U.S. Pharmacopeial Chapter <800>: Be Ready to Comply by July 2018 
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The U.S. Pharmacopeial Convention's "Chapter <800> Hazardous Drugs-Handling in Healthcare Settings" is a new part of the National Formulary that describes standards-expectations for practice-for all aspects of handling and administering hazardous drugs (HDs). Some of the standards will require changes in policies, procedures, and practices for nurses. This article provides an overview of the new standards and the impact they will have on nurses who prepare and administer chemotherapy and other HDs.
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Factors associated with prescribing restriction on oncology formulary drugs in Malaysia.

Background Drugs listed on formularies are often subjected to a variety of utilization restriction measures. However, the degree of restriction is influenced by multiple factors, including the characteristics and attributes of the listed drugs. Objective To identify the factors that are associated with the levels of prescribing restriction on oncology formulary drugs in Malaysia. Setting Oncology formulary in Malaysia. Method The Malaysia Drug Code assigned to each of the drug products on the Malaysia Ministry of Health (MOH) drug formulary was used to identify oncology drugs belonging to WHO ATC class L (antineoplastic and immunomodulating agents). Main outcome measures Categories of prescribing restrictions, therapeutic class, drug type, administration mode, number of sources and the post-approval use period. Results Oncology drugs having a shorter post-approval use period (p < 0.001), biologic oncology drugs (p = 0.01) and oncology drugs belonging to immunosuppressant therapeutic class (p = 0.03) were all significantly associated with a greater likelihood of being subjected to a higher level of prescribing restriction. Conclusion This study suggests that safety concerns, costs and potentials for inappropriate use were the important considerations influencing a higher level of prescribing restriction placement on oncology drugs in the Malaysia MOH drug formulary.

The heavy metals cadmium, lead and mercury in raw materials of animal origin: evaluation of data from practice.

Raw materials from animal origin are widely used in homoeopathy. Due to the lack of dedicated limits, the quality requirements for herbal drugs of the European Pharmacopoeia (Ph. Eur.) and/or the German Homoeopathic Pharmacopoeia (Homöopathisches Arzneibuch, HAB), including limits for heavy metals such as cadmium, lead and mercury, have been applied. A recent database evaluation shows that for some raw materials of animal origin the Ph. Eur. limits for herbal drugs cannot be met in practice. For this reason proposals for new limits for cadmium, lead and mercury are made based on recent experiences from the companies' daily practice. These specific limits are suggested to be included in the individual monographs of the Ph. Eur. or at least the German HAB, respectively, for Ambra grisea, Euspongia officinalis, Formica rufa and Sepia officinalis.

Avastin doesn't blind people, people blind people.

PURPOSE: To review the appropriate preparation of bevacizumab for intravitreal injection by compounding pharmacies with specific recommendations designed to prevent microbial contamination. DESIGN: Perspective. METHODS: A review and discussion of compounding issues with supporting literature, clinical experience, illustrations, and expert opinion. RESULTS: Closer examination of the events surrounding the recent clusters of infectious endophthalmitis cases occurring after the intravitreal injection of bevacizumab suggest that the vision loss is not the result of the drug or the injection technique, but rather of the compounding procedures used to prepare the syringes containing the bevacizumab. Noncompliance with recognized standards and poor aseptic technique are the most likely causes of these outbreaks. The key to preventing these catastrophic occurrences depends on the implementation of and strict adherence to United States Pharmacopoeia Chapter 797 requirements. CONCLUSIONS: Recommendations arising from a root cause analysis of infectious endophthalmitis outbreaks should focus on the procedures used by pharmacies to compound bevacizumab. Microbial contamination of bevacizumab-containing syringes prepared from the same vial of drug can be avoided by using a single vial of bevacizumab for each eye or by following strict adherence to United States Pharmacopoeia Chapter 797 requirements when compounding a single vial of bevacizumab into multiple syringes.

The application of ICH S6 to the preclinical safety evaluation of plasma derivative therapeutic products.

The ICH S6 guidance was developed to describe a rational science-based flexible approach to the preclinical evaluation for biotechnology-derived pharmaceutical products. It also suggested that some of the principles described may be suitable for plasma-derived therapeutics. Some of the specific concerns unique to protein-based therapeutics include complexity in structure and potential immunogenicity. S6 has been interpreted by some industry and regulatory authorities, often due to lack of experience with these types of products, as encouraging a broader or more conventional toxicology program similar to that normally conducted for small molecules. The guidance does encourage important and necessary preclinical evaluations but also recognizes the limitations of studies in non-relevant animal species because they are without pharmacological interaction with the biologic. In addition, studies of human proteins are often limited in useful chronic, reproductive and carcinogenic toxicity evaluations by the immunological response in animals. Thus the safety evaluation of biopharmaceuticals and plasma derivatives in animals has limitations that cannot be adequately addressed by the use of testing paradigms used for small molecule pharmaceuticals. S6 focuses evaluations on well-designed studies in relevant species for reasonable time periods to make the best use of available resources and enable clinical trials.

Differences in the availability of new anti-cancer drugs for Italian patients treated in different regions. Results of analysis conducted by the Italian Society Of Medical Oncology (AIOM).

AIMS AND BACKGROUND: Italy is divided into 20 regions. As a consequence of local autonomy, following marketing authorization by the Italian Medicines Agency, each drug for hospital use is not immediately available, because its approval needs to undergo further steps that can be different among regions. The Italian Society of Medical Oncology conducted the present study to describe the impact of the existence of sub-national pharmaceutical formularies on the disparity of access to new anti-cancer drugs among patients treated in different Italian regions. METHODS: The availability of 8 new anti-cancer drugs at a regional level and the coherence of regional authorizations compared with national authorizations approved by the Italian Medicines Agency were analyzed as of April 2009. RESULTS: Fourteen regions and autonomous province of Trento have a regional pharmaceutical formulary. In most cases, the regional pharmaceutical formularies include the eight analyzed drugs, with therapeutic indications coherent with national marketing authorization indications. Five drugs (bevacizumab, trastuzumab, rituximab, erlotinib, sunitinib) were included in all the existing regional pharmaceutical formularies, without restrictions, whereas three drugs (cetuximab, sorafenib, pemetrexed) were found to have restrictions in some regions. CONCLUSIONS: The presence of multiple hierarchical levels of drug evaluation creates a potential element of disparity in the access to pharmacological therapies for Italian citizens.

A practical approach for the validation of sterility, endotoxin and potency testing of bone marrow mononucleated cells used in cardiac regeneration in compliance with good manufacturing practice.

BACKGROUND: Main scope of the EU and FDA regulations is to establish a classification criterion for advanced therapy medicinal products (ATMP). Regulations require that ATMPs must be prepared under good manufacturing practice (GMP). We have validated a commercial system for the determination of bacterial endotoxins in compliance with EU Pharmacopoeia 2.6.14, the sterility testing in compliance with EU Pharmacopoeia 2.6.1 and a potency assay in an ATMP constituted of mononucleated cells used in cardiac regeneration. METHODS: For the potency assay, cells were placed in the upper part of a modified Boyden chamber containing Endocult Basal Medium with supplements and transmigrated cells were scored. The invasion index was expressed as the ratio between the numbers of invading cells relative to cell migration through a control insert membrane. For endotoxins, we used a commercially available system based on the kinetic chromogenic LAL-test. Validation of sterility was performed by direct inoculation of TSB and FTM media with the cell product following Eu Ph 2.6.1 guideline. RESULTS AND DISCUSSION: The calculated MVD and endotoxin limit were 780x and 39 EU/ml respectively. The 1:10 and 1:100 dilutions were selected for the validation. For sterility, all the FTM cultures were positive after 3 days. For TSB cultures, Mycetes and B. subtilis were positive after 5 and 3 days respectively. The detection limit was 1-10 colonies. A total of four invasion assay were performed: the calculated invasion index was 28.89 +/- 16.82% (mean +/- SD). CONCLUSION: We have validated a strategy for endotoxin, sterility and potency testing in an ATMP used in cardiac regeneration. Unlike pharmaceutical products, many stem-cell-based products may originate in hospitals where personnel are unfamiliar with the applicable regulations. As new ATMPs are developed, the regulatory framework is likely to evolve. Meanwhile, existing regulations provide an appropriate structure for ensuring the safety and efficacy of the next generation of ATMPs. Personnel must be adequately trained on relevant methods and their application to stem-cell-based products.

Systematic review: reliability of compendia methods for off-label oncology indications.

BACKGROUND: The Centers for Medicare & Medicaid Services limit coverage of cancer drugs for off-label indications to indications listed in specified compendia. PURPOSE: To assess whether compendia provide comprehensive, research-based, and timely information for off-label prescribing in oncology. DATA SOURCES: 6 drug compendia, English-language literature searches of MEDLINE and the Cochrane Central Register of Controlled Trials from 2006 and 2008, and American Society of Clinical Oncology annual meeting abstracts from 2004 to 2007. Data Assessment: The compendia's stated methods, literature related to off-label indications of 14 cancer drugs in 2006, updated literature related to 1 off-label indication between 2006 and 2008, and completeness of compendia content and citations were assessed. DATA SYNTHESIS: The compendia's stated methods varied greatly from their actual practices. Compendia cited little of the available evidence, often neither the most recent nor that of highest methodological quality. Compendia differed in evidence cited, terminology, detail, presentation, and referencing. For the 14 off-label indications studied, the compendia differed in the indications included and whether and how they recommended particular agents for particular types of cancer. Update schedules varied, and documentation practices made it difficult to determine whether and when compendia content was updated. For 1 indication, compendia citations did not increase between 2006 and 2008 despite newly published articles. LIMITATIONS: The 2006 analysis was limited to 14 off-label indications; the 2008 update examined 1 indication. Only off-label indications for cancer drugs were included, and results cannot be generalized to noncancer drugs or indications. CONCLUSION: Oncologists rely on compendia for up-to-date access to evidence and reimbursement information for off-label indications. Current compendia lack transparency, cite little current evidence, and lack systematic methods to review or update evidence.

Effect of two work practice changes on the microbial contamination rates of pharmacy-compounded sterile preparations.

PURPOSE: Using a multiple-step testing medium-risk-level compounding test procedure, the evaluation of two work-practice changes to determine if the changes could effectively reduce the potential for contamination occurrence was conducted. SUMMARY: Along with training and evaluation of aseptic sterile compounding techniques, each individual pharmacist and pharmacy technician at M. D. Anderson Cancer Center must successfully demonstrate aseptic preparation competency annually by performing the complicated multistep aseptic transfers of growth medium with no resulting growth of microorganisms. The multistep aseptic transfers are designed to simulate manual compounding of the most complicated medium-risk-level preparations anticipated as specified in the United States Pharmacopeia's chapter 797. An evaluation of two modest and simple work-practice changes was conducted: The use of bare hands and nonsterile gloves with only initial disinfection with 70% isopropyl alcohol (IPA) during years 1 and 2 (group A) was compared with the use of nonsterile chemotherapy gloves with initial and repeated disinfection with IPA for year 3 (group B) and the use of sterile gloves with initial and repeated disinfection with IPA for year 4 (group C). The process involved multiple discrete manipulations, including reconstitution of dry-growth medium; transfers of growth medium from vials and ampules using syringes, needles, a dispensing pin, and a filter straw; and transfers to an empty plastic i.v. bag. For groups B and C, significant reductions in contaminated samples were found compared with group A. CONCLUSION: The use of protective chemotherapy gloves that were repeatedly disinfected with IPA decreased the contamination rate of pharmacy-compounded sterile preparations.

Formulario nacional de medicamentos / National Formulary

El presente documento es la consolidación del esfuerzo de un grupo de especialistas del Centro para el Desarrollo de la Farmacoepidemiología y colaboradores de distintos centros y unidades de salud del Ministerio de Salud Pública de Cuba. Con este pretendemos dotar a los profesionales sanitarios de una bibliografía mínima e imprescindible, que sea una herramienta útil para alcanzar el objetivo propuesto.

Investigation of product quality between extemporaneously compounded progesterone vaginal suppositories and an approved progesterone vaginal gel.

The purpose of this investigation was to compare quality parameters, including product appearance, content uniformity, pH, weight uniformity, microbial limit testing and preservative effectiveness testing on extemporaneously compounded progesterone vaginal suppositories obtained from 10 randomly chosen compounding pharmacies (90 suppositories each) across the United States, to the Food and Drug Administration (FDA) approved prescription progesterone gel product (Prochieve/Crinone) which is manufactured in a cGMP regulated facility. The content uniformity and pH were determined using qualified methods. The microbial limits testing and preservative effectiveness testing were conducted according to compendial methods. Only one pharmacy provided suppositories that were all within the potency limits required for the prescription progesterone gel product. The other pharmacies provided at least some suppositories where progesterone content was either subpotent or superpotent for progesterone. The pH of most of the compounded suppository products was in the range of 4.22 to 7.68 with a median of 6.30 (normal vaginal pH is <5), whereas the gel product was 2.80. For compounded product from one of the pharmacies, microbial limits testing indicated CDC group IVC-2 and Comamonas acidovorans were detected. This data indicates that pharmacy compounded delivery systems for progesterone should be used with caution.

Standardization of the body surface area (BSA) formula to calculate the dose of anticancer agents in Japan.

BACKGROUND: The importance of deciding the appropriate dose of anticancer agents cannot be overemphasized. Body surface area (BSA) has been used to calculate the dose in anticancer therapy since the 1950s. Japanese oncologists, often use their own Japanese BSA formula instead of western BSA formulae. However, it is not widely known that some discrepancies exist between the BSA products of the Japanese and western styles. On the other hand, recently dose-calculations according to BSA were criticized from the standpoint of pharmacokinetics (PK). Lately, we have had many opportunities for international collaborations, which make it necessary to review these BSA formulae, and the BSA-based dosing method. A unified BSA formula in cancer therapy is needed in Japan. METHODS: We searched and compiled frequently used BSA formulae across the world using the MEDLINE search, oncology text, a web search on cancer clinical trial groups, and personally communicated with medical oncologists from western countries. Using these formulae, we calculated BSA for a typical Japanese individual, and compared their products. We calculated BSA using these formulae for individuals of widely varying physique, from 140 to 185 cm in height, and from 30 to 96 kg in weight, and estimated the amount of discrepancies among them. RESULTS: Among the various BSA formulae used in western countries, the DuBois formula is the standard. In Japan, the Fujimoto formula has been used frequently. The Fujimoto formula was based on a study of 201 Japanese subjects in 1949. For the average Japanese individual, the BSA calculated using the Fujimoto formula was about 3% lower than that which was calculated by western formulae. The BSA calculated for all heights and body weights using the Fujimoto formula, ranged between 0.7 and 4.8% less than those calculated by using the DuBois formula. The other western formulae showed larger discrepancies than the Fujimoto and DuBois formulae. CONCLUSION: BSA-based dosing has failed to standardize the variation in PK for most anticancer agents, and individual dosing techniques are currently being investigated. However, until their clinical utilities are confirmed, it is necessary to depend on the BSA-based calculation for determining the dose of most anticancer agents. The DuBois formula, which is the western standard formula, is validated to a greater extent and its accuracy has been confirmed more than others, including the Fujimoto formula. We recommend the use of the DuBois formula instead of the Fujimoto formula in cancer chemotherapy and propose the standardization of this formula in Japan.

Drug policy: making effective drugs available without bankrupting the healthcare system.

To the extent possible, drug policy should be based upon good quality evidence. This must extend beyond the traditional focus on efficacy and safety in carefully selected patients, to evidence about real-world effectiveness, cost-effectiveness and safety of drugs. This paper will consider methods of improving the quality of the evidence currently available, and the implications of requiring that evidence. Historically, there has been a direct link between research evidence and policy at the level of licensing - drugs are only made available after they have been shown to be safe and efficacious in well-designed and independently assessed research studies. We propose that this reliance on evidence be logically extended to cover the formulary inclusion and post-marketing surveillance aspects of modern prescription drug policy. More specifically we propose that the decision to initially list a drug on a benefit formulary be based on evidence from relevant head-to-head comparisons and well-designed cost-effectiveness analyses. This evidence would be produced by industry in cooperation with independent peer-reviewed funding agencies. Drugs could only be added to a formulary if they met specific predetermined criteria, and drugs could be removed as superior alternatives became available. The provincial governments are monopsony buyers of medicines, and they wield the power to determine public payer "market access'for medicines. This power (within and across provinces) could be used more effectively to negotiate price in the context of reimbursement. The effect of different methods of influencing prescribing (e.g., 'limited access?) upon drug utilization and patient outcomes should be rigorously assessed, including the randomization of groups of patients or communities to different strategies. We also propose that all drugs on the formulary would be subject to a well-designed post-marketing surveillance program. This program would build on the existing passive reporting of adverse events by adding a proactive system that would systematically describe the use and impact of drugs. The notion of drug safety would be extended to include not only adverse events, but also inappropriate use of drugs that results inpatients receiving drugs that do not benefit them. Inappropriate use wastes resources and can put patients and populations at risk.

Getting the cat back in the bag: reforming the way provinces manage drug expenditures to make them manageable.

The fiscal "cat" of healthcare spending - drug expenditures - is out of the bag: drug costs are now the fastest rising component of healthcare expenditures in Canada. Laupacis, Anderson and O'Brien describe the current process of listing drugs on the provincial drug formulary in Ontario, identify factors that may contribute to the rapid growth in drug expenditures, and make a number of recommendations for controlling drug expenditures, including (1) improving the evidence on cost-effectiveness; (2) disseminating the evidence to prescribers; (3) re-evaluating the evidence; and (4) increasing the transparency about the acquisition costs of drugs. These are recommendations that, if implemented, would theoretically help decision-makers make more rational decisions about which drugs to list on provincial formularies. The question of how to implement the recommendations remains to be elucidated, as does an evaluation of the trade-offs between costs and benefits of obtaining better information on cost-effectiveness.

Let evidence be the arbiter.

Methods for evaluating drugs to ensure there is value for money spent have been debated for years. There have been many attempts at controlling the use of drugs starting with formularies, limited listings for specific uses and the negotiation of prices. The strategy put forward by the lead authors would be helpful to all parties. Their proposal would allow evidence to be the arbiter and provide information that is understood by all concerned. It would take courage by all interested parties to accept these ideas. However, the time is right for the adoption of a better way to keep drug programs affordable without denying anyone the treatments that can make a difference to their health.