valproic acid (Rx)

Brand and Other Names:Depakene, Stavzor, more...Depacon
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Dosing & Uses

AdultPediatricGeriatric

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

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Interactions

Interaction Checker

and valproic acid

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            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

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            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

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            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.

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            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%)

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            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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            Images

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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