Usage
Divalproex sodium is an anticonvulsant medication prescribed for the treatment of various conditions:
- Epilepsy: Used to manage several types of seizures, including complex partial seizures, absence seizures, and tonic-clonic seizures, both as monotherapy and adjunctive therapy.
- Bipolar Disorder: Effective in treating acute manic or mixed episodes associated with bipolar disorder, even with psychotic features.
- Migraine Prophylaxis: Prescribed for the prevention of migraine headaches.
Pharmacological Classification: Anticonvulsant, Mood Stabilizer
Mechanism of Action: Divalproex increases the concentration of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, in the brain. It achieves this by inhibiting GABA transaminase, the enzyme responsible for breaking down GABA. This action results in enhanced GABAergic inhibition, which helps stabilize neuronal excitability and prevent seizures. It may also modulate voltage-gated sodium and calcium channels.
Alternate Names
- Valproic Acid (closely related compound)
- Sodium Valproate (component of Divalproex)
Brand Names: Depakote, Depakote ER, Depakote Sprinkles, Epival
How It Works
Pharmacodynamics: Divalproex exerts its anticonvulsant effects by enhancing GABAergic inhibition in the central nervous system (CNS). This reduces neuronal excitability and stabilizes nerve cell activity, preventing seizures. It also appears to have some effects on sodium and calcium channels, further contributing to its anticonvulsant properties. Its mood stabilizing effects likely involve similar mechanisms, although the precise nature remains incompletely understood.
Pharmacokinetics:
- Absorption: Well-absorbed orally. Delayed-release and extended-release formulations alter absorption rate, providing more sustained levels.
- Metabolism: Extensively metabolized in the liver, primarily through glucuronidation and beta-oxidation. CYP2C9 plays a minor role.
- Elimination: Primarily eliminated renally, with a small portion excreted in feces.
Mode of Action: Divalproex increases GABA levels by inhibiting GABA transaminase, the enzyme that degrades GABA. This leads to increased GABA in the synaptic cleft, augmenting inhibitory neurotransmission. It may also modulate voltage-gated sodium channels, reducing neuronal excitability.
Receptor Binding/Enzyme Inhibition: Inhibits GABA transaminase, potentially interacts with sodium and calcium channels.
Elimination Pathways: Renal excretion (as glucuronide conjugates and metabolites), minor fecal excretion.
Dosage
Standard Dosage
Adults:
- Epilepsy: Initial dose is 10-15 mg/kg/day, divided into 2-4 doses. Increase weekly by 5-10 mg/kg/day until seizures are controlled or side effects limit further increase. Maximum dose: 60 mg/kg/day.
- Mania: Initial dose (delayed-release): 750 mg/day divided into smaller doses. Initial dose (extended-release): 25 mg/kg/day once daily. Increase rapidly as needed. Maximum dose: 60 mg/kg/day.
- Migraine Prophylaxis: Initial dose (delayed-release): 250 mg twice daily. Initial dose (extended-release): 500 mg once daily. Increase as needed. Maximum dose: 1000 mg/day.
Children:
- Epilepsy: Similar to adults, starting with 10-15 mg/kg/day. Dose adjustments are weight-based. Maximum dose: 60 mg/kg/day. Use with caution in children younger than 2 years due to increased risk of hepatotoxicity.
- Mania: Efficacy and safety not well established in children under 18.
Special Cases:
- Elderly Patients: Lower starting dose and slower titration due to increased sensitivity to adverse effects, particularly somnolence. Monitor for dehydration and nutritional status.
- Patients with Renal Impairment: Monitor closely; dosage adjustments may be necessary due to reduced protein binding and potentially inaccurate total valproate concentration measurements.
- Patients with Hepatic Dysfunction: Contraindicated in severe hepatic impairment. Use lower doses with caution in mild to moderate impairment and monitor liver function tests (LFTs) closely.
- Patients with Comorbid Conditions: Caution in patients with metabolic disorders (e.g., urea cycle disorders), bleeding problems, and mitochondrial disorders.
Clinical Use Cases:
Dosing in these settings generally follows standard recommendations, with careful titration based on patient response and tolerance.
- Intubation: No specific dosage adjustments.
- Surgical Procedures: No specific dosage adjustments.
- Mechanical Ventilation: No specific dosage adjustments.
- Intensive Care Unit (ICU) Use: No specific dosage adjustments.
- Emergency Situations: For status epilepticus, intravenous (IV) administration of valproate (not divalproex) may be used.
Dosage Adjustments
Dosage should be individualized based on patient-specific factors, including:
- Renal function
- Hepatic function
- Concomitant medications
- Therapeutic drug monitoring (TDM) for epilepsy and mania to maintain valproate serum levels within therapeutic range.
Side Effects
Common Side Effects
Nausea, vomiting, tremor, dizziness, somnolence, weight gain, hair loss, diarrhea.
Rare but Serious Side Effects
Hepatotoxicity (especially in young children and those with mitochondrial disorders), pancreatitis, hyperammonemic encephalopathy, thrombocytopenia, suicidal ideation, multiorgan hypersensitivity reactions.
Long-Term Effects
Weight gain, hair thinning, polycystic ovary syndrome (PCOS), osteoporosis.
Adverse Drug Reactions (ADR)
Hepatotoxicity, pancreatitis, severe thrombocytopenia, Stevens-Johnson syndrome, toxic epidermal necrolysis, hyperammonemia, drug reaction with eosinophilia and systemic symptoms (DRESS).
Contraindications
- Hypersensitivity to divalproex or valproic acid
- Hepatic disease or significant hepatic dysfunction
- Urea cycle disorders
- Known or suspected mitochondrial disorders (especially POLG mutations), especially in children under 2.
- Pregnancy (especially first trimester) for migraine prevention.
Drug Interactions
Divalproex interacts with numerous medications. Key interactions include:
- CYP2C9 substrates: Divalproex may inhibit CYP2C9 metabolism of drugs like warfarin, increasing their levels and risk of bleeding.
- Enzyme-inducing antiepileptic drugs (e.g., phenytoin, carbamazepine): May decrease divalproex levels.
- Other anticonvulsants (e.g., lamotrigine, felbamate): Divalproex can increase levels of these medications.
- Aspirin: May increase valproate levels.
- Carbapenem antibiotics: May decrease valproate levels.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: D (high risk of fetal harm). Divalproex is contraindicated in pregnancy, especially the first trimester, due to a significant risk of neural tube defects (e.g., spina bifida), other major congenital malformations, and developmental delays. If use is unavoidable during pregnancy, use the lowest effective dose and supplement with folic acid.
- Breastfeeding: Divalproex is excreted in breast milk. The decision to breastfeed should be made considering the potential benefits versus the risks to the infant. Monitor infants for adverse effects like thrombocytopenia.
Drug Profile Summary
- Mechanism of Action: Increases GABA levels by inhibiting GABA transaminase.
- Side Effects: Nausea, vomiting, tremor, dizziness, weight gain, hair loss, hepatotoxicity, pancreatitis, thrombocytopenia.
- Contraindications: Liver disease, urea cycle disorders, mitochondrial disorders, hypersensitivity.
- Drug Interactions: Warfarin, phenytoin, carbamazepine, lamotrigine, aspirin, carbapenem antibiotics.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy for migraine prophylaxis; avoid in pregnancy for other uses unless benefits clearly outweigh risks. Excreted in breast milk.
- Dosage: See detailed dosing guidelines above.
- Monitoring Parameters: Liver function tests (LFTs), complete blood count (CBC) including platelets, valproate serum levels.
Popular Combinations
Divalproex may be used in combination with other antiepileptic drugs when monotherapy is insufficient. Common combinations are determined based on seizure type and individual patient response.
Precautions
- General Precautions: Monitor liver function and platelet counts. Screen for mitochondrial disorders, especially in children. Genetic testing may be considered.
- Specific Populations: Avoid in pregnancy, if possible. Use cautiously in breastfeeding mothers. Adjust dose in elderly patients and those with hepatic or renal impairment.
- Lifestyle Considerations: Avoid alcohol. Counsel patients on potential cognitive effects and driving restrictions.
FAQs
Q1: What is the recommended dosage for Divalproex?
A: See detailed dosage guidelines above.
Q2: What are the most serious side effects of Divalproex?
A: Hepatotoxicity, pancreatitis, hyperammonemic encephalopathy, thrombocytopenia, birth defects.
Q3: Can Divalproex be used during pregnancy?
A: Divalproex is contraindicated during pregnancy for migraine prevention. For other conditions, it should be avoided unless the benefits clearly outweigh the substantial risks of birth defects and developmental delays.
Q4: How does Divalproex interact with other antiepileptic drugs?
A: It can either increase or decrease the levels of other anticonvulsants depending on the specific medication and its metabolic pathways. Close monitoring and dose adjustments are often needed.
Q5: What should be monitored in patients taking Divalproex?
A: Liver function tests (LFTs), complete blood count (CBC) with platelets, and ammonia levels (especially if signs of encephalopathy develop). Therapeutic drug monitoring (TDM) of valproate serum levels is recommended for epilepsy and bipolar disorder.
Q6: What are the signs of divalproex-induced hepatotoxicity?
A: Nausea, vomiting, abdominal pain, fatigue, jaundice, dark urine.
Q7: Can patients with liver disease take Divalproex?
A: Divalproex is contraindicated in patients with significant hepatic impairment or active liver disease.
Q8: Is there a risk of withdrawal seizures if Divalproex is stopped abruptly?
A: Yes, abruptly discontinuing Divalproex can increase the risk of seizures, especially in patients with epilepsy. Dosage should be tapered gradually under medical supervision.
Q9: How does Divalproex affect platelet function?
A: It can cause thrombocytopenia (low platelet count), which increases the risk of bleeding. Platelet counts should be monitored regularly.
Q10: Does Divalproex interact with alcohol?
A: Yes, alcohol can increase the sedative effects of Divalproex. Patients should be advised to avoid alcohol while taking this medication.
