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
Antiepileptic + antiepileptic: valproate may increase ethosuximide levels.
Valproate inhibits CYP3A4, one of the metabolic pathways for ethosuximide. Levels may increase 20-30%.
Ethosuximide levels, signs of toxicity.
Monitor ethosuximide levels if combined with valproate.
DailyMed/FDA; EMC-EMC PT
Antimalarial + antiepileptic: valproate may interact with artesunate metabolism.
Valproate may partially inhibit UGT, slightly increasing DHA levels. Clinically modest effect but worth monitoring.
Valproate levels, blood count.
Monitor valproate levels and signs of toxicity.
drugs.com
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)
Ertapenem + valproate: ertapenem reduces valproic acid plasma levels, with inadequate seizure control (QUADRO 2).
Carbapenems, including ertapenem, rapidly and sometimes markedly reduce plasma concentrations of valproic acid/valproate, even after a few doses; the mechanism is not fully clarified (reduced intestinal reabsorption and reduced hydrolysis of the glucuronide with less recycling). The result is loss of seizure control in patients treated with valproate, and QUADRO 2 of Annex 7 explicitly lists ertapenem. The combination should be avoided; if the carbapenem is essential (severe resistant Gram-negative infection), alternative antiepileptic therapy should be considered and valproate levels monitored. The effect may persist for several days after antibiotic discontinuation, so seizure vigilance should continue in that period.
Ertapenem + valproate: ertapenem reduces valproic acid plasma levels — risk of seizures; avoid the combination and monitor levels.
Carbapenems (ertapenem) reduce valproic acid/valproate plasma levels — inadequate seizure control (QUADRO 2, Ertapenem: "May reduce plasma levels of valproic acid/valproate sodium with inadequate seizure control").
Monitor valproate levels and seizure control during the antibiotic.
Seizures (subtherapeutic valproate levels) during ertapenem.
Avoid the combination; if the carbapenem is required, consider alternative antiepileptic therapy and monitor valproate levels.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, QUADRO 2 (Ertapenem)
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)
Anticonvulsant + anticonvulsant: mutual pharmacokinetic interactions.
Carbamazepine induces UGT, increasing valproate glucuronidation. Valproate levels may decrease by 20-30%. The effect is clinically significant in epilepsy (risk of seizures). Monitor valproate levels (target: 50-100 μg/mL). It may be necessary to increase the valproate dose. Alternative: lamotrigine (does not significantly induce UGT).
Antiepileptic + CYP inducer: carbamazepine may reduce valproate levels by 20-30%. Monitor valproate levels.
Carbamazepine may increase valproate metabolism (glucuronidation induction). Valproate may inhibit carbamazepine epoxide metabolism. Close monitoring.
Carbamazepine and valproate levels, signs of toxicity.
Toxicity of both drugs.
Monitor levels of both drugs. Adjust doses as needed.
DailyMed/FDA
Combining Valproate with Lamotrigine increases Lamotrigine concentrations, with an increased risk of serious skin reactions, including Stevens-Johnson syndrome.
Lamotrigine is primarily metabolised by glucuronidation via UGT2B7 (and UGT1A4). Valproate potently inhibits these enzymes, increasing lamotrigine half-life from 25 h to 60 h and doubling steady-state levels. The most serious risk is Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), especially when the initial dose is high or titration is rapid. The Portuguese Prontuário Terapêutico recommends: initial dose 12.5 mg/day (instead of 25 mg), increases of 25 mg every 2 weeks (instead of weekly), and immediate discontinuation at any skin rash. Monitor for skin rashes daily during the first 8 weeks.
Valproate doubles lamotrigine levels via UGT2B7 inhibition. Risk of SJS/TEN especially at high initial doses.
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)
Antiepileptic + antiepileptic: both inhibit carbonic anhydrase. Risk of renal stones and metabolic acidosis.
Topiramate inhibits carbonic anhydrase (isoenzymes II and IV), causing hyperchloraemic metabolic acidosis (5-10% of patients) and renal stones (1-2%). Valproate also weakly inhibits carbonic anhydrase. The combination significantly increases these risks. Monitor serum bicarbonate quarterly, GFR, and consider annual renal ultrasound. Maintain adequate hydration (>2 L/day). Supplement potassium citrate if bicarbonate <20 mEq/L.
Both inhibit carbonic anhydrase. Additive risk of renal stones and metabolic acidosis.
Topiramate and valproate both inhibit carbonic anhydrase. The combination increases the risk of hyperchloraemic metabolic acidosis and renal stones. Valproate may slightly increase topiramate levels.
Bicarbonate, GFR, renal ultrasound.
Symptomatic metabolic acidosis, nephrolithiasis.
Monitor serum bicarbonate and GFR. Maintain adequate hydration. Consider bicarbonate supplementation.
DailyMed/FDA; EMC-UK
Antiepileptic + antiepileptic: additive effect on tremor and sedation.
Both can cause tremor and sedation as adverse effects. The effect is additive but there is no pharmacokinetic interaction — gabapentin is not metabolised by CYP and valproate does not affect gabapentin renal excretion. Monitor sedation and tremor, especially in the elderly.
Additive effect on tremor and sedation. No significant pharmacokinetic interaction.
Both can cause tremor and sedation. The effect is additive but there is no significant pharmacokinetic interaction.
Sedation, tremor.
Excessive sedation.
Monitor sedation and tremor. Adjust doses if necessary.
DailyMed/FDA; EMC-UK
Combining Phenytoin with Valproate may increase or decrease the free fraction of Phenytoin, with a risk of toxicity or loss of efficacy.
Valproate may displace phenytoin from plasma albumin, increasing the free fraction from 10% to 20-30%. The effect is complex: total phenytoin levels may decrease (first-order metabolism of the increased free fraction), but free (pharmacologically active) levels may increase. Measure FREE phenytoin levels, not just total. Adjust dose based on free levels (target: 1-2 μg/mL free).
Valproate displaces phenytoin from albumin, increasing free fraction. Monitor free levels.
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)
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
Risk of neural tube defects (1-2%), fetal valproate syndrome, cognitive impairment. Dose >1500 mg/day = higher risk.
Use minimum effective dose. Supplement folic acid 5 mg/day. Morphological ultrasound at 16-20 weeks.
DailyMed/FDA; EMC-UK
CONTRAINDICATED in hepatic impairment. Risk of fulminant hepatitis, especially in children <2 years.
Do not administer. Monitor AST/ALT if prolonged use.
DailyMed/FDA; EMC-UK
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 ; Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 2, Drugs and Breastfeeding: No useful information is available.
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.
