Can Depakote (valproate) be used in patients with Chronic Kidney Disease (CKD)?

From the Guidelines

Depakote (valproic acid/divalproex sodium) can be used in patients with chronic kidney disease (CKD), but requires careful monitoring and potential dose adjustments. Since valproic acid is primarily metabolized by the liver with minimal renal excretion (only about 3% excreted unchanged in urine), CKD itself doesn't significantly affect valproate clearance 1. However, patients with CKD often have altered protein binding, which can increase the free (active) fraction of the drug. Start with standard doses but monitor free valproate levels rather than total levels when possible, especially in patients with hypoalbuminemia or end-stage renal disease. No specific dose reduction is required based on glomerular filtration rate alone, but monitor closely for side effects including sedation, tremor, and hepatotoxicity. Regular liver function tests and complete blood counts are important. Be aware that valproate is highly protein-bound and may compete with other medications commonly used in CKD patients, potentially leading to drug interactions. Patients on hemodialysis typically don't require supplemental doses after dialysis as valproate is not significantly removed during treatment. Some key considerations for managing CKD patients include:

• Monitoring for signs of toxicity and adjusting doses as needed
• Being aware of potential drug interactions with other medications commonly used in CKD patients
• Regularly assessing liver function and complete blood counts
• Considering the use of alternative medications if necessary It's essential to weigh the benefits and risks of using Depakote in patients with CKD and to closely monitor their condition to minimize potential adverse effects 1.

From the FDA Drug Label

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.

• Key Points:
  • Slight reduction in unbound clearance of valproate in patients with renal failure
  • No dosage adjustment necessary in patients with renal failure
  • Protein binding substantially reduced in patients with renal failure
• Clinical Decision: Valproate can be used in patients with Chronic Kidney Disease (CKD), but monitoring of total concentrations may be misleading due to reduced protein binding. 2

From the Research

Medication Use in Chronic Kidney Disease (CKD)

The use of medications in patients with CKD requires careful consideration due to the potential for nephrotoxicity and altered drug pharmacokinetics.

• Several medications have been identified as increasing the risk of nephrotoxicity or accelerating CKD progression, including bisphosphonates and hypnotics 3.
• However, some medications such as Tenofovir alafenamide (TAF) and Tenofovir amibufenamide (TMF) have been found to have a favorable safety profile in patients with CKD 3.
• The principle of drug stewardship is essential in maximizing medication safety and effectiveness in patients with CKD, involving processes such as medication reconciliation, selection, and monitoring 4.

Specific Medications in CKD

Certain medications require dose adjustment or careful consideration in patients with CKD.

• For example, the use of Oral Nirmatrelvir/Ritonavir in patients with mild renal impairment requires no dosage adjustment, but the dosage is reduced in those with moderate renal impairment, and it is not recommended in patients with severe renal impairment 3.
• Molnupiravir does not require dose adjustment in patients with CKD 3.
• Calcium channel blockers (CCBs) are frequently used in combination with renin-angiotensin-aldosterone system inhibitors for CKD patients due to their strong BP-lowering properties and relatively few adverse side effects 5.

Depakote (Valproate) Use in CKD

There is no direct evidence provided regarding the use of Depakote (valproate) in patients with CKD.

• However, it is known that patients with CKD require appropriate adjustment of renally cleared medications to ensure safe and effective pharmacotherapy 6.
• The use of medications in patients with CKD should be guided by the principles of drug stewardship, taking into account the individual patient's kidney function, comorbidities, and other factors 4.