What are the side effects of Depakote (valproate) toxicity, particularly in patients with pre-existing liver or kidney disease?

Depakote (Valproate) Toxicity Side Effects

Depakote toxicity causes life-threatening hepatotoxicity (particularly in the first 6 months), hyperammonemic encephalopathy, severe hematologic abnormalities, and pancreatitis, with patients having pre-existing liver or kidney disease at substantially elevated risk for fatal outcomes. 1

Life-Threatening Hepatotoxicity

Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid, usually during the first six months of treatment. 1

• Fatal hepatotoxicity may be preceded by non-specific symptoms including malaise, weakness, lethargy, facial edema, anorexia, and vomiting 1
• In epilepsy patients, loss of seizure control may signal impending hepatotoxicity 1
• Liver function tests may not be abnormal in all instances of hepatotoxicity, requiring careful clinical monitoring beyond biochemistry 1
• Children under 2 years are at considerably increased risk of fatal hepatotoxicity, especially those with congenital metabolic disorders, severe seizure disorders with mental retardation, or organic brain disease 1
• Patients on multiple anticonvulsants are at particular risk for hepatotoxicity 1
• The overall incidence of liver toxicity is 1 in 20,000, but increases to 1 in 600-800 in high-risk groups 2
• Fatal hepatotoxicity can occur in adults without metabolic defects or underlying neurologic disease, with onset ranging from 7 days to 6 years after starting treatment 3
• Idiosyncratic hepatotoxicity can occur even at therapeutic drug levels in chronic users 4

Critical Action for Hepatotoxicity

The drug must be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent, though hepatic dysfunction has progressed despite discontinuation in some cases. 1

Hyperammonemic Encephalopathy

Hyperammonemic encephalopathy can occur in patients with normal liver function, despite normal doses and serum levels of valproate. 5

• Encephalopathy symptoms include altered mental status, lethargy, disorientation, and confusion 4, 5
• Hyperammonemia may be clinically significant even when valproate levels are therapeutic 5
• Severe anion gap metabolic acidosis can accompany hyperammonemic encephalopathy 4
• Treatment with L-carnitine may be beneficial in reducing ammonia levels 5

Check ammonia levels in all patients taking valproate who present with alterations in mental status. 5

Hematologic Toxicity

Valproate causes multiple severe hematologic abnormalities that can be fatal:

• Thrombocytopenia occurs in approximately 27% of patients, with probability increasing significantly at total valproate concentrations ≤110 µg/mL (females) or ≥135 µg/mL (males) 1
• Drug-induced leukopenia, neutropenia, agranulocytosis, and thrombocytopenic purpura can occur 1
• Evidence of hemorrhage, bruising, or coagulation disorders indicates need for dose reduction or withdrawal 1
• Platelet counts and coagulation tests are recommended before initiating therapy and at periodic intervals 1
• Coagulopathy can develop as part of the toxicity syndrome 4

Monitor patients for platelet count and coagulation parameters prior to planned surgery. 1

Pancreatitis

• Life-threatening pancreatitis can occur in both children and adults 1
• Abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis requiring immediate medical evaluation 1
• Elevations of serum lipase, sometimes with clinical manifestations of pancreatitis, have been reported 6

Special Considerations in Patients with Pre-existing Disease

Hepatic Disease

Liver disease impairs the capacity to eliminate valproate, with clearance of free valproate decreased by 50% in cirrhosis patients and 16% in acute hepatitis patients. 1

• The half-life of valproate increases from 12 to 18 hours in hepatic disease 1
• Decreased albumin concentrations result in 2 to 2.6-fold increase in unbound fractions 1
• Monitoring total concentrations may be misleading since free concentrations may be substantially elevated while total concentrations appear normal 1
• Patients with prior history of hepatic disease require extreme caution 1
• Chronic hepatitis B or C infection increases risk of hepatotoxicity 6

Renal Disease

A 27% reduction in unbound clearance occurs in patients with renal failure (creatinine clearance <10 mL/minute). 1

• Protein binding is substantially reduced in renal disease, making total concentration monitoring misleading 1
• Hemodialysis typically reduces valproate concentrations by about 20% 1
• No dosage adjustment appears necessary in renal failure, but free drug levels should guide therapy 1

Additional Serious Toxicities

Teratogenicity

Valproate produces teratogenic effects with an increased incidence of congenital malformations, including a 1-3% risk of neural tube defects. 1, 2

• Valproate should be considered for women of childbearing potential only after risks have been thoroughly discussed 1
• The drug crosses the placenta and should not be used in pregnancy when treating conditions not associated with permanent injury or death 1

Multi-organ Hypersensitivity

• Multi-organ hypersensitivity reactions occur rarely, with median time to detection of 21 days (range 1-40 days) 1
• Patients typically present with fever and rash associated with other organ system involvement 1
• Manifestations include lymphadenopathy, hepatitis, hematological abnormalities (eosinophilia, thrombocytopenia, neutropenia), nephritis, oliguria, and hepato-renal syndrome 1
• At least one death has been reported from this syndrome 1

If multi-organ hypersensitivity is suspected, valproate must be discontinued immediately and alternative treatment started. 1

Other Notable Toxicities

• Gastrointestinal disturbances, tremor, and body weight gain are common 2
• Platelet disorders affecting hemostasis can occur 2
• Altered thyroid function tests have been reported 1
• False interpretation of urine ketone tests may occur due to keto-metabolite excretion 1

Monitoring Requirements

Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months. 1

• Platelet counts should be monitored at 4-6 week intervals during first months, then every 1-3 months 6
• Ammonia levels should be checked in any patient with altered mental status 5
• Close monitoring is required in patients with risk factors including advanced age, renal impairment, absence of folate supplementation, and drug interactions 6