrations (due to inhibition of liver catabolism), may occur with sedation, most often in children. Clinical monitoring during the first 2 weeks of the combination and immediate Phenobarbital dose reduction when signs of sedation develop, if necessary, monitor plasma Phenobarbital levels.

Phenytoin: generally, increases total phenytoin concentrations. In particular, increase in the concentrations of phenytoin, which may lead to signs of overdosage (valproic acid displaces phenytoin from its plasma protein binding site and slows its liver catabolism). Clinical monitoring is recommended. If plasma phenytoin are determined, the free form is the most important to consider.

Primidone: increase in plasma primidone levels with enhancement of its adverse effects (sedation). After prolonged use, this interaction ceases. Clinical monitoring recommended and if necessary, primidone dosage adjustments should be considered, especially at the beginning of the co-administration.

Lamotrigine: valproate may reduce lamotrigine metabolism necessitating dosage reduction of latter.

Mefloquine: increases valproic acid metabolism and has a convulsant effect; therefore epileptic seizures may occur in combined therapy.

In case of concomitant use of valproate and highly bound protein drugs (like aspirin), free serum levels of valproate may be increased.

The serum levels of valproate may be increased in case of concomitant use with cimetidine or erythromycin.

Close monitoring of prothrombin time should be performed in case of concomitant use of vitamin K dependent anticoagulant.

Dosage and administration

The daily dosage is usually 10-15mg/kg, then doses are titrated up to the optimum dosage. This is generally within the range 20-30mg/kg. Nevertheless, where seizures control is not achieved within this range, the dose may be further increase adequate; patients should be carefully monitored when receiving daily doses higher than 50mg/kg.

  • In children, usual dosage is about 30mg/kg per day.
  • In adults, usual dosage is within the range 20-30mg/kg per day
  • In elderly, although the pharmacokinetics of valproate are modified, they have limited clinical significance and dosage should be determined by seizure control.

The use of a sustained release form allows giving the drug once daily. It may be use in children provided that they are able to take such a form. To be swallowed whole. Do not chew.


The clinical picture of massive acute intoxication usually includes coma, with hypotonia, decreased reflexes, myosis, and decreased respiratory function. Seizures have also been reported in presence of very high plasma levels.

The following measures should be implemented in hospitals: gastric lavage useful up to 10 to 12 hours following ingestion, institution of forced diuresis, cardio respiratory monitoring. In very severe cases, dialysis or exchange transfusion may be necessary. Naloxone has been successfully used in 1 case. Such intoxications has usually have a good prognosis, though deaths have occurred following massive overdosage.

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