divalproex sodium DEPAKOTE

Class: AED/​Mood Stabilizer
FDA Indications: Seizure Disorders, Acute Mania, Migraine Prophylaxis
Off-Label Use: Bipolar Disorder Prophylaxis, Mixed, Rapid-cycling Bipolar, Aggression, Schizophrenia (adjunctive)
Prescribing
Forms: 125, 250, 500mg tablet; 250, 500mg Extended-Release Tablet (Depakote ER); 125mg sprinkle; 250 mg/5 ml po soln; 100mg/mL IM
Dose Range: 750-2000 mg/day
Starting: Outpatient: 250mg bid-tid and gradually increase
Inpatient for acute manic → loading dose 20mg/kg; max 60 mg/kg/day
Stopping: Abrupt discontinuation ↑'s risk of relapse in bipolar disorder, so taper over 1 month
Monitoring: VPA level (therapeutic range 50-125 mcg/mL for acute mania, 50-125 mcg/mL for maintenance), CBC & LFTs

NAMI drug fact sheet

Precautions
Contraindications: Significant hepatic dysfunction; known urea cycle disorders; use in prophylaxis of migraine headaches in pregnant women; -related mitochondrial disease
Serious Side Effects: , pancreatitis (1:40,000), ↑'d suicidality, thrombocytopenia (17.7%), hyperammonemia (16-52%) & VHE, hypothermia, DRESS
Side Effects: sedation/somnolence, dizziness, ataxia, visual changes, weakness/asthenia, constipation, tremor, nausea, anorexia, rash, vomiting, weight gain (57%), alopecia (12%), PCOS (10%)
Pharmacodynamics
1° MOA: ↑'s inhibitory effect of GABA, possibly by activation of glutamic acid decarboxylase or inhibition of GABA-transaminase; blockade of high-frequency repetitive firing by slowing the rate of Na+ recovery from inactivation, blocks the low-threshold T-type Ca2+ channel.
Pharmacokinetics
t½: 14 (9-18)° TMAX: 2-3°
Substrate of: UGT1A3, UGT2B7, mitochondrial β-oxidation; 2C9, 2A6, 2B6
Inhibits: 2C9 (major), 2C19 & 3A4 (minor), UGT1A4 & UGT2B7; Induces:
Active Metabolites:
DDIs
  • - inhibits metabolism of lamotrigine; so when coadministered lamotrigine dose should be halved
  • - aspirin increases levels by ↓ its protein binding
  • - highly (≥90%) bound to plasma proteins & ∴ subject to displacement interactions, e.g. phenytoin, carbamazepine, warfarin, tolbutamide, diazepam (unbound levels ↑ twofold)
Misc
  • - first-line treatment for mania and mixed states; may not be as effective for treating bipolar depression
  • - extended release is ~80% as bioavailable as IR, so plasma levels will ↓ ~20% when converting from immediate to extended-release
  • - selenium & zinc supplementation may help prevent hair loss
  • - more effective in preventing mania than treating depressive episodes, "a better ceiling than a floor"
Special Populations

Category D*AVOID* High rate of neural tube defects; the absolute risk of producing a child with neural tube defects when used between the 17th and 30th days after fertilization is 1%–2%! Also associated with ↓ IQ scores and autism.

Though RID's up to as high as 15% have been measured, the American Academy of Pediatrics classified valproic acid as compatible with breastfeeding

Elderly are especially prone to somnolence


No dosage adjustment necessary


Contraindicated in patients with hepatic impairment

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Last updated December 05 2018 19:19:12. Disclaimer: This website does not provide medical advice, nor is it a substitute for clinical judgment.