Dosing & Uses
Dosage Forms & Strengths
capsule (Depakene)
- 250mg
capsule/tablet, delayed-release (Stavzor)
- 125mg
- 250mg
- 500mg
tablet, extended release
- 250mg
- 500mg
capsule delayed release sprinkle
- 125mg
syrup (Depakene)
- 250mg/5mL
injectable solution (Depacon as valproate sodium)
- 100mg/mL
Complex Partial Seizures
Indicated as monotherapy and adjunctive therapy for complex partial seizures that occur either in isolation or in association with other types of seizures
IV (valproate sodium): 10-15 mg/kg/day IV divided q12hr infused over 1 hr; maximum dose 60 mg/kg/day; do not exceed 14 days (switch to PO as soon as possible)
PO: 10-15 mg/kg/day PO initially; increase by 5-10 mg/kg/day at weekly intervals; may increase dose up to 60 mg/kg/day
Delayed release and extended release formulations
- Delayed release formulations are usually administered at the same daily dose and frequency (BID/QID) as the regular release when converting from regular release to delayed release; once therapy is stabilized, the frequency of the delayed release formulation is adjusted to BID/TID
- Extended release formulation is usually administered once daily in patients who convert from either regular or delayed release formulations; may require an increase in total daily dose between 8-20% to maintain similar serum concentrations
Conversion to monotherapy from adjunctive therapy
- Decrease concomitant antiepileptic drug (AED) by approximately 25% q2wk; may reduce dosage of concomitant AED when valproate therapy is initiated or 1 to 2 weeks following valproate initiation
Simple & Complex Absence Seizures
Also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures
IV (valproate sodium): 10-15 mg/kg/day IV divided q12hr infused over 1 hr; maximum dose 60 mg/kg/day; do not exceed 14 days (switch to PO as soon as possible)
PO (Depakene, Stavzor): 15 mg/kg/day PO initially, divided q6-12hr; increase by 5-10 mg/kg/day at weekly intervals; may increase dose up to 60 mg/kg/day
Delayed release and extended release formulations
- Delayed release formulations are usually administered at the same daily dose and frequency (BID/QID) as the regular release when converting from regular release to delayed release; once therapy is stabilized, the frequency of the delayed release formulation is adjusted to BID/TID
- Extended release formulation is usually administered once daily in patients who convert from either regular or delayed release formulations; may require an increase in total daily dose between 8-20% to maintain similar serum concentrations
Conversion to monotherapy from adjunctive therapy
- Decrease concomitant antiepileptic drug (AED) by approximately 25% q2wk; may reduce dosage of concomitant AED when valproate therapy is initiated or 1 to 2 weeks following valproate initiation
Migraine
Indicated for prophylaxis of migraine headaches; there is no evidence of use for acute treatment
Stavzor: 250 mg PO q12hr; adjust dose based on clinical response, not to exceed 1000 mg/day
Depakote ER: 500 mg PO qDay for 7 days; based on patient response, may increase and adjust dose to 500-1000 mg/day
Bipolar Mania
Indicated for treatment of manic episodes associated with bipolar disorder
Stavzor: 750 mg/day PO in divided doses; adjust dose as rapidly as possible to desired therapeutic effect; not to exceed 60 mg/kg/day
Depakote ER: 25 mg/kg/day PO qDay; adjust dose to desired clinical effect, as rapidly as possible; not to exceed 60 mg/kg/day
Dosage Modifications
Renal impairment
- No adjustment necessary; protein binding is reduced and may cause measurement of total valproate concentrations to be inaccurate
Hepatic impairment
- Mild to moderate impairment: Not recommended; clearance is decreased
- Contraindicated in severe impairment
Dosing Considerations
Monitor LFT's
Therapeutic range
- Low serum albumin levels may cause an increase in unbound drug (while total concentration may appear normal)
- Epilepsy: 50-100 mcg/mL total valproate
- Mania: 50-125 mcg/mL total valproate
- Toxicity: ≥110 mcg/mL (females); ≥135 mcg/mL (males)
Fragile X Syndrome (Orphan)
Orphan indication sponsor
- Neuropharm Ltd; Fetcham Park House; Surrey KT22 9HD; UK
Familial Adenomatous Polyposis (Orphan)
Orphan indication sponsor
- Topotarget A/S; Fruebjergvej 3; DK-2100; Copenhagen; Denmark
Lymphoma (Orphan)
Orphan designation for treatment of diffuse large B-cell lymphoma
Sponsor
- Valcuria AB; Scheelevägen 2; Lund, Sweden
Dosage Forms & Strengths
capsule (Depakene)
- 250mg
capsule, delayed-release (Stavzor)
- 125mg
- 250mg
- 500mg
tablet, extended release
- 250mg
- 500mg
capsule delayed release sprinkle
- 125mg
syrup (Depakene)
- 250mg/5mL
injectable solution (Depacon as valproate sodium)
- 100mg/mL
Complex Partial Seizures
Indicated as monotherapy and adjunctive therapy for complex partial seizures that occur either in isolation or in association with other types of seizures
<10 years: Safety and efficacy not established
(IV) valproate sodium: 10-15 mg/kg/day IV divided q12hr infused over 1 hr; maximum dose 60 mg/kg/day; do not exceed 14 days (switch to PO as soon as possible)
PO (Depakene or Stavzor): 10-15 mg/kg/day PO initially; increase by 5-10 mg/kg/day at weekly intervals; may increase dose up to 60 mg/kg/day
Delayed release and extended release formulations
- Delayed release formulations are usually administered at the same daily dose and frequency (BID/QID) as the regular release when converting from regular release to delayed release; once therapy is stabilized, the frequency of the delayed release formulation is adjusted to BID/TID
- Extended release formulation is usually administered once daily in patients who convert from either regular or delayed release formulations; may require an increase in total daily dose between 8-20% to maintain similar serum concentrations
Simple & Complex Absence Seizures
Indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures
<10 years: Safety and efficacy not established
≥10 years
- IV (valproate sodium): 10-15 mg/kg/day IV divided q12hr infused over 1 hr; maximum dose 60 mg/kg/day; do not exceed 14 days (switch to PO as soon as possible)
- Stavzor: 250 mg PO q12hr; adjust dose based on clinical response up to 1000 mg/day
Delayed release and extended release formulations
- Delayed release formulations are usually administered at the same daily dose and frequency (BID/QID) as the regular release when converting from regular release to delayed release; once therapy is stabilized, the frequency of the delayed release formulation is adjusted to BID/TID
- Extended release formulation is usually administered once daily in patients who convert from either regular or delayed release formulations; may require an increase in total daily dose between 8-20% to maintain similar serum concentrations
Dosage Modifications
Renal impairment
- No adjustment necessary; protein binding is reduced and may cause measurement of total valproate concentrations to be inaccurate
Hepatic impairment
- Mild to moderate impairment: Not recommended; clearance is decreased
- Contraindicated in severe impairment
Dosing Considerations
Monitor LFT's
Therapeutic range
- Low serum albumin levels may cause an increase in unbound drug (while total concentration may appear normal)
- Epilepsy: 50-100 mcg/mL total valproate
Wolfram Syndrome (Orphan)
Orphan designation for treatment of Wolfram syndrome
Sponsor
- The University of Birmingham; Birmingham Research Park - Vincent Drive; Birmingham B15 2SQ
Administer as in adults, but may need to initiate at lower dose; dose adjustments should be increased cautiously
Interactions
Interaction Checker
No Results

Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor

Adverse Effects
>10%
Nausea (31%)
Headache (<31%)
Increased bleeding time (26-30%)
Thrombocytopenia (26-30%)
Tremor (25%)
Alopecia (<24%)
Asthenia (16-20%)
Infection (16-20%)
Somnolence (16-20%)
Amblyopia (11-15%)
Diarrhea (11-15%)
Diplopia (11-15%)
Dizziness (11-15%)
Dyspepsia (11-15%)
Nystagmus (11-15%)
Tinnitus (11-15%)
Vomiting (11-15%)
1-10%
Ataxia (<8%)
Increased appetite (<6%)
Rash (<6%)
Abdominal pain (<5%)
Tremor (<5%)
Back pain (<5%)
Mood changes (<5%)
Anxiety (<5%)
Confusion (<5%)
Abnormal gait (<5%)
Paresthesia (<5%)
Hallucinations (<5%)
Catatonia (<5%)
Dysarthria (<5%)
Tardive dyskinesia (<5%)
Vertigo (<5%)
Irregular menses (<5%)
Weight gain (4%)
Frequency Not Defined
Anorexia
Acute pancreatitis (may be life-threatening)
Hepatic toxicity
Hyperammonemia
Weight loss
Fractures
Osteoporosis
Osteopenia
Decreased bone mineral density
Cerebral pseudoatrophy (acute or subacute cognitive decline and behavioral changes (apathy or irritability)
Postmarketing Report
Hair texture change
Hair color change
Photosensitivity
Erythema multiforme
Toxic epidermal necrolysis
Stevens-Johnson syndrome
Elevated testosterone level
Hyperandrogenism
Hirsutism
Nail and nailbed disorders
Weight gain
Aspermia, azoospermia, decreased sperm count, decreased spermatozoa motility, male infertility, and abnormal spermatozoa morphology
Paradoxical convulsion
Parkinsonism
Body as a Whole: Chest pain, chills, chills and fever, fever, neck pain, neck rigidity
Cardiovascular System: Hypertension, hypotension, palpitations, postural hypotension, tachycardia, vasodilation
Digestive System: Anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal abscess
Hemic and Lymphatic System: Ecchymosis
Metabolic and Nutritional Disorders: Edema, peripheral edema, SGOT increase, and SGPT increase
Musculoskeletal System: Arthralgia, arthrosis, leg cramps, twitching, myalgia
Nervous System: Abnormal dreams, depression, hypertonia, hypokinesia, insomnia, reflexes increased, thinking abnormalities,
Respiratory System: Dyspnea, rhinitis, cough increased, and sinusitis
Skin and Appendages: Alopecia, discoid lupus erythematosus, dry skin, furunculosis, maculopapular rash, seborrhea, pruritus, and rash
Special Senses: Conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus, taste perversion
Urogenital System: Dysmenorrhea, dysuria, urinary incontinence, cystitis, metrorrhagia, and vaginal hemorrhage
Hemic and Lymphatic System: Ecchymosis
Warnings
Black Box Warnings
Hepatotoxicity
- Hepatic failure resulting in fatalities has occurred
- Children younger than 2 years are at increased risk for fatal hepatotoxicity, particularly patients on multiple anticonvulsants, as well as those with congenital metabolic disorders, severe seizure disorders accompanied by mental retardation, or organic brain disease
- Increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA polymerase-gamma (POLG) gene (eg, Alpers Huttenlocher Syndrome)
- If used in children with these conditions, it should be administered with extreme caution as a sole agent
- Hepatotoxicity usually occurs during the first 6 months of treatment and may be preceded by malaise, weakness, lethargy, facial edema, anorexia, and vomiting
Patients with mitochondrial disease
- There is increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of mitochondrial DNA polymerase gamma (POLG) gene; therapy is contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase-gamma (POLG; eg, Alpers-Huttenlocher Syndrome) and children <2 years of age who are suspected of having a POLG-related disorder; in patients >2 years, clinically suspected having hereditary mitochondrial disease, only use after other anticonvulsants have failed; closely monitor older group of patients for development of acute liver injury; perform regular clinical assessments and serum liver testing; perform POLG mutation screening according to current clinical practice
Teratogenicity
- Do not use in women of childbearing age unless the drug is essential to the management of the medical condition; all non-pregnant women of childbearing potential should use effective birth control if taking valproate products (see Contraindications and Pregnancy sections)
- May cause neural tube defects
- Children exposed in utero have increased risk for lower cognitive test scores compared with those exposed in utero to other antiseizure medications
- Alternative medications that have a lower risk for adverse birth outcomes should be considered
- Patients should not stop taking valproate without talking to a health-care professional
- Not for administration to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable
Pancreatitis
- Cases of life-threatening pancreatitis have been reported in children and adults
- Some cases have been described as hemorrhagic with a rapid progression from initial symptoms to death
Contraindications
Hypersensitivity
Liver disease, significant hepatic impairment
Urea cycle disorder
Mitochondrial disorders caused by mutations in mitochondrial DNA polymerase-gamma (POLG; eg, Alpers-Huttenlocher Syndrome) and children <2 years of age who are suspected of having a POLG-related disorder
Migraine headache prevention in women who are pregnant or plan to become pregnant
Cautions
Probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations exceed 110 mcg/mL in females and 135 mcg/mL in males
Medication residue in the stool reported; some patients have had anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times; in some reports, medication residues have occurred in the context of diarrhea; recommended that plasma valproate levels be checked in patients who experience medication residue in the stool, and patients’ clinical condition monitored; If clinically indicated, may consider alternative treatment
Bleeding and other hematopoietic disorders may occur; monitor platelet counts and coagulation tests
Hepatotoxic (age <2 years, higher risk of fatal hepatotoxicity); evaluate high risk populations and monitor serum liver tests; risk factors include organic brain disease, mental retardation with severe seizure disorders, congenital metabolic disorders, and patients on multiple anticonvulsants; discontinue immediately with signs/symptoms of significant or suspected impairment
POLG mutations; see Contraindications and Black Box Warnings
Discontinue if hyperammonemia occurs; check ammonia level if emesis occurs or if the patient displays lethargy or abnormal behavior; evaluate patient for urea cycle disorder (see Contraindications) or hepatotoxicity (see Black Box Warnings)
Pancreatitis, including fatalities reported (see Black Box Warnings)
Porphyria may occur
May produce false-positive urine ketone test and alter TFTs
May cause CNS depression, which may impair physical or mental to perform tasks requiring mental alertness
Birth defects and decreased IQ following in utero exposure compared with 3 other common AEDs (carbamazepine, lamotrigine, phenytoin); only use to treat pregnant women with epilepsy if other medications are unacceptable; should not be administered to a woman of childbearing potential unless essential; reversible and irreversible cerebellar atrophy reported; monitor motor and cognitive function routinely
Drug reaction with eosinophilia and systemic symptoms (DRESS)/multiorgan hypersensitivity reaction reported; discontinue therapy; monitor for possible disparate manifestations associated with lymphatic, renal, hepatic, and/or hematologic organ systems; therapy should be discontinued and not be resumed if an alternative etiology for signs or symptoms cannot be established
Not recommended for post-traumatic seizure prophylaxis in patients with acute head trauma (may increase mortality
Hypothermia reported during valproate therapy with or without associated hyperammonemia; this adverse reaction can also occur in patients using concomitant topiramate
Somnolence in the elderly can occur; valproic acid dosage should be increased slowly and with regular monitoring for fluid and nutritional intake
Irreversible and reversible brain atrophhy reported; routinely monitor motor and cognitive function to assess for signs and symptoms of brain atrophy
Serious, sometimes fatal drug reaction with eosinophilia and systemic symptoms (DRESS) reported; monitor for symptoms; may require discontinuation and conversion to alternate therapy
Suicidal thoughts, behavior may occur; monitor patients for changes in behavior that might indicate suicidal thoughts or depression
Pregnancy & Lactation
Pregnancy
A pregnancy exposure registry monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), during pregnancy; encourage women on therapy during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling toll-free 1-888-233-2334 or visiting the website, http://www.aedpregnancyregistry.org/.; must be done by the patient herself
Contraindicated for use in prophylaxis of migraine headaches in women who are pregnant and in women of childbearing potential who are not using effective contraception; for epilepsy or bipolar disorder, drug should not be used to treat women who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable
Women with epilepsy who become pregnant while taking valproate should not discontinue therapy abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life; discontinuation of the drug may be considered prior to and during pregnancy in individual cases if seizure disorder severity and frequency do not pose serious threat to patient
Maternal valproate use during pregnancy for any indication increases risk of congenital malformations, particularly neural tube defects including spina bifida, but also malformations involving other body systems (e.g., craniofacial defects including oral clefts, cardiovascular malformations, hypospadias, limb malformations)
Risk is dose-dependent; a threshold dose below which no risk exists cannot be established; valproate polytherapy with other AEDs has been associated with increased frequency of congenital malformations compared with AED monotherapy; risk of major structural abnormalities is greatest during first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy
There have been reports of hypoglycemia in neonates and fatal cases of hepatic failure in infants following maternal use of valproate during pregnancy
Pregnant women taking valproate may develop hepatic failure or clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death
Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases risk for congenital neural tube defects in general population; not known whether risk of neural tube defects or decreased IQ in offspring of women receiving valproate is reduced by folic acid supplementation; dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate
There have been reports of male infertility coincident with valproate therapy; in animal studies, oral administration at clinically relevant doses resulted in adverse reproductive effects in males
Lactation
Drug is excreted in human milk; data in the published literature describe presence of valproate in human milk; there are no data to assess effects of drug on milk production or excretion
Developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed child from drug or from underlying maternal condition
Monitor breastfed infant for signs of liver damage including jaundice and unusual bruising or bleeding; there have been reports of hepatic failure and clotting abnormalities in offspring of women who used valproate during pregnancy
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
May increase levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in brain; may enhance or mimic action of GABA at postsynaptic receptor sites; may also inhibit sodium and calcium channels
Absorption
Bioavailability: Extended-release 81-89% of delayed-release
Peak plasma time: 2 hr (Stavzor)
Peak plasma concentration: 115-145 mcg/mL (IV)
Distribution
Protein bound: 80-90%
Vd: 92 L/1.73 m²
Metabolism
Metabolized by liver
Enzymes inhibited: CYP2C9
Metabolites: 2-propyl-3-ketopentanoic acid
Elimination
Half-life: 7-13 hr (>2 months); 9-16 hr (adults)
Dialyzable: Yes
Total body clearance: 4.6 L•hr/1.73 m² (50% higher in children <10 years)
Excretion: Urine (30-50%)
Administration
IV Preparation
Dilute with at least 50 mL of compatible diluent (eg, D5W; NS; LR)
Stable for at least 24 hr when stored in glass or PVC at 15-30°C (59-86°F)
IV Administration
Infuse over 60 min at <20 mg/min
Has been administered as rapid infusion over 5-10 min (1.5-3 mg/kg/min) (not per label; rapid infusion associated with increased AE risk, but in limited studies was well-tolerated)
Oral Administration
Swallow whole, do not chew or crush
Capsules may be opened and sprinkled on spoonful of soft food immediately before administration
If dose is skipped, do not double next dose
If daily oral dose >250 mg/day, give as divided dose
Storage
Store vials at 15-30°C (59-86°F)
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Patient Handout
Formulary
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