Safety assessment of combination therapies in the treatment of obesity: focus on naltrexone/bupropion extended release and phentermine-topiramate extended release.

INTRODUCTION: Few studies on combination therapies for the treatment of obesity had been conducted until recently, when two fixed-dose combinations, bupropion-naltrexone ER fixed-dose combination and phentermine-topiramate ER titrated-dose combinations were evaluated in clinical studies that ultimately led to FDA approval. Areas covered: In this review, we discuss safety concerns about both combinations, the rationale and history of combination therapies for obesity (including phentermine plus fenfluramine), and possible future new combinations. Expert opinion: Combination therapies are a promising new area in obesity treatment, similar to what occurs with diabetes and hypertension. Safety assessment is highly important due to the high number of potential users on a chronic basis.

Topiramate-Associated Weight Loss in a Veteran Population.

OBJECTIVE: This study aims to see whether patients in a real-world setting taking topiramate for varied indications experience significant weight loss. METHODS: This was a retrospective cohort study from the Veterans Affairs San Diego Healthcare System. Patients were new topiramate users between January 1, 2000 and December 31, 2013 with body mass index > 25 kg/m(2) and medication possession ratio > 0.5. Primary outcome determined if topiramate users experienced significant changes in weight and body mass index. Secondary outcome analyzed predictive factors associated with 5% weight loss using logistic regression models. Patients were followed up 1 year post index date. RESULTS: A total of 767 patients were included in the final analysis. Patients lost an average of 5.6 lbs (216.1 lbs preweight vs. 210.5 lbs postweight) at an average follow-up of 7.8 months. A total of 43.2% (92/213) of females lost 5% of their body weight compared to 29.4% (163/554) of males. Females (odds ratio 1.73; 95% confidence interval 1.21-2.48; p = 0.003), topiramate indication other than headache, and adherent patients (odds ratio 1.78; 95% confidence interval 1.28-2.49; p = 0.001) were more likely to lose 5% of body weight. CONCLUSION: Topiramate should be considered with higher priority in overweight and obese patients for nonweight loss indications for dual benefit.

Balancing risk and benefit in heavy drinkers treated with topiramate: implications for personalized care.

BACKGROUND: Despite topiramate's ability to reduce heavy drinking, its adverse effects may limit its clinical utility. METHOD: To evaluate the risks and benefits of topiramate, we reanalyzed data from a completed trial of the medication in 138 heavy drinkers whose goal was to reduce their drinking to safe levels. We used the number of patients who had no heavy drinking days during the last 4 weeks of treatment to calculate topiramate's number needed to treat (NNT). To balance the risks and benefits of topiramate, we adjusted the NNT using 2 different levels of adverse event severity: moderate or greater (NNT-AEmod+) and severe or greater (NNT-AEsev+). This measure helps to guide the clinical use of topiramate in heavy drinkers by incorporating both its beneficial and adverse effects in a single measure. Because a polymorphism (rs2832407) in the gene encoding a kainate receptor subunit appears to moderate topiramate's effects in heavy drinkers, we repeated the analyses based on rs2832407 genotype (C-homozygote vs A-allele carrier) in the European American subsample (n = 122). RESULTS: Overall, the NNT for topiramate was 5.29, the NNT-AEmod+ was 7.52, and the NNT-AEsev+ was 6.12. Among European Americans with the rs2832407*CC genotype, the NNT was 2.28, the NNT-AEmod+ was 2.63, and the NNT-AEsev+ was 2.56. In contrast, for rs2832407*A-allele carriers, the NNT was 180.00, the NNT-AEmod+ was 322.16, and the NNT-AEsev+ was 217.45. CONCLUSIONS: In this sample of heavy drinkers, topiramate had a clinically important treatment effect that was most evident in European Americans with the rs2832407*CC genotype. In that group, in particular, it had a robust treatment effect, even when adjusted for adverse events. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00626925.

Assessment of the quality of harms reporting in non-randomised studies and randomised controlled studies of topiramate for the treatment of epilepsy using CONSORT criteria.

PURPOSE: Treatment decisions should be informed by high quality evidence of both the potential benefit and harms of treatment alternatives. Randomised controlled trials (RCTs) provide the best evidence regarding benefits; however information relating to serious, rare and long-term harms is usually available only from non-randomised studies (NRSs). The aim of this study was to use a checklist based on the CONSORT (Consolidating Standards for Reporting Trials) extension for harms recommendations to assess the quality of reporting of harms data in both NRSs and RCTs of antiepileptic drugs, using studies of topiramate as an example. RESULTS: Seventy-eight studies were included from an online search of seven databases. Harms data was extracted from each study using a 25-point checklist. The mean number of items met was 11.5 (SD 2.96) per study. Commercially funded studies met on average 12.7 items and non-commercially funded studies met 10.08 (p value < 0.001). RCTs met on average 13.0 items and NRSs met 10.8 (p = 0.001). Multi-centre studies and commercially funded studies met significantly more items than single centre and non-commercially funded studies respectively. There was no significant difference in the mean number of items met by studies that had included adult vs. child participants, or studies published pre- vs. post-CONSORT extension for harms in 2004. CONCLUSIONS: Reporting of harms is significantly better in RCTs than in NRSs of TPM, but is suboptimal overall and has not improved since the publication of CONSORT extension for harms in 2004. There is a need to improve the reporting of harms in order to better inform treatment decisions.

Assessment and treatment of insomnia in adult patients with alcohol use disorders.

Insomnia in patients with alcohol dependence has increasingly become a target of treatment due to its prevalence, persistence, and associations with relapse and suicidal thoughts, as well as randomized controlled studies demonstrating efficacy with behavior therapies and non-addictive medications. This article focuses on assessing and treating insomnia that persists despite 4 or more weeks of sobriety in alcohol-dependent adults. Selecting among the various options for treatment follows a comprehensive assessment of insomnia and its multifactorial causes. In addition to chronic, heavy alcohol consumption and its effects on sleep regulatory systems, contributing factors include premorbid insomnia; co-occurring medical, psychiatric, and other sleep disorders; use of other substances and medications; stress; environmental factors; and inadequate sleep hygiene. The assessment makes use of history, rating scales, and sleep diaries as well as physical, mental status, and laboratory examinations to rule out these factors. Polysomnography is indicated when another sleep disorder is suspected, such as sleep apnea or periodic limb movement disorder, or when insomnia is resistant to treatment. Sobriety remains a necessary, first-line treatment for insomnia, and most patients will have some improvement. If insomnia-specific treatment is needed, then brief behavioral therapies are the treatment of choice, because they have shown long-lasting benefit without worsening of drinking outcomes. Medications work faster, but they generally work only as long as they are taken. Melatonin agonists; sedating antidepressants, anticonvulsants, and antipsychotics; and benzodiazepine receptor agonists each have their benefits and risks, which must be weighed and monitored to optimize outcomes. Some relapse prevention medications may also have sleep-promoting activity. Although it is assumed that treatment for insomnia will help prevent relapse, this has not been firmly established. Therefore, insomnia and alcohol dependence might be best thought of as co-occurring disorders, each of which requires its own treatment.

Cost-effectiveness analysis of interventions for migraine in four low- and middle-income countries.

BACKGROUND: Evidence of the cost and effects of interventions for reducing the global burden of migraine remains scarce. Our objective was to estimate the population-level cost-effectiveness of evidence-based migraine interventions and their contributions towards reducing current burden in low- and middle-income countries. METHODS: Using a standard WHO approach to cost-effectiveness analysis (CHOICE), we modelled core set intervention strategies for migraine, taking account of coverage and efficacy as well as non-adherence. The setting was primary health care including pharmacies. We modelled 26 intervention strategies implemented during 10 years. These included first-line acute and prophylactic drugs, and the expected consequences of adding consumer-education and provider-training. Total population-level costs and effectiveness (healthy life years [HLY] gained) were combined to form average and incremental cost-effectiveness ratios. We executed runs of the model for the general populations of China, India, Russia and Zambia. RESULTS: Of the strategies considered, acute treatment of attacks with acetylsalicylic acid (ASA) was by far the most cost-effective and generated a HLY for less than US$ 100. Adding educational actions increased annual costs by 1-2 US cents per capita of the population. Cost-effectiveness ratios then became slightly less favourable but still less than US$ 100 per HLY gained for ASA. An incremental cost of > US$ 10,000 would have to be paid per extra HLY by adding a triptan in a stepped-care treatment paradigm. For prophylaxis, amitriptyline was more cost-effective than propranolol or topiramate. CONCLUSIONS: Self-management with simple analgesics was by far the most cost-effective strategy for migraine treatment in low- and middle-income countries and represents a highly efficient use of health resources. Consumer education and provider training are expected to accelerate progress towards desired levels of coverage and adherence, cost relatively little to implement, and can therefore be considered also economically attractive. Evidence-based interventions for migraine should have as much a claim on scarce health resources as those for other chronic, non-communicable conditions that impose a significant burden on societies.

Cost-Effectiveness Analysis of Qsymia for Weight Loss.

BACKGROUND: Phase 3 clinical trial results reveal that Qsymia is a clinically effective long-term treatment for obesity, but whether this treatment is cost-effective compared to a diet and lifestyle intervention has yet to be explored. OBJECTIVE: To quantify the incremental cost-effectiveness of Qsymia (phentermine and topiramate extended-release) for health-related quality of life improvements. STUDY DESIGN AND METHODS: Estimates are based on cost and quality of life outcomes from a 56-week, multicenter, placebo-controlled, phase 3 clinical trial undertaken in 93 health centers in the US. Participants were overweight and obese adults (aged 18-70 years) with a body-mass index of 27-45 kg/m(2) and two or more comorbidities (hypertension, dyslipidemia, diabetes or pre-diabetes or abdominal obesity). The intervention was diet and lifestyle advice plus the recommended dose of Qsymia (phentermine 7.5 mg plus topiramate 46.0 mg) vs. control, which included diet and lifestyle advice plus placebo. The study was from the payer perspective. Costs included the prescription cost, medication cost offsets and physician appointment costs. Effectiveness was measured in terms of quality-adjusted life years gained (QALYs). The main outcome measure was incremental cost per QALY gained of the intervention relative to control. RESULTS: Our base-case model, in which participants take Qsymia for 1 year with benefits linearly decaying over the subsequent 2 years, generates an incremental cost-effectiveness ratio (ICER) of $48,340 per QALY gained. Using the base-case assumptions, probabilistic sensitivity analyses reveal that the ICER is below $50,000 per QALY in 54 % of simulations. However, results are highly dependent on the extent to which benefits are maintained post medication cessation. If benefits persist for only 1 year post cessation, the ICER increases to $74,480. CONCLUSION: Although base-case results suggest that Qsymia is cost-effective, this result hinges on the time on Qsymia and the extent to which benefits are maintained post medication cessation. This should be an area of future research.

The Paediatric migraine disability assessment score is a useful tool for evaluating prophylactic migraine treatment.

AIM: There is a need for an objective assessment scoring system to evaluate the effectiveness of prophylactic drugs in paediatric migraine, and the aim of this study was to evaluate the Paediatric Migraine Disability Assessment Score (PedMIDAS). METHODS: We recruited 88 children aged between 6 and 17 years of age with migraine. The 53 children in the treatment group were divided into three groups according to the prophylactic drug they received topiramate, flunarizine and propranolol and assessed using PedMIDAS before the start of treatment and 3 and 6 months after treatment. The 35 patients in the control group did not receive prophylactic treatment and were assessed with PedMIDAS on three occasions, 3 months apart. RESULTS: Topiramate, propranolol and flunarizine treatments significantly decreased PedMIDASs and were shown to be effective in improving the patients' quality of life. Topiramate and propranolol were more effective than flunarizine. The number of days on analgesic treatment significantly decreased in the patients who had received topiramate and propranolol treatments (p < 0.05), but remained unchanged in the flunarizine prophylaxis group (p > 0.05). CONCLUSION: The PedMIDAS scoring system is useful in evaluating the efficacy of prophylactic therapy in paediatric migraine. Topiramate and propranolol lowered the PedMIDASs better than flunarizine.

Antiepileptic drug utilization in Bangladesh: experience from Dhaka Medical College Hospital.

BACKGROUND: Epilepsy is a common health problem which carries a huge medical social psychological and economic impact for a developing country. The aim of this hospital-based study was to get an insight into the effectiveness and tolerability of low cost antiepileptic drugs (AEDs) in Bangladeshi people with epilepsy. METHODS: This retrospective chart review was done from hospital records in weekly Epilepsy outdoor clinic of Department of Neurology, Dhaka Medical College Hospital (DMCH) from October 1998 to February 2013. A total of 854 epilepsy patients met the eligibility criteria (had a complete record of two years of follow up data) from hospital database. A checklist was used to take demographics (age and gender), epilepsy treatment and adverse event related data. At least two years of follow up data were considered for analysis. RESULTS: Out of 854 patients selected, majority of the patients attending outdoor clinic were >11-30 years age group (55.2%) with a mean age of 20.3 ± 9 years and with a male (53%) predominance. Focal epilepsy were more common (53%), among whom secondary generalized epilepsy was the most frequent diagnosis (67%) followed by complex partial seizure (21%). Among those with Idiopathic Generalized Epilepsy (46%), generalized tonic clonic seizure was encountered in 74% and absence seizure was observed in 13%. The number of patients on monotherapy and dual AED therapy were 67% and 24% respectively and polytherapy (i.e. >3 AEDs) was used only in 9%. CBZ (67%) was the most frequently prescribed AED, followed by VPA (43%), PHB (17%), and PHT (8%). CBZ was prescribed in 37% patients as monotherapy followed by VPA in 21% and PHB in 8% patients. Newer generation drugs eg lemotrigine and topiramate were used only as add on therapy in combination with CBZ and VPA in only 2% patients. The treatment retention rates over the follow up period for the AEDs in monotherapy varied between 86 and 91% and were highest for CBZ, followed by VPA. Most of the combination regimens had a treatment retention rate of 100%. The effectiveness of AED in terms of reduction of seizure frequency was highest for PHT (100%) and PHB (98%) followed by CBZ (96%) and VPA (95%). PHB and PHT were the cheapest of all AEDs (42 I$ and 56 I$/ year respectively). The costs of VPA and CBZ were two times and LTG and TOP were six to eight times higher. Adverse drug reaction (ADR) were observed among 140 (24.5%) of those with monotherapy. PHT (64%) was the most common drug to cause ADR, CBZ was at the bottom of the list to cause adverse effect (11.6%). VPA and PHB caused weight gain commonly. Adjustment of drug dose or withdrawal due to ADRs was necessary in 39% with PHT and 26% with PHB. CONCLUSION: Though PHT and PHB are cheapest and efficacious among all, CBZ and VPA are less costly, effective and well tolerated drug for seizure control in context of Bangladesh.

Obesity drug therapy.

Obesity is a chronic disease, and it requires chronic therapy. Hypertension, dyslipidemia, diabetes and cardiovascular diseases are leading causes of mortality in the modern world. All of them are strongly linked to obesity. While treating obesity, those conditions are also managed. Obese patients should always be treated through lifestyle interventions, though the results of such interventions are modest. Pharmacotherapy is a second step in the treatment of obesity, approved only when weight loss targets were not reached through lifestyle intervention. During the history of antiobesity drugs, many of them were withdrawn because of their side effects. Various guidelines recommend prescribing drug therapy for obesity through consideration of the potential benefits and limitations. Orlistat deactivates intestinal lipase and inhibits intestinal fat lipolysis. It is actually the only drug on the European market approved for the treatment of obesity. Orlistat therapy reduces weight to a modest extent, but it reduces the incidence of diabetes beyond the result achieved with lifestyle changes. Recently, some effective antiobesity drugs like sibutramine and rimonabant have been removed from the market due to their side effects. The new combination of topimarate and fentermine is approved in the US but not in Europe. The cost effectiveness of long-term pharmacotherapy of obesity is still an unresolved question.

Long-term assessment of topiramate for epilepsy: an open-label, single-arm, multicentre, prospective study in a naturalistic setting.

BACKGROUND AND OBJECTIVE: Most patients with epilepsy require long-term medical therapy. Newer antiepileptic drugs (AEDs) appear to be overall similarly effective to older agents but may be better tolerated. However, most of the clinical data available for newer AEDs derive from a number of short-term studies. The objective of this study was to explore long-term outcomes in patients with epilepsy treated with topiramate in routine clinical practice. METHODS: This was an open-label, multicentre, optional follow-up monotherapy study that included adolescents and adults with epilepsy who completed two similarly designed 28- or 30-week studies and agreed to participate for an additional 52 weeks. Seizure types and frequency, topiramate dose, vital signs and treatment-emergent adverse events (TEAEs) after 12, 26, 39 and 52 weeks were documented. Post hoc analyses to explore differences between males and females were conducted. RESULTS: 114 patients (49.0% women, mean ± SD age 43 ± 17.5 years) with a mean ± SD disease duration of 61 ± 118 months (men 54 ± 96 vs women 68 ± 138 months) were followed up for a median of 18.5 months. Seventy-eight percent of patients completed the study. Reasons for premature discontinuation were: loss to follow-up (10.5%), TEAE (5.3%), lack of efficacy (2.6%), non-adherence (0.9%) and other reasons (4.4%). Seizure frequency per 4 weeks decreased from a mean ± SD 5.0 ± 28.3 at baseline to 0.6 ± 2.1 during the whole observation period. Fifty-four patients (52.9%) were seizure free during the whole observation period. In addition, 69 of 95 patients (72.6%) whose topiramate therapy was stable within a range of ±50 mg/day for a period of at least 12 months (maintenance phase) were seizure free while treated with a median topiramate dose of 100 mg/day. The most frequently reported TEAEs were paraesthesias (13.2% of patients), dizziness (7.0%) and seizure-related events (7.0%). No significant differences between males and females were found for treatment response or retention. CONCLUSION: Topiramate is an effective and well tolerated long-term treatment option for adolescents and adults with epilepsy.

Clinical comparability of the new antiepileptic drugs in refractory partial epilepsy: a systematic review and meta-analysis.

PURPOSE: Evaluate the clinical comparability of new antiepileptic drugs (AEDs) in partial refractory epilepsy. METHODS: Systematic review of randomized trials (RCTs) comparing a new AED (add-on treatment) with placebo or another AED. PRIMARY OUTCOMES: responder (≥50% seizure reduction) and withdrawal (tolerability) rates. Pooled estimates of odds ratios (ORs) and number needed treat/harm (NNT/NNH) taking into account baseline risk were derived by random-effects meta-analysis. Adjusted frequentist indirect comparisons between AEDs were estimated. KEY FINDINGS: Sixty-two placebo-controlled (12,902 patients) and eight head-to-head RCTs (1,370 patients) were included. Pooled ORs for responder and withdrawal rates (vs. placebo) were 3.00 [95% confidence interval (CI) 2.63-3.41] and 1.48 (1.30-1.68), respectively. Indirect comparisons of responder rate based on relative measurements of treatment effect (ORs) favored topiramate (1.52; 1.06-2.20) in comparison to all other AEDs, whereas gabapentin (0.67; 0.46-0.97) and lacosamide (0.66; 0.48-0.92) were less efficacious, without significant heterogeneity. When analyses were based on absolute estimates (NNTs), topiramate and levetiracetam were more efficacious, whereas gabapentin and tiagabine were less efficacious. Withdrawal rate was higher with oxcarbazepine (OR 1.60; 1.12-2.29) and topiramate (OR 1.68; 1.07-2.63), and lower with gabapentin (OR 0.65; 0.42-1.00) and levetiracetam (OR 0.62; 0.43-0.89). SIGNIFICANCE: The differences found are of relatively small magnitude to allow a definitive conclusion about which new AED(s) has superior effectiveness. This uncertainty probably reflects the limitations of conclusions based on indirect evidence. The process of pharmacologic clinical decision making in partial refractory epilepsy probably depends more on other aspects, such as individual patient characteristics and pharmacoeconomics, than on available controlled randomized evidence.

Metabolic acidosis with topiramate and zonisamide: an assessment of its severity and predictors.

OBJECTIVE: Carbonic anhydrase (CA) inhibitors topiramate and zonisamide can induce metabolic acidosis in some patients. Our aims were to assess the prevalence and severity of this acidosis and to determine its predictors. METHODS: For 70 patients established on treatment with topiramate (n=55) or zonisamide (n=14) or both (n=1), we measured electrolytes, and genotyped single nucleotide polymorphisms (SNPs) in the main renal CA isoenzymes (II, IV and XII). RESULTS: Twenty-six percent of patients had a metabolic acidosis (serum bicarbonate <20 mmol/l). The mean serum bicarbonate of patients taking topiramate was significantly lower than those taking zonisamide (P=0.002). We found no association between serum bicarbonate and the dose of drug or the duration of treatment. Serum bicarbonate levels were associated with the CA type XII SNPs rs2306719 (P=0.006 by one-way analysis of variance) and rs4984241 (P=0.015), but this association was not strong enough to survive correction for multiple testing. CONCLUSION: The development of acidosis with topiramate and zonisamide is not determined by drug dose or by treatment duration, but may be influenced by polymorphisms in the gene for CA type XII. The aforementioned SNPs lie 9.8 kb apart in intron 1 of the CA type XII gene, and deserve further study in a larger cohort of patients.

Pharmacokinetic-pharmacodynamic assessment of topiramate dosing regimens for children with epilepsy 2 to <10 years of age.

PURPOSE: To identify and validate the efficacious monotherapy dosing regimen for topiramate in children aged 2 to <10 years with newly diagnosed epilepsy using pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation bridging. METHODS: Several models were developed in pediatric and adult populations to relate steady-state trough plasma concentrations (C(min)) of topiramate to the magnitude of clinical effect in monotherapy and adjunctive settings. These models were integrated to derive and support the monotherapy dosing regimen for pediatric patients. KEY FINDINGS: A two-compartmental population PK model with first-order absorption described the time course of topiramate C(min) as a function of dosing regimen. Disposition of topiramate was related to age, body weight, and use of various concomitant antiepileptic drugs. The PK-PD model for monotherapy indicated that the hazard of time to first seizure decreased with increasing C(min) and time since randomization. Higher baseline seizure frequency increased risk for seizures. Age did not significantly influence hazard of time to first seizure after randomization to monotherapy. For adjunctive therapy, the distribution of drug and placebo responses was not significantly different among age groups. Based on the available PK-PD modeling data, the dosing regimen expected to achieve a 65-75% seizure freedom rate after 1 year for pediatric patients age 2-10 years is approximately 6-9 mg/kg per day. SIGNIFICANCE: This analysis indicated no difference in PK-PD of topiramate between adult and pediatric patients. Effects of indication and body weight on PK were adequately integrated into the model, and monotherapy dosing regimens were identified for children 2-10 years of age.

Boron neutron capture therapy for newly diagnosed glioblastoma multiforme: an assessment of clinical potential.

The purpose of this study was to assess the potential of boron neutron capture therapy (BNCT), with a 6-h infusion of the boron carrier l-boronophenylalanine as a fructose preparation (BPA-f), as first-line radiotherapy for newly diagnosed glioblastoma multiforme (GBM). Patient survival data from a Phase II study using BNCT were compared with retrospective data from the two arms of a Phase III study using conventional radiotherapy (RT) in the reference arm and using RT plus concomitant and adjuvant medication with temozolomide (TMZ) in the experimental arm, and were also compared with small subgroups of these patients for whom the methylation status of the MGMT (O(6)-methylguanine-DNA methyltransferase) DNA repair gene was known. Differences in the baseline characteristics, salvage therapy after recurrence and levels of severe adverse events were also considered. The results indicate that BNCT offers a treatment that is at least as effective as conventional RT alone. For patients with an unmethylated MGMT DNA repair gene, a possible clinical advantage of BNCT over RT/TMZ was suggested. BNCT is a single-day treatment, which is of convenience to patients, with mild side effects, which would offer an initial 6 weeks of good-quality life during the time when patients would otherwise be undergoing daily treatments with RT and TMZ. It is suggested that the use of BNCT with a 6-h infusion of BPA-f should be explored in a stratified randomised Phase II trial in which patients with the unmethylated MGMT DNA repair gene are offered BNCT in the experimental arm and RT plus TMZ in the reference arm.

The cost effectiveness of rufinamide in the treatment of Lennox-Gastaut syndrome in the UK.

Lennox-Gastaut syndrome (LGS) is a catastrophic childhood form of epilepsy. The syndrome is characterized by mental impairment, frequent seizures of multiple types that are particularly resistant to treatment, and high rates of seizure-related injury. With the introduction of newer, but more costly, antiepileptic drugs (AEDs), it is important that decision makers are able to assess their value in the management of this rare and difficult-to-treat condition. To evaluate the cost effectiveness, from the UK NHS perspective, of rufinamide in patients with LGS. An individual patient-simulation model was developed to estimate the total treatment-related costs and clinical benefits of rufinamide compared with topiramate and lamotrigine over a 3-year time horizon. The model examines the treatment scenarios of adding rufinamide, lamotrigine or topiramate to older AEDs (standard therapy), or standard therapy alone within a primary-care or community setting. Three placebo-controlled clinical trials of adjunctive AED treatment for children with LGS were analysed. There are no head-to-head comparator studies. Between 98 and 139 patients were randomized in each study and the mean age in each study was 10, 11 and 14 years. A mixed-treatment comparison using a random-effects model was carried out on the number of patients in each response category, using the placebo arms of the respective trials. The primary outcome measure was the percentage of successfully treated patients, defined as >50% reduction in the frequency of total seizures and drop attacks. The hypothesis being tested was formulated after data collection. Costs ( pound, year 2006/07 values) of patient monitoring, switching treatments, hospitalization due to seizure, treatment of adverse effects, and personal and social services were included in the analysis. Results of 10,000 Monte Carlo simulations were bootstrapped to conduct probabilistic sensitivity analysis. Over 3 years, adjunctive rufinamide resulted in higher total costs than topiramate and lamotrigine; however, with more patients being treated successfully, this leads to acceptable incremental cost-effectiveness ratios. If society is prepared to pay at least 250 pounds for a 1% increase in the number of successfully treated LGS patients, in terms of a 50% reduction in the frequency of drop attacks, the probability of the treatment with rufinamide being cost effective is >80%. This cost-effectiveness analysis suggests that rufinamide results in more LGS patients being treated successfully at a reasonable cost from a UK NHS perspective.

[Off-label use of acetazolamide in a patient with familial hemiplegic migraine and concomitant psychotic episodes]. / Off-label-Behandlung eines Patienten mit rezidivierender familiärer hemiplegischer Migräne und begleitenden vorübergehenden psychotischen Episoden.

A 42-year-old patient with cognitive deficits due to childhood meningitis suffered from recurrent episodes of familial hemiplegic migraine. Additionally, he developed concomitant psychotic episodes requiring subsequent in-patient psychiatric treatment. Following combined neurological and psychiatric treatment he always recovered from the episodes within a few weeks time. Prophylactic treatment of migraine using topiramate and acetazolamide (off-label) prevented attacks for several months. When off-label compensation was refused and, as a consequence, the drug discontinued, hemiplegia relapsed within a few days. Hence, acetazolamide was prescribed again and the family paid for the medication. Since that time, the patient did not show severe attacks for at least 8 months apart from a transient attack induced by acute flu-like illness.

Cost-utility analysis of rufinamide versus topiramate and lamotrigine for the treatment of children with Lennox-Gastaut Syndrome in the United Kingdom.

PURPOSE: To estimate the cost-effectiveness of rufinamide relative to topiramate and lamotrigine as adjunctive treatment for children with Lennox-Gastaut Syndrome (LGS). METHODS: A Markov decision analytic model was developed to estimate the incremental cost-effectiveness ratio over a three-year time horizon in patients with LGS uncontrolled by up to three antiepileptic drugs. Utilities were assigned to health states, defined according to a patient's response to treatment (> or =75%, > or =50% and <75%, and <50% reduction in tonic-atonic [drop attack] seizure frequency and death). Efficacy and safety estimates were made using indirect/mixed-treatment comparisons of data obtained from published literature. Outcomes included costs and quality-adjusted life-years (QALYs), allowing the incremental cost-effectiveness ratio to be estimated as cost per QALY gained. RESULTS: Over three years, the total cumulative costs for rufinamide, topiramate, and lamotrigine were pound24,992, pound23,360, and pound21,783, respectively. Rufinamide resulted in an incremental QALY gain of 0.079 relative to topiramate and 0.021 relative to lamotrigine. The incremental costs of rufinamide were pound1632 and pound3209, relative to topiramate and lamotrigine, resulting in an incremental cost per QALY gained of pound20,538 and pound154,831, respectively. CONCLUSIONS: Considering the underlying assumptions, this current economic evaluation demonstrates that rufinamide is likely to be a cost-effective alternative to topiramate as adjunctive treatment for children with LGS in the UK. In addition, when compared to lamotrigine, which is an inexpensive treatment, rufinamide should be considered as a cost-effective alternative due to the importance of patient choice and equity of access in such a rare and devastating condition.