Interchangeability among carbamazepine formulations: the impact over epilepsy patients

Abstract The treatment of epilepsy is complex and a matter of concern is the interchangeability among different formulations available for antiepileptic drugs. To evaluate the effects of interchangeability among carbamazepine formulations on patients with epilepsy. This is a prospective cohort study that included adult outpatients diagnosed with epilepsy and under pharmacological treatment with carbamazepine. Before switching the brand/manufacturer, the "Interchangeable Pharmaceutical Product in the Treatment of Epilepsies" questionnaire was applied. The questionnaires "Adverse Events Profile" and Quality of Life in Epilepsy-31, so as the plasma carbamazepine concentrations, were evaluated before and after the brand/ manufacturer switch. Physical-chemical tests aiming to assess tablets quality were performed in accordance with the Brazilian Pharmacopoeia 5th edition. The study population was composed by 14 patients (mean age: 44.6 years), with 10 of females. From those interviewed, 10 had no knowledge about the three antiepileptic drugs formulations available. The frequency of adverse event "problems with skin" incresead (p=0.023) and "upset stomach" decreased (p=0.041) after the changeover. The adverse events profile was associated with only two quality of life domains: "energy/fatigue" (p=0.048) and "total score" (p=0.018). Divergent results between generic and reference formulations were observed in purity-water test (reference: 1.96%, generic: 4.84%) and dissolution test, in which the generic formulation presented 66.27 to 85.77% of carbamazepine dissolved after the third level. Conclusions: Objective differences before and after the brand/manufacturer switch were not observed, in spite of patients' perceptions. Despite that, more studies in the field are necessary, especially on the interchangeability among generic antiepileptics, in order to better elucidate switching consequences on patients' life.

Estudio comparativo de la calidad biofarmacéutica de Alprazolam 0, 5 mg comercializadas en el mercado peruano / Comparative study of the biopharmaceutical quality of Alprazolam 0. 5 mg commercialized in the Peruvian market

El Alprazolam pertenece a las benzodiazepinas. Sus efectos se atribuyen a que actúa sobre receptores de membrana específicos, lo cual facilita la acción inhibitoria presináptica y postsináptica del ácido γ-aminobutírico (GABA), especialmente en la formación reticular ascendente. Se utiliza para el tratamiento de los estados de ansiedad, crisis de angustia, ataques de pánico y estrés intenso. Este estudio se realizó para analizar los parámetros comparativos de control de calidad in vitro mediante la evaluación de la variación de peso, friabilidad, dureza, tiempo de desintegración, perfil y eficiencia de disolución entre el medicamento innovador (Xanax®) y multifuentes que son comercializados en el mercado peruano. Para realizarlo, se seleccionaron tabletas de Alprazolam 0,5 mg multifuente de diferentes laboratorios comparándolos con el medicamento innovador y se evaluaron las características fisicoquímicas y biofarmacéuticas. Los ensayos farmacopeicos se evaluaron según lo establecido en la USP 42. Los resultados de las pruebas fisicoquímicas indicaron que las muestras analizadas no tenían diferencia significativa y estaban dentro de lo establecido en la farmacopea, así mismo el perfil y eficiencia de disolución permitieron establecer que el comportamiento biofarmacéutico de las mismas era muy similar para ambos tipos de molécula. Se estableció que las tabletas multifuentes de Alprazolam 0,5 mg de esta investigación son bioequivalentes con el innovador, por lo que permite proponer a la comunidad científica la determinación de la equivalencia biofarmacéutica como elemento de apoyo en la toma de decisiones de compra en el servicio farmacéutico

Alprazolam belongs to benzodiazepines. Its effects are attributed to the fact that it acts on specific membrane receptors, which facilitates the presynaptic and postsynaptic inhibitory action of γ-aminobutyric acid (GABA), especially in the ascending reticular formation. It is used to treat anxiety states, panic attacks, and intense stress. This study was carried out to analyze comparative parameters of in vitro quality control by evaluating the variation in weight, friability, hardness, disintegration time, profile and dissolution efficiency between the innovative drug (Xanax®) and multi-sources tablets that are marketed in the Peruvian market. To perform this, Alprazolam 0.5 mg multi-source tablets were selected from different laboratories comparing them with the innovative medicine and the physicochemical and biopharmaceutical characteristics were evaluated. Pharmacopoeial trials were evaluated as established in USP 42. The results of physicochemical tests indicated that analyzed samples did not have a significant difference and were within the established in the pharmacopoeia, as well as the profile and dissolution efficiency allowed to establish that their biopharmaceutical behavior was very similar for both types of molecules. It was established that Alprazolam 0.5 mg multi-source tablets from this research are bioequivalent with innovator, which makes it possible to propose to scientific community determination of biopharmaceutical equivalency as a support element in decision-making process for purchasing services pharmacist

Comparative Study on Regulatory Measures of Biosimilars in China ，the United States ，Japan and Europe / 中国药房

OBJECTIVE：To provi de reference for drug admini stration supervision of biosimilars in China. METHODS ： Referring to the authoritative documents of the official websites of National Medical Products Administration of China ，FDA of the United States ，European Drug A dministration and Japan ’s D rug and M edical Devices Agency ，and comparing their regulatory measures on the definition ，effectiveness，safety and clinical application of biosimilars，the suggestions were put forward for the improvement of regulatory measures of biosimilars in China. RESULTS & CONCLUSIONS ：Although the definitions biosimilars in different countries/regions were different ，they all required that biosimilars should have the same drug quality ，safety and effectiveness as their corresponding reference drugs. The United States ，the European Union and Japan required enterprises to provide studies on the similarity of early pharmacy ，non-clinical studies such as pharmacology and toxicology ，and clinical studies on immunogenicity ，pharmacokinetics and pharmacodynamics of biosimilars and reference drugs. However ，the similarity between biosimilars and reference drugs had not been required in China. All countries/regions supported the extrapolation of indications of biosimilars. Among which the United States and the European Union required manufacturers to provide detailed data ；Japan only mentioned the relevant concepts of indications extrapolation of biosimilars，but did not mention the specific data requirements. The relevant description of the conditions for the extrapolation of biosimilars in China was not clear enough ，and its application in China was still facing great challenges. In terms of drug interchangeability ，although the United States allowed the use of interchangeable biosimilars to replace reference drugs under the conditions permitted by state laws ，no relevant biosimilars had been approved；European countries had different regulations on the interchangeability of biosimilars；but there was no document explicitly mentioned in China and Japan on the interchangeability of biosimilars. It is suggested that the principle of comparison should be further improved and strict requirements should be appropriately enforced in ensuring the effectiveness and safety of biosimilars；in the field of indication extrapolation ，more detailed data requirements should be put forward ，and the possible risks after extrapolation should be evaluated scientifically ；in terms of the interchangeability of biosimilars ，it is suggested to try to implement the principle of conversion of biosimilars ，but it should be used after consultation among doctors ，pharmacists and patients，and drug use safety should be monitored timely. Meanwhile ，a sound traceability system should be established to ensure drug safety of patients.

La farmacia de los medicamentos genéricos / The pharmacy of generic drugs

RESUMEN Los medicamentos genéricos son una alternativa para mejorar el acceso a las medicinas que la población necesita y, además, hacen más sostenibles los programas de salud públicos y privados. Se ha seleccionado información y evidencia científica sobre este tipo de medicamentos de tal manera que los lectores -médicos, financiadores, organismos públicos y privados-puedan conformar su propia opinión y ayudar a tomar las decisiones más efectivas y eficientes. La relación existente entre los precios de estos productos y la protección de la propiedad intelectual a través de las patentes de los medicamentos es un centro de conflictos entre la industria farmacéutica y los sistemas de salud. En los Estados Unidos, la ley Hatch-Waxman ha cumplido una función muy importante al estimular el desarrollo de medicamentos genéricos. En un mismo intento, la Unión Europea (UE) ha desarrollado, a través de la Agencia Europea del Medicamento (EMA), una homogeneización en materia de autorización de medicamentos y exclusividad de los datos.

SUMMARY Generic medicines give the chance to improve access to medicaments that the population needs, and the possibility of making public and private health programs more sustainable. Information and scientific evidence on this type of medicines has been selected in such a way that the readers - doctors, financiers, public and private organizations - can shape their own opinion and help take the most effective and efficient decisions. The relationship between the prices of these products and the protection of intellectual property through patents for medicines is a center of conflicts between the Pharmaceutical Industry and health systems. In the United States, the Hatch-Waxman Act has played a very important role in stimulating the development of generic drugs. By his side, the European Union (EU) has developed, through the European Medicines Agency (EMA), a homogenization in terms of authorization of medicines and exclusivity of data.

El papel de los biosimilares en la enfermedad inflamatoria intestinal: una realidad en nuestro país / The Role of Biosimilars in Inflammatory Bowel Disease: A Reality in our Country

Resumen La enfermedad inflamatoria intestinal (EII) es un término con el que se conocen varias entidades, las 2 más importantes son: la colitis ulcerativa idiopática (CUI) y la enfermedad de Crohn (EC), cuyo origen es multifactorial y se caracterizan por un fenómeno inflamatorio, crónico, recurrente con diferentes grados de severidad del tubo digestivo; pero además con afectación potencial de otros órganos. En la última década ha habido un renovado interés en dichas entidades, debido a una incidencia creciente de estas, pero también debido al desarrollo de medicamentos que por primera vez están cambiando la historia natural de estas enfermedades: son los medicamentos llamados biológicos, que son aquellos producidos o derivados de organismos vivos y representan el sector de mayor crecimiento en la industria farmacéutica mundial. Debido al interés comercial, se han desarrollado y sometido a las autoridades reguladoras productos no originadores; similares, pero no idénticos a los productos de referencia. La Agencia Europea de Medicamentos (EMA) aprobó el primer biosimilar del infliximab para todas las indicaciones en las cuales este estaba aprobado, incluidas: colitis ulcerativa moderada a severa en todas las edades, EC moderada a severa en todas las edades, al igual que EC fistulizante, artritis psoriásica (AP), psoriasis, espondilitis anquilosante (EA) y artritis reumatoide (AR) (1). En esta revisión nos proponemos definir lo que son estos productos al igual que algunos conceptos relacionados (extrapolación, sustitución e intercambiabilidad), además hacer una revisión histórica de su desarrollo, sus indicaciones actuales, las posiciones de las diferentes asociaciones científicas al respecto y, lo más importante, brindar datos de la vida real en cuanto a su efectividad, seguridad y costos en los diferentes países donde se han estado usando.

Abstract The term Inflammatory Bowel Disease (IBD) is used to identify several entities, the two most important of which are Idiopathic Ulcerative Colitis (IUC) and Crohn's Disease (EC). Both are multifactorial in origin, are chronic and recurrent, are characterized by inflammation, have varying degrees of severity, and potentially involve other organs. In the last decade there has been renewed interest in these entities due to growing incidence and to the development of drugs called biologicals. For the first time, these drugs have changed the natural history of these diseases. They are produced or derived from living organisms and represent the fastest growing sector in the global pharmaceutical industry. Due to commercial interest, products similar but not identical to the original products have been developed and submitted to regulatory authorities. The European Medicines Agency has approved the first biosimilar for infliximab for all indications for which it has been approved. These include moderate to severe ulcerative colitis (UC) at all ages, moderate to severe Crohn's disease (CD) at all ages, fistulizing Crohn's disease, Psoriasic arthritis, Psoriasis, Ankylosing Spondylitis, and Rheumatoid Arthritis. 1 In this review, we define what these products are, as well as some concepts coined for their usage including extrapolation, substitution and interchangeability. We also make a historical review of their development, current indications, the positions of various scientific associations with respect to them, and - most importantly - provide real-life data regarding their effectiveness, safety and costs in countries where they have been used.

Biologics and Biosimilars: Differences and Clinical Implications.

Biologics or biopharmaceuticals are drugs derived from living organisms by recombinant technology. Biologics have made a significant contribution to the management of certain chronic diseases such as cancer, rheumatoid, arthritis, ankylosing spondylitis, psoriasis and other immune mediated disorders. Biologics are produced by genetically modifying cells and, are highly complex and expensive to manufacture. Many of them are now facing patent expiry which has paved the way for the development of biosimilars. Biosimilars are biologic medicine that is similar in terms of quality, safety and efficacy but not the same as a registered innovator biologic. The manufacturing of biosimilars has many complexities, such as consistency of manufacturing process, conformation of manufacturing standards and demonstration of product consistency Also, powered clinical trials have to be executed to demonstrate similarity to the innovator biologic. Registration of biosimilars requires a more stringent evaluation than that is required for conventional generics. Biosimilars have the potential to be the molecules of the future as long as they are developed strictly in accordance with comparative procedures mandated by regulatory authorities such as EMA and USFDA. It is believed that the advent of biosimilars will improve patient access to expensive biologics for chronic illnesses. However, it is important that clinicians distinguish between innovator biologics and biosimilars. Physicians should avoid substituting biosimilars for innovators as well as avoid interchangeability as biosimilars are not generics. In addition, pharmacovigilance will be the need of the hour to track down any safety and efficacy problems arising from the use of biosimilars.

Intercambialidade entre medicamentos genéricos e similares de um mesmo medicamento de referência / Interchangeability among generic and similar drug products of a same reference drug product

A implementação de medicamentos genéricos no Brasil e de programas e políticas para garantir o acesso da população a medicamentos com qualidade, segurança e eficácia resultaram em mais de 3.800 medicamentos genéricos de 445 fármacos registrados na Agência Nacional de Vigilância Sanitária (ANVISA) desde 1999. Os medicamentos genéricos comprovaram a sua equivalência terapêutica e, portanto, intercambialidade com seus respectivos medicamentos de referência por meio de estudos de bioequivalência. Em 2014, a ANVISA estendeu a intercambialidade aos medicamentos similares, aumentando o número de medicamentos intercambiáveis para cada medicamento de referência. As normas para prescrição e dispensação permitem apenas a substituição de medicamento de referência por seu medicamento genérico ou similar intercambiável e vice-versa. Entretanto, o que se observa na prática é a substituição entre medicamentos genéricos e similares de um mesmo fármaco, tanto na rede privada onde os descontos chegam até 90% do preço estabelecido para a venda, como na rede pública, em função da disponibilidade dos medicamentos, visto que as compras públicas se baseiam no menor preço ofertado pelos fabricantes. Entretanto, a bioequivalência e a intercambialidade entre os medicamentos genéricos ou similares de um mesmo referência não pode ser garantida pois os mesmos não foram testados entre si. A ausência de bioequivalência entre medicamentos substituídos pode provocar ineficácia terapêutica ou aparecimento de eventos adversos ou até mesmo intoxicação em pacientes. Consequentemente, podem ocorrer desperdício, gastos com tratamento de eventos adversos, abandono do tratamento e adoção de segunda linha de tratamentos. Este trabalho avaliou a bioequivalência entre os medicamentos genéricos e similares de um mesmo medicamento de referência por meio do método de metanálise, empregando dados de estudos de bioequivalência realizados para o registro de medicamentos genéricos e similares na ANVISA. Foram incluídos na análise estudos de aciclovir, amoxicilina, cefalexina, doxazosina, fenitoína, fluoxetina, levofloxacino e quetiapina. Os resultados demonstraram a ausência de bioequivalência entre a maioria dos medicamentos genéricos e similares contendo o mesmo fármaco. os resultados comprovam que medicamentos genéricos e similares de mesmo fármaco não são obrigatoriamente intercambiáveis e a substituição, principalmente para aqueles usados no tratamento de doenças crônicas, podem trazer graves consequências clínicas. Esta preocupação é aumentada para os fármacos com estreita faixa terapêutica e aqueles com alta variabilidade no processo de absorção. A adoção de uma lista de medicamentos não substituíveis, a exemplo de outros países, e o investimento na divulgação de informações sobre intercambialidade de medicamentos, tanto para profissionais de saúde como para a população, podem contribuir para a redução da substituição entre medicamentos não intercambiáveis, a promoção do uso racional dos medicamentos, a redução de gastos com medicamentos e tratamento de eventos adversos e o aumento da adesão do paciente ao tratamento

The implementation of generic drugs in Brazil, as well as programs and policies to ensure access to medicines with quality, safety and efficacy to the overall population, resulted in more than 3,800 generic drug products of 445 drugs registered in the National Health Surveillance Agency (ANVISA) since 1999. Generic drug products proved their therapeutic equivalence in bioequivalence studies and, therefore, the interchangeability with their respective reference drug product. In 2014, ANVISA expanded the interchangeability to similar drug products, increasing the number of interchangeable drug products for each reference drug product. Regulations for the prescription and dispensation of medicine only allow the substitution of a reference drug product for a generic or an interchangeable similar drug product or vice versa. However, in practice, it appears that there is a substitution between generic and similar drug products of a same reference drug product in private pharmacy chains - where discounts reach up to 90% of the selling price - as well as in public pharmacy, depending on the medicine availability, because public purchases are based on the lower price offered by the manufacturers. Nevertheless, the bioequivalence and interchangeability between generic and similar drug products of the same reference drug product cannot be guaranteed because they haven't been evaluated. Lack of bioequivalence between substituted drug products may result in therapeutic ineffectiveness or the occurrence of adverse events and even to patient intoxication. As a consequence, there might be waste, expenses due to adverse events treatment, no adherence to the treatment or the adoption of second-line treatment. This study evaluated the bioequivalence between generic and similar drugs of the same reference drug product through a meta-analysis, using data from bioequivalence studies carried out for the registration of generic and similar drug products at ANVISA. The drugs included in the study were acyclovir, amoxicillin, cephalexin, doxazosin, phenytoin, fluoxetine, levofloxacin and quetiapine. Results showed lack of bioequivalence between most of the generic and similar drugs containing the same drug and prove that generic and similar drug products of the reference drug product are not necessarily interchangeable. Moreover, the substitution of drugs used for chronic illnesses could lead to serious clinical consequences. This concern increases for drugs with narrow therapeutic index and those with high variable absorption process. The adoption of a list of non-interchangeable medicines - like in other countries - and investment in the dissemination of information about interchangeability between drug products to health professionals and to the population may contribute to reduce the substitution of drugs which are not interchangeable, promote a rational use of medicines, the reduction of expenses with drugs and adverse effects treatment and to improve treatment adherence

Intercambialidade entre medicamentos genéricos e similares de um mesmo medicamento de referência / Interchangeability among generic and similar drug products of a same reference drug product

A implementação de medicamentos genéricos no Brasil e de programas e políticas para garantir o acesso da população a medicamentos com qualidade, segurança e eficácia resultaram em mais de 3.800 medicamentos genéricos de 445 fármacos registrados na Agência Nacional de Vigilância Sanitária (ANVISA) desde 1999. Os medicamentos genéricos comprovaram a sua equivalência terapêutica e, portanto, intercambialidade com seus respectivos medicamentos de referência por meio de estudos de bioequivalência. Em 2014, a ANVISA estendeu a intercambialidade aos medicamentos similares, aumentando o número de medicamentos intercambiáveis para cada medicamento de referência. As normas para prescrição e dispensação permitem apenas a substituição de medicamento de referência por seu medicamento genérico ou similar intercambiável e vice-versa. Entretanto, o que se observa na prática é a substituição entre medicamentos genéricos e similares de um mesmo fármaco, tanto na rede privada onde os descontos chegam até 90% do preço estabelecido para a venda, como na rede pública, em função da disponibilidade dos medicamentos, visto que as compras públicas se baseiam no menor preço ofertado pelos fabricantes. Entretanto, a bioequivalência e a intercambialidade entre os medicamentos genéricos ou similares de um mesmo referência não pode ser garantida pois os mesmos não foram testados entre si. A ausência de bioequivalência entre medicamentos substituídos pode provocar ineficácia terapêutica ou aparecimento de eventos adversos ou até mesmo intoxicação em pacientes. Consequentemente, podem ocorrer desperdício, gastos com tratamento de eventos adversos, abandono do tratamento e adoção de segunda linha de tratamentos. Este trabalho avaliou a bioequivalência entre os medicamentos genéricos e similares de um mesmo medicamento de referência por meio do método de metanálise, empregando dados de estudos de bioequivalência realizados para o registro de medicamentos genéricos e similares na ANVISA. Foram incluídos na análise estudos de aciclovir, amoxicilina, cefalexina, doxazosina, fenitoína, fluoxetina, levofloxacino e quetiapina. Os resultados demonstraram a ausência de bioequivalência entre a maioria dos medicamentos genéricos e similares contendo o mesmo fármaco. os resultados comprovam que medicamentos genéricos e similares de mesmo fármaco não são obrigatoriamente intercambiáveis e a substituição, principalmente para aqueles usados no tratamento de doenças crônicas, podem trazer graves consequências clínicas. Esta preocupação é aumentada para os fármacos com estreita faixa terapêutica e aqueles com alta variabilidade no processo de absorção. A adoção de uma lista de medicamentos não substituíveis, a exemplo de outros países, e o investimento na divulgação de informações sobre intercambialidade de medicamentos, tanto para profissionais de saúde como para a população, podem contribuir para a redução da substituição entre medicamentos não intercambiáveis, a promoção do uso racional dos medicamentos, a redução de gastos com medicamentos e tratamento de eventos adversos e o aumento da adesão do paciente ao tratamento

The implementation of generic drugs in Brazil, as well as programs and policies to ensure access to medicines with quality, safety and efficacy to the overall population, resulted in more than 3,800 generic drug products of 445 drugs registered in the National Health Surveillance Agency (ANVISA) since 1999. Generic drug products proved their therapeutic equivalence in bioequivalence studies and, therefore, the interchangeability with their respective reference drug product. In 2014, ANVISA expanded the interchangeability to similar drug products, increasing the number of interchangeable drug products for each reference drug product. Regulations for the prescription and dispensation of medicine only allow the substitution of a reference drug product for a generic or an interchangeable similar drug product or vice versa. However, in practice, it appears that there is a substitution between generic and similar drug products of a same reference drug product in private pharmacy chains - where discounts reach up to 90% of the selling price - as well as in public pharmacy, depending on the medicine availability, because public purchases are based on the lower price offered by the manufacturers. Nevertheless, the bioequivalence and interchangeability between generic and similar drug products of the same reference drug product cannot be guaranteed because they haven't been evaluated. Lack of bioequivalence between substituted drug products may result in therapeutic ineffectiveness or the occurrence of adverse events and even to patient intoxication. As a consequence, there might be waste, expenses due to adverse events treatment, no adherence to the treatment or the adoption of second-line treatment. This study evaluated the bioequivalence between generic and similar drugs of the same reference drug product through a meta-analysis, using data from bioequivalence studies carried out for the registration of generic and similar drug products at ANVISA. The drugs included in the study were acyclovir, amoxicillin, cephalexin, doxazosin, phenytoin, fluoxetine, levofloxacin and quetiapine. Results showed lack of bioequivalence between most of the generic and similar drugs containing the same drug and prove that generic and similar drug products of the reference drug product are not necessarily interchangeable. Moreover, the substitution of drugs used for chronic illnesses could lead to serious clinical consequences. This concern increases for drugs with narrow therapeutic index and those with high variable absorption process. The adoption of a list of non-interchangeable medicines - like in other countries - and investment in the dissemination of information about interchangeability between drug products to health professionals and to the population may contribute to reduce the substitution of drugs which are not interchangeable, promote a rational use of medicines, the reduction of expenses with drugs and adverse effects treatment and to improve treatment adherence

Inter-changeability between generic medicines and brand-name medicines / 中国药学杂志

OBJECTIVE: To describe the basic concepts of pharmaceutical inter-changeability and to discuss issues involved in the process of medicine substitution as well as the present situation of medicine substitution in our and other countries. METHODS: Collecting literatures on pharmaceutical inter-changeability, generic medicines and brand-name medicines, after analyzing and summarizing the information on pharmaceutical inter-changeability and medicine substitution were reviewed. RESULTS: The substitution of generic medicines with brand-name medicines involves in issues about bioequivalence, therapeutic equivalence, benefit, harm and so on. Our and other countries take appropriate measures to carry out the substitution of generic medicines with brand-name medicines. CONCLUSION: With following certain rules, generic medicines can substitute for brand-name medicines. This can be better to ensure the safety of drug use in clinical practice.

Physicochemical and Bioequivalence Studies on Some Brands of Levofloxacin Tablets Registered in Nigeria.

Aims: This study was aimed at comparing the physicochemical and bioavailability profiles of some brands of Levofloxacin 500mg tablets that are registered in Nigeria by her regulatory authority and to examine the feasibility of interchangeability of the brands. Methodology: The physicochemical equivalence of ten brands of Levofloxacin 500 mg tablets (LEV-1 to LEV-10) were evaluated using both official and unofficial standards including weight variation, hardness, friability test, chemical assay, disintegration, dissolution rate and drug content. Five of the brands were also evaluated for bioavailability profiles using a single dose randomized two period cross–over designs measuring the concentration of drugs in the urine. Urinary samples before dosing and at various appropriate time intervals up to 12 hours were analyzed by validated Double Beam U. V. Spectrophotometer method with 99.8% extraction recovery. Pharmacokinetic parameters for bioequivalence evaluation Cmax, Tmax and AUC were determined. Results: The resultsshowed that 60% of the levofloxacin brands (LEV-2, LEV-4, LEV-5, LEV-7, LEV-8 and LEV-9) failed in at least one of the tested physicochemical parameters. The statistical comparison of the physicochemical parameters showed no difference between the innovator brand (LEV-1) and three of the tested generic brands (LEV-3, LEV- 6 and LEV-10). Unlike LEV-5, the results obtained from the reference ratios of the parameters from bioavailability studies for the physicochemical equivalent brands were found to be within bioequivalence acceptable range with the reference brand indicating that they are bioequivalent in terms of Cmax and AUC to the innovator brand. Conclusion: The study indicates that 60% of the brands may not be used interchangeably with the innovator brand; consequently, the therapeutic substitution of these brands is not advisable. The formulation and/or the manufacturing process affect the weight uniformity, content uniformity, dissolution and thus the bioavailability of the drug products.

Nanotechnology in Dermatology

The scientific community and general public have been exposed to a series of achievements attributed to a new area of knowledge: Nanotechnology. Both abroad and in Brazil, funding agencies have launched programs aimed at encouraging this type of research. Indeed, for many who come into contact with this subject it will be clear the key role that chemical knowledge will play in the evolution of this subject. And even more, will see that it is a science in which the basic structure is formed by distilling different areas of inter-and multidisciplinary knowledge along the lines of new paradigms. In this article, we attempt to clarify the foundations of nanotechnology, and demonstrate their contribution to new advances in dermatology as well as medicine in general. Nanotechnology is clearly the future. .

Levotiroxina e o problema da permutabilidade de drogas de estreito intervalo terapêutico / Levothyroxine and the problem of interchangeability of drugs with narrow therapeutic index

Tem se tornado prática comum em nosso país a troca de medicamentos prescritos por outros similares, por produtos genéricos e até mesmo por produtos manipulados, muitas vezes ignorando-se preceitos básicos de bioequivalência, permutabilidade, estabilidade e características específicas do composto farmacêutico. No caso de drogas de índice terapêutico estreito, como a levotiroxina, esses problemas se agravam colocando em sério risco a eficácia do tratamento e a saúde do paciente. Revemos a legislação pertinente ressaltando as características da levotiroxina e os efeitos adversos que limitam a permutabilidade do composto.

The exchange of a prescribed drug by other similar, by generic products and even by custom products has become common practice in our country, often ignoring basic tenets of bioequivalence, interchangeability, stability and characteristics of the pharmaceutical compounds. In the case of drugs of narrow therapeutic index, such as levothyroxine, these problems are intensified, putting the effectiveness of treatment and patient health at serious risk. We review the pertinent legislation, emphasizing the characteristics of levothyroxine and adverse effects that limit the interchangeability of the compound.

Facetas da prescrição de medicamentos do Brasil: genérico, similar, referência e intercambialidade / Aspects of drugs prescription in Brazil: generic, similar, reference and interchangeability

A Política Nacional de Medicamentos foi a diretriz inicial que culminou com o surgimento dos medicamentos genéricos, uma opção de prescrição, ao lado dos medicamentos inovadores e similares, já existentes no mercadobrasileiro, o que mudou radicalmente o mercado farmacêutico brasileiro e introduziu vários conceitos, tais como equivalência farmacêutica e terapêutica, biodisponibilidade e bioequivalência. Com a consolidação dos medicamentos genéricos no mercado brasileiro foi necessária também a comprovação da equivalência terapêutica para a comercializaçãodos medicamentos similares, tanto para os que seriam ainda lançados quanto para os que já estavam sendo comercializados. No entanto, devido ao prazo dado para que essa comprovação ocorra, até 2014 haverá no mercado medicamentos similares intercambiáveis e não intercambiáveis pelos respectivos medicamentos de referência. Até que a adequação do mercado não ocorra, permanece a dúvida entre os prescritores quanto à melhor opção terapêutica - medicamento de referência, genérico ou similar? - no que se refere à qualidade, eficácia e segurança. Assim, oobjetivo deste trabalho foi comparar entre si as três categorias de medicamentos existentes no Brasil e apresentar um paralelo entre elas, ao lado de uma breve história da evolução dos medicamentos no País.

The National Drug Policy sparked off the generic drugs in Brazil, an option to prescription, besides the previous existent drug classes (similar and innovative drugs), radically changing the Brazilian pharmaceutical market and introducing a number of concepts such as pharmaceutical and therapeutic equivalence, bioavailability and bioequivalence.The consolidation of generic drugs in Brazilian market led to a need to also prove the therapeutic equivalence between similar and reference drug for both those scheduled to be launched onto the market and those thatwere already available for sale. However, due to deadlines for proving such equivalency, by 2014, according to their reference medicines, there will be interchangeable and not interchangeable similar drugs on the market. Until then, among health professionals, the doubt about the best therapeutic option remains: Should professionals prescribe the innovative (reference), generic or similar drug? - as to quality, efficacy and security. Thus, the aim of this work was to compare these drug categories, including a brief history of the pharmaceutical evolution in Brazil.

Estudios de bioexención (in vitro) para establecer equivalencia de medicamentos / Biowaiver studies (in vitro) to establish equivalence of drugs

En el presente trabajo se hace un análisis de los conceptos, normativas y propuestas sobre la equivalencia terapéutica de medicamentos similares con respecto a los innovadores, desde una perspectiva internacional y nacional, explicando las bases científicas de los estudios de bioexención in vitro para determinar la intercambiabilidad de aquellos medicamentos similares provenientes de diferentes fuentes que se han liberado de los estudios de bioequivalencia (in vivo). Además, se presentan algunos resultados de estudios de test de disolución para dar a conocer la metodología usada en la bioexención y se detallan los requisitos para aprobar un Centro de Bioequivalencia in vitro.

In this review, the concepts, guidelines and proposals regarding the determination of therapeutic equivalence of similar drug products are analyzed from a national and international point of view. The scientific background of the in vitro biowaiver studies that may result in the interchange ability of multisource drug product that have been waived from the demonstration of in vivo bioequivalence studies is also explained. In order to explain the methods in biowaiver studies, results of dissolution kinetics are shown as well as the requirements to approve an in vitro biopharmaceutic center.

Medicamentos genéricos no tratamento das epilepsias: uma reflexão: [revisão] / Generics in the treatment of epilepsy: a reflection: [review]

OBJETIVOS: Discutimos aspectos controversos para a prescrição de medicamentos genéricos no tratamento das epilepsias e problemas relacionados à biodisponilidade e bioequivalência. Algumas drogas antiepilépticas (DAE) apresentam baixa solubilidade em água, apresentam cinética não linear e faixa terapêutica estreita, dados sugestivos da ocorrência de problemas relacionados à bioequivalência. MÉTODOS: Revisão da literatura. RESULTADOS E CONCLUSÕES: Há mais informações sobre as DAE tradicionais (fenitoína, carbamazepina e valproato) e apenas uma comunicação em congresso foi encontrada sobre a substituição de uma nova DAE, a lamotrigina. O nível de evidência é fraco, baseado em séries de casos e opinião de especialistas, com exceção talvez da fenitoína para a qual há alguns estudos analíticos. Podemos permitir o uso de genéricos para o tratamento das epilepsias, desde que tenhamos em mente que este abrirá a possibilidade de substituições sucessivas de formulações durante o tratamento, com conseqüências imprevisíveis como a recorrência de crises e suas conseqüências ou o aparecimento de efeitos adversos.

OBJECTIVE: We discuss some controversial aspects with prescription of generic drugs (GD) and the problems concerning bioequivalence in the treatment of epilepsy. Some antiepileptic drugs (AED) are poorly soluble in water, have nonlinear kinetics and a narrow therapeutic range, implying that problems with bioequivalence are likely to occur. There are clearly advantages (cost saving) and disadvantages (loss of seizure control or drug toxicity) in prescribing generics AED. METHODS: Review of literature. RESULTS AND CONCLUSION: The main information is about classical AED (phenytoin, carbamazepine and valproate). Regarding the new AED we found only one poster presentation related to lamotrigine substitution. The level of evidence is, generally, weak, based on case-series and expert opinion without explicit critical appraisal (except in phenytoin with level of evidence moderate, based on some analytical studies). We may allow the use of generics for epilepsy treatment. However, this opens the possibility of successive substitution of different formulations which may even be life threatening.