Meta-analysis and cost-effectiveness of second-line antiepileptic drugs for status epilepticus.

OBJECTIVE: Compare the cost and effectiveness of nonbenzodiazepine antiepileptic drugs (non-BZD AEDs) for treatment of BZD-resistant convulsive status epilepticus (SE). METHODS: Decision analysis model populated with effectiveness data from a systematic review and meta-analysis of the literature, and cost data from publicly available prices. The primary outcome was cost per seizure stopped ($/SS). Sensitivity analyses evaluated the robustness of the results across a wide variation of the input parameters. RESULTS: We included 24 studies with 1,185 SE episodes. The most effective non-BZD AED was phenobarbital (PB) with a probability of SS of 0.8 (95% confidence interval [CI]: 0.69-0.88), followed by valproate (VPA) (0.71 [95% CI: 0.61-0.79]), lacosamide (0.66 [95% CI: 0.51-0.79]), levetiracetam (LEV) (0.62 [95% CI: 0.5-0.73]), and phenytoin/fosphenytoin (PHT) (0.53 [95% CI: 0.39-0.67]). In pairwise comparisons, PB was more effective than PHT (p = 0.002), VPA was more effective than PHT (p = 0.043), and PB was more effective than LEV (p = 0.018). The most cost-effective non-BZD AED was LEV (incremental cost-effectiveness ratio [ICER]: $18.55/SS), followed by VPA (ICER: $94.44/SS), and lastly PB (ICER: $847.22/SS). PHT and lacosamide were not cost-effective compared to the other options. Sensitivity analyses showed marked overlap in cost-effectiveness, but PHT was consistently less cost-effective than LEV, VPA, and PB. CONCLUSION: VPA and PB were more effective than PHT for SE. There is substantial overlap in the cost-effectiveness of non-BZD AEDs for SE, but available evidence does not support the preeminence of PHT, neither in terms of effectiveness nor in terms of cost-effectiveness.

Overview of accessibility and quality of antiepileptic drugs in Madagascar.

PURPOSE: To determine the accessibility of treatment and the quality of antiepileptic drugs (AEDs) in the Haute Matsiatra district of Madagascar. METHODS: Cross-sectional descriptive study and interviews. Samples of 10 units of each available AED were collected, and the active ingredient was quantified by reversed-phase high-performance liquid chromatography (RP-HPLC) with photodiode-array UV detection. The quality of an AED was considered satisfactory if the quantity of active ingredient in each tablet was in the range ±15% of the average value according to the European Pharmacopeia (6th edition, 2008). RESULTS: The area was well served with health infrastructure but rescue facilities were poorly distributed. Available AEDs were all first-generation, and 73% were generic formulations. People with epilepsy (PWE) surveyed consulted traditional healers and most were treated with plants. PWE did not consider themselves sick but believed they were "possessed"; they consulted a doctor only immediately after a seizure, following the advice of traditional healers. The most prescribed AED was phenobarbital, costing between 0.03 and 0.12 US Dollar (US$) per 100mg. The purchase of full treatment was difficult for 77% of PWE and as a result, 39% took nothing. The quality of AEDs were considered unsatisfactory in 2.8% of cases. CONCLUSION: The AEDs collected in Haute Matsiatra were globally of good quality. The main limiting elements were a lack of knowledge among PWE that epilepsy is a disease, and the cost of traditional treatments.

Drugs, money, and power: the Canadian drug shortage.

This article describes the shortage of generic injectable medications in Canada that affected hospitals in 2012. It traces the events leading up to the drug shortage, the causes of the shortage, and the responses by health administrators, pharmacists, and ethicists. The article argues that generic drug shortages are an ethical problem because health care organizations and governments have an obligation to avoid exposing patients to resource scarcity. The article also discusses some options governments could pursue in order to secure the drug supply and thereby fulfill their ethical obligations.

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.

Treatment gap for people living with epilepsy in Madagascar.

Using an indirect assessment technique we assessed the epilepsy treatment gap (ETG) in Madagascar. We estimate the ETG in Madagascar to be 92%. However, given the sociological, economic and sanitary conditions of the country, it is likely that the true ETG is even higher than our estimate. Our study also documents the lack of access to treatment for patients in this developing country. The indirect method could be used to assess the treatment gaps of other chronic medical conditions.

Availability and costs of antiepileptic drugs and quality of phenobarbital in Vientiane municipality, Lao PDR.

PURPOSE: In developing countries, availability and quality of drugs are critical factors for effective management and control of epilepsy. This study investigated the availability and costs of antiepileptic drugs (AEDs), and the quality of phenobarbital in Vientiane Municipality, Lao PDR. METHODS: In March 2004, we enrolled all pharmacies (categories I and II) of four central districts of Vientiane eligible to sell AEDs. Two hundred and eight pharmacies of category III (75.1% of all registered pharmacies) were excluded as the sale of AEDs was not authorized. All pharmacists were interviewed with a standard questionnaire. Whenever phenobarbital was available, a sample was purchased and assayed by liquid chromatography. Phenobarbital was defined as being of correct quality if the active substance average content corresponded to +/-15% of the indicated amount. RESULTS: 66 pharmacies were enrolled (13 and 45 of categories I and II, respectively, and 8 hospital pharmacies). Six generics of AEDs were found (phenobarbital, phenytoin, valproic acid, clonazepam, carbamazepine, diazepam) and all pharmacies sold at least 1 AED. The 2 most widely available drugs were diazepam (5 mg) and phenobarbital (100 mg), present in 87.9 and 53.0% of the pharmacies, respectively. All 34 phenobarbital samples examined showed a correct concentration of the active compound. However, the concentration of phenobarbital 100 mg tablets produced in Lao PDR (mean concentration 94.7 mg) was significantly lower (p = 0.005) than the imported equivalent (mean concentration 99.7 mg). The direct drug costs of a yearly treatment with phenobarbital were estimated to be at least 25.2 USD. CONCLUSIONS: A variety of AEDs are present. Their availability, particularly of phenobarbital, is restricted to higher-category pharmacies and within those it is rather limited. To meet the costs of AEDs in this setting is a major challenge for people with epilepsy. However, the quality of the available phenobarbital was rather satisfactory.

Phenobarbital for the treatment of epilepsy in the 21st century: a critical review.

SUMMARY: Phenobarbital (PB) is the most widely used antiepileptic drug (AED) in the developing world and remains a popular choice in many industrialized countries. Meta-analyses of randomized controlled trials suggest that few differences in efficacy exist between PB and other established AEDs, but its possible deleterious cognitive and behavioral side effects remain a concern in the developed world. In contrast, high degrees of efficacy and tolerability in everyday clinical use have been demonstrated consistently in observational studies in developing countries. We propose that a pragmatic, comprehensive outcomes program be carried out, perhaps under the aegis of the Global Campaign Against Epilepsy, to optimize the conditions of the use of PB, so that more people around the world can benefit from this cost-effective medication and live more fulfilling lives.

Cost of epilepsy in patients attending a secondary-level hospital in India.

The study objective was out to provide an estimate of cost of epilepsy in a secondary level hospital in northern India where a once a week epilepsy clinic is run. Cost data were based on existing information on costs of the hospital and market rates for drugs and investigations. Other necessary information was extracted from patient records for the year 2001. Both direct (consultation fees, cost of investigation, drugs and facility costs) and indirect (traveling and loss of productivity) were estimated. A 25% loss of productivity was assumed based on interviews with the epilepsy patients attending the clinic. There were a total of 184 patients attending the epilepsy clinic during the year 2001. The annual drug cost of epilepsy treatment using phenobarbitone was 11 US dollars. The cost of drugs was in the ratio 1:2:3:4 for phenobarbitone, phenytoin, carbamazepine and sodium valproate. The average annual cost of outpatient treatment of epilepsy was found to be 47 US dollars per patient. The annual cost incurred in emergency and inpatient management was estimated at 810.50 US dollars and 168.30 US dollars for all the patients attending the secondary hospital during the year 2001. The total annual treatment cost for patients attending the hospital was 11,470 US dollars. The annual productivity loss for the same patients was estimated at 20,475 US dollars. Applying these to the estimated 5 million epilepsy patients in India, it comes to about 0.2% of the GNP of the country. As disease cost is much lower than productivity loss, epilepsy treatment is a worthwhile investment for the society. Treating epilepsy patients at primary level using phenobarbitone will increase the treatment coverage and reduce treatment costs. Simultaneous efforts must be made to bring the epilepsy patients on mainstream so as to reduce the productivity loss.

Clinical pharmacology of topiramate versus lamotrigine versus phenobarbital: comparison of efficacy and side effects using odds ratios.

Clinical pharmacologists, neurologists, internists, and all health care givers must consider the efficacy, safety, and side effect profile of a given antiepileptic drug (AED) when determining which drug is best for a given patient. The first purpose of this paper is to address whether the "new" AEDs have advantages over the "old" drugs. The second purpose is to teach those interested in clinical pharmacology about the use of Web-based information access to answer a neurology/clinical pharmacology problem: to compare the efficacy and side effects of topiramate versus lamotrigine versus phenobarbital using odds ratios. Cost of all three AEDs was also compared. A number of new AEDs, including topiramate and lamotrigine, have been developed for chronic focal and secondarily generalized epileptic seizures. Efficacy of these drugs as anticonvulsants does not seem to be superior to that of traditional anticonvulsants such as phenobarbital. However, the advantage of the new drugs is a different spectrum of possible adverse events. Newer AEDs may or may not induce sedation and may minimize noncompliance by reducing side effects of lethargy and cognitive impairment. The difficulty in achieving therapeutic dosage because of side effects makes one consider whether these agents are "better" than the oldest and most side effect-prone AED, phenobarbital. The new AEDs have less frequent interactions, leading to improved tolerability with comedication. This exercise compares two "new" AEDs, topiramate and lamotrigine, with phenobarbital by evaluating efficacies and side effects using relative odds ratios, a method commonly used in drug development research. Development of new algorithms and/or new knowledge will bring beneficial tools to all clinical pharmacologists.

Treatment with phenobarbital and monitoring of epileptic patients in rural Mali.

OBJECTIVE: To assess the efficacy of phenobarbital treatment for epileptic patients in rural Mali. METHODS: Epileptic patients were treated at home with phenobarbital at daily dosages ranging from 50 mg for children to 200 mg for adults and their condition was monitored. Advice was given to patients, their families, and the village authorities in order to achieve compliance. An uninterrupted supply of generic phenobarbital was provided and a rural physician made two follow-up visits to each village to ensure that the drug was taken in the correct doses. The physician gave information to the population, distributed the phenobarbital in sufficient quantities to cover the periods between visits, and monitored the patients' responses to treatment. During the first year the physician visited the patients every two months. The frequency of visits was subsequently reduced to once every four months. FINDINGS: In the six months preceding treatment the average rate of seizures among patients exceeded four per month. After a year of treatment, 80.2% of the patients experienced no seizures for at least five months. A total of 15.7% of patients experienced a reduction in seizures. In many cases no further seizures occurred and there were improvements in physical health, mental health and social status. There were very few side-effects and no cases of poisoning were reported. The cost of treatment per patient per year was 7 US dollars for generic phenobarbital and 8.4 US dollars for logistics. CONCLUSION: Low doses of phenobarbital were very effective against epilepsy. However, there is an urgent need for programmes involving increased numbers of physicians in rural areas and, at the national level, for the inclusion of epilepsy treatment in the activities of health care facilities. Internationally, an epilepsy control programme providing free treatment should be developed.

Treatment of febrile seizures: the influence of treatment efficacy and side-effect profile on value to parents.

OBJECTIVES: We examined parents' perception of the value of treatments designed to reduce the risk of febrile seizure recurrence. STUDY DESIGN: The families of 42 children with febrile seizures were recruited after pediatric or neuropediatric consultation. A mail questionnaire addressed the family's willingness to pay for a hypothetical treatment for febrile seizures with risk reductions for future febrile seizures of 25%, 50%, 75%, and 100%. The hypothetical clinical scenario was then modified to include the side- effect profiles of either daily phenobarbital or valproic acid, or intermittent diazepam prophylaxis. Covariates included the nature of the child's febrile seizure(s), parents' familiarity with febrile seizures, experiences at the time of febrile seizures or with medication side effects, education and income, and mastery and trait anxiety. RESULTS: Thirty-eight parents, representing 22 of 42 families, completed questionnaires. There was a dramatic inflection in parents' willingness to pay for 100% risk reduction as opposed to 75% or lower risk reductions. Introduction of side effects dramatically reduced the value attached to each level of treatment benefit. Nevertheless, a few parents (3/38) would pay "as much as it takes" to be rid of their child's recurrence risk. CONCLUSIONS: Given the range of value assigned to prophylactic medication for febrile seizures, management strategies for children with febrile seizures must be responsive to the needs and values of individual families.

Antiepileptic therapies in the Mifi Province in Cameroon.

PURPOSE: To evaluate the availability and accessibility of antiepileptic drugs (AEDs) in two health districts in Cameroon. METHODS: The study included 33 patients with epilepsy, 26 physicians, 13 private pharmacists, eight hospital pharmacists, three distributors, and eight traditional healers. Structured questionnaires were used to assess the knowledge of the disease, treatment accessibility, the methods of prescriptions, and the availability and the frequency of delivery of drugs. RESULTS: Only one of 33 patients did not take modern treatment; 91% of the patients were followed up by a traditional healer, and 78%, by an hospital physician. Phenobarbitone (PB) was the most frequently prescribed drug by 69% of the doctors; 54% of the physicians considered the traditional therapies to be incompatible with modern drug treatment. By pharmacists, PB was delivered regularly. Other drugs went out of stock frequently. The number of packages in stock varied significantly directly with the frequency of delivery. The mean price per package and the mean number of packages in stock were higher in the public hospital pharmacies than in the private pharmacies. A majority of healers explained epilepsy as the presence of excess foam in the abdomen. The remedies proposed were to stop foam secretion. CONCLUSIONS: Availability of AEDs was quite high, but with no strict correspondence between the rate of prescriptions and the supply of the drugs.

Appropriateness of antiepileptic drug level monitoring.

OBJECTIVES: To develop explicit, reliable appropriateness criteria for antiepileptic drug level monitoring and to assess the appropriateness of monitoring in one tertiary care institution. DESIGN: Appropriateness criteria derived from the literature and through expert opinion were used to evaluate a stratified random sample of antiepileptic drug level determinations obtained from chart review. SETTING: Tertiary care center performing more than 10,000 antiepileptic drug level determinations per year. PATIENTS: A total of 330 inpatients in whom antiepileptic drug levels were measured a total of 855 times. METHODS: Drug levels were assessed at least 200 times for each of four antiepileptic drugs (phenytoin, carbamazepine, phenobarbital, and valproic acid). MAIN OUTCOME MEASURES: The proportion of antiepileptic drug levels with an appropriate indication and, of those, the proportion sampled appropriately. RESULTS: Overall, 27% (95% confidence interval, 24% to 30%) of levels had an appropriate indication. Interrater agreement for appropriateness was substantial (kappa = 0.61). There was no significant difference in the appropriateness rate among the four drugs (range, 25% to 29%). Of the 624 antiepileptic drug level determinations considered inappropriate (73%), only four (0.6%) were more than 20% higher than the upper limit of normal, and none of the four patients had clinical signs of drug toxicity. A median of six levels (range, one through 69) was determined per patient, and the median interval between level determinations was 24 hours. Of the 27% of level determinations with an appropriate indication, 51% were sampled correctly, resulting in an overall appropriateness rate of 14%. CONCLUSIONS: Only 27% of antiepileptic drug level determinations had an appropriate indication, and half of these were not sampled correctly. Routine daily monitoring without pharmacological justification accounted for most of the inappropriate drug level determinations. Efforts to decrease inappropriate monitoring may result in substantial cost reductions without missing important clinical results.