Valproic acid


Concise Prescribing Info
Indications/Uses
Listed in Dosage.
Dosage/Direction for Use
Adult : PO Migraine prophylaxis Initial: 250 mg bid. Max: 1 g/day; extended-release 500 mg once daily for 7 days, increased to 1 g once daily. Usual dose: 500-1000 mg/day. Acute manic episodes of bipolar disorder As valproate semisodium: Initial: 750 mg/day in divided doses, increase as needed based on response. Max: 60 mg/kg/day. Complex partial seizures As valproic acid or valproate semisodium: ≥10 yr Initial: 10-15 mg/kg/day in 2-4 divided doses, increase if needed. Max: 60 mg/kg/day. As Na valproate: 600 mg/day in 2 divided doses, increase if needed. Usual: 1-2 g/day. Max: 2.5 g/day. Simple and complex absence seizures As monotherapy, conversion to monotherapy or adjunctive therapy. As valproic acid or valproate semisodium: ≥10 yr Initial: 15 mg/kg/day in 2-4 divided doses, increase if needed. Max: 60 mg/kg/day. Bipolar disorder As valpromide: 0.6-1.8 g/day in 2 divided doses. Usual: 1.2 g/day. May increase slowly to reach optimal dose w/ simultaneous and progressive dose reduction of concurrent psychotropic drugs. IV Complex partial seizures; Simple and complex absence seizures As monotherapy, conversion to monotherapy or adjunctive therapy. As Na valproate: Initial: 10-15 mg/kg/day, increase slowly until control is achieved. Usual: 20-30 mg/kg/day. Daily doses to be given in 2-4 divided doses. Max: 60 mg/kg/day.
Dosage Details
Intravenous
Complex partial seizures, Simple and complex absence seizures
Adult: As monotherapy, conversion to monotherapy or adjunctive therapy. Given as sodium valproate: ≥10 yr Initially 10-15 mg/kg/day in 2-4 divided doses, increased by 5-10 mg/kg/wk. Usual dose: 20-30 mg/kg/day. Each dose to be given as slow IV inj over 3-5 min or by infusion in 0.9% saline, 5% dextrose or lactated ringer's inj over 60 min (Max rate: 20 mg/min). Max: 2.5 g/day.
Child: As monotherapy, conversion to monotherapy or adjunctive therapy. Given as sodium valproate: Initially 10 mg/kg/day in 2-4 divided doses, increased until control is achieved. Usual range: 20-30 mg/kg/day. Max: 40 mg/kg/day w/ plasma valproic acid levels monitoring.
Elderly: Initiate at lower dose and increase slowly.

Oral
Prophylaxis of migraine
Adult: As valproate semisodium: Initially, 250 mg bid. Max: 1 g/day; extended-release: 500 mg once daily for 7 days then increase to 1 g once daily. Usual range: 500-1000 mg/day.
Elderly: Initiate at lower dose and increase slowly.

Oral
Acute manic episodes of bipolar disorder
Adult: As valproate semisodium: Initially, 750 mg/day in divided doses or 25 mg/kg once daily as extended-release, increase dose rapidly as possible to achieve optimal response or trough plasma concentration range between 50-125 mcg/mL. Max: 60 mg/kg/day.
Elderly: Initiate at lower dose and increase slowly.

Oral
Simple and complex absence seizures
Adult: As monotherapy, conversion to monotherapy or adjunctive therapy. Given as valproic acid or valproate semisodium: ≥10 yr Initially 15 mg/kg/day in 2-4 divided doses, increased by 5-10 mg/kg/wk. Max: 60 mg/kg/day.
Child: As monotherapy, conversion to monotherapy or adjunctive therapy: Given as sodium valproate: >20 kg: 400 mg/day in 2 divided doses, increased gradually until control is achieved. Usual range: 20-30 mg/kg/day. Max: 35 mg/kg/day. <20 kg: 20 mg/kg/day in 2 divided doses, increased to 40 mg/kg/day.
Elderly: Initiate at lower dose and increase slowly.

Oral
Bipolar disorder
Adult: As valpromide: 600-1800 mg/day in 2 divided doses. Usual dose: 1200 mg/day. Initiate at required dose or dosage may be increased every 2-3 days to reach optimal dose in 2 wk w/ simultaneous and progressive dose reduction of concurrent psychotropic drugs.

Oral
Complex partial seizures
Adult: As monotherapy, conversion to monotherapy or adjunctive therapy. Given as valproic acid or valproate semisodium: ≥10 yr Initially 10-15 mg/kg/day in 2-4 divided doses, increased by 5-10 mg/kg/wk. Max: 60 mg/kg/day. Given as sodium valproate: 600 mg/day in 2 divided doses, increased by 150-300 mg every 3 days. Usual range: 1-2 g/day (20-30 mg/kg/day). Max: 2.5 g/day.
Child: As monotherapy, conversion to monotherapy or adjunctive therapy. Given as sodium valproate: >20 kg: 400 mg/day in 2 divided doses, increased gradually until control is achieved. Usual range: 20-30 mg/kg/day. Max: 35 mg/kg/day. <20 kg: 20 mg/kg/day in 2 divided doses, increased to 40 mg/kg/day.
Elderly: Initiate at lower dose and increase slowly.
Special Patient Group
Mutations of mitochondrial DNA polymerase γ (POLG) causes hereditary neurometabolic syndromes such as Alpers-Huttenlocher syndrome (AHS). The A467T and W748S mutations are present in approximately 2/3 of patients with autosomal recessive POLG-related disorders. Risk of valproate-induced acute liver failure and death is increased in these patients. Severe hepatotoxic reaction on valproic acid administration has been reported in several patients carrying POLG mutations, especially in children with AHS. According to studies, approx 1/3 of AHS patients developed liver failure within 3 months of exposure to valproic acid. To identify individuals who are at high risk of developing valproic acid hepatotoxicity, POLG mutation testing should be performed in accordance with current clinical practice.
Renal Impairment
Dose adjustments may be needed.
Hepatic Impairment
Contraindicated.
Administration
Should be taken with food.
Contraindications
Pre-existing or family history of hepatic dysfunction, porphyria, urea cycle disorders, known mitochondrial disorders caused by POLG mutation and in children (<2 years) who are suspected of having a mitochondrial disorder. Hepatic impairment. Pregnancy (prophylaxis of migraine).
Special Precautions
Patients with HIV, cytomegalovirus (CMV) infection, SLE. Renal impairment. Children (<2 years on anticonvulsant polytherapy, with congenital metabolic disorders, severe seizure disorders, mental retardation, organic brain disease). Use in children ≥2 years of age who are suspected of having POLG-related disorder only after other anticonvulsants have failed. Lactation.
Adverse Reactions
Headache, nausea, vomiting, diarrhoea, anorexia, increased appetite, wt gain, nystagmus, somnolence, dizziness, fatigue, hyperammonaemic encephalopathy, hypothermia, hallucinations. Thrombocytopenia (dose related), tremors, LFT elevation. Chronic use may lead to carnitine deficiency.
Potentially Fatal: Fatal hepatotoxicity esp in childn <2 yr, multi-organ and dermatologic hypersensitivty reactions (e.g. Stevens-Johnson syndrome, erythema multiforme), pancreatitis, blood dyscrasias.
IV/Parenteral/PO: D, X (when used for migraine prophylaxis); PO: D, X (when used for migraine prophylaxis)
Patient Counseling Information
Seek medical advice during first signs of pancreatitis (e.g. abdominal pain, nausea, vomiting and anorexia), blood and liver toxicity.
MonitoringParameters
Monitor LFT before and during the 1st 6 mth of therapy. Monitor blood cell count (including platelet count), bleeding time and coagulation tests before the start of therapy or before surgery, and in cases of spontaneous bruising or bleeding. Monitor for atypical behaviour (e.g. suicidal ideation and behaviour) during and after therapy.
Overdosage
Symptoms: Somnolence, CNS depression, heart block, deep coma, respiratory insufficiency, multiple organ failure, death. Management: Activated charcoal may be given orally to adults and childn who present w/in 1 hr of ingesting >100 mg/kg; alternatively gastric lavage or emesis may be useful in reducing drug absorption but effectiveness may vary w/ time since ingestion. Due to saturable protein binding, haemodialysis may be useful in removing unbound drug. Treatment is supportive and it is important to maintain adequate urinary output. Naloxone may be useful in reversing the CNS depressant effects of valproate overdosage but it should be used w/ caution in patients w/ epilepsy as it may reverse the antiepileptic effects of valproate.
Drug Interactions
Increased risk of toxicity w/ bupropion. Increased risk of convulsions w/ mefloquine. Increased risk of carnitine deficiency w/ pivmecillinam and pivampicillin. Increased risk of hepatotoxicity and carbamazepine toxicity w/ a decrease in valproic acid levels w/ concurrent carbamazepine. Decreased valproic acid and increased ethosuximide serum levels w/ ethosuximide. Decreased valproic acid levels w/ carbapenems, rifampicin, phenytoin, phenobarbital (or primidone) and antineoplastic drug regimens. Increased valproic acid levels w/ felbamate and aspirin. Increased risk of hepatotoxicity w/ olanzepine. Concurrent use increased phenobarbital, nimodipine, nifedipine, lamotrigine, zidovudine, amitriptyline, nortriptyline and benzodiazepines levels. Concurrent use decreased tigabine and clozapine levels. Increased risk of absence status w/ clonazepam. Increased risk of hyperammonaemia w/ topiramate. Increased free valproic acid concentrations w/ highly protein bound drugs.
Potentially Fatal: Concomitant carbapenem is not recommended as this may decrease valproate levels. Avoid concurrent salicylates in childn <3 yr due too risk of hepatotoxicity. Increased risk of hepatotoxicity w/ cosyntropin. Avoid ethanol as this may increase CNS depression.
Lab Interference
May cause false positive for urinary ketones. May alter thyroid function test.
Action
Description: Valproate is a generic term used to describe valproic acid, its salts and derivatives. It is available in various forms including the sodium salts (valproate semisodium and sodium valproate), the amide derivative (valpromide), or as valproic acid. Valproate is a carboxylic acid anticonvulsant. It has been suggested that its antiepileptic activity is related to increased brain levels of γ-aminobutyric acid (GABA).
Pharmacokinetics:
Absorption: Valproic acid is rapidly and completely absorbed from the GI tract while valpromide is absorbed slower than valproic acid. Time to peak plasma concentration: Oral: Approx 4 hr; extended release: 4-17 hr. Bioavailability: Extended release: Approx 90%.
Distribution: Plasma protein binding (concentration dependent): 80-90%; free fraction: Increases from approx 10% at 40 mcg/mL to approx 18.5% at 130 mcg/mL; decreases in the elderly and patients w/ hepatic or renal impairment. Crosses the placenta; enters breast milk.
Metabolism: Valpromide is almost completely and rapidly metabolised in the liver to valproic acid. Valproic acid is extensively metabolised by liver, via glucuronidation and mitochondrial β-oxidation.
Excretion: Excreted in urine (30-50% as glucuronide conjugate; <3% as unchanged drug), small amounts in faeces and expired air. Elimination half-life: Adult: 5-20 hr; >2 mth: 7-13 hr.
Storage
Store between 15-30°C.
References
Sitarz K, Elliott H, Karaman B et al. Valproic acid triggers increased mitochondrial biogenesis in POLG-deficient fibroblasts. Molecular Genetics and Metabolism. 2014 May;112(1):57-63. doi: 10.1016/j.ymgme.2014.03.006. Accessed 22/11/2019. PMID: 24725338

Stewart JD, Horvath R, Baruffini E et al. POLG determines the risk of sodium valproate induced liver toxicity. Hepatology. 2010 Nov;52(5). doi: 10.1002/hep.23891. Accessed 25/09/2018. PMID: 21038416

Stewart JD, Horvath R, Baruffini E et al. Polymerase γ gene POLG determines the risk of sodium valproate-induced liver toxicity. Hepatology. 2010 Nov;52(5). doi: 10.1002/hep.23891. Accessed 22/11/2019. PMID: 21038416

Wong L, Naviaux R, Brunetti-Pierri N et al. Molecular and Clinical Genetics of Mitochondrial Diseases Due to POLG Mutations. Human Mutation. 2008 Sep;29(9):150-172. doi: 10.1002/humu.20824. Accessed 26/09/2018. PMID: 18546365

Annotation of FDA Label for Valproic acid and POLG. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 22/11/2019.

Annotation of HCSC Label for Valproic acid and OTC, POLG. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 25/09/2018.

Anon. Valproic acid and Derivatives. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 22/11/2019.

Clinical Annotation for rs3087374 (POLG); Valproic acid; Toxic Liver Disease. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 22/11/2019.

Depakene Capsules, Oral Solution (AbbVie Inc.). U.S. FDA. https://www.fda.gov/. Accessed 22/11/2019.

Disclaimer: This information is independently developed by MIMS based on Valproic acid from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2020 MIMS. All rights reserved. Powered by MIMS.com
  • Epilim/Epilim Chrono
  • Orfiril Long
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Sign up for free
Already a member? Sign in