1
Datas
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Original Paper
Phenobarbital: effect of interchangeability on the
profile of adverse effect, on quality of life and on
plasma concentrations - a pilot study
Abstract
Introduction: Phenobarbital is one of the drugs most used in the treatment of epilepsy, with different formulations available on the market today. Objectives: The objective of this study was to evaluate the effect of interchangeability on the profile of the adverse effect, on quality of life and on plasma concentrations before and after the exchange of phenobarbital formulations in patients with epilepsy. Methods: This is a before and after study, in which adult patients with a diagnosis of epilepsy were included in outpatient treatment with phenobarbital. The Adverse Events Profile (AEP) and Quality of Life in Epilepsy-31 (QOLIE) questionnaires were applied before and after the brand change in phenobarbital, as well as the determination of the plasma concentration of phenobarbital. In the first meeting, the “Interchangeable Pharmaceutical Product in the Treatment of Epilepsy” questionnaire was also applied. Physical-chemical tests to evaluate the quality of the tablets were performed according to the parameters of the Brazilian pharmacopoeia. Results: The population was composed of eight patients; six were females, with a mean age of 51.4 (SD=5.4) years old and four did not have a full first degree. Of the interviewees, six had no knowledge of the three types of existing antiepileptic formulations. Significant differences were found for the “Emotional wellbeing” domain of quality of life before and after the formulation change (p=0.016) and no significant difference between frequencies of adverse effects and plasma concentrations. Conclusion: The results suggest the importance of pharmacovigilance, in addition to being able to subsidize new clinical studies regarding the interchangeability between antiepileptics. In addition, the physical-chemical tests point to the need to strengthen health surveillance actions.
Keywords: epilepsy, anticonvulsant, phenobarbital.
Fenobarbital: efeito da intercambialidade sobre
o perfil de efeito adverso, qualidade de vida e
concentrações plasmáticas - um estudo piloto
Resumo
Introdução: O fenobarbital é um dos fármacos mais utilizados no tratamento da epilepsia, com diferentes formulações disponíveis atualmente no mercado. Objetivos: O objetivo deste estudo foi avaliar o efeito da intercambialidade sobre o perfil de efeito adverso, qualidade de vida e concentrações plasmáticas antes e após a troca de formulações de fenobarbital em pacientes com epilepsia. Métodos: Trata-se de um estudo do tipo antes e depois, em que foram incluídos pacientes adultos, com diagnóstico de epilepsia, em tratamento ambulatorial com fenobarbital. Os questionários Adverse Events Profile Questionnaire (AEP) e Quality of Life in Epilepsy-31 (Qolie) foram aplicados antes e após a troca de marca de fenobarbital, bem como a determinação
da concentração plasmática do mesmo. No primeiro encontro aplicou-se também o questionário “Produto Farmacêutico Intercambiável no Tratamento das Epilepsias”. Testes físico-químicos para avaliar a qualidade dos comprimidos foram realizados de acordo com os parâmetros da farmacopeia brasileira. Resultados: A população foi composta por oito pacientes, seis eram do sexo feminino, com idade média de 51,4 (DP=5,4) anos e quatro não possuíam o primeiro grau completo. Dos entrevistados, seis não possuíam conhecimento dos três tipos de formulações de antiepilépticos existentes. Foram encontradas diferenças significativas para o domínio “Bem-estar emocional” de qualidade de vida antes e após a troca de formulação (p=0,016) e nenhum resultado significativo entre as frequências de efeitos adversos e concentrações plasmáticas. Conclusão: Os resultados encontrados sugerem a importância da farmacovigilância, além de poderem subsidiar novos estudos clínicos a respeito da intercambialidade entre antiepilépticos. Ademais, os testes físico-químicos apontam para a necessidade de fortalecer as ações de vigilância sanitária.
Palavras-chave: epilepsia, anticonvulsivantes, fenobarbital.
Corresponding Author:
Virgínia Paula Frade
virginiafrade20@yahoo.com.br
1 Universidade Federal de
São João del Rei
2 Universidade Federal
de Minas Gerais
3 Universidade Federal de Alfenas
4 Centro Universitário Barão de Mauá
Ribeirão Preto/SP
Virgínia PAULA FRADE
1Maria José NUNES PAIVA
2Isarita SAKAKIBARA
3Whocely VICTOR DE CASTRO
1Vinícius SILVA BELO
1Priscila de FREITAS LIMA
4André OLIVEIRA BALDON
1Cristina SANCHES
1Submitted: 27/03/18
Resubmitted:10/08/18
Accepted: 30/03/19
Blind reviewers
DOI: 10.30968 rbfhss.2019.101.0410
ISSN online: 2316-7750
Introduction
The diagnosis and treatment of epilepsy have a major impact on the lives of the patients and their families. The main objective of the treatment of the disease is the absence of seizures with minimal toxic effects.1,2 In the clinical practice, the interchangeability among different commercially available antiepileptic formulations is of concern to users, health care professionals and researchers.3,4
In Brazil, the bio-equivalence legislation allows interchangeability between generic and similar formulations with their respective branded counterparts.5 In 2014, the interchangeability between a reference medication and a similar one was well defined by RDC 58/2014.6
However, there is evidence that small differences in bio-availability among products, even those within the narrow allowable range that determine bio-equivalence, can lead to adverse clinical outcomes when switching drug brands, especially those with narrow therapeutic ranges, such as phenobarbital.7 In addition to the narrow therapeutic range, features such as poor water solubility and nonlinear kinetics also hinder interchangeability.8,9 Based on this, the Brazilian Epilepsy Association (Associação Brasileira de Epilepsia, ABE) proposed
that antiepileptics should be considered a special group in relation to Generic and Similar Medications Public Policies, despite the low financial impact generated by such formulations.10,11
However, clinical differences between reference, generic and similar drugs have not been consistently confirmed by clinical trial data.10,12 There are few controlled studies on adverse effects or clinical decompensation at the time of substitution and the evidence is based mainly on the opinion of specialists.7 Thus, the aim of the present study was to evaluate the effect of interchangeability on the profile of the adverse effect, on quality of life and on plasma concentrations before and after the exchange of phenobarbital formulations in epilepsy patients.
Method
Designing
This is a before and after study, in which there were two meetings, one before and one after the phenobarbital trademark/laboratory change.
Context
This study was conducted at the Psychosocial Care Center (Centro
de Atenção Psicossocial, CAPS) of the city of Divinópolis, state of Minas Gerais,
Brazil, which has about 18,000 registered patients, users attended by the Unified Health System.
For convenience, the patients were recruited for a period of four months. The time interval between the first and second study visits ranged from six to 12 months, which is the minimum time required for a possible change of formulations to take place, based on the municipality’s procurement system.
Recruitment of the participants
All the patients with scheduled medical appointments at the CAPS were considered eligible. The survey included those who met the following criteria: 1) 18 years of age or older 2) using phenobarbital for epilepsy treatment for at least five weeks, provided by the Unified Health System (Sistema Único de Saúde, SUS).
The exclusion criteria were the following: 1) pregnant and lactating women. First, the patients with epilepsy using phenobarbital were identified through medical records. Through a medical appointment schedule available at the health unit, it was verified which would have appointments scheduled during the recruitment period. The potential participants were then invited to participate in the study by telephone seven days before their next medical appointment, which would also consist of the first meeting with the researcher.
The participants were instructed on the need for blood collection and on the application of four research instruments, and were instructed to carry the box or carton of the drug on the day of the meeting, so that information about the manufacturer, lot and validity of it be registered. At the time of blood collection, the time the participant used to take the medication and the time of his last intake were recorded.
At the second meeting, approximately six months to one year after the first meeting, a new telephone contact was made with the participants for the procedure to be repeated. At this stage, individuals were excluded who: 1) no longer used antiepileptic drugs; 2) did not change brands/laboratory during the research period.
Data collection instruments
The first questionnaire applied was “Interchangeable Pharmaceutical for the Treatment of Epilepsies”, consisting of eleven questions.10 Seven questions assess the participants’ knowledge of the three types of existing antiepileptic formulations: reference, generic and similar. For these, a template was made, which was corrected and scored, ranging from 0 to 100%. Four are related to evidence of clinical changes during previous changes of such formulations, assessed through questions about increased adverse effects and/or crises arising from these changes. This instrument was applied only on the first meeting.
The second questionnaire was Adverse Events Profile (AEP), which quantitatively assesses the adverse effects of the most commonly reported antiepileptics by patients over the past four weeks. It has a total score of 19 to 76 points, where 4 points are awarded when the effect occurs frequently, 3 when it occurs from time to time, 2 when the effect is unusual and 1 when it never occurred. Higher scores indicate a higher frequency of adverse effects.13
The third instrument applied was Quality of Life in Epilepsy-31 (QOLIE31), which assesses the quality of life of the patients with epilepsy based on their perception, also of the last four weeks In it, the participant classifies their quality of life and answers the questions about their disposition, nervousness, concern with crises, decreased social activities, among others. The score ranges from 0 to 100 points, with higher values indicating a better quality of life.14 These two questionnaires were applied at both meetings of the study.
Phenobarbital therapeutic monitoring
Phenobarbital plasma concentrations were determined in the patients before and after the trademark/laboratory change. A serial collection of two blood samples at intervals of 30 to 60 minutes (3 mL each at the dose interval) was performed at both meetings. Plasma separation was performed in a centrifuge at 2000 rpm for 20 minutes and the samples were identified and kept in a freezer at -20°C until the date of analysis. The quantification of the drug in a biological matrix was performed by the technique of high performance liquid chromatography (HPLC) with ultraviolet (UV) detection according to Queiroz et al., 2000,15 with a linear equation of y=36185x +102009, R²=0.9998.
For the minimal plasma concentrations, reference values were used in the range of 15 to 40 µg/mL.16
Estimation of the minimal plasma concentrations
To estimate whether the patient was within or outside the therapeutic range, the minimal plasma concentration was predicted using the following equation:
Cmin=e-[Kel (T
2-T1) - lnC1], where: Kel = elimination constant (calculated two hours after administration); T
2 = time according to the frequency of the dose administered; T
1 = time of the first collection in relation to the dose administered; lnC1 = natural logarithm of the plasma concentration of the first collection.17
Quality assessment of the phenobarbital tablets
The quality was evaluated of the generic phenobarbital lot tablets used by the participants during the second meeting period, distributed by the health system of the municipality, and its commercially available counterpart during the same period. The reference chemical used was from Harmna Finochem Ltd., lot 0809003 and with declared content of 99.62%. All the trials performed followed the parameters of the Brazilian Pharmacopoeia (5th edition), namely: weight determination, friability test, hardness test, unit dose uniformity (through the content uniformity method), dissolution and assay. In the trial, the ultraviolet spectrophotometry method was used.18-19
Statistical analysis
For data recording and analysis, the Statistical Package for Social Sciences (SPSS) version 19 software was used. Their distribution pattern was analyzed by means of normal quantile plots and by the Shappiro’s test. The differences in the values of all the variables quantified before and after the brand change were analyzed using the Wilcoxon test, using a significance level of 5%.
Ethical aspects
The project was approved by the Research Ethics Committee of the Federal University of São João Del-Rei (CAAE: Opinion No 461,538).
Results
Of the 18,000 people enrolled in the CAPS, 116 used phenobarbital and, of all the patients with scheduled medical appointments during the data collection period, 15 agreed to participate in the study, who met the inclusion criteria. The main reason for refusal was that two blood samples had to be taken. Of these, 53.3% (n=8) completed both stages. “There were four follow-up losses, three male and one female. Of these, one patient changed municipality, one refused to participate again and two were not found. Three patients were excluded for not having made a trademark/laboratory change.” The determination of the plasma concentrations was performed in both meetings, in six individuals, who accepted the collection.
The individuals who completed the survey had a mean age of 51.4 years old (SD=5.4), six were female and, as regard schooling, four of the respondents have not completed high school (Table 01).
Regarding the knowledge of the three types of existing antiepileptic formulations (reference, generic and similar), the mean of correct answers was 52.4%, and only 46.7% of the interviewed people answered 50.0% or more of the questions.
Table 1. Sociodemographic data of the patients using phenobarbital (n=8) Variables Frequency (n) Gender Male 2 Female 6 Age (years old) 18-59 7 60 or more 1 Schooling (n=6)
Incomplete elementary school 4
Secondary school completed 2
Of the respondents, six reported receiving the antiepileptic with names other than those prescribed by their doctor and three admitted changing names/ laboratories during the past year. Of these, two reported increased seizures and two increased adverse effects after some change.
Of the respondents, six reported receiving the antiepileptic with names other than those prescribed by their doctor and three admitted changing names/ laboratories during the past year. Of these, two reported increased seizures and two increased adverse effects after some change.
In assessing the frequency of adverse effects, of quality of life and of minimal concentrations before and after the trademark/laboratory change, significant differences were noted only in the “Emotional Wellbeing” domain of Quality of Life (p=0.016) in which the patients had lower scores after the replacement (Table 03). Of the final elements of the study with blood samples in both encounters (n=6), only one was within the therapeutic range (15 to 40 μg/mL) and the others were in subtherapy. Two individuals changed the plasma levels between the meetings, one of which went from therapeutic to subtherapy and one from therapeutics to subtherapy. However, there was no significant difference between the concentrations before (median (AIQ)=7,03 (11,22)) and after the trademark change (median (AIQ)=6.80 (13,12); p=0.688).
In addition, the profile of the adverse effect was observed to improve in three patients and to worsen in four after the exchange (Table 02).
Table 2. Analysis of the profile of the adverse effect of the patients using phenobarbital before and after the trademark/laboratory change (n=8)
Variable First meeting Median (AIQ) Second meeting Median (AIQ) P value*
Body balance difficulty 2.5(3.0) 3.5(2.5) 1.000
Tiredness 3.0(3.0) 2.5(2.8) 1.000
Agitation 4.0(0.8) 3.5(2.5) 0.688
Nervousness and/or aggressiveness 4.0(1.8) 4.0(2.3) 1.000
Willingness to attack 1.0(1.8) 2.0(3.0) 0.250
Headache 3.0(2.8) 2.5(2.8) 0.625
Loss of hair 2.5(3.0) 4.0(3.0) 1.000
Skin problems (pimples and allergy) 1.0(0.0) 1.0(0.0) 1.000
Double or blurred vision 3.0(3.0) 2.5(3.0) 1.000
Stomach irritation 1.0(2.5) 1.0(0.8) 0.625
Concentration difficulty 2.5(3.0) 4.0(2.5) 0.625
Mouth or gum problems 1.0(2.3) 1.0(0.0) 0.500
Shaking hands 1.0(1.5) 2.0(1.8) 0.688 Weight gain 1.5(1.8) 1.0(0.8) 0.625 Dizziness 2.5(2.8) 3.0(2.8) 1.000 Sleepiness 3.0(2.8) 4.0(1.0) 0.375 Depression 3.0(2.5) 4.0(2.8) 0.688 Memory issues 4.0(2.8) 4.0(2.5) 1.000 Disturbed/Interrupted sleep 1.0(2.8) 1.0(3.0) 1.000
Total Adverse Effect 41.5(18.8) 45.5(7.5) 0.727
AIQ = Interquartile range; *Wilcoxon test.
Table 3. Quality of life analysis of the patients on phenobarbital before and after the trademark/laboratory change (n=8)
Variable Median (AIQ)First meeting meeting Second
Median (AIQ) P value*
Concern about the crisis 13.5(85.3) 40.0(53.8) 0.453
Adverse effects 60.8(83.3) 37.5(100.0) 1.000
Social function 49.5(56.3) 40.0(33.8) 0.727
Cognitive function 58.0(62.3) 16.7(73.6) 0.453
Vitality (Energy) 47.5(42.5) 20.0(76.3) 0.453
Emotional well-being 58.0(49.0) 34.0(46.0) 0.016
Overall quality of life 57.5(39.4) 50.0(21.9) 0.727
Total score 48.2(49.6) 33.5(36.0) 0.727
AIQ = Interquartile range; *Wilcoxon test.
Regarding the physicochemical tests, both phenobarbital products analyzed complied with the recommended weight determination technical specifications, and no unit presented a variation of ±7.5%. In the disintegration test, both the generic and the reference drug disintegrated before 30 minutes and, in the friability test, both presented a weight loss below 1.5% (Table 04).
Table 4. Determination of weight, hardness, disintegration and friability of generic and reference phenobarbital tablets according to the Brazilian Pharmacopoeia (5th Edition).
Test Specifications Reference Phenobarbital Generic Phenobarbital
Weight determination (mg) (n = 20) ±7.5% variation limit Agreed (80.00±12.46) Agreed (-2.51 to 3.37)
Hardness (N) (n=10) Informative test 80.00±12.46 58.50±6.0
Disintegration (n=6) All units disintegrate within 30 minutes. Agreed Agreed
In the dosing test, both the generic and the reference drug presented contents within the specified limits. While in the content uniformity test, only the generic phenobarbital presented values within the recommended range. When
Discussion
The present study evaluated the effects of phenobarbital formulations interchangeability in patients with epilepsy and, despite potential problems observed by the patients due to the antiepileptic substitution, no significant differences in the adverse effect profile and the minimal concentration were found before and after treatment exchange.
The possible replacement-related problems include emergence of adverse effects, increased seizure frequency, and bio-equivalence-related problems.3,20 In the present study, it was observed that phenobarbital brand/ laboratory exchange was frequent among participants and that, although reports at the first meeting of increased adverse effects and crises after a replacement, most respondents were unaware about the three types of formulations available (generic, similar and reference) for the treatment of epilepsy. Additionally, significant differences were found before and after the replacement for only one quality of life domain. However, divergent results were found between the generic drug analyzed and reference in the tests that evaluated its quality.
According to the physicochemical tests, the quality of generic phenobarbital was proven by all tests performed. While the reference medication was in disagreement with the content uniformity test. Tamizi et al. (2012)21 found similar results in one of the phenobarbital products they tested, but the evidence that it was not uniform was between tablets from the same batch. Nizard et al. (2016)22 also demonstrated an off-limits sample of the generic drug; however, only the first stage of the test was performed due to the lack of sufficient pills. According to Couto & Tavares (2011),23 the content uniformity analysis is extremely important as it ensures the amount of active ingredient present in the formulation to be administered. A deviation in dosage may lead to a loss of efficacy and/or safety of the medication, especially in those with a narrow therapeutic range, such as anti-epileptic drugs.23 Thus, greater attention is required in the evaluation of the manufactured products, so that the finished product that reaches the user has the desired quality; since divergences even among tablets from the same batch were observed, demonstrating intra-batch non-interchangeability.
When assessing differences in the domains of quality of life before and after the trademark/laboratory change, it was noticed that, before the replacement, the patients showed higher scores in the Emotional Well-being domain. According to Perucca & Tomson (2011),24 improved quality of life occurs with the reduction in the frequency of seizures and in the severity of the adverse effects to which individuals with epilepsy are exposed, which was not observed after the exchange. Girolineto et al. (2012),4 who evaluated this effect in lamotrigine patients, concluded that interchangeability makes it difficult to maintain high scores in the quality of life domains, which is due to the likelihood of increased seizure numbers, adverse effects and changes in plasma concentration.
Although there were no significant differences between the meetings, a large variability in minimal concentrations and changes in plasma levels were noted. Atif et al. (2016)3 point out that monitoring serum concentrations of antiepileptics collected during a substitution provides the opportunity to assess bio-equivalence in routine care and to identify potential patient risk formulations. However, existing studies based on trademark change studies yield conflicting results.25-26 According to Stepanova & Beran (2015),27 replacing
the dissolution test was performed, it was noted that both the generic and the reference drug presented individual unit values greater than 75% in 45 minutes, thus complying with the test (Table 05).
Table 5. Uniformity of content, dosage and dissolution of the generic and reference phenobarbital tablets according to the Brazilian Pharmacopoeia (5th Edition).
Test Specifications Reference Phenobarbital Generic Phenobarbital
Content uniformity (AV) (mg) 10 units: AV not greater than L1
30 units: AV not greater than L1 and active component quantity of any individual unit less than (1 – L2 × 0.01) M or
greater than (1 + L2 × 0.01) M. L1=15 and L2=25
AV=27.0**; (419.0-491.0) Agreed
AV=14.5*; (420.0 -503.0)
Dosing (%) (n=10) 90.0 to 110.0 96.0 94.5
Dissolution (%) Not less than 75.0% of the declared amount dissolves in
45 minutes. (88.6 to 100.9)Agreed (99.9 to 113.2)Agreed
AV=Acceptance Value; L1=15; L2=25; *AV for 10 units tested; **AV for 30 units tested
a branded antiepileptic with a generic one may fluctuate considerably, or even drugs from different suppliers, resulting in an altered availability. On the other hand, the substitution between two generics is not yet recommended due to the unavailability of bio-equivalence data.3 Thus, the importance of further controlled studies based on the antiepileptic substitution, including generic exchanges, is scarce.
The interchangeability between antiepileptic drugs has been widely discussed, especially since it is not possible to prove what is observed in the clinical practice before and after a replacement. Girolineto et al. (2012)4 point out that the safety, efficacy and quality of medications may change, which is relevant in epilepsy, as a small variation may promote increased adverse effects or seizures, due to the narrow therapeutic index of antiepileptics. Thus, it is believed that, regardless of the formulation to be used, interchangeability among antiepileptics may compromise disease control.4,28
The present study has limitations, such as the small sample size, which occurred due to the lack of medications in the health system during the data collection period, besides the fact that the sample was of voluntary response. In addition, tests to evaluate the quality of phenobarbital tablets were performed with only one batch of one of the formulations that were distributed in the city and could not be extended to the others. The fact that patients kept medication supplies at home, often mixing batches, was also a limiting factor. Moreover, there was no control of factors that could influence the greater variation found in the domain “Emotional Well-being” of quality of life. On the other hand, it is important to highlight the potentialities of the work, of which it can be mentioned that few studies investigate plasma concentrations and seizure control after a replacement. In addition, those that confirm bio-equivalence are limited to the standard tests imposed by the regulatory agencies.26
Conclusions
Despite potential problems reported by the patients, the absence of significant differences between the adverse effect profile and the plasma concentration before and after the brand change of phenobarbital points to the need for further clinical studies on antiepileptic interchangeability. In addition, the physicochemical tests point to the need to strengthen health surveillance actions and to a greater care with the finished product that reaches the user.
Financing source
This work was carried out with the support of the Coordination of Improvement of Higher Level Staff - Brazil (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, CAPES) - Financing Code 001.
Contributors:
Conception and design or analysis and interpretation of data: VPF, MJNP, WVC, VSB and CS.
Writing of the article or relevant critical review of intellectual content: VPF, MJNP, IMS, PFL, AOB, CS.
Acknowledgments
The authors thank the Federal University of São João del Rei (Universidade Federal de São João del-Rei, UFSJ), the Psychosocial Care Center (Centro de Atenção Psicossocial, CAPS) of the city of Divinópolis and the Federal University
of Alfenas (Universidade Federal de Alfenas, UNIFAL-MG), in particular to
Dr. Patrícia Penido Maia.
Conflict of interest
The authors declare no conflict of interest.
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