Dosing and uses of Depakene, Stavzor (valproic acid)
Adult dosage forms and strengths
capsule (Depakene)
- 250mg
capsule, delayed-release (Stavzor)
- 125mg
- 250mg
- 500mg
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
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
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
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
Dosage modifications
Renal impairment
- No adjustment necessary; protein binding is reduced and may cause measurement of total valproate concentrations to be inaccurate
Hepatic impairment
- Administer lower doses
- 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
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
Pediatric dosage forms and strengths
capsule (Depakene)
- 250mg
capsule, delayed-release (Stavzor)
- 125mg
- 250mg
- 500mg
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
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
Dosage modifications
Renal impairment
- No adjustment necessary; protein binding is reduced and may cause measurement of total valproate concentrations to be inaccurate
Hepatic impairment
- Administer lower doses
- 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
Geriatric dosage forms and strengths
Administer as in adults, but may need to initiate at lower dose; the increment in dose should also be slow
Depakene, Stavzor (valproic acid) adverse (side) 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
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
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
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
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
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; see Black box warnings
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;
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
Pregnancy and lactation
Pregnancy category: D for seizures or manic episodes associated with bipolar disorder that are unresponsive to other treatments
Pregnancy category: X for migraine headache prevention
Results from epidemiologic studies concluded that children born to women who take valproate sodium or related products (valproic acid, divalproex sodium) during pregnancy have an increased risk for lower cognitive test scores, compared with children exposed to other antiseizure medications during pregnancy
Known to cause neural tube defects; evidence suggests that folic acid supplementation prior to conception and during the first trimester decreases risk for congenital neural tube defects
Lactation: Excreted in milk; use caution (AAP and ACOG say compatible)
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 of Depakene, Stavzor (valproic acid)
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)
