Clinical feasibility of immediate overnight switching from slow-release carbamazepine to oxcarbazepine in Korean patients with refractory partial epilepsy
Article Outline
- Abstract
- 1. Introduction
- 2. Methods
- 3. Results
- 4. Discussion
- 5. Conclusion
- Acknowledgment
- References
- Copyright
Abstract
We assessed the clinical variables predicting the feasibility of immediate overnight switching from slow-release carbamazepine to oxcarbazepine in Korean patients with refractory partial epilepsy. Thirty patients aged 15 years or older with refractory partial epilepsy, who had been treated with slow-release carbamazepine as monotherapy or in combination therapy, were switched overnight from slow-release carbamazepine (mean dose at switching, 900
mg/day) to oxcarbazepine. Of these 30 patients, 29 (96.7%) had been treated with a slow-release formulation of carbamazepine. The proportion of patients with polytherapy was 85.3%. Overall, 9 of 30 (30%) switched patients experienced clinically significant adverse events until 2 weeks after switching, including 2 with seizure aggravation. The only clinical variable related to the failure of overnight switching was the number of seizures at baseline.
Abbreviations: OXC, oxcarbazepine, AED, antiepileptic drug, CBZ, carbamazepine
Keywords: Carbamazepine, Oxcarbazepine, Switching, Partial epilepsy
1. Introduction
Oxcarbazepine (OXC) is an antiepileptic drug (AED) with a chemical structure similar to that of carbamazepine (CBZ). OXC may have some further pharmacological actions, but the main anticonvulsant effect is very likely due to mechanisms shared with CBZ.1, 2 In patients with inadequate seizure control on CBZ alone, switching to OXC or adding OXC to CBZ has been shown to be effective in controlling.3, 4, 5
To avoid increasing the overall drug burden of a patient, substitution therapy has been regarded as preferable to add-on therapy. Although physicians generally choose to switch patients progressively from one AED to another, CBZ and OXC may be safely substituted for each other overnight.6, 7, 8 In a trial conducted by Albani et al.,9 90% of patients experienced no clinically significant adverse events after overnight switching, indicating that overnight switching is as well tolerated as is progressive switching and that overnight switching from CBZ to OXC was feasible in most patients on polytherapy.9
In investigating the therapeutic efficacy of immediate overnight switching from slow-release CBZ to OXC in patients with refractory partial epilepsy, we found that a large proportion of patients experienced intolerable side effects, leading to early termination of our study. We reviewed these results to identify clinical variables predicting the feasibility of overnight switching from slow-release CBZ to OXC in Korean patients with refractory partial epilepsy.
2. Methods
2.1. Patients
Patients aged ≥15 years with a diagnosis of partial epilepsy were recruited. Subjects were included if they had at least three seizures during a baseline period and were being treated with at least 400mg/day CBZ, either as monotherapy or as combination therapy (maximum, three AEDs). Patients were excluded if they had been exposed previously to OXC, if they experienced status epilepticus within the previous year, or if they had a clinically relevant medical illness or significant psychiatric disorder.
The study was approved by our local ethics committees and was conducted in accordance with Good Clinical Practice and the Declaration of Helsinki. Each participant gave written informed consent.
2.2. Study design
This was an observational, multicenter, open-label, single-arm study. The study consisted of a 12-week baseline and a 12-week treatment phase. Unless seizure type and frequency could be obtained retrospectively from a patient diary, patients entered the prospective baseline phase.
At the end of the baseline phase, patients were switched from slow-release CBZ to OXC overnight. The conversion ratio (CBZ:OXC) was 1:1.5 for slow-release CBZ doses of 400–800mg/day. However, because of autoinduction with CBZ at doses greater than 1000mg/day, a reduced ratio of 1:1.2 was used for slow-release CBZ doses of 900–1600mg/day. There were three scheduled visits, after 2, 6, and 12 weeks of treatment. The dose of OXC could be optimized based on individual tolerability and seizure control during the study from the next day after overnight switch. However, no dose adjustment of any associated AED was allowed during the study.
2.3. Assessments
We assessed the proportion of patients who experienced any clinically significant adverse event during the 2 weeks after the switch. Such events were defined as events that required specific medical intervention or led to modification or interruption of OXC therapy. Clinical variables predicting the clinical feasibility of overnight switching were evaluated.
2.4. Statistical analysis
The occurrence of clinically significant adverse events was correlated with clinical variables using Fisher's exact test and the Mann–Whitney U-test. P-values less than 0.05 were considered statistically significant. Data were analyzed using SPSS version 12.0 (SPSS Inc., Chicago, IL).
3. Results
Of a total of 33 patients enrolled, 30 underwent a switch from slow-release CBZ to OXC. Three patients dropped out before the switch because of violations of inclusion criteria. The baseline characteristics of all switched patients are shown in Table 1. Of the 30 patients, 29 (96.7%) were being treated with a slow-release formulation of CBZ, and 25 (83.3%) were being treated with polytherapy. Mean slow-release CBZ dosage before the switch was 900mg/day (range, 400–1200mg/day).
Table 1. Baseline characteristics of patients undergoing immediate overnight switching from carbamazepine to oxcarbazepine.
| Patients with CSAE (n=9) | Patients without CSAE (n=21) | Total (n=30) | |
|---|---|---|---|
| Age, mean years (SD) | 38.7 (9.1) | 38.9 (11.8) | 38.8 (10.9) |
| Male (%) | 3 (33.3) | 9 (42.9) | 12 (40) |
| Duration of epilepsy, mean years (SD) | 19.2 (10.6) | 18.7 (9.9) | 18.9 (9.9) |
| *Total seizures during the baseline period, mean (SD) | 10.3 (8.0) | 6.7 (5.5) | 7.8 (6.4) |
| Generalized seizures during the baseline period, mean (SD) | 0.33 (1.00) | 0.62 (1.36) | 0.53 (1.25) |
| Etiology of epilepsy, symptomatic:cryptogenic | 3:6 | 13:8 | 16:14 |
| Type of seizures | |||
| Simple partial | 0 | 4 | 4 (13.4%) |
| Complex partial | 8 | 12 | 20 (66.7%) |
| Partial to secondary generalization | 1 | 5 | 6 (20.0%) |
| Type of carbamazepine received | |||
| Regular form | 0 | 1 | 1 |
| Slow-release form | 9 | 20 | 29 |
| Last daily dosage of carbamazepine, mean mg (range) | 933 (600–1200) | 885 (400–1200) | 900 (400–1200) |
| Last daily dosage of carbamazepine | |||
| ≤800mg | 5 (26.3%) | 14 (73.7%) | 19 (63.3%) |
| ≥1000mg | 4 (36.4%) | 7 (63.6%) | 11 (36.7%) |
| Initial daily dosage of oxcarbazepine, mean mg (range) | 1266 (600–1500) | 1228 (600–1500) | 1240 (600–1500) |
| Initial daily dosage of oxcarbazepine | |||
| ≤900mg | 1 (25%) | 3 (75%) | 4 (13.3%) |
| 1200mg | 5 (29.4%) | 12 (70.6%) | 17 (56.7%) |
| 1500mg | 3 (33.3%) | 6 (66.7%) | 9 (30.0%) |
| Antiepileptic drugs | |||
| carbamazepine monotherapy | 3 | 2 | 5 (16.7%) |
| carbamazepine plus one AED | 4 | 12 | 16 (55.3%) |
| carbamazepine plus two AEDs | 2 | 7 | 9 (30%) |
| Co-antiepileptic drugs | |||
| Topiramate | 1 | 9 | 10 |
| Levetiracetam | 2 | 7 | 9 |
| Pregabalin | 2 | 3 | 5 |
| Zonisamide | 3 | 0 | 3 |
| Valproic acid | 0 | 5 | 5 |
| Phenobarbital | 0 | 2 | 2 |
| Clonazepam | 0 | 1 | 1 |
| Lamotrigine | 0 | 1 | 1 |
| Patients receiving non-AED concomitant medications, n | 3 | 7 | 10 (33.3%) |
Overall, 9 (30%) of 30 switched patients experienced clinically significant adverse events during the first 2 weeks after switching; of these, 2 experienced seizure aggravation, and 7 experienced side effects (vertigo, headache, diplopia, somnolence, insomnia, skin rashes, and a tingling sensation). All these patients discontinued the study. An additional five patients (16.7%) dropped out during the 2–12 weeks after a switch; four because of seizure aggravation and one who was lost to follow-up. Sixteen (53.3%) of the 30 patients successfully completed the study, to 12 weeks after switching. Among these, five patients experienced seizure reduction of over 50%.
The final slow-release CBZ or initial OXC dosages did not differ significantly between patients who successfully switched and those who failed switching. The only clinical variable related to the occurrence of clinically significant adverse events was the number of seizures during the 12-week baseline period, which was significantly higher in those with adverse events than those without them (10.3 vs. 6.7, P<0.05). The number of seizures during baseline period was not significantly related to the final slow-release CBZ, initial OXC dosages, or the number of antiepileptic drugs.
4. Discussion
Immediate overnight switching from CBZ to OXC has been suggested to be safe,8, 9, 10 with about 90% of patients experiencing no clinically significant adverse events, indicating that immediate overnight switching appears feasible in most patients on monotherapy or polytherapy.8, 9 In contrast, we found that 30% of patients experienced clinically significant adverse events after overnight switching and that all of these patients discontinued the study.
In this study, the only clinical variable related to the occurrence of clinically significant adverse events was the number of seizures during the baseline period, which was significantly higher in those with adverse events than those without them. But our patients with more frequent seizures did not have higher dosage of slow-release CBZ and/or take on polytherapy, which might be contributing to failure rate of overnight switching.
Several potential factors may explain these differences between studies in the proportion of patients experiencing adverse events after overnight switching. One is the final dosage of slow-release CBZ before switching. Although the CBZ dosages did not differ significantly between patients who failed switching and those who successfully switched in this study, we cannot exclude the possibility of small sample size effects. Comparing to CBZ dose (mean 786mg/day) in a previous study,8 a mean slow-release CBZ dose (900mg/day) in this study was higher. So it is possible that a higher slow-release CBZ dosage prior to switching may have contributed to the greater rate of switch failures.
Another factor that may have contributed to the difference between studies was AED polytherapy. The proportion of patients on polytherapy was higher in our study than in a previous study (83.3% vs. 47.1%).9 Because of the possibility of an enhanced level of adverse events after overnight switching in patients receiving polytherapy compared to those on monotherapy, it has been recommended that the former class of patients be gradually switched over 2–3 weeks.1, 5 Other potential factors affecting the occurrence of adverse events after switching may be the use of concomitant drugs that induce or inhibit hepatic enzymes.11 This factor, however, was not likely to affect our results because none of our patients who failed switching had been treated with hepatic enzyme-inducing or -inhibiting drugs.
Because of pharmacokinetic differences, a CBZ:OXZ conversion ratio of 1:1–1.2 is generally recommended for replacement of the slow-release formulation of CBZ, whereas a conversion ratio of 1:1.5 is recommended when the conventional formulation of CBZ is employed.2, 8, 11 Almost all of our patients (96.7%) were being treated with a slow-release formulation of CBZ prior to switching, compared with 56.6% and 60% of patients in previous studies,8, 9 suggesting a relationship between the higher proportion of patients taking the slow-release formulation of CBZ and the elevated rate of switch-failed patients in the present study.
Finally, ethnic differences cannot be excluded. A certain proportion of patients may experience increased side effects during a switch, especially an overnight switch. This is thought to be attributable to variation in CBZ autoinduction from patient to patient. Using equivalent doses of OXC in such a situation is clearly inappropriate. Because of autoinduction with CBZ at doses greater than 800mg/day, a slightly lower ratio has been recommended, thus, 1:1.2 to 1:1.4.1 This variability in CBZ autoinduction may be influenced by ethnic differences.
Although clinical experience supports the feasibility of an overnight switch from CBZ to OXC, a gradual conversion scheme has been recommended, by initiating OXC at 150mg b.i.d., and titrating upwards by 150mg every 2 days.1 This switch method remains rapid and ensures that patients achieve seizure control quickly. CBZ dosage should be reduced by 25% prior to titration of OXC, to avoid problems of increased drug load, which may lead to an increase in tolerability problems.
5. Conclusion
Patients with a higher baseline seizure frequency may be at higher risk of failure of immediate overnight switching from slow-release CBZ to OXC.
Acknowledgment
This study was supported by a grant from Novartis Korea.
References
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PII: S1059-1311(10)00106-8
doi:10.1016/j.seizure.2010.05.002
© 2010 British Epilepsy Association. Published by Elsevier Inc. All rights reserved.
