Assessment of implementation of antibiotic stewardship program in surgical prophylaxis at a secondary care hospital in Ras Al Khaimah, United Arab Emirates.

Antibiotic overuse is a major factor for causing antibiotic resistance globally. However, only few studies reported the implementation and evaluation of antimicrobial stewardship programs in Gulf Cooperation Council. This study was conducted within 8-months periods to evaluate the effect of the newly implemented antibiotic stewardship program on improving the prescribing practice of surgical antibiotic prophylaxis in a secondary care hospital in the United Arab Emirates by releasing local hospital guidelines. The data of 493 in patients were documented in the predesigned patient profile form and the prescribing practice of surgical antibiotic prophylaxis for clean and clean-contaminant surgical procedures was compared and analyzed two months' prior (period A) and post (period B) the implementation of antibiotic stewardship program. The 347 patient's data (PD) were analyzed during period A and 146 PD during period B. The prescription of piperacillin/tazobactam was decreased from 2.4% from all surgical prophylaxis antibiotic orders in period A to 0% in period B. The appropriateness of the antibiotic therapy was found to differ non significantly for the selection of prophylactic antibiotic (p = 0.552) and for the timing of first dose administration (p = 0.061) between A and B periods. The total compliance was decreased non significantly (P = 0.08) from 45.3 to 40.2%. Overall, the guidelines have improved the prescribing practice of antibiotics prior to surgery. However, further improvement can be achieved by initiating educational intervention via cyclic auditing strategy.

Lesson Learnt from Recall of Valsartan and Other Angiotensin II Receptor Blocker Drugs Containing NDMA and NDEA Impurities.

The presence of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) impurities in angiotensin II receptor blocker (ARB) drugs containing tetrazole ring has triggered worldwide product recalls. The purpose of this article is to identify the potential gap area in current pharmaceutical industry practice that might have led to the NMDA and NDEA impurities escaping the drug manufacturer's and FDA's attention. The impact of process change was not adequately assessed by the manufacturer of contaminated APIs (active pharmaceutical ingredients), and potential for generation of mutagenic or other toxic impurities was not considered. The safety and risk associated with a chemical synthetic process was also not evaluated. This is primarily due to current industry practice which focuses on controlling the impurities above reporting threshold. ICH Q3A and FDA guidance on genotoxic and carcinogenic impurities in drug substances and products need to be integrated so that the ICH Q3A decision tree (attachment 3) begins by checking whether the synthetic process has been evaluated for the potential to generate toxic impurities. The compliance with ICH Q3A limits should be carried out only after the process has been determined to be safe without the risk of generating mutagenic and carcinogenic impurities.

Is the demonstration of bioequivalence for clavulanic acid required in amoxicillin-clavulanic acid orally administered immediate-release products?

OBJECTIVES: Bioequivalence (BE) criteria for amoxicillin-clavulanic acid (Co-amoxiclav) oral formulations are based on 90% confidence interval for both amoxicillin and clavulanic acid. The aim of this work is to explore the relevance of demonstrating BE of clavulanic acid in Co-amoxiclav oral formulations and also to assess the impact on safety and efficacy of product due to bioinequivalent clavulanic acid. METHODS AND KEY FINDINGS: The subtherapeutic levels of clavulanic acid would continue to exert their action against ß-lactamases due to postß-lactamase inhibitor effect. Additionally, only minute quantities are required to inhibit ß-lactamases. Majority of adverse effects associated with Co-amoxiclav are of less serious nature, therefore, risk due to suprabioavailable clavulanic acid was determined to be low. 'Very rapid clavulanic acid release' in in vitro dissolution test would ensure that clinically significant differences between test and reference formulations if any are detected in advance. As an additional risk mitigation strategy, WHO recommends qualitative and quantitative composition similarity between test and reference formulations to ensure excipients do not adversely impact bioavailability. CONCLUSIONS: Co-amoxiclav with non-bioequivalent clavulanic acid, but bioequivalent amoxicillin would still achieve its therapeutic objectives without exposing patients to unwanted adverse effects. Therefore, the current regulatory criterion of demonstrating BE of clavulanic acid appears conservative.

Drug utilization review of cephalosporins in a secondary care hospital in United Arab Emirates.

Background Cephalosporins are one of the most commonly used antibiotics in United Arab Emirates (UAE). Few studies have been carried out to evaluate the antibiotic utilization pattern in UAE in spite of the obvious increase in cephalosporins resistance during the past decade. Objective To assess the prescriptions pattern of cephalosporins among physicians at a secondary care hospital in Ras Al Khaimah, UAE. Method This observational prospective study was carried out during October 2013 to April 2014. The data of in patients were documented in the predesigned patient profile form and was analyzed for patient's, drug's and drug's therapy related parameters. Results The 3rd generation cephalosporins constituted 83.6 % of the prescriptions, with ceftriaxone being the most commonly used one (81.1 %). They were mainly prescribed for the treatment of the lower respiratory tract infections (60.2 %). Seven (3.5 %) different ADRs linked to cephalosporin use were observed ranging from oral thrush to clostridium difficile infection. A total of 1039 antimicrobial and nonantimicrobial medications were prescribed concomitantly with cephalosporins. Conclusion The 3rd generation cephalosporins were commonly prescribed by parenteral route. Thus, there is a strong need for rationalizing their use to preserve their efficacy and prevent the development of resistance in the region.

Significance of metabolites in bioequivalence: losartan potassium as a case study.

Estimation of metabolite data as a supportive evidence of comparable therapeutic outcome is recommended by various guidance documents. However, a consensus on using it solely to establish bioequivalence (BE) is lacking as parent drug is believed to detect pharmacokinetic differences between test and reference formulations better. Four BE studies of losartan potassium reported in the literature are reviewed. In all the four studies, 90% confidence intervals (CIs) of geometric mean ratios of the test and reference formulations for maximum blood drug concentration (Cmax ) of losartan potassium were outside the acceptable range of 80%-125%, whereas, 90% CIs for its active metabolite, losartan carboxylic acid (LCA), were within the acceptance criteria. Although BE with respect to area under the plasma concentration versus time profile curve was demonstrated in all the cases, BE with respect to Cmax could not be established. However, marketing authorization in all the four cases was granted based on scientific evidence that LCA is 10-40 times more potent than losartan, LCA exhibited higher plasma concentration levels than losartan, pharmacodynamic effects correlate with LCA, and losartan shows wide therapeutic index. Further, widened CI limits for losartan were accepted. Losartan presents an opportunity in the diligence of the principles of quality risk management for selecting moiety on which BE decision must be based.

Pediatric drug development: formulation considerations.

Absence of safe, effective and appropriate treatment is one of the main causes of high mortality and morbidity rates among the pediatric group. This review provides an overview of pharmacokinetic differences between pediatric and adult population and their implications in pharmaceutical development. Different pediatric dosage forms, their merits and demerits are discussed. Food and Drug Administration Act of 1997 and the Best Pharmaceuticals for Children Act 2002 added 6 months patent extension and exclusivity incentives to pharmaceutical companies for evaluation of medicinal products in children. Prescription Drug User Fee Act and Food and Drug Administration Amendments Act of 2007 made it mandatory for pharmaceutical companies to perform pediatric clinical studies on new drug products. Drug development program should include additional clinical bridge studies to evaluate differences in pharmacokinetics and pharmacodynamics of drugs in adult and child populations. Additionally, pharmaceutical development should consider ease of administration, palatability, appropriate excipients, stability and therapeutic equivalency of pediatric dosage forms. Pediatric population is diverse with individual preferences and demand for custom made dosage formulations. Practically it is not feasible to have different pharmaceutical dosage forms for each group. Hence, an appropriate dosage form that can be administered across pediatric population is warranted.

Quality risk management in pharmaceutical development.

The objective of ICH Q8, Q9 and Q10 documents is application of systemic and science based approach to formulation development for building quality into product. There is always some uncertainty in new product development. Good risk management practice is essential for success of new product development in decreasing this uncertainty. In quality by design paradigm, the product performance properties relevant to the patient are predefined in target product profile (TPP). Together with prior knowledge and experience, TPP helps in identification of critical quality attributes (CQA's). Initial risk assessment which identifies risks to these CQA's provides impetus for product development. Product and process are designed to gain knowledge about these risks, devise strategies to eliminate or mitigate these risks and meet objectives set in TPP. By laying more emphasis on high risk events the protection level of patient is increased. The process being scientifically driven improves the transparency and reliability of the manufacturer. The focus on risk to the patient together with flexible development approach saves invaluable resources, increases confidence on quality and reduces compliance risk. The knowledge acquired in analysing risks to CQA's permits construction of meaningful design space. Within the boundaries of the design space, variation in critical material characteristics and process parameters must be managed in order to yield a product having the desired characteristics. Specifications based on product and process understanding are established such that product will meet the specifications if tested. In this way, the product is amenable to real time release, since specifications only confirm quality but they do not serve as a means of effective process control.