What are the side effects and adverse effects of Depakote (valproate) ER?

Side Effects and Adverse Effects of Depakote ER (Valproate)

Depakote ER (valproate) has significant side effects including gastrointestinal disturbances, tremor, weight gain, hair loss, thrombocytopenia, and rare but serious risks of hepatotoxicity, pancreatitis, and teratogenicity. 1

Common Side Effects

Gastrointestinal Effects

• Nausea (most common, occurring in up to 48% of patients)
• Vomiting (up to 27%)
• Abdominal pain (up to 23%)
• Diarrhea (up to 23%)
• Dyspepsia/indigestion (up to 11%)
• Constipation (up to 5%)
• Anorexia with weight loss or increased appetite with weight gain 1

These gastrointestinal effects are usually transient and rarely require discontinuation of therapy. Taking Depakote ER with food or slowly increasing the dose from an initial low level may help reduce GI irritation. 1

Neurological Effects

• Somnolence/sedation (up to 30%)
• Tremor (up to 57%, may be dose-related)
• Dizziness (up to 25%)
• Headache (up to 31%)
• Ataxia (up to 8%)
• Nystagmus (up to 8%)
• Diplopia/blurred vision (up to 16%)
• Paresthesia
• Incoordination 1

Dermatological Effects

• Transient hair loss/alopecia (up to 24%)
• Skin rash
• Photosensitivity
• Generalized pruritus 1, 2

Hematological Effects

• Thrombocytopenia (up to 24%, dose-related)
• The risk of thrombocytopenia increases significantly at valproate concentrations ≥110 μg/mL in females or ≥135 μg/mL in males
• Bruising, petechiae, hematoma formation
• Relative lymphocytosis
• Macrocytosis
• Hypofibrinogenemia 1

Metabolic/Endocrine Effects

• Weight gain (up to 9%)
• Peripheral edema (up to 8%)
• Irregular menses, secondary amenorrhea
• Breast enlargement, galactorrhea
• Polycystic ovary syndrome (PCOS) - particularly in women taking valproate monotherapy 3

Serious Adverse Effects

Hepatotoxicity

• Elevated liver enzymes (SGOT/SGPT) are common and dose-related
• Serious hepatotoxicity is rare but potentially fatal (overall incidence 1 in 20,000)
• Higher risk in children under 2 years of age (as high as 1 in 600-800)
• Can occur idiosyncratically even at therapeutic drug levels 1, 2, 4

Hyperammonemic Encephalopathy

• Can occur with or without liver dysfunction
• Symptoms include lethargy, vomiting, altered mental status, and increased seizure frequency
• Particularly dangerous in patients with underlying urea cycle disorders 1

Pancreatitis

• Rare but potentially life-threatening
• Presents with abdominal pain, nausea, vomiting, and elevated pancreatic enzymes 2

Teratogenicity

• 1-3% risk of neural tube defects when used during pregnancy
• Increased risk of other congenital malformations
• FDA requires Risk Evaluation and Mitigation Strategy to inform women of reproductive potential about these risks 2

Reproductive Disorders in Women

• Menstrual irregularities (amenorrhea, oligomenorrhea, prolonged cycles)
• Polycystic ovaries (up to 60% of women on valproate monotherapy)
• Hyperandrogenism (elevated testosterone levels in up to 30%)
• Hyperinsulinemia 3

Special Populations and Monitoring

Elderly Patients

• Increased sensitivity to somnolence
• Decreased unbound clearance of valproate
• Require lower starting doses and slower dose increases
• Need regular monitoring for fluid and nutritional intake, dehydration, and somnolence 1

Monitoring Recommendations

• Regular monitoring of complete blood count with platelets
• Liver function tests
• Drug levels (therapeutic range typically 50-100 μg/mL)
• Careful observation for signs of hepatotoxicity (jaundice, anorexia, malaise)
• Consider discontinuation if significant thrombocytopenia or liver enzyme elevations occur 1

Drug Interactions

• Carbapenem antibiotics can significantly reduce valproate levels
• Valproate can increase levels of other antiepileptic drugs (phenobarbital, lamotrigine)
• Enzyme-inducing drugs (phenytoin, carbamazepine, barbiturates) can decrease valproate half-life 1, 2

Discontinuation Considerations

• Abrupt discontinuation should be avoided due to risk of precipitating status epilepticus
• Dose should be tapered gradually when discontinuing therapy
• Consider discontinuation if 5% weight loss is not achieved after 12 weeks on maximum dose when used for weight management 1

Practical Considerations

• Depakote ER should be discontinued or dose adjusted if thrombocytopenia or significant liver enzyme elevations occur
• Taking with food may reduce GI side effects
• Regular monitoring of drug levels can help minimize dose-related adverse effects
• Women of childbearing potential should be counseled about reproductive risks and use effective contraception 1