Environmental contamination, product contamination and workers exposure using a robotic system for antineoplastic drug preparation.

Environmental contamination, product contamination and technicians exposure were measured following preparation of iv bags with cyclophosphamide using the robotic system CytoCare. Wipe samples were taken inside CytoCare, in the clean room environment, from vials, and prepared iv bags including ports and analysed for contamination with cyclophosphamide. Contamination with cyclophosphamide was also measured in environmental air and on the technicians hands and gloves used for handling the drugs. Exposure of the technicians to cyclophosphamide was measured by analysis of cyclophosphamide in urine. Contamination with cyclophosphamide was mainly observed inside CytoCare, before preparation, after preparation and after daily routine cleaning. Contamination outside CytoCare was incidentally found. All vials with reconstituted cyclophosphamide entering CytoCare were contaminated on the outside but vials with powdered cyclophosphamide were not contaminated on the outside. Contaminated bags entering CytoCare were also contaminated after preparation but non-contaminated bags were not contaminated after preparation. Cyclophosphamide was detected on the ports of all prepared bags. Almost all outer pairs of gloves used for preparation and daily routine cleaning were contaminated with cyclophosphamide. Cyclophosphamide was not found on the inner pairs of gloves and on the hands of the technicians. Cyclophosphamide was not detected in the stationary and personal air samples and in the urine samples of the technicians. CytoCare enables the preparation of cyclophosphamide with low levels of environmental contamination and product contamination and no measurable exposure of the technicians.

Assessment of the risk of needlestick injuries associated with intravitreal injections.

PURPOSE: To assess the overall risk of needlestick injuries (NSIs) associated with intravitreal injection, and more specifically related to the practice of compounding pharmacies of applying informational adhesive stickers to repackaged bevacizumab injection syringes. METHODS: This cross-sectional study involved an online survey of retina specialists in the United States. RESULTS: Of the 717 invited retina specialists, 158 (22%) responded to the online survey. The respondents reported using 1 pair of gloves (51%), no gloves (46%), or 2 pairs of gloves (3%) during intravitreal injection. Repackaged bevacizumab syringes distributed by compounding pharmacy were used by 89% of the respondents, and 63% reported that the adhesive sticker was applied directly to the syringe. Unintentional adhesion between the sticker and hand or glove was experienced by 9% of respondents. At least 1 NSI during intravitreal injection was experienced by 8% of respondents, and sticker-related injury was reported by 3%. The sticker was perceived to increase risk for NSI by 33% of respondents. CONCLUSION: This survey showed that 8% of the responding physicians surveyed have experienced at least one NSI during intravitreal injections, of which approximately one third was attributed to the adhesive sticker. Direct application of misfitting stickers to repackaged syringes by compounding pharmacies may be a practice that can aggravate the risk of NSI.

Sensitization to omeprazole in the occupational setting.

BACKGROUND: Omeprazole is a proton pump inhibitor for the treatment of gastric acid-related disorders. In recent years, reports of dermatitis upon exposure to omeprazole during manufacture have been noted. OBJECTIVE: To present diagnostic findings in workers who reported suspected hypersensitivity reactions resulting from occupational exposure to omeprazole. METHODS: Ninety-six workers exposed to omeprazole during the manufacturing process underwent investigation by the AstraZeneca Occupational Health Centre (Södertälje, Sweden) for suspected allergy. All subjects underwent a lymphocyte transformation test (LTT) and a skin test within 6 months of the clinical reaction. Predictive tests on guinea-pigs were conducted to establish omeprazole's sensitizing potential. RESULTS: Thirty-one subjects with clinical symptoms had a positive LTT result. Twenty-eight subjects had positive patch test results; of these, 23 also had a positive LTT result (sensitivity of the LTT: 82%). Fifty-six subjects had negative patch test results; 46 of these had a negative LTT result (specificity: 82%). All subjects who underwent prick testing (n = 18) had negative results. Delayed contact hypersensitivity was observed in 18 of 20 test animals. CONCLUSIONS: These findings confirm the risk of sensitization to omeprazole from occupational exposure. They are of importance for the development of new formulations of omeprazole, or its enantiomers, in light of the potential for inducing skin allergy.

Occupational airborne contact dermatitis from benzodiazepines and other drugs.

BACKGROUND: Healthcare workers (or relatives) crushing drug tablets for patients with difficulties in swallowing are at risk of developing sensitization via airborne exposure. Tetrazepam, in particular, is increasingly being described as an important occupational allergen in this regard, although other drugs are also involved. OBJECTIVES: To identify the allergenic culprits in 4 patients, namely 2 nurses, 1 pharmacy assistant, and 1 spouse, who all regularly crushed tablets of systemic drugs and presented with severe airborne dermatitis. METHODS: The patients were patch tested with all of the drugs that they handled, as well as with potential cross-sensitizing molecules. RESULTS: All 4 patients reacted to tetrazepam and other benzodiazepines, some of which they had not previously come into contact with, which favours cross-reactivity rather than concomitant sensitization. These patients also had positive reactions to several other non-structurally related drugs for which, in some cases, there was no history of exposure. CONCLUSIONS: Subjects having to crush drugs, in either an occupational or a non-occupational context, and who present with dermatitis suspected of being airborne-induced, should be patch tested with all contacted medicaments, as well as with possible cross-reacting molecules. Prevention by the use of crushing devices and protective measures (gloves and masks) when medications are handled should be advised.

Variability in compounding of oral liquids for pediatric patients: a patient safety concern.

OBJECTIVE: To determine the degree in variation of oral liquid pediatric compounding practices in Michigan pharmacies. DESIGN: Cross-sectional survey study. SETTING: All types of inpatient and outpatient pharmacies across the state of Michigan, excluding nuclear pharmacies and long-term care facilities. PARTICIPANTS: 244 Michigan pharmacies. INTERVENTION: An online survey tool was used to assess the current compounding practices of 147 oral liquid pediatric medications. The survey was e-mailed or faxed to hospitals, chain pharmacies, and independent pharmacies. Pharmacists were also mailed a follow-up postcard, and the Michigan Pharmacists Association publicized the project through its journal and annual meeting. MAIN OUTCOME MEASURES: Pharmacy demographics; number of compounding pharmacies; number of medications compounded; awareness of compounding errors; results of compounding errors; and number of concentrations compounded per medication. RESULTS: The majority of respondents were from outpatient pharmacies, but inpatient and other types of pharmacies were also represented. The majority of participating pharmacies compound fewer than five oral liquid medications per week. Awareness of errors was low overall, with no errors believed to result in permanent harm or death. The number of concentrations compounded per medication ranged from 1 to 9, with the majority of pharmacies compounding more than 3 concentrations per medication. CONCLUSION: There is a considerable degree of variation in current oral pediatric liquid compounding practices in Michigan pharmacies. This variability poses a significant risk to patient safety.

How gaps in regulation of compounding pharmacy set the stage for a multistate fungal meningitis outbreak.

OBJECTIVE: To provide an overview of the regulation issues surrounding compounding pharmacy that allowed the United States fungal meningitis outbreak to occur and the changes in regulation that ensued. SUMMARY: In September 2012, a single case report sparked an investigation into a nationwide outbreak of fungal meningitis due to contaminated injectable drugs. The source of the contamination, New England Compounding Center (NECC), was in violation of several state and federal laws and had a history of such violations. The regulation of compounding pharmacies has historically been left to the states, while manufacturing fell under the jurisdiction of the Food and Drug Administration. However, as more compounders took part in large-scale interstate distribution of drugs, the current state-based regulatory system became less equipped to provide oversight. The lack of a clear definition of "compounding pharmacy" further obscures proper oversight and regulation. Congress and several states have taken steps to build safeguards against large-scale compounding by increasing inspections, adopting stricter licensing requirements, and enacting the Drug Quality and Security Act of 2013. CONCLUSION: While the current compounding regulation changes are a necessary step forward, it remains to be seen how effective they will be in safeguarding the public.

An integrated approach to individualized optimal dose estimation of medication by means of dosing adjustment measures and Bi-Digital O-Ring Test.

Posology concerns science and system of dosage. Conventionally the dosage systems of measurement are the apothecaries' and metric systems and the dosage calculation for each individual patient has been suggested according to several available methods, namely Clark's Rule, Fried's Rule, Young's Rule, body surface area, or mg/kg, etc. There are many factors affect the availability of a drug to its site of action in the body, and their relation to the time course of drug action and variation in each drug response with or without the other drugs taken simultaneously. The correct dosage requires meticulous and accurate calculation. In busy offices, some may feel the dosage calculation is tedious. This article reviews the conventional methods of dosage calculations and the allergy tests, followed by describing a simple way to determine the proper dosage for each patient by simplifying the Clark's concept based on the body weight and verify the optimum dosage with Bi-Digital O-Ring Test minimize the adverse drug reactions and to increase safety for drug administration.

Determinants of immunogenic response to protein therapeutics.

Protein therapeutics occupy a very significant position in the biopharmaceutical market. In addition to the preclinical, clinical and post marketing challenges common to other drugs, unwanted immunogenicity is known to affect efficacy and/or safety of most biotherapeutics. A standard set of immunogenicity risk factors are routinely used to inform monitoring strategies in clinical studies. A number of in-silico, in vivo and in vitro approaches have also been employed to predict immunogenicity of biotherapeutics, but with limited success. Emerging data also indicates the role of immune tolerance mechanisms and impact of several product-related factors on modulating host immune responses. Thus, a comprehensive discussion of the impact of innate and adaptive mechanisms and molecules involved in induction of host immune responses on immunogenicity of protein therapeutics is needed. A detailed understanding of these issues is essential in order to fully exploit the therapeutic potential of this class of drugs. This Roundtable Session was designed to provide a common platform for discussing basic immunobiological and pharmacological issues related to the role of biotherapeutic-associated risk factors, as well as host immune system in immunogenicity against protein therapeutics. The session included overview presentations from three speakers, followed by a panel discussion with audience participation.

Medical device on pharmacists' work-related musculoskeletal complaints and burnouts.

This study analysed the total number of consumed vials of chemotherapy drugs during the year 2007 to determine workloads, and investigated the effects of using the Spike medical device in contrast to the use of traditional needles on oncology pharmacists' dispensing time, muscle soreness, work-related burnout and fatigue symptoms. Work-related burnout and physiological symptoms were measured using the Copenhagen Burnout Inventory (CBI) and a visual analogue pain scale. The Spike device significantly reduced the time spent in drawing up fluorouracil (39.46 ± 9.43 s vs. 57.13 ± 13.47 s) or cisplatin (29.65 ± 11.22 s vs. 60.93 ± 20.54 s) compared with traditional needles (P < 0.001). The CBI burnout score improved significantly with the Spike device (53.21 ± 8.58 vs. 73.21 ± 5.42; P = 0.007) because finger and palm muscle soreness complaints and subjective fatigue symptoms for eye tiredness and shoulder-wrist pain were significantly reduced (P < 0.05). Practitioner Summary The pharmacist needs to exert hand strength to counter the vial back-suction pressure to draw out the medical liquid, and confirm the volume during the drawing antineoplastic drug procedure. This study aimed to determine the effects of using a medical device, instead of a needle, on pharmacists' work-related musculoskeletal complaints and burnouts.

Compounding errors in 2 dogs receiving anticonvulsants.

Two cases that involve drug compounding errors are described. One dog exhibited increased seizure activity due to a compounded, flavored phenobarbital solution that deteriorated before the expiration date provided by the compounder. The other dog developed clinical signs of hyperkalemia and bromine toxicity following a 5-fold compounding error in the concentration of potassium bromide (KBr).

Occupational kidney disease among Chinese herbalists exposed to herbs containing aristolochic acids.

OBJECTIVE: Many Chinese herbs contain aristolochic acids (ALAs) which are nephrotoxic and carcinogenic. The objective of this study was to identify whether exposure to herbs containing ALAs increased the risk of kidney disease among Chinese herbalists. METHODS: A nested case-control study was carried out on 6538 Chinese herbalists registered between 1985 and 1998. All incident cases of chronic renal failure reported to the Database of Catastrophic Illness of the National Health Insurance Bureau between 1995 and 2000 were defined as the case group. Up to four controls without renal failure were randomly matched to each case by sex and year of birth. A structured questionnaire survey was administered between November and December 2002. The Mantel-Haenszel method and conditional logistic regression were used to estimate the risks. RESULTS: 40 cases and 98 matched controls were included in the final analysis. After adjusting for age, frequent analgesic use, and habitual consumption of alcohol, fermented or smoked food, we found manufacturing and selling Chinese herbal medicine (OR 3.43, 95% CI 1.16 to 10.19), processing, selling or dispensing herbal medicines containing Fangji (OR 4.17, 95% CI 1.36 to 12.81), living in the workplace (OR 3.14, 95% CI 1.11 to 8.84) and a history of taking of herbal medicines containing Fangji (frequently or occasionally) (OR 5.42, 95% CI 1.18 to 24.96) were significantly associated with renal failure. CONCLUSION: Occupational exposure to and consumption of herbs containing ALAs increases the risk of renal failure in Chinese herbalists.

Effectiveness of compounded bioidentical hormone replacement therapy: an observational cohort study.

BACKGROUND: Bioidentical Hormone Replacement Therapy (BHRT) is believed it to be a safer and equally effective alternative to Conventional Hormone Therapy for the relief of menopausal symptoms; however, data are needed to support these claims. The objective of this study is to evaluate the effectiveness of compounded BHRT provided in six community pharmacies. METHODS: This was an observational cohort study of women between the ages of 18-89 who received a compounded BHRT product from January 1, 2003 to April 30, 2010 in six community pharmacies. Data included patient demographics, comorbidities, therapeutic outcomes, and hormone therapies. Women self-rated menopausal symptoms as absent, mild, moderate, or severe. Descriptive statistics were used to characterize the patient population, BHRT use, and adverse events. Patient symptom severity was compared at baseline and 3 to 6 months follow-up using the Wilcoxon signed-rank test. RESULTS: Women (n = 296) receiving BHRT at Oakdell Pharmacy had a mean (standard deviation) age of 52 (9) years. The most common BHRT dosage forms utilized were topical (71%) and oral (43%). Compounded BHRT regimens were generally initiated at low doses regardless of route. Women experienced a 25% decrease in emotional lability (p < 0.01), a 25% decrease in irritability (p < 0.01), and a 22% reduction in anxiety (p = 0.01) within 3 to 6 months. These women also experienced a 14% reduction in night sweats (p = 0.09) and a 6% reduction in hot flashes (p = 0.50). CONCLUSIONS: This study demonstrates that compounded BHRT improves mood symptoms. Larger studies are needed to examine the impact on vasomotor symptoms, myocardial infarction and breast cancer.

Ocular injuries from shake and bake methamphetamine labs.

PURPOSE: To review ocular injuries resulting from "shake and bake" methamphetamine labs. METHOD: Retrospective case series of 4 patients with ocular injuries sustained from "shake and bake" lab explosions. RESULTS: Four men ages 20-39 underwent complete ophthalmologic examination after an injury from a "shake and bake" methamphetamine lab explosion.The mechanism of injury was initially misrepresented in each case; the physical findings were suggestive of thermal and alkali injury. Visual acuity ranged widely from 20/20 to light perception only. Treatment in the acute setting included irrigation, pH monitoring, and intraocular pressure lowering. CONCLUSION: Methamphetamine production by means of the"shake and bake" method can result in combined thermal and alkali ocular injury. Patients who sustain this type of injury may not accurately report the mechanism of exposure. Increased awareness of this type of ocular injury may increase the rapidity of diagnosis, avoid early misdiagnosis, and ultimately improve outcomes.

Magnetic resonance spectroscopy for evaluation of liposome-encapsulated hemoglobin as a resuscitation fluid.

Liposome-encapsulated hemoglobin (LEH) based on a novel, synthetic, non-phospholipid was developed, and evaluated for cerebral energy metabolism in a 40% hemorrhage rat model. The markers of tissue energetics were monitored by (1)H- and (31)P-magnetic resonance spectroscopy (MRS). After hemorrhage, (1)H-MRS showed an increase in the levels of lactate and pyruvate. These markers returned to baseline values following LEH resuscitation. Both LEH and saline were able to exert a neuron-protective effect as indicated by the recovery of N-acetylaspartate. (31)P MRS showed a fall in phosphocreatine after hemorrhage, which upon LEH or saline resuscitation returned to the baseline values. Similarly, inorganic phosphate increased after bleeding, but returned to normal after resuscitation. LEH resuscitation also recovered beta-ATP levels, but saline resuscitation provided only a modest recovery. The results indicate the utility of MRS to monitor cerebral metabolism in hemorrhage/resuscitation. The data is also supportive of the new LEH formulation as an oxygen carrier.

Effect of processing methods on colouration of human serum albumin preparations.

Human serum albumin is a well tolerated therapeutic for the treatment of hypovolemia. Despite all commercial human albumin preparations being derived from plasma, these products can have a highly variable colour. Albumin samples derived from ethanol precipitation and chromatographic fractionation procedures were evaluated for bilirubin and biliverdin levels and by spectrophotometry. It was shown that albumin derived from a chromatographic process, which had a bilirubin:albumin ratio similar to that observed in plasma, had a vibrant yellow appearance. The albumin derived from ethanol precipitation had undetectable levels of bilirubin, and the amber colour of this product was attributed mainly to residual haem. The presence of bilirubin during pasteurisation led to oxidation to biliverdin, with a resultant colour change from yellow to yellow/green. Given that the antioxidant properties of bilirubin are well established, it is possible that bilirubin helps protect albumin from oxidation during the pasteurisation step.

Commercial premixed parenteral nutrition: Is it right for your institution?

Two-compartment premixed parenteral nutrition (PN) products are heavily promoted in the United States. These products may present safety advantages over PN solutions mixed by a local pharmacy, although clinical data to support this assertion are scarce. Multicompartment products can be labor-saving for pharmacy and therefore may be cost-effective for some institutions. Before adopting such products for use, an institution must determine that standardized PN solutions are acceptable for many or most of their patients compared with customized PN compounded specifically for individual patients. A larger selection of premixed products is available in Europe and some other parts of the world compared with the United States. Availability of a broader selection of products in the United States, including 3-compartment bags and a wider range of macronutrient concentrations and volumes, may make the use of such products more desirable in the future.

Compounded medicines and 'off label' prescribing - a case for more guidance.

BACKGROUND: Interest by prescribers and pharmacists in the provision of individualised pharmaceutical therapy in the form of compounded medicines has grown in recent times. However, there have also been a number of case reports of patient harm associated with these medicines. OBJECTIVE: To highlight areas for clinicians and pharmacists to consider when prescribing or dispensing compounded medicines, which are consistent with quality use of medicines principles. DISCUSSION: Regulators of pharmaceutical products have expressed concerns with the production, marketing and use of compounded medicines dispensed by pharmacists. This has prompted debate over the need for more regulation of these products. We propose an expansion of off label prescribing guidelines to include a risk based assessment of pharmaceutical quality, a consumer information/education strategy and the development of a code of practice for pharmacists engaging in compounding. These strategies recognise a shared responsibility among prescribers, dispensers and regulators to achieve contemporary quality, safety, and efficacy standards and support the quality use of compounded medicines.

Spill and leakage using a drug preparation system based on double-filter technology.

Occupational exposure to cytotoxic drugs has frequently been reported during recent years. Various drug-handling systems have been applied to reduce the spill and leakage that cause this exposure. Some of these systems have also been tested for spill and leakage using independent test methods. In this paper, a new drug-handling system has been tested for spill and leakage during drug preparation. The handling system, Tevadaptortrade mark, was tested using a modification of an independent test method, the Technetium test method, based on the use of Technetium m-99 as tracer substance. The test results showed that the spill was <100 nl for all 75 preparations and was <1 nl for 70 of the preparations. This is comparable with other tested drug-handling system, e.g. isolators, PhaSealtrade mark. The test shows that the Tevadaptor drug-handling system has similar performance as drug-handling systems regarded as closed systems.