Keppra Drug Interactions: What to Avoid and What to Tell Your Doctor

One of the major advantages of Keppra (levetiracetam) over older anti-seizure medications is its favorable drug interaction profile. Because it is minimally metabolized by the liver and has low protein binding (under 10%), it avoids most of the pharmacokinetic interactions that make drugs like phenytoin and carbamazepine difficult to manage. However, there are still important interactions to know about.

Why Does Keppra Have Fewer Interactions Than Other Anti-Seizure Drugs?

Most drug-drug interactions occur because two medications compete for the same liver enzymes (the CYP450 system) during metabolism. Levetiracetam only uses the CYP450 system to a very minor degree (about 2.5%). Most of it is excreted unchanged by the kidneys. Additionally, since it's less than 10% protein-bound, it doesn't displace other highly protein-bound drugs from their binding sites.

Studies have confirmed that levetiracetam does not meaningfully affect the levels of phenytoin, valproate, carbamazepine, gabapentin, lamotrigine, phenobarbital, primidone, warfarin, digoxin, or oral contraceptives. This is one reason why it's a popular choice for patients on complex medication regimens.

Interaction 1: CNS Depressants (Major — Avoid or Use With Caution)

The most clinically significant interaction category for levetiracetam is with other central nervous system (CNS) depressants. Keppra itself causes drowsiness and sedation, and combining it with other CNS-depressant drugs amplifies this effect. Drugs to be cautious with include:

Opioid pain medications (hydrocodone, oxycodone, morphine, codeine, fentanyl) — significantly increase sedation

Benzodiazepines (alprazolam, clonazepam, diazepam) — additive sedation and CNS depression

Sleep medications (zolpidem, eszopiclone) — combined effect on sedation

Muscle relaxants (baclofen, cyclobenzaprine) — additive drowsiness

Antihistamines (diphenhydramine in Benadryl, etc.) — additive sedation, even in OTC products

Thalidomide — this combination is contraindicated due to severe additive sedation

If you need to take one of these medications while on Keppra, your doctor will assess whether the combination is appropriate. The guideline is typically to limit use to patients who have no adequate alternatives, and to monitor carefully for excessive sedation.

Interaction 2: Probenecid (Moderate)

Probenecid (used to treat gout) reduces the kidney's ability to excrete levetiracetam, which can approximately double the concentration of Keppra in your bloodstream. Higher drug levels mean more intense side effects — particularly sedation and behavioral effects. If you take probenecid and Keppra together, your doctor will likely need to lower your Keppra dose.

Interaction 3: Alcohol (Important — Avoid or Limit)

Alcohol is a CNS depressant. Combining it with Keppra increases drowsiness and dizziness — and more importantly, alcohol itself lowers the seizure threshold, making it a dangerous combination for people with epilepsy regardless of what medication they're taking. The recommendation is to avoid alcohol or limit it significantly while on Keppra.

Interaction 4: Enzyme-Inducing Anti-Seizure Drugs

Some older anti-seizure medications are "enzyme inducers" — they increase the liver's drug-metabolizing activity, which in turn speeds up the elimination of other drugs. Phenytoin and carbamazepine, for example, increase levetiracetam clearance by approximately 9–22%, potentially reducing its effectiveness at the same dose. Your neurologist may need to account for this when dosing. Conversely, valproate slightly decreases levetiracetam clearance by about 18.8% — a modest effect that rarely requires dose changes.

What About Food Interactions?

There are no known clinically significant interactions between levetiracetam and food or drinks (other than alcohol). You can take Keppra with or without food. Eating does not significantly affect the absorption of levetiracetam, though some patients report that taking it with food reduces stomach upset.

What to Tell Your Doctor and Pharmacist

Always share a complete list of your current medications — prescription and over-the-counter — with your doctor and pharmacist when starting or refilling Keppra. Be sure to mention:

All other seizure medications you take

Any pain medications, including OTC pain relievers and prescription opioids

Sleep aids and sedatives

Antihistamines (including products like NyQuil, Benadryl, etc.)

Gout medications (especially probenecid)

Any herbal supplements or cannabis products

For a broader overview of Keppra's safety profile, see our guide on Keppra side effects. If you're looking for Keppra at a pharmacy, medfinder can help locate it near you.