Veltila-500

Sodium valproate, valproic acid.

Each tablet contains 333.0 mg sodium valproate and 145.0 mg valproic acid equivalent to 500 mg sodium valproate.

Pharmacology: Pharmacodynamics: Sodium valproate has anticonvulsant properties. The exact mode of action is unknown. However, the most likely mode of action for valproate is related to increased brain concentrations of gamma amino butyric acid (GABA) through an action on the synthesis or metabolism of GABA.
Pharmacokinetics: Valproic acid is rapidly absorbed from gastrointestinal tract, slight delay when taken with food. For delayed-release tablets the time to peak serum concentration could be 3 or 4 hours.
Valproic acid concentration in cerebrospinal fluid is close to free plasma concentration.
Valproate is highly bound to plasma proteins (90-95%). Protein binding decreased in the elderly and with hepatic or renal dysfunction.
Valproic acid is extensively metabolized in the liver. Most of the medicine is converted to the conjugate ester of glucuronic acid, while mitochondrial metabolism, principally by means of beta-oxidation. Some of the metabolites have anticonvulsant activity.
Sodium valproate is mainly excreted in urine following metabolism via glucuro-conjugation and beta-oxidation.
The elimination half-life of sodium valproate varies from approximately 6 to 16 hours. It is usually shorter in children.

In the treatment of generalized epilepsy, particularly with the following patterns of seizures: absence, clonic, tonic, myoclonic, tonic-clonic, atonic, mixed, specific syndromes (West, Lennox-Gastaut); as well as, for partial epilepsy: simple or complex seizures, secondary generalized seizures.
For the treatment and prevention of mania associated with bipolar disorders.

VELTILA-500 tablets are for oral administration.
VELTILA should preferably be taken with or after food. The tablets should be swallowed whole and not crushed or chewed.
VELTILA is a controlled release formulation, which reduces peak concentration and ensures a more even plasma concentration throughout the day. VELTILA may be given once or twice daily.
Daily dosage requirements vary according to age and body weight.
In patients where adequate control has been achieved, sodium valproate formulations are interchangeable with other conventional or controlled release formulations on an equivalent daily dosage basis.
For epilepsy: Initial daily dosage is usually 10 to 15 mg/kg. The dosage should be increased by successive dose level at 2-3 day intervals to reach the optimum dosage in about one week.
Adults: This is generally within the range of 1000 to 2000 mg/day (i.e. 20 - 30 mg/kg body mass). If adequate control has not been achieved after two weeks, the dose may be further increased to 2500 mg/day, or one other anti-epileptic agent may be added at a low dosage.
Children: This is usually within the range of 20 to 30 mg/kg of body mass per day. Where adequate control is not achieved within this range, the dose may be increased to 35 mg/kg body mass per day.
VELTILA for the treatment and prevention of mania associated with bipolar disorders: The recommended initial dose is 1000 mg/day. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose, the dose may be increased to not more than 3000 mg daily which produces the desired clinical effect.
Doses should be adjusted according to individual clinical response.
Prophylactic treatment should be established individually with the lowest effective dose.
Use in the elderly: Although the pharmacokinetics of VELTILA is modified in the elderly, this is of limited clinical significance and dosage should be determined by seizure control. The volume of distribution is increased in the elderly, and because of decreased binding to serum albumin, the proportion of free drug is increased. This will affect the clinical interpretation of plasma valproic acid levels.
In patients with renal insufficiency: It may be necessary to decrease dosage. Dosage should be adjusted according to clinical monitoring since monitoring of plasma concentrations may be misleading (see "Pharmacology: Pharmacokinetics under Actions").
Combined therapy: When starting VELTILA in patients already on other anticonvulsants, substitution with VELTILA should then be gradual, with target dose being reached after about 2 weeks. And other anticonvulsants should be tapered slowly then stopped. In certain cases it may be necessary to raise the dose by 5 to 10 mg/kg/day when used in combination with anticonvulsants, which induce liver enzyme activity, e.g. phenytoin, phenobarbitone and carbamazepine. Once known enzyme inducers have been withdrawn, or if side-effects, such as tremor, are experienced, it may be possible to maintain seizure control on a reduced dose of VELTILA. When barbiturates are being administered concomitantly and particularly if sedation is observed (particularly in children) the dosage of barbiturate should be reduced.
General considerations: The concentration of valproate in plasma that appears to be associated with therapeutic effects is approximately 30-100 mcg/ml. Optimum dosage is mainly determined by seizure control and routine measurement of plasma levels is unnecessary. However, a method for measurement of plasma levels is available and may be helpful where there is poor control or side-effects are suspected (see "Pharmacology: Pharmacokinetics under Actions").

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT: Clinical signs of acute massive overdose usually include a coma, with muscular hypotonia, hyporeflexia, miosis and impaired respiratory functions. Deaths have occurred following massive overdose; nevertheless, a favourable outcome is usual.
Symptoms may however be variable and seizures have been reported in the presence of very high plasma levels. Cases of intracranial hypertension related to cerebral oedema have been reported. Hospital management of overdose should be symptomatic: gastric lavage (which is useful up to 10 to 12 hours following ingestion), cardio-respiratory monitoring, assisted ventilation and other supportive measures are recommended. Haemodialysis and haemoperfusion have been used successfully. Naloxone has been successfully used in a few isolated cases.

Hypersensitivity to sodium valproate.
Use of VELTILA in pregnancy should be avoided (see "Use in Pregnancy & Lactation").
Active liver disease, including the following: Acute hepatitis, Chronic hepatitis, Personal or family history of hepatic dysfunction especially drug related, Hepatic porphyria.

Liver dysfunction: Conditions of occurrence: Cases of severe liver damage resulting sometimes in fatalities have been reported.
Experience in epilepsy has indicated that patients most at risk especially in cases of multiple anticonvulsant therapy are infants and young children under the age of 3 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 reduced and 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 (see "Conditions of occurrence" as previously mentioned): non-specific symptoms, usually of sudden onset, such as asthenia, anorexia, lethargy, drowsiness, which are sometimes associated with repeated vomiting and abdominal pain; in patients with epilepsy, recurrence of seizures.
Patients (or their family for 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 performed before and then 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 VELTILA 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.
Pancreatitis: Severe pancreatitis, which may result in fatalities, has been rarely reported. Young children are at particular risk. This risk decreased with increasing age. Severe seizures, neurological impairment or anticonvulsant therapy may be risk factors. Hepatic failure with pancreatitis increases the risk of fatal outcome.

Liver function tests should be carried out before therapy (see "Contraindications"), and periodically during the first 6 months especially in patients at risk (see "Warnings").
As with most anti-epileptic drugs, mild increased liver enzymes may be noted, particularly at the beginning of 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.
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 "Side Effects").
In patients with renal insufficiency, it may be necessary to decrease dosage. As monitoring of plasma concentrations may be misleading, dosage should be adjusted according to clinical monitoring (see "Pharmacology: Pharmacokinetics under Actions").
Although immune disorders have been only exceptionally noted during the use of VELTILA, the potential benefit of VELTILA 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 a prompt medical evaluation. In case of pancreatitis, valproate should be interrupted.
When a urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed prior to treatment because of the risk of hyperammonemia with valproate.
Patients should be warned of the risk of weight gain at the initiation of therapy; and appropriate strategies should be adopted to minimise it (see "Side Effects").
Diabetic patients: VELTILA is eliminated mainly through the kidneys, partly in the form of ketone bodies, and this may give false positive readings in the urine testing of possible diabetics.
Effect on ability to drive and use machines: Patient should be warned of the risk of somnolence especially in cases of anticonvulsant polytherapy or association with benzodiazepines (see "Interactions").
Use in Children: Monotherapy is recommended in children under the age of 3 years when prescribing VELTILA, but the potential benefit of VELTILA should be weighed against the risk of liver damage or pancreatitis in such patients prior to initiation of therapy (see "Warnings").
The concomitant use of salicylates should be avoided in those children under 3 due to the risk of liver toxicity.

Pregnancy: From experience in treated epileptic mothers, the risk associated with the use of VELTILA during pregnancy has been described as follows: Risk associated with epilepsy and anti-epileptics: In offspring born to mothers with epilepsy receiving any anti-epileptic treatment, the global rate of malformations has been demonstrated to be 2 to 3 times higher than the rate (approximately 3%) reported in the general population. Although an increased number of children with malformations have 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.
Developmental delay has been very rarely reported in children born to mothers with epilepsy. It is not possible to differentiate what may be due to genetic, social, environmental factors, maternal epilepsy or anti-epileptic treatment.
Not withstanding those potential risks, no sudden discontinuation in the anti-epileptic therapy should be undertaken as this may lead to breakthrough seizures, which could have serious consequences for both the mother and the foetus.
Risk associated with sodium valproate: In animals: teratogenic effects have been demonstrated in the mouse, rat and rabbit.
In humans: cases of facial dysmorphia have been reported. A few cases of multiple malformations, particularly of the limbs have been observed. The frequency of those effects has not been yet clearly established. Nevertheless sodium valproate preferably induces neural tube defects (1 to 2%): anencephaly, myelomeningocele and spina bifida.
In view of the previously mentioned data: If a woman plans a pregnancy, it is the opportunity of reviewing the indication for VELTILA therapy. During pregnancy, VELTILA treatment should be reviewed and the risks and benefits should be carefully considered and discussed with the patient. If considered appropriate, folate supplementation should be started before pregnancy and at relevant dosage as it may minimise the risk of neural tube defects. Monotherapy at the minimum effective daily dosage. The administration in several divided doses over the day and the use of a controlled release formulation is preferable.
Specialised prenatal monitoring should be instituted in order to detect the possible occurrence of neural tube defect or another malformation.
Risk in the neonate: Cases of haemorrhagic syndrome have been reported in neonates whose mothers have taken sodium valproate during pregnancy. This haemorrhagic syndrome is related to hypofibrinogenemia; afibrinogenemia has also been reported and may be fatal. Hypofibrinogenemia is possibly associated with decrease of coagulation factors.
Therefore, platelet count, fibrinogen plasma level, coagulation tests and coagulation factors should be investigated in neonates.
Lactation: VELTILA crosses the placenta. When given to breast-feeding mothers, VELTILA is excreted in breast milk. Excretion of valproate in breast milk results in a concentration between 1% and 10% of maternal serum levels.
In bipolar disorders indication, cessation of valproate therapy should be considered.

Where applicable, the following frequency rating has been used: Very common (> 1/10); common (> 1/100 to 1/10); uncommon (> 1/1000 to 1/100); rare (> 1/10000 to 1/1000); very rare (1/10000), including "isolated reports".
Congenital and familial/genetic disorders: (See "Use in Pregnancy & Lactation").
Hepato-biliary disorders: Rare cases of liver dysfunction (see "Warnings").
Gastrointestinal disorders: Nausea, gastralgia, diarrhoea frequently occurs in some patients at the start of treatment, but they usually disappear after a few days without discontinuing the treatment.
Cases of pancreatitis: Very rare, sometimes lethal, have been reported (see "Warnings").
Nervous system disorders: Confusion; a few cases of stupor or lethargy sometimes leading to transient coma (encephalopathy) have been described during sodium valproate therapy; they were isolated or associated with an increase in the occurrence of convulsions whilst on therapy, and they decreased 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. Very rare cases of reversible dementia associated with reversible cerebral atrophy have been reported. Isolated reversible Parkinsonism has been reported. Transient and (or) dose related fine postural tremor and somnolence have often been reported.
Metabolic disorders: Cases of isolated and moderate hyperammonemia without change in liver function tests may frequently occur and should not cause treatment discontinuation. Hyperammonemia associated with neurological symptoms have also been reported. In such cases further investigations should be considered (see "Precautions").
Blood and lymphatic system disorders: Frequent occurrences of thrombocytopenia, rare cases of anaemia, leucopenia or pancytopenia have been reported.
Isolated reduction of fibrinogen or increase in bleeding time has been reported, usually without associated clinical signs and particularly with high doses (sodium valproate has an inhibitory effect on the second phase of platelet aggregation) (see also "Pregnancy under Use in Pregnancy & Lactation").
Skin and subcutaneous tissue disorders: The following side-effects have been reported and the frequencies are unknown: Cutaneous reactions may occur with valproate such as exanthematous rash. In exceptional cases, toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme have been reported.
Transient and (or) dose related hair loss has often been reported. Regrowth normally begins within six months, although the hair may become curlier than previously.
Reproductive system disorders: The following side-effects have been reported and the frequencies are unknown: Amenorrhoea and irregular periods have been reported.
Vascular disorders: The following side-effects have been reported and the frequencies are unknown: The occurrence of vasculitis has been reported.
Ear disorders: Hearing loss, either reversible or irreversible, has been reported rarely; however a cause and effect relationship has not been established.
Renal and urinary disorders: There have been isolated reports of a reversible Fanconi's syndrome (a defect in proximal renal tubular function) associated with valproate therapy but the mode of action is as yet unclear.
Immune system disorders: The following side-effects have been reported and the frequencies are unknown: Allergic reactions have been reported.
General disorders: Very rare cases of non-severe peripheral oedema have been reported. The following side-effects have been reported and the frequencies are unknown: Increase in weight may also occur. Weight gain being a risk factor for polycystic ovary syndrome, it should be carefully monitored (see "Precautions").

Effects of VELTILA on other medicines: Neuroleptics, MAO inhibitors, antidepressants and benzodiazepines: VELTILA may potentiate the effect of other psychotropics such as neuroleptics, MAO inhibitors, antidepressants and benzodiazepines; therefore clinical monitoring is advised and dosage should be adjusted when appropriate.
Phenobarbital: VELTILA 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: VELTILA increases primidone plasma levels with exacerbation of its adverse effects (such as 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: VELTILA decreases phenytoin total plasma concentration. Moreover VELTILA increases phenytoin 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.
Carbamazepine: Clinical toxicity has been reported when VELTILA was administered with carbamazepine as valproate may potentiate toxic effect of carbamazepine. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.
Lamotrigine: VELTILA may reduce lamotrigine metabolism and increase its mean half-life; dosages should be adjusted (lamotrigine dosage decreased) when appropriate. There are suggestions, yet to be proven, that the risk of rash may be increased by co-administration of lamotrigine with VELTILA.
Zidovudine: VELTILA may raise zidovudine plasma concentration leading to increase zidovudine toxicity.
Effects of other medicines on VELTILA: Antidepressants and neuroleptics may antagonize the anti-epileptic activity of VELTILA by lowering the seizure threshold. This may require VELTILA dosage adjustments.
Anti-epileptics with enzyme inducing effect (including phenytoin, phenobarbital, carbamazepine) decrease valproate serum concentrations. Dosages should be adjusted according to blood levels incase of combined therapy.
On the other hand, combination of Felbamate and VELTILA may increase valproate serum concentration. Valproate dosage should be monitored.
Mefloquine increases valproic acid metabolism and has a convulsing effect; therefore epileptic seizures may occur in cases of combined therapy. Chloroquine may also lower the seizure threshold.
In case of concomitant use of VELTILA and highly protein bound agents (Aspirin), valproate free serum levels may be increased.
Close monitoring of INR should be performed in case of concomitant use of vitamin K dependent factor anticoagulants (e.g. warfarin and other coumarin anticoagulants) because the anticoagulant effect of these agents may be increased due to displacement from plasma protein binding sites by VELTILA. Valproate serum levels may be increased (as a result of reduced hepatic metabolism) in case of concomitant use with Cimetidine or Erythromycin.
Carbapenem antibiotics (panipenem/meropenem): Decrease in valproate blood level sometimes associated with convulsions has been observed when panipenem or meropenem were combined. If these antibiotics have to be administered, close monitoring of valproate blood level is recommended.
Other interactions: VELTILA usually has no enzyme inducing effect; as a consequence, VELTILA does not reduce efficacy of oestrogen and/or progestogen containing medicines in women receiving hormonal contraception.

The tablets, being hygroscopic, must be kept in their protective pack until taken. Pack should not be cut. Store below 30°C in a dry place. Protect from light.

Anticonvulsants / Antipsychotics

N03AG01 - valproic acid ; Belongs to the class of fatty acid derivatives antiepileptic.

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