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- Patients and Methods
Rufinamide (RUF) is a novel antiepileptic drug considered as second-line therapy in the treatment of Lennox-Gastaut syndrome. Treatment-emergent adverse events (AEs) have consisted mainly of drowsiness, irritability, vomiting, and loss of appetite. RUF is considered as a “weight-neutral” drug. We found clinically significant weight loss in 7 of 15 consecutive adult patients (47%; 3 male, 4 female, aged 18–31 years) treated with RUF as add-on therapy (800–2,400 mg/day: 23.5–57.1 mg/kg/day). The body mass index (BMI) decreased by 7.3–18.7%. Two patients were obese class I before RUF. Five patients (71%) were underweight before RUF (mild in one case, moderate in two cases, and severe in two cases). Four of these patients stopped RUF because of this adverse effect. RUF was recommenced in two patients using a lower and slower dosing strategy; one patient showed improvement in seizure control and no weight loss but RUF was re-stopped in the second patient because of continued weight loss. Despite of weight loss, RUF was continued in two other patients because it reduced seizure activity. We primarily related weight loss to reduced food intake, that is, loss of appetite and nausea, although in two patients no obvious loss of appetite was reported. RUF can cause clinically significant weight loss in adult patients, even at low dose. This AE can affect patients who are already underweight. There is a possibility that lower starting doses and slower escalation might minimize weight loss, but further information is required to determine whether this is the case.
Rufinamide (RUF) is an oral, novel compound that is structurally distinct from other anticonvulsant drugs. It is a triazole derivative that can block sodium channels. In a randomized, double-blind, placebo-controlled trial, it was effective as an adjunctive treatment for Lennox-Gastaut syndrome (Glauser et al., 2008). RUF therapy has been also studied in patients with different types of childhood-onset refractory epileptic encephalopathies other than Lennox-Gastaut syndrome: RUF appeared to reduce seizure frequency, especially in patients with drop attacks and (bi)frontal spike-wave discharges (Coppola et al., 2011). RUF is also efficacious for refractory focal seizures as an add-on therapy for adults and adolescents (Biton et al., 2011). In general, RUF is well tolerated. In placebo-controlled studies, the most common adverse events (AEs) were somnolence, vomiting, and headache (Wheless et al., 2009). Changes in weight were generally clinically insignificant (Wheless et al., 2009).
We report on 15 consecutive adult patients, of whom 7 had clinically significant weight loss related to RUF given as an add-on therapy for the treatment of refractory epilepsy.
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- Patients and Methods
Of the 15 consecutive adult patients treated with RUF, 7 (47%) had a clinically significant weight loss, which they related to their treatment. No difference between genders was observed. Our cohort included three male and four female patients. Age ranged from 18–31 years with a mean age of 24.5 years. The mean daily dose of RUF was 1885.7 mg/day (range 800–2,400 mg/day; 23.5–57.1 mg/kg/day). All patients received lamotrigine (mean dose 214 mg/day; range 100–300) combined with valproate in four (mean dose 1,875 mg/day, range 1,750–2,000). Other drugs used were zonisamide in three patients (500 mg/day), topiramate (three cases; mean dose 316 mg/day; range 200–450), phenytoin (two cases; 200 and 300 mg/day, respectively), carbamazepine (one case; 1,600 mg/day), ethosuximide (one case; 1,000 mg/day) and benzodiazepines (four cases). Five patients had vagus nerve stimulation. There was no change in antiepileptic drug regimens during RUF therapy. Of the seven patients, five had cryptogenic Lennox-Gastaut syndrome, one had another epileptic encephalopathy, and another had symptomatic focal occipital lobe epilepsy with numerous falls. Weight loss began in every case after the introduction of RUF. Although careful review of the records did not allow precise information to be obtained with regard to the time between commencing rufinamide and the point at which weight loss was observed, in all cases weight loss was apparent by 3–12 weeks.
The BMI decreased by 7.3–18.7%. Five of the seven patients were underweight before RUF therapy (mild in one case, moderate in two cases, and severe in two cases). The other two patients were obese class I before RUF. The patients or their families reported loss of appetite with reduced intake in five patients (cases 1, 2, 3, 4, and 6), associated with nausea in three patients (cases 2, 4, and 6). Two patients did not have an explanation for their weight loss (cases 5 and 7).
RUF was stopped in four patients because of weight loss (cases 2, 3, 6, and 7; weight loss range 3.7–7 kg; BMI change range from −8.3% to −13.6%). The family of patient 6 was frightened by the weight loss (−3.7 kg; BMI 12.8), and the drug was quickly stopped. In the three other patients (cases 1, 2, and 6), appetite returned after RUF was stopped and BMI increased by 5–8% within 3–6 months, but it did not return to the previous level. Patient 1, who was obese class I before RUF therapy, was happy with the weight loss (−14 kg; BMI 24.4) but regained 5 kg by 6 months after RUF cessation, despite a low-calorie diet. RUF was stopped in this patient because of lack of efficacy. In patient 3 the weight returned to the previous level; patient 7 did not gain weight.
Because of worsening seizure activity after cessation of RUF, two patients were recommenced on the agent. Using a lower and slower dosing strategy, patient 3 then presented with improvement in seizure control and no weight loss. In this case RUF was recommenced when the patient had recovered his baseline weight. In contrast, RUF was stopped again for patient 2 because the weight loss recurred. Patients 4 and 5 had weight loss (BMI change −7.3% and −13.8%, respectively), but continued RUF because of its efficacy at reducing seizure activity. Patient 4’s weight had increased by 5 kg (BMI increased by 6.5%) at 3 months after having decreased RUF to 25%. The weight of patient 5 tended to plateau after the first 4 months. Clinical data, concomitant drugs, and weight data are summarized in Table 1. The course of the weight and BMI changes are presented in Table 2.
Table 1. Clinical characteristics
|Patient||Sex||Age at onset of epilepsy||Epileptic syndrome||Age at introduction of RUF (years)||Daily dose of RUF (mg/day)||Daily dose of RUF (mg/kg/day)||Concomitant antiepileptic drugs at onset of RUF (mg/day)||Other treatments|
|1||F|| 4 years||Cryptogenic Lennox-Gastaut Syndrome||31||2,400||32||VPA: 2,000 LTG: 100 ZNS: 500||Vagus nerve stimulation|
|2||F|| 6 months||Cryptogenic Lennox-Gastaut syndrome History of West syndrome||23||2,000||38.5||LTG: 200 TPM: 200||Vagus nerve stimulation|
|3||M|| 4 months||Cryptogenic Lennox-Gastaut syndrome History of West syndrome||28||2,400||48||VPA: 2,000 LTG: 250 ZNS: 500 DZP: 5||Vagus nerve stimulation|
|4||F|| 3 years||Symptomatic left occipital lobe epilepsy||25||2,400||29||TPM: 450 CNZ: 1 CBZ: 1,600 PHE: 300 LTG: 2,000 CLB: 20||Vagus nerve stimulation|
|5||F||10 years||Cryptogenic Lennox-Gastaut Syndrome||27||2,000||57.1||VPA: 1,750 LTG: 250 ZNS: 500 CNZ: 2||Vagus nerve stimulation|
|6||M|| 8 months||Cryptogenic Lennox-Gastaut syndrome History of West syndrome||18||800||23.5||VPA: 1,750 LTG: 200 ESM: 1,000||None|
|7||M||12 months||Epileptic encephalopathy||20||1,200||27.3||LTG: 300 PHE: 200 TPM: 300||None|
Table 2. Weight and BMI course
|Patient||Baseline Weight (kg) Height (cm)||Weight loss (kg)||Baseline BMI||BMI after RUF introduction||BMI change (%)||Perception of weight lossa||Explanation of weight loss||Action||Weight gain after action (kg)||BMI change after action (%)||RUF recommenced|
|1|| 75 158||14||30 Obese class I||24.4 Normal range||−18.7||Acceptable||Reduced intake||Off RUF because of lack of efficacy||+5||+8|| |
|2||52 168||7||18.4 Mild thinness||15.9 Severe thinness||−13.6||Unacceptable||Reduced intake and nausea||Off RUF because of weight loss||+2||+5||Weight loss again OFF RUF|
|3||50 172||4||16.9 Moderate thinness||15.5 Severe thinness||−8.3||Unacceptable||Reduced intake||Off RUF because of weight loss||+4||+8.3||No weight loss ON RUF|
|4||83 162||6||31.6 Obese class I||29.3 Preobese||−7.3||Acceptable||Reduced intake and nausea||On RUF decrease daily dose by 25%||+5||+6.5|| |
|5||35 145||5||16.6 Moderate thinness||14.3 Severe thinness||−13.8||Acceptable||No explanation||On RUF||No|| || |
|6||34 154||3.7||14.3 Severe thinness||12.8 Severe thinness||−10.5||Unacceptable||Reduced intake and nausea||Off RUF because of weight loss||+2.1||+7|| |
|7||44 169||5||15.4 Severe thinness||13.7 Severe thinness||−11||Unacceptable||No explanation||Off RUF because of weight loss||No|| || |
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- Patients and Methods
Antiepileptic drugs that have adverse effects on weight are not rare. Valproate, vigabatrin, and pregabalin are among the antiepileptic drugs that can increase the BMI (Gelisse et al., 2007; Härmark et al., 2011). In contrast, topiramate, felbamate, zonisamide, and levetiracetam have been associated with weight loss in some patients (Gelisse et al., 2007). Topiramate is the agent with the best-documented effect in this respect. Weight loss appears to be greatest in overweight people and in women, although the mechanism of weight loss is unclear.
An up-to-date review of AEs in pediatric patients treated with RUF included 11 clinical studies: no major safety concerns have been revealed after long-term administration (Coppola et al., 2011). The frequency of AEs was 23.2–70%. The most common AEs were vomiting (13.3–30.6%), drowsiness, irritability, and loss of appetite (2–50%) (Coppola, 2011). Other AEs included fatigue, sedation, irritability, pyrexia, rash, dizziness, diplopia, and ataxia. In controlled clinical trials, no significant changes in body weight were observed in patients treated with RUF for Lennox-Gastaut syndrome (Wheless et al., 2009) and, no data have been published on its weight-loss effects.
Our findings suggest that RUF can be associated with clinically significant weight loss, even at a low maintenance dose. This AE occurred frequently: it was observed in approximately 50% of our adult patients, most of whom were underweight (71%) before RUF therapy. We primarily related weight-loss to reduced food intake, that is, loss of appetite and nausea, although in two patients no obvious loss of appetite was reported. RUF was stopped in four patients because of this AE. RUF was recommenced in two patients using a lower and slower dosing strategy: one patient showed improvement in seizure control and no weight loss but RUF was restopped in the second patient because the weight loss recurred.
RUF was an add-on therapy. All patients except one (patient 6) were treated with topiramate or zonisamide. Comedication with these drugs may have affected the weight loss, as a result of a pharmacodynamic or pharmacokinetic interaction. However, the weight loss could not have been attributed solely to topiramate or zonisamide because the weight was unchanged before RUF introduction, decreased after RUF introduction, and increased again after RUF cessation. Therefore, in our patients, a link between RUF and weight loss seems likely.
This was an observational study and therefore had the inherent weaknesses of such studies. The small number of cases did not allow us to define a specific risk-group in terms of clinical characteristics such as gender or drug dose. Further studies with large numbers of patients are required to confirm the role of RUF in weight loss and to examine relationship between RUF dose/blood level and weight loss as well as the role of cotherapy with other drugs known to cause weight loss such as topiramate and zonisamide.
In conclusion, this study provides evidence that RUF can be associated with clinically significant weight loss in adults patients. This AE can affect patients who are already underweight. Supervision of the BMI before and during treatment appears necessary. There is a possibility that lower starting doses and slower escalation might minimize weight loss, but further information is required to determine whether this is the case.