Long-term safety and tolerability of oxcarbazepine in children: a review of clinical experience

Relatively few well-designed studies have demonstrated the long-term safety and tolerability of newer antiepileptic drugs (AEDs) in a large group of children. Extensive clinical data from the worldwide Clinical Development Program (CDP) and a compassionate use program on the safety and tolerability of oxcarbazepine in children are presented. Oxcarbazepine is a newer AED that is indicated for use as monotherapy and adjunctive therapy in children (United States 4 years of age, Europe 6 years of age) with partial epilepsy. The most common adverse events (10%) in the CDP were headache (32.5%), somnolence (31.5%), vomiting (27.6%), and dizziness (23.1%), whereas in the compassionate use program (clinical practice situation), the most common adverse events (1%) reported were rash (2.7%), fatigue (1.6%), nausea (1.2%), and somnolence (1.2%). These data indicate that oxcarbazepine has a good long-term safety and tolerability profile, whether given as monotherapy or adjunctive therapy, in children with partial seizures.     

Effective treatment with oxcarbazepine in paroxysmal kinesigenic choreoathetosis

Paroxysmal kinesigenic choreoathetosis is often responsive to anticonvulsants such as carbamazepine and phenytoin. We report a boy with paroxysmal kinesigenic choreoathetosis, which is dramatically relieved by oxcarbazepine even after unsatisfactory treatment with carbamazepine and other medications.     

Long-term treatment of panic disorder with agoraphobia in private practice

The author followed 67 patients with panic disorder with agoraphobia (PDA) for a minimum of 5 years in a private practice setting. They were treated with a combination of pharmacotherapy (antidepressants or benzodiazepines) and cognitive-behavioral psychotherapy. The author examines outcomes for three groups: A) 11 male patients, 10 of whom had comorbid conditions; B) 21 female patients with comorbid conditions; and C) 35 female patients without comorbid conditions. Symptom severity was assessed using the Panic Disorder Severity Scale (PDSS). Patients in all groups showed marked improvement in all the domains measured by the PDSS, with the greatest improvement in PDSS scores occurring during the first year in all three groups. Patients in groups A and B tended to plateau after 5 years of treatment and show no additional improvement thereafter, whereas patients in group C (women with "pure PDA") continued to improve, although at a gradually slower rate. However, after an average of 11 years of treatment, the majority of patients remained symptomatic. The presence of comorbid alcohol abuse or depression was associated with poorer outcomes. The results in this effectiveness study are generally not as good as the outcomes of published PDA follow-up efficacy studies, but appear to be superior to outcomes in cohorts of chronically anxious patients treated decades ago.     

Therapeutic experiences with 947 epileptic out-patients in oxcarbazepine treatment

Efficacy and tolerability of the new antiepileptic drug oxcarbazepine, was evaluated in a retrospective multicentre study. The records of all 947 epilepsy patients treated with oxcarbazepine in the eight participating centres from 1981 through 1990 were examined. The median daily dose of oxcarbazepine was 30 mg/kg in children, 18 mg/kg in adults, and 15 mg/kg in elderly patients, given b.i.d. or t.i.d. The mean plasma levels of the main active metabolite of oxcarbazepine was 88, 79, and 68 μmol/l in children, adults, and elderly, respectively. In patients shifted to oxcarbazepine treatment, seizure frequency was unchanged in 51-66%, 32-48% had a decrease, and 1-10% an increase in seizure frequency, considering the individual seizure types separately. Adverse events were reported in one third of patients, most frequently affecting the CNS (dizziness: 6%; sedation: 6%; fatigue: 6%). Rash was reported in 6% of patients, half of these patients had previously had an allergic reaction to carbamazepine. Hyponatremia was found in about a quarter of the patients from whom data were available. No congenital malformations were seen in nine live-born, first trimester oxcarbazepine-exposed children.     

Long-term safety and tolerability of oxcarbazepine in painful diabetic neuropathy

BACKGROUND: Painful diabetic neuropathy is a common complication of diabetes and often resistant to treatment with standard analgesics. Treatment of diabetic neuropathy with antiepileptic drugs may provide pain relief. AIM: To evaluate the long-term safety and tolerability of oxcarbazepine in two studies investigating the treatment of diabetic neuropathy. OBJECTIVES: Patients with diabetes and a history of neuropathic pain were included. Study 1 was a multicenter, open-label study comprising a screening and 12-month treatment phase. Study 2 was a multicenter, open-label extension to a double-blind, randomized study. Oxcarbazepine was initiated at 300 mg/day and titrated over 4 weeks to tolerability or a maximum dose of 900 mg b.i.d. Safety was assessed by monitoring adverse events (AEs), serious AEs (SAEs), hematology, blood chemistry, urinalysis values, and vital signs. RESULTS: Adverse events were most frequently reported in the nervous and gastrointestinal systems; 20.5% and 21.6% of patients withdrew because of AEs in study 1 and study 2, respectively. SAEs were reported in 13.7% and 14.4% of patients in study 1 and study 2, respectively. CONCLUSIONS: Long-term treatment with oxcarbazepine is generally well tolerated in patients with painful diabetic neuropathy. Rapid titration of oxcarbazepine may be responsible for discontinuations resulting from AEs during early stages of treatment.     

Long-term effectiveness of glatiramer acetate in clinical practice conditions

Glatiramer acetate currently represents one of the main treatments for relapsing-remitting multiple sclerosis (RRMS). However, the information available about its long-term effect in clinical practice is still limited. Thus, this multicenter retrospective cohort study aimed to assess the long-term effectiveness of glatiramer acetate in this setting. The study population included RRMS patients treated with glatiramer acetate for at least 5 years after its marketing authorization and the primary endpoint was long-term clinical effectiveness, defined as absence of disability progression for at least five consecutive years. A total of 149 patients were included into the study, who had received glatiramer acetate for a mean of 6.9 ± 1.4 years (5 years, n = 149; 6 years, n = 112; 7 years, n = 63; 8 years, n = 32; 9 years, n = 21). More than 85% of patients remained free from disability progression through years 1 to 9 of glatiramer acetate treatment, and 75.2% showed absence of disability progression for at least five consecutive years. Expanded Disability Status Scale (EDSS) scores were maintained, with most patients showing stable/improved EDSS and 92.6% sustaining EDSS <6. Decreased annual relapse rates and increased proportion of relapse-free patients were maintained during the whole glatiramer acetate treatment compared to the year prior to its authorization (p < 0.001). The number of gadolinium-enhanced T1-weighted lesions also decreased from pre-glatiramer-acetate assessment to last follow-up whilst on glatiramer acetate (p < 0.05). In conclusion, administration of glatiramer acetate shows long-term clinical effectiveness for RRMS treatment; its effect under clinical practice conditions slowed disability progression and reduced relapse occurrence for up to 9 years.     

Prospective study on long-term treatment with oxcarbazepine in pediatric epilepsy

Following a previous preliminary report on a group of children suffering from partial epilepsies, we present the final considerations on the same group in order to evaluate the long-term efficacy, tolerability and safety of oxcarbazepine (OXC). We enrolled 36 patients (mean age 8.5), between January 2003 and December 2004, with new diagnosis of partial epilepsy: 25 patients were affected by idiopathic partial epilepsy, eight by symptomatic epilepsy and three by cryptogenic epilepsy. Each patient was scheduled to attend the center four times after the initial examination: 3 months (T1), 12 months (T2), 24 (T3) months and 36 (T4) months after the beginning of OXC-monotherapy (T0). At the end of our study, 20 patients were seizure free (SF): nine stopped OXC because of SF for at least 2 years, 11 were still on therapy. One patient showed a reduction of seizure frequency ≥50%, three were non responders (but still on therapy), nine stopped OXC due to a non-responder condition during follow-up before T4 and one because of adverse effects. At the end of the study no EEG focal abnormalities became generalized because of treatment. Normalization of EEG was observed in ten patients. Our preliminary findings have been confirmed. OXC can be considered an effective and well tolerated first line drug for long-term monotherapy in children with epilepsy, both for idiopathic and symptomatic/cryptogenic forms.     

奥卡西平治疗癫癎的临床研究

目的观察奥卡西平(OXC)治疗癫癎的疗效、耐受性和安全性。方法294例患者,120例加用OXC治疗,174例单用OXC治疗。通过逐步加量的方法达到目标剂量。结果本组总有效率为86.05%,完全控制为39.8%;其中单药治疗组控制率45.98%,总有效率为89.08%,添加治疗组控制率为30.83%,总有效率为81.67%。单药治疗组不良反应总发生率为15.52%,添加组不良反应发生率为26.67%,2组比较,添加治疗组出现的反应相对多于单药治疗组。结论奥卡西平治疗癫癎有效、安全、稳定。     

A pilot clinical trial of oxcarbazepine in adults with attention-deficit hyperactivity disorder

Despite the increasing recognition of attention-deficit hyperactivity disorder (ADHD) in adults, there is a paucity of controlled pharmacological trials. Recent reports have suggested the potential usefulness of mood stabilizing drugs for ADHD. To this end, the authors completed a pilot study with oxcarbazepine for the treatment of adults with ADHD. This was an open pilot study of oxcarbazepine (300-1,500 mg daily dosage) in adults who met DSM-IV criteria for ADHD. The treatment period was 8 weeks. Of the 9 subjects enrolled in the study (4 men, 5 women), 8 patients could be included in the analysis. At the endpoint of the active treatment, a significantly high proportion of subjects was considered improved while receiving oxcarbazepine. ADHD symptom checklist scores (ADHD-IV rating scale, Conners ADHD adult rating scale, ADHD self-rating [ADHD-SR] scale) showed significant reduction during the treatment period. Treatment with oxcarbazepine was relatively well tolerated; dizziness, sedation and nausea were the most frequently reported adverse effects. The results of this investigation indicate that oxcarbazepine may be a potentially useful agent for the treatment of ADHD in adults. However, placebo-controlled randomized trials are needed to provide evidence.     

Long-term rivastigmine treatment in a routine clinical setting

Objective – The aim of the study was to observe the effects of long‐term rivastigmine treatment in patients with mild to moderate Alzheimer’s disease (AD) in a routine clinical setting. Methods – This was a prospective, open‐label, observational, multicentre, non‐randomized study. Outcome measures included the Mini Mental State Examination (MMSE), the Clinician’s Interview‐Based Impression of Change (CIBIC) and the Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS‐cog). Results – Of 217 patients initiated into rivastigmine treatment, 62% (n = 135) remained on treatment for 24 months. Most patients droped out due to nursing home placement or side effects. Eighty per cent and 67% of completers exhibited a symptomatic attenuation of cognitive decline (≤ 4‐point deterioration) as assessed by using the MMSE and ADAS‐cog respectively. Forty‐four per cent showed an unchanged/improved CIBIC rating. Conclusions – Over 60% of patients remained on treatment for 2 years in this routine clinical setting. In patients who remained on treatment, rivastigmine appeared to stabilize their condition and prevented or delayed symptomatic decline.     

Long-term use of oxcarbazepine oral suspension in childhood epilepsy: open-label study

Studies designed specifically for the pediatric population are needed to assess the tolerability and safety of the new antiepileptic drugs. The purpose of this study was to document the safety, ease of dosing, and acceptance of oxcarbazepine oral suspension in pediatric patients in monotherapy and polytherapy. A prospective, multicenter, open-label study was conducted at the neurology services of three pediatric university hospitals over 12 months. After obtaining signed informed consent, we enrolled a series of 62 patients with epilepsy aged between 2 months and 14 years who began oxcarbazepine treatment in monotherapy or in combination with other antiepileptic drugs to assess the seizure frequency, safety (adverse events), and acceptance of the pharmaceutical form by the patient's family. Fifty patients (80.6%) reduced seizures by at least 50%, 44 (71%) saw a reduction in seizure frequency of over 75%, and 29 (46.8%) were seizure free at the end of the study. The difference in the number of seizures before and after the study was statistically significant, both overall and by type of pathology. Adverse events occurred in four patients (6.4%) and required withdrawal of the drug in two cases (skin rash); three patients (4.8%) withdrew for inefficacy. Five patients (8.1%) withdrew from the treatment. We concluded that, in this series of patients, oxcarbazepine in oral suspension form was seen to help reduce seizure frequency, to have few side effects, and to be accepted by parents and patients.     

Long-term assessment of oxcarbazepine in a naturalistic setting: a retrospective study

Background –  New antiepileptics seem to be better tolerated by patients. The retention rate of an antiepileptic would be a useful indicator of its practical usefulness.
Aims –  To assess the long-term outcome of oxcarbazepine (OXC) in a naturalistic setting by determining the retention rate.
Methods –  This is a retrospective study. All epilepsy patients treated with OXC at a tertiary care epilepsy center during a period of 3.5 years were included in this study. Retention rates of OXC at 1 and 3 years were estimated for each cohort group using Kaplan–Meier estimates and corresponding 95% confidence intervals.
Results –  A total of 98 patients were studied. OXC was used as monotherapy in 14 (14.3%) and as add-on therapy in 84 (85.7%). The mean daily dose was 947 ± 492 mg and 60% received ≤900 mg/day. Using the Kaplan–Meier survival analysis, the retention rates of OXC at 1 and 3 years were estimated to be 0.853 (0.749–0.956) and 0.737 (0.570–0.904), respectively.
Conclusions –  OXC is well tolerated by patients as both monotherapy and add-on therapy.     

Recommendations on the clinical use of oxcarbazepine in the treatment of epilepsy: a consensus view

Extensive clinical use and a series of clinical trials have shown that oxcarbazepine is a valuable antiepileptic drug for the treatment of adults and children with partial onset seizures both in initial monotherapy, for conversion to monotherapy and as adjunctive therapy. The clinically recommended titration scheme for all forms of therapy in adults is to start with 150 mg/day at night and to increase by 150 mg/day every second day until a target dose of 900-1200 mg/day is reached. If necessary, one can go faster and start with up to 600 mg/day and titrate with weekly increments of up to 600 mg/day. In children, treatment can be initiated with 8-10 mg/kg/day body weight in two to three divided doses. Dosage can be increased by 8-10 mg/kg/day in weekly increments if necessary for seizure control. Hyponatremia (serum sodium <125 mmol/l) can develop gradually during the first months of oxcarbazepine therapy in approximately 3% of patients with a previously normal serum sodium. However, there is no need to measure baseline serum sodium concentrations unless the patient has renal disease, is taking medication which may lower serum sodium levels (such as diuretics, oral contraceptives or nonsteroidal anti-inflammatory drugs) or--in rare cases--has clinical symptoms of hyponatremia. During oxcarbazepine maintenance therapy measurement of serum sodium levels should also be considered if medications known to decrease sodium levels are added or symptoms of hyponatremia develop. Oxcarbazepine does not appear to have any clinically notable effects on other safety parameters such as renal and liver function or haematological test results. In summary, oxcarbazepine is a safe and well tolerated antiepileptic drug for partial epilepsy.     

Long-term treatment with vigabatrin - 10 years of clinical experience.

This report describes the long-term follow-up of 56 patients with refractory partial epilepsy who, within 3 months of vigabatrin add-on therapy (3 g/day), showed a reduction in monthly seizure frequency of more than 50%. The short-term (6 months) and long-term (5 years) effects of vigabatrin on seizure frequency in this patient cohort have been published separately. The reduction in seizure frequency appeared to be long-lasting in the patients followed-up (n = 36) and, importantly, a significant number of the patients (n = 7) became seizure-free, especially during long-term treatment. Thus, the efficacy of vigabatrin appears to be progressive, at least in patients who show an early response to treatment. These results are consistent with experimental findings that suggest that vigabatrin may have anti-epileptogenic and neuroprotective effects.     

奥卡西平治疗儿童部分性发作的临床疗效及安全性观察

目的观察及评价奥卡西平（OXC）对儿童部分性发作的临床疗效和安全性。方法2006年3月-2007年5月经门诊诊断的PS／CPS或sGTCS儿童患者81例，其中27例采用奥卡西平添加治疗，54例单药治疗，经4～6周加量期和12周稳定期观察后进行评价。结果OXC添加治疗组及单药治疗组总有效率分别为81．5％和83．3％，完全控制率分别为37．0％和40．7％，且不良反应较轻，耐受性良好。结论奥卡西平治疗儿童部分性发作有效且安全，可用于儿童部分性发作的单药治疗和添加治疗。     

Central hypothyroidism with oxcarbazepine therapy

Abnormalities in thyroid function with the use of several antiepileptic medications are thought to result from increased metabolism of thyroid hormone and interference with the hypothalamic-pituitary axis. Oxcarbazepine was developed to attempt to reduce the side effects that have traditionally been observed with antiepileptic drugs that induce the hepatic enzyme system. Increased metabolism of thyroid hormone should not occur in patients on oxcarbazepine as the hepatic enzyme system has minimal involvement in the metabolism of this medication. This report describes three patients who developed central hypothyroidism associated with oxcarbazepine treatment, suggesting that oxcarbazepine interferes with the hypothalamic-pituitary axis.     

Effects of chronic treatment with valproate and oxcarbazepine on ovarian folliculogenesis in rats

Purpose : We aimed to define the morphologic effects of valproate (VPA) and oxcarbazepine (OXC) on ovarian folliculogenesis in rats.
Methods : Forty female wistar rats (21–24 days old and weighted between 46.4 and 55.3 g) were divided equally into 4 experimental groups, which were applied tap water (control group), 300 mg/kg/day VPA, 100 mg/kg/day OXC, and both VPA and OXC via gavage for 90 days. Ovaries of the rats on proestrous and diesterous phase of estrous cycle according to daily vaginal smear were taken out and placed in a fixation solution. Immunohistochemical and apoptosis (TUNEL) staining protocols were applied.
Results : The number of follicles decreased and that of corpora lutea increased significantly in OXC, VPA, and OXC+VPA treated groups compared with control group (p < 0.05). The number of TUNEL positive ovarian follicles was 1.40 ± 0.52 in control group, but it significantly increased to 3.50 ± 0.53, 3.50 ± 0.53, and 4.90 ± 0.88 in VPA, OXC, and VPA+OXC groups (p < 0.0001). The increase in the number of TUNEL positive granulosa cells was also significant for OXC and VPA+OXC groups (p < 0.0001). Immunohistochemical HSCORE decreased for TGFβ1 and IGF1 staining and increased for P53 staining in all drug groups compared with control group (p < 0.001). Intensity of P53 labeling increased, while intensity of TGFβ1, IGF-1, and GDF-9 immunoreactivity decreased significantly in all drug groups compared with control group (p < 0.001).
Conclusion : Long-term treatment with VPA or OXC from prepuberty to adulthood causes apoptosis and deterioration of folliculogenesis in rat ovarian follicles.     

Integrating pediatric obesity treatment into clinical practice

Childhood obesity has reached epidemic proportions in the United States and other industrialized nations. Despite the significant psychosocial consequences, mental health professionals have been reluctant to provide direct treatment for these children and their parents. The author proposes a practice model for agency, clinic, and private settings, with the mental health practitioner as primary clinician. On the basis of intervention research methodology, the model presents consensus generalizations and clinical applications for evaluation and treatment. A typology of diagnostic profiles with corresponding strategies for combining diet, activity, and mental health interventions is included.