Sodium Valproate + Valproic Acid

Usage

• Medical Conditions: Sodium Valproate + Valproic Acid is an anticonvulsant medication prescribed primarily for epilepsy (various seizure types, including generalized tonic-clonic, absence, and partial seizures), bipolar disorder (for managing manic episodes and preventing relapse), and migraine prevention. It’s sometimes used off-label for other conditions, but evidence for these uses may be limited.
• Pharmacological Classification: Anticonvulsant, mood stabilizer.
• Mechanism of Action: The precise mechanism is not fully understood, but it’s thought to involve multiple actions: increasing levels of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter; modulating voltage-gated sodium and calcium channels, thus affecting neuronal excitability; and potentially impacting other neurotransmitter systems.

Alternate Names

• Alternate Names: Valproate sodium, valproic acid, divalproex sodium
• Brand Names: Epilim, Depakene, Depakote, Stavzor, Depacon, Epilim Chrono, Epilim Chronosphere, Dyzantil.

How It Works

• Pharmacodynamics: Sodium valproate increases GABA levels in the brain, leading to enhanced inhibitory neurotransmission. It also appears to block voltage-gated sodium channels, reducing the repetitive firing of neurons. Modulation of T-type calcium channels may also contribute to its anti-epileptic effects.
• Pharmacokinetics: Sodium valproate is rapidly and almost completely absorbed after oral administration. It is highly protein-bound, primarily to albumin. Metabolism occurs extensively in the liver, mainly through glucuronidation and mitochondrial beta-oxidation. Elimination is primarily through renal excretion of metabolites. Valproic acid has a relatively short half-life (around 9-16 hours), necessitating multiple daily doses.
• Mode of Action: The drug increases GABAergic inhibition, probably by inhibiting GABA transaminase, the enzyme that breaks down GABA. It also reduces neuronal excitability by blocking voltage-gated sodium channels. This combination of actions reduces the likelihood of seizure activity.
• Receptor Binding, Enzyme Inhibition, Neurotransmitter Modulation: Primarily inhibits GABA transaminase, thus increasing GABA availability. Also modulates sodium and T-type calcium channels and potentially influences other neurotransmitter systems.
• Elimination Pathways: Mostly hepatic metabolism (glucuronidation and beta-oxidation) followed by renal excretion of metabolites. A small fraction is excreted unchanged in urine.

Dosage

Standard Dosage

Adults:

• Epilepsy/Bipolar: Initial 10-15 mg/kg/day orally, divided into 2-3 doses; increase weekly by 5-10 mg/kg/day until control is achieved or up to a maximum of 60 mg/kg/day. Dosage above 250mg should be divided.
• Migraine Prevention: 500-1000 mg/day orally, divided into 2-3 doses.

Children:

• Epilepsy: Initial 10-15 mg/kg/day orally, divided into 1-2 doses (for children 2-11 years old). Increase weekly by 5-10 mg/kg/day as needed, with a maximum of 60 mg/kg/day or 12.5 to 15 mg/kg twice daily if needed, not exceeding 600mg twice daily. For children 12 years and over, refer to adult dosage recommendations.

Special Cases:

• Elderly Patients: Start with lower doses and titrate cautiously, monitoring for adverse effects.
• Patients with Renal Impairment: Dose reduction may be necessary. Closely monitor renal function.
• Patients with Hepatic Dysfunction: Contraindicated in patients with significant hepatic impairment. Exercise caution in patients with mild to moderate hepatic dysfunction.
• Patients with Comorbid Conditions: Carefully assess patients with diabetes, cardiovascular disease, or other conditions, as valproate may interact with other medications or exacerbate certain conditions.

Clinical Use Cases

• Intubation/Surgical Procedures/Mechanical Ventilation/ICU Use/Emergency Situations: IV valproate sodium may be used for rapid control of seizures, especially in status epilepticus. 10-15 mg/kg IV over 1 hour, followed by continuous infusion or repeated doses, with maximum daily dose of 60 mg/kg/day. Do not administer IM due to risk of tissue necrosis. Transition to oral therapy as soon as possible.

Dosage Adjustments

Dose adjustments are necessary based on individual response, tolerability, plasma levels (if monitored), and the presence of renal or hepatic impairment. Genetic polymorphisms affecting drug metabolism might necessitate specific considerations.

Side Effects

Common Side Effects

Nausea, vomiting, diarrhea, tremor, weight gain, hair loss, dizziness, drowsiness, blurred/double vision, changes in menstrual periods, tinnitus.

Rare but Serious Side Effects

Hepatotoxicity (especially in children under 2 years old), pancreatitis, hyperammonemic encephalopathy, thrombocytopenia, leukopenia, suicidal ideation, Stevens-Johnson syndrome.

Long-Term Effects

Polycystic ovary syndrome, bone mineral density reduction, cognitive impairment (with chronic use), peripheral neuropathy.

Adverse Drug Reactions (ADR)

Severe hepatotoxicity, pancreatitis, hyperammonemia, blood dyscrasias, angioedema, drug reaction with eosinophilia and systemic symptoms (DRESS).

Contraindications

• Absolute: Known hypersensitivity, significant hepatic impairment, urea cycle disorders, known or suspected mitochondrial disorders (especially Alpers-Huttenlocher Syndrome).
• Relative: Pregnancy (especially for migraine prevention), active liver disease, family history of liver dysfunction, porphyria.

Drug Interactions

• CYP450 Interactions: Valproate inhibits CYP2C9, potentially increasing levels of drugs metabolized by this enzyme (e.g., warfarin, phenytoin). It is also metabolized by CYP2C9 and CYP2C19.
• Other Interactions: Enzyme-inducing antiepileptic drugs (e.g., carbamazepine, phenytoin, phenobarbital) can decrease valproate levels. Valproate may increase levels of lamotrigine and ethosuximide. Other interactions include those with carbapenems, salicylates, rifampicin, some antidepressants.
• Food and Lifestyle Factors: Alcohol may potentiate the sedative effects of valproate.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: D (according to the Australian classification) / X (according to the U.S. FDA classification for migraine prophylaxis)
• Fetal Risks: High risk of neural tube defects (e.g., spina bifida), congenital malformations, developmental disorders (including cognitive deficits and autism spectrum disorder). High dose folic acid supplementation (5 mg/day) is recommended for women taking valproate who are considering or who become pregnant.
• Breastfeeding: Valproate is excreted in breast milk, but at low levels. Breastfeeding is generally considered acceptable if closely monitored. Observe the infant for sedation, hepatotoxicity, and bleeding.

Drug Profile Summary

• Mechanism of Action: Increases GABA levels, modulates sodium and calcium channels.
• Side Effects: Nausea, vomiting, tremor, weight gain, hepatotoxicity, pancreatitis, suicidal thoughts.
• Contraindications: Liver disease, urea cycle disorders, mitochondrial disorders, pregnancy (for migraine prophylaxis).
• Drug Interactions: Enzyme-inducing antiepileptics, lamotrigine, warfarin, carbapenems.
• Pregnancy & Breastfeeding: High risk of birth defects and developmental problems; use with caution during breastfeeding.
• Dosage: Start low and titrate; adjust for age, renal/hepatic function.
• Monitoring Parameters: Liver function tests, complete blood count, ammonia levels, valproate serum levels (if indicated).

Popular Combinations

Valproate is often used in combination with other antiepileptic drugs when monotherapy is insufficient. The choice of combination depends on the specific seizure type and patient characteristics.

Precautions

• General Precautions: Baseline liver function tests, complete blood count, assessing for suicidal ideation.
• Specific Populations: Avoid in pregnancy (especially for migraine); cautious use in breastfeeding and in patients with hepatic or renal dysfunction.
• Lifestyle Considerations: Avoid alcohol. May impair driving ability.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Sodium Valproate + Valproic Acid?

A: The dosage varies based on indication, age, and individual response. For epilepsy, typical starting doses are 10-15 mg/kg/day, gradually increased as needed. Maximum daily dose is usually 60 mg/kg/day.

Q2: What are the most serious side effects of Sodium Valproate + Valproic Acid?

A: The most serious side effects include hepatotoxicity (particularly in children under 2), pancreatitis, and hyperammonemic encephalopathy. Suicidal thoughts and behaviors have also been reported.

Q3: Can Sodium Valproate + Valproic Acid be used during pregnancy?

A: Valproate is contraindicated during pregnancy, especially for migraine prevention. It carries a high risk of birth defects (neural tube defects, congenital malformations) and neurodevelopmental problems. If a woman becomes pregnant while taking valproate, she should consult her doctor immediately.

Q4: What are the common drug interactions with Sodium Valproate + Valproic Acid?

A: Valproate interacts with many medications, including other antiepileptics (e.g., carbamazepine, phenytoin, lamotrigine), warfarin, and some antibiotics (carbapenems).

Q5: How should Sodium Valproate + Valproic Acid be administered?

A: Oral formulations (tablets, capsules, solution) are generally taken with food to reduce gastrointestinal upset. IV formulations (valproate sodium) are used in acute settings like status epilepticus. IM administration is contraindicated.

Q6: What monitoring is required for patients on Sodium Valproate + Valproic Acid?

A: Patients should undergo regular monitoring, including liver function tests, complete blood count, and ammonia levels. Valproate serum levels may be monitored to assess therapeutic range and compliance, although correlation with efficacy is not always clear.

Q7: Can Sodium Valproate + Valproic Acid be used in patients with liver disease?

A: Valproate is contraindicated in patients with significant hepatic impairment and used cautiously in those with mild to moderate dysfunction. Liver function tests should be performed before and during treatment.

Q8: How does Sodium Valproate + Valproic Acid affect patients with renal impairment?

A: Dose reduction may be required in patients with renal impairment. Careful monitoring of renal function is necessary.

Q9: What are the symptoms of valproate toxicity?

A: Symptoms of valproate toxicity may include drowsiness, confusion, nausea, vomiting, tremor, respiratory depression, coma, and liver failure.

Q10: What patient education is crucial for Sodium Valproate + Valproic Acid?

A: Patients should be counseled about the risk of birth defects if taken during pregnancy, the importance of contraception, the potential for side effects (including hepatotoxicity and pancreatitis), and the need for regular monitoring. They should also be informed about drug interactions and the importance of reporting any unusual symptoms.