Time Course of Adverse Events in Patients with Localization‐related Epilepsy Receiving Topiramate Added to Carbamazepine

Abstract

Summary:Purpose: To explore the time course of treatmentemergent adverse events (AEs) during topiramate (TPM) adjunctive therapy.Methods: Post hoc analyses were performed by using data from a large (264 subjects) multicenter, double-blind, placebocontrolled trial in which 200 mg/day TPM was added to carbamazepine (CBZ) with or without another antiepileptic drug (AED) in adults with treatment-resistant partial-onset seizures. The daily incidence and mean duration of the most common (≥5% incidence) AEs were calculated for patients completing the 12-week study.Results: The daily incidence of somnolence, headache, loss of appetite, nervousness, fatigue, dizziness, upper respiratory tract infection, and vertigo peaked during titration and declined to rates similar to that of placebo after the target TPM dose had been reached. In contrast, the daily incidence of paresthesia increased during titration and was maintained for the study duration. Relatively few patients had cognitive symptoms (9% with TPM, 5% with placebo), but these were the most common AEs associated with treatment discontinuation. Patient/investigator reports of weight loss increased gradually over the course of the trial, corresponding with the pattern of change in weight measured at study visits.Conclusions: This study demonstrates that most of the more common AEs with TPM adjunctive therapy are transient. Patients can be counseled that most AEs emerging when TPM is initially added to CBZ can be expected to diminish with continued therapy. Key Words: Antiepileptic drug-TopiramateCarbamazepine-Side effects-Time course-Polytherapy.In the medical literature related to antiepileptic drugs (AEDs), adverse event (AE) reporting is typically limited to information about the incidence of the most common AEs, with discontinuation rate(s) serving as a measure of AE severity. Although these data are valuable information for counseling patients, little attention is given to the time course of AEs (i.e., when they emerge and whether they resolve over time). Such information also would be useful in counseling patients.Topiramate (TPM) is a newer AED with a broadspectrum antiseizure effect as adjunctive therapy (1-7) and monotherapy (8,9). Compared with other newer AEDs, TPM has been proved effective over an exceptionally wide dose range (200-1,000 mg/day) as add-on therapy (1-7). In early double-blind, placebo-controlled trials, nearly 80% of patients were assigned to dosages in excess of what are now recognized as the most useful dosages in clinical practice (100-300 mg/day) (10,11). The studies also were Accepted January 13, 2005. Address correspondence and reprint requests to Dr. J.C. Van Oene at Janssen-Cilag, Department Medical Affairs EMEA, P.O. Box 90240, 5000 LT Tilburg, The Netherlands. E-mail: jvoene@jacnl.jnj.com characterized by high starting doses (100 mg/day), rapid dose escalation (100-to 200-mg/day increments at weekly intervals), and combination with multiple AEDs, which further magnified adverse CNS effects. However, they showed that most AEs emer...

Experimental and Clinical Evidence for Loss of Effect (Tolerance) during Prolonged Treatment with Antiepileptic Drugs

“…When titrations to 400 mg within 3 and 8 weeks were compared, fewer adverse effects and discontinuations were noted in the slow‐titration group (139). In a post hoc analysis of a placebo‐controlled add‐on study of 200 mg/day TPM, the daily incidence of somnolence, headache, loss of appetite, nervousness, fatigue, and dizziness diminished with continued therapy and declined to rates similar to that of placebo after the target TPM dose had been reached (140). However, other side effects such as weight loss or paresthesias did increase with continued treatment (140).…”

“…In a post hoc analysis of a placebo‐controlled add‐on study of 200 mg/day TPM, the daily incidence of somnolence, headache, loss of appetite, nervousness, fatigue, and dizziness diminished with continued therapy and declined to rates similar to that of placebo after the target TPM dose had been reached (140). However, other side effects such as weight loss or paresthesias did increase with continued treatment (140). For our discussion on tolerance, it is tempting to speculate that one possible contributing factor to why lower doses and slower titration schedules are better tolerated is that the patient has more time to develop tolerance to adverse effects and that tolerance to adverse effects caused by low doses develops more easily than tolerance to more‐severe adverse effects seen at higher doses.…”

Topiramate in the treatment of partial and generalized epilepsy

“…Early side effects usually subside within a few weeks (Majkowski et al 2005). Reduction of the dosage of concomitant antiepilepsy drugs is often effective in reducing central nervous system symptoms (Naritoku et al 2005); in one open-label study discontinuations dropped from 23% to 14% when other drug dosages were lowered (Dodson et al 2003).…”

The cognitive impact of antiepileptic drugs

“…Although some studies argue that topiramate may be more commonly linked to CAEs, there are some reports indicating these effects are rather infrequent [Brandl et al 2010;Majkowski et al 2005;Reith et al 2003;Baker et al 2002]. The rate of discontinuation due to CAEs may also be low, especially with low doses [Arroyo et al 2005].…”