Presentation and Status in Health Basket
30 X 500 mg
In female children, female adolescents, women of childbearing potential and pregnant women: Depalept chrono should be initiated and supervised by a specialist experienced in the management of epilepsy or bipolar disorder. Treatment should only be initiated if other treatments are ineffective or not
tolerated and the benefit and risk should be carefully reconsidered at regular treatment reviews. Preferably Depalept chrono should be prescribed as monotherapy and at the lowest effective dose, if possible as a prolonged release formulation. The daily dose should be divided into at least two single doses.
Depalept Chrono is a prolonged-release formulation of Depalept which reduces peak plasma concentrations and ensures more regular plasma levels over a 24-hour period.
In view of the dosage strength this medicinal product is for use in adults and children weighing over than 17 kg only.
This dosage form is not appropriate for children under the age of 6 years (risk of choking).
Dosage: The Initial daily dosage is usually 10-15 mg/kg, after which doses are increased up to the optimum dose (see Initiation of treatment).
The mean dosage is 20 -30 mg/kg per day. However, if seizures are not brought under control at this dosage it may be increased and patients must be closely monitored.
− In children, the usual dosage is about 30 mg/kg per day.
− In adults, the usual dosage is 20 to 30 mg/kg per day.
− In elderly patients, the dosage should be determined based on the control of seizures.
The daily dosage should determined based on age and body weight, however, the significant variations in inter-individual sensitivity to valproate must be taken into account.
No clear correlation between the daily dose, serum levels and the therapeutic effect has been established: the dosage should be determined on the basis of the clinical response.
Determination of valproic acid plasma levels should be considered along with clinical monitoring when control of seizures is not achieved or when adverse effects are suspected. The effective therapeutic range is usually between 40 and 100 mg/L (300 to 700 μmol/L).
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.
Method of administration: Oral use. The daily dose should be administered in 1 dose or 2 divided doses, preferably during meals.
Administration of a single daily dose is possible in well controlled epilepsy.
In view of the sustained release process and the nature of the excipients in the formula, the inert matrix is not absorbed by the digestive tract; it is eliminated in the stools after the active substances have been released.
Initiation of Depalept therapy (oral administration):
• In patients in whom appropriate control has been obtained with immediate-release forms of Depalept, it is recommended that the daily dose be maintained when replacing treatment with Depalept Chrono.
• If the patient is already being treated and is taking other antiepileptics, begin administering Depalept Chrono 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 step-wise 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.
• Liver function tests should be performed before starting treatment and then periodically for the first 6 months, particularly in patients at risk.
• Blood tests (complete blood count including platelets, bleeding time and coagulation parameters) are recommended prior to treatment, then after 15 days and at the end of treatment, and also before any surgery, and in the event of hematomas or spontaneous bleeding.
Treatment and prevention of manic episodes in the context of bipolar disorders: The recommended initial dose is 1000mg/day. The dose should be increased as fast as possible to the lowest dose that brings about the desired clinical effect. The recommended maintenance dose for the treatment of bipolar disorders is between 1000mg and 2000mg daily. In exceptional cases the dose may be increased to a maximum of 3000mg daily. Dosage should be adjusted individually on the basis of clinical response.
Preventive treatment of mania should be adjusted for the individual patient using the lowest effective dose.
Epilepsy: Treatment of generalized or partial epilepsy secondary epilepsy and mixed forms of epilepsy.
Bipolar disorders: Treatment and/or prevention of acute manic episodes in the context of bipolar disorders.
History of hypersensitivity to valproate, divalproate, valpromide or to one of the ingredients of the medicinal product.
Hepatic porphyria .
Personal or familial history of severe hepatitis, in particular drug-related.
Combination use with mefloquine and St.-John`s-wort.
Patients known to have mitochondrial disorders caused by mutations in the nuclear gene encoding mitochondrial enzyme polymerase γ (POLG, e.g. Alpers-Huttenlocher Syndrome) and in children under two years of age who are suspected of having a POLG-related disorder.
Patients with known urea cycle disorders.
Female children/Female adolescents/Woman of childbearing potential/Pregnancy: Depalept chrono should not be used in female children, in female adolescents, in women of child-bearing potential and in pregnant women unless alternative treatments are ineffective or not tolerated, because of its high teratogenic potential and risk of neuro-developmental disorders in infants exposed in- utero to valproate.
The introduction of an antiepileptic may, in rare cases, be followed by an increase in seizures or the onset of a new type of seizure in the patient, independently of the spontaneous fluctuations observed in some types of epilepsy. In the case of valproate, this mainly involves a change in concomitant antiepileptic treatment or a pharmacokinetic interaction, toxicity (liver disease or encephalopathy) or overdose.
Since this medicinal product is transformed into valproic acid in the body, it should not be combined with other medicinal products undergoing the same type of transformation in order to prevent any overdose of valproic acid (for example: divalproate, valpromide).
Conditions of onset: Exceptional cases of liver damage with a severe or sometimes fatal outcome have been reported.
Infants and young children under the age of 3, especially in cases of multiple anticonvulsant therapy, presenting with severe epilepsy and, in particular, epilepsy associated with brain damage, mental retardation and/or a genetic metabolic or degenerative disease are the most at risk. Over the age of 3, the incidence of onset is significantly reduced and gradually decreases with age.
In the great majority of cases, such liver damage has been observed within the first 6 months of treatment, usually between the 2nd and 12th week and generally during multiple-agent antiepileptic treatment. See prescribing information for full details.
Bleeding and other hematopoietic disorders: Valproate is associated with dose-related thrombocytopenia. Valproate use has also been associated with
decreases in other cell lines and myelodysplasia. Because of reports of cytopenias, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen, coagulation factor deficiencies, acquired von Willebrand’s disease), measurements of complete blood counts count including platelets, bleeding time and and coagulation tests are recommended before initiating therapy and at periodic intervals and also before any surgery, and in the event of hematomas or spontaneous bleeding.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reaction: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported in patients taking valproate. DRESS may be fatal or life-threatening.
DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present.
Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Valproate should be discontinued and not be resumed if an alternative etiology for the signs or symptoms cannot be established.
Pancreatitis: Pancreatitis with a sometimes fatal outcome has been reported in exceptional cases. This can be observed irrespective of age and treatment duration, with young children appearing to be particularly at risk.
Pancreatitis with an unfavorable outcome is generally observed in young children or in patients with severe epilepsy, brain damage or those taking multiple-agent antiepileptic treatments.
If pancreatitis is associated with hepatic insufficiency, the risk of a fatal outcome is increased.
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.
Risk of suicide: Suicidal ideation and behavior have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomized, placebo controlled trials of anti-epileptic drugs has also shown a
small increased risk of suicidal ideation and behavior. The causes of this risk are unknown and the available data do not make it possible to rule out an increased risk with valproate.
Consequently, patients must be closely monitored for any signs of suicidal ideation and behavior, and appropriate treatment should be considered. Patients (and their care providers) should be advised to seek medical advice if there are signs of suicidal ideation or behavior emerge.
Patients with known or suspected mitochondrial disease: Valproate may trigger or worsen clinical signs of underlying mitochondrial diseases caused by
mutations of mitochondrial DNA as well as the nuclear- encoded POLG gene. In particular, acute liver failure and liver-related deaths have been associated with valproate treatment at a higher rate in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial enzyme polymerase γ (POLG; e.g. Alpers-Huttenlocher Syndrome). POLG-related
disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to un-explained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be
performed in accordance with current clinical practice for the diagnostic evaluation of such disorders.
It should be emphasized that, as with most anti-epileptics, 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 time), 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 single-agent treatment, after having weighed the therapeutic value against the risk of liver disease and pancreatitis in patients in this age group.
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 blood ammonia 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.
As valproate is excreted primarily in the urine, partly in the forms of ketone bodies, ketone body excretion test for ketonuria may yield false positive results in patients with diabetes.
Patients with an underlying carnitine palmitoyltransferase (CPT) type II deficiency should be warned of the greater risk of rhabdomyolysis when taking valproate.
Use of alcohol is not recommended during treatment with Sodium Valporate.
See prescribing information for full details.
Very common: Tremor, nausea.
Common: Anemia, thrombocytopenia, weight gain*, extrapyramidal disorder, stupor*, sedation, seizures*, memory disorders, headache, nystagmus, dizziness, deafness, vomiting, gingival disorder (mainly gingival hyperplasia), stomatitis, abdominal pain upper, diarrhea frequently occur at the start of treatment, but they usually disappear after a few days without discontinuing treatment, hypersensitivity, transient and/or dose related alopecia, nail and nail bed disorders, hyponatraemia, bleeding, liver disease, menstrual irregularities,
confused state, hallucinations, aggression*, agitation*, attention deficit disorders.
* These ADRs effects are mainly observed in children.
See prescribing information for full details.
The concomitant use of proconvulsant medicines or those that lower the epileptogenic threshold should be taken into account or may even be advised against or contraindicated depending on the severity of the risk encountered. These medicines notably include most antidepressants (imipramine antidepressants, selective serotonin reuptake inhibitors) and Benzodiazepines, neuroleptics (phenothiazine and butyrophenones), mefloquine, Bupropion, tramadol.
Contraindicated combination: Mefloquine, St John’s Wort.
Inadvisable combination: Salicylic derivatives, Lamotrigine, Penems.
Combinations requiring special precautions for use: Aztreonam,
Carbamazepine, Felbamate, Phenobarbital (and by extrapolation, primidone), Phenytoin (and by extrapolation fosphenytoin),
Rifampicin, Topiramate or acetazolamide, Zidovudine, Olanzapine, Rufinamide, Cimetidine, Erythromycin, Vitamin K dependent factor anticoagulant, Aspirin.
Combination to be taken into account: Nimodipine (oral route and, by extrapolation, injectable route).
See prescribing information for full details.
Pregnancy and Lactation
Pregnancy: Depalept Chrono should not be used in female children, in female adolescents, in women of childbearing potential and in pregnant women unless other treatments are ineffective or not tolerated. Women of childbearing potential have to use effective contraception during treatment.
In women planning to become pregnant all efforts should be made to switch to appropriate alternative treatment prior to conception, if possible.
Both valproate monotherapy and valproate polytherapy are associated with abnormal pregnancy outcomes. Available data suggest that antiepileptic polytherapy including valproate is associated with a greater risk of congenital malformations than valproate monotherapy.
Studies have shown that exposure to valproate in utero increases the risk of neuro-developmental disorders of the exposed children.
Available data show that children exposed to valproate in utero are at increased risk of pervasive developmental disorders (autism spectrum disorders) (approximately three-fold) and childhood autism (approximately five-fold) compared with the general study population.
Limited data to date suggests that children exposed to valproate in utero may be more likely to develop symptoms of attention deficit/hyperactivity disorder (ADHD).
Lactation: Valproate is excreted in human milk with a concentration ranging from 1% to 10% of maternal serum levels. Hematological disorders have been shown in breast-fed newborns/infants of treated women.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Depalept chrono therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
See prescribing information for full details.
The clinical signs of massive acute poisoning usually include a calm coma, which may be more or less deep, with muscule hypotonia, hyporeflexia, miosis, reduced respiratory autonomy and metabolic acidosis, hypotension and collapse/ cardiovascular shock.
A few cases of intracranial hypertension related to cerebral edema have been described.
Patient management in a hospital setting includes: gastric lavage if indicated, maintenance of effective diuresis, cardiorespiratory monitoring. In very serious cases, extra-renal purification may be performed if necessary.
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.
In the event of overdose, the sodium content in formulations containing valproate can lead to hypernatremia.