What are the potential drug interactions with levetiracetam (antiepileptic medication)?

From the Guidelines

Levetiracetam has a minimal interaction profile compared to other antiepileptic medications, making it a favorable choice in clinical practice, especially in patients with multiple medications, elderly patients, and those with hepatic impairment. This is due to its low protein binding (less than 10%) and lack of significant induction or inhibition of liver enzymes, reducing the risk of displacement interactions with other highly protein-bound drugs 1. However, potential interactions should still be monitored, such as additive sedative effects when combined with central nervous system depressants like benzodiazepines, antidepressants, or opioids.

Some key points to consider:

• Levetiracetam does not significantly affect the metabolism of other medications, unlike some older antiepileptic drugs that can induce or inhibit the cytochrome P450 system 1.
• Carbamazepine may decrease levetiracetam levels, potentially requiring dosage adjustments 1.
• Oral contraceptives remain effective when taken with levetiracetam, unlike with enzyme-inducing antiepileptics 1.
• Alcohol consumption should be limited as it may increase side effects like sedation and impaired coordination.
• Levetiracetam is primarily eliminated unchanged through the kidneys, so medications affecting renal function could potentially alter its clearance, necessitating dose adjustments in patients with renal impairment 1.

Given its favorable interaction profile, levetiracetam is particularly useful in patients with complex medication regimens or specific organ impairments, though careful monitoring and potential dose adjustments are necessary to ensure optimal efficacy and safety 1.

From the FDA Drug Label

In vitro data on metabolic interactions indicate that levetiracetam is unlikely to produce, or be subject to, pharmacokinetic interactions Levetiracetam and its major metabolite, at concentrations well above Cmax levels achieved within the therapeutic dose range, are neither inhibitors of nor high affinity substrates for human liver cytochrome P450 isoforms, epoxide hydrolase or UDP glucuronidation enzymes. Potential pharmacokinetic interactions were assessed in clinical pharmacokinetic studies (phenytoin, valproate, oral contraceptive, digoxin, warfarin, probenecid) and through pharmacokinetic screening in the placebo-controlled clinical studies in epilepsy patients Drug-Drug Interactions Between Levetiracetam And Other Antiepileptic Drugs (AEDs) Phenytoin Levetiracetam (3000 mg daily) had no effect on the pharmacokinetic disposition of phenytoin in patients with refractory epilepsy. Valproate Levetiracetam (1500 mg twice daily) did not alter the pharmacokinetics of valproate in healthy volunteers. Other Drug Interactions Oral Contraceptives Levetiracetam (500 mg twice daily) did not influence the pharmacokinetics of an oral contraceptive containing 0.03 mg ethinyl estradiol and 0. 15 mg levonorgestrel, or of the luteinizing hormone and progesterone levels, indicating that impairment of contraceptive efficacy is unlikely. Digoxin Levetiracetam (1000 mg twice daily) did not influence the pharmacokinetics and pharmacodynamics (ECG) of digoxin given as a 0. 25 mg dose every day. Warfarin Levetiracetam (1000 mg twice daily) did not influence the pharmacokinetics of R and S warfarin. Probenecid Probenecid, a renal tubular secretion blocking agent, administered at a dose of 500 mg four times a day, did not change the pharmacokinetics of levetiracetam 1000 mg twice daily.

The potential drug interactions with levetiracetam are as follows:

• No significant interactions with other antiepileptic drugs (AEDs) such as phenytoin, valproate, carbamazepine, gabapentin, lamotrigine, phenobarbital, and primidone.
• No effect on oral contraceptives, indicating that impairment of contraceptive efficacy is unlikely.
• No influence on digoxin pharmacokinetics and pharmacodynamics.
• No influence on warfarin pharmacokinetics.
• Probenecid did not change the pharmacokinetics of levetiracetam, but the renal clearance of the metabolite ucb L057 decreased by 60% in the presence of probenecid. 2

From the Research

Potential Drug Interactions with Levetiracetam

• Levetiracetam is not associated with clinically significant pharmacokinetic interactions with other drugs, including other antiepileptic drugs 3, 4, 5
• It lacks cytochrome P450 isoenzyme-inducing potential, which reduces the risk of drug interactions 3, 4
• However, a study found that concomitant administration of levetiracetam and carbamazepine may increase the risk of carbamazepine toxicity 6
• The odds of developing manifestations of carbamazepine toxicity were 16.65 times higher in patients receiving both carbamazepine and levetiracetam compared to those receiving carbamazepine alone 6
• A dose ratio of 1.86 for levetiracetam to carbamazepine was identified as a threshold for differentiating between toxic and non-toxic serum concentrations of carbamazepine 6

Mechanism of Action and Pharmacokinetics

• Levetiracetam has a unique mechanism of action, involving binding to synaptic vesicle protein 2A and modulating seizure activity 3, 7
• It has a favorable pharmacokinetic profile, with rapid and complete absorption, high oral bioavailability, and minimal metabolism 3, 4, 5
• Levetiracetam is primarily eliminated through the kidneys, which reduces the risk of drug interactions with other medications that are metabolized by the liver 3, 4, 5

Clinical Implications

• Levetiracetam is generally well tolerated and has a low potential for drug interactions, making it a useful option for patients with epilepsy who are taking other medications 3, 4, 5
• However, patients receiving concomitant carbamazepine and levetiracetam should be monitored closely for signs of carbamazepine toxicity 6
• The dose ratio of levetiracetam to carbamazepine should be carefully considered to minimize the risk of toxicity 6