Association of compounded bevacizumab with postinjection endophthalmitis.

IMPORTANCE: Current draft guidelines set forth by the US Food and Drug Administration for compounded or repackaged medications would greatly limit the availability and use of bevacizumab by ophthalmologists across the country. Little evidence beyond highly publicized case reports exists for or against the need for additional regulation of compounded bevacizumab. OBJECTIVE: To determine whether the distribution of bevacizumab through compounding pharmacies increases the risk for endophthalmitis compared with the distribution of single-use vials of ranibizumab from the manufacturer. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study using medical claims data from ambulatory care centers across the United States that were submitted to a large, national US insurer. Cohorts were created using information on 530 382 intravitreal injections administered from January 1, 2005, through December 31, 2012. Any individual from this data set who received an intravitreal injection of bevacizumab or ranibizumab (n=383 810) and had at least 6 months of data before and 1 month after the injection was eligible. After exclusions (any previous diagnosis of endophthalmitis, multiple injected drugs given on the index day, or intraocular surgery within 15 days of the injection or between the injection and a diagnosis of endophthalmitis), our analysis involved 383 810 intravitreal injections given to 58 612 patients. Data collection and analysis occurred from February 16 through April 7, 2015. MAIN OUTCOMES AND MEASURES: The odds of developing endophthalmitis after an intravitreal injection of bevacizumab compared with ranibizumab. RESULTS: In total, 296 565 injections of bevacizumab were given to 51 116 patients and 87 245 injections of ranibizumab were given to 7496 patients. We found 71 cases of endophthalmitis (49 in the bevacizumab cohort and 22 in the ranibizumab cohort) for an endophthalmitis rate of 0.017% (95% CI, 0.012%-0.021%; 1 case per 6061 injections) for bevacizumab and 0.025% (95% CI, 0.015%-0.036%; 1 case per 3968 injections) for ranibizumab. After controlling for age, race, sex, injection-related diagnosis, and year of injection, we found no significant association with development of endophthalmitis after a bevacizumab injection compared with ranibizumab (odds ratio, 0.66 [95% CI, 0.39-1.09]; P = .11). CONCLUSIONS AND RELEVANCE: The results of this study suggest bevacizumab as currently used across the United States does not increase the risk for endophthalmitis; therefore, additional regulations on the use of repackaged bevacizumab may be unnecessary.

Transient macular edema after intracameral injection of a moderately elevated dose of cefuroxime during phacoemulsification surgery.

IMPORTANCE: Intracameral injection of cefuroxime sodium (1 mg/0.1 mL) has been reported to reduce the risk of endophthalmitis following cataract surgery. In the United States it must be compounded, which is subject to dilution error. We describe a series of 13 eyes that received intracameral injection of cefuroxime sodium, 9 mg/0.1 mL, intraoperatively. OBSERVATIONS: On postoperative day 1, 6 of 13 eyes (46%; 95% CI, 19%-75%) had visual acuity of 20/70 or worse and macular edema. Spectral-domain optical coherence tomography of 2 eyes revealed central subfield thicknesses of 909 and 873 µm. On postoperative day 4, the mean (SD) central subfield thickness was 309 (78) µm in the 6 eyes with diagnosed macular edema, 279 (23) µm in the fellow eyes, and 271 (38) µm in the 7 exposed eyes without macular edema. The mean (SD) time to resolution of macular edema was 5.2 (1.3) days; the final central subfield thickness ranged from 193 to 293 µm. All eyes, except 2 with preexisting ocular comorbidity, had a best-corrected final visual acuity at 1 month of 20/30 or better. Significant corneal edema was not observed. CONCLUSIONS AND RELEVANCE: Intracameral injection of cefuroxime sodium at a dose of 9 mg/0.1 mL was associated with transient macular edema and diminished visual acuity in 6 of 13 exposed eyes (46%), resolving largely within 1 week.

Long-term management of severe ocular surface injury due to methamphetamine production accidents.

PURPOSE: The aim of this study was to report the clinical features and management of patients with ocular surface damage during methamphetamine production accidents. METHODS: This is a retrospective noncomparative interventional case series of 5 patients with methamphetamine production-related ocular injuries referred to the Cincinnati Eye Institute between 1999 and 2014. RESULTS: Four of 5 cases were white young men with severe bilateral ocular injury and extremely poor vision. All except 1 eye (9 of 10) were diagnosed with total or near-total ocular surface failure. Limbal stem cell transplantation was performed in 8 of 10 eyes. Keratolimbal allograft was followed by penetrating keratoplasty in 7 of 10 eyes. Ocular surface stability was achieved in 7 of 10 eyes after keratolimabl allograft. Postoperative visual acuity was better than 20/200 in 4 of 10 of eyes. Keratolimbal graft rejection occurred in 3 of 10 eyes; the rate of rejection of penetrating keratoplasty was also 3 out of 10 eyes. CONCLUSIONS: Methamphetamine-related accidents can lead to severe bilateral ocular injuries. Although stem cell transplantation procedure success is guarded in most of these patients because of severe conjunctival inflammation and accompanying ocular comorbidities, as well as personality issues, compliant patients can achieve good visual function with ocular surface transplantation and subsequent keratoplasty.

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.

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.

Establishing powder-handling workflow practices and standard operating procedures: compounding pharmacy and safety.

This is an ongoing discussion and analysis of powder-handling safety in the compounding pharmacy laboratory that started in the November/December 2013 issue of the International Journal of Pharmaceutical Compounding. In the previous technical article, we established that most chemical powders handled during compounding procedures have an established occupational exposure limits and that powders are micronized during manipulation. All micronized powders handled on an open bench create health hazards to the technicians and create a potential for cross-contamination to the lab environment. Proper identification of the chemical hazard and established standard operating procedures in direct correlation to Good Lab Practices when working inside a powder hood will positively improve the compounding pharmacy's work environment.

Risk and liabilities of prescribing compounded medications.

Complications resulting from the use of compounded medications have become a troubling trend nationwide. There is a significant potential for patients to suffer serious harm from the use of substandard medications prepared by compounding pharmacies, and the reality of this problem has been demonstrated in several well-publicized incidences of serious medical complications, including patient deaths, that directly resulted from the use of medications prepared at compounding pharmacies. Unlike US Food and Drug Administration (FDA)-approved drugs, compounded products are not required to meet evidentiary standards for establishing safety and efficacy. Moreover, these products are not held to Good Manufacturing Practices, which require regular inspections, quality control testing, and rejection of material not meeting specifications. Physicians, as well as other prescribers, need to be aware that when a patient suffers harm from using a compounded medication, those injured patients may bring negligence and malpractice claims, not only against the pharmacy and the pharmacist responsible for preparing the medication, but also against the prescribing physician and the physician's practice. Consequently, the best way for physicians to manage professional risk and avoid both litigation and potential negative patient outcomes related to compounded pharmaceuticals is to not use these products if there is an FDA-approved product available. However, if the use of a compounded medication is medically necessary, then physicians should adhere to the FDA guidance concerning traditional compounding. Moreover, it would be prudent for any physician who intends to either resell or participate in the distribution of compounded products beyond the direct treatment of their patients to consider obtaining the appropriate insurance coverage for this activity.

Risks and effectiveness of compounded bioidentical hormone therapy: a case series.

After the publication of the Women's Health Initiative, attitudes towards management of menopausal symptoms changed dramatically. One alternative that has received much media attention is the use of bioidentical hormone therapy (BHT). The media and celebrity endorsements have promoted a number of misconceptions about the risks and benefits associated with the various forms of BHT. This article will review the available evidence regarding the safety and efficacy of BHT in comparison to conventional hormone therapy. We will also review several cases seen in our midlife women's referral clinics, which demonstrate concerns for the safety and efficacy of BHT, including unexplained endometrial cancer in otherwise healthy BHT users. Due to the lack of sufficient data to support the efficacy or safety of BHT, we recommend the use of United States Food and Drug Administration-approved regimens in the management of menopausal symptoms.

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.

Determination of risk for sterile preparations.

A quick and reliable system is described to quantify risk assessment for compounded sterile pharmaceuticals, which are "compounded in anticipation" for hospitals and clinics, having shelf lives assessed on documented literature and other criteria. These shelf lives are well in excess of the recommendations of the United States Pharmacopeia without placing patients at risk due to inadequate safety, quality, or efficacy.

Normal saline to dilute parenteral drugs and to keep catheters open is a major and preventable source of hypernatremia acquired in the intensive care unit.

PURPOSE: We wanted to identify modifiable risk factors for intensive care unit (ICU)-acquired hypernatremia. MATERIALS AND METHODS: We retrospectively studied sodium and fluid loads and balances up to 7 days prior to the development of hypernatremia (first serum sodium concentration, [Na+], >150 mmol/L; H) vs control (maximum [Na+] ≤150 mmol/L; N), in consecutive patients admitted into the ICU with a normal serum sodium (<145 mmol/L) and without cerebral disease, within a period of 8 months. RESULTS: There were 57 H and 150 N patients. Severity of disease and organ failure was greater, and length of stay and mechanical ventilation in the ICU were longer in H (P<.001), with a mortality rate of 28% vs 16% in N (P=.002). Sodium input was higher in H than in N, particularly from 0.9% saline to dissolve drugs for infusion and to keep catheters open during the week prior to the first day of hypernatremia (P<.001). Fluid balances were positive and did not differ from N on most days in the presence of slightly higher plasma creatinine and more frequent administration of furosemide, at higher doses, in H than in N. CONCLUSIONS: High sodium input by 0.9% saline used to dilute drugs and keep catheters open is a modifiable risk factor for ICU-acquired H. Dissolving drugs in dextrose 5% may partially prevent potentially harmful sodium overloading and H.

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.

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.