Does levetiracetam (Keppra) cause hypokalemia or hypomagnesemia?

Levetiracetam and Electrolyte Disturbances

Yes, levetiracetam (Keppra) can cause both hypokalemia and hypomagnesemia, though these are rare adverse effects that are not widely recognized in clinical practice.

Evidence for Levetiracetam-Induced Electrolyte Abnormalities

The association between levetiracetam and electrolyte disturbances is supported by emerging case reports and real-world data, though this is not mentioned in standard safety profiles or guidelines for seizure management 1.

Hypokalemia

• A case report documented severe refractory hypokalemia (dropping to 2.0 mmol/L) in a patient within 24 hours of starting levetiracetam 1000 mg twice daily, despite aggressive potassium repletion and normalized magnesium levels 2
• The hypokalemia resolved 36 hours after switching from levetiracetam to lacosamide, with potassium normalizing to 3.9 mmol/L within 5 days without further supplementation 2
• A real-world cohort study of 8,982 patients found an incidence rate of hypokalemia of 303 cases per 10,000 patient-years in levetiracetam users compared to 57 cases per 10,000 patient-years in carbamazepine users 3
• The adjusted hazard ratio for levetiracetam-induced hypokalemia was 1.99 (95% CI 0.88-4.49) compared to carbamazepine, though this did not reach statistical significance 3

Hypomagnesemia

• A case report described concurrent hypokalemia (3.1 mmol/L) and hypomagnesemia (0.56 mmol/L) developing one month after initiating levetiracetam 4
• Both electrolyte abnormalities normalized after discontinuing levetiracetam and switching to lamotrigine 4
• The mechanism may involve renal tubular dysfunction, as interstitial nephritis and renal failure have been reported with levetiracetam use 4

Clinical Implications and Monitoring

Monitor serum potassium and magnesium levels in patients started on levetiracetam, particularly if they develop unexplained weakness, fatigue, or cardiac symptoms.

When to Suspect Levetiracetam-Induced Electrolyte Disturbances

• Onset of hypokalemia or hypomagnesemia within days to weeks of starting levetiracetam 2, 4
• Refractory hypokalemia that fails to correct despite aggressive potassium repletion and normalized magnesium levels 2
• No other identifiable cause for electrolyte depletion (normal renal function, no diuretic use, no gastrointestinal losses) 4

Management Algorithm

1. Check baseline electrolytes before starting levetiracetam, including potassium, magnesium, and renal function 4

2. Recheck electrolytes 1-2 weeks after initiating therapy and with any dose increases 2, 4

3. If hypokalemia develops:

   • First correct magnesium levels, as hypomagnesemia causes refractory hypokalemia through dysfunction of potassium transport systems 5
   • Attempt potassium repletion with normalized magnesium 2
   • If hypokalemia remains refractory despite adequate magnesium and aggressive potassium supplementation, consider levetiracetam as the culprit 2

4. If levetiracetam-induced electrolyte disturbance is suspected:

   • Switch to an alternative antiepileptic medication (lacosamide, lamotrigine, or other appropriate agent based on seizure type) 2, 4
   • Monitor electrolytes closely after the switch; expect normalization within 36 hours to 5 days 2, 4

Important Caveats

• These electrolyte disturbances are not listed in standard levetiracetam safety profiles from clinical trials, where the most common adverse effects were somnolence, irritability, dizziness, and behavioral changes 6, 7
• Safety studies of levetiracetam loading (including doses up to 60 mg/kg IV) reported no significant changes in blood pressure or ECG abnormalities, but did not specifically monitor for electrolyte disturbances 1
• The mechanism remains unclear but may involve renal tubular dysfunction 4
• This is a rare but potentially serious adverse effect that clinicians should be aware of, particularly given levetiracetam's widespread use 2, 4, 3

The evidence suggests that while uncommon, levetiracetam can cause clinically significant hypokalemia and hypomagnesemia that may be refractory to standard repletion strategies and require medication discontinuation.