Valproic Acid Side Effects
Valproic acid has numerous significant side effects including hepatotoxicity, thrombocytopenia, weight gain, tremor, gastrointestinal disturbances, and hematologic toxicities, with the risk of these adverse effects often outweighing the benefits in many patient populations. 1
Common Side Effects
Gastrointestinal effects: Nausea, vomiting, abdominal pain, dyspepsia, diarrhea, anorexia, and constipation are frequently reported, particularly at the initiation of therapy. These effects are usually transient but can be severe enough to require discontinuation of the medication 1
Neurological effects: Somnolence (27%), tremor (25%), dizziness (25%), diplopia (16%), blurred vision (12%), ataxia (8%), and nystagmus (8%) are common neurological side effects 1
Weight changes: Both weight gain and weight loss have been reported, with weight gain being more common. An increase of 2 kg after 1 month of treatment should prompt consideration of alternative therapy 2
Hair loss: Transient alopecia occurs in approximately 6% of patients 1
Serious Side Effects
Hepatotoxicity
- Fatal hepatotoxicity is a rare but serious adverse effect, particularly in children under 2 years of age 3
- Minor elevations of transaminases (SGOT and SGPT) and LDH are frequent and dose-related 1
- Regular monitoring of liver function tests is essential during valproic acid therapy 1
Hematologic Effects
- Thrombocytopenia is a significant concern, especially in patients with brain tumors on chemotherapy 3
- Other hematologic effects include altered bleeding time, petechiae, bruising, epistaxis, and frank hemorrhage 1
- Less common but reported effects include relative lymphocytosis, macrocytosis, hypofibrinogenemia, leukopenia, eosinophilia, anemia, bone marrow suppression, pancytopenia, and aplastic anemia 1
Pancreatic Effects
- Acute pancreatitis, including fatal cases, has been reported 1
Metabolic and Endocrine Effects
- Hyperammonemia and hyperammonemic encephalopathy 1, 4
- Hyponatremia and inappropriate ADH secretion 1
- Irregular menses, secondary amenorrhea, breast enlargement, and polycystic ovary disease 1
Population-Specific Concerns
Brain Tumor Patients
- In patients with brain tumors receiving chemotherapy, valproic acid is associated with higher hematologic toxicities compared to other antiepileptic drugs 3
- Levetiracetam is better tolerated than valproic acid in brain tumor patients 3
- There is insufficient evidence to support prescribing valproic acid with the intent to prolong progression-free or overall survival in brain tumor patients 3
Children
- Fatal hepatotoxicity risk is highest in children under 2 years 3
- Behavioral disturbances, irritability, and sleep disturbances are common 3
- Fanconi's syndrome has been reported primarily in children 1
Pregnant Women
- Associated with neural tube defects, predominantly spina bifida aperta, with an estimated risk of 1-2% 5
- Pregnant women who ingest valproic acid should be evaluated for potential maternal and fetal risk 6
Drug Interactions
- Valproic acid inhibits hepatic drug metabolism and can displace other highly protein-bound drugs from their binding sites 5
- When combined with enzyme-inducing antiepileptic drugs, valproic acid metabolism may increase, necessitating dosage adjustments 5
- Serious skin reactions have been reported with concomitant administration of lamotrigine and valproate 1
Monitoring Recommendations
- Regular monitoring of:
Clinical Decision Making
- For patients with brain tumors, levetiracetam is preferred over valproic acid due to fewer side effects 3
- For patients experiencing significant weight gain (>2 kg in first month), consider alternative therapy 2
- For patients with liver disease or at high risk for hepatotoxicity, avoid valproic acid 1
- For women of childbearing potential, consider alternative therapies due to teratogenic risk 5