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
- absence seizures
- agitation
- attention-deficit hyperactivity disorder (ADHD)
- bipolar disorder
- diabetic neuropathy
- mania
- migraine prophylaxis
- myoclonic seizures
- nystagmus
- partial seizures
- singultus (hiccups)
- status epilepticus
- 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
- abdominal pain
- afibrinogenemia
- agitation
- agranulocytosis
- alopecia
- amblyopia
- amenorrhea
- amnesia
- anaphylactoid reactions
- anemia
- anorexia
- anxiety
- aplastic anemia
- appetite stimulation
- arrhythmia exacerbation
- arthralgia
- arthropathy
- asterixis
- asthenia
- ataxia
- azoospermia
- back pain
- bleeding
- blurred vision
- bone fractures
- bone pain
- bradycardia
- breast enlargement
- bullous rash
- chest pain (unspecified)
- chills
- coma
- confusion
- conjunctivitis
- constipation
- cough
- cystitis
- depression
- diarrhea
- diplopia
- dizziness
- drowsiness
- Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
- dysarthria
- dysgeusia
- dysmenorrhea
- dyspepsia
- dysphagia
- dyspnea
- dysuria
- ecchymosis
- edema
- elevated hepatic enzymes
- emotional lability
- encephalopathy
- eosinophilia
- epistaxis
- eructation
- erythema multiforme
- erythema nodosum
- euphoria
- Fanconi syndrome
- fecal incontinence
- fever
- flatulence
- folate deficiency
- furunculosis
- galactorrhea
- gastritis
- glomerulonephritis
- glossitis
- hair discoloration
- hallucinations
- headache
- hearing loss
- hematemesis
- hematoma
- hepatitis
- hepatotoxicity
- hiccups
- hirsutism
- hostility
- hyperactivity
- hyperammonemia
- hyperhidrosis
- hyperreflexia
- hypertension
- hypertonia
- hypoesthesia
- hyponatremia
- hypotension
- hypothermia
- hypothyroidism
- impaired cognition
- increased urinary frequency
- infection
- infertility
- influenza
- infusion-related reactions
- injection site reaction
- insomnia
- interstitial nephritis
- irritability
- jaundice
- lethargy
- leukopenia
- lupus-like symptoms
- lymphadenopathy
- lymphocytosis
- macrocytosis
- maculopapular rash
- malaise
- menstrual irregularity
- muscle cramps
- myalgia
- myasthenia
- nausea
- neutropenia
- nystagmus
- ocular pain
- oligomenorrhea
- oliguria
- oral ulceration
- orthostatic hypotension
- osteopenia
- osteoporosis
- otalgia
- palpitations
- pancreatitis
- pancytopenia
- paresthesias
- peripheral edema
- peripheral vasodilation
- petechiae
- pharyngitis
- photophobia
- photosensitivity
- porphyria
- prolonged bleeding time
- pruritus
- pseudoparkinsonism
- psychosis
- rash
- red cell aplasia
- rhinitis
- seborrhea
- SIADH
- sinus tachycardia
- sinusitis
- Stevens-Johnson syndrome
- stomatitis
- suicidal ideation
- tardive dyskinesia
- teratogenesis
- thrombocytopenia
- tinnitus
- toxic epidermal necrolysis
- tremor
- urinary incontinence
- vaginal bleeding
- vaginitis
- vasculitis
- vertigo
- vesicular rash
- visual impairment
- vitamin D deficiency
- vomiting
- weakness
- weight gain
- weight loss
- xerophthalmia
- xerosis
- 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
