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Keywords:

  • Rufinamide;
  • Weight loss;
  • Epilepsy

Summary

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Disclosure
  7. References

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.

Patients and Methods

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Disclosure
  7. References

All patients treated with RUF and seen at the epilepsy unit of Montpellier were included in a prospective database to investigate efficacy and safety of RUF. Weight and height were assessed at the first visit. We determined body mass index (BMI; kg/m2) as the critical value (normal weight, 18.5–24.99; overweight, 25–29.99; obesity, ≥30) (World Health Organization definition). A clinically significant weight change was set as a 7% change from baseline.

Results

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Disclosure
  7. References

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
PatientSexAge at onset of epilepsyEpileptic syndromeAge 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. CBZ, carbamazepine; CLB, clobazam; CNZ, clonazepam; DZP, diazepam; ESM, ethosuximide; LTG, lamotrigine; PHE, phenytoin; RUF, rufinamide; TPM, topiramate; VPA, valproate; ZNS, zonisamide.

1F 4 yearsCryptogenic Lennox-Gastaut Syndrome312,40032VPA: 2,000 LTG: 100 ZNS: 500Vagus nerve stimulation
2F 6 monthsCryptogenic Lennox-Gastaut syndrome   History of West syndrome232,00038.5LTG: 200 TPM: 200Vagus nerve stimulation
3M 4 monthsCryptogenic Lennox-Gastaut syndrome   History of West syndrome282,40048VPA: 2,000 LTG: 250 ZNS: 500 DZP: 5Vagus nerve stimulation
4F 3 yearsSymptomatic left occipital lobe epilepsy252,40029TPM: 450 CNZ: 1 CBZ: 1,600 PHE: 300 LTG: 2,000 CLB: 20Vagus nerve stimulation
5F10 yearsCryptogenic Lennox-Gastaut Syndrome272,00057.1VPA: 1,750 LTG: 250 ZNS: 500 CNZ: 2Vagus nerve stimulation
6M 8 monthsCryptogenic Lennox-Gastaut syndrome   History of West syndrome1880023.5VPA: 1,750 LTG: 200 ESM: 1,000None
7M12 monthsEpileptic encephalopathy201,20027.3LTG: 300 PHE: 200 TPM: 300None
Table 2.   Weight and BMI course
PatientBaseline Weight (kg) Height (cm)Weight loss (kg)Baseline BMIBMI after RUF introductionBMI change (%)Perception of weight lossaExplanation of weight lossActionWeight gain after action (kg)BMI change after action (%)RUF recommenced
  1. RUF, rufinamide.

  2. aRefer to the views of the carer and/or the patients.

1  75 1581430 Obese class I24.4 Normal range−18.7AcceptableReduced intakeOff RUF because of lack of efficacy+5+8 
252 168718.4 Mild thinness15.9 Severe thinness−13.6UnacceptableReduced intake and nauseaOff RUF because of weight loss+2+5Weight loss again OFF RUF
350 172416.9 Moderate thinness15.5 Severe thinness−8.3UnacceptableReduced intakeOff RUF because of weight loss+4+8.3No weight loss ON RUF
483 162631.6 Obese class I29.3 Preobese−7.3AcceptableReduced intake and nauseaOn RUF decrease daily dose by 25%+5+6.5 
535 145516.6 Moderate thinness14.3 Severe thinness−13.8AcceptableNo explanationOn RUFNo  
634 1543.714.3 Severe thinness12.8 Severe thinness−10.5UnacceptableReduced intake and nauseaOff RUF because of weight loss+2.1+7 
744 169515.4 Severe thinness13.7 Severe thinness−11UnacceptableNo explanationOff RUF because of weight lossNo  

Discussion

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Disclosure
  7. References

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.

Disclosure

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Disclosure
  7. References

Dr. Crespel and Dr. Gelisse have received support from pharmaceutical companies for teaching programs (Sanofi-Aventis, UCB). Dr. Crespel was a board member for Eisai-France for zonisamide. Dr. Gelisse was a paid consultant for Eisai-France in 2011. The remaining authors have no conflicts of interest. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Disclosure
  7. References
  • Biton V, Krauss G, Vasquez-Santana B, Bibbiani F, Mann A, Perdomo C, Narurkar M. (2011) A randomized, double-blind, placebo-controlled, parallel-group study of rufinamide as adjunctive therapy for refractory partial-onset seizures. Epilepsia52:234242.
  • Coppola G. (2011) Update on rufinamide in childhood epilepsy. Neuropsychiatr Dis Treat7:399407.
  • Coppola G, Grosso S, Franzoni E, Veggiotti P, Zamponi N, Parisi P, Spalice A, Habetswallner F, Fels A, Verrotti A, D’Aniello A, Mangano S, Balestri A, Curatolo P, Pascotto A. (2011) Rufinamide in refractory childhood epileptic encephalopathies other than Lennox–Gastaut syndrome. Eur J Neurol18:246251.
  • Gelisse P, Juntas-Morales R, Genton P, Hillaire-Buys D, Diaz O, Coubes P, Crespell A. (2007) Dramatic weight loss with levetiracetam. Epilepsia49:3083015.
  • Glauser T, Kluger G, Sachdeo R, Krauss G, Perdomo C, Arroyo S. (2008) Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome. Neurology70:19501958.
  • Härmark L, van Puijenbroek E, Straus S, van Grootheest K. (2011) Intensive monitoring of pregabalin: results from an observational, Web-based, prospective cohort study in the Netherlands using patients as a source of information. Drug Saf34:221231.
  • Wheless JW, Conry J, Krauss G, Mann A, LoPresti A, Narurkar M. (2009) Safety and tolerability of rufinamide in children with epilepsy: a pooled analysis of seven clinical studies. J Child Neurol24:15201525.