Valproic Acid (VPA) (Trade name: Epival) and Divalproex (DVP) are mood stabilizers and anti-epileptics used primarily to treat epilepsy and bipolar disorder. Divalproex (DVP) is converted to valproic acid (VPA) in the gastrointestinal tract.
Valproic acid was first synthesized in 1882 by chemist the American chemist Beverly Burton and used as an inert solvent.[2] It was first used to treat epilepsy starting in the 1960s in France. Valproate sodium was later synthesized in the 1980s, and followed by divalproex, which combined valproic acid and valproate sodium in a 1:1 molar ratio. Valproic acid, valproate sodium, and divalproex all convert to the valproate ion, which is the active component.
| Absorption | Valproate ions are absorbed in the GI tract. The rate of absorption depends on the compound preparation (gel, liquid, capsule) and GI tract (e.g. fasting or full). Side effects and metabolism also vary as a result of this. Peak concentration = 1 to 2 hours |
|---|---|
| Distribution | Small volume of distribution (0.1 to 0.4 L/kg), highly bound to plasma protein (90%) |
| Metabolism | Liver, about 50% via glucoronidation (Phase II). However, the free VPA plasma level doubles in renal impairment, so the total valproate level may be misleading. |
| Elimination | Urine |
| Half-life | 10 to 16 hours |
| Substrate of (Metabolized by) | None significant |
|---|---|
| Induces | - |
| Inhibits | - |
treatment for prevention of future mood (both depressive and manic) episodes
| Starting | • Outpatient: 250 mg BID to reduce the incidence of stomach upset • Inpatient: 500 mg BID, and consolidate the dose into a single dose after 1 week |
|---|---|
| Titration | Titrate every 2-3 days as tolerated until you reach target serum level |
| Maximum | 3000 mg PO daily (or 60 mg/kg/day) |
| Taper | Gradually over 2 to 6 months (if used for seizures), or reduce by 20-25% per week in psychiatric disorders. |
The target dose of valproic acid depends on the illness being treated and the serum level required. There is some evidence for a linear relationship between serum divalproex level and therapeutic efficacy in treating acute mania, with higher levels associated with greater efficacy.[3]
| Indication | Level |
|---|---|
| Epilepsy | 50-100 mcg/mL |
| Acute mania | 50-100 mcg/mL (350-700 mM/L) |
| Maintenance | Unknown (maintain within accepted laboratory values) |
| Toxicity | >175 mcg/mL |
| Stage of Treatment | Everyone | High Risk |
|---|---|---|
| Pre-treatment | • CBC, platelets • Fasting glucose, fasting lipid profile (TC, LDL, HDL, TG) • Electrolytes, calcium • Liver enzymes, albumin, bilirubin (LFTs), PT/PTT, Cr (eGFR) • TSH • Baseline ECG • Baseline weight • Pregnancy test (if female), prolactin |
|
| Starting | • Check VPA level, CBC, LFTs after 1 week of treatment • Then check again at 1 to 2 months (or when patient's symptoms stabilize) |
|
| Maintenance | • CBC, platelets q6 months • LFTs, platelets q6 months (don't forget albumin!) | • CBC, platelets q3 months • LFTs, platelets q3 months (don't forget albumin!) |
| Surgery or Acute Mental Status Change | • Serum drug levels, ammonia levels | |
| If hypoalbuminemia at any point* | • Draw a free level of valproic acid instead of total level | |
| Stopping | • Taper slowly over the course of 1 month | |
| Drug | Interaction |
|---|---|
| Carbamazepine | Valproic acid will ↑ levels of carbamazepine |
| Lamotrigine | Valproic acid can increase lamotrigine plasma levels significantly by inhibiting lamotrigine’s glucuronidation.[5] This effect of valproate is dose-dependent. There is an increased risk of skin rashes, which requires close monitoring.[6] |
Approximately 25% of patients can develop a tremor within the first year of starting treatment.[7] There is a dose-response relationship. Reducing the dose or a change to a slow‐release formulation can improve symptoms. Alternatively, carbamazepine can be used in patients who experience significant tremors.[8]
There is an increased prevalence of polycystic ovary syndrome (PCOS) associated with valproic acid, and this has been reported in both women with epilepsy and bipolar disorder.[9]
Valproate hepatotoxicity varies in severity from transient asymptomatic ALT elevations to severe toxicity with jaundice, hepatic synthetic dysfunction, coma and death. Monitoring of symptoms and serum aminotransferase levels is recommended for children for the first 6 months of valproate therapy.
Drug-induced acute pancreatitis can occur. It does not depend on the serum level and can occur at any time after the onset of therapy.[10]
Neutropenia can occur.
Up to a quarter of individuals on valproic acid may experience temporary alopecia (hair loss), most commonly associated with long-term valproate pharmacotherapy. It appears to be dose-related and may be more common in women than in men.[11]
All antiepileptics are associated with reductions in bone density in postmenopausal women and men older than 65 years. Adverse effects on bone metabolism (particularly phenytoin) are also seen in younger patients. The mechanisms behind bone loss behind cytochrome P450 enzyme-inducing antiepileptics (e.g. - phenytoin, phenobarbital, and carbamazepine) are thought to be due to accelerated inactivation of vitamin D which decreases calcium uptake, drives secondary hyperparathyroidism and accelerates bone loss. It is unclear how non cytochrome P450 enzyme-inducing antiepileptics (e.g. - valproic acid) reduce bone mineral density and increase the risks of fractures. However, valproic acid has been associated with fractures due to the development of hypophosphatemia secondary to Fanconi syndrome.[12]
Weight gain has been found to occur in 57% of adults and 58% of older children and teenagers.[13]
Valproate-induced hyperammonemic encephalopathy (VHE) is an unusual complication characterized by a decreasing level of consciousness, focal neurological deficits, cognitive slowing, vomiting, drowsiness, and lethargy.[14][15] Blood ammonia levels should be measured in patients with new onset neurological symptoms as it can be due to hyperammonemic encephalopathy, even when valproate levels are in the normal range and liver function tests are normal.