Drug information of Valproate sodium

Valproate sodium

Drug group: Anticonvulsants

Valproic acid affects chemicals in the body that may be involved in causing seizures.

Mechanism of effect

The mechanisms by which Valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA).

Pharmacodynamic

Causes increased availability of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, to brain neurons or may enhance the action of GABA or mimic its action at postsynaptic receptor sites.

Divalproex sodium is a compound of sodium valproate and valproic acid; divalproex dissociates to valproate in the GI tract.

Pharmacokinetics

Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy.

The plasma protein binding of valproate is concentration dependent . Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. 

Drug indications

Epilepsy

Dosage

** Usual Adult Dose for Epilepsy

  • Complex partial seizures:

Initial dose: 10 to 15 mg/kg orally or IV daily; increase by 5 to 10 mg/kg per week if necessary according to clinical response

Maintenance dose: 10 to 60 mg/kg daily

Maximum dose: 60 mg/kg daily

  • Simple and complex absence seizures:

Initial dose: 15 mg/kg orally or IV daily; increase by 5 to 10 mg/kg per week if necessary according to clinical response

Maintenance dose: 10 to 60 mg/kg daily

Maximum dose: 60 mg/kg daily

** Usual Adult Dose for Mania

  • Delayed-release tablets:

Initial dose: 750 mg orally per day in divided doses
Titration: The dose should be rapidly titrated to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations.
Maximum dose: 60 mg/kg/day

  • Extended-release tablets:
    Initial dose: 25 mg/kg orally once a day
    Titration: Increase as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations.
    Maximum dose: 60 mg/kg/day

    Use: For the treatment of the manic episodes associated with bipolar disorder

** Usual Adult Dose for Migraine Prophylaxis

Delayed-release tablets:
Initial dose: 250 mg orally 2 times a day
Maintenance dose: Some patients may benefit from doses up to 1000 mg per day.

Extended-release tablets:
Initial dose: 500 mg orally once a day for 1 week
Maintenance dose: May increase to 1000 mg orally once a day 

  • Usual Pediatric Dose for Epilepsy

10 years or older:

Complex partial seizures:

Initial dose: 10 to 15 mg/kg orally or IV daily; increase by 5 to 10 mg/kg per week if necessary according to clinical response

Maintenance dose: 10 to 60 mg/kg daily

Maximum dose: 60 mg/kg daily

  • Simple and complex absence seizures:

Initial dose: 15 mg/kg orally or IV daily; increase by 5 to 10 mg/kg per week if necessary according to clinical response

Maintenance dose: 10 to 60 mg/kg daily

Maximum dose: 60 mg/kg daily

*** Comment:

-The IV formulation should be administered as a 60-minute infusion (but not more than 20 mg/min) with the same frequency as the oral products, although plasma concentration monitoring and dosage adjustments may be necessary.

Drug contraindications

hypersensitivity to this drug

Alerts

  • Hepatic failure resulting in fatalities has occurred in patients receiving Valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur.
  • Patients should be monitored closely for appearance of these symptoms. 
  • Valproate is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder. 
  • Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data show that maternal Valproate use can cause neural tube defects and other structural abnormalities (e.g., craniofacial defects, cardiovascular malformations, hypospadias, limb malformations).
  • The rate of congenital malformations among babies born to mothers using Valproate is about four times higher than the rate among babies born to epileptic mothers using other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population.
  • Because of the risk to the fetus of decreased IQ and major congenital malformations (including neural tube defects), which may occur very early in pregnancy, Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when Valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). 
  • Women should use effective contraception while using Valproate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of Valproate use during pregnancy, and alternative therapeutic options should be considered for these patients.
  • To prevent major seizures, Valproate should not be discontinued abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. 
  • Cases of life-threatening pancreatitis have been reported in both children and adults receiving Valproate. 
  • Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. 
  • Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of Valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. 
  • Valproate is associated with dose-related thrombocytopenia. 
  • Concomitant administration of topiramate and Valproate has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia. 
  • Hypothermia, defined as an unintentional drop in body core temperature to < 35°C (95°F), has been reported in association with Valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with Valproate after starting topiramate treatment or after increasing the daily dose of topiramate.

Points of recommendation

You should not use valproic acid if you are allergic to it, or if you have:

  • liver disease;
  • a urea cycle disorder; or
  • a genetic mitochondrial (MYE-toe-KON-dree-al) disorder such as Alpers' disease or Alpers-Huttenlocher syndrome, especially in a child younger than 2 years old.

To make sure valproic acid is safe for you, tell your doctor if you have:

  • liver problems caused by a genetic mitochondrial disorder;
  • a history of depression, mental illness, or suicidal thoughts or actions;
  • a family history of a urea cycle disorder or infant deaths with unknown cause; or
  • HIV or CMV (cytomegalovirus) infection.

Valproic acid can cause liver failure that may be fatal, especially in children under age 2 and in people with liver problems caused by a genetic mitochondrial disorder.

Do not use valproic acid to prevent migraine headaches if you are pregnant. 

If you take valproic acid for seizures or manic episodes: Do not start or stop taking the medicine during pregnancy without your doctor's advice.

Valproic acid can cause liver failure that may be fatal, especially in children under age 2 and in people with liver problems caused by a genetic mitochondrial (MYE-toe-KON-dree-al) disorder. 

Call your doctor at once if the person taking this medicine has signs of liver or pancreas problems, such as: loss of appetite, upper stomach pain (that may spread to your back), ongoing nausea or vomiting, dark urine, swelling in the face, or jaundice (yellowing of the skin or eyes).

Drink plenty of water while you are taking this medication. Your dose may need to be changed if you do not get enough fluids each day. 

Take with food if this medicine upsets your stomach. 

Measure liquid medicine with a special dose-measuring spoon or medicine cup. If you do not have a dose-measuring device, ask your pharmacist for one.

Do not crush, chew, break, or open a delayed-release capsule. Swallow it whole. 

While using valproic acid, you may need frequent blood tests.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Pregnancy level

D


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