Valproic Acid (VPA) / Divalproex (DVP) (Epival)

Primer

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.

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 (DVP).
  • Pharmacokinetically, VPA is very similar, but not the same as DVP.
  • DVP is also an enteric-coated (coated for stomach protection) ester preparation of VPA
  • VPA is more cost-effective than DVP, but DVP causes less stomach upset than VPA.
  • Evidence has shown that both have similar efficacy in treatment of psychiatric disorders.[1]

History

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.

Pharmacokinetics

Pharmacokinetics of Valproic Acid (VPA) / Divalproex (DVP)

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

Valproic Acid (VPA) / Divalproex (DVP): Cytochrome P450 Metabolism

Substrate of (Metabolized by) None significant
Induces -
Inhibits -

Pharmacodynamics

Mechanism of Action

  • The mechanism of action remains unknown, but it is thought increases Na+ channel inactivation, which leads to increase/potentiation of GABA (gamma-aminobutyric acid) function
  • This is thought to 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).

Indications

  • Seizures in adults and children (extreme caution recommended for children <2 years old)
  • Migraine prophylaxis
  • Bipolar disorder in adults
    • It is a first-line treatment for mania, second-line for depression, and first-line

treatment for prevention of future mood (both depressive and manic) episodes

  • Not approved for any psychiatric indication in children or adolescents in Canada or USA, though it is used:
    • Off-Label for prevention of depression and mania in bipolar disorder
    • Off-label for symptoms of impulsivity, rage, and aggression

Dosing

Dosing for Valproic Acid (VPA) / Divalproex (DVP)

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.

Target Dose and Level

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]

Valproic Acid Serum Target Levels

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

Formulations

  • 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)

Monitoring

What Time Should the Bloodwork 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, 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
* = Drawing a free valproic acid is important in patients with altered or unpredictable protein binding capacity because valproic acid has variable, dose-dependent protein binding.

Total and Free Levels

What's the Difference Between Free and Total Valproic Acid Levels?

  • Remember that valproic acid is highly protein bound and binds strongly to albumin (almost 90% of it sticks to albumin). This means it's the remaining 10% of free floating valproic acid that exerts the therapeutic effect, NOT the valproic acid that is albumin-bound.[4]
  • Thus, if a patient has hypoalbuminemia (low albumin), this means there will be much more free floating active valproic acid; this can increase the risk for toxicity!
  • The usual valproic acid level reflects the total level, thus may not be accurate if someone is hypoalbuminemic. Therefore, you will want to specifically order a free valproic acid level to see how much of the free-floating valproic acid is actually there!
  • See also: Hermida, J., & Tutor, J. C. (2005). A theoretical method for normalizing total serum valproic acid concentration in hypoalbuminemic patients. Journal of pharmacological sciences, 97(4), 489-493. for a formula to approximate the free level if your laboratory only gives total levels.

Contraindications

Absolute

  • Contraindicated in pregnancy due to risk for neural tube defects (5%).
  • Women of child-bearing age should always be on an oral contraceptive when taking valproic acid.

Relative

Drug-Drug Interactions

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.[5] This effect of valproate is dose-dependent. There is an increased risk of skin rashes, which requires close monitoring.[6]

Side Effects

  • 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

Tremors

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]

Polycystic Ovary Syndrome (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.[9]

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.[10]

Thrombocytopenia

Neutropenia can occur.

Alopecia (Hair loss)

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]

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.[12]

Weight gain

Weight gain has been found to occur in 57% of adults and 58% of older children and teenagers.[13]

Adverse Events

Teratogen

Dermatological

  • In rare cases, Steven-Johnsons Syndrome can develop

Hyperammonemic Encephalopathy

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.

Clinical Pearls

  • Divalproex has less GI upset due to enteric coating (compared to valproic acid)

Special Populations

Geriatric

Pediatric

Obstetric and Fetal

  • Valproic acid is teratogenic and can cause neural tube defects (up to 5%). There is also an elevated risk for other congenital abnormalities, autism spectrum disorder,[16] and developmental delay. Women wishing to become pregnant should work with their clinician to switch off from valproate.
  • High dose folic acid and prenatal vitamins are recommended at all times because of this risk.

Medically Ill

Resources

References

1) Schwartz, T. L., Massa, J. L., Gupta, S., Al-Samarrai, S., Devitt, P., & Masand, P. S. (2000). Divalproex sodium versus valproic acid in hospital treatment of psychotic disorders. Primary care companion to the Journal of clinical psychiatry, 2(2), 45.
2) [([[https://www.ncbi.nlm.nih.gov/pubmed/28463122|Tomson, T., Battino, D., & Perucca, E. (2016). The remarkable story of valproic acid. The Lancet Neurology, 15(2), 141.
3) Linear Relationship of Valproate Serum Concentration to Response and Optimal Serum Levels for Acute Mania
4) DeVane, C. L. (2003). Pharmacokinetics, drug interactions, and tolerability of valproate. Psychopharmacology bulletin, 37, 25-42.
5) Kanner, A. M. (2004). When thinking of lamotrigine and valproic acid, think “pharmacokinetically”!. Epilepsy currents, 4(5), 206.
6) Chang, C. C., Shiah, I. S., Chang, H. A., & Huang, S. Y. (2006). Toxic epidermal necrolysis with combination lamotrigine and valproate in bipolar disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 30(1), 147-150.
7) Morgan, J. C., & Sethi, K. D. (2005). Drug-induced tremors. The Lancet Neurology, 4(12), 866-876.
8) Arbaizar, B., Gómez‐Acebo, I., & Llorca, J. (2008). Postural induced‐tremor in psychiatry. Psychiatry and clinical neurosciences, 62(6), 638-645.
9) Bilo, L., & Meo, R. (2008). Polycystic ovary syndrome in women using valproate: a review. Gynecological Endocrinology, 24(10), 562-570.
10) Werlin, S. L., & Fish, D. L. (2006). The spectrum of valproic acid–associated pancreatitis. Pediatrics, 118(4), 1660-1663.
11) Mercke, Y., Sheng, H., Khan, T., & Lippmann, S. (2000). Hair loss in psychopharmacology. Annals of clinical psychiatry, 12(1), 35-42.
12) Panday, K., Gona, A., & Humphrey, M. B. (2014). Medication-induced osteoporosis: screening and treatment strategies. Therapeutic advances in musculoskeletal disease, 6(5), 185-202.
13) Martin, C. K., Han, H., Anton, S. D., Greenway, F. L., & Smith, S. R. (2009). Effect of valproic acid on body weight, food intake, physical activity and hormones: results of a randomized controlled trial. Journal of Psychopharmacology, 23(7), 814-825.
14) Verrotti, A., Trotta, D., Morgese, G., & Chiarelli, F. (2002). Valproate-induced hyperammonemic encephalopathy. Metabolic brain disease, 17(4), 367-373.
15) Segura‐Bruna, N., Rodriguez‐Campello, A., Puente, V., & Roquer, J. (2006). Valproate‐induced hyperammonemic encephalopathy. Acta Neurologica Scandinavica, 114(1), 1-7.
16) Christensen, J., Grønborg, T. K., Sørensen, M. J., Schendel, D., Parner, E. T., Pedersen, L. H., & Vestergaard, M. (2013). Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. Jama, 309(16), 1696-1703.