Valproic Acid Divalproex Sodium

What is Valproic Acid Divalproex Sodium

Valproic acid and divalproex sodium are anticonvulsants that are chemically unrelated to other anticonvulsants.

Valproic acid was synthesized over a century ago, but its anticonvulsant properties were not discovered until 1963. Sodium valproate is the sodium salt of valproic acid. Divalproex sodium contains sodium valproate and valproic acid in a 1:1 molar stable co-ordination compound.

Valproic acid, sodium valproate, and divalproex share the same pharmacology; however, there are pharmacokinetic differences among products. For example, the delayed-release action of divalproex allows for less frequent dosing than valproic acid in some patients.

Although valproic acid was initially used for absence seizures, data published in 1992 confirmed that it was as effective as carbamazepine for the treatment of generalized tonic-clonic seizures.

It is also active in the treatment of complex partial seizures, absence seizures, and myoclonic seizures.

Valproic acid and divalproex are important adjuncts to the treatment of agitation and aggression in elderly patients with dementia, although these are off-label uses.

A small pilot study indicated that divalproex is effective in reducing the symptoms of depression and anxiety in bipolar depression; however, larger multi-site trials are needed for this indication.

A 20 month clinical trial of valproate compared to lithium for treatment of adult patients with rapid-cycling bipolar disorder (n=60) did not demonstrate superiority of divalproex over lithium.

The rates of relapse into any mood episode for those given lithium versus divalproex were 56% and 50%, respectively; the rates were 34% and 29% for a depressive relapse and 19% and 22% for a hypomania/mania relapse.

Valproic acid (Depakene) was initially approved by the FDA in 1978. Divalproex (Depakote) was approved by the FDA in 1983. In May 1995, valproic acid was approved for bipolar disorder and in March 1996 it was approved for migraine prophylaxis.

An intravenous dosage form of valproate sodium (Depacon) was approved in January 1997. A once-daily Depakote® ER tablet was approved by the FDA in August 2000 for use in migraine prophylaxis. In December 2002 the once-daily formulation was approved for adults and in September 2003 for children >= 10 years of age as single and adjunctive therapy for complex partial seizures and simple and complex absence seizures.

In December 2005 divalproex sodium extended-release (Depakote ER) was approved for adults as monotherapy for acute manic or mixed episodes associated with bipolar I disorder, with or without psychotic features.

In July 2008, a delayed-release valproic acid capsule formulation (Stavzor) received FDA approval ; however, the manufacturer discontinued marketing of the brand in 2014 and all lots of medication expired by February 2015; Stavzor is no longer commercially available.

Indications

  1. absence seizures
  2. agitation
  3. attention-deficit hyperactivity disorder (ADHD)
  4. bipolar disorder
  5. diabetic neuropathy
  6. mania
  7. migraine prophylaxis
  8. myoclonic seizures
  9. nystagmus
  10. partial seizures
  11. singultus (hiccups)
  12. status epilepticus
  13. tonic-clonic seizures

For the monotherapy or adjunct treatment of simple absence seizures, complex absence seizures, or complex partial seizures, and adjunctively for other seizure types that include absence or partial complex seizures (e.g., tonic-clonic seizures, myoclonic seizures)

Side Effects

  1. abdominal pain
  2. afibrinogenemia
  3. agitation
  4. agranulocytosis
  5. alopecia
  6. amblyopia
  7. amenorrhea
  8. amnesia
  9. anaphylactoid reactions
  10. anemia
  11. anorexia
  12. anxiety
  13. aplastic anemia
  14. appetite stimulation
  15. arrhythmia exacerbation
  16. arthralgia
  17. arthropathy
  18. asterixis
  19. asthenia
  20. ataxia
  21. azoospermia
  22. back pain
  23. bleeding
  24. blurred vision
  25. bone fractures
  26. bone pain
  27. bradycardia
  28. breast enlargement
  29. bullous rash
  30. chest pain (unspecified)
  31. chills
  32. coma
  33. confusion
  34. conjunctivitis
  35. constipation
  36. cough
  37. cystitis
  38. depression
  39. diarrhea
  40. diplopia
  41. dizziness
  42. drowsiness
  43. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
  44. dysarthria
  45. dysgeusia
  46. dysmenorrhea
  47. dyspepsia
  48. dysphagia
  49. dyspnea
  50. dysuria
  51. ecchymosis
  52. edema
  53. elevated hepatic enzymes
  54. emotional lability
  55. encephalopathy
  56. eosinophilia
  57. epistaxis
  58. eructation
  59. erythema multiforme
  60. erythema nodosum
  61. euphoria
  62. Fanconi syndrome
  63. fecal incontinence
  64. fever
  65. flatulence
  66. folate deficiency
  67. furunculosis
  68. galactorrhea
  69. gastritis
  70. glomerulonephritis
  71. glossitis
  72. hair discoloration
  73. hallucinations
  74. headache
  75. hearing loss
  76. hematemesis
  77. hematoma
  78. hepatitis
  79. hepatotoxicity
  80. hiccups
  81. hirsutism
  82. hostility
  83. hyperactivity
  84. hyperammonemia
  85. hyperhidrosis
  86. hyperreflexia
  87. hypertension
  88. hypertonia
  89. hypoesthesia
  90. hyponatremia
  91. hypotension
  92. hypothermia
  93. hypothyroidism
  94. impaired cognition
  95. increased urinary frequency
  96. infection
  97. infertility
  98. influenza
  99. infusion-related reactions
  100. injection site reaction
  101. insomnia
  102. interstitial nephritis
  103. irritability
  104. jaundice
  105. lethargy
  106. leukopenia
  107. lupus-like symptoms
  108. lymphadenopathy
  109. lymphocytosis
  110. macrocytosis
  111. maculopapular rash
  112. malaise
  113. menstrual irregularity
  114. muscle cramps
  115. myalgia
  116. myasthenia
  117. nausea
  118. neutropenia
  119. nystagmus
  120. ocular pain
  121. oligomenorrhea
  122. oliguria
  123. oral ulceration
  124. orthostatic hypotension
  125. osteopenia
  126. osteoporosis
  127. otalgia
  128. palpitations
  129. pancreatitis
  130. pancytopenia
  131. paresthesias
  132. peripheral edema
  133. peripheral vasodilation
  134. petechiae
  135. pharyngitis
  136. photophobia
  137. photosensitivity
  138. porphyria
  139. prolonged bleeding time
  140. pruritus
  141. pseudoparkinsonism
  142. psychosis
  143. rash
  144. red cell aplasia
  145. rhinitis
  146. seborrhea
  147. SIADH
  148. sinus tachycardia
  149. sinusitis
  150. Stevens-Johnson syndrome
  151. stomatitis
  152. suicidal ideation
  153. tardive dyskinesia
  154. teratogenesis
  155. thrombocytopenia
  156. tinnitus
  157. toxic epidermal necrolysis
  158. tremor
  159. urinary incontinence
  160. vaginal bleeding
  161. vaginitis
  162. vasculitis
  163. vertigo
  164. vesicular rash
  165. visual impairment
  166. vitamin D deficiency
  167. vomiting
  168. weakness
  169. weight gain
  170. weight loss
  171. xerophthalmia
  172. xerosis
  173. xerostomia

Monitoring Parameters

  • CBC
  • LFTs
  • plasma ammonia concentrations

Contraindications

  • abrupt discontinuation
  • bleeding
  • breast-feeding
  • carnitine deficiency
  • children
  • coagulopathy
  • colostomy
  • contraception requirements
  • depression
  • diarrhea
  • driving or operating machinery
  • encephalopathy
  • ethanol ingestion
  • geriatric
  • head trauma
  • hepatic disease
  • hepatotoxicity
  • human immunodeficiency virus (HIV) infection
  • hypoalbuminemia
  • ileostomy
  • infants
  • infertility
  • laboratory test interference
  • mitochondrial disease
  • neonates
  • organic brain syndrome
  • pancreatitis
  • pregnancy
  • renal failure
  • renal impairment
  • reproductive risk
  • serious rash
  • suicidal ideation
  • surgery
  • thrombocytopenia

Interactions

  • Abacavir; Lamivudine, 3TC; Zidovudine, ZDV
  • Acetaminophen; Butalbital
  • Acetaminophen; Butalbital; Caffeine
  • Acetaminophen; Butalbital; Caffeine; Codeine
  • Acetaminophen; Caffeine; Dihydrocodeine
  • Acetaminophen; Codeine
  • Acetaminophen; Hydrocodone
  • Acetaminophen; Oxycodone
  • Acetaminophen; Tramadol
  • Aldesleukin, IL-2
  • Alfentanil
  • Aliskiren; Amlodipine
  • Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ
  • Alprazolam
  • Aluminum Hydroxide
  • Aluminum Hydroxide; Magnesium Carbonate
  • Aluminum Hydroxide; Magnesium Hydroxide
  • Aluminum Hydroxide; Magnesium Hydroxide; Simethicone
  • Aluminum Hydroxide; Magnesium Trisilicate
  • Amitriptyline
  • Amitriptyline; Chlordiazepoxide
  • Amlodipine
  • Amlodipine; Atorvastatin
  • Amlodipine; Benazepril
  • Amlodipine; Celecoxib
  • Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan
  • Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan
  • Amlodipine; Olmesartan
  • Amlodipine; Telmisartan
  • Amlodipine; Valsartan
  • Amobarbital
  • Amoxicillin; Clarithromycin; Lansoprazole
  • Amoxicillin; Clarithromycin; Omeprazole
  • Amphetamine
  • Amphetamine; Dextroamphetamine
  • Amphetamines
  • Apalutamide
  • Aprepitant, Fosaprepitant
  • Aripiprazole
  • Articaine; Epinephrine
  • Aspirin, ASA; Butalbital; Caffeine
  • Aspirin, ASA; Butalbital; Caffeine; Codeine
  • Aspirin, ASA; Caffeine; Dihydrocodeine
  • Aspirin, ASA; Carisoprodol; Codeine
  • Aspirin, ASA; Citric Acid; Sodium Bicarbonate
  • Aspirin, ASA; Oxycodone
  • Atazanavir
  • Atazanavir; Cobicistat
  • Atropine; Hyoscyamine; Phenobarbital; Scopolamine
  • Belladonna Alkaloids; Ergotamine; Phenobarbital
  • Belladonna; Opium
  • Benzhydrocodone; Acetaminophen
  • Benzphetamine
  • Brompheniramine; Guaifenesin; Hydrocodone
  • Brompheniramine; Hydrocodone; Pseudoephedrine
  • Bupivacaine
  • Bupivacaine Liposomal
  • Bupivacaine; Lidocaine
  • Bupropion
  • Bupropion; Naltrexone
  • Butabarbital
  • Calcium Carbonate
  • Calcium Carbonate; Magnesium Hydroxide
  • Calcium Carbonate; Risedronate
  • Calcium Carbonate; Simethicone
  • Cannabidiol
  • Carbamazepine
  • Carbapenems
  • Carbinoxamine; Hydrocodone; Phenylephrine
  • Carbinoxamine; Hydrocodone; Pseudoephedrine
  • Cenobamate
  • Cetirizine
  • Cetirizine; Pseudoephedrine
  • Chloroprocaine
  • Chlorpheniramine; Codeine
  • Chlorpheniramine; Dihydrocodeine; Phenylephrine
  • Chlorpheniramine; Dihydrocodeine; Pseudoephedrine
  • Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine
  • Chlorpheniramine; Hydrocodone
  • Chlorpheniramine; Hydrocodone; Phenylephrine
  • Chlorpheniramine; Hydrocodone; Pseudoephedrine
  • Cholestyramine
  • Citalopram
  • Clarithromycin
  • Clomipramine
  • Clonazepam
  • Clozapine
  • Cobicistat
  • Cobimetinib
  • Codeine
  • Codeine; Guaifenesin
  • Codeine; Phenylephrine; Promethazine
  • Codeine; Promethazine
  • Colesevelam
  • COMT inhibitors
  • Conjugated Estrogens
  • Conjugated Estrogens; Bazedoxifene
  • Conjugated Estrogens; Medroxyprogesterone
  • Cyclophosphamide
  • Darunavir
  • Darunavir; Cobicistat
  • Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide
  • Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir
  • Desipramine
  • Deutetrabenazine
  • Dextroamphetamine
  • Diazepam
  • Dienogest; Estradiol valerate
  • Dihydrocodeine; Guaifenesin; Pseudoephedrine
  • Diphenhydramine; Hydrocodone; Phenylephrine
  • Doripenem
  • Doxepin
  • Doxorubicin
  • Dronabinol
  • Drospirenone; Ethinyl Estradiol
  • Drospirenone; Ethinyl Estradiol; Levomefolate
  • Elbasvir; Grazoprevir
  • Eliglustat
  • Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide
  • Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate
  • Enzalutamide
  • Erdafitinib
  • Ertapenem
  • Esketamine
  • Esterified Estrogens
  • Esterified Estrogens; Methyltestosterone
  • Estradiol
  • Estradiol Cypionate; Medroxyprogesterone
  • Estropipate
  • Ethanol
  • Ethinyl Estradiol
  • Ethinyl Estradiol; Desogestrel
  • Ethinyl Estradiol; Ethynodiol Diacetate
  • Ethinyl Estradiol; Etonogestrel
  • Ethinyl Estradiol; Levonorgestrel
  • Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate
  • Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate
  • Ethinyl Estradiol; Norelgestromin
  • Ethinyl Estradiol; Norethindrone
  • Ethinyl Estradiol; Norethindrone Acetate
  • Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate
  • Ethinyl Estradiol; Norethindrone; Ferrous fumarate
  • Ethinyl Estradiol; Norgestimate
  • Ethinyl Estradiol; Norgestrel
  • Ethosuximide
  • Felbamate
  • Fentanyl
  • food
  • Fosamprenavir
  • Gabapentin
  • Glimepiride
  • Glimepiride; Pioglitazone
  • Glimepiride; Rosiglitazone
  • Glycerol Phenylbutyrate
  • Guaifenesin; Hydrocodone
  • Guaifenesin; Hydrocodone; Pseudoephedrine
  • Haloperidol
  • Homatropine; Hydrocodone
  • Hydantoins
  • Hydrocodone
  • Hydrocodone; Ibuprofen
  • Hydrocodone; Phenylephrine
  • Hydrocodone; Potassium Guaiacolsulfonate
  • Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine
  • Hydrocodone; Pseudoephedrine
  • Hydromorphone
  • Hydroxychloroquine
  • Ibuprofen; Oxycodone
  • Imipenem; Cilastatin
  • Imipenem; Cilastatin; Relebactam
  • Imipramine
  • Isoniazid, INH
  • Isoniazid, INH; Pyrazinamide, PZA; Rifampin
  • Isoniazid, INH; Rifampin
  • Lacosamide
  • Lamivudine, 3TC; Zidovudine, ZDV
  • Lamotrigine
  • Lanthanum Carbonate
  • Lasmiditan
  • Lemborexant
  • Lesinurad
  • Lesinurad; Allopurinol
  • Levocetirizine
  • Levomefolate
  • Levorphanol
  • Lidocaine
  • Lidocaine; Prilocaine
  • Lisdexamfetamine
  • Lofexidine
  • Loperamide
  • Loperamide; Simethicone
  • Lopinavir; Ritonavir
  • Lorazepam
  • Loxapine
  • Lumateperone
  • Magnesium Hydroxide
  • Maprotiline
  • Maraviroc
  • Mefloquine
  • Meloxicam
  • Meperidine
  • Meperidine; Promethazine
  • Mephobarbital
  • Mepivacaine
  • Mepivacaine; Levonordefrin
  • Meropenem
  • Meropenem; Vaborbactam
  • Mestranol; Norethindrone
  • Methadone
  • Methamphetamine
  • Methohexital
  • Methsuximide
  • Molindone
  • Monoamine oxidase inhibitors
  • Morphine
  • Morphine; Naltrexone
  • Nimodipine
  • Nortriptyline
  • Ombitasvir; Paritaprevir; Ritonavir
  • Omeprazole; Sodium Bicarbonate
  • Oritavancin
  • Oxycodone
  • Oxymorphone
  • Paliperidone
  • Pemoline
  • Penicillin G Benzathine; Penicillin G Procaine
  • Penicillin G Procaine
  • Pentobarbital
  • Perindopril; Amlodipine
  • Perphenazine; Amitriptyline
  • Pexidartinib
  • Phenobarbital
  • Phenothiazines
  • Phentermine; Topiramate
  • Pregabalin
  • Prilocaine
  • Prilocaine; Epinephrine
  • Primidone
  • Propofol
  • Protriptyline
  • Quetiapine
  • Remifentanil
  • Rifampin
  • Riluzole
  • Risperidone
  • Ritonavir
  • Ropivacaine
  • Rufinamide
  • Salicylates
  • Sapropterin
  • Secobarbital
  • Segesterone Acetate; Ethinyl Estradiol
  • Silodosin
  • Sodium Benzoate; Sodium Phenylacetate
  • Sodium Bicarbonate
  • Sodium Oxybate
  • Sodium Phenylbutyrate
  • Sofosbuvir; Velpatasvir
  • Sofosbuvir; Velpatasvir; Voxilaprevir
  • Sufentanil
  • Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole
  • Tapentadol
  • Teduglutide
  • Telotristat Ethyl
  • Temozolomide
  • Tenofovir Alafenamide
  • Terbinafine
  • Tetracaine
  • Thiopental
  • Thiothixene
  • Tiagabine
  • Tipranavir
  • Tolbutamide
  • Topiramate
  • Tramadol
  • Trimethoprim
  • Trimipramine
  • Ubrogepant
  • Vincristine
  • Vincristine Liposomal
  • Voriconazole
  • Vorinostat
  • Warfarin
  • Zidovudine, ZDV
  • Zolpidem
  • Zonisamide
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