Generic drugs: benefit/risk ratio

The review discusses the interchangeability of medications, approaches to the registration of original and generic drugs, and types of their equivalence, as well as problems with generics in clinical practice. Results of pharmacoepidemiological studies, which have been widely carried out recently, speak of insufficient understanding of the impact of generics on remote outcomes of chronic diseases, including mortality. The longterm economic prospects of generic drug administration continue to remain unclear. Among the primary differences between generics and brandname drugs are the differences in active ingredient synthesis methods and the composition of adjuvants and additives. Comparative studies on the therapeutic equivalence of generics with their originals or between themselves are rarely conducted. They are often affected by methodological flaws, which cannot ensure their comparable efficacy and safety. In this regard, automatic replacement of drugs containing the same active ingredient should be avoided without the participation of the attending physician.

Current Approaches to Demonstration of Therapeutic Equivalence of Locally-Acting Gastrointestinal Drugs

Evolution of knowledge about pharmacokinetics and pharmacodynamics of locally acting products, and an increase in the number of generics and medicines under development have laid the ground for the development of new scientific approaches to planning and conducting of therapeutic equivalence studies of medicinal products acting locally in the gastrointestinal (GI) tract. To date, many international guidelines on planning and conducting of bioequivalence (BE) studies of locally acting GI products have been updated, however, there are still no such guidelines in the Russian Federation and the Eurasian Economic Union (EAEU). Therefore, elaboration of common methodological approaches to the planning of clinical studies of these products is of particular relevance for the EAEU. The aim of the study was to analyse foreign approaches to planning, conducting, and evaluation of therapeutic equivalence studies of locally acting GI products. The paper analyses the guidelines of the European Medicines Agency and the US Food and Drug Administration on the planning, conduct, and evaluation of BE studies of locally acting GI products. The analysis demonstrated that BE clinical trials are giving way to in vitro studies providing a sensitive and accurate assessment of the differences between a locally acting GI product and the reference product, based on careful consideration of the medicine’s mechanism of action, dosage form, and site of action. The paper gives examples of test methods applied to medicinal products with a complex biopharmaceutical profile whose bioequivalence assessment is challenging, with a special focus on mesalazine products. The results of the analysis may be used for elaboration of a harmonised methodological approach to planning and conducting therapeutic equivalence studies of locally acting GI products in the Russian Federation and EAEU.

Examining therapeutic equivalence between branded and generic warfarin in Brazil: The WARFA crossover randomized controlled trial

Objectives To determine whether the generic and branded warfarins used as anticoagulants in Brazil are therapeutic equivalents based on their international normalized ratio (INR) results. Methods This crossover randomized controlled trial had four periods. We used the branded Marevan and two generic versions of warfarin sodium tablets, manufactured by União Química and Teuto laboratories, all purchased from retail drugstores. Eligible participants were outpatients from an anticoagulation clinic at a university hospital in São Paulo, Brazil. They had atrial fibrillation or flutter and had been using warfarin for at least 2 months with an INR therapeutic range of 2.0–3.0. Randomization was by numbered, opaque, sealed envelopes. Healthcare personnel and outcome assessors were blinded to treatments, but patients were not. The primary outcome was the variability in the INR (ΔINR) and secondary outcomes included mean INR. We accepted formulations as equivalent if the 95% confidence interval (CI) of the comparison of ΔINR between branded and generic formulations was within the limit of ±0.49. Results One hundred patients were recruited and randomized to six sequences of treatment (four sequences with n = 17 and two sequences with n = 16). União Química generic warfarin had equivalent variability in the INR to Marevan (ΔINR +0.09 [95% CI -0.29 to +0.46], n = 84). Comparison between Teuto generic warfarin and Marevan was inconclusive (ΔINR +0.29 [95% CI -0.09 to +0.68], n = 84). Conclusions Marevan and União Química warfarin had equivalent therapeutic effectiveness and both could be confidently used for anticoagulation. The comparison between Marevan and TW was inconclusive and does not warrant a statement of equivalence. Our methods are especially important for comparing generic and branded drugs that raise concerns and may be subject of future investigations by regulatory agents. Trial registration ClinicalTrials.gov NCT02017197.

Therapeutic equivalence of ivermectin 1% and two novel formulations combined of ivermectin 1% + fluazuron 12.5% for the control of Rhipicephalus (Boophilus) microplus in beef cattle from Uruguay

Background: Novel combinations of ivermectin (IVM) and fluazuron (FLU) are presented as an alternative for the control of ticks in cattle. Applying a combination of drugs with the aim to affect different stages of the parasite’s life cycle is established as a potential measure to achieve the control of ticks in cattle. Aim: To determine the therapeutic equivalence between two novel formulations of IVM 1% combined with FLU 12.5% tested on bovines naturally infested with Rhipicephalus (Boophilus) microplus. Methods: Forty adult beef cattle were randomized into four groups (n = 10): IVM [1% (0.2 mg/kg)], combinations groups A and B [IVM 1% (0.2 mg/kg) + FLU 12.5% (2.5 mg/kg), each], and control [untreated]). On days 14, 27, and 49 after administration, the presence of ticks was ranked as null, low, medium, and high; a cumulative link model was adjusted to evaluate treatment response. Results: Although all groups had some animals with the presence of ticks until day 27, on day 14 IVM [odds ratios (OR) 0.013, CI95%: 0.001–0.014, p < 0.01], A (OR 0.01, CI95%: 0.00–0.07, p < 0.01) and B (OR 0.01, CI95%: 0.00–0.148, p < 0.01) groups were different when compared to the control group, unlike on day 27 where only groups A (OR 0.02, CI95%: 0.00–0.17, p < 0.01) and B (OR 0.06, CI95%: 0.00–0.46, p < 0.01) remained different from the control group. On day 49 post-administration, IVM and B did not differ from the control group, with 0.95 probability (CI95% 0.92–1.02) of high parasite burden. At day 49 post-administration, group A was the only group free of ticks (OR 0.01, CI95%: 0.00–0.13, p < 0.01). Conclusions: Pharmacotechnical differences in combined formulations should be considered in therapeutic equivalence studies.

HYPOGLYCEMIC ACTIVITY OF THE AQUEOUS EXTRACT OF CAESALPINIA PULCHERRIMA FLOWERS IS INDEPENDENT OF INSULIN STIMULATION AND SUPPRESSED IN THE PRESENCE OF METFORMIN

Considering the high prevalence of insulin resistance, antidiabetic strategies that enhance insulin action or act independent of insulin are desirable. Caesalpinia pulcherrima (CP) flowers are known to have antidiabetic properties, but more work is required with respect to this action in insulin resistant adipocytes, particularly, its dependence on insulin and its therapeutic equivalence and/or interactions with other antidiabetic drugs. The purpose of this study was therefore to investigate the insulindependency of the water extract of CP flowers (CP extract) hypoglycemic effects, compare its antidiabetic action in diabetic and non-diabetic glucose loads, and explore its therapeutic equivalence and interactions with metformin. CP extract was prepared by boiling the air-dried flowers in cell culture media prepared in Krebs Ringer Bicarbonate buffer for 5mins. Metformin solution was prepared from a Metformin hydrochloride extended-release tablet to obtain low and therapeutic levels of metformin (0.8-2.4mg/L and). Insulin resistant (IR) adipocytes were exposed to CP extract in cell culture containing either 8mM or 18mM glucose and one of three insulin concentrations. CPextract allowed an efficient glucose disposal in the IR adipocytes in an insulin independent manner (p<0.0001). The percentage of glucose uptake did not significantly differ by models of diabetic and non-diabetic conditions (p=0.4727) although the significantly higher glucose concentration taken up by the IR adipocytes in the presence of IR adipocytes suggest an enhancement of antidiabetic action in hyperglycemic conditions. Expectedly metformin had a higher potency than the CP extract with its therapeutic dose of 1.8-2.4mg/L corresponding to 280mg/l of CP extract (p=0.9996). Additionally, metformin and CP extract appear to compete for similar sites which suppressed the hypoglycemic activity of CPextract.

Therapeutic equivalence of fixed combination of indapamide with perindopril (Perindopril plus) in geriatric patients

Purpose. To study the therapeutic equivalence of the generic fixed combination of indapamide with perindopril (Perindopril plus, Severnaya Zvezda, Russia) in relation to the original drug in geriatric patients with hypertension (GB) and chronic heart failure (CHF). Material and methods. A study was conducted in 105 patients with GB and CHF (68.6 % of men with average age 80.3 ± 0.7 years), which evaluated the antihypertensive effect, the ability to correct heart failure, the presence of organ protection, the safety of both drugs. Results and discussion. When using a generic fixed combination, the achievement of the target value of office blood pressure was observed after a month of observation in all cases with stable maintenance by 6 months of the study; significant (p < 0.05) decrease in the level of home monitoring of systolic blood pressure (SBP) / diastolic blood pressure (DBP), after a month of research, by 26.1 % / 28.0 %, 6 months – by 26.8 % / 30.1 %; a significant (p < 0.05) decrease in the average daily SBP / DBP after a month of observation by 28.1 % / 28.6 % (after 6 months by 29.7 % / 29.5 %), the average daily – after a month of observation by 27.2 % / 28.2 % (after 6 months by 28.4 % / 31.7 %), average nightly – after a month of observation by 22.4 % / 24.1 % (after 6 months by 24.3 % / 27.1 %); a reliable (p < 0.05) decrease after a month of monitoring the average daily pulse pressure by 27.9 % (average daily pulse pressure by 25.8 %, average nightly pulse pressure by 20.1 %), after 6 months by 30.4 %, 23.5 %, 20.3 % respectively; a significant (p < 0.05) decrease in the carotid femoral pulse wave propagation velocity after a month by 17.9 %, after 6 months – by 26.8 %; after 6 months of observation, a reliable (p < 0.05) decrease in the final systolic volume of the left ventricle (LV) by 10.6 %, the final diastolic volume of the LV – by 7.5 %, the LV myocardial mass index – by 11.5 %, significant (p < 0.05) increase in LV ejection fraction by 2.9 %; significant (p < 0.05) decrease in FC of CHF by 20.7 % by the end of the study. According to the degree of change in these indicators, a generic fixed combination was comparable to the original drug. No side effects were observed in the comparison groups requiring discontinuation of treatment. Conclusions. The generic fixed combination of indapamide with perindopril (Perindopril plus, Severnaya Zvezda, Russia) has therapeutic equivalence with respect to the original drug.