Adult Dosing

Mania associated with bipolar disorder

• Extended Release
• Start dose: 25 mg/kg/day PO daily; increase rapidly to achieve the lowest therapeutic dose
• Max: 60 mg/kg/day

• Delayed Release
• Start dose: 750 mg/day PO in divided doses; increase rapidly to achieve the lowest therapeutic dose
• Max: 60 mg/kg/day

Complex Partial Seizures

Monotherapy

• Extended Release
• Initial dose: 10-15 mg/kg/day PO daily; increase by 5-10 mg/kg qwk to achieve optimal clinical response and plasma level of 50 to 100 mcg/mL
• Max: 60 mg/kg/day

• Delayed release
• Initial dose: 10-15 mg/kg/day in divided doses; increase by 5-10 mg/kg qwk to achieve optimal clinical response and plasma level of 50 to 100 mcg/mL
• Max: 60 mg/kg/day

Conversion to Monotherapy

• Extended Release
• Initial dose: 10-15 mg/kg/day PO daily; increase by 5-10 mg/kg qwk to achieve optimal clinical response and plasma level of 50 to 100 mcg/mL
• Max: 60 mg/kg/day
• Reduce concomitant antiepilepsy drug dosage by 25% q2 wks, at the initiation of divalproex sodium

• Delayed release
• Initial dose: 10-15 mg/kg/day PO in divided doses; increase by 5-10 mg/kg qwk to achieve optimal clinical response and plasma level of 50 to 100 mcg/mL
• Max: 60 mg/kg/day
• Reduce concomitant antiepilepsy drug dosage by 25% q2 wks, at the initiation of divalproex sodium

Adjunctive Therapy

• Extended Release
• Initial dose: 10-15 mg/kg/day PO daily; increase by 5-10 mg/kg qwk to achieve optimal clinical response and plasma level of 50 to 100 mcg/mL
• Max: 60 mg/kg/day

• Delayed release
• Initial dose: 10-15 mg/kg/day PO in divided doses; increase by 5-10 mg/kg qwk to achieve optimal clinical response and plasma level of 50 to 100 mcg/mL
• Max: 60 mg/kg/day

Simple and Complex Absence Seizures

• Extended Release
• Initial dose: 15 mg/kg/day PO daily; increase by 5-10 mg/kg/day qwk
• Max: 60 mg/kg/day

• Delayed release
• Initial dose: 15 mg/kg/day PO in divided doses; increase by 5-10 mg/kg/day qwk
• Max: 60 mg/kg/day

Prophylaxis of migraine

• Extended Release
• Initial dose: 500 mg PO daily x 1 wk, then increase to 1000 mg PO qd
• Max: 1000 mg/day

• Delayed release
• Initial dose: 250 mg PO bid
• Max: 1000 mg/day

• When converting from delayed release tablet to extended release tablet, administer ETABS once daily at a dose 8-20% higher than the total daily dose of delayed release tablet
• Use lower starting dose in elderly patients

Pediatric Dosing

Complex Partial Seizures (>10 yrs)

Monotherapy

• Extended Release
• Initial dose: 10-15 mg/kg/day PO daily; increase by 5-10 mg/kg qwk to achieve optimal clinical response and plasma level of 50 to 100 mcg/mL
• Max: 60 mg/kg/day

• Delayed release
• Initial dose: 10-15 mg/kg/day in divided doses; increase by 5-10 mg/kg qwk to achieve optimal clinical response and plasma level of 50 to 100 mcg/mL
• Max: 60 mg/kg/day

Conversion to Monotherapy

• Extended Release
• Initial dose: 10-15 mg/kg/day PO daily; increase by 5-10 mg/kg qwk to achieve optimal clinical response and plasma level of 50 to 100 mcg/mL
• Max: 60 mg/kg/day
• Reduce concomitant antiepilepsy drug dosage by 25% q2 wks at the initiation of divalproex sodium

• Delayed release
• Initial dose: 10-15 mg/kg/day PO in divided doses; increase by 5-10 mg/kg qwk to achieve optimal clinical response and plasma level of 50 to 100 mcg/mL
• Max: 60 mg/kg/day
• Reduce concomitant antiepilepsy drug dosage by 25% q2 wks at the initiation of divalproex sodium

Adjunctive Therapy

• Extended Release
• Initial dose: 10-15 mg/kg/day PO daily; increase by 5-10 mg/kg qwk to achieve optimal clinical response and plasma level of 50 to 100 mcg/mL
• Max: 60 mg/kg/day

• Delayed release
• Initial dose: 10-15 mg/kg/day PO in divided doses; increase by 5-10 mg/kg qwk to achieve optimal clinical response and plasma level of 50 to 100 mcg/mL
• Max: 60 mg/kg/day

Simple and Complex Absence Seizures (>10 yrs)

• Extended Release
• Initial dose: 15 mg/kg/day PO daily; increase by 5-10 mg/kg/day qwk
• Max: 60 mg/kg/day

• Delayed release
• Initial dose: 15 mg/kg/day PO in divided doses; increase by 5-10 mg/kg/day qwk
• Max: 60 mg/kg/day

Note:

• When converting from delayed release tablet to extended release tablet, administer ER TABS once daily at a dose 8-20% higher than the total daily dose of delayed release tablet

[Outline]

• Adult Dosing
• Pediatric Dosing

• Monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures
• Adjunctive therapy in patients with multiple seizure types that include absence seizures
• Prophylaxis of migraine headaches
• Treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features

Note:

• Do not use in women of childbearing age unless the drug is essential for disease management; as it may cause decreased IQ, neural tube defects and other congenital malformations

• Hypersensitivity to any of the ingredients of the product
• Hepatic disease
• Hepatic dysfunction
• Urea cycle disorders

• Fatal hepatic failure has occurred in patients receiving valproic acid usually during the first six month of treatment. Children under 2 years of age and on multiple anticonvulsants or have congenital metabolic disorder, severe seizure disorders accompanied by mental retardation and organic brain disease are at higher risk of developing hepatotoxicity. Use with extreme caution in these patients and only if potential benefit outweighed against risk
• Incidence of hepatotoxicity decreases in progressively older patients
• Patients should be closely monitor for appearance of any of these symptoms of fatal liver diseases such as malaise, weakness, lethargy, anorexia, vomiting, facial edema, and loss of seizure control in epilepsy patients. Liver function test should be performed at the baseline and at frequent interval during the treatment especially in first 6 months
• Teratogenicity such as neural tube defect have occurred with the therapy, hence use valproate product in women of child bearing age only if potential benefit outweighed against risk to the fetus or other antiseizure medications have failed to control the symptoms. Therapy can also cause lower cognitive test scores following in utero exposure
• Women of childbearing potential should use effective contraception while taking valproate products
• Life threatening pancreatitis, hemorrhagic with rapid progression from initial symptoms to death has been reported in both children and adults receiving valproate. Monitor the patients for symptoms of pancreatitis such as abdominal pain, nausea, vomiting, anorexia if pancreatitis is diagnosed, immediately discontinue the drug and provide alternative treatment for underlying medical condition

Renal Dose Adjustments

• Renal impairment: No dose adjustments

Hepatic Dose Adjustments

• Hepatic impairment: Contraindicated

See Supplemental Patient Information

• Fatal hepatic failure has occurred in patients receiving valproic acid, especially in the first six months of treatment. Closely monitor the patients and perform LFT at base line and at frequent intervals during the treatment [US Black box warning]
• Valproate and any other antiepileptic drug may be teratogenic, eg causing neural tube defects. Use cautiously during pregnancy and in women of childbearing age, and only if potential benefit to mother outweighs the risk to the fetus . Therapy can also cause decreased IQ scores following in utero exposure [US Black box warning]
• Valproate causes clotting disorder. Use of valproate during pregnancy in women with low fibrinogen levels may cause afibrinogenemia in infants and lead to hemorrhagic death
• Maternal use of valproate during pregnancy causes hepatotoxicity in infants
• Do not discontinue the antiepileptic drug abruptly in patients with major seizures as it can precipitate status epilepticus with attendant hypoxia and threat to life
• Life-threatening pancreatitis has occurred in both children and adults receiving valproate [US Black box warning]
• Avoid use of valproic acid in patients with known urea cycle disorders, as it causes hyperammonemic encephalopathy in such patients
• Before starting valproic acid therapy evaluate for urea cycle disorder (UCD) in patients with a history of unexplained encephalopathy or coma, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine, cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance, family history of UCD or a family history of unexplained infant deaths. Immediately discontinue the drug if patient develops unexplained hyperammonemic encephalopathy and provide prompt treatment
• Monitor the patient receiving any antiepileptic drug including valproate for the signs of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior, as antiepileptic drugs increase the risk of suicidal tendencies in the patients
• Thrombocytopenia occurs with total valproate concentrations of 110 mcg/mL (female) - 135 mcg/mL (male). Monitor platelet counts and coagulation before starting the treatment and periodically thereafter
• Hyperammonemia has been reported with valproate therapy. Patients developing unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy, hypothermia should be evaluated for hyperammonemia. Discontinue the drug if high ammonia level is observed and initiate appropriate treatment for hyperammonemia
• Concomitant use of topiramate and valproic acid causes hyperammonemia with or without encephalopathy. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity are at higher risk
• Valproate causes hypothermia; discontinue the drug on development of hypothermia manifested by lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Monitor blood ammonia levels
• Multi-organ hypersensitivity reactions with variable sign and symptoms resulting in to hospitalization or death have occurred with valproate therapy in adult and pediatric patients. Discontinue the drug if this reaction is suspected and start an alternative treatment
• Concomitant use of carbapenem antibiotic with valproate reduce serum valproic acid concentrations to subtherapeutic levels, resulting in loss of seizure control
• Valproic acid causes somnolence in elderly patients and also dehydration and weight loss. Use valproic acid cautiously in elderly patients and increase dosage slowly, with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse events. Consider dose reduction or discontinuation of valproate in patients with decreased food or fluid intake and excessive somnolence
• Valproic acid is partially eliminated as ketometabolite in the urine and lead to false interpretation of urine ketone test and also alters the thyroid function test
• Consider periodic determinations of valproate and concomitant drugs during the early course of therapy, as valproic acid may interact with concurrently administered drugs which are capable of enzyme induction
• Increased risk of lower cognitive function has been reported in children born to mothers exposed to valproate sodium or related products throughout their pregnancy, as compared to the children born to mothers exposed to other anti-seizure medications
• If patient experiences medication residue in feces , then monitor plasma valproate levels and consider alternative therapy if clinically indicated

Cautions: Use cautiously in

• Renal impairment
• History of liver disease
• Pediatric patients
• Organic brain disease
• Head injury
• History of depression
• Mental retardation with seizure disorder
• Congenital metabolic disorders
• Multiple anticonvulsants use
• Myelosuppression
• Bleeding tendencies

Supplemental Patient Information

• As valproate causes CNS depression patients are advised not to drive an automobile or operate dangerous machinery
• Women those who are planning to become pregnant or have become pregnant should inform their doctors as valproate is known to cause teratogenic effect in fetus
• Patients should immediately report to the physician if there is fever associated with other organ system involvement (rash, lymphadenopathy, etc.) during the treatment

Pregnancy Category:D

Breastfeeding: Divalproex results in valproic acid in the maternal bloodstream. Low level of valproic acid is excreted in breastmilk; no unquestionable adverse reactions to valproic acid have been reported during breastfeeding. Monitor infant serum valproate levels, platelets and liver enzymes during maternal therapy as breastfed infants are at risk for valproate induced hepatotoxicity and thrombocytopenia. Monitor infants for jaundice and other signs of liver damage, unusual bruising or bleeding. Combination therapy with sedating anticonvulsants or psychotropics may result in infant sedation or withdrawal reactions. This information is based upon LactMed database (available at http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT last accessed 20 May 2011). Valproate is excreted in breast milk 1-10% of serum concentrations. Manufacturer advises to discontinue nursing when valproate is administered to a nursing woman.

• CNS: Somnolence, dizziness, amnesia, insomnia, headache, hypothermia, encephalopathy, coma, abnormal gait
• PSYCHIATRY: Suicidal thoughts, emotional liability, abnormal thinking, depression, hallucinations, psychosis, agitation, confusion
• NEURO: Paresthesia, tremor, ataxia
• CV: Peripheral edema, vasodilatation,
• EENT: Visual disturbances, blurred vision, tinnitus, nystagmus, diplopia, amblyopia
• GI: Hepatotoxicity, pancreatitis, abdominal pain, anorexia, dyspepsia, nausea, vomiting, constipation, diarrhea, appetite change, elevated ALT, AST
• DERM: Alopecia, rashes, erythema multiforme, Stevens Johnson syndrome, toxic epidermal necrolysis
• RESP: Flu syndrome, infection, bronchitis, rhinitis, pharyngitis, dyspnea, pneumonia
• REPRODUCTIVE: Congenital anomalies, congenital neural tube defects
• HEMA: Leukopenia, thrombocytopenia, ecchymosis, myleosuppression, aplastic anemia, pancytopenia
• METABOLIC: Weight gain, hyperammonemia, hyponatremia
• MUSC: Myalgia, back pain
• MISC: Asthenia, fever, influenza, multi organ hypersensitivity reaction, photosensitivity, accidental injury

• GABA agent; increases concentration of GABA in brain, by inhibiting enzymes that catabolize GABA or block the reuptake of GABA into glia and nerve endings
• Metabolized entirely by liver
• Renally excreted (<3 % unchanged)
• Half-life: 9-16 hrs

US Trade Name(s)

• Depakote
• Depakote ER

US Availability

divalproex sodium (generic)

• Delayed Release TABS: 125, 250, 500 mg
• CAPS (Sprinkles): 125 mg
• ETABS: 250, 500 mg

Depakote

• Delayed Release TABS: 125, 250, 500 mg
• CAPS (Sprinkles): 125 mg

Depakote ER

• ETABS: 250, 500 mg

Canadian Trade Name(s)

• Epival

Canadian Availability

divalproex sodium (generic)

• TABS: 125, 250, 500 mg

Epival

• TABS: 125, 250, 500 mg

UK Trade Name(s)

• N/A

UK Availability

• N/A

Australian Trade Name(s)

• N/A

Australian Availability

• N/A

[Outline]

Neurologic

Anticonvulsants

Fatty Acid Derivative Anticonvulsants

Pricing data from www.DrugStore.com in U.S.A.

• Depakote 125 MG TBEC [Bottle] (ABBOTT)
  60 mg = $70.99
  180 mg = $200.97
• Divalproex Sodium 125 MG CPSP [Bottle] (ZYDUS PHARMACEUTICALS (USA))
  30 mg = $25.99
  90 mg = $65.97
• Divalproex Sodium 500 MG TBEC [Bottle] (UPSHER-SMITH)
  100 mg = $49.99
  300 mg = $129.96
• Divalproex Sodium 250 MG TB24 [Bottle] (MYLAN)
  100 mg = $139.99
  300 mg = $389.99
• Divalproex Sodium 125 MG TBEC [Bottle] (UPSHER-SMITH)
  100 mg = $24.99
  300 mg = $59.97
• Depakote ER 500 MG TB24 [Bottle] (ABBOTT)
  30 mg = $111.99
  90 mg = $307.97
• Depakote 250 MG TBEC [Bottle] (ABBOTT)
  60 mg = $136.99
  180 mg = $385.98
• Depakote Sprinkles 125 MG CPSP [Bottle] (ABBOTT)
  60 mg = $71.99
  180 mg = $199.96
• Divalproex Sodium 500 MG TB24 [Bottle] (MYLAN)
  100 mg = $59.99
  300 mg = $179.96
• Divalproex Sodium 250 MG TBEC [Bottle] (UPSHER-SMITH)
  100 mg = $29.99
  300 mg = $69.96
• Depakote ER 250 MG TB24 [Bottle] (ABBOTT)
  30 mg = $67.99
  90 mg = $180.96

Warning: This pricing information is subject to change at the sole discretion of DS Pharmacy. For the most current and up-to-date pricing information, please visit drugstore.com.

• DIVALPROEX SODIUM 500 mg (Physicians Total Care, Inc.)
• Depakote 125 MG Enteric Coated Capsule (Abbott Laboratories)
• Depakote 125 MG Enteric Coated Tablet (Abbott Laboratories)
• Depakote 250 MG Enteric Coated Tablet (Abbott Laboratories)
• Depakote 500 MG Enteric Coated Tablet (Abbott Laboratories)
• Divalproex Sodium (VALPROIC ACID 250 mg) (TEVA Pharmaceuticals USA Inc)
• Divalproex Sodium (VALPROIC ACID 500 mg) (Physicians Total Care, Inc.)