Transitional polytherapy: tricks of the trade for monotherapy to monotherapy AED conversions

Abstract

The goal of epilepsy therapy is to help patients achieve seizure freedom without adverse effects. While monotherapy is preferable in epilepsy treatment, many patients fail a first drug due to lack of efficacy or failure to tolerate an initial medication, necessitating an alteration in therapy. Sudden changes between monotherapies are rarely feasible and sometimes deleterious given potential hazards of acute seizure exacerbation or intolerable adverse effects. The preferred method for converting between monotherapies is transitional polytherapy, a process involving initiation of a new antiepileptic drug (AED) and adjusting it toward a target dose while maintaining or reducing the dose of the baseline medication. A fixed-dose titration strategy of maintaining the baseline drug dose while titrating the new medication is preferable when breakthrough seizures are occurring and no adverse effects are present. However, a flexible titration strategy involving reduction of the baseline drug dose to ensure adequate tolerability of the new adjunctive medication is preferred when patients are already experiencing adverse effects. This article reviews pharmacokinetic considerations pertinent for ensuring successful transitional polytherapy with the standard and newer antiepileptic drugs. Practical consensus recommendations "from an expect panel (SPECTRA, Study by a Panel of Experts Considerations for Therapy Replacement and Antiepileptics) for a successful monotherapy" AED conversions are then summarized. Transitional polytherapy is most successful when clinicians appropriately manage the titration strategy and consider pharmacokinetic factors germane to the baseline and new adjunctive medication.

Keywords: Epilepsy; antiepileptic drugs; conversion; monotherapy; pharmacokinetics.; polytherapy; titration.

Fig. (1)

Suggested Algorithmic Approach for Initiating and Carrying Out Transitional Polytherapy. There are two potential pathways for using the algorithm which consider the alternative common clinical scenarios of either breakthrough seizures (beginning in upper left corner) or adverse effects (lower right corner) during initial monotherapy. If a patient experiences breakthrough seizures without adverse effects on monotherapy, the algorithm suggests further titration of high dose monotherapy until a “therapeutic plateau” (i.e., a maximal level of seizure reduction response) is reached, then progressing to a “Fixed-dose” transitional polytherapy strategy. Alternatively, if the patient experiences adverse effects, a “Flex-dose” strategy is most appropriate, which involves simultaneous reduction and tapering of the primary baseline antiepileptic drug (AED) while titrating the new adjunctive AED. The anticipated successful outcomes of these strategies would be seizure freedom on high dose monotherapy, seizure freedom following conversion to a new monotherapy, or a trial of chronic maintenance polytherapy with both the baseline and adjunctive AED.

Fig. (2)

General Tapering Method. Note that phenobarbital, with a 10-25% reduction of original dose every month, is not illustrated. CBZ, carbamazepine; FBM, felbamate; GBP, gabapentin; LEV, levetiracetam; LTG, lamotrigine; OXC, oxcarbazepine; PB, phenobarbital; PHT, phenytoin; TGB, tiagabine; TPM, topiramate; VPA, valproate; ZNS, zonisamide. (reproduced with kind permission from Elsevier, Inc. St. Louis et al; Conversions between monotherapies in epilepsy: expert consensus. Epilepsy and Behavior 2007; 11: 224).