Central Nervous System-Anticonvulsants
= Additional active ingredients
PRESENTATION AND DOSSAGE
E.C. TABS: 40 X 200 mg.
E.C. TABS: 40 X 500 mg.
SYRUP: 110 ml X 200 mg/5 ml.
S.R. TABS: 30 X 500 mg
ORAL SOL 50 ML
SYR SF 110 ML
All forms of epilepsy (grand, petit, mixed or partial), porphyria.
History of hypersensitivity to valproate , divalproate, valpromide or to one of the ingredients of the medicinal product.
Personal or familial history of severe hepatitis, in particular drug related.
Combination use with mefloquine and.
Liver function tests should be performed before starting treatment and then periodically for the first 6 months, particularly in patients at risk. It should be emphasized that, as with most antiepileptics, an isolated and transient, moderate elevation in transaminase levels may be observed, without any clinical signs, particularly at the start of treatment. Should this occur, it is recommended that a more complete laboratory workup be performed (in particular, prothrombin rate), that the dosage be re-evaluated if necessary, and that the tests be repeated based on changes in the parameters. In children under the age of 3, it is recommended that sodium valproate only be used as singleagent treatment, after having weighed the therapeutic value against the risk of liver disease and pancreatitis in patients belonging to this age group. Blood tests (complete blood count including platelets, bleeding time and coagulation parameters) are recommended prior to treatment and also before any surgery, and in the event of hematomas or spontaneous bleeding. In children, avoid the simultaneous prescription of salicylate derivatives, due to the risk of hepatotoxicity and the risk of bleeding. In patients with renal insufficiency, elevated circulating valproic acid concentrations in the blood should be taken into account and the dosage should be reduced accordingly. In the event of acute abdominal pain or gastrointestinal signs such as nausea, vomiting and/or anorexia, a diagnosis of pancreatitis must be considered and, in patients with elevated pancreatic enzymes, treatment should be discontinued, and the necessary alternative therapeutic measures implemented. This medicinal product is not recommended in patients with urea cycle enzyme deficiencies. A few cases of hyperammonemia associated with stupor or coma have been described in these patients. In children with a history of unexplained hepatic and gastrointestinal disturbances (anorexia, vomiting, cytolytic episodes), episodes of lethargy or coma, mental retardation or with a family history of neonatal or infant death, metabolic tests and, in particular, fasting and post prandial ammonemia tests must be performed prior to any valproate treatment. Although it is recognized that this medicinal product only causes immunological disturbances in exceptional cases, the benefit/risk ratio should be carefully weighed for use in patients with systemic lupus erythematosus. When initiating treatment, the patient should be informed of the risk of weight gain and of the appropriate measures which are mainly dietary to be taken to minimize this effect. When initiating treatment, it should be established that women of childbearing age are not pregnant, and that effective contraception is being used before starting treatment. Alcohol intake is not recommended during treatment with Sodium Valporate. In renal insufficiency, it may be necessary to decrease the dosage. As monitoring of plasma concentrations may be misleading, dosage should be adjusted according to clinical monitoring. Long term use of Depalept is associated with a decrease in bone density that may lead to Osteoperosis, Osteopenia and an increased risk of breaks. Pregnancy and lactation, in patients with pre-existent nonketotic hyperglycinema, driving a car or operating machinery.
Blood and lymphatic system disorders: Common: (≥1 and <10%): anemia, thrombocytopenia.
Investigations: Common: (≥1 and <10%): weight increased (it should be carefully monitored since it is factor for polycystic ovary
Nervous system disorders: Very common (≥1) : tremor. Common: (≥1 and <10%): extrapyramidal disorder, stupor*, somnolence, convulsion*, memory impairment, headache, nystagmus,
Ear and labyrinth disorders: Common: (≥1 and <10%): deafness, Respiratory, thoracic and mediastinal disorders.
Gastrointestinal disorders: Very common: (≥1) Nausea*. Common: (≥1 and <10%): vomiting, abdominal pain upper, diarrhea frequently occur in some patients at the startof treatment, but they usually disappear after a few days without discontinuing the treatment.
Skin and subcutaneous tissue disorders: Common: (≥1 and <10%): hypersensitivity, transient and/or dose related alopecia.
Metabolism and nutrition disorders: Common: (≥1 and <10%): hyponatraemia.
Vascular disorders: Common: (≥1 and <10%): haemorrhage.
Hepatobiliary disorders: Common: (≥1 and <10%): liver injury.
Reproductive system and breast disorders: Common: (≥1 and <10%): dysmenorrhea.
Psychiatric disorders: Common: (≥1 and <10%): confusional state, aggression, agitation, disturbance in attention.
Musculoskeletal and connective tissue disorders: Sodium valproate is associated with decreased bone mineral density that may lead to osteopenia, osteoporosis, and increased fractures in at-risk patients.
Congenital, familial and genetic disorder: Teratogenic risk.
The concomitant use of seizure-inducing drugs, or drugs lowering the seizure threshold, is to be taken into account, or even be advised against or contraindicated depending on the seriousness of the potential risk. Such medicinal products include, in particular, most antidepressants (imipramines, selective serotonin reuptake inhibitors), neuroleptics (phenothiazines and butyrophenones), mefloquine, bupropion, tramadol. As the syrup contains sucrose and sorbitol, it must not be taken if you have fructose intolerance, glucose and
galactose malabsorption syndrome or sucrase-isomaltase deficiency. Contraindicated combinations.
Mefloquine: In epileptic patients, risk of onset of epileptic seizures due to the increased metabolism of valproic acid and the seizure-inducing effect of mefloquine.
St.-John`s-Wort: Combination use with St.-John`s-wort is contraindicated due to the risk of reduced plasma concentrations and efficacy of the anticonvulsant.
Combinations requiring special precautions for use:
Aztreonam, Imipenem, Meropenem, Carbapenem, Panipenem: Risk of onset of convulsive episodes due to reduced valproic acid plasma concentrations. Clinical monitoring, plasma assays and possibly dose adjustment of the anticonvulsant during treatment with the anti-infective agent and after its discontinuation.
Carbamazepine: Clinical monitoring, plasma assays and adjustment of the dosage of two antiepileptics. Increased plasma concentrations of the active metabolite of carbamazepine with signs of overdose. In addition, reduced valproic acid plasma concentrations due to increased hepatic metabolism by carbamazepine. Clinical monitoring, plasma assays and dose adjustment of both anticonvulsants.
Felbamate: Increased valproic acid serum concentrations, with a risk of overdose, by decrease s valporic acid clearance by 22% to 50%, and decrease the felbamate mean clearance by up to 16%. Clinical and laboratory monitoring and possible valproate dose adjustment during treatment with felbamate and after its discontinuation.
Phenobarbital, primidone: Increased plasma concentrations of phenobarbital or primidone with signs of overdose, due to inhibition of hepatic metabolism, occurring most often in children. In addition, reduced valproic acid plasma concentrations due to an increase in its hepatic metabolism by phenobarbital or primidone. Clinical monitoring for the first 15 days of combined administration and immediate reduction of phenobarbital or primidone doses if any signs of sedation occur; in particular, plasma concentrations of the two anticonvulsants should be monitored.
Phenytoin (and by extrapolation fosphenytoin): Valporic acid decreases phenytoin total plasma concentration. Moreover, Valporic acid increases the phenytoin free form with possible overdose symptoms (Valporic acid displace phenytoin from its plasma protein binding sites and reduces its hepatic catabolism). Clinical monitoring, plasma assays and possible dose adjustment of both anticonvulsants.
Topiramate: Risk of onset of hyperammonaemia and/or encephalopathy, generally attributed to valproate when administered concomitantly with topiramate. Increased clinical and laboratory monitoring at the beginning of treatment and in the event of symptoms suggesting this effect.
Rifampicin:Rifampicin may decrease the valproate blood levels resulting in a lack of therapeutic effect, due to increased hepatic metabolism of valproate by rifampicin. Therefore, valproate dosage adjustment may be necessary when it is co-administered with rifampicin.
Zidovudine: Risk of increased adverse effects of Zidovudine, particularly hematological effects, due to decreased metabolism by valporic acid. Regular clinical and laboratory monitoring. A blood count should be performed to test for anemia during the first two months of the combination.
Cimetidine, Erythromycin: Valproate serum levels may be increased in case of concomitant use, as a result of reduced hepatic metabolism.
Vitamin K dependent factor anticoagulant: Close monitoring of prothrombin rate should be performed in case of concomitant use of vitamin K dependent factor anticoagulant.
Aspirin: In case of concomitant use of valproate and highly protein bound agents, valporic acid free serum levels may be increased.
Combination to be taken into account:
Nimodipine (oral route and by extrapolation, injectable route) Risk of enhanced hypotensive effect of nimodipine due to an increase in its plasma concentrations (decreased metabolism by valproic acid).
Other forms of interaction
Oral contraceptives: As valproate has no enzyme-inducing activity, it does not reduce the efficacy of estrogenprogestogen in women using hormonal contraception.
Average daily dosage
Infants and children: 30 mg per kg (the syrup or oral solution forms should preferably be used) in divided doses.
Adolscents and adults: 20 to 30 mg per kg (the tablet or chrono tablet forms should preferably be used) in divided doses.
Initiation of treatment :
If the patient is already being treated and is taking other antiepileptics, begin administering sodium valproate gradually, to reach the optimal dose in approximately two weeks, then reduce the concomitant treatments if necessary on the basis of treatment efficacy.
If the patient is not taking any other antiepileptics, the dosage should preferably be increased stepwise every 2 or 3 days, in order to reach the optimal dose in approximately one week.
If necessary, combination treatment with other antiepileptics should be instituted gradually. The optimum dose 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; patients should be carefully monitored when receiving daily doses higher than 50 mg/kg.
The clinical picture for massive acute poisoning usually includes a calm coma, which may be more or less deep, with muscle hypotonia, hyporeflexia, myosis, reduced respiratory autonomy and metabolic acidosis. Symptoms may however be variable and seizures have been reported in the presence of very high plasma levels. A few cases of intracranial hypertension related to cerebral oedema have been described. Measures to be undertaken in a hospital setting are: gastric evacuation may be useful up to 10 to 12 hours following ingestion, maintenance of effective diuresis, and monitoring of cardio-respiratory function. Dialysis will be carried out in very severe cases, if need be. Naloxone has been successfully used in a few isolated cases. In case of massive overdose, hemodialysis and hemoperfusion have been used successfully. The prognosis of such poisoning is generally favorable, However a few deaths have been reported.
PREGNANCY & LACTATION
Pregnancy: Risk associated with seizures: During pregnancy, maternal tonic clonic seizures and status epilepticus with hypoxia carry a particular risk of death for mother and for the unborn child.
Risk associated with sodium valproate:
In animals: teratogenic effects have been demonstrated in the mice, rats and rabbits.
In humans: Available data suggest an increased incidence of minor or major malformations including, in particular, neural tube defects, craniofacial defects, malformation of the limbs, cardiovascular malformations ,hyposapadias and multiple anomalies involving various body systems in offspring born to mothers treated with valproate, when compared to the incidence for certain other antiepileptic drugs.
Data from a meta-analysis has shown an incidence of congenital malformations in children born to epileptic women exposed to valproate monotherapy during pregnancy at 10.73%. Available data indicate dosedependency of this effect. Data suggest that antiepileptic polytherapy including valproate induces a higher teratogenic risk than monotherapy with valproate only. Data suggest an association between in-utero valporate exposure and a risk of developmental delay, particularly of verbal IQ and lower cognitive test scores, in children born to mothers suffering from epilepsy and treated with valproate. Developmental delay is frequently associated with malformations and/or dysmorphic features. However, it is difficult to establish causal relationship in view of possible confounding factors such as low maternal or paternal IQ, genetic, social and environmental factors, and poor maternal seizure control during pregnancy. Autism spectrum disorders have also been reported in children exposed to valproate in utero. Both valproate monotherapy and valproate polytherapy are associated with abnormal pregnancy outcome. Available data suggest that antiepileptic polytherapy including valproate is associated with higher risk of abnormal pregnancy outcome that valproate monotherapy.
In view of the above data: Women of childbearing potential should be informed of the risks and benefits of the use of valproate during pregnancy. Specialist advice is required and physicians are strongly encouraged to discuss reproductive issues with their patients, before sodium valproate is prescribed for the first time or a woman already treated with sodium valporate is planning a pregnancy. If a woman plans a pregnancy, valporate therapy should be reassessed whatever the indication. In bipolar disorders indication, cessation of valporate prophylaxis should be considered. If, in any indication, further to a careful evaluation of the risks and benefits, valporate treatment is continued during the pregnancy, it is recommended to use valporate in divided doses over the day at the lowest effective dose. The use of a prolonged release formulation may be preferable to any other treatment form. In addition, if appropriate, folate supplementation should be started before pregnancy and at relevant dosage (5 mg daily) as it may minimize the risk of neural tube defects. During pregnancy, valproate therapy should not be discontinued without reassessment of the benefit/risk. Specialized prenatal monitoring should be instituted in order to detect the possible occurrence of neural tube defects or other malformations.
Risk in the neonate: Exceptional cases of hemorrhagic syndrome have been reported in neonates whose mothers have taken sodium valproate during pregnancy. This hemorrhagic syndrome is related to thrombocytopenia, hypofibrinogenemia and/or to decrease in other coagulation factors; afibrinogenemia has also been reported and may be fatal.. However, this syndrome must be distinguished from the decrease of the vitamin-K factors induced by phenobarbital and enzymatic inducers. Therefore, platelet count, fibrinogen plasma level, coagulation tests and coagulation factors should be investigated in neonates. Therefore, platelet count, fibrinogen plasma level, coagulation tests and coagulation factors should be investigated in neonates. Cases of hypoglycaemia have been reported in neonates whose mothers have taken valproate during the third trimester of the pregnancy. Cases of hypothyroidism have been reported in neonates whose mothers have taken valproate during pregnancy.
Lactation: Sodium valproate excretion in breast milk is low (between 1%-10% of maternal serum levels). Based on literature and clinical experience, breastfeeding can be envisaged, taking into account the valproate safety profile, especially hematological disorders. However, given the questions raised by data relating to decreased verbal ability in infants exposed to the drug in utero, patients should preferably be advised not to breast-feed.
MANUFACTURER & DISTRIBUTER:
Manufacturer: Sanofi Synthelabo
License Holder: CTS Chemical Ind. Ltd.