Nonbioequivalent prescription drug interchangeability, concerns on patient safety and drug market dynamics in Brazil / Intercambialidade de medicamentos não-bioequivalentes, segurança do paciente e dinâmica do mercado farmacêutico no Brasil

Abstract Since the enforcement of Generics Act (1999), three types of pharmaceutically equivalent products are marketed in Brazil: innovative reference (REF), "similar" (S) and generic (G) drugs. The S (brand name) and G (generic name) borrow from REF (brand name) clinical data on safety and efficacy and dosage regimen. G (but not S) is bioequivalent to and interchangeable with REF. Starting in 2003, Brazilian Sanitary Surveillance Agency (Anvisa) has required data on relative bioavailability tests (with REF) to approve (or renew registration of) S drugs. In 2014, Anvisa extended interchangeability notion to similar drugs with a "comparable" bioavailability, i.e., an "equivalent" similar drug (EQ). Drugs for chronic diseases and "critical dose medicines" are listed among the EQ drugs approved. Interchangeability of nonbioequivalent medicines raises deep concerns regarding therapeutic failures and adverse events. Concerns are even more worrisome if patients switch from one drug to another during an ongoing treatment for illnesses such as epilepsy, congestive heart failure, hypertension, diabetes and/or substitutable drugs have a narrow therapeutic index.

Resumo A partir da vigência da lei dos genéricos (1999), três tipos de produtos farmaceuticamente equivalentes são comercializados no Brasil: o medicamento inovador de refência (REF), o produto "similar" (S), e o genérico (G). O similar (nome de fantasia) e o genérico (nome genérico) tomam de empréstimo do REF (nome de fantasia) os dados clínicos de segurança e eficácia e a posologia. G (mas não S) é bioequivalente ao, e intercambiável com REF. Desde 2003, a Agência Nacional de Vigilância Sanitária (Anvisa) exige dados de testes de biodisponibilidade relativa para registrar (ou renovar o registro de) medicamentos S. Em 2014, a Anvisa estendeu o conceito de intercambialidade aos medicamentos similares com biodisponibilidade "comparável", i.e., um medicamento similar "equivalente" (EQ). Medicamentos para doenças crônicas e "fármacos de dose crítica" estão listados entre os produtos EQ aprovados. A intercambialidade de medicamentos não-bioequivalentes suscita grande preocupação quanto a falhas terapêuticas e eventos adversos. Os receios são ainda maiores se os pacientes trocam um medicamento por outro durante o tratamento de doenças como epilepsia, insuficiência cardíaca, hipertensão, diabetes e/ou os produtos farmacêuticos substituídos tem um índice terapêutico estreito.

Original salbutamol versus similar salbutamol in children with asthma exacerbation: A randomized, controlled, double-blind study / Salbutamol original contra salbutamol similar en niños con crisis de asma: Estudio aleatorizado, controlado y doble ciego

Introduction.There is clinical evidence suggesting that original salbutamol is more effective than a similar salbutamol product to revert symptoms in acute asthma exacerbation.. Objective. To evaluate the bronchodilator response of both salbutamol medicinal products in children with asthma and to establish, based on the forced expiratory volume, if there is a difference between the group treated with the original salbutamol and the group treated with similar salbutamol. Design. Prospective, randomized, controlled, double-blind study. Material and Methods. One hundred and twenty six children (63 boys, age 9.18 ± 2.83 years old) were included. They were administered a dose of 20 drops (5 mg) of the original salbutamol or similar salbutamol product in nebulizing solution diluted only once in 2 ml saline solution. Preand post-bronchodilator, intra- and inter-group forced expiratory volume was compared at baseline and at 30 minutes. The weight of salbutamol drops was determined by gravimetry, the concentration by chromatography and the number of drops by bottle. Results. The bronchodilator response between the pre- and post-bronchodilator forced expiratory volume was 225 ml (95% CI: 164-286) and 224 ml (95% CI: 163-284) for original salbutamol and similar salbutamol, respectively (p < 0.001). The Delta difference was 1.3 ml (95% CI: -86+83) (p = 0.97). The mean, standard deviation and variation coefficient percentage of the weight of the drop was 364.75 mg (± 6.01, 1.65) and 543.88 mg (± 56.09, 10.31) (p < 0.001) for original salbutamol and similar salbutamol, respectively. Conclusion. There were no differences in the bronchodilator response measured by FEV1 between the original salbutamol and a similar salbutamol product.

Introducción. Existe evidencia clínica que sugiere que el salbutamol original sería más eficaz que el salbutamol similar para revertir los síntomas en el episodio agudo de asma. Objetivo. Evaluar la respuesta broncodilatadora de ambas especialidades farmacéuticas de salbutamol en niños con asma y establecer, mediante el volumen espiratorio forzado, si difiere entre los grupos tratados con salbutamol original y similar. Diseño. Estudio prospectivo, aleatorizado, controlado, a doble ciego. Material y métodos. Se incluyeron 126 niños (63 varones, edad 9,18 ± 2,83 años), que recibieron una dosis de 20 gotas (5 mg) de salbutamol original o similar en solución para nebulizar diluida en 2 ml de solución fisiológica por única vez. Se comparó el volumen espiratorio forzado prebroncodilatador y posbroncodilatador, intragrupos e intergrupos, al inicio y a los 30 minutos. Se determinó el peso de las gotas de salbutamol por gravimetría, la concentración por cromatografía y el número de gotas por envase. Resultados. La respuesta broncodilatadora entre el volumen espiratorio forzado prebroncodilatador y posbroncodilatador fue de 225 ml (IC 95%: 164-286) y 224 ml (IC 95%: 163-284) para salbutamol original y similar, respectivamente (p <0,001). El delta de la diferencia fue de 1,3 ml (IC 95%: -86+83) (p= 0,97). La media, desvío estándar y porcentaje del coeficiente de variación del peso de las gotas fue de 364,75 mg (± 6,01, 1,65) y 543,88 mg (± 56,09, 10,31) (p <0,001) para salbutamol original y similar, respectivamente. Conclusión. No hubo diferencias en la respuesta broncodilatadora medida por el VEF1 entre salbutamol original y similar.

The Impact of Generic Clopidogrel Bisulfate on Platelet Inhibition in Patients with Coronary Artery Stents: Results of the ACCEL-GENERIC Study

BACKGROUND/AIMS: In patients with coronary artery stents, the cost of clopidogrel has been cited as a factor in the premature discontinuation of therapy. Thus, the introduction of lower-cost generic clopidogrel may increase patient compliance. However, platelet inhibition by generic clopidogrel has not been compared to the original clopidogrel formulation in patients with coronary artery stents. METHODS: We prospectively enrolled 20 patients receiving chronic therapy with the original clopidogrel bisulfate (Plavix(R)). After assessing patient compliance with Plavix(R), maintenance therapy was switched to generic clopidogrel bisulfate (Plavitor(R)). Platelet reactivity was assessed at baseline and 30-day after the switch using conventional aggregometry and the VerifyNow P2Y12 assay. RESULTS: All patients completed maintenance therapy with Plavitor(R). Before and after switching therapy maximal (36.5 +/- 7.9% vs. 39.8 +/- 16.2%, p = 0.280) and late platelet aggregation (23.5 +/- 10.9% vs. 29.1 +/- 18.3%, p = 0.156) with 5 micromol/L adenosine diphosphate (ADP) stimulus did not differ. Likewise, 20 micromol/L ADP-induced platelet aggregation and P2Y12 reaction unit in patients on Plavitor(R) therapy was comparable to that in patients on Plavix(R) therapy. However, Bland-Altman analysis showed wide limits of agreement between measured platelet reactivity on Plavix(R) vs. Plavitor(R) therapies. CONCLUSIONS: Among patients on Plavix(R) maintenance therapy with coronary stents, replacement with Plavitor(R) shows a comparable inhibition of ADP-induced platelet aggregation. However, due to poor inter-therapy agreement, between two regimens, physicians may be cautious when introducing generic clopidogrel bisulfate.

A randomized, crossover, open label pilot study to evaluate the efficacy and safety of Xalatan in comparison with generic Latanoprost (Latoprost) in subjects with primary open angle glaucoma or ocular hypertension.

AIM: To compare the efficacy and tolerability of Xalatan with generic latanoprost (Latoprost) in subjects with primary open angle glaucoma (POAG) or ocular hypertension (OH). MATERIALS AND METHODS: This was a single-center, randomized, open label, crossover, two period comparative study. At the baseline visit, subjects were randomized to two groups. Group A received Xalatan for weeks 1-12 followed by Latoprost for weeks 13-24. Group B received Latoprost for weeks 1-12 followed by Xalatan for weeks 13-24. RESULTS: 30 subjects were recruited, 12 in Group A and 18 in Group B. In subjects administered Xalatan, intraocular pressure (IOP) showed a greater decrease (P < 0.001) from 23.64 +/- 3.13 mmHg at baseline to 14.29 +/- 1.61 mmHg at week 12 (fall of 9.35 +/- 3.55 mmHg, 38.66% +/- 10.29) than that seen in the Latoprost group (22.74 +/- 2.47 mmHg to 16.98 +/- 2.49 mmHg, fall of 5.76 +/- 1.41 mmHg; 25.42% +/- 5.98). In period 2 when subjects were crossed over to Xalatan from Latoprost, there was a further fall from 16.98 +/- 2.49 mmHg to 16.09 +/- 1.49 at week 24 (fall of 0.89 +/- 1.59 mmHg; 4.3% +/- 8.76). However, when subjects were crossed over to Latoprost from Xalatan, the IOP rose from 14.29 +/- 1.61 mmHg to 15.36 +/- 1.71 mmHg at week 24 (8.86% +/- 17.76). There was no significant difference in incidence of conjunctival hyperemia or any other adverse events in both the groups. CONCLUSION: The magnitude of IOP lowering in patients with POAG and OH with Xalatan and Latoprost is different. In our study, the IOP lowering with Xalatan was higher than that with Latoprost.

Efficacy of a generic fixed-dose combination of stavudine, lamivudine and nevirapine (GPO-VIR) in Thai HIV-infected patients.

BACKGROUND: GPO-VIR, fixed-dose combination of stavudine 30/40 mg, lamivudine 150 mg, and nevirapine 200 mg are widely used in Thailand. OBJECTIVE: Determine the efficacy and tolerability of GPO-VIR in naive HIV-infected patients. MATERIAL AND METHOD: Primary outcome was the time of initiation to achieve the goal of therapy, which was HIV RNA < 50 copies/mL or 50% increased of CD4 cell count. Ninety patients were eligible for the present study. Mean +/- SD age was 35 +/- 7 years and 51% were male. Median baseline CD4 and HIV RNA were 52 cells/ mm3 and 280,000 (5.4 log10) copies/mL, respectively. Sixty-two (69%) patients had previous opportunistic infections. RESULTS: In a median follow-up period of 15 weeks, 49 (54%) patients achieved the goal of therapy. The probability of goal achievement showed that 12-, 24-, 36- and 48- weeks success rates were 8.5% [95% confidence interval (CI): 3.9-18.0%], 62.7% (95% CI: 50.8-74.6%), 80.0% (95% CI: 67.3-90.1%), and 93.3% (95% CI: 76.3-99.4%), respectively. The median success time to achieve the goal was 21 weeks. Eleven (12%) patients needed to discontinue GPO-VIR because of adverse drugs reaction. CONCLUSION: GPO-VIR may be one of the antiretroviral regimens for HIV-infected patients in Thailand and other resource-limited countries. Its efficacy is good in patients with advanced HIV infection.

Efficacy and safety of generic fixed-dose combination of stavudine, lamivudine and nevirapine (GPO-vir) in advanced HIV infection.

OBJECTIVES: To assess the efficacy and safety of generic fixed-dose combination of stavudine, lamivudine and nevirapine; GPO-vir in advanced HIV infection. MATERIAL AND METHOD: Open-label combined prospective and retrospective study involving 102 HIV infected patients with baseline CD4 cell count < 100 cells/mm3. All patients received GPO-vir for 48 weeks. The CD4 cell count and plasma viral load (pVL) was measured at 48 weeks. RESULTS: The median baseline CD4 cell count and pVL were 13 cells/mm3 and 363,500 copies/ml, respectively. At 48 weeks, the median CD4 cell count increased to 191 cells/mm3 and 63.7% in intention-to treat and 82.3% in on-treatment analysis had pVL < 50 copies/ml. There was no significant difference in pVL between patients with baseline pVL > 100,000 or < or = 100,000 copies/ml (p = 0.312). The incidence of hepatotoxicity, rash and peripheral neuropathy was 4.9%, 14.7% and 6.9%, respectively. CONCLUSION: GPO-vir was well tolerated and effective in increasing CD4 cell count and suppressing plasma viremia in advanced HIV infection during the 48 weeks follow-up period.

Comparação do volume da gota e custo do tratamento dos genéricos de maleato de timolol 0, 5 por cento / Drop volume and cost of treatment with generic 0.5 percent timolol maleate preparations

OBJETIVO: Comparar o volume da gota das medicações genéricas de maleato de timolol a fim de determinar o custo real do tratamento em relação à medicação de referência. MÉTODOS: Foi determinado o volume da gota do Timoptol® 0,5 por cento (Merck Sharp & Dome) e dos genéricos maleato de timolol 0,5 por cento dos laboratórios Allergan-Lok, Cristália e Falcon. Cinco frascos de 5 ml de cada medicação foram adquiridos no mercado. Dez gotas de cada frasco foram pesadas em balança de precisão individualmente, bem como, um mililitro de cada frasco para a determinação do volume da gota. Com base no volume da gota foi calculada a duração média em dias e o custo anual, considerando-se o gasto diário de 4 gotas e o preço máximo ao consumidor publicado em maio de 2003 com alíquota de 18 por cento. RESULTADOS: Observaram-se diferenças estatisticamente significantes do volume da gota entre as medicações (p<0,0001 por cento). A maior gota foi a do maleato de timolol 0,5 por cento Allergan-Lok (35,1 æl) e a menor do maleato de timolol Falcon (27,3 æl). A medicação de referência (Timoptol®) proporcionou gota média de 27,9 æl. O custo anual do tratamento foi de R$ 68,87 para o Timoptol, de R$ 72,76 para o maleato de timolol Allergan-Lok, de R$ 50,00 para o maleato de timolol Cristália e de R$ 43,11 para o maleato de timolol Falcon (p<0,0001). O maleato de timolol Allergan-Lok foi estatisticamente mais caro que os demais sendo 68,8 por cento mais oneroso que o mais barato. CONCLUSAO: Existem diferenças no volume da gota das medicações genéricas acarretando diferenças no custo anual do tratamento. O volume da gota deve ser considerado na análise de qualidade dos medicamentos antiglaucomatosos genéricos.

Comparative study of the efficacy of topical corticosteroid: five locally made and one brand name creams.

The aim of this study was to evaluate the efficacy of 5 locally made clobetasol propionate creams compared with a brand name product. The study was divided into 3 parts 1) pharmacological study, 2) vasoconstriction test, and 3) double blind clinical trial. The results showed that the pharmacological properties of the locally made products were not different from the brand name product. Product C and D could diffuse through cellulose acetate membrane 3 fold more than the brand name product. Product D and E caused less vasoconstriction than the brand name product. This double blind study showed that all locally made products could improve psoriasis to the same extent as the brand name product, but there was more recurrence of psoriasis while using all the locally made products. It was concluded that locally made products were as effective as the brand name product in the treatment of psoriasis evaluated over a 2 week peroid, but more recurrence was observed with locally made products.

A randomized crossover study to evaluate LDL-cholesterol lowering effect of a generic product of simvastatin (Unison Company) compared to simvastatin (Zocor) in hypercholesterolemic subjects.

It is agreed that people with a high blood LDL-cholesterol level will have a higher risk of coronary heart disease (CAD) than those with low blood LDL-cholesterol level. Because of the present National Drug Strategy of Thailand, the promotion of "in-country production" of a generic drug has been established. Simvastatin is one of the drugs in this strategy. In this, the primary report of a randomized crossover study with washout period for a cholesterol lowering effect in a generic product of simvastatin (Unison company) which was compared to the original simvastatin (Zocor) hypercholesterolemic to the subjects were presented. Simvastatin used in this study were derived from two sources. The first group was the original product (Zocor), dosage 10 mg, Lot No IC4/36(N) from Merck Sharp & Dohme Company and the second group was a generic product, dosage 10 mg, Lot No T05/080 and T06/109 from Unison Company. All simvastatin tablets from the first and second sources were inserted into closed capsule of the same shape and called drug A and drug B, respectively. Both the physician in-charge and the subjects in this study were blinded for the content inside the capsule (Double blind). Thirty drug capsules were put into a sachet and distributed to the subject at each visit. The interval between each visit was 4 weeks. All subjects were asked to bring back the residual capsule within the sachet to the researcher at each visit in order to evaluate the subject's compliance. All subjects had physical examination and blood tests at each visit. Furthermore, all subjects were advised to practice diet control and regular in-take of the drug capsule daily after their evening meal. All 48 subjects were randomly allocated into 2 groups. This study was run as a randomized crossover study. After taking the drugs for the first 8 weeks, no statistically significant difference of blood LDL-cholesterol between the first and second group was detected. After a 4 week washout period, crossover and taking the drugs for the last 8 weeks, no statistically significant difference of blood LDL-cholesterol between the first and second group was detected. At the end of this study, comparing both groups by ANOVA crossover test, no statistically significant difference of blood LDL-cholesterol between the first and second group was detected.

Medicamentos genericos versus originales / Generic drugs versus brand name medications

La literatura médica muestra una cantidad enorme de estudios comparativos entre medicamentos genérico y originales. El área médica directamente relacionada com este tema es la farmacologica. Recientimente fue publicado um artículo donde farmacólogos intentan educar a los médicos sobre los medicamentos genéricos...

Plasma pharmacokinetics of a generic amoxycillin and the innovator brand: a comparison.

OBJECTIVE: To compare the bioavailability and plasma pharmacokinetics of a generic brand of amoxycillin (State Pharmaceutical Manufacturing Coporation) selected from the lower price range, with that of the innovation brand (Amoxil, Beecham). DESIGN: Sixteen healthy adult volunteers were allotted to two groups and each group was given a test dose of amoxycillin from each brand. Blood samples were collected at 0, 2, 3 and 4 hours thereafter plasma levels were assayed using high performance liquid chromatography. RESULTS: Analysis of results show that the generic product had similar bioavailability and pharmacokinetics when compared with the innovator product. CONCLUSION: The quality assured generic amoxycillin tested had similar bioavailability as a more costly branded version.