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Medications: Depakote® – valproic acid/divalproex

MEDICATIONS

Depakote® – valproic acid/divalproex (View the FDA label)

Depakote is an anti-epileptic drug indicated for:

  • Treatment of manic episodes associated with bipolar disorder (1.1)
  • 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 (1.2)
  • Prophylaxis of migraine headaches (1.3)

DOSAGE AND ADMINISTRATION

Depakote is administered orally in divided doses. Depakote should be swallowed whole and should not be crushed or chewed (2.1, 2.2).

Mania: Initial dose is 750 mg daily, increasing as rapidly as possible to achieve therapeutic response or desired plasma level (2.1). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2).

Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response; if response is not satisfactory, check valproate plasma level; see full prescribing information for conversion to monotherapy (2.2). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2).

Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day until seizure control or limiting side effects (2.2). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2).

Migraine: The recommended starting dose is 250 mg twice daily, thereafter increasing to a maximum of 1000 mg/day as needed (2.3).

Most common adverse reactions (reported >5%) reported in patients are abdominal pain, accidental injury, alopecia, ambylopia/blurred vision, amnesia, anorexia, asthenia, ataxia, back pain, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome, headache, increased appetite, infection, insomnia, nausea, nervousness, nystagmus, peripheral edema, pharyngitis, rash, rhinitis, somnolence, thinking abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss (6.1, 6.2, 6.3).

The safety and tolerability of valproate in pediatric patients were shown to be comparable to those in adults (8.4).

Hepatotoxicity; evaluate high risk populations and monitor serum liver tests (5.1)

Birth defects and decreased IQ following in utero exposure; only use to treat pregnant women with epilepsy or bipolar disorder if other medications are unacceptable; should not be administered to a woman of childbearing potential unless essential (5.2, 5.3, 5.4)

Pancreatitis; Depakote should ordinarily be discontinued (5.5)

Suicidal behavior or ideation; Antiepileptic drugs, including Depakote, increase the risk of suicidal thoughts or behavior (5.7)

Thrombocytopenia; monitor platelet counts and coagulation tests (5.8)

Hyperammonemia and hyperammonemic encephalopathy; measure ammonia level if unexplained lethargy and vomiting or changes in mental status, and also with concomitant topiramate use; consider discontinuation of valproate therapy (5.6, 5.9, 5.10)

Hypothermia; Hypothermia has been reported during valproate therapy with or without associated hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate (5.11)

Multi-organ hypersensitivity reaction; discontinue Depakote (5.12)

Somnolence in the elderly can occur. Depakote dosage should be increased slowly and with regular monitoring for fluid and nutritional intake (5.14)

Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, primidone, phenobarbital, rifampin) can increase valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance. Therefore increased monitoring of valproate and concomitant drug concentrations and dose adjustment is indicated whenever enzyme- inducing or inhibiting drugs are introduced or withdrawn (7.1)

Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations are recommended (7.1)

Co-administration of valproate can affect the pharmacokinetics of other drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting their metabolism or protein binding displacement (7.2)

Dosage adjustment of amitryptyline/nortryptyline, warfarin, and zidovudine may be necessary if used concomitantly with Depakote (7.2)

Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3)

Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been reported; however patients have recovered from valproate levels as high as 2,120 mcg/mL.

In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time since ingestion. General supportive measures should be applied with particular attention to the maintenance of adequate urinary output.

Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy.

Uses

Depakote is an anti-epileptic drug indicated for:

  • Treatment of manic episodes associated with bipolar disorder (1.1)
  • 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 (1.2)
  • Prophylaxis of migraine headaches (1.3)

DOSAGE AND ADMINISTRATION

Depakote is administered orally in divided doses. Depakote should be swallowed whole and should not be crushed or chewed (2.1, 2.2).

Mania: Initial dose is 750 mg daily, increasing as rapidly as possible to achieve therapeutic response or desired plasma level (2.1). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2).

Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response; if response is not satisfactory, check valproate plasma level; see full prescribing information for conversion to monotherapy (2.2). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2).

Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day until seizure control or limiting side effects (2.2). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2).

Migraine: The recommended starting dose is 250 mg twice daily, thereafter increasing to a maximum of 1000 mg/day as needed (2.3).

Side Effects

Most common adverse reactions (reported >5%) reported in patients are abdominal pain, accidental injury, alopecia, ambylopia/blurred vision, amnesia, anorexia, asthenia, ataxia, back pain, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome, headache, increased appetite, infection, insomnia, nausea, nervousness, nystagmus, peripheral edema, pharyngitis, rash, rhinitis, somnolence, thinking abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss (6.1, 6.2, 6.3).

The safety and tolerability of valproate in pediatric patients were shown to be comparable to those in adults (8.4).

Precautions

Hepatotoxicity; evaluate high risk populations and monitor serum liver tests (5.1)

Birth defects and decreased IQ following in utero exposure; only use to treat pregnant women with epilepsy or bipolar disorder if other medications are unacceptable; should not be administered to a woman of childbearing potential unless essential (5.2, 5.3, 5.4)

Pancreatitis; Depakote should ordinarily be discontinued (5.5)

Suicidal behavior or ideation; Antiepileptic drugs, including Depakote, increase the risk of suicidal thoughts or behavior (5.7)

Thrombocytopenia; monitor platelet counts and coagulation tests (5.8)

Hyperammonemia and hyperammonemic encephalopathy; measure ammonia level if unexplained lethargy and vomiting or changes in mental status, and also with concomitant topiramate use; consider discontinuation of valproate therapy (5.6, 5.9, 5.10)

Hypothermia; Hypothermia has been reported during valproate therapy with or without associated hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate (5.11)

Multi-organ hypersensitivity reaction; discontinue Depakote (5.12)

Somnolence in the elderly can occur. Depakote dosage should be increased slowly and with regular monitoring for fluid and nutritional intake (5.14)

Interactions

Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, primidone, phenobarbital, rifampin) can increase valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance. Therefore increased monitoring of valproate and concomitant drug concentrations and dose adjustment is indicated whenever enzyme- inducing or inhibiting drugs are introduced or withdrawn (7.1)

Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations are recommended (7.1)

Co-administration of valproate can affect the pharmacokinetics of other drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting their metabolism or protein binding displacement (7.2)

Dosage adjustment of amitryptyline/nortryptyline, warfarin, and zidovudine may be necessary if used concomitantly with Depakote (7.2)

Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3)

Overdose

Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been reported; however patients have recovered from valproate levels as high as 2,120 mcg/mL.

In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time since ingestion. General supportive measures should be applied with particular attention to the maintenance of adequate urinary output.

Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy.

Interpreting the GeneSight® Test:
Gene-Drug Interaction Chart

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