Valproic Acid / Divalproex

Valproic Acid (VPA) is a mood stabilizer and anti-epileptic used primarily to treat epilepsy and bipolar disorder. There is also its derivative, divalproex (Epival), which is pharmacokinetically similar. Divalproex is converted to valproic acid in the gastrointestinal tract.

What's the Difference Between Valproic Acid and Divalproex?

Valproic acid (VPA) is an organic weak acid, while its conjugate base is called valproate. The sodium salt of the acid is called sodium valproate and a coordination complex of the two is known as divalproex sodium. Pharmacokinetically then, valproic acid is very similar, but not the same as divalproex sodium. Valproic acid is more cost-effective than divalproex. Evidence has shown that both have similar efficacy in treatment of psychiatric disorders. Divalproex has been noted to have less gastrointestinal side effects.[1]

The mechanism of action remains unknown, but it is thought to increase/potentiate GABA (gamma-aminobutyric acid) function, have direct neuronal effects on sodium influx and potassium efflux, and numerous other effects (e.g. - interactions with gamma-hydroxybutyrate (GHB), decreasing dopamine turnover, altering serotonin function, decreasing N-methyl-D-aspartate (NMDA)-mediated currents).

  • 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

Valproic acid was first synthesized in 1882 by chemist the American chemist Beverly S, 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.

  • Seizures in adults and children (extreme caution recommended for children < 2 years old)
  • Acute mania in adults (> 18 years) with bipolar disorder
  • Not approved for any psychiatric indication in children or adolescents in Canada or USA
    • Off-Label use for prevention of depression and mania in bipolar disorder
    • Off-label use for symptoms of impulsivity, rage, and aggression
  • Valproic acid (Tradename: Depakene)
    • Also available as gel capsules and syrup (Tradename: Depakene)
  • Divalproex sodium (DVP) (Tradename: Epival)
    • Available in Canada as an enteric-coated tablet (Tradename: Epival)
  • Valproate sodium (Tradename: Depacon)
  • Starting dose can be 250mg BID to reduce the incidents of stomach upset.
    • For inpatients, can start with 500mg BID, and consolidate the dose into a single dose after 1 week
  • Check VPA level, CBC, LFTs after one week of treatment, at 1-2 months, then Q 6-12 months
  • Valproic acid is highly protein bound – if hypoalbumin, level is even higher than what the lab work states
  • It is currently unknown what levels of divalproex offer optimum efficacy in maintenance treatment as no study to date has systematically assessed the relationship between serum divalproex level and the maintenance efficacy. Therefore, clinician are advised to maintain serum divalproex levels within the accepted laboratory range values during maintenance treatment and carefully monitor patients for emerging mood symptoms and tolerability and adjust the dose of divalproex as needed in order to achieve optimum efficacy and tolerability.

The target dose of valproic acid depends on the illness being treated and the serum level required:

What time should the blood work be done?

Plasma valproic acid levels should be taken 10–14 hours (ideally 12 hours) after the last dose. Therefore, your patients should not be taking it the morning of the bloodwork! They can take their dose again after their blood work.

Valproic Acid Monitoring

Stage of treatment Everyone High Risk
Pre-treatment • CBC, platelets
• Fasting glucose, fasting lipid profile (TC, LDL, HDL, TG)
• Electrolytes, calcium
• Liver enzymes, bilirubin, PT/PTT, Cr (eGFR)
• TSH
• Baseline ECG
• Baseline weight
• Pregnancy test (if female), prolactin
Starting • Frequent intervals thereafter especially during the first 6 months
Ongoing • CBC, platelets q6 months
• LFTs, platelets q6 months
Stopping Taper slowly over the course of 1 month
  • LFTs, coagulation tests at baseline
  • Before planned surgery: serum drug levels, ammonia
  • Measure serum trough level in the morning on day 5 just before morning dose to obtain the trough level (i.e. - 12 hours after last dose)
  • Time to Steady State: 2-4 days
  • Info: draw a free level if patient has hypoalbuminemia

Drug-Drug Interactions

Drug Interaction
Carbamazepine Valproic acid will ↑ levels of carbamazepine
Lamotrigine Valproic acid can increase lamotrigine plasma levels significantly by inhibiting lamotrigine’s glucuronidation.[3] This effect of valproate is dose-dependent. There is an increased risk of skin rashes, which requires close monitoring.[4]

Common side effects include: GI side effects (anorexia, indigestion, nausea, vomiting, heartburn, diarrhea), weight gain, increased appetite, sedation, tremors, menstrual disturbances, and transient alopecia. Transient elevated liver enzymes can also occur. In rare cases, Steven-Johnsons Syndrome can develop.

Tremors

Approximately 25% of patients can develop a tremor within the first year of starting treatment.[5] 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.[6]

PCOS

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.[7]

Hepatotoxicity

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.

Pancreatitis

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.[8]

Thrombocytopenia
Osteoporosis

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.[9]

Weight gain

Weight gain has been found to occur in 57% of adults and 58% of older children and teenagers.[10]

  • Divalproex has less GI upset due to enteric coating

Valproic acid is teratogenic and can cause neural tube defects.

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.[11][12] 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.