Sodium Valproate Aguettant

Sodium Valproate Aguettant

valproic acid

Manufacturer:

Aguettant

Distributor:

Indochina Healthcare
Full Prescribing Info
Contents
Sodium valproate.
Description
Each 4 mL of solution for injection contains sodium valproate 400 mg.
Excipients/Inactive Ingredients: Water for injection.
Action
Pharmacotherapeutic Class: Antiepileptic. ATC Code: N03AG01.
Pharmacology: Pharmacodynamics: Valproate produces its pharmacological effects mainly on the central nervous system.
The anticonvulsant properties act on very different types of seizures in animals and in cases of epilepsy in humans.
Experimental and clinical studies on valproate suggest two types of anticonvulsant action.
The first is a direct pharmacological effect related to valproate concentrations in the plasma and the brain.
The second apparently is indirect and probably related to the metabolites of valproate persisting in the brain or changes in neurotransmitters or with direct membrane effects. The most widely accepted hypothesis is that of the action of gamma aminobutyric acid (GABA) whose concentration increases after the administration of valproate.
Valproate decreases the duration of the intermediate phases of sleep, with a concomitant increase in slow sleep.
Pharmacokinetics: Different pharmacokinetic studies performed with valproate have demonstrated that: After oral or IV administration, the blood bioavailability of valproate is close to 100%.
The volume of distribution is limited mainly in the blood and in the extracellular fluid with rapid exchange. Valproate passes into the CSF and into the brain.
The half life is 15 to 17 hours.
Therapeutic efficacy usually requires minimum serum concentrations of 40-50 mg/l, with a broad range between 40 and 100 mg/l. If higher plasma concentrations prove necessary, the expected benefits should be weighed against the risk of occurrence of undesirable effects, particularly dose-dependent effects. Nonetheless, if concentrations remain above 150 mg/l, this requires a reduction in dosage.
After an oral dose, plasma concentrations at the steady state are reached in 3 to 4 days; with the injectable form this can be reached within a few minutes and maintained by intravenous infusion.
Valproate binds extensively to plasma proteins. This is a dose-dependent and saturable process.
Valproate is excreted mainly by the kidney after metabolism via glucuroconjugation and beta-oxidation.
The valproate compound is dialyzable, but haemodialysis acts only on the unbound fraction of serum valproate (approximately 10%).
Valproate is not an enzyme inducer involved in the cytochrome P450 metabolic system, unlike the majority of anti-epileptic agents. Consequently it does not accelerate its own breakdown or that of other substances such as oestroprogestatives and oral anti-vitamin K anticoagulants.
Indications/Uses
For the temporary treatment of epilepsy in adults and children, as a replacement for the oral form when oral therapy is temporarily unusable.
Dosage/Direction for Use
Female children, adolescents, women of childbearing age and pregnant women: Treatment with SODIUM VALPROATE AGUETTANT should be initiated and monitored by an epilepsy specialist physician.
Treatment should be initiated only in case of inefficacy of or intolerance to other treatment (see Precautions and Use in Pregnancy & Lactation) and the risk/benefit ratio should be carefully re-evaluated at regular intervals during treatment. SODIUM VALPROATE AGUETTANT should preferably be prescribed as monotherapy and at the lowest effective dose.
In the case of simple replacement (for example, in the event of planned surgery): Between 4 and 6 hours after the last oral dose, administer sodium valproate intravenously in a solution of 0.9% sodium chloride solution for injection: Either in continuous infusion for 24 hours or in fractionated doses in 4 one hour infusions per day at the previous dosage (mean usual posology is 20 to 30 mg/kg/day).
In cases that require effective plasma concentration to be reached rapidly and then maintained: Intravenous injection of a bolus dose of 15 mg/kg is given over 5 minutes before continuous infusion with a 1 mg/kg/hour flow rate to be adjusted progressively to reach valproic acid blood levels in the region of 75 mg/L. Then adjust the flow rate according to the course of the clinical condition.
As soon as the infusion is stopped, resumption of the oral therapy will make it possible to ensure the immediate compensation of the quantities eliminated. It will be given either at the previous dosage or after dosage adjustment.
Mode of Administration: Solution for injection.
Overdosage
Usually, the presentation of massive acute toxicity includes coma vigil, of variable depth, muscle hypotonia, hyporeflexia myosis, impaired respiratory function, metabolic acidosis, hypotension and collapsus/cardiovascular shock.
A few cases of intracranial hypertension related to cerebral oedema have been reported.
Hospital management of overdose includes gastric evacuation if indicated maintenance of effective diuresis and cardio-respiratory, monitoring, in very severe cases renal replacement therapy may be used.
The prognosis in such cases of toxicity generally is favourable. However, a few deaths have been reported.
The presence of sodium in formulations that contain valproate can cause hypernatremia in case of overdose.
Contraindications
History of hypersensitivity to valproate, divalproate, valpromide or to any of the excipients.
Acute hepatitis.
Chronic hepatitis.
Personal or family history of severe hepatitis, in particular, drug-related.
Hepatic porphyria.
Combination with mefloquine St. John's wort (see Interactions).
Warnings
Female children and adolescents, women of childbearing age and pregnant women.
SODIUM VALPROATE AGUETTANT should not be used in girls, female adolescents, women of childbearing age and pregnant women except in cases of inefficacy of or intolerance of alternative medicinal products because of its high teratogenic potential and the risk of neurodevelopmental disorders in children exposed to valproate in utero.
The risk/benefit ratio should be carefully re-evaluated at regular intervals during treatment at puberty and urgently if a woman of childbearing age, treated with SODIUM VALPROATE AGUETTANT is planning to become pregnant or becomes pregnant.
Women of childbearing age must use effective contraception during treatment and should be fully informed about the risks associated with the use of SODIUM VALPROATE AGUETTANT during pregnancy (see Use in Pregnancy & Lactation).
The physician must ensure that the patient has been provided with ample information about the risks, using documents such as the patient information leaflet to help her understand the risks and that she has duly completed and signed the Acknowledgement of Risk form.
The physician should in particular, ensure that the patient has understood: The nature and extent of the risks of exposure during pregnancy, especially the teratogeninc risk and the risk of neurodevelopmental disorders; the need to use effective contraception; the need to regularly re-evaluate the treatment; the need to quickly consult her physician if she is planning to become pregnant or thinks she is pregnant.
In women who are planning to become pregnant all measures must be taken to switch to another treatment before conception, if possible (see Use in Pregnancy & Lactation).
Treatment with a valproate-based proprietary medicinal product may only be maintained after re-evaluation of the benefit/risk ratio of the treatment by an epilepsy specialist physician.
The initiation of an anti-epileptic medicinal product can, in rare instances, be followed by a recurrence of seizures or the occurrence of a new type of seizure in the patient, independently of spontaneous fluctuations observed in some epileptic disorders. Concerning valproate, this involves mainly a change in concomitant antiepileptic treatment or a pharmacokinetic interaction (see Interactions), toxicity (liver dysfunction or encephalopathy or an overdose).
Since this medicinal product is converted into valproic acid in the body, it is advisable not to use it in combination with other medicinal products (for example: divalproate, valpromide) which undergo this same conversion, to prevent an overdose of valproic acid.
Risk of Local Tissue Necrosis: This product should be administered strictly by intravenous route. Do not administer by intramuscular injection.
Liver Dysfunction: Conditions of Occurrence: Severe liver damage, sometimes fatal, has been reported in very rare instances.
Infants and young children under 3 years of age with severe epilepsy and in particular epilepsy associated with brain disorders, psychomotor retardation, and (or) a congenital metabolic or degenerative disease are most at risk.
After the age of 3, the incidence of occurrence is significantly reduced and progressively decreases with age.
In the majority of cases, such liver damage occurred during the first 6 months of treatment, most often between weeks 2 and 12 and generally in case of antiepileptic therapy with multiple agents.
Indicators: Clinical symptoms are essential for early diagnosis. In particular the following 2 conditions which may precede jaundice, should be taken into consideration, especially in patients at risk (see Conditions of Occurrence in the previous text): Firstly, non-specific symptoms, usually of sudden onset such as asthenia, anorexia, depression and drowsiness, which are sometimes associated with repeated vomiting and abdominal pain. Secondly, recurrence of epileptic seizures even though treatment is properly followed.
Patients, or their family for children should be instructed to immediately report any such signs to a physician should they occur. Apart from a clinical examination, this should include an immediate biological assessment of live function.
Detection: Liver function should be monitored periodically during the first 6 months of therapy.
Among usual investigations, tests which reflect protein synthesis, particularly prothrombin time, are the most relevant. Confirmation of an abnormally low prothrombin time, particularly in association with other abnormal laboratory test data (significant decrease in fibrinogen and coagulation factors, increased bilirubin levels and elevated transaminases see Precautions), should lead to discontinuation of valproate (as well as discontinuation of salicylates if they have been concomitantly prescribed, because they follow the same metabolic pathway).
Pancreatitis: Pancreatitis which may be fatal has been reported in very rare instances. It can occur whatever the patient's age and duration of treatment, and young children are at particular risk.
Generally, pancreatitis with an unfavourable outcome has been observed in young children or in patients with severe, epilepsy, brain lesions or who are receiving antiepileptic therapy with multiple agents.
Liver dysfunction associated with pancreatitis increases the risk of a fatal outcome.
In case of an acute abdominal pain syndrome, as in the case of gastrointestinal symptoms such as nausea, vomiting and/or anorexia, the diagnosis of pancreatitis should be considered in case of elevation of pancreatic enzymes and treatment should be discontinued, and required alternative therapeutic measures adopted.
Risk of Suicide: Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomised, placebo-controlled trials of antiepileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not rule out the possibility of increased risk of sodium valproate.
Therefore, patients should be monitored closely for signs of suicidal ideation and behaviour, and appropriate treatments should be considered. Patients (and their caregivers) should be advised to seek medical advice if signs of suicidal ideation or behaviour emerge.
Drug Interactions: Administration of this medicinal product is not advisable in combination with lamotrigine and penems (see Interactions).
Sodium: This medicinal product contains sodium. This medicinal product contains 2.41 mmol (or 55.32 mg) sodium per ampoule. To be taken into consideration in patients on a strict sodium diet.
Thai FDA Warning: Drug may cause drowsiness. Do not drive vehicles or work with machinery and do not drink alcohol or alcoholic mixtures, while taking this medication.
Drug can cause blood cell disorders.
Do not use in pregnancy, because it may cause fetal disabilities.
Care should be exercised if using this drug with patients with liver diseases.
Special Precautions
A laboratory test assessment of liver function should be performed prior to the start of therapy (see Contraindications) and then periodic monitoring during the first 6 months of therapy, in particular in high-risk patients (see Warnings).
It should be emphasised that, as with most anti-epileptic agents, an isolated, moderate and transient increase in transaminases can be observed, in particular at the start of treatment, in the absence of any clinical signs.
In such a case, it is advisable to order a more complete laboratory test assessment (in particular prothrombin time), possibly reconsider the dosage and repeat laboratory tests depending on the change in these parameters.
In children under 3 years of age, it is advisable to use valproate only as monotherapy, after evaluating the therapeutic utility compared to the risk of liver dysfunction and pancreatitis in patients in this age category (see Warnings and the following text).
A haematological examination (CBC including platelets, bleeding time and coagulation tests) is recommended prior to the initiation of therapy then after 15 days and at the end of therapy as well as prior to surgery and in case of spontaneous haematoma or bleeding (see Adverse Reactions).
In children, avoid the concomitant prescription of salicylates, considering the risk of hepatic toxicity (see Warnings) and of bleeding.
In patients with renal insufficiency, an increase in serum concentrations of unbound valproic acid should be taken into account and consequently dosage should be decreased.
This medicinal product is not advisable in patients with a urea cycle enzyme deficiency. A few cases of hyperammonaemia associated with stupor or coma, have been described in such patients.
In children with a history of unexplained hepatic or digestive disorders (anorexia, vomiting, episode of cytolysis), bouts of lethargy or coma, mental retardation or in the case of a family history of neonatal death or death in childhood, metabolic investigations, in particular fasting and post­ prandial serum ammonia, should be performed prior to treatment with valproate.
Although this medicinal product is recognised as very rarely resulting in immune disorders, its use in patients with systemic lupus erythematosus should be weighed, based on the benefit/risk ratio.
When treatment is initiated, patients should be warned of the risk of weight gain and appropriate measures, mainly dietary-related, should be taken to minimise it.
Excretion of valproate is mainly via urine, partly in the form of ketone bodies, the search for urine ketones may give false positives in diabetic patients.
Patients with Type II carnitine palmitoyltransferase (CPT-II) deficiency should be warned of the increased risk of rhabdomyolysis when taking valproate.
Alcohol consumption is not recommended during treatment with SODIUM VALPROATE AGUETTANT.
Effects on the Ability to Drive or Operate Machinery: Patients, particularly drivers and machine operators, should be warned about the risk of drowsiness, especially in cases of anticonvulsant polytherapy or combination with other medicinal products that may increase drowsiness.
Use In Pregnancy & Lactation
Use in Pregnancy: SODIUM VALPROATE AGUETTANT should not be used in girls, female adolescents, women of childbearing age, and pregnant women except in case of inefficacy of or intolerance to drug alternatives. Women of childbearing age should 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.
Risks associated with Exposure to Valproate During Pregnancy: The use of valproate, whether as monotherapy or as polytherapy is associated with abnormal pregnancy outcomes. Available data suggests that anti-epileptic therapy with multiple agents including valproate is associated with a higher risk of congenital malformations than valproate monotherapy.
Congenital Malformations: Data derived from a meta-analysis (including registries and cohort studies) has shown that 10.73% of children of epileptic women exposed to valproate monotherapy during pregnancy suffer from congenital malformations (95% CI: 8.16-13.29). This is a greater risk of major malformations than for the general population, for whom the risk is about 2-3%. The risk is dose-dependent but a threshold dose as follows which no risk exists cannot be established.
Available data shows an increased incidence of minor and major malformations. The most common types of malformations include neural tube defects (about 2-3% facial dysmorphism, cleft lip and palate, craniostenosis, cardiac, renal and urogenital defects (including hypospadias), limb defects (including bilateral aplasia of the radius), and multiple anomalies involving various parts of the body.
Neurodevelopmental Disorders: Studies show that valproate increases the risk of neurovedelopmental disorders in children exposed to it in utero. The risk seems to be dose-dependent but a threshold dose below which no risk exists cannot be established based on available data. The possibility of a risk throughout the entire pregnancy period cannot be ruled out.
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.
The Intelligence quotient (IQ) measured in school-age children (6 years) with a history of valproate exposure in utero was on average 7-10 points lower than those children exposed to other anti-epileptic agents. Although the role of confounding factors cannot be ruled out, there is evidence that the IQ impairment observed in children exposed to valproate in utero is independent of maternal IQ.
Data on the outcome of these disorders in the long-term is limited.
Available data shows that children exposed to valproate in utero are at increased risk of developing pervasive developmental disorders (autistic spectrum type disorders) (approximately 3 times more frequent) and childhood autism (approximately 5 times more frequent) as compared with the control population.
Limited data suggests that children exposed to valproate in utero are more likely to develop symptoms of attention deficit hyperactivity disorder (ADHD).
Female Children, Female Adolescents and Women of Childbearing Age (see previous text and Precautions): SODIUM VALPROATE AGUETTANT should not be used in girls, female adolescents, women of childbearing age and pregnant women except in case of inefficacy of or intolerance to drug alternatives. Women of childbearing age should use effective contraception during treatment.
In women planning to become pregnant or who are pregnant: Valproate therapy should be reassessed.
All efforts should be made to switch to appropriate alternative treatment prior to conception;
Pre-conception consultation is recommended.
Valproate therapy should not be discontinued without a re-assessment of the benefit/risk ratio of the treatment for the patient by a physician experience in the management of epilepsy. During pregnancy, tonic-clonic seizures and status epilepticus with hypoxia in the mother can lead to serious or even fatal consequences for mother and the foetus.
If, after careful assessment of the risks and benefits, valproate therapy must be absolutely maintained during pregnancy (no alternative). It is recommended to: Use the lowest effective dose and divide the daily dose into several small doses to be taken throughout the day. The use of a prolonged-release formulation may be preferable in order to avoid high peak plasma concentrations.
Folate supplementation before the pregnancy may decrease the risk of neural tube defects common to all pregnancies. However, the available data does not suggest that the action of folic acid prevents the malformations associated with valproate exposure.
Initiate specialised prenatal monitoring in order to detect the possible occurrence of neural tube defects or other malformations.
Before Delivery: Perform a coagulation investigation including platelet count, fibrinogen assay and clotting time (Activated Partial Thromboplastin Time, APTT) in the mother before delivery.
Risk in the Neonate: Cases of haemorrhagic syndrome have been reported very rarely in neonates of mothers treated with valproate during pregnancy. This haemorrhagic 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. A normal haemostasis assessment in the mother does not allow the elimination of abnormalities of haemostasis in the neonate. Therefor platelet count fibrinogen plasma level, coagulation tests and coagulation factors should be investigated in neonates.
Cases of hypoglycaemia have been reported in neonates of mothers treated with valproate during the third trimester of pregnancy.
Cases of hypothyroidism have been reported in neonates of mothers treated with valproate during pregnancy.
Withdrawal symptoms (particularly agitation, irritability, hyper-excitability, nervousness, hyperkinesia, tonicity disorders, tremors, convulsions and feeding disorders) may occur in neonates of mothers treated with valproate during the third trimester of pregnancy.
Use in Lactation: Valproate is excreted in human milk in a concentration ranging between 1% and 10% of maternal serum levels. Haematological disorders have been observed in neonates/infants breastfed by women on treatment (see Adverse Reactions).
The decision to suspend breastfeeding or discontinue treatment with SODIUM VALPROATE AGUETTANT must take account of the benefit of breastfeeding for the child and the benefit of therapy for the mother.
Fertility: Cases of amenorrhoea polycystic ovaries and increased testosterone levels have been reported in women treated with valproate (see Adverse Reactions). In men, the administration of valproate may also affect fertility (decreased sperm mobility in particular) (see Adverse Reactions). Case reports indicated that fertility disorders are reversible after discontinuation of treatment.
Adverse Reactions
Classification of expected frequencies: Very common (≥10%), Common (≥1% to <10% ), Uncommon (≥0.1% to <1%); Rare (≥0.01% to <0.1%); Very rare (<0.01%); Not Known (cannot be estimated from the available data).
Congenital, Family and Genetic Disorders: Congenital malformations, neurodevelopmental disorders (see Warnings, Precautions and Use in Pregnancy & Lactation).
Haematological and Lymphatic System Disorders: Common: Anaemia, thrombocytopenia.
Cases of dose-related thrombocytopenia, usually discovered systemically and without any clinical repercussions, have been described.
In the case of asymptomatic thrombocytopenia, if the platelet count and control of epileptic disease so allow a decrease in the dosage of this medicinal product alone frequently results in the regression of thrombocytopenia.
Uncommon: Leucopenia, pancytopenia.
Rare: Global aplastic anaemia or pure red cell aplasia, agranulocytosis, macrocytic anaemia, macrocytosis.
Investigations: Common: Weight gain.*
Rare: Decrease of at least one clotting factor, abnormal coagulation tests (such as prolonged prothrombin time, prolonged activated partial thromboplastin time, prolonged thrombin time, increased INR) (see Warnings, Precautions and Use in Pregnancy & Lactation), vitamin B8 (biotin) deficiency/biotinidase deficiency.
*Given that weight gain is a risk factor for the onset of polycystic ovary syndrome, patients weight must be carefully monitored (see Warnings and Precautions).
Nervous System Disorders: Very common: Tremors.
Common: Extrapyramidal disorders, stupor*, sedation, convulsion*, memory impairment, headache, nystagmus.
Uncommon: Coma*, encephalopathy*, lethargy, reversible parkinsonian syndromes, ataxia, paresthesia.
Rare: Insidious and progressive cognitive disorders (that may be associated with dementia) reversible a few weeks to months after discontinuation of treatment.
*Cases of stupor or lethargy sometimes leading to a transient coma (encephalopathy) with valproate have been observed regressing upon treatment disconinuation or dose reduction. These conditions occur most frequently during polytherapies (especially phenobarbital and topiramate) or sudden increase in valproate doses.
Ear and Labyrinth Disorders: Common: Hearing loss.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Pleural effusion.
Gastrointestinal Disorders: Very common: Nausea.
Common: Vomiting, gingival disorders (mainly gingival hyperplasia), stomatitis, epigastric pain, diarrhoea that may occur in some patients at the start of treatment, but usually disappear after a few days without discontinuing treatment.
Uncommon: Pancreatitis sometimes fatal and that requires early treatment discontinuation (see Warnings and Precautions).
Renal and Urinary Disorders: Uncommon: Renal insufficiency.
Rare: Enuresis, urinary incontinence, tubulointerstitial nephritis.
Skin and Subcutaneous Tissue Disorders: Common: Transient and/or dose-dependent, hair loss.
Uncommon: Angioedema, skin reactions, hair disorders (such as abnormal hair texture, changes in hair colour, abnormal hair growth).
Rare: Lyell syndrome (toxic epidermal necrolysis), Stevens-Johnson syndrome, erythema multiforme, DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) syndrome.
Endocrine Disorders: Uncommon: Syndrome of inappropriate antidiuretic hormone secretion (SIADH), hyperandrogenism (hirsutism, virilization, acne, adrogenic, alopecia and/or increased androgenic hormone levels).
Rare: Hypothyroidism (see Use in Pregnancy & Lactation).
Metabolic and Nutritional Disorders: Common: Hyponatraemia.
Rare: Hyperammonaemia*(see Warnings and Precautions).
*Cases of isolated and moderate hyperammonaemia without change in liver function tests may occur, especially in case of polytherapy and should not cause treatment discontinuation.
However cases of hyperammonaemia with neurological symptoms (including coma) have also been reported thereby requiring further investigations (see Warnings and Precautions).
Benign, Malignant and Unspecified Tumour (including Cysts and Polyps): Rare: Myelodysplastic syndrome.
Vascular Disorders: Common bleeding (see Warnings, Precautions and Adverse Reactions).
General Disorders and Administration Site Anomalies: Common: Within minutes following the injection, nausea or dizziness may occur which spontaneously disappear within a few minutes.
Uncommon: Hypothermia, non-severe peripheral oedema.
Unknown: Risk of local tissue necrosis in case of repeated injections.
Hepatobiliary Disorders: Common: Liver dysfunction (see Warnings and Precautions).
Reproductive Organ and Breast Disorders: Common: Menstrual irregularities.
Uncommon: Amenorrhoea.
Rare: Impact on spermatogenesis (reduction in sperm mobility in particular) (see Precautions) polycystic ovaries.
Musculoskeletal and Systemic Disorders: Uncommon: Decreased bone mineral density, osteopenia, osteoporosis and fractures in patients treated long term with Sodium Valproate Aguettant. The way that SODIUM VALPROATE AGUETTANT acts on bone metabolism is not known.
Rare: Systemic lupus erythematosus (see Warnings and Precautions), rhabdomyolysis (see Warnings and Precautions).
Psychiatric Disorders: Common: Confusion, hallucinations*, aggression*, agitation*, attention disorders*.
Rare: Abnormal behaviour*, psychomotor hyperactivity*, learning difficulties*.
*These reactions are mostly seen in the paediatric population.
Reporting of Suspected Adverse Reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
Drug Interactions
Contraindicated Combinations: Mefloquine: In epileptic patients, risk of the occurrence of epileptic seizures due to the increase in the metabolism of valproic acid and the seizure-inducing effect of mefloquine.
St. John's Wort: Risk of decreased plasma concentrations and efficacy of the anticonvulsant.
Inadvisable Combinations: Lamotrigine: Increased risk of increased toxicity of lamotrigine particularly severe skin reactions (toxic epidermal necrolysis).
Furthermore, an increase in the plasma concentrations of lamotrigine (decreased hepatic metabolism by valproate).
If such a combination is necessary, close clinical monitoring is necessary.
Penems: Risk for the occurrence of seizures due to fast decrease in the plasma concentrations of valproic acid that could be undetectable.
Combinations Requiring Precautions for Use: Aztreonam: Risk of the occurrence of seizures due to a decrease of the plasma concentrations of valproic acid.
Clinical monitoring, measurement of the plasma concentrations and dose adjustment of the anticonvulsant may be required during treatment with the anti-infective and after its discontinuation.
Carbamazepine: Increased plasma concentrations of the active metabolite of carbamezepine with signs of overdose. In addition, a decrease in the plasma concentrations of valproic acid due to an increase in its metabolism in the liver by carbamazepine can occur.
Clinical monitoring, monitoring of plasma concentrations, and dosage adjustment of the two anticonvulsants is necessary.
Felbamate: Increased serum concentrations of valproic acid, by 22% to 50% decrease of its clearance with risk of an overdose. Clinical monitoring, monitoring of laboratory test data and possible dosage adjustment of valproate during treatment with felbamate and after its discontinuation are necessary. Moreover, valproic acid may decrease the felbamate mean clearance by up to 16%.
Phenobarbital and by Extrapolation Primidone: Increased plasma concentrations of phenobarbital with signs of an overdose due to the inhibition of its metabolism in the liver, most frequently in children. Furthermore, decrease plasma concentrations of valproic acid due to its increased metabolism in the liver by phenorbabital.
Clinical monitoring during the first 15 days of the combination treatment and immediate reduction of the doses of phenobarbital in the event that the first signs of sedation occur; in particular, the plasma concentrations of the two anticonvulsants should be monitored.
Phenytoin (and by extrapolation fosphenytoin): Change in the plasma concentrations of phenytoin. Furthermore, risk of decreased plasma concentrations of valproic acid due to its increased metabolism in the liver by phenytoin.
Clinical monitoring, monitoring of plasma concentrations and possible dosage adjustment of the two anticonvulsants are necessary.
Rifampicin: Risk of the occurrence of seizures due to its increased metabolism in the liver by rifampicin. Clinical monitoring measurement of the plasma concentrations and possible dosage adjustment of the anticonvulsant should be performed during treatment with rifampicin and after its discontinuation.
Topiramate: Risk of the occurrence of hyperammoniemia or encephalopathy, generally attributed to valproic acid, when it is used in combination with topiramate.
More intensified clinical monitoring at the start of treatment and laboratory test in the event of suggestive symptoms.
Zidovudine: Enhanced risk of zidovudine toxicity (haematological) due to increase in zidovudine plasma concentration (decreasedhepatic metabolism by valproate).
Regular clinical and biological monitoring is recommended. A complete blood count for investigation of anaemia should be performed during the first two months of the combination.
Combinations that are Subject to Precautions for Use: Nimodipine (oral route and by extrapolation, injectable route): Risk of the enhancement of the hypotensive effect of nimodipine due to its increased plasma concentrations (decrease in its metabolism by valproic acid).
Other Forms of Interactions: Oral Contraceptives: Due to the absence of an enzyme-inducing effect, valproate does not decrease the efficacy of oestro-progestative agents in women receiving hormonal contraception.
Lithium: SODIUM VALPROATE AGUETTANT has no effect on serum lithium levels.
Storage
Shelf-Life: 3 years.
After dilution in 0.9% sodium chloride, the physicochemical stability of this diluted solution has been demonstrated for 24 hours. Nonetheless, from a microbiological standpoint, the product should be used immediately.
No special precautions for storage.
MIMS Class
ATC Classification
N03AG01 - valproic acid ; Belongs to the class of fatty acid derivatives antiepileptic.
Presentation/Packing
Inj (amp) 400 mg/4 mL x 5 mL x 10's.
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