Identification of Substandard and Falsified Medicines: Influence of Different Tolerance Limits and Use of Authenticity Inquiries.

Substandard and falsified medicines have severe public health and socioeconomic effects, especially in low- and middle-income countries. The WHO has emphasized the need for reliable estimates of the prevalence of such medicines to efficiently respond to this problem. In the present study, we used 601 medicine samples collected in Cameroon, the DR Congo, and Malawi to assess the rates of substandard and falsified medicines based on different criteria. Based on the specifications of the U.S. Pharmacopoeia for the amount of the active pharmaceutical ingredients, the rate of out-of-specification medicines was 9.3%. By contrast, this rate ranged from 3.3% up to 35.0% if the tolerance limits of other pharmacopoeias or recently published medicine quality studies were used. This shows an urgent need for harmonization. Principal methods to assess the rate of falsified medicines are packaging analysis, chemical analysis, and authenticity inquiries. In the present study, we carried out an authenticity inquiry for the aforementioned medicine samples, contacting 126 manufacturers and 42 distributors. Response rates were higher for samples stated to be manufactured in Asia (52.4%) or Europe (53.8%) than for samples manufactured in Africa (27.4%; P < 0.001). One sample had been identified as falsified by packaging analysis by the local researchers and two additional ones by chemical analysis. Notably, seven additional falsified samples were identified by the authenticity inquiries. The total rate of falsified medicines resulted as 1.7%. Considerations are discussed for assessing the rates of "substandard" and "falsified" medicines in future medicine quality studies.

Review of economic data on closed system transfer drug for preparation and administration of hazardous drugs.

OBJECTIVES: The objectives of this study were to review economic data on the use of closed system drug transfer devices (CSTDs) for preparing and administering hazardous drugs, and to evaluate the quality of data reporting as defined by the Consolidated Health Economic Evaluation Reporting Standards (CHEERS). METHODS: All references from a recent Cochrane review about CSTDs were evaluated for inclusion. A literature review was also conducted. Articles containing economic data about the use of CSTDs were retained for analysis. Two researchers independently graded the articles according to the 24-item CHEERS checklist. RESULTS: Of the 138 articles identified initially, 12 were retained for analysis. Nine of these studies did not report acquisition costs or did not detail acquisition costs. Six studies reported economic benefits associated with the used of CSTDs, all related to extending the beyond-use date. The mean number of CHEERS criteria fulfilled by the included articles was 9.2 (SD 2.4). CONCLUSIONS: CSTDs are costly to acquire. However, few studies have examined the economic impact of these devices, and the existing studies are incomplete. As a result, hospitals planning to implement these devices will be unable to make a sound economic evaluation. Robust economic evaluation of CSTDs is needed.

Vaccine dose usage and wastage in the Metropolitan Region of Porto Alegre, Rio Grande do Sul, Brazil: a descriptive study, 2015-2017. / Utilização e perda de doses de vacinas na Região Metropolitana de Porto Alegre, Rio Grande do Sul: um estudo descritivo de 2015-2017.

OBJECTIVE: to estimate usage and wastage of multi-dose and single-dose vaccine vials in the Metropolitan Region of Porto Alegre, Rio Grande do Sul, Brazil, from 2015 to 2017. METHODS: a descriptive study was carried out based on secondary data from the National Immunization Program Information System (SIPNI) and the Strategic Health Supplies Information System (SIES). RESULTS: a total of 12,342 records were examined; mean wastage rate was 45.8% (95%CI 39.5;51.7), while usage rate was 54.2% (95%CI 48.3;60.5); vaccines with the highest mean annual wastage rate were MMR (68.8% - 95%CI 66.5;71.1), BCG (68.1% - 95%CI 65.4;70.7), Hepatitis B (56.4% - 95%CI 53.0-59.7) and Yellow Fever (55.9% - 95%CI 51.4;60.4). CONCLUSION: the highest rates of vaccine wastage were for multi-dose vials; although single-dose vaccines also exceeded the acceptable limit defined by the World Health Organization.

Assessment of "look-alike" packaging designs related to medication errors using information technology.

This study aimed to assess the similarity among press-through pack (PTP) sheets of pharmaceutical products in Japan. The appearance of PTPs was assessed using a pharmaceutical design database (PDD) of 2,750 pharmaceutical tablets comprising approximately 40 % of the 6,840 products marketed in Japan. Package sheet color (Sc), tablet color (Tc), character color (Cc), sheet line color (SLc), and upper color (Uc) were used to evaluate the uniformity of PTP sheet design. To assess the risk of misidentification, 1,000 prescriptions for 82,273 cancer patients were retrieved from 21,026,742 records in the claims database of the Japan Medical Data Center Co. Ltd., Tokyo, Japan. The most frequent PTP sheet colors for 143 drugs were Sc (silver), Tc (white), Cc (blue), SLc (none), and Uc (silver). The prescribing pattern of 1000 randomly chosen prescriptions was analyzed. Database records of prescriptions without tablets (n = 69), including only one PTP tablet (n = 292), and those with lack of PDD prescription data (n = 388) were excluded. Eventually, 236 prescriptions were evaluated. Fourteen prescriptions (5.9%) had PTP sheets with five matching elements and 29 had with four matching elements (12.3%). This novel PDD database for information technology concept easily identified similar PTP sheets involved in prescriptions dispensed in 18 % of evaluated cancer patients. The concept seems to be applicable for preventing look-alike dispensing errors.

Drug identification by the patient: Perception of patients, physicians and pharmacists.

INTRODUCTION: Faced with the increasing number of pharmaceutical products on the market, several pharmacovigilance notifications regarding confusion between look-alike and sound-alike drugs have been reported. This study of perception among patients, family physicians and pharmacists aims to evaluate drug identification factors and the risk of errors of confusion for patients. MATERIAL AND METHODS: Patients were systematically approached in randomly selected pharmacies within the Midi-Pyrénées region in France and invited to complete a questionnaire. Two other questionnaires were respectively sent to family physicians and pharmacists in the same region asking for their opinion on patients' perception of the identification of prescribed medicines. RESULTS: Of the 768 patients interviewed, most report identifying their medications by name (brand name: 50%; generic: 21%), while a smaller number cite physical appearance (box: 16%, tablet: 7% and blister packaging: 3%). In practice the factors considered most likely to cause confusion by patients relate to drug appearance (look-alike tablets: 28%, look-alike boxes: 20% and look-alike blister packaging: 13%). In contrast, look-alike and sound-alike names (generic and brand names combined) were cited in 31% of cases. Physicians (n=345) and pharmacists (n=198) understimate that patients identify their treatment by name (physicians: 46%; pharmacists: 26% vs. patients: 71%), reporting instead that problems arise mainly from the appearance of medicines (physicians: identification: 52% and risk factors for confusion: 74%; pharmacists: identification: 74% and risk factors for confusion: 83%; versus patients: identification: 26%; risk factors for confusion: 61%). DISCUSSION: Our study highlights the critical role of medication name in identifying drugs among patients. However, confusion of look-alike tablets or pills figures prominently among fears surrounding medication errors. Despite several notifications of pharmacovigilance, this issue appears to be underestimated within the body of medical literature. Proper identification of medicines by patients is essential to improving medication safety and therapeutic compliance. Concrete measures can be undertaken to reach this goal.

Little filtered cigars: US sales, flavours, package sizes and prices.

OBJECTIVE: At least four varieties of little filtered cigars (LFCs) violate the US prohibition on flavoured cigarettes other than menthol. This study characterises the sales of prohibited products and other LFCs by flavour category and pack size, as well as the price of LFCs relative to cigarettes. METHODS: Using retail sales data for 2016, we computed the sales volume in dollars and equivalent units and the percentage of total sales by flavour and pack size for the USA by region and state. Paired t-tests compared the prices for LFCs and cigarettes sold in same-sized packs and cartons. RESULTS: LFC sales totalled 24 033 equivalent units per 100 000 persons in 2016. Flavoured LFC varieties accounted for almost half (47.5%) of the total sales. LFCs were sold in 12 different pack sizes, but 79.7% of sales were packs of 20. The price of 20-packs averaged $2.41 (SD=$1.49), which was significantly less than cigarettes (M=$5.90, SD=$0.85). Regional differences suggest a greater proportion of menthol/mint LFCs and lower prices in the South than in other regions. CONCLUSION: Classifying all LFCs as cigarettes would require that they be offered in a minimum package of 20, eliminate flavoured varieties other than menthol and increase prices through applicable state and local cigarette taxes.

Readability assessment of package inserts of biological medicinal products from the European medicines agency website.

BACKGROUND: Package inserts that accompany medicines are a common source of information aimed at patients and should match patient abilities in terms of readability. OBJECTIVE: Our objective was to determine the degree of readability of the package inserts for biological medicinal products commercially available in 2007 and compare them with the readability of the same package inserts in 2010. METHODS: A total of 33 package inserts were selected and classified into five groups according to the type of medicine: monoclonal antibody-based products, cytokines, therapeutic enzymes, recombinant blood factors and other blood-related products, and recombinant hormones. The package inserts were downloaded from the European Medicines Agency website in 2007 and 2010. Readability was evaluated for the entire text of five of the six sections of the package inserts and for the 'Annex' when there was one. Three readability formulas were used: SMOG (Simple Measure of Gobbledygook) grade, Flesh-Kincaid grade level, and Szigriszt's perspicuity index. RESULTS: No significant differences were found between the readability results for the 2007 package inserts and those from 2010 according to any of the three readability indices studied (p>0.05). However, there were significant differences (p<0.05) between the readability scores of the sections of the package inserts in both 2007 and 2010. The readability of the package inserts was above the recommended sixth grade reading level (ages 11-12) and may lead to difficulties of understanding for people with limited literacy. CONCLUSIONS: All the sections should be easy to read and, therefore, the readability of the medicine package inserts studied should be improved.

Long term effect of reduced pack sizes of paracetamol on poisoning deaths and liver transplant activity in England and Wales: interrupted time series analyses.

OBJECTIVE: To assess the long term effect of United Kingdom legislation introduced in September 1998 to restrict pack sizes of paracetamol on deaths from paracetamol poisoning and liver unit activity. DESIGN: Interrupted time series analyses to assess mean quarterly changes from October 1998 to the end of 2009 relative to projected deaths without the legislation based on pre-legislation trends. SETTING: Mortality (1993-2009) and liver unit activity (1995-2009) in England and Wales, using information from the Office for National Statistics and NHS Blood and Transplant, respectively. PARTICIPANTS: Residents of England and Wales. MAIN OUTCOME MEASURES: Suicide, deaths of undetermined intent, and accidental poisoning deaths involving single drug ingestion of paracetamol and paracetamol compounds in people aged 10 years and over, and liver unit registrations and transplantations for paracetamol induced hepatotoxicity. RESULTS: Compared with the pre-legislation level, following the legislation there was an estimated average reduction of 17 (95% confidence interval -25 to -9) deaths per quarter in England and Wales involving paracetamol alone (with or without alcohol) that received suicide or undetermined verdicts. This decrease represented a 43% reduction or an estimated 765 fewer deaths over the 11¼ years after the legislation. A similar effect was found when accidental poisoning deaths were included, and when a conservative method of analysis was used. This decrease was largely unaltered after controlling for a non-significant reduction in deaths involving other methods of poisoning and also suicides by all methods. There was a 61% reduction in registrations for liver transplantation for paracetamol induced hepatotoxicity (-11 (-20 to -1) registrations per quarter). But no reduction was seen in actual transplantations (-3 (-12 to 6)), nor in registrations after a conservative method of analysis was used. CONCLUSIONS: UK legislation to reduce pack sizes of paracetamol was followed by significant reductions in deaths due to paracetamol overdose, with some indication of fewer registrations for transplantation at liver units during the 11 years after the legislation. The continuing toll of deaths suggests, however, that further preventive measures should be sought.

Storage and wastage of drug products in Jordanian households: a cross-sectional survey.

OBJECTIVE: Appropriate household storage and use of drug products can reduce drug wastage and unnecessary hazards. We aimed to quantify the amounts and types of medications that were stored in Jordanian households and the extent of drug wastage in terms of the amount and cost of these medications. METHODS: The setting was households in Amman, Jordan. This was a cross-sectional survey study using a pre-piloted questionnaire. Family members were interviewed in person about use of drug products, and where drug products were stored. The main outcomes were types, storage methods, cost and quantities of drug products in every household. KEY FINDINGS: Two hundred and forty-three households were approached, out of which 219 agreed to participate. A total of 2393 (mean 10.9, SD 5.2) drug products were recorded from the 219 households surveyed. A significant positive correlation was noted between the number of drug products in a household and family size (r = 0.19, P < 0.01), the level of the mother's education (r = 0.24, P < 0.01), the level of the father's education (r = 0.28, P < 0.01) and income (r = 0.14, P = 0.034). Eighty nine (40.6%) households had at least one child younger than 6 years of age, and 1122 (46.9%) drug products were stored in unsafe places in the houses, within the reach of children. More than a quarter of drug products (1509, 27.2%) were not in their original containers, 360 (15%) were unused since dispensing, 261 (10.9%) had expired and 44 (1.8%) had no clear expiry date. We estimated that the cost of drug wastage in the 219 households was US$5414. Paracetamol (202, 8.4%), diclofenac (98, 4.1%) and amoxicillin (79, 3.3%) were the most commonly reportedly stored individual drugs. CONCLUSION: Drug products are stored in large quantities in Jordanian households. Unsafe storage practices have the potential to pose safety hazards, especially to children.

Pattern of extemporaneous prescriptions and preparations in a tertiary health institution: a five-year assessment.

Due to the increasing rate in the demand of extemporaneous formulations, it became necessary to assess the pattern of prescription and preparation in a developing institution. The purpose of this study was to assess the pattern of extemporaneous prescription and preparation in the University of Benin Teaching Hospital, Benin City, Nigeria. Records of prescription and preparation of extemporaneous formulations were assessed retrospectively between 2007 and 2011. Fifty-nine different types of drugs were prescribed with a frequency of 6,882 times during the period. These were indicated for eight classes of systemic disease. Eighteen drugs were indicated for central nervous diseases, followed by 16 drugs for cardiovascular diseases. Of the 18 drugs indicated for central nervous diseases, pyridoxine was the most common. Rifampicin for tuberculosis was the most frequently formulated, followed by spironolactone for cardiovascular disorders. Most preparations were labeled to be used for a maximum of two weeks. They were all liquid preparations packaged in amber-colored bottles. Distilled water was the most common vehicle utilized for trituration; while ascorbic acid syrup was commonly used to bulk the solution and as a sweetening agent. None of the patients reported with any form of pharmaceutical degradation or toxicity within two weeks of expected use. There were reports of spillages due to poor handling. Maximum volume prepared was 75 mL. The study suggests an adequate setup of a quality-control unit in the institution to meet the increasing demand for specific agents. This will enhance an effective healthcare delivery among patients.

Combining a hybrid genetic algorithm and a heat transfer model to optimise an insulated box for use in the transport of perishables.

Temperature sensitive products are often transported in non-refrigerated systems, protected from environmental temperatures by thermal insulation and the provision of a source of cold inside the package. This work presents a method for optimising the design of thermally insulated boxes for lowest cost (while ensuring that product temperatures are maintained within set limits) by combining a heat transfer model with genetic algorithm optimisation. An example optimisation problem is presented in which a temperature sensitive product is transported across the US and must be maintained between -1 and 8 degrees C. Independent optimisation operations successfully identified solutions that were very similar, though not identical, thereby providing confidence in the approach to determine optimal solutions to complex problems. The system developed provides a rapid method to optimise the design of an insulated box for minimum cost while maintaining the product in the appropriate temperature range.

Optimizing information on drug exposure by collection of package code information in questionnaire surveys.

PURPOSE: The thorough analysis of special drug characteristics requires information on the specific brand of a drug. This information is often not sought in pharmacoepidemiologic surveys although in many countries packages are labelled with an unequivocal code (in Germany called Pharmazentralnummer (PZN)). We aimed to assess the benefit and quality of PZN information collected in self-completed questionnaires. METHODS: We performed a survey in 905 ambulatory patients who were asked to list brand name, strength, and the PZN of all drugs they were taking. RESULTS: The medication list was completed by 97.5% (n = 882) of the responding patients (mean age 67.3 years). Altogether 5543 drugs (100%) were mentioned in the questionnaires and for 4230 (76.3%) the exact drug package could be allocated on the basis of the PZN. When PZN was considered in addition to the drug name the quality of drug coding was significantly improved (p < 0.001) with regard to the allocation of drug package (74% versus 2%), brand (90% versus 70%), and strength (96% versus 86%). The time needed for drug coding was three times shorter. CONCLUSIONS: The high response rate and high fraction of correct PZN indicate that the collection of package code information is a valuable method to achieve more accurate drug data in questionnaire surveys and to facilitate the drug coding procedure.

Nonsteroidal antiinflammatory drug starter packs for chronic musculoskeletal pain.

STUDY OBJECTIVE: To determine whether prescribing a nonsteroidal antiinflammatory drug (NSAID) starter pack for chronic musculoskeletal pain expedites the process of finding an appropriate drug for a given patient. DESIGN: Prospective patient interviews. SETTING: Veterans Affairs Medical Center. PATIENTS: Sixty-four patients with chronic musculoskeletal pain were prescribed NSAID starter packs. Of those, 42% were interviewed and their data evaluated. INTERVENTION: Between March and June 2001, patients received starter packs containing 1-week supplies of the following NSAIDs: ibuprofen, salsalate, etodolac, naproxen, sulindac, and piroxicam. The patients took one drug each week, then returned to their providers to receive a prescription for the agent that was considered most effective and tolerable. MEASUREMENTS AND MAIN RESULTS: Patients assessed pain each day based on a numeric pain-rating scale. During telephone interviews, seven patients reported better pain control when they were able to select a drug from the starter pack than when they were prescribed a specific drug by their providers. Providers rated the starter pack as easy to use by patients and generally effective for finding the best NSAID for a particular patient. Drugs prescribed after completing the starter pack were salsalate 25.9%, piroxicam 22.2%, etodolac 14.8%, ibuprofen 14.8%, naproxen 11.1%, celecoxib 7.4%, and an opiate 3.7%. CONCLUSION: The NSAID starter pack appears to be a successful method for quickly and easily finding an NSAID that is effective and tolerated.

Progress and problems in the prescribing/dispensing split and "divided package sales" by wholesalers.

Given the rapid progress of the prescribing/dispensing split, the ability of pharmacies to obtain and stock a small quantity of pharmaceuticals is seen as essential. Toho Yakuhin's experience in "divided package sales" (wholesalers open an original package supplied by the manufacturer and sell only a part of the contents) shows that the number of orders and sales amount, and the number of pharmacies ordering in sales have remarkably increased. One or two kinds of pharmaceuticals were ordered in 73% cases, and one or two units in about 50%. This implies that "divided package sales" are utilized to obtain rarely prescribed drugs. On the other hand, five or more kinds of pharmaceuticals were ordered in 10% of cases, and ten or more units in 17%. "Divided package sales" were more used for low-price drugs. These indicated that "divided package sales" seemed to be looked upon by pharmacies as a means of obtaining a small quantity of pharmaceuticals, and seemed to be used not only in an emergency but also routinely. There are several problems for wholesalers in operating "divided package sales", such as frequent delivery, delivery cost and information supply. Pharmacies should obtain a small quantity of pharmaceuticals by the routine delivery and should share the delivery cost. Pharmaceutical manufacturers' cooperation in printing necessary information on each immediate container will be useful. Though there could be alternative ways of obtaining a small quantity of pharmaceuticals, all of them have the matter of delivery. We believe "divided package sales" will contribute to this situation.

Waste generation of drug product samples versus prescriptions obtained through pharmacy dispensing.

Drug samples are often packaged differently from bulk packaging and thus they may contain a disproportionate amount of waste material. Fifteen drug samples were obtained from seven pharmaceutical companies and the packaging materials were weighed after the samples were removed. The waste produced by the samples was determined for a standard amount of drug and compared with the weight of the waste produced when the same quantity of drug was dispensed through a pharmacy. The average weight of the sample package for a standard course of therapy was significantly greater (p< or =0.05) than that of the pharmacy-dispensed prescription waste weight. The former was 5+/-4.5-fold heavier than the latter. The waste generated by drug samples in the United States was determined to be 5740 metric tons/year.

Pharmacists' use of safety caps on refilled prescriptions.

Investigations have shown that pharmacists' use of child-resistant containers for dispensing prescriptions has been inconsistent. Use of new child-resistant containers when refilling prescription orders, however, has not been studied. For this study, an investigator presented a prescription order for 30 amitriptyline 50-mg tablets to 50 randomly selected pharmacies in Memphis. Approximately three weeks later, the investigator returned the empty prescription vials to the pharmacies for refills. Of the 44 pharmacies that completed the study, 39 (89%) dispensed the original drug in child-resistant containers, and 38 (86%) dispensed the refill in child-resistant containers. Only 29 (66%) refilled prescriptions were placed in new prescription vials, as specified by federal regulation. Chain pharmacies were twice as likely (p < 0.005) to dispense the refills in new containers as were independent pharmacies.

Two-stage sampling in pharmaceutical applications.

In the pharmaceutical industry, some tests for quality assurance before, during and after the manufacture of a drug product involve a two-stage sampling technique. We propose statistical testing procedures in a two-stage sampling problem with large within-class sample sizes. We also derive a two-stage sampling plan by minimizing the expected squared volume (or the generalized variance) of the confidence region related to the test. We present two examples to illustrate the proposed methods.