Regulatory and Clinical Experiences with Biosimilar Filgrastim in the U.S., the European Union, Japan, and Canada.

Biosimilar filgrastims are primarily indicated for chemotherapy-induced neutropenia prevention. They are less expensive formulations of branded filgrastim, and biosimilar filgrastim was the first biosimilar oncology drug administered in European Union (EU) countries, Japan, and the U.S. Fourteen biosimilar filgrastims have been marketed in EU countries, Japan, the U.S., and Canada since 2008, 2012, 2015, and 2016, respectively. We reviewed experiences and policies for biosimilar filgrastim markets in EU countries and Japan, where uptake has been rapid, and in the U.S. and Canada, where experience is rapidly emerging. U.S. regulations for designating biosimilar interchangeability are under development, and such regulations have not been developed in most other countries. Pharmaceutical substitution is allowed for new filgrastim starts in some EU countries and in Canada, but not Japan and the U.S. In EU countries, biosimilar adoption is facilitated with favorable hospital tender offers. U.S. adoption is reportedly 24%, while the second filgrastim biosimilar is priced 30% lower than branded filgrastim and 20% lower than the first biosimilar filgrastim approved by the U.S. Food and Drug Administration. Utilization is about 60% in EU countries, where biosimilar filgrastim is marketed at a 30%-40% discount. In Japan, biosimilar filgrastim utilization is 45%, primarily because of 35% discounts negotiated by Central Insurance and hospital-only markets. Overall, biosimilar filgrastim adoption barriers are small in many EU countries and Japan and are diminishing in Canada in the U.S. Policies facilitating improved U.S. adoption of biosimilar filgrastim, based on positive experiences in EU countries and Japan, including favorable insurance coverage; larger price discount relative to reference filgrastim pricing; closing of the "rebate trap" with transparent pricing information; formal educational efforts of patients, physicians, caregivers, and providers; and allowance of pharmaceutical substitution of biosimilar versus reference filgrastim, should be considered. IMPLICATIONS FOR PRACTICE: We reviewed experiences and policies for biosimilar filgrastims in Europe, Japan, Canada, and the U.S. Postmarketing harmonization of regulatory policies for biosimilar filgrastims has not occurred. Acceptance of biosimilar filgrastims for branded filgrastim, increasing in the U.S. and in Canada, is commonplace in Japan and Europe. In the U.S., some factors, accepted in Europe or Japan, could improve uptake, including acceptance of biosimilars as safe and effective; larger cost savings, decreasing "rebate traps" where pharmaceutical benefit managers support branded filgrastim, decreased use of patent litigation/challenges, and allowing pharmacists to routinely substitute biosimilar for branded filgrastim.

Investigating Serious Adverse Drug Reactions in Patients Receiving Erythropoiesis-Stimulating Agents: A Root Cause Analysis Using the "ANTICIPATE" Framework.

BACKGROUND: Unexpected serious adverse drug reactions (sADRs) affecting patients with chronic kidney disease (CKD) who received erythropoiesis-stimulating agents were identified by study co-authors. These included pure red cell aplasia (PRCA) after administration of the Eprex formulation of epoetin or the epoetin biosimilar HX575 and fatal anaphylaxis associated with peginesatide, an erythropoietin receptor agonist. We developed and applied a structured framework to describe these sADRs, including root cause analyses and eradication efforts. METHODS: A 10-step framework termed "ANTICIPATE," focusing on signal identification, incidence, causality, and eradication guided our evaluations. RESULTS: Initial cases were identified by a hematologist (Eprex), clinical study monitors (HX575), and 4 nurses (peginesatide). The number of persons with individual ADRs was 13 PRCA cases for epoetin, 2 antibody-mediated PRCA cases for HX575, and 5 fatal anaphylaxis cases for peginesatide. Initial incidence estimates per 1000 treated persons were 0.27 for Eprex-associated PRCA, 11 for HX575-associated PRCA, and 0.38 for peginesatide fatalities. Likely causes were subcutaneous administration of epoetin formulated with polysorbate 80 (Eprex), tungsten leaching from pins included in product syringes (HX575), and inclusion of a phenol stabilizer (peginesatide). Eradication strategies included restricting Eprex administration to the intravenous route, excluding tungsten from HX575 syringes, and for peginesatide, proposed eradication was to return to single-dose vials without preservatives. CONCLUSION: Although the number of cases of each sADR was small, eradication was successful for 2 sADRs, and a proposed eradication was developed for a third sADR. The structured framework used to describe the above 3 sADRs in patients with CKD can also be used in other clinical settings.

Pharmacists' roles in oncology pharmacy services: Results of a global survey.

Background Oncology pharmacists are capable of providing medication therapy management (MTM) because of their level of training, practice experiences, and responsibilities. Very little data exist about their current practice, including changing roles in the multidisciplinary team, overall impact, and effects in the education of patients and healthcare professionals. Methods A 70-item survey about oncology pharmacists' activities in oral chemotherapy programs, MTM, and collaborative practice agreements (CPAs) was deployed using a web survey tool (Qualtrics, Provo, UT, USA), targeting pharmacist members of American College of Clinical Pharmacy (ACCP) Hematology/Oncology Practice and Research Network (PRN). The objective of this study was to determine oncology pharmacists' activities in areas of oral chemotherapy programs, MTM, and CPAs. A cross-sectional survey was distributed to the ACCP Hematology/Oncology PRN membership. Investigational Review Board approval was obtained. Results Of the 795 members who were sent the survey, 81 members (10%) responded; 33 respondents (47%) are involved with an oral chemotherapy program; with 42% measuring outcomes of programs. Only six pharmacists (19%) have published or presented their data. A total of 28 (35%) respondents provide MTM services, with almost half (43%) of these MTM services being dictated by CPAs. A small fraction of these pharmacists (21.4%) reported conducting quality assurance evaluations of their MTM services and three pharmacists (10.7%) reported publishing their results. Those pharmacists practicing under CPAs ( n = 28) were surveyed as to activities included in their CPA. The most common activities included adjusting medication, ordering, interpreting, and monitoring lab tests, developing therapeutic plans and educating patients. Reimbursement for providing these services was uncommon: MTM (4%), oral chemotherapy program (6%), and CPA services (11%). Reported obstacles to reimbursement included lack of understanding, administrative assistance, or time with setting up reimbursement models within the institution. Conclusion Many oncology pharmacists are participating in oral chemotherapy programs, MTM, and/or CPAs and perceived barriers were identified. Increased efforts should be directed toward prospectively reporting and assessing the impact these services have on patient care.

Generic oncology drugs: are they all safe?

Although the availability of generic oncology drugs allows access to contemporary care and reduces costs, there is international variability in the safety of this class of drugs. In this Series paper, we review clinical, policy, safety, and regulatory considerations for generic oncology drugs focusing on the USA, Canada, the European Union (EU), Japan, China, and India. Safety information about generic formulations is reviewed from one agent in each class, for heavy metal drugs (cisplatin), targeted agents (imatinib), and cytotoxic agents (docetaxel). We also review regulatory reports from Japan and the USA, countries with the largest pharmaceutical expenditures. Empirical studies did not identify safety concerns in the USA, Canada, the EU, and Japan, where regulations and enforcement are strong. Although manufacturing problems for generic pharmaceuticals exist in India, where 40% of all generic pharmaceuticals used in the USA are manufactured, increased inspections and communication by the US Food and Drug Administration are occurring, facilitating oversight and enforcement. No safety outbreaks among generic oncology drugs were reported in developed countries. For developing countries, oversight is less intensive, and concerns around drug safety still exist. Regulatory agencies should collaboratively develop procedures to monitor the production, shipment, storage, and post-marketing safety of generic oncology drugs. Regulatory agencies for each country should also aim towards identical definitions of bioequivalence, the cornerstone of regulatory approval.

Progressive multifocal leukoencephalopathy associated with brentuximab vedotin therapy: a report of 5 cases from the Southern Network on Adverse Reactions (SONAR) project.

BACKGROUND: Brentuximab vedotin (BV) is an anti-CD30 monoclonal antibody-drug conjugate that was approved in 2011 for the treatment of patients with anaplastic large cell and Hodgkin lymphomas. The product label indicates that 3 patients who were treated with BV developed progressive multifocal leukoencephalopathy (PML), a frequently fatal JC virus-induced central nervous system infection. Prior immunosuppressive therapy and compromised immune systems were postulated risk factors. In the current study, the authors reported 5 patients who developed BV-associated PML, including 2 immunocompetent patients. METHODS: Case information was obtained from clinicians (4 patients) or a US Food and Drug Administration database (1 patient). RESULTS: All 5 patients had lymphoid malignancies. Two patients with cutaneous T-cell lymphomas had not previously received chemotherapy. PML developed after a median of 3 BV doses (range, 2 doses-6 doses) and within a median of 7 weeks after BV initiation (range, 3 weeks-34 weeks). Presenting findings included aphasia, dysarthria, confusion, hemiparesis, and gait dysfunction; JC virus in the cerebrospinal fluid (2 patients) or central nervous system biopsy (3 patients); and brain magnetic resonance imaging scans with white matter abnormalities (5 patients). Four patients died at a median of 8 weeks (range, 6 weeks-16 weeks) after PML diagnosis. The sole survivor developed immune reconstitution inflammatory syndrome. CONCLUSIONS: PML can develop after a few BV doses and within weeks of BV initiation. Clinicians should be aware of this syndrome, particularly when neurologic changes develop after the initiation of BV treatment. The decision to administer BV to patients with indolent cutaneous lymphomas should be based on consideration of risk-benefit profiles and of alternative options.

Linking drugs to obscure illnesses: lessons from pure red cell aplasia, nephrogenic systemic fibrosis, and Reye's syndrome. a report from the Southern Network on Adverse Reactions (SONAR).

Identification of serious adverse drug reactions (sADRS) associated with commonly used drugs can elude detection for years. Reye's syndrome (RS), nephrogenic systemic fibrosis (NSF), and pure red cell aplasia (PRCA) among chronic kidney disease (CKD) patients were recognized in 1951, 2000, and 1998, respectively. Reports associating these syndromes with aspirin, gadodiamide, and epoetin, were published 29, 6, and 4 years later, respectively. We obtained primary information from clinicians who identified causes of these sADRs and reviewed factors contributing to delayed identification of these toxicities. Overall, 3,500 aspirin-associated RS cases in the United States, 1,605 gadolinium-associated NSF cases, and 181 epoetin-associated PRCA cases were reported. Delays in FDA regulation of over-the- counter medications and administration of aspirin to children contributed to development of RS. For NSF, in 1996, the Danish Medicine Agency approved high-dose gadodiamide administration to chronic kidney disease (CKD) patients undergoing MR scans. Overall, 88 % of Danish NSF cases were from two hospitals and 97 % of United States' NSF cases were from 60 hospitals. These hospitals frequently administered high-doses of gadodiamide to CKD patients. Another factor was the decision to administer linear chelated contrast agents versus lower risk macrocyclic chelated agents. For PRCA, increased use of subcutaneous epoetin formulations to CKD patients, in part due to convenience and cost-savings considerations, and a European regulatory requirement requiring removal of albumin as a stabilizer, led to toxicity. Overall, 81, 13, and 17 years elapsed between drug introduction into practice and identification of a causal relationship for aspirin, erythropoietin, and gadodiamide, respectively. A substantial decline in new cases of these sADRs occurred within two years of identification of the offending drug. Clinicians should be vigilant for sADRs, even for frequently-prescribed pharmaceuticals, particularly in settings where formulation or regulatory changes have occurred, or when over-the-counter, off-label, or pediatric use is common.

Assessing pharmacy residents' knowledge of biostatistics and research study design.

BACKGROUND: Historically, clinicians have demonstrated a lack of confidence and poor aptitude for biostatistics as a tool for medical literature interpretation. Evaluation of pharmacy residents' ability to interpret biostatistics commonly used in peer-reviewed literature has not been previously conducted. OBJECTIVE: To evaluate the level of understanding and perception of biostatistics concepts among pharmacy residents. METHODS: A survey of postgraduate year 1 (PGY1) residents in American Society of Health-System Pharmacists-accredited residency programs was conducted in May 2009. The survey instrument consisted of 27 items, including 10 knowledge-based questions, and was distributed to residency programs for anonymous reporting via SurveyMonkey. The primary outcome of interest was biostatistics knowledge, defined as the percent total score of correct knowledge items. Statistical attitude and confidence questions were rated on a 5-point Likert-type scale (1 = strongly disagree, 5 = strongly agree). The t-test or 1-way analysis of variance was conducted, as appropriate, to assess for differences in mean biostatistics knowledge scores by respondent characteristics. Forward stepwise regression was used to identify which characteristics were independently associated with biostatistics knowledge. RESULTS: A total of 214 PGY1 residents responded to the online survey assessment, and a subset of respondents (n = 166) answered 1 or more of the biostatistics knowledge questions. Of those who responded to at least 1 knowledge assessment, the overall mean (SD) biostatistics knowledge score was 47.3% (18.50%; range 0-90). Overall, respondents were predominantly female (74%) and younger than 30 years (81%). Residents scored highest in the recognition of the purpose of a double-blind study (92.6%; 95% CI 88.52 to 96.67), interpretation of relative risk (75.8%; 95% CI 69.02 to 82.57), and identification of the appropriate analytic method for a nominal variable (69.4%; 95% CI 62.16 to 76.59). Bivariate analyses showed that there were statistically significant mean differences in knowledge scores by attitude (p = 0.001) and confidence (p < 0.001). The multivariate model showed that above-average confidence ratings were associated with an absolute increase of 7.6% in biostatistics knowledge score (p < 0.019) compared to those whose confidence rating was at or below average. CONCLUSIONS: Overall, pharmacy residents' perception and understanding of biostatistics were poor in this assessment, which correlates with previous reports. Enhanced training in biostatistics and literature evaluation of both mentors and trainees should be incorporated in PharmD programs and residency training sites.

Major hemorrhage in chronic lymphocytic leukemia patients in the US Veterans Health Administration system in the pre-ibrutinib era: Incidence and risk factors.

Chronic lymphocytic leukemia (CLL) patients are at increased risk for major hemorrhage (MH). We examined incidence of and risk factors for MH in CLL patients before introduction of newer CLL therapies such as ibrutinib, which includes bleeding risk. This study included 24 198 CLL patients treated in the VA system before FDA approval of ibrutinib as CLL therapy. Data came from VA databases from 1999 to 2013. MH incidence was 1.9/100 person-years (95% CI: 1.8-1.9), with cumulative incidences of 2.3%, 5.2%, and 7.3% by year 1, 3, and 5, respectively. Median time from CLL diagnosis to MH was 2.8 years (range: 0-15.7 years). In multivariate analyses, concurrent anticoagulant and antiplatelet use (HR: 4.2; 95% CI: 3.2-5.6), anticoagulant use only (HR: 2.6; 95% CI: 2.3-3.1), and antiplatelet use only (HR: 1.5; 95% CI: 1.3-1.7) increased MH risk vs not receiving those medications; being nonwhite, male, having MH history, renal impairment, anemia, thrombocytopenia, and alcohol abuse were associated with increased MH risk. These pre-ibrutinib data are important for providing context for interpreting MH risk in ibrutinib-treated patients. As ibrutinib clinical use is increasing, updated analyses of MH risk among ibrutinib-treated VA patients with CLL may provide additional useful insight.

Hepatitis B Virus Reactivation: Risk Factors and Current Management Strategies.

Hepatitis B virus (HBV) is a global disease with significant morbidity and mortality. Worldwide, ~257 million people are chronically infected with HBV, defined as having a positive hepatitis B surface antigen, but millions more have prior HBV exposure indicated by positive hepatitis B core antibody. Reactivation of hepatitis B implies a sudden increase in viral replication in a patient with chronic HBV infection or prior HBV exposure. Hepatitis B virus reactivation (HBVr) can occur spontaneously, but it is more commonly triggered by immunosuppressive therapies for cancer, immunologic diseases, or transplantation. Elimination of hepatitis C virus (HCV) in HBV-HCV coinfected individuals treated with direct-acting antivirals (DAAs) has also been identified as an important cause of HBVr. Hepatitis B virus reactivation is an underappreciated but important complication of common medical therapies that can delay treatment or result in clinical episodes of hepatitis, hepatic failure, or death. In this review, factors associated with HBVr, particularly medication-related risks, are explored. We review data involving rituximab and ofatumumab, doxorubicin, corticosteroids, tumor necrosis factor antagonists, tyrosine kinases, bortezomib, hematologic stem cell transplantation, and DAAs for HCV treatment. In addition, we discuss screening strategies, choice of antiviral prophylaxis, and the optimal duration of therapy for HBVr. With additional awareness, screening, and appropriate antiviral therapy, it is expected that most cases of HBVr can be prevented.

Systematic review of antimicrobial lock therapy for prevention of central-line-associated bloodstream infections in adult and pediatric cancer patients.

BACKGROUND: Central venous catheter (CVC) use is commonplace in cancer patients. Antimicrobial lock therapy (ALT), the instillation of a concentrated antimicrobial solution into the catheter lumen, is one method for preventing infection among CVCs. This systematic review discusses the effectiveness and safety of prophylactic ALT in cancer patients with CVCs. METHODS: A literature search was performed using the Medline database and Google Scholar from inception until April 2016. The following terms were used: 'antimicrobial lock solution', 'antibiotic lock solution', 'oncology', 'hematology', 'pediatrics', 'prevention', 'cancer', 'catheter related bloodstream infections', 'central-line associated bloodstream infection' (CLABSI) and 'central venous catheter'. Studies evaluating prophylactic ALT in cancer patients alone were eligible for inclusion. Case reports, case series and in-vitro studies were excluded. RESULTS: In total, 78 articles were identified. Following all exclusions, 13 articles (three adult and 10 pediatric) were selected for evaluation. The most common agents utilized were vancomycin with heparin; ethanol; taurolidine; and minocycline with EDTA. Quality of evidence was moderate to high in adult studies and low to moderate in pediatric studies. Use of ALT decreased the incidence of CLABSI in the majority of studies; however, there were significant differences in definitions of CVC-related infection, dwell times and lock solutions. CONCLUSION: Lock therapy may be an adjunct in high-risk cancer patients for the prevention of CLABSI; higher quality evidence is needed for specific ALT recommendations.

Tale of Two Erythropoiesis-Stimulating Agents: Utilization, Dosing, Litigation, and Costs of Darbepoetin and Epoetin Among South Carolina Medicaid-Covered Patients With Cancer and Chemotherapy-Induced Anemia.

PURPOSE: The US Food and Drug Administration (FDA) has approved epoetin and darbepoetin for chemotherapy-induced anemia (CIA). Approved epoetin and darbepoetin dosing schedules were three times per week and weekly, respectively, although off-label, less frequent scheduling was common. In 2004, 2007, and 2008, a US Food and Drug Administration Advisory Committees warned of risks associated with erythropoiesis-stimulating agents. During this period, lawsuits alleging illegal darbepoetin marketing practices have concluded, resulting in $1.1 billion in fines and settlements and one criminal conviction. No prior study, to our knowledge, has reported on the use of darbepoetin versus epoetin for CIA. METHODS: We evaluated the dosing, utilization, and costs of erythropoiesis-stimulating agents among 3,761 South Carolina Medicaid patients with CIA. RESULTS: Epoetin and darbepoetin utilization rates were 22% and 28% in 2003, 10% and 33% in 2007, and 3% and 7% in 2010, respectively. Mean per-patient per-administration epoetin and darbepoetin doses were 40,983 IU and 191 µg, respectively, in 2003 and 47,753 IU and 369 µg, respectively, in 2010. Mean monthly patient costs for epoetin and darbepoetin were $1,030 and $981, respectively, in 2003 and $932 and $1,352, respectively, in 2010. Epoetin use decreased steadily between 2002 and 2010; darbepoetin use increased steadily between 2003 and 2007 and then decreased steadily thereafter. Per-patient dosing of darbepoetin, but not epoetin, increased steadily between 2003 and 2010, and monthly per-patient epoetin costs decreased 3% while the per-patients costs of darbepoetin increased 30% between 2003 and 2010. CONCLUSION: To our knowledge, our findings are the first data reporting on epoetin versus darbepoetin use for CIA and support recently concluded lawsuits involving allegations of illegal marketing practices of the manufacturer of darbepoetin.

Melanoma complicating treatment with natalizumab for multiple sclerosis: A report from the Southern Network on Adverse Reactions (SONAR).

A 43-year-old female with multiple sclerosis developed urethral melanoma. The only potential risk factor was treatment with natalizumab, a humanized monoclonal antibody against α4 integrins. To investigate the risk-exposure relationship, we reviewed this case, all other published cases, and cases of natalizumab-associated melanoma reported to regulatory agencies. Data sources included the Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS) (2004-2014), a FDA Advisory Committee Meeting Report, and peer-reviewed publications. In the United States, the manufacturer maintains an FDA-mandated Tysabri Safety Surveillance Program (part of the Tysabri Outcomes Unified Commitment to Health (TOUCH)) of natalizumab-treated patients. We statistically compared reporting completeness for natalizumab-associated melanoma cases in FAERs for which information was obtained entirely from the TOUCH program versus cases where FAERS information was supplemented by TOUCH program information. FAERS included 137 natalizumab-associated melanoma reports in patients with multiple sclerosis. Median age at melanoma diagnosis was 45 years (range: 21-74 years). Changes in preexisting nevi occurred in 16%, history of cutaneous nevi occurred in 22%, diagnosis within 2 years of beginning natalizumab occurred in 34%, and 74% had primary surgical treatment. Among seven natalizumab-treated MS patients who developed biopsy-confirmed melanoma on treatment and reported in the literature, median age at diagnosis was 41 years (range: 38-48 years); and the melanoma diagnosis occurred following a median of 12 natalizumab doses (range: 1-77 doses). A history of mole or nevi was noted in four patients and a history of prior melanoma was noted in one patient. Completeness scores for reports were significantly lower for FAERS cases reported from the TOUCH program versus FAERS cases supplemented by TOUCH information (median score of 2 vs. 4 items out of 8-possible items, P < 0.0007). Clinicians should monitor existing nevi and maintain suspicion for melanoma developing in natalizumab-treated patients. The TOUCH Safety Surveillance Program, currently focused on progressive multifocal leukoencephalopathy, should be expanded to include information on other serious complications including malignancies, particularly if they are immunologic in nature.

Fluoroquinolone-related neuropsychiatric and mitochondrial toxicity: a collaborative investigation by scientists and members of a social network.

BACKGROUND: The 3 fluoroquinolone (FQ) antibiotics - ciprofoxacin, levofoxacin, and moxifoxacin - are commonly administered to oncology patients. Although these oral antibiotics are approved by the US Food and Drug Administration (FDA) for treatment of urinary tract infections, acute bacterial sinusitis, or bacterial infection in patients with chronic obstructive pulmonary disease, they are commonly prescribed off-label to neutropenic cancer patients for the prevention and treatment of infections associated with febrile neutropenia. New serious FQ-associated safety concerns have been identified through novel collaborations between FQ-treated persons who have developed long-term neuropsychiatric (NP) toxicity, pharmacovigilance experts, and basic scientists. OBJECTIVE: To conduct basic science and clinical investigations of a newly identified adverse drug reaction, termed FQ-associated disability. METHODS: 5 groups of C57BL/6 mice receiving the antibiotic ciprofoxacin in 10-mg increments (10 mg/kg-50 mg/kg) and 1 group of control mice were evaluated. The Southern Network on Adverse Reactions (SONAR) and a social network of FQ-treated persons with long-term NP toxicity (the Floxed Network) conducted a web-based survey. The clinical toxicity manifestations reported by 94 respondents to the web-based survey of persons who had received 1 or more doses of an FQ prescribed for any indication (generally at FDA-approved dosages) and who subsequently experienced possible adverse drug reactions were compared with adverse event information included on the product label for levofoxacin and with FQ-associated adverse events reported to the FDA's MedWatch program. RESULTS: Mice treated with ciprofoxacin had lower grip strengths, reduced balance, and depressive behavior compared with the controls. For the survey, 93 of 94 respondents reported FQ-associated events including anxiety, depression, insomnia, panic attacks, clouded thinking, depersonalization, suicidal thoughts, psychosis, nightmares, and impaired memory beginning within days of FQ initiation or days to months of FQ discontinuation. The FDA Adverse Event Reporting System (FAERS) included 210,705 adverse events and 2,991 fatalities for FQs. Levofoxacin and ciprofoxacin toxicities were neurologic (30% and 26%, respectively), tendon damage (8% and 6%), and psychiatric (10% and 2%). In 2013, an FDA safety review reported that FQs affect mammalian topoisomerase II, especially in mitochondria. In 2013 and 2014, SONAR fled citizen petitions requesting black box revisions identifying neuropsychiatric toxicities and mitochrondrial toxicity as serious levofoxacin-associated adverse drug reactions. In 2015, FDA advisors recommended that FQ product labels be revised to include information about this newly identified disability syndrome termed "FQ-associated disability" (FQAD). LIMITATIONS: Basic science studies evaluated NP toxicity for only 1 FQ, ciprofoxacin. CONCLUSION: Pharmacovigilance investigators, a social network, and basic scientists can collaborate on pharmacovigilance investigations. Revised product labels describing a new serious adverse drug reaction, levofoxacin-associated long-term disability, as recommended by an FDA advisory committee, are advised.

Stability and compatibility of antimicrobial lock solutions.

PURPOSE: Published stability and compatibility data on a growing array of solutions used for antimicrobial lock therapy (ALT) are reviewed. SUMMARY: ALT involves the instillation of a highly concentrated antimicrobial, often in combination with an anticoagulant, into a central venous catheter (CVC) lumen; this technique is often used for prophylaxis after CVC insertion or as an adjunctive treatment in cases of central line-associated bloodstream infection (CLABSI) if catheter removal is not feasible. Optimal selection of stable and compatible antimicrobials and additives can maximize catheter dwell times, streamline pharmacy compounding practices, and help ensure patient safety. Of 98 articles on ALT solutions identified in a literature search, 17 met the prespecified criteria for the use of validated stability and compatibility methodology. Antimicrobials active against common CLABSI pathogens that may be appropriate for ALT include cefazolin, cefotaxime, ceftazidime, ciprofloxacin, daptomycin, gentamicin, linezolid, telavancin, ticarcillin-clavulanic acid, and vancomycin; validated data demonstrate the stability of these agents in solution with heparin or nonheparin anticoagulants over 72-96 hours or longer. Other antifungal agents and antiinfectives (e.g., ethyl alcohol) have been used in specific patients and ALT situations. The prolonged stability of several antimicrobial-additive combinations may allow for extended dwell times and less frequent lock solution exchanges. CONCLUSION: Pharmacists' knowledge of diverse combinations of antimicrobial agents and additives in lock solutions, including several shown to be stable and compatible for extended periods, can help expand and optimize the use of ALT in both treatment and prophylactic modalities.

Gadolinium-induced nephrogenic systemic fibrosis: the rise and fall of an iatrogenic disease.

BACKGROUND.: In 2006, nephrologists in Denmark unexpectedly identified chronic kidney disease (CKD) patients with a new syndrome, nephrogenic systemic fibrosis (NSF). Subsequently, 1603 NSF patients were reported to the Food and Drug Administration. Sixty hospitals in the USA account for 93% of these cases, and two hospitals in Denmark account for 4% of these reports. We review Denmark's identification and subsequent rapid eradication of NSF. METHODS.: NSF reports from clinicians, the Danish Medicines Agency (DMA) and gadolinium-based contrast agents (GBCAs) manufacturers were reviewed (2002-11). RESULTS.: In 1994, the DMA approved a non-ionic linear GBCA, gadodiamide (0.1 mmol/kg), for magnetic resonance imagings (MRIs), with a renal insufficiency contraindication. In 1996, 0.3 mmol/kg dosing received DMA approval. In 1998, the DMA removed renal contraindications. In 1997 and 2002, radiologists at Skejby Hospital and Herlev Hospital, respectively, began performing gadodiamide-enhanced magnetic resonance angiography scans (0.3 mmol/kg) of CKD patients. In 2005, Herlev clinicians requested assistance in evaluating etiological causes of NSF occurring among 10 CKD patients who had developed NSF. This investigation, focusing on infectious agents, was inconclusive. In 2006, Herlev clinicians reported that of 108 CKD patients who had received gadodiamide-enhanced MRI, 20 had developed probable NSF. Herlev radiologists voluntarily discontinued administering gadodiamide to all patients and no new NSF cases at Herlev Hospital developed subsequently. After meeting with Herlev radiologists, Skejby radiologists also discontinued administering gadodiamide to all patients. In 2007, the European Medicines Agency and the DMA contraindicated gadodiamide administration to CKD patients. In 2008, in response to these advisories, radiologists at the other 36 Danish hospitals discontinued administering gadodiamide to all patients, following on practices adopted at Skejby and Herlev Hospitals. In 2009, clinicians at Skejby Hospital reported that a look-back survey identified 33 CKD patients with NSF developing after undergoing GBCA-enhanced MRIs between 1999 and 2007. In 2010, an independent review, commissioned by the Minister of Health, concluded that the DMA had erred in rescinding gadodiamide's renal insufficiency contraindication in 1998 and that this error was a key factor in the development of NSF in Denmark. In 2011, three NSF cases associated with macrocyclic GBCA-associated NSF and three NSF patients with Stages 3 and 4 CKD disease from Skejby Hospital were reported. CONCLUSION.: A confluence of factors led to the development and eradication of NSF in Denmark.

Description of anaphylactic reactions to paclitaxel and docetaxel reported to the FDA, with a focus on the role of premedication.

PURPOSE: Anaphylactic reactions (ARs) have been frequently reported with taxanes. The authors' purpose was to summarize published case reports and describe ARs from taxanes reported to the Food and Drug Administration (FDA) with a focus on use of package insert-specified prophylactic premedications (PPMs). METHODS: The authors searched PubMed for the relevant literature. The authors obtained cases of ARs reported to the FDA through 31 December 2009 using the drug names and preferred terms for ARs. The authors used χ² and Student's t-tests to compare ARs from paclitaxel and docetaxel. The authors compared mortality based on presence/absence of PPMs. For signal detection, the authors calculated empirical Bayes geometric mean (EBGM) values. RESULTS: There was one docetaxel and eight paclitaxel case report articles describing ARs. The authors found 290 and 683 FDA reports of ARs from docetaxel and paclitaxel, respectively. More docetaxel cases were associated with mortality (54 vs 29%, p < 0.001). When PPMs were administered, mortality occurred in more docetaxel cases (52 vs 18%, p < 0.001). EBGM signals were 1.74 for docetaxel and 2.50 for paclitaxel. CONCLUSIONS: Mortality was reported in more docetaxel ARs than paclitaxel. Documented use of PPMs did not significantly impact mortality from ARs with docetaxel, but was associated with significantly lower mortality from ARs with paclitaxel.