Depalept Chrono

/ Sanofi

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.

This medicinal product is contraindicated in the following situations:
• Hypersensitivity to the active substance or to any of the excipients
• A personal or family history of liver disease or manifest severe hepatic or pancreatic dysfunction
• Disorders of hepatic function with a fatal outcome during valproic acid treatment in siblings
• Hepatic porphyria
• Blood coagulation disorders
• Mitochondrial disorders caused by mutations in the nuclear gene encoding the 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 disorders
• Known urea cycle disorders
• In uncorrected systemic primary carnitine deficiency
Treatment of epilepsy:
• In pregnancy unless there is no suitable alternative treatment
• In women of childbearing potential, unless the conditions of the Pregnancy Prevention Program are fulfilled. See prescribing information for more information on the Pregnancy Prevention Program.
Treatment of bipolar disorder:
• In pregnancy
• In women of childbearing potential, unless the conditions of the Pregnancy Prevention Program are fulfilled. See prescribing information for more information on the Pregnancy Prevention Program.

Damage to the liver and/or pancreas: Uncommon cases of severe liver damage and rare cases of damage to the pancreas have been observed. Infants and young children under 3 years of age who suffer from severe epileptic seizures are most often affected.
The risk of liver or pancreatic damage is increased, especially in combination treatment with multiple antiepileptic drugs or in the case of brain damage, mental retardation and/or a congenital metabolic disease including mitochondrial diseases such as carnitine deficiency, urea cycle disorders, POLG mutations or degenerative disease. In these patients, valproic acid should be used with particular caution and as monotherapy.
In the majority of cases, liver damage was observed within the first six months of treatment and in particular between the second and twelfth week. The incidence of disorders decreases considerably in children over 3 years of age and particularly over the age of 10.
These disorders can be fatal. If hepatitis and pancreatitis occur together, the risk of a fatal outcome increases.
Signs of damage to the liver and/or pancreas.
Serious or fatal damage to the liver and/or pancreas may be preceded by non-specific symptoms. If the aforementioned symptoms are persistent or serious, appropriate laboratory tests should be performed in addition to a thorough examination. However, as the blood test results of patients with a disorder may not necessarily be abnormal, the treating doctor should not rely exclusively on changes in blood test results. Particularly at the start of treatment, in isolated cases, liver enzyme values can be temporarily elevated even independent of any impairment of hepatic function. Therefore, medical history and the clinical picture are always of critical importance to the assessment.
In case salicylates are taken concomitantly they should be discontinued as a precautionary measure, since they follow the same metabolic pathway as valproic acid.
Measures for the early detection of damage to the liver and/or pancreas
Baseline and periodic monitoring of clinical status and laboratory parameters (e.g. PTT, fibrinogen, coagulation factors, INR, total protein, blood count with platelets, bilirubin, AST, ALT, gamma-GT, lipase, alpha-amylase in the blood, blood sugar) is required during treatment to ensure early detection of hepatic or pancreatic injury. See prescribing information for full details.
Bleeding and other hematopoietic disorders: Valproate is associated with dose-related thrombocytopenia. The therapeutic benefit which may accompany the higher doses should be weighed against the possibility of a greater incidence of adverse effects. 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 and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving valproic acid capsules be monitored for blood counts and coagulation parameters prior to planned surgery and during pregnancy. Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.
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. This disorder is variable in its expression. 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.
Immediate withdrawal of the treatment should be considered in the event of:
an inexplicable disturbance in the patient’s general condition, clinical signs of a hepatic or pancreatic disorder or a bleeding tendency, a more than two- to three-fold increase in liver transaminases, even in the absence of clinical signs (consider enzyme induction by any concomitant medication), a slight (one and a half- to two-fold) increase in liver transaminases with a concomitant acute febrile infection, or a severe coagulation disorder.
Pregnancy Prevention Program: Valproate has a high teratogenic potential and children exposed in utero to valproate have a high risk for congenital malformations and neurodevelopmental disorders. See prescribing information for more information on the Pregnancy Prevention Program.
Suicidal ideation and suicidal behaviour: Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for valproic acid. Therefore, patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.
Severe skin reactions and angio-oedema: Severe skin reactions such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme and angio-oedema have been reported in association with valproate treatment. Patients should be informed of the symptoms of severe skin reactions and closely monitored. If symptoms of severe skin reactions or angio-oedema are observed, immediate evaluation is required, and treatment must be discontinued if the diagnosis of a severe skin reaction or angio-oedema is confirmed.
Carbapenem agents: The concomitant use of valproic acid/valproates and carbapenem agents is not recommended.
Alcohol should be avoided during treatment with valproate.
Urea cycle disorders and risk of hyperammonaemia: An increase in the ammonia serum level (hyperammonaemia) may occur during treatment with products containing valproic acid. Therefore, serum levels of ammonia and valproic acid should be determined in the event of symptoms such as apathy, somnolence, vomiting, hypotension, and an increase in seizure frequency; the dose of the product should be reduced if necessary.
When an urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed before starting valproic acid therapy to avoid the occurrence of hyperammonaemia.
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, valproate-induced acute liver failure and liver-related deaths have been reported 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 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.
Patients at risk of hypocarnitinaemia: Valproate administration may trigger occurrence or worsening of hypocarnitinaemia that can result in hyperammonaemia (that may lead to hyperammonemic encephalopathy). Other symptoms such as liver toxicity, hypoketotic hypoglycaemia, myopathy including cardiomyopathy, rhabdomyolysis, Fanconi syndrome have been observed, mainly in patients with risk factors for hypocarnitinaemia or pre-existing hypocarnitinaemia. Patients at increased risk for symptomatic hypocarnitinaemia when treated with valproate include patients with metabolic disorders including mitochondrial disorders related to carnitine, impairment in carnitine nutritional intake, patients younger than 10 years old, concomitant use of pivalate-conjugated medicines or of other antiepileptics.
Patients should be warned to report immediately any signs of hyperammonaemia such as ataxia, impaired consciousness, vomiting. Carnitine supplementation should be considered when symptoms of hypocarnitinaemia are observed.
Patients with systemic primary carnitine deficiency and corrected for hypocarnitinaemia may only be treated with valproate if the benefits of valproate treatment outweigh the risks in these patients and there is no therapeutic alternative. In these patients, carnitine monitoring should be implemented.
Patients with an underlying carnitine palmitoyltransferase (CPT) type II deficiency should be warned of the greater risk of rhabdomyolysis when treated with valproic acid. Carnitine supplementation should be considered in these patients.
Aggravated convulsions: As with other antiepileptic drugs, some patients may experience, instead of an improvement, a reversible worsening of convulsion frequency and severity (including status epilepticus), or the onset of new types of convulsions with valproate. In case of aggravated convulsions, the patients should be advised to consult their physician immediately.
Bone marrow damage: Patients with previous bone marrow damage must be strictly monitored.
Immune system reactions: Although immune system disorders have only rarely been observed during treatment with medicinal products containing valproic acid, the latter should not be used in patients with systemic lupus erythematosus until a strict risk-benefit analysis has been carried out.
Renal insufficiency and hypoproteinaemia: In patients with renal insufficiency and hypoproteinaemia, the rise in free valproic acid in serum must be considered and the dose reduced accordingly. In patients receiving haemodialysis, it may be necessary to increase the dosage. Valproate is dialysable. As monitoring of plasma concentrations alone may be misleading, dosage should be adjusted according to the clinical picture.
Investigations: It should be noted that, as with other anti-epileptics, transaminases can rise temporarily without any clinical symptoms at the start of treatment with valproic acid. In these cases, more extensive laboratory tests (including INR) are recommended. In rare cases, harmless, usually temporary nausea, sometimes with vomiting and loss of appetite, can also occur and regresses spontaneously or after a reduction in the dose.
Coagulation status should be checked before a surgical procedure and in case of injuries or spontaneous bleeding (including blood cell count with platelets, bleeding time and coagulation factors).
If the patient is taking a vitamin K antagonist concomitantly, close monitoring of the INR is recommended.
Patients should be informed about possible weight gain at the start of treatment. Suitable weight control measures should be taken.
Further note: If undesirable effects that are not dose-dependent are observed, withdrawal of the medicinal product is indicated.
Paediatric population: Monotherapy is recommended in children under the age of 3 years when prescribing this drug, but the potential benefit should be weighed against risk of liver damage or pancreatitis in such patients prior to initiation of therapy. Concomitant treatment with salicylates in children under 12 years of age should be avoided due to the risk of liver damage.
See prescribing information for full details.

Very common: Hyperammonaemia, Tremor, nausea.
Common: Anemia, thrombocytopenia or leucopenia, weight gain or weight decrease, increased appetite or also loss of appetite, extrapyramidal disorder (may be irreversible), stupor, somnolence, paraesthesia, reversible or irreversible hearing loss, haemorrhage, vomiting, gingival disorder (mainly gingival hyperplasia), stomatitis, diarrhea, Serious (sometimes fatal) non-dose-dependent liver injuries, hypersensitivity, transient and/or dose related alopecia, nail and nail bed disorders, urinary incontinence, dysmenorrhoea.
See prescribing information for full details.

Effects of other medicinal products on valproic acid:

• Enzyme-inducing anti-epileptics such as phenobarbital, primidone, phenytoin and carbamazepine reduce serum levels of valproic acid, thereby reducing the effect. In the case of combined therapy, the dosage should be adjusted in accordance with the clinical efficacy and serum level.

Valproic acid metabolites levels may be increased in case of concomitant use with phenytoin or phenobarbital. Therefore, patients treated with those two drugs should be carefully monitored for signs and symptoms of hyperammonemia.

• Mefloquine increases the degradation of valproic acid and also has potential convulsant effects. Concomitant use can therefore lead to epileptic seizures.
• Decreases in serum concentrations of valproic acid have been reported when it is co-administered with carbapenems, resulting in a 60−100 % decrease in valproic acid levels in about two days. Due to the rapid onset and the extent of the decrease, the consequences of an interaction between valproic acid and carbapenems in patients stabilised on valproic acid are considered to be unmanageable and therefore co-administration should be avoided. If treatment with these antibiotics cannot be avoided, the blood level of valproic acid should be closely monitored.
• Serum valproic acid concentrations may be increased by concomitant administration of cimetidine or erythromycin, as a result of a reduced metabolism in the liver.
• Serum valproic acid concentrations may also be increased by concomitant administration of fluoxetine. However, a decrease has also been reported.
• Medicinal products with high plasma protein binding, such as acetylsalicylic acid, can competitively displace valproic acid from its protein binding sites and increase the concentration of free valproic acid in serum.

Medicinal products containing valproic acid and acetylsalicylic acid should not be administered concomitantly in infants and children with febrile disorders and only on the express instructions of a doctor in adolescents with febrile disorders.

• If vitamin K antagonists are administered concomitantly, close monitoring of the INR is recommended.
• Rifampicin may decrease the serum valproic acid levels, resulting in a lack of therapeutic effect. Therefore, valproic acid dosage adjustment may be necessary when it is co-administered with rifampicin.
• Valproate plasma level is decreased in case of concomitant use with protease inhibitors such as lopinavir or ritonavir.
• 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 the clearance of valproate, which would result in decreased serum concentration of valproate and potentially decreased valproate efficacy. Consider monitoring of valproate serum levels. On the opposite, valproate does not reduce efficacy of oestroprogestative agents in women receiving hormonal contraception.
• 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.
• Some case reports describe a significant decrease in valproate serum levels after methotrexate administration, with occurrence of seizures. Prescribers should monitor clinical response (seizure control or mood control) and consider monitoring valproate serum levels as appropriate.

Effects of valproic acid on other medicinal products:

• The valproic acid-induced increase in the phenobarbital concentration, which can manifest itself in the form of severe sedation (particularly in children), is of particular clinical significance. If this occurs, the phenobarbital or primidone dose must be reduced (primidone is partially metabolised to phenobarbital). Careful monitoring is therefore recommended, particularly in the first 15 days of combination treatment.
• In patients who are already taking phenytoin, additional administration or an increase in the dose of medicinal products containing valproic acid can cause the amount of free phenytoin to rise without an increase in total serum levels of phenytoin. This can increase the risk of undesirable effects, particularly brain damage. Clinical monitoring is therefore recommended; if plasma phenytoin concentrations are determined, the free form should be measured.
• During combination treatment with carbamazepine and valproic acid, symptoms have been described that may be attributable to potentiation of carbamazepine toxicity by valproic acid. Clinical monitoring is indicated, particularly at the start of combination treatment, and the dose should be adjusted if necessary.
• Valproic acid inhibits the metabolism of lamotrigine and almost doubles its mean half-life. Combination of lamotrigine and medicinal products containing valproic acid may increase the risk of skin reactions; individual cases of severe skin reactions have been reported occurring within 6 weeks of starting combination treatment and, in some cases, not regressing until the medication was withdrawn or appropriate treatment administered. Clinical monitoring is therefore recommended and, if necessary, the lamotrigine dosage should be adjusted.
• In combination with benzodiazepines, barbiturates and neuroleptics, MAO inhibitors and antidepressants, valproic acid can increase the central depressant effect of these medicinal products. Patients taking corresponding combinations should be monitored carefully and doses adjusted if necessary.
• Valproic acid may increase the serum concentration of zidovudine, which can lead to an increase in zidovudine toxicity.
• Concomitant administration of medicinal products containing valproic acid and anticoagulants or anti-aggregants can result in an increased tendency to bleed. Regular monitoring of blood coagulation is therefore recommended in the event of concomitant use.
• In children, serum levels of phenytoin may increase after concomitant administration of clonazepam and valproic acid.
• Valproic acid may lead to an increase in plasma level of rufinamide. This increase is dependent on concentration of valproic acid. Caution should be exercised, in particular in children, as this effect is larger in this population.
• Valproic acid may lead to an increased blood level of propofol. When co-administered with valproate, a reduction of the dose of propofol should be considered.

Other interactions

• Risk of liver damage: The concomitant use of salicylates should be avoided in children under 12 years due to the risk of liver toxicity. Concomitant use of valproate and multiple anticonvulsant therapy increases the risk of liver damage, especially in young children. Concomitant use with cannabidiol increases the incidence of transaminases enzyme elevation. Appropriate liver monitoring should be exercised when valproate is concomitantly used with other anticonvulsants with potential hepatotoxicity, including cannabidiol, and dose reductions or discontinuation should be considered in case of significant anomalies of liver parameters.

It is pointed out that potentially hepatotoxic medicinal products as well as alcohol can increase the hepatotoxicity of valproic acid.

With concomitant administration of valproic acid and topiramate, encephalopathy and/or an increase in ammonia blood levels (hyperammonaemia) has been reported. Also, concomitant use of valproic acid and acetazolamide may lead to hyperammonaemia and therefore there might be an increased risk of encephalopathy. Patients treated with those two drugs should be carefully monitored for signs and symptoms of hyperammonaemic encephalopathy.

• Pivalate-conjugated medicinal products: Concomitant administration of valproate and pivalate-conjugated medicines (such as cefditorenpivoxil, adefovir dipivoxil, pivmecillinam and pivampicillin) should be avoided due to an increased risk of carnitine depletion. Patients in whom coadministration cannot be avoided should be carefully monitored for signs and symptoms of hypocarnitinaemia.
• Clozapine: Concomitant treatment with valproate and clozapine may increase the risk of neutropenia and clozapine-induced myocarditis. If concomitant use of valproate and clozapine is required, careful monitoring for both adverse reactions is required.
• Co-administration of valproate and quetiapine may increase the risk of neutropenia/leucopenia.
• As valproic acid is partially metabolised to ketone bodies, consideration should be given to the possibility of a false positive reaction to a test for ketone bodies in diabetics with suspected ketoacidosis.
• Absences occurred in patients with a history of this type of seizure after concomitant treatment with medicinal products containing valproic acid and clonazepam.
• Catatonia occurred in a female patient with a schizoaffective disorder after concomitant treatment with valproic acid, sertraline (antidepressant) and risperidone (neuroleptic).

• The bioavailability of sodium valproate/valproic acid in the prolonged-release formulation is not significantly affected by the concomitant intake of food.
See prescribing information for full details.

Pregnancy: Valproate is contraindicated during pregnancy for all indications except in epilepsy where no suitable alternative treatment exists. In females, both valproate monotherapy and valproate polytherapy including other antiepileptics are frequently associated with abnormal pregnancy outcomes. Available data 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.
Teratogenic Effects from In Utero Exposure: Available data show an increased incidence of minor and major malformations. The most common types of malformations include neural tube defects, facial dysmorphism, cleft lip and palate, craniostenosis, cardiac, renal and urogenital defects, 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 or deafness 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 did not recover.
In utero exposure to valproate may result in eye malformations (including coloboma and microphthalmia), that have been reported in conjunction with other congenital malformations. These eye malformations can affect vision.
The risk is dose-dependent in valproate monotherapy, and available data suggest it is dose-dependent in polytherapy. However, a threshold dose below which no risk exists cannot be established.
Neurodevelopmental Disorders from In Utero Exposure: Data have shown that exposure to valproate in utero can have adverse effects on mental and physical development of the exposed children. The risk of neurodevelopmental disorders (including 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 exact gestational 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 preschool 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 (age 6) with a history of valproate exposure in utero was on average 7−10 points lower than those children exposed to other anti-epileptics. Although the role of confounding factors cannot be excluded, there is evidence in children exposed to valproate that the risk of intellectual impairment may be independent from maternal IQ.
There are limited data on the long-term outcomes.
Small for Gestational Age (SGA): Some epidemiological studies indicate an increased risk of being born too small for gestational age in children exposed to valproate in the womb compared to non-exposed or lamotrigine-exposed children. The available data on humans do not allow any conclusion to be drawn about a possible dose-dependent effect.
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, it is recommended to use the lowest effective dose and divide the daily dose of valproate 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 Teratology center for evaluation and counselling regarding the exposed pregnancy. Specialized prenatal monitoring should take place to detect the possible occurrence of neural tube defects or other malformations. Folate supplementation before the pregnancy may decrease the risk of neural tube defects which may occur in all pregnancies. However, the available evidence does not suggest that it prevents the birth defects or malformations due to valproate exposure.
Serum concentrations of valproic acid should be checked regularly, as they apparently fluctuate considerably in the course of a pregnancy, even if the dose remains constant. After remaining roughly, the same for the first and second trimester, a three-fold increase in the concentration.
Lactation: Valproate is excreted in human milk with a concentration ranging from 1% to 10% of maternal serum levels. Haematological 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 Valproate 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.

Every assessment of intoxication should consider the possibility of multiple intoxication, e.g. taking several medicinal products, perhaps with suicidal intent.
At therapeutic serum levels (40−100 mg/l), valproic acid has relatively low toxicity. Acute valproic acid intoxication with serum levels of over 100 mg/l has been very rare in both adults and children. There are isolated cases of acute and chronic overdose with a fatal outcome in the literature.
Symptoms of intoxication
The symptoms of intoxication are characterised by states of confusion, sedation to the point of coma, muscle weakness, hyporeflexia and areflexia. Miosis, respiratory disorders, metabolic acidosis, cardiovascular disorders, hypotension and circulatory collapse/shock have been observed. Deaths have occurred sporadically following a massive overdose.
High serum levels have caused abnormal neurological disorders, e.g. increased tendency to seizures and behavioural changes, in adults and in children. Cases of increased intracranial pressure associated with cerebral oedema have been reported.
The presence of sodium content in the valproate formulations may lead to hypernatraemia when taken in overdose.
Treatment of overdose
There is no known specific antidote. Clinical measures depend on the symptoms. The Administration of activated charcoal or gastric lavage may be useful up to 12 hours after the overdose. Vital signs should be monitored and, if necessary, supported.
Haemodialysis and forced diuresis can be effective at removing the valproic acid that is not bound to protein from the blood. Peritoneal dialysis is of little use. Experience of the efficacy of complete plasma replacement and transfusion is inadequate. For this reason, intensive general measures that do not include specific detoxification procedures, particularly in children, but which include monitoring of serum concentration are recommended.
Intravenous administration of naloxone to improve a reduced level of consciousness has been described as effective in some cases. In case of massive overdose, haemodialysis and haemoperfusion have been used successfully.
In case of valproate overdose resulting in hyperammonaemia, carnitine can be given through IV route to attempt to normalise ammonia levels.