Depakine/Depakine Chrono

Depakine/Depakine Chrono

valproic acid

Manufacturer:

Sanofi-Aventis

Distributor:

DKSH
Full Prescribing Info
Contents
Sodium valproate.
Action
Anticonvulsant.
Pharmacology: Sodium valproate is a broad-spectrum antiepileptic agent. Valproate exerts its effects mainly on central nervous system.
Pharmacological studies in animals have demonstrated that Depakine/Chrono has anticonvulsant properties in various models of experimental epilepsy. (Primary generalized and partial seizures.)
In humans, Depakine/Chrono has also demonstrated antiepileptic activity in various types of epilepsy. Its main mechanism of action seems to be related to a reinforcement of the gabanergic pathway.
Pharmacokinetics: Sodium valproate bioavailability is close to 100% following oral or IV administration. The volume of distribution is mainly limited to blood and rapid exchange extracellular liquid. Valproic acid concentration in cerebrospinal fluid is close to free plasma concentration. Depakine is transferred through placenta. When given to breastfeeding mothers, Depakine is excreted in breast milk at very low concentrations (between 1-10% of the total serum concentration).
Steady-state plasma concentration is reached rapidly (3-4 days) following oral administration; with IV form, steady-state plasma concentration may be reached in a few minutes and then maintained with IV infusion.
Valproate is highly bound to plasma protein, is dose-dependent and saturable.
Valproate molecule can be dialysed but only the free form (approximately 10%) is excreted.
Unlike the other antiepileptics, sodium valproate does not increase its own degradation neither that of other agents eg, estroprogestatives. This is due to the absence of enzyme-inducing effect involving cytochrome P-450.
Half-life is approximately 15-17 hrs.
Sodium valproate is mainly excreted in urine following metabolism via glucuro-conjugation and β-oxidation.
Depakine Chrono: Compared with the enteric-coated form, the slow-release form (Depakine Chrono) is characterized, at equivalent doses, by: Disappearance of lag time following administration; extended absorption; similar bioavailability; total and free peak plasma concentrations (Cmax) are lower (decrease in Cmax of approximately 25% but with a relatively stable plateau from 4-14 hrs after administration); as a result of these loped peaks, valproic acid concentrations are more regular and have a more homogenous distribution among nycthemerus: Following twice-daily administration of a same dose, the range of plasma fluctuations is reduced by half; more linear correlation between doses and plasma concentrations (total and free).
Indications/Uses
Treatment of generalized epilepsy (clonic, tonic, tonic-clonic, absence, myoclonic or atonic seizures). Lennox-Gastaut syndrome. Treatment of partial epilepsy: Partial seizures with or without secondary generalization. Treatment and prevention of mania associated with bipolar disorders.
Dosage/Direction for Use
Daily dosage should be established according to age and body weight; nevertheless, the wide individual sensitivity to valproate should also be considered.
Optimum dosage should be determined essentially according to the clinical response; the determination of valproic acid plasma levels may be considered in addition to clinical monitoring when adequate seizure control is not achieved or when adverse effects are suspected. The reported effective range is usually between 40-100 mg/L (300-700 micromole/L).
Initiation of Depakine Therapy (Oral Administration): In patients without other antiepileptic drugs, the dosage should be preferably increased by successive dose levels at 2- to 3- day intervals in order to reach the optimum dosage in about 1 week.
In patients previously receiving antiepileptic agents, substitution with Depakine should be progressive, the optimum dosage being reached in about 2 weeks and other treatments being tapered then stopped.
Addition of another antiepileptic agent should be done progressively where it is necessary (see Interactions).
Dosage: Epilepsy: Initial daily dosage is usually 10-15 mg/kg then doses are titrated up to the optimum dosage (see Initiation of Depakine Therapy in previous text).
This is generally within the range 20-30 mg/kg. Nevertheless, where seizure control is not achieved within this range, the dose may be further increased adequately; patients should be carefully monitored when receiving daily doses >50 mg/kg. (See Precautions.)
Adults: Usual dosage is within the range 20-30 mg/kg/day.
Children: Usual dosage is about 30 mg/kg/day.
Elderly: Although the pharmacokinetics of Depakine is modified, they have limited clinical significance and dosage should be determined by seizure control.
Mania: Initial Dose: 1000 mg/day. The recommended maintenance dosage is 1000-2000 mg daily. The dose may be increased to not more than 3000 mg daily. Doses should be adjusted according to individual clinical response.
Administration: Tablets, liquid and syrup may be given twice daily.
The use of a sustained-release form (Depakine Chrono) allows the drug to be given once daily.
Depakine Chrono may be used in children provided that they are able to take such a form.
Depakine IV Administration: Patients being treated satisfactorily with oral Depakine may be continued at their current dosage using continuous or repeated infusion ie, a patient stabilized on 25 mg/kg administered daily should be continued with an infusion at the rate of 1 mg/kg/hr.
Other patients may initially be given a slow IV injection (>3 min), usually 15 mg/kg followed by an infusion at the usual rate of 1-2 mg/kg/hr and adjusted on the clinical response.
Overdosage
Symptoms: Clinical signs of acute massive overdosage usually include a coma, with muscular hypotonia, hyporeflexia, miosis, impaired respiratory functions.
Symptoms may however be variable and seizures have been reported in the presence of very high plasma levels.
Treatment: Hospital management of overdosage should include: Gastric lavage, that is useful up to 10-12 hrs following ingestion; osmotic diuresis and cardiac and respiratory monitoring. In very severe cases, dialysis or exchange transfusion may be performed. Naloxone has been successfully used in one case.
Death has occurred following massive overdosage; nevertheless, a favourable outcome is usual.
Contraindications
Acute and chronic hepatitis; personal or family history of severe hepatitis, especially drug-related and hypersensitivity to sodium valproate.
Special Precautions
Liver Dysfunction: Conditions of Occurrence: Severe liver damage resulting sometimes in fatalities have been exceptionally reported. Patients most at risk especially in cases of multiple anticonvulsant therapy are infants and young children <3 years with severe seizure disorders, particularly those with brain damage, mental retardation and/or congenital metabolic or degenerative disease. After the age of 3, the incidence of occurrence is significantly reduced and progressively decreases with age.
In most cases, such liver damage occurred during the first 6 months of therapy.
Suggestive Signs: Clinical symptoms are essential for early diagnosis. In particular, the following conditions which may precede jaundice should be taken into consideration, especially in patients at risk: Nonspecific symptoms, usually of sudden onset eg, asthenia, anorexia, lethargy, drowsiness, which are sometimes associated with repeated vomiting and abdominal pain and recurrence of seizures.
Patients (or their family or children) should be instructed to report immediately any such signs to a physician should they occur. Investigations including clinical examination and biological assessment of liver function should be undertaken immediately.
Detection: Liver function should be periodically monitored during the first 6 months of therapy. Amongst usual investigations, tests which reflect protein synthesis particularly prothrombin rate, are most relevant. Confirmation of an abnormally low prothrombin rate, particularly in association with other biological abnormalities (significant decrease in fibrinogen and coagulation factors; increased bilirubin level and raised transaminases) requires cessation of Depakine therapy. As a matter of precaution and in case they are taken concomitantly, salicylates should also be discontinued since they employ the same metabolic pathway.
Liver function test should be carried out before therapy (see Contraindications) and periodically during the first 6 months especially in patients at risk.
As with most antiepileptic drugs, increased liver enzymes may be noted, particularly at the beginning of the therapy; they are transient and isolated, without clinical sign.
More extensive biological investigations (including prothrombin rate) are recommended in those patients; an adjustment of dosage may be considered when appropriate, and tests should be repeated as necessary.
Monotherapy is recommended in children <1 year when prescribing Depakine, but the potential benefit of Depakine should be weighed against the risk of liver damage in such patients prior to initiation of therapy. The concomitant use of salicylates should be avoided in those children <1 year due to the risk of liver toxicity.
Blood tests (blood cell count, including platelet count, bleeding time and coagulation tests) are recommended prior to initiation of therapy or before surgery, and in case of spontaneous bruising or bleeding (see Adverse Reactions).
In patients with renal insufficiency, it may be necessary to decrease dosage as a result of increase in free serum valproic acid levels.
Although immune disorders have been only exceptionally noted during the use of Depakine, the potential benefit of Depakine should be weighed against its potential risk in patients with systemic lupus erythematosus.
Exceptional cases of pancreatitis have been reported; therefore, patients experiencing acute abdominal pain should have their serum amylase estimated prior to surgery.
Use in Pregnancy: Risk Associated with Epilepsy and Antiepileptics: In offsprings born to mothers with epilepsy receiving any epileptic treatment, the global rate of malformations has been demonstrated to be 2-3 times higher than the rate (approximately 3%) reported in formation. Although an increased number of children with malformations has been reported in case of multiple drug therapy, the respective part of treatments and disease has not been formally established. Malformations most frequently encountered are labial clefts and cardiovascular malformations.
Sudden discontinuation in the antiepileptic therapy may be associated with a worsening of the disease in the mother and subsequent untoward effects in the foetus.
Risk Associated with Sodium Valproate: In animals: Teratogenic effects have been demonstrated in the mouse, rat and rabbit.
In humans: The global risk of malformations in women receiving valproate during the 1st trimester of pregnancy is not higher than the risk described with other antiepileptics. A few cases of multiple malformations and facial dysmorphia have been reported. The frequency of those effects has not yet been clearly established. Nevertheless sodium valproate preferably induces neutral tube defects: Myelomeningocele, spina bifida and malformations of which antenatal diagnosis is possible. The frequency of this effect is estimated to be 1-2%.
In view of the aforementioned; should a woman expect to become pregnant, review the indication for antiepileptic therapy; folate supplementation may be considered.
During pregnancy, valproate antiepileptic treatment should not be discontinued if it has been effective.
Monotherapy is to be recommended; the minimum effective daily dosage should be used, in several divided doses over the day. Nevertheless, specialized antenatal monitoring should be instituted in order to detect the possible occurrence of neutral tube effect.
Use in Lactation: Excretion of valproate in breast milk is low, with a concentration between 1-10% of maternal serum levels: Up to now, breastfed children that have been monitored during the neonatal period have not experienced clinical effects.
Use In Pregnancy & Lactation
Use in Pregnancy: Risk Associated with Epilepsy and Antiepileptics: In offsprings born to mothers with epilepsy receiving any epileptic treatment, the global rate of malformations has been demonstrated to be 2-3 times higher than the rate (approximately 3%) reported in formation. Although an increased number of children with malformations has been reported in case of multiple drug therapy, the respective part of treatments and disease has not been formally established. Malformations most frequently encountered are labial clefts and cardiovascular malformations.
Sudden discontinuation in the antiepileptic therapy may be associated with a worsening of the disease in the mother and subsequent untoward effects in the foetus.
Risk Associated with Sodium Valproate: In animals: Teratogenic effects have been demonstrated in the mouse, rat and rabbit.
In humans: The global risk of malformations in women receiving valproate during the 1st trimester of pregnancy is not higher than the risk described with other antiepileptics. A few cases of multiple malformations and facial dysmorphia have been reported. The frequency of those effects has not yet been clearly established. Nevertheless sodium valproate preferably induces neutral tube defects: Myelomeningocele, spina bifida and malformations of which antenatal diagnosis is possible. The frequency of this effect is estimated to be 1-2%.
In view of the aforementioned; should a woman expect to become pregnant, review the indication for antiepileptic therapy; folate supplementation may be considered.
During pregnancy, valproate antiepileptic treatment should not be discontinued if it has been effective.
Monotherapy is to be recommended; the minimum effective daily dosage should be used, in several divided doses over the day. Nevertheless, specialized antenatal monitoring should be instituted in order to detect the possible occurrence of neutral tube effect.
Use in Lactation: Excretion of valproate in breast milk is low, with a concentration between 1-10% of maternal serum levels: Up to now, breastfed children that have been monitored during the neonatal period have not experienced clinical effects.
Adverse Reactions
Liver dysfunction (see Precautions).
Teratogenic risk (see Precautions).
Confusion or Convulsions: Few cases of stupor have been described during sodium valproate therapy; they were isolated or associated with an increase in the occurrence of seizures whilst on therapy, and they decrease on withdrawal of treatment or reduction of dosage. These cases have most often been reported during combined therapy (in particular with phenobarbital) or after a sudden increase in valproate doses.
Digestive disorders (nausea, gastralgia) may occur in some patients at the start of treatment, but they usually disappear after a few days without discontinuing the treatment.
Transient and/or dose-related undesirable effects have been reported: Hair loss, fine postural tremor, hyperammononaemia without changes in hepatic tests. When using Depakine IV, nausea or dizziness may occur a few minutes after injection: They disappear spontaneously within a few minutes.
Isolated reduction of fibrinogen or increase in bleeding time have been reported, usually without associated clinical signs and particularly with high doses (sodium valproate has inhibitory effect on the 2nd phase of platelet aggregation).
Anaemia, leucopaenia, thrombocytopaenia or pancytopaenia have also been reported.
Pancreatitis, sometimes resulting in fatalities, have been described.
The occurrence of vasculitis has been reported.
Increase in weight may occur; amenorrhea and irregular periods have also been reported.
Hearing loss, either reversible or irreversible, has been reported; however, a cause-and-effect relationship has not been established.
Drug Interactions
Effects of Valproate on Other Drugs: Neuroleptics, MAO Inhibitors and Antidepressants: Depakine may potentiate the effect of other psychotropics eg, neuroleptics, MAOIs and antidepressants; therefore, clinical monitoring is advised and dosage should be adjusted when appropriate.
Phenobarbital: Depakine increases phenobarbital plasma concentrations (due to inhibition of hepatic catabolism) and sedation may occur particularly in children. Therefore, clinical monitoring is recommended throughout the first 15 days of combined treatment with immediate reduction of phenobarbital doses if sedation occurs and determination of phenobarbital plasma levels when appropriate.
Primidone: Depakine increases primidone plasma levels with exacerbation of its adverse effects (eg, sedation); these signs cease with long-term treatment. Clinical monitoring is recommended, especially at the beginning of combined therapy with dosage adjustment when appropriate.
Phenytoin: Depakine increases phenytoin total plasma concentration. Moreover, Depakine increases phenytoin in its free form with possible overdosage symptoms (valproic acid displaces phenytoin from its plasma protein-binding sites and reduces its hepatic catabolism). Therefore, clinical monitoring is recommended; when phenytoin plasma levels are determined, the free form should be evaluated.
Effects of Other Drugs on Valproate: Antiepileptics with enzyme-inducing effect (including phenytoin, phenobarbital and carbamazepine) decrease valproate serum concentrations. Dosage should be adjusted according to blood levels in case of combined therapy.
Mefloquine increases valproic acid metabolism and has a convulsant effect: Therefore, epileptic seizures may occur in cases of combined therapy.
In case of concomitant use of valproate and highly protein-bound agents (aspirin), valproate free serum levels may be increased.
Valproate serum levels may be increased (as a result of reduced hepatic metabolism) in case of concomitant use with cimetidine or erythromycin.
Other Interactions: Valproate usually has no enzyme-inducing effect: As a consequence, valproate does not reduce efficacy of estroprogestative agents in women receiving hormonal contraception. Close monitoring of prothrombin rate should be performed in case of concomitant use of vitamin K-dependent factor anticoagulant.
Caution For Usage
Dilutions: If it is necessary to dilute Depakine oral solution, the recommended diluent is Syrup BP, but syrup containing sulfur dioxide (SO2) as a preservative should not be used. The diluted product will have a 14-day shelf-life.
Storage
Depakine tablets are hygroscopic and must be kept in their protective bottle until taken; they should be stored in a dry place. Depakine oral solution should be kept cool and away from direct sunlight.
MIMS Class
ATC Classification
N03AG01 - valproic acid ; Belongs to the class of fatty acid derivatives antiepileptic.
Presentation/Packing
Depakine: EC tab 200 mg x 40's. Oral soln 200 mg/mL x 60 mL. Powd for inj (vial) 400 mg/4 mL x 4's.
Depakine Chrono: CR tab 500 mg x 30's.
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