Antiepileptic (membrane stabilizer; GABA transaminase inhibitor)
Valproate is a medicine used to control certain types of epileptic seizures (partial and absence). It is very effective, but has important risks — mainly for the liver and in pregnancy — so treatment is closely monitored by the doctor.
Also known as: Depakene, Depakote, ácido valpróico, valproato de sódio
Combining Valproate with Lamotrigine increases Lamotrigine concentrations, with an increased risk of serious skin reactions, including Stevens-Johnson syndrome.
The lamotrigine label documents that "valproate inhibits glucuronidation and decreases the apparent clearance of lamotrigine" — in practice it doubles the lamotrigine half-life and may double its concentrations, so the lamotrigine starting dose and titration must be halved when given with valproate. The same label identifies valproate as one of the factors associated with a higher risk of serious skin reactions (including Stevens-Johnson syndrome), especially when the starting dose is exceeded or titration is rapid. Monitor the patient for skin eruption, fever, lymphadenopathy or mucosal involvement (signs of serious hypersensitivity) — stop lamotrigine at the first sign of rash, unless clearly unrelated.
Lamotrigine + valproate: valproate inhibits lamotrigine glucuronidation (half-life ~2x, levels up) — higher risk of serious rash. Titrate slowly and watch for skin eruption.
Valproate inhibits the glucuronidation of Lamotrigine, doubling its half-life and raising its concentrations; the risk of severe rash is highest in the first months.
Watch for rash, fever, lymphadenopathy or flu-like symptoms in the first 8 weeks.
Any rash or symptoms suggestive of a serious reaction require immediate discontinuation of Lamotrigine and medical evaluation.
Reduce the Lamotrigine dose (approximately half) when given with Valproate and increase it very gradually.
DailyMed/FDA (NIH/NLM) — approved Valproic acid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a33f7657-ad0f-43e9-ba48-024746e6d08e ; approved Lamotrigine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=57f04b9b-06cd-8044-e063-6394a90ae733 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Combining Phenytoin with Valproate may increase or decrease the free fraction of Phenytoin, with a risk of toxicity or loss of efficacy.
Valproate displaces phenytoin from plasma protein binding and inhibits its metabolism, potentially raising the free fraction of phenytoin even with apparently normal total levels — the valproate label states that "phenobarbital and/or phenytoin concentrations may be affected" and recommends "periodic plasma concentration determinations of concomitant antiepileptics during the early course of therapy"; phenytoin, in turn, is an enzyme inducer and "may lower valproate levels" (the phenytoin label classifies its effect on valproate as unpredictable). A raised phenytoin free fraction increases the risk of toxicity (nystagmus, ataxia, confusion) with total levels in the therapeutic range. Monitor free phenytoin (or clinical symptoms), toxicity signs and adjust doses; do not interpret total levels in isolation in patients with hypoalbuminaemia or renal impairment.
Phenytoin + valproate: valproate displaces phenytoin from protein binding and inhibits its metabolism (free fraction up); phenytoin may lower valproate levels. Monitor levels and toxicity signs.
Valproate displaces Phenytoin from plasma proteins and inhibits its metabolism; the effect on the free fraction is variable. Phenytoin may in turn lower Valproate levels.
Nystagmus, ataxia, sedation or worsening seizure control require reassessment.
Signs of Phenytoin toxicity or worsening seizures require level assessment.
Monitor Phenytoin levels (ideally the free fraction) and clinical signs of toxicity.
DailyMed/FDA (NIH/NLM) — approved Phenytoin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ef4e97a7-cd18-47a9-a016-2eca5481a87e ; approved Valproic acid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a33f7657-ad0f-43e9-ba48-024746e6d08e — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Combining Phenobarbital with Valproate increases Phenobarbital concentrations, with a risk of sedation and toxicity.
The phenobarbital label explicitly states that "valproate and valproic acid increase the phenobarbital serum levels; therefore, phenobarbital blood levels should be closely monitored and appropriate dosage adjustments made as clinically indicated". The valproate label confirms that "valproate inhibits the metabolism of phenobarbital". Raised phenobarbital levels potentiate CNS depression (sedation, somnolence, ataxia, respiratory compromise at high doses), mainly in the elderly. When starting valproate in patients stabilised on phenobarbital, monitor phenobarbital levels and clinical toxicity signs, reducing the phenobarbital dose if needed (usually 20–30%).
Phenobarbital + valproate: valproate inhibits phenobarbital metabolism and raises its levels (sedation up). Monitor levels and CNS depression.
Valproate inhibits Phenobarbital metabolism, raising its serum levels and potentiating its depressant effect.
Monitor sedation and, if available, Phenobarbital levels.
Excessive sedation or respiratory depression require discontinuation and evaluation.
Monitor signs of sedation and, if available, Phenobarbital levels; consider reducing the dose.
DailyMed/FDA (NIH/NLM) — approved Phenobarbital label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fa09b4f2-edb0-4594-a2d2-b16f7b9686b4 ; approved Valproic acid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a33f7657-ad0f-43e9-ba48-024746e6d08e — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Combining Valproate with Warfarin may increase the anticoagulant effect and the risk of bleeding.
Valproate is extensively protein-bound (90% or more) and can displace warfarin from its binding sites, increasing the active free fraction and the anticoagulant effect; it can also interfere with warfarin metabolism. Reports exist of INR elevation and bleeding when valproate is added to warfarin. The INR should be monitored at initiation and during treatment and the warfarin dose adjusted; the effect is more relevant in patients with hypoalbuminaemia (elderly, liver disease), in whom the free fraction of both drugs is higher.
Valproate is protein-bound and can displace warfarin, raising the INR. Monitor the INR when starting and adjust the dose.
Valproate displaces Warfarin from plasma proteins, potentially increasing the free fraction and the anticoagulant effect.
Monitor the INR and signs of bleeding.
A high INR or active bleeding require anticoagulant adjustment.
Monitor the INR and watch for bleeding signs.
DailyMed/FDA (NIH/NLM) — approved Valproic acid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a33f7657-ad0f-43e9-ba48-024746e6d08e ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Alcohol potentiates the central nervous system depression of valproate and increases the risk of hepatotoxicity.
Avoid alcohol intake during treatment.
DailyMed/FDA (NIH/NLM) — approved Valproate label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a33f7657-ad0f-43e9-ba48-024746e6d08e
Valproate can be administered with or without food; taking it with food may reduce gastrointestinal irritation.
Take at the same time every day, with or without food.
DailyMed/FDA (NIH/NLM) — approved Valproate label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a33f7657-ad0f-43e9-ba48-024746e6d08e
Valproate is contraindicated in patients with significant hepatic disease or severe hepatic dysfunction (risk of fatal hepatic failure).
Do not use in liver disease; assess liver function before and during treatment.
DailyMed/FDA (NIH/NLM) — approved Valproate label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a33f7657-ad0f-43e9-ba48-024746e6d08e
Valproate is contraindicated in patients with mitochondrial disorders such as Leber disease (risk of hepatic failure).
Do not use; consider an alternative anticonvulsant.
DailyMed/FDA (NIH/NLM) — approved Valproate label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a33f7657-ad0f-43e9-ba48-024746e6d08e
Valproate is strongly teratogenic (neural tube defects, facial and cardiovascular malformations) and lowers the child IQ.
Contraindicated in pregnancy; in women of childbearing age, use only with a pregnancy prevention programme.
Present in breast milk in small amounts; generally avoided during breastfeeding.
Mandatory effective contraception; reassess the pregnancy prevention programme annually.
DailyMed/FDA (NIH/NLM) — approved Valproate label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a33f7657-ad0f-43e9-ba48-024746e6d08e
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Broad-spectrum anticonvulsant (also a mood stabiliser). The relationship between plasma concentration and clinical response is not well documented; concentration-dependent protein binding affects clearance, so monitoring of total valproate may not reliably reflect the bioactive fraction.
The exact mechanism has not been established; it has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA).
With extended-release tablets, Tmax ranges from 4 to 17 hours; the drug is well absorbed. Plasma protein binding is concentration-dependent: the free fraction increases from about 10% (40 mcg/ml) to 18.5% (130 mcg/ml); in cerebrospinal fluid, concentrations approximate the unbound plasma fraction.
Metabolised almost entirely in the liver: on monotherapy, 30 to 50% of the dose appears in urine as a glucuronide conjugate; mitochondrial beta-oxidation is the other major pathway (over 40% of the dose); less than 3% is excreted unchanged in urine.
The mean terminal half-life on monotherapy ranges from 9 to 16 hours after oral doses of 250 to 1,000 mg.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
