Chemical formula: C₈H₁₆O₂ Molecular mass: 144.211 g/mol PubChem compound: 3121
Valproic acid interacts in the following cases:
Valproic acid may potentiate the effect of MAO inhibitors; therefore, clinical monitoring is advised and the dosage of the other psychotropics should be adjusted when appropriate.
The anticoagulant effect of warfarin and other coumarin anticoagulants may be increased following displacement from plasma protein binding sites by valproic acid. The prothrombin time should be closely monitored.
Oestrogens 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 has no enzyme inducing effect; as a consequence, valproate does not reduce efficacy of oestroprogestative agents in women receiving hormonal contraception.
Protease inhibitors such as lopinavir and ritonavir decrease valproate plasma level when co-administered.
Valproic acid may potentiate the effect of other antipsychotics; therefore, clinical monitoring is advised and the dosage of the other psychotropics should be adjusted when appropriate.
Valproic acid may potentiate the effect of benzodiazepines; therefore, clinical monitoring is advised and the dosage of the other psychotropics should be adjusted when appropriate.
Valproic acid may potentiate the effect of antidepressants; therefore, clinical monitoring is advised and the dosage of the other psychotropics should be adjusted when appropriate.
Amenorrhoea, polycystic ovaries and increased testosterone levels have been reported in women using valproate. Valproic acid administration may also impair fertility in men. Case reports indicate that fertility dysfunctions are reversible after treatment discontinuation.
Concomitant administration of valproate and acetazolamide has been associated with encephalopathy and/or hyperammonaemia. In patients taking these two drugs, careful monitoring for signs and symptoms is advised in particularly at-risk patients such as those with pre-existing encephalopathy.
In case of concomitant use of sodium valproate and highly protein bound agents (e.g. aspirin), free valproic acid plasma levels may be increased.
Clinical toxicity has been reported when valproic acid was administered with carbamazepine as valproic acid may potentiate toxic effects of carbamazepine. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.
Anti-epileptics with enzyme inducing effect (including carbamazepine) decrease valproic acid plasma concentrations. Dosages should be adjusted according to clinical response and blood levels in case of combined therapy.
Chloroquine increase valproic acid metabolism and may lower the seizure threshold; therefore epileptic seizures may occur in cases of combined therapy. Accordingly, the dosage of valproic acid may need adjustment.
Cholestyramine may lead to a decrease in plasma level of valproate when co-administered.
Valproic acid plasma levels may be increased (as a result of reduced hepatic metabolism) in case of concomitant use with cimetidine.
Valproic acid plasma levels may be increased (as a result of reduced hepatic metabolism) in case of concomitant use with erythromycin.
Valproic acid may decrease the felbamate mean clearance by up to 16%.
On the other hand, combination of felbamate and valproic acid decreases valproic acid clearance by 22%–50% and consequently increase the valproic acid plasma concentrations. Valproic acid dosage should be monitored.
Decreases in blood levels of valproic acid have been reported when it is co-administered with carbapenem agents resulting in a 60%–100% decrease in valproic acid levels within two days, sometimes associated with convulsions. Due to the rapid onset and the extent of the decrease, co-administration of carbapenem agents in patients stabilised on valproic acid should be avoided. If treatment with these antibiotics cannot be avoided, close monitoring of valproic acid blood levels should be performed.
Valproic acid reduces the metabolism of lamotrigine and increases the lamotrigine mean half-life by nearly two fold. This interaction may lead to increased lamotrigine toxicity, in particular serious skin rashes. Therefore clinical monitoring is recommended and dosages should be adjusted (lamotrigine dosage decreased) when appropriate.
Mefloquine increases valproic acid metabolism and may lower the seizure threshold; therefore epileptic seizures may occur in cases of combined therapy. Accordingly, the dosage of valproic acid may need adjustment.
Decreases in blood levels of valproic acid have been reported when it is co-administered with carbapenem agents resulting in a 60–100% decrease in valproic acid levels within two days, sometimes associated with convulsions. Due to the rapid onset and the extent of the decrease, co-administration of carbapenem agents in patients stabilised on valproic acid should be avoided. If treatment with these antibiotics cannot be avoided, close monitoring of valproic acid blood levels should be performed.
In patients concomitantly treated with sodium valproate and nimodipine the exposure to nimodipine can be increased by 50%. The nimodipine dose should therefore be decreased in case of hypotension.
Valproic acid may decrease the olanzapine plasma concentration.
Valproic acid increases phenobarbital plasma concentrations (due to inhibition of hepatic catabolism) and sedation may occur, particularly in children. Therefore, clinical monitoring is recommended throughout the first 15 days of combined treatment with immediate reduction of phenobarbital doses if sedation occurs and determination of phenobarbital plasma levels when appropriate.
Anti-epileptics with enzyme inducing effect (including phenobarbital) decrease valproic acid plasma concentrations. Dosages should be adjusted according to clinical response and blood levels in case of combined therapy.
Valproic acid metabolite levels may be increased in the case of concomitant use with phenobarbital. Therefore patients treated with those two drugs should be carefully monitored for signs and symptoms of hyperammonaemia.
Valproic acid decreases phenytoin total plasma concentration. Moreover valproic acid increases phenytoin free form with possible overdose symptoms (valproic acid displaces phenytoin from its plasma protein binding sites and reduces its hepatic catabolism). Therefore clinical monitoring is recommended; when phenytoin plasma levels are determined, the free form should be evaluated.
Anti-epileptics with enzyme inducing effect (including phenytoin) decrease valproic acid plasma concentrations. Dosages should be adjusted according to clinical response and blood levels in case of combined therapy.
Valproic acid metabolite levels may be increased in the case of concomitant use with phenytoin. Therefore patients treated with those two drugs should be carefully monitored for signs and symptoms of hyperammonaemia.
Valproic acid increases primidone plasma levels with exacerbation of its adverse effects (such as sedation); these signs cease with long term treatment. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.
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.
Co-administration of valproate acid and quetiapine may increase the risk of neutropenia/leucopenia.
Rifampicin may decrease the valproic acid blood levels resulting in a lack of therapeutic effect. Therefore, valproate dosage adjustment may be necessary when it is co-administered with rifampicin.
Valproic acid may lead to an increase in plasma levels 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.
Co-administration of temozolomide and valproic acid may cause a small decrease in the clearance of temozolomide that is not thought to be clinically relevant.
Concomitant administration of valproate and topiramate has been associated with encephalopathy and/or hyperammonaemia. In patients taking these two drugs, careful monitoring for signs and symptoms is advised in particularly at-risk patients such as those with pre-existing encephalopathy.
Valproic acid may raise zidovudine plasma concentration leading to increased zidovudine toxicity.
Decreases in blood levels of valproic acid have been reported when it is co-administered with carbapenem agents resulting in a 60%–100% decrease in valproic acid levels within two days, sometimes associated with convulsions. Due to the rapid onset and the extent of the decrease, co-administration of carbapenem agents in patients stabilised on valproic acid should be avoided. If treatment with these antibiotics cannot be avoided, close monitoring of valproic acid blood levels should be performed.
Valproate is contraindicated as treatment for epilepsy during pregnancy unless there is no suitable alternative to treat epilepsy.
Valproate is contraindicated for use in women of childbearing potential unless the conditions of the Pregnancy Prevention Programme are fulfilled.
Both valproate monotherapy and valproate polytherapy are associated with abnormal pregnancy outcomes. Available data suggest that anti-epileptic polytherapy including valproate is associated with a greater risk of congenital malformations than valproate monotherapy.
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 the mother and the unborn child. If in exceptional circumstances, despite the known risks of valproate in pregnancy and after careful consideration of alternative treatment, a pregnant woman must receive valproate for epilepsy, it is recommended to:
All patients with valproate-exposed pregnancy and their partners should be referred to a specialist experienced in prenatal medicine for evaluation and counselling regarding the exposed pregnancy. Specialised 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 it prevents the birth defects or malformations due to valproate exposure.
Valproate is excreted in human milk with a concentration ranging from 1%-10% of maternal serum levels. Haematological disorders have been shown in breastfed 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.
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 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, 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.
Data have shown that exposure to valproate in utero can have adverse effects on mental and physical development of the exposed children. The risk seems to be dose-dependent but a threshold dose below which no risk exists, cannot be established based on available data. The exact gestational period of risk for these effects is uncertain and the possibility of a risk throughout the entire pregnancy cannot be excluded.
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.
Available data show that children exposed to valproate in utero are at increased risk of autistic spectrum disorder (approximately three-fold) and childhood autism (approximately five-fold) compared with the general study population.
Limited data suggests that children exposed to valproate in utero may be more likely to develop symptoms of attention deficit/hyperactivity disorder (ADHD).
Oestrogen-containing products, including oestrogen-containing hormonal contraceptives, may increase the clearance of valproate, which would result in decreased serum concentration of valproate and potentially decreased valproate efficacy.
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 counselling regarding the risks of valproate for the unborn child to support her informed decision-making regarding family planning.
Amenorrhoea, polycystic ovaries and increased testosterone levels have been reported in women using valproate. Valproate administration may also impair fertility in men. Case reports indicate that fertility dysfunctions are reversible after treatment discontinuation.
Not applicable – use of intravenous formulation restricted to patients unable to take oral therapy.
Use of valproic acid may provide seizure control such that the patient may be eligible to hold a driving licence.
Patients should be warned of the risk of transient drowsiness, especially in cases of anti-convulsant polytherapy or association with benzodiazepines.
The following CIOMS frequency rating is used, when applicable: very common (≥1/10); common (≥1/100 to ≤1/10); uncommon (≥1/1,000 to ≤1/100); rare (≥1/10,000 to ≤1/1,000); very rare (≤1/10,000); not k nown (cannot be estimated from the available data).
Common: liver injury
Severe liver damage, including hepatic failure sometimes resulting in death, has been reported. Increased liver enzymes are common, particularly early in treatment, and may be transient.
Very common: nausea
Common: vomiting, gingival disorder (mainly gingival hyperplasia), stomatitis, gastralgia, diarrhoea
The above adverse events frequently occur at the start of treatment, but they usually disappear after a few days without discontinuing treatment. These problems can usually be overcome by taking valproic acid with or after food.
Uncommon: pancreatitis, sometimes lethal
Very common: tremor
Common: extrapyramidal disorder, stupor*, somnolence, convulsion*, memory impairment, headache, nystagmus, dizziness may occur within a few minutes and it usually resolves spontaneously within a few minutes.
Uncommon: coma*, encephalopathy, lethargy* (see below), reversible parkinsonism, ataxia, paraesthesia, aggravated convulsions
Rare: reversible dementia associated with reversible cerebral atrophy, cognitive disorder
Sedation has been reported occasionally, usually when in combination with other anti-convulsants. In monotherapy it occurred early in treatment on rare occasions, and is usually transient.
* Rare cases of lethargy, occasionally progressing to stupor, sometimes with associated hallucinations or convulsions, have been reported. Encephalopathy and coma have very rarely been observed. These cases have often been associated with too high a starting dose or too rapid a dose escalation, or concomitant use of other anti-convulsants, notably phenobarbital or topiramate. They have usually been reversible on withdrawal of treatment or reduction of dosage.
An increase in alertness may occur; this is generally beneficial, but occasionally aggression, hyperactivity and behavioural deterioration have been reported.
Common: confusional state, hallucinations, aggression*, agitation*, disturbance in attention*
Rare: abnormal behaviour*, psychomotor hyperactivity*, learning disorder*
* These ADRs are principally observed in the paediatric population.
Common: hyponatraemia, weight increased*
* Weight increase should be carefully monitored since it is a factor for polycystic ovary syndrome.
Rare: hyperammonaemia*, obesity
* Cases of isolated and moderate hyperammonaemia without change in liver function tests may occur, are usually transient and should not cause treatment discontinuation. However, they may present clinically as vomiting, ataxia, and increasing clouding of consciousness. Should these symptoms occur valproic acid should be discontinued.
Hyperammonaemia associated with neurological symptoms has also been reported. In such cases further investigations should be considered.
Uncommon: Syndrome of Inappropriate Secretion of ADH (SIADH), hyperandrogenism (hirsutism, virilism, acne, male pattern alopecia, and/or androgen increase)
Rare: hypothyroidism
Common: anaemia, thrombocytopenia
Uncommon: pancytopenia, leucopenia
Rare: bone marrow failure, including pure red cell aplasia, agranulocytosis, anaemia macrocytic, macrocytosis
The blood picture returned to normal when the drug was discontinued.
Isolated findings of a reduction in blood fibrinogen and/or an increase in prothrombin time have been reported, usually without associated clinical signs and particularly with high doses (valproic acid has an inhibitory effect on the second phase of platelet aggregation). Spontaneous bruising or bleeding is an indication for withdrawal of medication pending investigations.
Common: hypersensitivity, transient and/or dose related alopecia (hair loss), nail and nail bed disorders. Regrowth normally begins within six months, although the hair may become more curly than previously.
Uncommon: angioedema, rash, hair disorder (such as abnormal hair texture, hair colour changes, abnormal hair growth)
Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome
Common: dysmenorrhea
Uncommon: amenorrhea
Rare: male infertility, polycystic ovaries
Very rarely gynaecomastia has occurred.
Common: haemorrhage
Uncommon: vasculitis
Rare: diplopia
Common: deafness, a cause and effect relationship has not been established.
Common: urinary incontinence
Uncommon: renal failure
Rare: enuresis, tubulointerstitial nephritis, reversible Fanconi syndrome (a defect in proximal renal tubular function giving rise to glycosuria, amino aciduria, phosphaturia, and uricosuria) associated with valproic acid therapy, but the mode of action is as yet unclear.
Uncommon: hypothermia, non-severe peripheral oedema
Uncommon: bone mineral density decreased, osteopenia, osteoporosis and fractures in patients on long-term therapy with valproic acid. The mechanism by which valproic acid affects bone metabolism has not been identified.
Rare: systemic lupus erythematosus, rhabdomyolysis
Uncommon: pleural effusion
Rare: coagulation factors decreased (at least one), abnormal coagulation tests (such as prothrombin time prolonged, activated partial thromboplastin time prolonged, thrombin time prolonged, INR prolonged)
Rare: myelodysplastic syndrome
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