Sodium Valproate

Mono-therapy and adjunctive therapy for treatment of simple and complex absence seizures, and complex partial seizures. Adjunctive therapy for multiple seizure types, including absence seizures.

Oral

Prophylaxis of migraine
Adult: As valproate semisodium: Initially, 250 mg bid. Max: 1 g daily. 
Elderly: Initiate at lower dose and increase slowly.
Renal impairment: Dose adjustments may be needed. 
Hepatic impairment: Avoid. 
Oral
Acute manic episodes of bipolar disorder
Adult: As valproate semisodium: Initially, 750 mg daily in divided doses, increase as fast as possible to achieve optimal response or desired range of trough plasma concentrations between 50-125 mcg/ml. Max: 60 mg/kg daily. 
Elderly: Initiate at lower dose and increase slowly.
Renal impairment: Dose adjustments may be needed.
Hepatic impairment: Avoid. 
Oral
Complex partial seizures
Adult: As monotherapy, conversion to monotherapy or adjunctive therapy: Given as valproic acid or valproate semisodium, initially 10-15 mg/kg/day in 2-4 divided doses, increased by 5-10 mg/kg/wk. Max: 30mg/kg/day. Given as sodium valproate, 600 mg daily in 2 divided doses, increased by 200 mg every 3 days. Usual range: 1-2 g daily (20 - 30 mg/kg daily). Max: 2.5 g daily.
Child: As monotherapy, conversion to monotherapy or adjunctive therapy: Given as sodium valproate: >20kg: 400 mg/day in 2 divided doses, increased gradually until control achieved. Usual range: 20-30 mg/kg/day. Max: 35mg/kg/day. <20kg: 20mg/kg daily in 2 divided doses, increased to 40mg/kg daily in severe cases, with serum valproic acid monitoring. Monitor clinical chemistry and haematological parameters if doses >40mg/kg daily used. Given as valproic acid or valproate semisodium for ≥10 yr: initially, 10-15 mg/kg/day in 2-4 divided doses, increased by 5-10 mg/kg/wk. Max: 30mg/kg/day. 
Elderly: Initiate at lower dose and increase slowly.
Renal impairment: Dose adjustments may be needed.
Hepatic impairment: Avoid.
Oral
Simple and complex absence seizures
Adult: As monotherapy, conversion to monotherapy or adjunctive therapy: Given as valproic acid or valproate semisodium, initially 15 mg/kg/day in 2-4 divided doses, increased by 5-10 mg/kg/wk. Max: 30 mg/kg/day.
Child: As monotherapy, conversion to monotherapy or adjunctive therapy: Given as sodium valproate: >20kg: 400 mg/day in 2 divided doses, increased gradually until control achieved. Usual range: 20-30 mg/kg/day. Max: 35mg/kg/day. <20kg: 20mg/kg daily in 2 divided doses, increased to 40mg/kg daily with serum valproic acid monitoring in severe cases. Monitor clinical chemistry and haematological parameters if > 40mg/kg daily. 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: 30mg/kg/day.
Elderly: Initiate at lower dose and increase slowly.
Renal impairment: Dose adjustments may be needed. 
Hepatic impairment: Avoid.
Oral
Bipolar disorder
Adult: As valpromide: 900-1800 mg daily in 2 divided doses. Usual dose: 1200 mg daily. Initiate at required dose or dosage may be increased every 2-3 days to reach optimal dose in 2 wk with simultaneous and progressive dose reduction of concurrent psychotropic drugs. 
Intravenous
Complex partial seizures
Adult: Given as sodium valproate: Initially 400-800 mg daily increasing by 150-300 mg every 3 days until control is achieved. Usual dose: 20-30 mg/kg/day. Daily doses to be given in 3-4 divided doses. Each dose to be given as slow IV Inj over 3-5 minutes or by infusion in 0.9% saline or 5% dextrose over 60 minutes (Max rate: 20 mg/minute). Max: 2.5 g daily. 
Child: Given as sodium valproate: Initially 300mg/day increased until control is achieved. Usual range: 20-30 mg/kg/day. Max: 40 mg/kg/day with plasma valproic acid levels monitoring. 
Elderly: Initiate at lower dose and increase slowly.
Renal impairment: Dose adjustments may be needed. 
Hepatic impairment: Avoid.
Intravenous
Simple and complex absence seizures
Adult: Given as sodium valproate: Initially 400-800 mg daily increasing by 150-300 mg every 3 days until control is achieved. Usual dose: 20-30 mg/kg/day. Daily doses to be given in 3-4 divided doses. Each dose to be given as slow IV Inj over 3-5 minutes or by infusion in 0.9% saline or 5% dextrose over 60 minutes (Max rate: 20 mg/minute). Max: 2.5 g daily. 
Child: Given as sodium valproate: Initially 300mg/day increased until control is achieved. Usual range: 20-30 mg/kg/day. Max: 40 mg/kg/day with plasma valproic acid levels monitoring. 
Elderly: Initiate at lower dose and increase slowly.
Renal impairment: Dose adjustments may be needed. 
Hepatic impairment: Avoid.

Preexisting or family history of hepatic dysfunction, active liver disease, porphyria, urea cycle disorders. Pregnancy.

Boxed Warning:

Fatal hepatic failure may occur, especially in children <2 yrs on multiple anticonvulsants, with congenital metabolic disorders, severe seizure disorders with mental retardation, or organic brain disease. Hepatotoxicity may be preceded by nonspecific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting, or loss of seizure control in patients with epilepsy. Monitor LFTs prior to therapy, frequently during 1st 6 months of treatment and at frequent intervals thereafter. Teratogenic effects (eg, neural tube defects), and life-threatening pancreatitis reported; d/c if pancreatitis diagnosed and initiate appropriate treatment.

Increased risk of suicidal thoughts or behavior; monitor for emergence or worsening of depression. Hyperammonemic encephalopathy in urea cycle disorders (UCD) patients; d/c if this occurs

May worsen HIV or cytomegalovirus (CMV) infection; renal impairment; SLE; lactation. 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. Watch out for signs of pancreatitis (e.g. abdominal pain, nausea, vomiting and anorexia), blood and liver toxicity and seek prompt medical advice. Decrease dose or discontinue in patients with excessive somnolence, decreased food or fluid intake. Gradual withdrawal or transition to and from another type of antiepileptic therapy. Suspect hyperammonemic encephalopathy and measure ammonia levels in patients who develop unexplained lethargy, vomiting or changes in mental status. Decrease GI side effects by taking with meals, starting with low dose or taking the enteric coated formulations.

Anorexia, nausea, vomiting, diarrhoea, increased appetite, wt gain, nystagmus, ataxia, somnolence, dizziness, fatigue, hyperammonaemia, hallucinations. Thrombocytopenia (dose related), tremours, elevations of LFT.
Potentially Fatal: Fatal hepatotoxicity esp in children <2 yr, multi-organ hypersensitivty reactions, pancreatitis, blood dyscrasias.

Overdose:

Symptoms: Somnolence, heart block, deep coma, death.

Management: Gastric lavage or emesis may be useful in reducing drug absorption but effectiveness depends on 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 with caution in patients with epilepsy as it may reverse the antiepileptic effects of valproate.

Carbapenem antibiotics may reduce serum valproic concentration to subtherapeutic levels, leading to loss of seizure control. Oral clearance increased by rifampin. Concomitant administration with clonazepam may induce absence status in patients with history thereof. Increases T_1/2 of lamotrigine; may result in serious skin reaction with lamotrigine. Reports of breakthrough seizures with the combination of valproate and phenytoin; monitor levels of both. Concomitant use with ASA decreases protein binding and metabolism of valproate. Reduces the clearance of amitriptyline, nortriptyline, zidovudine, and lorazepam. Induces metabolism of carbamazepine. Displaces protein-bound diazepam and decreases its V_d and clearance. Inhibits metabolism and decreases clearance of ethosuximide. Concomitant use with felbamate leads to an increase in valproate C_max. Inhibits the metabolism of phenobarbital. Monitor for neurological toxicity when used with barbiturates. Displaces protein-bound tolbutamide, and warfarin; monitor coagulation tests. Concomitant use with topiramate has been associated with hyperammonemia with or without encephalopathy and hypothermia. Drugs that affect the level of expression of hepatic enzymes (eg, phenytoin, carbamazepine, phenobarbital, primidone) may increase valproate clearance. Additive CNS depression with other CNS depressants (eg, alcohol). Increased plasma level with chlorpromazine.
Potentially Fatal: Increased risk of convulsions with mefloquine. Increased risk of carnitine deficiency with pivmecillinam and pivampicillin. Increased risk of toxicity with bupropion.

False positive for urinary ketones. May alter thyroid function test.

Valproate is a generic term used to describe valproic acid, its salts and esters. 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 an antiepileptic which dissociates to the valproate ion in the GI tract. It has been suggested that its antiepileptic activity is related to increased brain levels of gamma-aminobutyric acid (GABA).
Absorption: The sodium salts of valproate are rapidly converted to valproic acid in the GI tract. Valproic acid is rapidly and completely absorbed from the GI tract while valpromide is absorbed slower than valproic acid. Rate, but not the extent, of absorption of valproic acid is delayed when given with or after food.
Distribution: Crosses the placenta; enters breast milk. Protein-binding: Extensive, saturable and concentration dependent.
Metabolism: Valpromide is rapidly and almost completely metabolised in the liver to valproic acid. Valproic acid is extensively metabolised by liver, mainly by glucuronidation.
Excretion: Urine (mainly as metabolites), small amounts in faeces and expired air; 5-20 hr (elimination half-life).

D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.