New antiepileptic drug review FROM JAMA

Gabapentin

– Mechanism: possibly due to its structural similarity to GABA, but precise mechanism remains unknown.
– Currently indicated as adjunctive therapy for partial seizures, but also used in off label indications eg neuropathic pain, muscle spasm.
– Gabapentin as monotherapy for partial seizures:

  • Two large monotherapy trials have looked at this.
  • This first compared different doses of gabapentin (600,1200 and 1800 mg) and showed no significant difference with completion rate ranging from 15-26 percent.
  • Another compared gabapentin 1800 mg/day vs carbamazepine 600 mg/day and also found no significant difference with complete rate 37 and 38 percent.
  • Both trials suggest that gabapentin as monotherapy is just at least as good as traditional carbamazepine, but this is not FDA indicated.

– Good thing about gabapentin is its mild side effect which is fatigue.
– It does not undergo hepatic metabolism, and is excreted in urine unchanged. It also does not have DDI with other antiepileptic drugs.

Lamotrigine

– Mechanism: blockade of Na channel
– Broad spectrum antiepileptic, now indicated as adjunctive for partial seizue, generalized seizure associated with Lennox-Gastaut syndrome (a form of childhood epilepsy difficult to control) and as monotherapy,
– As monotherapy, Lamotrigine is as effective as valproate/phenytoin or carbamazepine but with a lesser side effect profile.
– Most common side effect: rash, rarely SJS (risk increases with use of valproate as it reduces lamotrigine metabolism).
– Hepatic metabolism but does not induce/inhibit hepatic enzymes so no significant DDI.

Topiramate
– Adjunctive for partial seizures and seizures associated with LGS.
– Mechanism: possibly a mix of blockade of Na channel, GABA potentiation, glutamate receptor antagonism.
– As monotherapy for partial seizure, it is not FDA indicated. But a small pseudo-placebo controlled monotherapy trial (comparing 1000 mg/d vs 100 mg/d of topiramate) showed a significant completion rate in higher dose lamotrigine.
– Adverse effects: Fatigue, dizziness, ataxia, topiramate induced nephrolithiasis.
– No significant DDI with other antiepileptic drugs.

Levetiracetam
– Unknown mechanism
– Adjunctive therapy for partial seizures.
– Till now, no trials have evaluated its role as monotherapy for partial seizures.
– Does not undergo hepatic metabolism, renally excreted. (similar to gabapentin)
– Common side effects: fatigue, somnolence.
– Also no significant DDI with other antiepileptic drugs.

Note that all of these newer drugs do not show superiority in their efficacy to traditional antiepileptic drugs (carbamazepine, phenytoin, valproate and phenobarbital).
– But they show milder side effects and lesser DDI.
– Antiepileptics which induce P450: phenobarbital, carbamazepine, phenytoin
– Antiepileptics which inhibit P450: sodium valproate

For patients with renal disease: which drugs should be dose adjusted?
– Gabapentin
– Levetiracetam
– Topiramate
– Not sure about lamotrigine

How about hepatic disease?
– Not information available to make any recommendation, but gabapentin and levetiracetam are not metabolized by liver so should be safe.

Learning points:

  1. Most of the newer drugs are FDA-indicated as adjunctive therapy for partial and generalized seizure.
  2. Only lamotrigine is FDA indicated as monotherapy for partial seizures.
  3. Gabapentine and levetiracetam are not hepatically metabolized, and therefore should be safe in patients with liver diseases.
  4. Newer drugs have minimal DDI.

Reference:
Suzette M.LaRoche, MD, Sandra L.Helmers, MD. The New Antiepileptic Drugs. Scientific Review. JAMA 2004:291:60-614

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