In a 56‑year‑old woman with a serum creatinine of 4 mg/dL (severe renal impairment), should the doses of aripiprazole, cyclobenzaprine, divalproex (valproate), furosemide, gabapentin, levetiracetam (Keppra), lamotrigine, and sodium bicarbonate be adjusted or discontinued?

Medication Adjustments Required for Severe Renal Impairment (Creatinine 4 mg/dL)

Yes, several medications require immediate dose adjustments: gabapentin, levetiracetam (Keppra), and lamotrigine all need substantial dose reductions, while furosemide may require dose increases to maintain efficacy. 1, 2

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Medications Requiring Dose Reduction

Gabapentin – CRITICAL ADJUSTMENT NEEDED

• Gabapentin is eliminated unchanged by the kidneys and requires significant dose reduction in severe renal impairment (creatinine 4 mg/dL suggests eGFR <15-20 mL/min). 3, 4
• Standard dosing in severe renal failure can lead to accumulation and clinical toxicity, including sedation, confusion, and myoclonus. 3
• Dose should be reduced by 75-90% or more depending on the exact eGFR; typical dosing in severe CKD is 100-300 mg once daily rather than standard doses of 900-3600 mg/day. 5, 4
• This is one of the highest-priority adjustments because gabapentin is entirely renally cleared and toxicity is common when doses are not adjusted. 4

Levetiracetam (Keppra) – CRITICAL ADJUSTMENT NEEDED

• Levetiracetam is eliminated by a combination of renal excretion (66%) and minimal metabolism, requiring dose adjustment based on creatinine clearance. 4
• At creatinine 4 mg/dL (eGFR <30 mL/min), the dose should be reduced by 50% or more; typical adjustment is 500-1000 mg twice daily instead of the standard 1500 mg twice daily. 4
• Failure to adjust leads to elevated clearance times, accumulation, and increased risk of neuropsychiatric side effects. 6, 4
• Levetiracetam is significantly removed by hemodialysis, so if the patient progresses to dialysis, supplemental dosing after each session will be required. 4

Lamotrigine – MODERATE ADJUSTMENT NEEDED

• Lamotrigine undergoes hepatic glucuronidation, but its metabolites are renally excreted; severe renal impairment can prolong elimination. 4
• Dose reduction of 25-50% is recommended in severe CKD to prevent accumulation of active metabolites. 4
• Monitor closely for signs of toxicity including rash, ataxia, and diplopia, which may indicate excessive drug levels. 4

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Medications Requiring Dose Increase or Monitoring

Furosemide – MAY REQUIRE DOSE INCREASE

• Loop diuretics like furosemide are less effective in severe renal impairment because reduced GFR limits drug delivery to the loop of Henle. 1
• Higher doses (often 2-3 times the usual dose) may be needed to achieve adequate diuresis in patients with creatinine 4 mg/dL. 1
• Monitor volume status, electrolytes (especially potassium), and renal function closely when adjusting furosemide doses. 1

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Medications Requiring NO Dose Adjustment

Aripiprazole – NO ADJUSTMENT NEEDED

• Aripiprazole pharmacokinetics are not meaningfully altered by renal impairment; a study of patients with severe renal impairment (CrCl <30 mL/min) showed no significant differences in clearance or exposure. 7
• No dose adjustment is required regardless of the degree of renal dysfunction. 7

Divalproex (Valproate) – NO ADJUSTMENT NEEDED, BUT MONITOR CLOSELY

• Valproate is eliminated predominantly by hepatic biotransformation, not renal excretion. 4
• However, renal failure reduces protein binding of valproate, which can lead to higher free (unbound) drug levels even when total serum concentrations appear normal. 4
• Monitor free valproate levels rather than total levels if available, and watch for signs of toxicity (tremor, sedation, thrombocytopenia). 4
• No routine dose adjustment is required, but closer clinical monitoring is warranted. 4

Cyclobenzaprine – NO ADJUSTMENT NEEDED, BUT USE WITH CAUTION

• Cyclobenzaprine is hepatically metabolized and does not require renal dose adjustment. 5
• However, sedation and anticholinergic effects may be more pronounced in patients with uremia; consider reducing dose empirically if excessive sedation occurs. 5

Sodium Bicarbonate – NO ADJUSTMENT NEEDED

• Sodium bicarbonate is often used to treat metabolic acidosis in CKD and does not require dose adjustment based on renal function. 1
• Monitor serum bicarbonate, pH, and sodium levels to guide dosing rather than adjusting for GFR. 1

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Critical Monitoring Parameters

• Check serum creatinine, eGFR, and electrolytes (especially potassium) at least weekly during dose adjustments. 1, 2
• Obtain therapeutic drug monitoring for medications with narrow therapeutic windows (valproate free levels, lamotrigine levels if available). 1, 4
• Assess for signs of drug accumulation: confusion, sedation, ataxia, myoclonus, or new neurologic symptoms. 3, 4
• Review all medications at every clinical encounter to reassess continued indication and potential drug interactions. 1

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Common Pitfalls to Avoid

• Do not rely on serum creatinine alone; calculate eGFR or creatinine clearance (Cockcroft-Gault) to guide dosing decisions, especially for drugs with narrow therapeutic indices. 2
• Do not assume all antiepileptics require the same adjustment; gabapentin and levetiracetam are renally cleared, while valproate is not. 4
• Do not overlook protein-binding changes; valproate and other highly protein-bound drugs may have misleadingly "normal" total levels despite toxic free levels in renal failure. 4
• Avoid nephrotoxic agents (NSAIDs, aminoglycosides, IV contrast) in this patient, as they can precipitate further renal decline. 1, 2