Depalept

/ CTS

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.
Patients with renal insufficiency
It may be necessary to decrease the dosage in patients with renal insufficiency, and it may be necessary to increase the dosage in patients on dialysis. Sodium valproate is dialysable. Dosage should be adjusted according to clinical monitoring of the patient.
For full details see prescribing information

Depalept is indicated for the treatment of generalized or partial epilepsy secondary generalized epilepsy and mixed forms of epilepsy.

– History of hypersensitivity to valproate , divalproate, valpromide or to one of the ingredients of the medicinal product.
– Acute hepatitis.
– Chronic hepatitis.
– Personal or familial history of severe hepatitis, in particular drug related.
– Hepatic porphyria.
– Combination use with mefloquine,
– St. John’s wort.

Exacerbation of seizures:
As with other antiepileptics, administration of valproate may, instead of improvement, lead to a reversible exacerbation of seizure frequency and severity (including status epilepticus), or the onset of a new type of seizure. These seizures should be differentiated from those that may occur due to a pharmacokinetic interaction, toxicity (liver disease or encephalopathy) or overdose.
Since this medicinal product is metabolized into valproic acid, it should not be combined with other medicinal products undergoing the same transformation to avoid an overdose of valproic acid (e.g. valproate semisodium, valpromide).
Severe Liver damage:
Severe liver damage resulting sometimes in fatalities has exceptionally been reported.
Patients most at risk are infants and young children under the age of 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 years, the risk is significantly reduced and it progressively decreases with age.
In most cases, such liver damage occurred during the first 6 months of therapy, usually between the 2nd and 12th week and generally during antiepileptic polytherapy.
Liver function tests should be performed before therapy and regularly during the first 6 months of therapy, especially in patients at risk.
If concomitant treatments known for their liver toxicity are changed (dose increase or new treatment), liver function tests must be carried out again.
Among the 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 requires cessation of therapy with this medicinal product.
Pancreatitis:
Pancreatitis, which may result in fatalities, has been very rarely reported. Young children are at particular risk but this can be observed irrespective of age and treatment duration.
Pancreatitis with an unfavorable outcome is generally observed in young children or in patients with severe seizures, neurological impairment or anticonvulsant polytherapy.
Hepatic failure with pancreatitis increases the risk of fatal outcome.
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 discontinued, and the necessary alternative therapeutic measures implemented.
Suicidal ideation and behavior:
Suicidal ideation and behavior have been reported in patients treated with antiepileptics in several indications. A meta-analysis of data from randomized, placebo-controlled trials of antiepileptic drugs has also shown a slight increase in 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.
Therefore, patients should be closely monitored for signs of suicidal ideation and behavior, and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should 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 gene encoding the mitochondrial enzyme polymerase gamma (POLG).
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 POLG gene, 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 unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia, 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.
Interaction with other medicinal products:
Concomitant use of this medicinal product with lamotrigine and/or penems (carbapenems) is not recommended.
Cognitive or extrapyramidal disorders:
Cognitive or extrapyramidal disorders can be associated with imaging findings of cerebral atrophy. This type of clinical picture can thus be confused with dementia or Parkinson’s disease. These disorders are reversible on treatment discontinuation.
Information related to excipients:
The 200 mg, the 500 mg, the syrup and the oral Solution products contains 28 mg, 70mg, 29 mg and 28 sodium respectively per tablet, 5ml and 1 ml respectively equivalent to 1.4%, 3.5%, 1.5% and 1.4% respectively of the WHO recommended maximum daily intake of 2 g sodium for an adult.
The syrup containes sorbitol and sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
Precautions for use:
Liver function tests should be performed before starting therapy and then periodically during the first 6 months, particularly in patients at risk.
It should be emphasized that, as with most antiepileptic drugs, a moderate, transient and isolated increase in liver enzymes may be noted without any clinical signs, particularly at the beginning of the therapy.
More extensive biological investigations (including prothrombin rate) are recommended in this case; 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 parameters) are recommended prior to treatment, then after 15 days and at the end of treatment or before surgery, and in case of spontaneous bruising or 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.
This medicinal product is contraindicated in patients with urea cycle enzyme deficiencies. A few cases of hyperammonemia with stupor or coma have been described in these patients.
Although immune disorders have been noted only exceptionally during the use of this medicinal product, its potential benefit should be weighed against its potential risk in patients with systemic lupus erythematosus.
Patients should be warned of the risk of weight gain at the initiation of therapy and appropriate strategies should be adopted to minimize the risk.
Since valproate is excreted mainly in the urine partly in the forms of ketone bodies, ketone body excretion test may give false positive results in diabetic patients.
Patients with carnitine palmitoyltransferase (CPT) type II deficiency should be warned of the greater risk of rhabdomyolysis when taking valproate.
Alcohol intake is not recommended during treatment with Depalept.
Children:
Monotherapy is recommended in children under the age of 3 years when prescribing valproate, but the potential benefit should be weighed against the risk of liver damage or pancreatitis in such patients prior to initiation of therapy.
The simultaneous prescription of salicylates should be avoided in children under 3 years due to the risk of hepatotoxicity and the risk of bleeding.
In children with a history of unexplained hepatic and gastrointestinal disorders (anorexia, vomiting, acute episodes of cytolysis), 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.
See prescribing information for full details.

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
syndrome).
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.
For full details see prescribing information

Contraindicated combinations:
– St. John’s Wort:
There is a risk of decreased plasma concentrations and reduced efficacy of the antiepileptic.
Inadvisable combinations:
– Lamotrigine:
There is a higher risk of serious skin reactions (toxic epidermal necrolysis).
Furthermore, an increase in lamotrigine plasma concentrations may occur (decreased hepatic metabolism by sodium valproate).
If coadministration proves necessary, close clinical monitoring is required.
– Penems:
There is a risk of seizures due to a rapid decrease in valproic acid plasma concentrations, which may become undetectable.
Co-administration of valproic acid and carbapenems has led to decreases in plasma concentrations of valproic acid of approximately 60 to 100% in around two days. Due to the rapid onset and the extent of the decreased plasma concentrations, simultaneous administration of carbapenems in patients stabilised on valproic acid who cannot be monitored should therefore be avoided.
Combinations requiring precautions for use:
– Acetazolamide:
Increased hyperammonemia with increased risk of encephalopathy may occur.
Regular monitoring of clinical and laboratory parameters is required.
– Aztreonam:
There is a risk of seizures due to a decrease in valproic acid plasma concentrations.
Clinical monitoring, plasma assays and possible dose adjustment of the anticonvulsant are required during treatment with the anti-infective agent and after its discontinuation.
– Carbamazepine:
Increased plasma concentrations of the active metabolite of carbamazepine with signs of overdose may occur. In addition, reduced valproic acid plasma concentrations may occur due to its increased hepatic metabolism by carbamazepine.
Clinical monitoring, plasma assays and dose adjustment of both anticonvulsants are required.
– Felbamate:
Increased serum valproic acid concentrations with a risk of overdose may occur.
Clinical monitoring and monitoring of laboratory parameters and possible valproate dose adjustment are required during treatment with felbamate and after its discontinuation.
– Estrogen-containing products, including estrogen-containing hormonal contraceptives:
Estrogens are inducers of the UDP-glucuronosyl transferase (UGT) isoforms involved in valproate glucuronidation and may increase valproate clearance, which in turn is thought to cause a decrease in
serum valproate concentrations and to potentially reduce valproate efficacy. Consider monitoring valproate serum levels.
Conversely, valproate has no enzyme-inducing effect; as a consequence, valproate does not reduce the efficacy of estro-progestative agents in women receiving hormonal contraception.
– Metamizole:
Metamizole may decrease valproate serum levels when co-administered, which may result in potentially decreased valproate clinical efficacy.
Prescribers should monitor clinical response (seizure control or mood control) and consider monitoring valproate serum levels as appropriate.
– Nimodipine (oral route and, by extrapolation, by injection)
There is a risk of a 50% increase in plasma nimodipine concentrations. Therefore, nimodipine dose reduction is necessary in hypotensive patients.
– Phenobarbital, and by extrapolation primidone:
Increased hyperammonemia with increased risk of encephalopathy may occur.
Regular monitoring of clinical and laboratory parameters is required.
– Phenytoin, and by extrapolation fosphenytoin:
Increased hyperammonemia with increased risk of encephalopathy may occur.
Regular monitoring of clinical and laboratory parameters is required.
– Propofol:
A possible increase in propofol blood levels may occur. When coadministered with valproate, a reduction in propofol dose should be considered.
– Rifampicin:
There is a risk of seizures due to increased hepatic metabolism of valproate by rifampicin.
Clinical monitoring and monitoring of laboratory parameters and possible anticonvulsant dose adjustment are required during treatment with rifampicin and after its discontinuation.
– Rufinamide:
A possible increase in rufinamide concentrations may occur, in particular in children weighing less than 30 kg.
In children weighing less than 30 kg: the total dose of 600 mg/day after dose titration should not be exceeded.
– Topiramate:
Increased hyperammonemia with increased risk of encephalopathy may occur.
Regular monitoring of clinical and laboratory parameters is required.
– Zidovudine:
There is a risk of increased adverse effects of zidovudine, particularly hematological effects, due to decrease in its metabolism by valproic acid.
Regular monitoring of clinical and laboratory parameters is required. A blood count should be performed to test for anemia during the first 2 months of the combination.
– Zonisamide:
Increased hyperammonemia with increased risk of encephalopathy may occur.
Regular monitoring of clinical and laboratory parameters is required.
Other forms of interaction:
Lithium: this medicinal product has no effect on serum lithium levels.
Risk of liver damage: The concomitant use of salicylates should be avoided in children under 3 years due to the risk of liver toxicity.
Concomitant use of valproate and other anticonvulsants increases the risk of liver damage, especially in young children.
Concomitant use with cannabidiol increases the incidence of raised transaminases. In patients of all ages receiving concomitantly cannabidiol at doses of 10 to 25 mg/kg and valproate, clinical trials have reported ALT increases greater than 3 times the upper limit of normal in 19% of patients. Appropriate liver monitoring should be exercised when valproate is used concomitantly with other anticonvulsants with potential hepatotoxicity, including cannabidiol. Dose reductions or therapy cessation should be considered in case of significant anomalies of liver parameters.
See prescribing information for full details.

Valproate is contraindicated:
• during pregnancy unless there is no suitable alternative treatment.
• in women of childbearing potential, unless the conditions listed in section 4.4 are fulfilled.
Pregnancy:
Teratogenicity and neuro-developmental effects
Both valproate monotherapy and valproate polytherapy including other antiepileptics are frequently associated with abnormal pregnancy outcomes. show an increased risk of major congenital malformations and neurodevelopmental disorders in both valproate monotherapy and polytherapy compared to the population not exposed to valproate. Valproate was shown to cross the placental barrier both in animal species and in humans. In animals, teratogenic effects have been demonstrated in mice, rats and rabbits.
• Congenital malformations
A meta-analysis (including registries and cohort studies) showed that about 11% of children of epileptic women exposed to valproate monotherapy during pregnancy had major congenital malformations . This is greater than the risk of major malformations in the general population (about 2-3%).
The risk of major congenital malformations in children after in utero exposure to anti-epileptic polytherapy including valproate is higher than that of anti-epileptic drugs polytherapy not including valproate.
This risk is dose-dependent in valproate monotherapy, and available data suggest it is dose-dependent in valproate polytherapy. However a threshold dose below which no risk exists cannot be established.
Available data show an increased incidence of minor and major malformations. The most common types of malformations include neural tube defects (approximately 2-3%), facial dysmorphism, cleft lip and palate, craniostenosis, cardiac, renal and urogenital defects (in particular, hypospadias), limb defects (including bilateral aplasia of the radius), and multiple anomalies involving various body systems.
In utero exposure to valproate may also result in hearing impairment/loss due to ear and/or nose malformations (secondary effect) and/or to direct toxicity on the hearing function. Cases describe both unilateral and bilateral deafness or hearing impairment. Outcomes were not reported for all cases. When outcomes were reported, the majority of the cases had not resolved.
In utero exposure to valproate may result in congenital eye disorders (including coloboma and microphthalmia), which were reported in association with other congenital anomalies. These congenital eye disorders may affect visual ability.
• Neuro-developmental disorders
Studies have shown that exposure to valproate in utero increases the risk of neuro-developmental disorders in exposed children. The risk of neurodevelopmental disorders (including that of autism) seems to be dose-dependent when valproate is used in monotherapy but a threshold dose below which no risk exists, cannot be established based on available data. When valproate is administered in polytherapy with other anti-epileptic drugs during pregnancy, the risks of neurodevelopment disorders in the offspring were also significantly increased as compared with those in children from general population or born to untreated epileptic mothers.
The period of risk for these effects is uncertain and the possibility of a risk throughout the entire pregnancy cannot be excluded.
When valproate is administered in monotherapy, studies in pre-school children exposed in utero to valproate show that up to 30-40% experience delays in their early development such as talking and walking later, lower intellectual abilities, poor language skills (speaking and understanding) and memory problems.
Intelligence quotient (IQ) measured in school-aged children (aged 6) with a history of valproate exposure in utero was on average 7-10 points lower than those children exposed to other antiepileptics. Although the role of confounding factors cannot be excluded, there is evidence in children exposed to valproate in utero that the decrease in IQ may be independent from maternal IQ.
There are limited data on the long-term outcomes.
Available data from a population-based study show that children exposed to valproate in utero are at increased risk of autism spectrum disorders (approximately 3-fold) and childhood autism (approximately 5-fold) compared with the unexposed study population.
Available data from another population-based study show that children exposed to valproate in utero are at increased risk of developing attention deficit/hyperactivity disorder (ADHD) (approximately 1.5-fold) compared with the unexposed study population.
Women of childbearing potential
Depalept should not be used in women of childbearing potential unless other treatments are ineffective or not tolerated. If no other treatment is possible, treatment can only be initiated if the conditions is complied with:
• the patient is not pregnant (plasma pregnancy test with a sensitivity of at least 25 mIU/mL negative at the start of treatment and at regular intervals during treatment).
• the patient is using at least 1 effective method of contraception.
• and the patient is informed of the risks associated with using valproate during pregnancy.
In women of childbearing potential, the benefit-risk balance must be carefully reevaluated at regular intervals during treatment (at least annually).
Estrogen-containing products
Estrogen-containing products, including estrogen-containing hormonal contraceptives, may increase the clearance of valproate, which may result in decreased serum concentration of valproate and potentially decreased valproate efficacy.
If a woman plans a pregnancy
If a woman is planning to become pregnant, a specialist experienced in the management of epilepsy must reassess valproate therapy and consider alternative treatment options. Every effort should be made to switch to appropriate alternative treatment prior to conception, and before contraception is discontinued. If switching is not possible, the woman should receive further counseling regarding the valproate risks for the unborn child to support her informed decision-making regarding family planning.
Folate supplementation before pregnancy and at the beginning of pregnancy may decrease the risk of neural tube defects common to all pregnancies. However, the available evidence does not suggest it prevents the birth defects or malformations due to valproate exposure.
Pregnant women
Valproate as treatment for epilepsy is contraindicated in pregnancy unless there is no suitable alternative treatment.
If a woman using valproate becomes pregnant, she must be immediately referred to a specialist to consider alternative treatment options. During pregnancy, maternal tonic-clonic seizures and status epilepticus with hypoxia may carry a particular risk of death for mother and the unborn child.
If, despite the known risks of valproate in pregnancy and after careful consideration of alternative treatment, in exceptional circumstances a pregnant woman must receive valproate for epilepsy:
• the lowest effective dose must be used
• the daily dose of valproate should be divided into several small doses to be taken throughout the day. The use of a prolonged-release formulation may be preferable to other treatment formulations in order to avoid high peak plasma concentrations.
All patients with a valproate-exposed pregnancy and their partners should be referred to a specialist experienced in teratology for evaluation and counseling regarding the exposed pregnancy.
• Specialized prenatal monitoring should take place to detect the possible occurrence of neural tube defects or other malformations.
Before delivery:
Coagulation tests should be performed in the mother before delivery, including in particular a platelet count, fibrinogen levels and coagulation time (activated partial thromboplastin time: aPTT).
Risk in the neonate
• Cases of hemorrhagic syndrome have been reported very rarely in neonates whose mothers have taken valproate during pregnancy. This hemorrhagic syndrome is related to thrombocytopenia,
hypofibrinogenemia and/or to a 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. Normal hemostasis test results in the mother do not make it possible to rule out hemostasis abnormalities in the neonate. Therefore, platelet count, fibrinogen plasma level, coagulation tests and coagulation factors should be investigated in neonates at birth. • Cases of hypoglycemia have been reported in neonates whose mothers have taken valproate during the third trimester of their pregnancy.
• Cases of hypothyroidism have been reported in neonates whose mothers have taken valproate during pregnancy.
• Withdrawal syndrome (in particular, agitation, irritability, hyper-excitability, jitteriness, hyperkinesia, tonicity disorders, tremor, convulsions and feeding disorders) may occur in neonates whose mothers have taken valproate during the last trimester of their pregnancy.
Post-natal monitoring/monitoring of children:
Close monitoring of the neuro-developmental behavior must be implemented in children exposed to valproate during pregnancy and suitable treatment initiated as early as possible if necessary.
Breast-feeding:
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 therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility:
Amenorrhea, polycystic ovaries and increased testosterone levels have been reported in women treated with valproate. In men, the administration of valproate may also impair fertility (reduced sperm motility in particular). In some cases, these fertility disorders are reversible after discontinuing treatment for at least 3 months. In a limited number of cases, it was reported that a significant reduction in dosage can improve fertility. However, in other cases, the reversibility of this male infertility is not known.

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.