What are the special population considerations for valproate (valproic acid)?

From the Guidelines

Valproate requires special considerations for several populations, particularly pregnant women, where it should be avoided due to high risk of birth defects and neurodevelopmental disorders in offspring, as noted in the most recent guideline 1. In pregnant women, valproate is contraindicated unless absolutely necessary due to its teratogenic effects, making it essential to use effective contraception and folate supplements if valproate is required 1.

Special Considerations

• In elderly patients, lower doses are recommended with careful monitoring for sedation and drug interactions.
• Children may need higher weight-based dosing but require monitoring for hepatotoxicity, especially those under 2 years old or with metabolic disorders.
• Patients with liver disease need dose reductions and regular liver function monitoring.
• Those with kidney disease generally don't need dose adjustments but should be monitored for free drug levels.
• Valproate should be used cautiously in patients with pancreatitis history, thrombocytopenia, or bleeding disorders.

Monitoring and Titration

The medication requires gradual titration when starting and tapering to minimize side effects, with therapeutic drug monitoring recommended to maintain blood levels between 50-100 μg/mL for most indications 1.

Additional Considerations

Valproate has been associated with endocrine disorders, including polycystic ovary syndrome (PCOS) and hyperandrogenism, particularly in women of childbearing potential, as reported in studies 1. Given the potential risks and the availability of alternative treatments, the use of valproate should be carefully considered and monitored, especially in vulnerable populations, as suggested by recent clinical practice guidelines 1.

From the FDA Drug Label

Special Populations Effect of Age: Neonates Children within the first two months of life have a markedly decreased ability to eliminate valproate compared to older children and adults This is a result of reduced clearance (perhaps due to delay in development of glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due to decreased plasma protein binding) For example, in one study, the half-life in children under 10 days ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2 months. Children Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. Elderly The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44% Accordingly, the initial dosage should be reduced in the elderly. Effect of Gender There are no differences in the body surface area adjusted unbound clearance between males and females (4.8 ± 0.17 and 4.7 ± 0.07 L/hr per 1. 73 m , respectively). Effect of Race The effects of race on the kinetics of valproate have not been studied. Effect of Disease Liver Disease Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2. 6 fold increase) of valproate. Renal Disease A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading.

The special population considerations for valproate include:

• Neonates: have a decreased ability to eliminate valproate, with a half-life ranging from 10 to 67 hours in children under 10 days.
• Children: pediatric patients between 3 months and 10 years have 50% higher clearances than adults, while those over 10 years have pharmacokinetic parameters similar to adults.
• Elderly: have a reduced capacity to eliminate valproate, with intrinsic clearance reduced by 39% and the free fraction increased by 44%, requiring a reduced initial dosage.
• Liver Disease: impairs the capacity to eliminate valproate, with decreased clearance and increased half-life.
• Renal Disease: has a slight reduction in unbound clearance, but no dosage adjustment is necessary. 2 2

From the Research

Special Population Considerations for Valproate

The use of valproate in certain populations requires special consideration due to its potential risks.

• Women of childbearing age: Valproate has a significant fetal risk, with a risk of malformation development of 8.6% 3. The UK has banned valproate use in women who are not in a pregnancy prevention programme 4.
• Pregnant women: Valproate has been associated with a variety of major and minor malformations, including neural tube defects, cleft lip and palate, cardiovascular abnormalities, and developmental delay 5.
• Patients with certain risk factors: The risk of hepatotoxicity and pancreatitis is higher in patients with certain risk factors, such as those taking valproate 3, 6, 7.

Risk Factors and Adverse Outcomes

Several factors contribute to the teratogenicity of valproate, including:

• Polytherapy treatment: Increases the risk of teratogenicity in offspring 5.
• Drug dosage: High doses of valproate may cause high peak levels in the fetal serum, resulting in deleterious effects 5.
• Gestational age: The gestational age of the fetus at exposure may affect the risk of teratogenicity 5.
• Hereditary susceptibility: May play a role in the teratogenicity of valproate 5.

Monitoring and Prevention

To minimize the risks associated with valproate, clinicians should:

• Discuss the risks with patients and document the discussion 3.
• Consider monitoring requirements for the inherent fetal risk, such as through a Risk Evaluation and Mitigation Strategy program or institution-based policies and procedures 3.
• Account for contributing risk factors when monitoring for hepatotoxicity and pancreatitis 3, 6, 7.