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BACKGROUND: Real-world safety of bevacizumab in cancer patients is limited. OBJECTIVE: To review the adverse drug reactions (ADRs) due to bevacizumab in cancer patients, in published case reports. METHODS: PubMed was searched; case reports of patients with any type of cancer, administered with bevacizumab (monotherapy/combination) and reported ADRs were included. Causality of ADRs was presented as reported in individual papers. ADRs were classified using the information in the USFDA-approved prescribing information (PI) of bevacizumab as ‘Serious’, ‘Common’, and ‘Post-marketing surveillance’ ADRs; ADRs not mentioned in the bevacizumab PI were termed as ‘Non-label ADRs’. RESULTS: A total of 130 published papers comprising 154 cases from 22 different countries were included. Most papers (102/130; 78.46%) had moderate methodological quality. Age range of patients was 9-77 years. Off-label use of bevacizumab was found in 34/154 cases (22.08%). Ninety-six unique ADRs were found among 154 ADRs; most reported ADRs affected circulatory, digestive, and respiratory systems (33, 32, and 26 cases respectively). Most commonly reported ADRs were posterior leukoencephalopathy, fistulae, and gastrointestinal perforation (17, 17, and 16 cases respectively). Twenty-eight unique non-label ADRs (29.17%) were found. CONCLUSION: Bevacizumab is associated with more ADRs in the real world among cancer patients than those reported during clinical trials.

Aims A substantial number of Summaries of Product Characteristics (SmPCs)/Prescribing Information (PI) have warnings or contraindications on QT interval prolongation. The goal of this work was to quantify usage of QT interval prolonging drugs according to the CredibleMeds® database of the German outpatient drug prescription market and to evaluate discrepancies between German SmPCs/US PI and CredibleMeds® . Methods Drugs listed on CredibleMeds® with known, possible or conditional risk for torsade de pointes were evaluated from 2000 to 2020. The German drug prescription report was used as source for defined daily dose- (DDD-) based prescriptions of the German outpatient drug prescription market of the public health insurance system. German SmPCs and US PI of 253 CredibleMeds® -listed drugs were evaluated for contents regarding QT interval prolongation. Results Of the drugs currently listed on CredibleMeds® , 59.7% (95% confidence interval [CI] 53.5-65.5%) were listed after 2012. Due to newly listed drugs, the proportion of DDDs of CredibleMeds® drugs among all prescriptions increased from 4.6% in 2013 to 21.1% in 2019. DDD-based usage of the CredibleMeds® drugs already listed in 2013 was similar in 2019. Among the drugs with known QT risk according to CredibleMeds® , 7.5% (95% CI 2.6-19.9%) of German SmPCs and 21.1% (95% CI 11.1-36.3%) of US PI had no mention of QT issues whatsoever. Conclusion A significant proportion of all drugs prescribed in the outpatient sector is associated with QT risks according to CredibleMeds® . SmPCs and PI should systematically be evaluated for concordance with the widely used CredibleMeds® database to increase medication safety.

Introduction In 2000, the FDA began issuing advice about treatments for hypoactive sexual desire disorder (HSDD) in women. How its recommendations have evolved has not been reviewed. Its consistent preference for self-rating by patients over evaluation by an examining clinician has not been addressed. Objectives Recount the changes in FDA’s proposals about patient-reported outcomes and diagnostics. Compare the value of patient-reported measures and clinical interviews. Methods Historical review is based on draft guidances, publications, meetings, and prescribing information. Results The FDA has avoided clinician input into diagnosis and evaluation of the severity of HSDD in women. It abandoned its initial (2000) insistence on counts of satisfying sexual events to define efficacy in favor of symptom-related scales to evaluate desire and distress with daily self-ratings. By 2015, the FDA accepted the self-rated Female Sexual Function Index-Desire Domain (FSFI-D) to measure desire and the most relevant item of the Female Sexual Distress Scale-Revised (FSDS-R) to measure distress; retrospection for both is one month. The FDA rejected the one clinician-rated broad measure of HSDD, the Sexual Interest and Desire Inventory (SIDI-F), although well-validated and treatment-sensitive. Since 2005, the FDA has accepted the Decreased Sexual Desire Screener (DSDS) to diagnose HSDD by non-expert clinicians using self-ratings and exploring them in more depth in a clinical interview. Conclusion FDA’s decisions on how to measure HSDD in women may have stabilized on accepting 2 co-primary measures: the FSFI-D and the FSDS-R item on bother about low desire, and on accepting the DSDS for diagnosis. FDA’s rejection of clinician ratings of severity through interviews in clinical trials seems unsound because interviews can give broader assessments than (brief) self-ratings, although the agency’s logic was to avoid diagnostic controversies and help avoid overcommercialization. Semistructured clinical interviews for diagnosis (DSDS) and severity-rating (SIDI-F) are well validated and are recommended for clinical practice. Pyke RE. FDA Decisions on Measures of Hypoactive Sexual Desire Disorder in Women: A History, With Grounds to Consider Clinical Judgment. Sex Med Rev 2021;9:186–193.

Background Patient-reported outcomes (PROs) can provide valuable information about drug benefit-risk tradeoffs from the patient perspective and are particularly important to patients with breast cancer due to its symptoms and adverse events from breast cancer treatments. The United States Food and Drug Administration (U.S. FDA) has acknowledged PROs as important approval endpoints used in clinical trials of cancer drugs. However, previous studies found that PROs are rarely mentioned in cancer drug labels, a widely used and trusted source of information about drugs. Our objectives were to compare PRO data reported in FDA labeling versus FDA medical review documents for breast cancer drugs approved in the U.S. between 2000 and 2019 to identify possible causes for PRO-data labeling exclusions. Methods We included new molecular entities (NMEs) and biologic license applications (BLAs) initially approved for breast cancer treatment by the FDA between 1/1/2000 and 12/31/2019. Product labeling and FDA medical review documents were collected from the FDA-Approved Drugs database (Drugs@FDA). From these resources, details on PRO measures used in trials, design of trials using PRO measures, PRO-endpoint status, analytical methods, and FDA reviewer comments regarding PRO measurement were extracted. Results Of 633 FDA-approved drugs, 13 were indicated for breast cancer treatment; none of their prescribing information contained information about PROs. However, 11 of 13 (85%) included PRO measures and endpoint information in FDA medical review documents. PRO measures were used in 14 different clinical trials, and FDA reviewers’ comments regarding PRO measurement were related to lack of meaningfulness and clinical significance, lack of content validity, and inadequate analytical methods. Conclusions Despite the importance of PROs to patients with breast cancer, PRO measures were only described in FDA medical review documents of breast cancer drugs, but not in drug product labeling. Therefore, it appears that PRO data are often collected in breast cancer trials, but have not been methodologically acceptable to FDA reviewers. Collaborative efforts between the FDA and industry are warranted to increase the number of breast cancer drug applications with appropriate use of PRO measures and endpoints.

Objectives Omnitrope® (somatropin, Sandoz Inc.) is one of several recombinant human growth hormones (rhGH) approved in the United States (US) for use in pediatric indications, including growth hormone deficiency (GHD) and idiopathic short stature (ISS). We report data on the effectiveness and safety of Omnitrope® in the US cohort of the PATRO Children (international, longitudinal, non-interventional) study. Methods All visits and assessments are carried out according to routine clinical practice, and doses of Omnitrope® are given according to country-specific prescribing information. Results By September 2018, 294 US patients were recruited; the two largest groups were GHD (n=193) and ISS (n=62). Across all indications, HSDS improvement (ΔHSDS) from baseline at three years was +1.0 (rhGH-naïve, +1.2; pre-treated, +0.7). In pre-pubertal patients, ΔHSDS from baseline at three years was +0.94 (rhGH-naïve, +1.3; pre-treated, +0.7). Following three years of treatment, ΔHSDS from baseline was +1.3 in rhGH-naïve GHD patients and +1.1 in rhGH-naïve ISS patients. In pre-pubertal rhGH-naïve patients, ΔHSDS from baseline was +1.3 and +1.2 in GHD and ISS patients, respectively. Overall, 194 patients (66.0%) experienced adverse events (AEs; n=886 events); most were of mild-moderate intensity. Five patients (1.7%) had AEs that were suspected to be treatment-related (n=5 events). All reported neoplasms were benign, non-serious, and considered unrelated to rhGH therapy. No AEs of diabetes mellitus or hyperglycemia were reported. Conclusions Omnitrope® appears to be well tolerated and effective in the majority of patients, without evidence of an increased risk of developing unexpected AEs, diabetes mellitus, or new malignancies during treatment.

Background Recombinant human follitropin alfa (r-hFSH) is used for ovarian stimulation as part of medically assisted reproduction. There is a risk for ovarian hyperstimulation syndrome (OHSS) with r-hFSH treatment, and an increased risk for thromboembolic events in the presence of pregnancy with OHSS. Objectives To report the frequency of OHSS and thromboembolism with originator follitropin alfa (GONAL-f) based on the Global Safety Database of Merck KGaA, Darmstadt, Germany and a systematic review of published data. Data Sources Reports of OHSS and thromboembolism were obtained from the Global Safety Database of Merck KGaA, Darmstadt, Germany from 20 October 1995 to 19 October 2018. The systematic review was based on MEDLINE and Embase searches from inception to 19 October 2018. Study Eligibility Criteria Patients receiving GONAL-f for ovulation induction or ART, with a starting dose within the range included in the prescribing information and providing information on the occurrence of OHSS and/or thromboembolism. Study Appraisal and Synthesis Matches In the Global Safety Database of Merck KGaA, Darmstadt, Germany there were an estimated 16,525,975 treatment cycles since 20 October 1995; 1110 reported cases of OHSS and 80 reported cases of thromboembolic events (reporting rates 6.7 and 0.48 per 100,000 treatment cycles, respectively). The systematic review identified 45 studies (5186 patients exposed to GONAL-f; 5240 treatment cycles). There were 272 reports of OHSS (5190 [5.19%] per 100,000 treatment cycles), including 10 cases of severe OHSS (191 [0.19%] per 100,000 treatment cycles). Limitations There may be the potential for under-reporting of safety outcomes in the literature, and under-reporting is a well-known phenomenon in spontaneous reporting databases. Conclusion and Implications of Key Findings Our analyses demonstrate low rates of OHSS and thromboembolism with GONAL-f. Electronic Supplementary Material The online version of this article (10.1007/s12325-020-01512-w) contains supplementary material, which is available to authorized users.

Background Sublingual immunotherapy (SLIT) is administered via tablets (SLIT-T) or liquid drops (SLIT-D). In North America, currently 4 SLIT-T formulations are approved by the US Food and Drug Administration for allergy immunotherapy, and SLIT-D is an off-label use of subcutaneous immunotherapy (SCIT) extracts. Objective To compare and contrast aspects of SLIT-T and SLIT-D, including physical characteristics, mechanism of action, dosing, efficacy, safety, adherence, and cost. Data Sources PubMed literature review (no limits), product prescribing information, and manufacturer websites. Study Selections Publications related to physical characteristics, mechanism of action, dosing, efficacy, safety, and adherence. Results Published evidence indicates that tablet and drop formulations differ in regard to physical characteristics, dosing, and strength of evidence for efficacy. Whether there are any differences in absorption and mechanism of action between the 2 formulations is currently unknown. Optimal dosing, efficacy, and safety have been established for SLIT-T. In contrast, in North America there is little support for efficacy of SLIT-D from randomized double-blind, placebo-controlled trials, and dose ranges have not been appropriately evaluated. SLIT-T treats a single allergen, whereas in the United States SLIT-D often contains multiple allergens to treat polysensitization. The safety profiles of SLIT-T and SLIT-D appear similar, and both formulations are considered safer than SCIT. Conclusion Professional guidelines should make a clear distinction between SLIT-T and SLIT-D in their recommendations to minimize confusion with the umbrella term SLIT.

We report a 59-year-old male with left leg osteomyelitis caused by an XDR Pseudomonas aeruginosa strain following a road traffic accident. Limited treatment options and adverse antimicrobial reaction led to consideration of cefiderocol together with appropriate surgical intervention. Improved bony remodelling over the tibia and fibula was observed with good bony alignment and no adverse features. Physiotherapy support was continued for 4 months following treatment, which resulted in good functional mobility, improved proprioception and full ability to bear weight. This case also adds to multiple reports that describe safe and successful use of cefiderocol to treat MDR, aerobic Gram-negative infections. The prescribing information for cefiderocol is available at: https://shionogi-eu-content.com/gb/fetcroja/pi.

Experts of the Department for Evaluation of Medicinal Products’ Safety of the Scientific Centre for Expert Evaluation of Medicinal Products analysed administrative decisions of foreign regulatory authorities on the recall of medicines and/or the need to amend the prescribing information due to changes in their safety profile. The analysis helped to identify 11 administrative decisions that contain information on the following medicines registered in Russia: ranitidine, nizatidine, famotidine, pantoprazole, ondansetron, domperidone.

Objectives: Fear of opioid withdrawal syndrome (OWS) often dissuades opioid discontinuation. Lofexidine is an FDA-approved, alpha2-adrenergic receptor agonist for treatment of OWS. Pivotal trial results from the per-protocol statistical analyses have been published. However, the FDA prescribing information presents these efficacy results using a different, standardized statistical approach that does not transform data or impute missing values. This analysis is easier to interpret and allows comparison across studies. This reanalysis is presented here. Methods: Studies were double-blind, placebo-controlled for 7 days in Study 1 and 5 days in Study 2. Opioid-dependent adults received placebo or lofexidine; efficacy was assessed using the Short Opioid Withdrawal Scale of Gossop (SOWS-G) daily. Results: Study 1 (N = 602) mean SOWS-G scores were 6.1 (SE: 0.35), 6.5 (SE: 0.34), and 8.8 (SE: 0.47) over Days 1–7 for lofexidine 2.88 mg/day, 2.16 mg/day, and placebo, respectively (for 2.88, p

This chart is an update to the 2012 article published in Hospital Pharmacy on injectable drugs to be used with a filter. To update the chart, drugs approved from December 2011 to April 2019 were reviewed to determine if they require filtration and drugs included in the 2012 table were reviewed for accuracy. Readers are urged to review national standards of practice for information about clinical situations that warrant the use of a filter for medication preparation or administration, independent of the drug being given, and the reader should consult the Food and Drug Administration (FDA)-approved prescribing information for the most up-to-date information.

As the liver is vital for the metabolism of many anticancer drugs, determining the correct starting doses in cancer patients with liver impairment is key to safe prescription and prevention of unnecessary adverse effects. Clinicians typically use liver function tests when evaluating patients; however, prescribing information and summaries of product characteristics often suggest dosing of anticancer drugs in patients with liver impairment based on the Child-Pugh criteria, even though the criteria were not developed for this purpose. In this review, we assessed all the oncological small molecule and cytotoxic drugs approved by the United States Food and Drug Administration (FDA) over a 5-year period from 2014 to 2018. The various entry criteria related to these drugs—with respect to hepatic function—in key pivotal studies were compared with their approved dosing recommendations found in prescribing information and summaries of product characteristics. We found that 46% of drugs have dosing recommendations based on Child-Pugh criteria alone, despite the fact that only 8% of these drugs were tested within studies that used the Child-Pugh criteria as entry criteria. Moreover, we note that the data used to make recommendations based on Child-Pugh criteria are typically from small studies that may lack an appropriate patient population. We propose that these findings, along with details surrounding the development of the Child-Pugh criteria, call into question the validity and appropriateness of using Child-Pugh criteria for dosing recommendations of anticancer drugs., Highlights • Dosing information for anticancer drugs in patients with liver impairment is often based on the Child-Pugh criteria. • Clinical trials and clinicians typically use liver function tests when evaluating patients. • Of the 39 oncologic drugs examined, almost half (46%) had dosing recommendations based on Child-Pugh criteria alone. • We question whether using Child-Pugh criteria for dosing recommendations of anticancer drugs is the best approach.

WHAT IS KNOWN AND OBJECTIVE The United States Food and Drug Administration (FDA) recently issued a Drug Safety Communication requiring Boxed Warning updating and other changes in order to improve the safe use of the benzodiazepine drug class. These changes were prompted because 'The current prescribing information for benzodiazepines does not provide adequate warnings about [the] serious risks and harms associated with these medicines so they may be prescribed and used inappropriately'. COMMENT The FDA Communication points out that benzodiazepines can be an important option for treating disorders for which these drugs are indicated. However, the acknowledged problems of these drugs, which historically were considered an acceptable trade-off against their benefits, need to be reassessed in light of their widespread (over?) prescribing (for example, in 2019 an estimated 92 million benzodiazepine prescriptions were dispensed from US retail and mail-order pharmacies). WHAT IS NEW AND CONCLUSION The FDA Communication can be viewed as an important step in reminding healthcare providers of the 'serious risks and harms associated with these medicines', and validation of such reports by patients. Importantly, the FDA Communication includes an often-neglected aspect of benzodiazepine prescribing, namely how to discontinue use, and the perplexing protracted withdrawal syndrome experienced by some patients. The Communication advises to providers: 'No standard benzodiazepine tapering schedule is suitable for all patients; therefore, create a patient-specific plan to gradually reduce the dosage, and ensure ongoing monitoring and support as needed to avoid serious withdrawal symptoms or worsening of the patient's medical condition'.

Drug compendia are the source of safety prescribing information. We assessed the reporting concordance of drug–drug interactions between hormonal contraception and antiepileptic drugs (AEDs) among eight leading international drug compendia. Antiepileptic drugs reported to interact with ≥1 form of hormonal contraception were reviewed. Scaled concordance was quantified using linearly weighted percent agreement (wPA). Differences in interaction severity rankings between hormonal contraception forms were evaluated using the Wilcoxon signed-rank test. There was high agreement among compendia for interactions of combined hormonal contraception interactions with AEDs (wPA = 0.82–0.84), especially potent enzyme-inducing AEDs (wPA = 0.89). However, concordance was reduced for AED interactions with progestin-only contraception (wPA = 0.69–0.81). Extreme interaction reporting discrepancies were found for less potent enzyme-inducing AEDs. The greatest variability in interaction reporting was observed for injectable and intrauterine contraception (wPA = 0.69 and 0.70, respectively), which are the only hormonal contraception options currently classified as not interacting with enzyme-inducing AEDs. Drug–drug interaction reporting variability can have major clinical implications and highlights critical knowledge gaps in the care of women with epilepsy of childbearing age. Further research on AED–contraceptive interactions is needed to standardize compendia reporting and enhance evidence-based clinical guidelines for women with epilepsy.

Background Ocrelizumab is an approved MS treatment administered as two 300-mg intravenous infusions 2 weeks apart (Dose 1), each lasting approximately 2.5 hours, followed by single 600-mg infusions every 6 months lasting approximately 3.5 hours. Our objective was to evaluate shorter-duration ocrelizumab infusions in the Phase IIIb open-label SaROD study (NCT03606460). Methods Eligible patients received ocrelizumab 600-mg Dose 2 or 3 infused over approximately 2 hours (Cohort 1) or ocrelizumab 300-mg Dose 1, Infusion 2 over approximately 1.5 hours (Cohort 2). The primary endpoint was the number and proportion of patients experiencing Grade 3–4 infusion-related reactions (IRRs) in Cohort 1. Secondary endpoints included Grade 1–4 IRRs in both cohorts and Grade 3–4 IRRs in Cohort 2. Results Mean infusion times decreased by approximately 1.09 and 0.79 hours in Cohorts 1 and 2, respectively, compared with US prescribing information. IRRs, reported by 36% of 141 patients, were mild-to-moderate, with no observed Grade 3–4 IRRs. No IRR-related discontinuations occurred. No serious AEs, deaths, or new safety signals were observed. Conclusion The IRR rate with ocrelizumab shorter-duration infusions was similar to that observed in the pivotal Phase III trials. Ocrelizumab can be infused over a shorter time without sacrificing patient safety.

Background and ObjectivesThe Patient Registry of Intrathecal Ziconotide Management evaluated the long-term effectiveness and safety of intrathecal ziconotide.MethodsThe study was a prospective, multicenter observational study of intrathecal ziconotide in US clinical practice. Patients were adults with severe chronic pain that warranted intrathecal therapy. Ziconotide was initiated as the single agent in the pump; however, other intrathecal medications were permitted. The primary efficacy outcome was ≥30% reduction in numeric pain rating scale score from baseline at week 12. A secondary outcome was patient global impression of change. Adverse events were solicited at each visit.ResultsThe registry enrolled 93 patients. Seventy-four and 28 patients completed 12 weeks and 18 months of treatment, respectively. In the overall patient population, 17.4% had ≥30% pain reduction from baseline at week 12, with a mean reduction in pain of 10.9%. At month 18, 38.5% of patients had ≥30% pain reduction from baseline, with a mean pain reduction of 24.7%. Patient-rated improvement was reported in 67% of patients at week 12 and 71% at month 18. Almost all patients experienced adverse events, the most common of which were nausea (25.8%), confusional state (22.6%), and dizziness (20.4%).ConclusionsFinal study analyses showed that intrathecal ziconotide provided clinically meaningful pain relief in 17.4% and 38.5% of patients at week 12 and month 18, respectively. At these same time points, patient-rated improvement was reported in at least two-thirds of patients. The safety profile was consistent with that listed in the ziconotide prescribing information.

The aim was to analyze safety data associated with the maternal use of antiepileptic drugs in pregnancy and to assess the risk of cleft lip and/or palate (CL/P) as an outcome in the neonate. A parallel objective was to assess the completeness of the safety information concerning pregnancy exposures in the Summary of Product Characteristics (SmPCs) and the Patient Information (PI) in the USA and the UK.We analyzed individual case safety reports of CL/P associated with antiepileptic drugs in the FDA Adverse Event Reporting System. For the antiepileptic drugs with signals (EB05 ≥ 2), we reviewed Drug Analysis Prints for CL/P cases in the UK Medicines and Healthcare products Regulatory Agency (MHRA). We performed descriptive analyses of relevant SmPCs and PIs in the UK and the USA using a checklist of recommendations collected from the literature.In total 817 CL/P reports were identified for 12 antiepileptic drugs in the FDA Adverse Event Reporting System. Ten of the 12 antiepileptic drugs were associated with 156 CL/P cases in the MHRA Sentinel. Safety information concerning pregnancy was found to be more comprehensive in UK SmPCs than in the US equivalents.There is statistical disproportionality in individual case safety reports indicative of an increased risk of CL/P with 12 antiepileptic drugs studied. More studies are required to explore the association between in utero exposure to antiepileptic drugs and the risk of CL/P. There are inconsistencies between the UK and US safety labels. CL/P associated with antiepileptic drugs is an important topic and requires providing inclusive, unbiased, up-to-date information to prescribers and women of childbearing age.

Introduction Currently there are no general guidelines for diagnosis or management of suspected drug-induced (DI) interstitial lung disease (ILD). The objective was to survey a sample of current European practice in the diagnosis and management of DI-ILD, in the context of the prescribing information approved by regulatory authorities for 28 licenced drugs with a recognised risk of DI-ILD. Methods Consultant physicians working in specialist ILD centres across Europe were emailed two surveys via a website link. Initially, opinion was sought regarding various diagnostic and management options based on seven clinical ILD case vignettes and five general questions regarding DI-ILD. The second survey involved 29 statements regarding the diagnosis and management of DI-ILD, derived from the results of the first survey. Consensus agreement was defined as 75% or greater. Results When making a diagnosis of DI-ILD, the favoured investigations used (other than computed tomography) included pulmonary function tests, bronchoscopy and blood tests. The preferred method used to decide when to stop treatment was a pulmonary function test. In the second survey, the majority of the statements were accepted by the 33 respondents, with only four of 29 statements not achieving consensus when the responses “agree” and “strongly agree” were combined as one answer. Conclusion The two surveys provide guidance for clinicians regarding an approach to the diagnosis and management of DI-ILD in which the current evidence base is severely lacking, as demonstrated by the limited information provided by the manufacturers of the drugs associated with a high risk of DI-ILD that we reviewed., Two surveys illustrating current European practice in the diagnosis and management of drug-induced interstitial lung disease provide guidance for clinicians in a condition in which the present evidence base is lacking http://bit.ly/35A9YPk

Introduction: Multiple three drug combination regimens have been approved for the treatment of multiple myeloma in the last few years. Triplets have become the new standard of care for transplant eligible and ineligible patients with newly diagnosed as well as relapsed multiple myeloma. Novel agents have a unique profile of side effects. The management of toxicities is important to maintain quality of life and maximize treatment duration and benefit. Areas covered: This article reviews efficacy data, incidence of key adverse events and provide recommendations and expert opinion regarding how to manage common toxicities in triplet therapies. Relevant publications and abstracts were searched in PubMed, ASH, ASCO and EHA meetings. Guidelines from IMWG, NCCN, ESMO and ASCO, published trial protocols and prescribing information were used to formulate recommendations for the management of toxicities. Expert commentary: Side effects are a critical factor guiding the selection of optimal chemotherapy regimens for multiple myeloma. The majority of toxicities encountered with triplet therapies are reversible and can be readily managed with supportive care and dose modifications.

Introduction: Intramuscular antipsychotics are commonly used to manage agitated patients. In 2005, Eli Lilly placed a warning on olanzapine's prescribing information following post-marketing reports of fatal drug reactions when intramuscular olanzapine was used in the setting of benzodiazepines. Data is lacking examining this drug combination. Methods: A medication use evaluation was conducted at a county psychiatric hospital surveying the usage of concomitant intramuscular olanzapine and lorazepam from October 1, 2016, to July 20, 2017. A literature search was conducted to review available evidence. Results: Ninety-one instances of the drug combination were discovered, with no serious adverse events following administration. Of these 91 patients, 41 received both medications within 60 minutes of each other. No instances of hypotension, bradycardia, bradypnea, or oxygen desaturation occurred following administration. The literature review yielded 1 randomized, placebo-controlled clinical trial, 3 retrospective chart reviews, and several case studies. Discussion: Data detailing a causal relationship between olanzapine/benzodiazepine combinations and serious adverse effects is lacking. Available evidence does not consistently support a strong cause and effect relationship. The results of this medication use evaluation are not consistent with the Food and Drug Administration warning. Further controlled research is needed to help define the actual risk of using concomitant intramuscular olanzapine and benzodiazepines.

Objectives: To review the immunogenicity, efficacy, and safety of the herpes zoster subunit vaccine (HZ/su) for use in adult patients for the prevention of shingles. Data Sources: A literature search through PubMed was conducted (June 2008 to October 2017) using the terms shingles vaccine and varicella zoster virus. References from retrieved articles and the prescribing information were also reviewed for any additional material. Study Selection/Data Extraction: The literature search was limited to human studies published in English. Randomized controlled, multicenter trials were reviewed and included to evaluate the safety and efficacy of HZ/su. Literature on the epidemiology and pathology of herpes zoster virus infections and recommendations from the Advisory Committee on Immunization Practices (ACIP) were also reviewed. Data Synthesis: HZ/su is a new adjuvanted recombinant vaccine approved by the Food and Drug Administration for the prevention of herpes zoster in adults 50 years of age and older. HZ/su significantly reduced the risk of developing herpes zoster by more than 90% as compared with placebo and displayed a comparable adverse effect profile. The most common local adverse events were injection site pain, redness, and swelling, and the most common systemic adverse events were myalgia, fatigue, and headache. The ACIP recommends the routine use of HZ/su as the preferred vaccine for the prevention of herpes zoster in immunocompetent adults 50 years of age and older. Conclusions: Based on published immunogenicity, efficacy, and safety data, as well as the recent recommendations by the ACIP, HZ/su should be included on both hospital and community pharmacy formularies and recommended to all immunocompetent patients older than 50 years to prevent herpes zoster.

Introduction: Adverse event (AE) reporting in clinical trials (CT) informs the safety of investigational products. Once approved, safety information in the monograph and prescribing information mainly derive from CT data. Some studies have shown geographic variations in the AE reporting patterns in multinational CT; none of them assessed this variation in cancer CT. We conducted a study to analyze the geographic AE reporting patterns in two breast cancer (BC) CT conducted by Translational Research in Oncology (TRIO). Objective: To perform a quantitative and qualitative comparison of non-serious AE (NSAE) and serious AE (SAE) reporting patterns between several geographic regions, in breast cancer CT conducted by TRIO. Methodology: We retrospectively analyzed aggregated NSAE/SAE data (as reported by investigators) from all patients randomized in two completed phase 3, multinational CT of anticancer therapies in advanced BC. Participating countries were grouped in 7 regions according to their geographic location (East Asia, Eastern Europe, Latin America and Caribbean, Middle East and Africa, Non-Eastern Europe, North America, Oceania). Regions were kept masked and numbered from 1 thru 7. AE data were extracted from the clinical data bases. For each region we calculated the mean number of NSAE and SAE per patient (pt), the mean number of NSAE and SAE per cycle/per pt, and the percentage (%) of pt experiencing selected AE (fatigue, febrile neutropenia and emesis). Comparisons between regions were done using unequal variance t-test and Fisher´s exact test. Results: 1,863 patients from 35 countries and 310 sites were included. Mean number of pt per region was 331. We found significant variation in the number of NSAE/SAE reported across several regions. Two regions (1 and 6) reported the highest mean number of AE while region 4 the lowest rates. The mean number of NSAE reported in region 4 is approximately 3-fold lower than regions 1 and 6 (mean NSAE 22.8 [region 1] vs. 7.9 [region 4]; p NSAE and SAE reporting in selected regions (regions 1 and 4) Region 1 (mean)Region 4 (mean)p-valueNSAE per pt22.87.9 % of pt experiencing selected AE in selected regions (regions 1 and 4) Region 1Region 4p-valueFatigue84.1 %8.5 % Conclusion: NSAE and SAE reporting patterns vary markedly by geographic region and one region appears to systematically under report both NSAE and SAE. These data warrant confirmation, and if confirmed, may provide an important caveat on the interpretation of reported study safety data. Citation Format: González V, Machado A, Fung H, Spera G, Meyer C, Millán P, Mackey JR, Fresco R. Geographic variation in adverse event reporting patterns in breast cancer clinical trials [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-17-01.

Background:Guselkumab (GUS), a selective monoclonal antibody targeting the interleukin-23p19 subunit, has demonstrated efficacy in 2 pivotal Ph3 psoriatic arthritis (PsA) studies (DISCOVER-1,1 DISCOVER-22).Objectives:Evaluate GUS efficacy and safety in PsA patients (pts) with inadequate response (IR) to tumor-necrosis-factor inhibition (TNFi) through Week24 (W24) of the Ph3b COSMOS study.Methods:In this randomized, double-blind, placebo (PBO)-controlled trial, 285 pts with active PsA (≥3 swollen & ≥3 tender joints) who demonstrated lack of benefit or intolerance to 1-2 TNFi were randomized 2:1 to subcutaneous GUS 100mg (n=189) or PBO (n=96) at W0, W4, then every 8 weeks (Q8W) through W44 (with PBO crossover to GUS at W24). At W16, pts who met early escape (EE) criteria (Results:Baseline characteristics were similar across GUS and PBO pts, though a higher proportion of females and more severe joint symptoms were seen in the GUS group. At W24, 44.4% of GUS vs 19.8% of PBO pts achieved ACR20 (pTable 1.Baseline characteristics of, and adverse events reported by, randomized and treated COSMOS ptsGUS 100 mg Q8W (N=189)PBO (N=96) Age, y4949 Sex, Female54%46% Duration of PsA, y8.38.7 Body mass index, kg/m22931a Swollen (0-66) / tender (0-68) joint count10 / 219 / 18 Pt pain / Pt global arthritis / Physician global disease, 0-10 cm VAS6.5 / 6.5 / 6.96.0 / 6.2 / 6.4 Health Assessment Questionnaire-Disability Index, 0-31.3b1.2 C-reactive protein, mg/dL1.2b1.2 Methotrexate use at baseline56%53% Psoriatic body surface area, %17.913.4 Number of prior TNFi: 1 / 288% / 12%89% / 11% Reason for prior TNFi discontinuation: Efficacy / Safety84% / 16%* 81% / 19%*Pts with ≥1 AE / SAE37% / 3%48% / 3%Pts with ≥1 infection / serious infection18% / 0%20% / 0%Pts with ≥1 AE leading to study agent discontinuation2%2%Pts with ≥1 malignancy0.4%0Pts with ≥1 injection-site reaction2%1%Data shown are mean or %. aN=95; bN=188. *Missing for 1 pt. SAE – serious adverse events; VAS – visual analog scaleConclusion:In this Ph3b, placebo-controlled study of PsA pts with IR to 1-2 TNFi, GUS 100 mg Q8W elicited a significantly higher ACR20 response rate vs. PBO at W24; results of prespecified sensitivity and subgroup analyses were consistent. GUS safety in TNF-IR PsA pts through W24 is consistent with the favorable GUS safety profile in psoriasis and biologic-naïve PsA pts.3References:[1]Deodhar A. Lancet 2018;391: 2213–24.[2]Mease PJ. Lancet 2020;395: 1126–36.[3]Guselkumab Prescribing Information. Janssen Biotech, Inc.Disclosure of Interests:Laura C Coates Consultant of: AbbVie, Amgen, Biogen, BMS, Boehringer Ingelehim, Celgene, Domain, Eli Lilly, Gilead, Janssen, Medac, Novartis, Pfizer and UCB, Grant/research support from: AbbVie, Amgen, Celgene, Eli Lilly, Gilead, Novartis, Pfizer, Laure Gossec Consultant of: AbbVie, Amgen, BMS, Biogen, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Samsung Bioepis, Sanofi-Aventis, UCB, Grant/research support from: Amgen, Eli Lilly, Galapagos, Janssen, Pfizer, Sandoz, Sanofi, Elke Theander Shareholder of: Johnson & Johnson, Employee of: Janssen Scientific Affairs, LLC, Paul Bergmans Shareholder of: Johnson & Johnson, Employee of: Janssen, Marlies Neuhold Shareholder of: Johnson & Johnson, Employee of: Janssen Scientific Affairs, LLC, Chetan Karyekar Shareholder of: Johnson & Johnson, Employee of: Janssen Global Services, LLC, May Shawi Shareholder of: Johnson & Johnson, Employee of: Janssen Global Services, LLC, Wim Noel Shareholder of: Johnson & Johnson, Employee of: Janssen Scientific Affairs, LLC, Georg Schett: None declared, Iain McInnes Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, and UCB

Objective To provide an update on chronic hepatitis C virus (HCV) infections and the challenges of HCV management, using clinical case vignettes. Data sources Clinical guidelines from the American Association for the Study of Liver Diseases/Infectious Diseases Society of America, U.S. prescribing information, PubMed articles, and patient advocacy websites. Study selection At the authors' discretion based on relevance of information presented. Summary Despite the availability of curative therapies, chronic HCV infections pose a substantial health care burden. Interest in chronic HCV management increased with new drug approvals; however, concerns about cost of therapy continue to limit patient access to treatment. Criteria used to determine HCV treatment candidacy, including staging of liver disease and need for liver biopsy, alcohol and substance abuse screening, ability to use short-course therapy, challenges of geno-type 3 infection, and the potential pitfalls of strict restrictions during HCV therapy, are examined using clinical case scenarios. Although access to HCV therapy is improving nationally, restrictions continue to vary by state and payer. Conclusion Despite increasing options for highly effective HCV therapy, the HCV treatment landscape remains a dynamic challenge. Pharmacists need to be familiar with current treatment guidelines to successfully navigate patients into treatment and ultimately, to cure HCV infections.

Denosumab is a fully human monoclonal antibody against receptor activator of NF-κB ligand (RANKL) that decreases osteoclast formation, function and survival, and is approved for the treatment of postmenopausal women with osteoporosis at increased or high risk for fracture, among other indications. During the pivotal 3-year fracture trial FREEDOM, denosumab 60 mg subcutaneously every 6 months significantly reduced new vertebral (68%), hip (40%), and nonvertebral (20%) fractures; increased bone mineral density (BMD); and reduced bone turnover markers compared with placebo in postmenopausal women with osteoporosis. Questions have arisen regarding imbalances of certain low-frequency adverse events (AEs) observed in FREEDOM, as well as the top 5 most frequent adverse reactions listed in the United States prescribing information (USPI; back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis). We examined the incidences of these AEs in women who originally received placebo during FREEDOM and then received denosumab for up to 3 years during the FREEDOM Extension (Crossover Group). This provided a unique opportunity for comparison with the original 3-year denosumab FREEDOM observations. We also examined the incidences of these AEs over 6 years of denosumab treatment (Long-term Group; ie, comparing a second 3 years of treatment with findings in the first 3 years). There was no indication of increasing trends regarding the imbalances of either low-frequency AEs or common AEs observed in FREEDOM. © 2017 American Society for Bone and Mineral Research.

espanolIntroduccion: la cirugia bariatrica (CB) implica deficits nutricionales y de oligoelementos que pueden tener una repercusion negativa en caso de no tratarse adecuadamente, especialmente en situaciones como la gestacion. Caso clinico: paciente sometida a CB del tipo de la derivacion biliopancreatica, sin adherencia terapeutica posterior, que acude por edemas, confirmandose la presencia de una gestacion de 29 semanas (feto CIR de tipo I) y de anemia moderada. Se reinicio la suplementacion de vitaminas, oligoelementos, nutricion enteral y hierro intravenoso (FEIV). Debido a la escasa respuesta de la hemoglobina con depositos de hierro repletados, se asocio eritropoyetina humana recombinante (rHuEPO). Discusion: los deficits nutricionales mas frecuentes tras una CB malabsortiva son la ferropenia y la hipoproteinemia. La ferropenia y la anemia incrementan el riesgo del parto pretermino, el bajo peso y la mortalidad perinatal. En las pacientes sin adecuada respuesta al FEIV puede plantearse el tratamiento con rHuEPO, aunque su uso en gestantes sin insuficiencia renal cronica no dispone de indicacion en la ficha tecnica. EnglishIntroduction: bariatric surgery involves nutritional and trace element deficiencies that may have a negative impact if not treated properly, especially in situations such as pregnancy. Case report: a patient who underwent biliopancreatic diversion surgery without subsequent therapeutic adherence consults due to edema; findings included 29-week gestation (type 1 intrauterine growth restriction) and moderate anemia. Vitamin supplementation, oligoelements, enteral nutrition, and intravenous iron were restarted. Due to poor hemoglobin response with repleted iron deposits, recombinant human erythropoietin was associated. Discussion: the most frequent nutritional deficiencies after malabsorptive bariatric surgery are sideropenia and hypoproteinemia. Sideropenia and anemia increase the risk of preterm delivery, low weight, and perinatal mortality. In patients with inadequate response to intravenous iron, treatment with recombinant human erythropoietin may be considered, although its use in pregnant women without chronic renal failure has no indication in the prescribing information of this drug.

This letter to the editor acknowledges the contribution of Akbar et al. to the field of tardive dyskinesia (TD) and provides important regulatory information about the potential for parkinson-like symptoms in patients with TD who are treated with valbenazine.

IntroductionIn China, the indications of paliperidone extended in schizophrenia adolescents (12-17 years) was approved by National Medical Products Administration (NMPA) in 2017. But, the utilization of paliperidone in this group needs to be further investigated.ObjectivesTo assess paliperidone utilization in schizophrenia adolescents.MethodsThe study employed the electronic medical records (EMRs) database from a psychiatry specialized hospital (PH) and a general hospital (GH), respectively. General information, including birth date, gender, visit date, diagnosis (inpatient and outpatient) with ICD-10 coding, drug characterize, prescription date and dosage, was de-identified and standardized for analysis. Schizophrenia adolescents (ICD-10: F20.x) received at least one prescription of paliperidone between 2018 and 2019 were included in this study. Index date was defined as the date of first identified paliperidone prescription. The patients were followed up until the end of 2019 with the last record, or upon reaching 18 years. The database was analyzed based on days of supply, administration frequency, and daily dose.ResultsOverall, 112 and 117 eligible patients were included in the present study from PH and GH, respectively. The median drug supply was 179.0 days and 44.0 days, respectively, during which median number of prescriptions patients received was 6.0 and 3.0. Paliperidone was mostly initiated alone (57.1% and 88.9%) with frequency of once daily (97.3% and 88.9%), and the median of average daily dose during follow-up was 5.7 mg/day and 6.0 mg/day, respectively.ConclusionsThe duration of paliperidone usage was very different in two hospitals, but the dosages in both hospitals were generally agreed with prescribing information.

Safety concerns associated with many drugs indicated for the treatment of rheumatoid arthritis (RA) can be attenuated by the early identification of toxicity through routine laboratory monitoring; however, a comprehensive review of the recommended monitoring guidelines for the different available RA therapies is currently unavailable. The aim of this review is to summarize the current guidelines for laboratory monitoring in patients with RA and to provide an overview of the laboratory abnormality profiles associated with each drug indicated for RA. Recommendations for the frequency of laboratory monitoring of serum lipids, liver transaminases, serum creatinine, neutrophil counts, and platelet counts in patients with RA were compiled from a literature search for published recommendations and guidelines as well as the prescribing information for each drug. Laboratory abnormality profiles for each drug were compiled from the prescribing information for each drug and a literature search including meta-analyses and primary clinical trials data.

Information provided by most influenza vaccine manufacturers do not reflect the recommendations of WHO and/or national public health advisory groups with regard to the use of influenza vaccines in pregnant or lactating women. The majority of vaccines contain precautionary language which could discourage use in pregnant women and some include stronger language discouraging or contradicting use in pregnant or lactating women. Regulators and manufacturers should regularly assess the language of pregnancy and lactation sections in product information for vaccines and include information from national public health advisory groups regarding use by pregnant or lactating women and data from relevant studies.

Subcutaneous apomorphine injections provide prompt relief of OFF periods, but are considered an underused therapy. One reason for this might be the perception of difficulty in initiating apomorphine therapy. Over the past 30 years of use, Parkinson’s nurses have built a wealth of experience in how to initiate apomorphine in patients with motor fluctuations. The authors present here a case series of 24 Parkinson’s patients whose apomorphine dose was rapidly titrated according to the practice of the Parkinson’s nurse overseeing the titration. Most patients were successfully and safely titrated within 2 hours, indicating that this rapid schedule may be useful in reducing patient distress and making better use of available resources, compared to the slower schedule than is suggested in the UK apomorphine prescribing information. Patients were successfully initiated in a wide variety of settings, including day hospitals and within their own homes.

Objectives: Package inserts (PIs) are used by physicians and other health-care providers as ready source of approved prescribing information. In India, they are subject to statutory regulations that specify the information to be provided under various headings. Uniformity of PIs with optimal level of information is desirable, the absence of which may lead to medication errors. This observational study aimed to evaluate the information adequacy and accuracy of PIs available in the Indian market. Materials and Methods: PIs of drugs marketed in India, and approved by United States Food and Drug Administration, were collected from various retail pharmacies through purposive sampling. The adequacy and accuracy of the information in each PI were evaluated with the help of a 25-item checklist prepared as per stipulations mentioned in statutory guidelines. Each required item of information was scored 1 if present and appropriate or 0 if absent or deemed incomplete or inaccurate. A total information adequacy score (IAS), with maximum value 25, was thereby calculated. Results: From the total 135 PIs analyzed, the median IAS was 17 (interquartile range 15–19). Deficiencies were observed under important headings. For example, “references” were mentioned in only 6.67% and “date of last updating” in only 19.26% of PIs. Other notable shortcomings were in “disposal” (not mentioned in 92.59%), “effects on ability to drive and use machines” (76.30%), “pharmaceutical incompatibilities” (66.67%), “shelf life” (62.96%), “excipients” (60.00%), and “overdose” (17.78%) information. Information on “generic name,” “composition,” and “indications” were however provided by all (100%) PIs. Conclusions: The information provided by PIs in India being inadequate, may not be able to serve as a reliable source of information.

Introduction In clinical practice, waiting 14 days between the administration of pegfilgrastim and subsequent chemotherapy cycle (as recommended by the prescribing information) is sometimes not feasible with multi-cycle dose-dense regimens. This study evaluated the practice related to the use of pegfilgrastim in oncology patients at a multi-hospital health system. Methods Patients who received pegfilgrastim as primary prophylaxis following dose-dense chemotherapy scheduled every 14 days were included. The primary endpoint was the impact of Results One hundred and sixty four patients with breast cancer who received pegfilgrastim support for dose dense doxorubicin and cyclophosphamide (ddAC) qualified for the model. The mean age was 52 ± 12 years. Eighty-eight percent received pegfilgrastim on-body injector while 13% received pegfilgrastim injection. The mean number of elapsed days between pegfilgrastim and subsequent chemotherapy was 13 ± 0.5 days. The method of pegfilgrastim delivery and elapsed days between pegfilgrastim and chemotherapy administration had no significant effect on the change in ANC (p = 0.8663 and p = 0.8434 respectively); however, patient’s age (p = 0.0125) had a significant effect on the change in ANC. Conclusion The study findings suggest safety and efficacy when chemotherapy is administered 12–14 days from pegfilgrastim.

Background: In 2005, the European Medicines Agency (EMA) released guidance on pharmacokinetic studies in patients with hepatic impairment. This guidance describes the design of these studies and what information should be presented in the Summary of Product Characteristics (SmPC). We aim to evaluate the availability and clinical applicability of information on medicine use in patients with hepatic impairment in SmPCs and registrational dossiers of recently approved medicines.Methods: We reviewed SmPC information on use in patients with hepatic impairment of 51 new medicines authorized between 2015 and 2017. Per medicine, we assessed the availability of nine information items derived from the EMA guidance, i.e. type of hepatic disease studied; stratification by severity of hepatic impairment; influence of hepatic impairment on the pharmacokinetics; safety advice in mild, moderate, and severe hepatic impairments; and dosing recommendation in mild, moderate, and severe hepatic impairments. If unavailable, the European Public Assessment Report (EPAR) and study report were consulted consecutively. Of available items, clinical applicability was assessed by labeling information as "clear" or "ambiguous".Results: Of 51 medicines, 15 had no pharmacokinetic study in patients with hepatic impairment described in their SmPC. The other 36 SmPCs contained on average seven of the nine information items (range 4-9). One SmPC contained all 9 items, and after consulting, the study reports, 11 SmPCs were complete. The item "type of hepatic disease studied" was available in one SmPC, though it could be retrieved in 21 study reports. Regarding clinical applicability, there was no medicine with all information items available and clearly formulated in the SmPC. A total of 12 medicines (33%) contained only clearly formulated information, while 24 (67%) contained at least one ambiguously formulated information item (range 0-4). Items often ambiguously formulated were: "definition of mild, moderate, and severe hepatic impairment" (15 ambiguous SmPCs) and "safety advice in severe hepatic impairment" (17 ambiguous SmPCs).Conclusion: While SmPCs contain a large part of information requested by the EMA, clinical applicability seems low, as it is often unclear to which specific type of hepatic disease patient the advice applies. This can negatively influence the practical use by healthcare professionals.

In the past, the treatment of autosomal dominant polycystic kidney disease (ADPKD) has been limited to the management of its symptoms and complications. Recently, the US Food and Drug Administration (FDA) approved tolvaptan as the first drug treatment to slow kidney function decline in adults at risk of rapidly progressing ADPKD. Full prescribing information approved by the FDA provides helpful guidelines but does not address practical questions that are being raised by nephrologists, internists, and general practitioners taking care of patients with ADPKD, and by the patients themselves. In this review, we provide practical guidance and discuss steps that require consideration before and after prescribing tolvaptan to patients with ADPKD to ensure that this treatment is implemented safely and effectively. These steps include confirmation of diagnosis; identification of rapidly progressive disease; implementation of basic renal protective measures; counseling of patients on potential benefits and harms; exclusions to use; education of patients on aquaresis and its expected consequences; initiation, titration, and optimization of tolvaptan treatment; prevention of aquaresis-related complications; evaluation and management of liver enzyme elevations; and monitoring of treatment efficacy. Our recommendations are made on the basis of published evidence and our collective experiences during the randomized, clinical trials and open-label extension studies of tolvaptan in ADPKD.

To compare the evidence-of-risk and recommendation levels of new drugs' label information in pregnancy among US, UK, Japan, and Korea. Despite the importance of drug labels in guiding decisions, officially approved prescribing information in drug labels is often inconsistent across countries and contains misleading content. Women are unintentionally exposed to drugs during early stages of unplanned or unrecognized pregnancies when treated for medical conditions.We selected 81 drugs approved in all 4 countries mentioned above from 2008 to 2016. Evidence level was classified into five categories ("Definite," "Probable," "Possible," "Unlikely," and "Unclassified"), and recommendation level was classified into four categories ("Contraindicated," "Cautious," "Compatible," and "Unclassified"). We calculated kappa coefficient with 95% confidence intervals (CIs) to estimate the agreement of each category.For evidence level, "Unclassified" was the highest in Japan (33.3%), while representing a much smaller proportion in US (2.5%), UK (6.2%), and Korea (6.2%; p 0.01). For recommendation level, "Contraindicated" was the lowest in US (9.9%), while it was greater in UK (50.6%), Japan (50.6%), and Korea (42.0%; p 0.01). Korea-UK presented substantial agreement for both evidence-of-risk (kappa = 0.80, 95% CI: 0.67-0.94) and recommendation level (kappa = 0.64, 95% CI: 0.46-0.82), while Korea-Japan and Korea-US were in fair or moderate agreement.Label information in pregnancy was discrepant among the four countries. Discrepancies in labeling information among countries may cause confusion to patients and healthcare professionals alike. To better assist healthcare professionals and patients in the use of prescription drugs, global harmonization of safety information is needed to minimize confusion with potential risk.

BackgroundThe UK National Breast Screening Programme is estimated to reduce breast cancer mortality by 20%. To maximise the benefits of the programme, we first need to understand the underlying factors contributing to variations in screening uptake. One potentially significant factor which may contribute to these gradients in screening uptake is poor mental health. ObjectivesThe objectives of this study were to examine the impact of poor mental health on breast screening uptake, and whether this explained any of the previously observed socio-demographic gradients in screening uptake. MethodsBreast screening records were obtained from the National Breast Screening System (NBSS) and were subsequently linked to 2011 Census data within the Northern Ireland Longitudinal Study (NILS). The NILS encompasses 28\% of Census data. This was then linked to psychotropic prescribing information from the Enhanced Prescribing Database (EPD), to produce a de-identified research dataset containing 57,328 women. FindingsWomen with self-reported poor mental health were over 20% less likely to attend screening compared to their counterparts who didn't have poor mental health. Using psychotropic prescribing information as a proxy for the presence of mental illness yielded similar results, with those taking anxiolytics, antipsychotics or hypnotics in the three months before screening invitation significantly less likely to attend than those who were not. ConclusionWomen with poor mental health were significantly less likely to attend breast screening. However, poor mental health did not explain any of the previously determined socio-demographic gradients in screening uptake.

Background: Package inserts are printed leaflets accompanying marketed drug products and contain information regarding safe and effective use of drug according to regulatory guidelines. Package inserts are also known as prescription drug label or prescribing information. Need for the study: information’s given in package inserts are suboptimal and can lead to medication error. This study was undertaken to assess the presentation and completeness of clinical information provided in the currently available package inserts for anti-diabetic drugs in India. Methods: Around 146 package inserts were collected from pharmacies located at different areas of Bangalore. They were analysed based on criteria mentioned in Schedule D of drug and cosmetic act 1945. Results: Out of 146 package inserts, 56 (38%) belongs to grade A (including all injectable preparation) and remaining 90 (62%) belong to grade B. none of package inserts belong to grade C. Information in package inserts were inadequate in several aspects for example, they had unclear instructions about generic name of other ingredients used, about handling, side effects, shelf life, paediatric and geriatric use and guidelines for use of the drugs. Conclusions: The study concludes that the information provided in the package insert is not relevant for safe and effective use of medications. It is, therefore, recommended to update the existing package inserts based on criteria mentioned in the Schedule D of drug and cosmetic Act, 1945.

This supplement has been sponsored by Bayer HealthCare. Please see acknowledgements for full disclaimer. Prescribing Information can be found in the appendices. L.GB.COM.05.2015.11280. Date of preparation: June 2015 This paper provides expert recommendations on administration of aflibercept in wet age-related macular degeneration (AMD) after Year 1 (Y1), based on a roundtable discussion held in London, UK in November 2014. The goals of treatment after Y1 are to maintain visual and anatomical gains whilst minimising treatment burden and using resources effectively. The treatment decision should be made at the seventh injection visit (assuming the label has been followed) in Y1, and three approaches are proposed: (a) eyes with active disease on imaging/examination but with stable visual acuity (VA) at the end of Y1 should continue with fixed 8-weekly dosing; (b) eyes with inactive disease on imaging/examination and stable VA should be managed using a ‘treat and extend' (T&E) regimen. T&E involves treating and then extending the interval until the next treatment, by 2-week intervals, to a maximum of 12 weeks, provided the disease remains inactive. If there is new evidence of disease activity, treatment is administered and the interval to the next treatment shortened; and (c) if there has been no disease activity for ≥3 consecutive visits, a trial of monitoring without treatment may be appropriate, initiated at the end of Y1 or at any time during Y2. Where possible, VA testing, OCT imaging and injection should be performed at the same visit. The second eye should be monitored to detect fellow eye involvement. In bilateral disease, the re-treatment interval should be driven by the better-seeing eye or, if the VA is similar, the eye with the more active disease.

Fingolimod (Gilenya, Novartis) is an oral sphingosine-1-phosphate analogue used in the treatment of relapsing multiple sclerosis (MS). Fingolimod treatment is associated with relative lymphopenia and was associated with an increased risk of herpes infection in clinical trials. In the post-marketing setting, fingolimod has been associated with several cases of cryptococcal meningitis, recently prompting an update to its prescribing information. To date, all cases have been associated with active treatment with fingolimod. In this report, we describe the first case of cryptococcal meningitis diagnosed after fingolimod discontinuation.

Purpose/aim: AbobotulinumtoxinA (Dysport®, Ipsen Biopharmaceuticals, Inc., Basking Ridge, NJ, USA) is an acetylcholine release inhibitor and a neuromuscular blocking agent. The United States prescribing information for abobotulinumtoxinA previously indicated only one dilution for cervical dystonia: 500 U/1 mL. Clinical trial data supporting a larger volume with a 500 U/2 mL dilution would offer clinicians flexibility with injection volume to better meet patient needs.We conducted a 12-week, phase 3b, multicenter, randomized, double-blind, placebo-controlled trial (NCT01753310). Adult subjects with a primary diagnosis of cervical dystonia were randomized (2:1) to receive a single injection of either abobotulinumtoxinA, 500 U/2 mL dilution, or placebo. The primary efficacy endpoint was changed from baseline in Toronto Western Spasmodic Torticollis Rating Scale total score at Week 4.A total of 134 subjects (abobotulinumtoxinA, n = 89; placebo, n = 45) were randomized (intent-to-treat population) and 129 (abobotulinumtoxinA, n = 84; placebo, n = 45) completed the Week 4 primary endpoint evaluation (modified intent-to-treat population). In the modified intent-to-treat population, subjects receiving abobotulinumtoxinA experienced significantly greater changes from baseline versus placebo on the primary endpoint (weighted overall treatment difference -8.3, P0.001). The most common treatment-emergent adverse events (TEAEs) were dysphagia, muscle weakness, neck pain and headache. Overall, TEAEs were consistent with those reported in the abobotulinumtoxinA prescribing information (1 mL dilution) for cervical dystonia patients.This trial provides evidence that a 500 U/2 mL dilution is an effective treatment for cervical dystonia and exhibits a safety profile consistent with the known safety profile of abobotulinumtoxinA.

Radium-223 (Ra-223), strontium-89 (Sr-89), and samarium-153 (Sm-153) are radiopharmaceuticals approved in the United States and elsewhere for the treatment of painful skeletal metastases in select populations (Tables 30.1 and 30.2). The primary aim of this chapter is to provide a cohesive educational review of practice recommendations for these agents using guidelines from professional societies, prescribing information, and published observations.

It has been anecdotally reported that nocturnal leg cramps in pregnant women are worse in summer. We analyzed population-level data to determine whether the symptom burden of nocturnal leg cramps is seasonal in the general population.We examined time-series data for 2 independent measures of the symptom burden of leg cramps: (a) new quinine prescriptions (reflecting new or escalating treatment of leg cramps) from December 2001 to October 2007 among adults aged 50 years and older, which were obtained from linked health care databases that contain the prescribing information for the 4.2 million residents of British Columbia, Canada; and (b) the Internet search volume from February 2004 to March 2012 for the term "leg cramps" (reflecting public interest), which we obtained from Google Trends data and geographically limited to the United States and Australia. We assessed seasonality by determining how well a least-squares sinusoidal model predicted variability in the outcomes.New quinine prescriptions and Internet searches related to leg cramps were both seasonal, with highs in mid-summer and lows in mid-winter, and a peak-to-peak variability that was about two-thirds of the mean. Seasonality accounted for 88% of the observed monthly variability in new quinine prescriptions (p0.001) and 70% of the observed variability in Internet searches related to leg cramps (p0.001).New quinine prescriptions and Internet searches related to leg cramps were seasonal and roughly doubled between the winter lows and summer highs. Why a disorder of peripheral motor neurons displays such strong seasonality warrants exploration.

The boxed warning (also known as 'black box warning [BBW]') is one of the strongest drug safety actions that the U.S. FoodDrug Administration (FDA) can implement, and often warns of serious risks. The objective of this study was to comprehensively characterize BBWs issued for drugs after FDA approval.We identified all post-marketing BBWs from January 2008 through June 2015 listed on FDA's MedWatch and Drug Safety Communications websites. We used each drug's prescribing information to classify its BBW as new, major update to a preexisting BBW, or minor update. We then characterized these BBWs with respect to pre-specified BBW-specific and drug-specific features.There were 111 BBWs issued to drugs on the US market, of which 29% (n = 32) were new BBWs, 32% (n = 35) were major updates, and 40% (n = 44) were minor updates. New BBWs and major updates were most commonly issued for death (51%) and cardiovascular risk (27%). The new BBWs and major updates impacted 200 drug formulations over the study period, of which 64% were expected to be used chronically and 58% had available alternatives without a BBW.New BBWs and incremental updates to existing BBWs are frequently added to drug labels after regulatory approval.

To estimate the proportion of patients with moderate to severe chronic kidney disease (CKD) whose initial dipeptidyl-peptidase-4 inhibitor (DPP4-i) dosage was concordant with prescribing information (label) recommendations in the United States.Adult patients with type 2 diabetes mellitus (T2DM) who initiated a DPP4-i (linagliptin, sitagliptin, saxagliptin) between 1 January 2011 and 30 June 2014 were identified using electronic medical records and administrative claims, with index date being the date of first observed DPP4-i treatment. Patients were required to have chronic kidney disease (CKD) stage 3b, 4 or 5 (estimated Glomerular Filtration Rate [eGFR] value45 ml/min/1.73 mOf the 492 patients (323 sitagliptin, 57 saxagliptin, 112 linagliptin), 36.2% were prescribed doses that were not concordant with label recommendations (44.9% for sitagliptin, 57.9% for saxagliptin and 0% for linagliptin [which does not require dosage adjustment]). Concordant patients were slightly older (mean age 71 years vs. 68, p = .01) but had similar gender distribution (55% vs. 60% female, p = .31) compared to those who were not concordant. They had lower general health status (Charlson Comorbidity Score 2.6 vs. 2.2, p = .03), and had similar pre-index all-cause total costs ($25,245 vs. $21,972, p = .68) and lower pre-index T2DM-related costs ($1618 vs. $1922, p = .05).More than a third of DPP4-i patients with CKD stage 3b or higher were prescribed doses not concordant with DPP4-i label dosage recommendations.

ImportanceCase reports describe persistent erectile dysfunction (PED) associated with exposure to 5α-reductase inhibitors (5α-RIs). Clinical trial reports and the manufacturers’ full prescribing information (FPI) for finasteride and dutasteride state that risk of sexual adverse effects is not increased by longer duration of 5α-RI exposure and that sexual adverse effects of 5α-RIs resolve in men who discontinue exposure.ObjectiveOur chief objective was to assess whether longer duration of 5α-RI exposure increases risk of PED, independent of age and other known risk factors. Men with shorter 5α-RI exposure served as a comparison control group for those with longer exposure.DesignWe used a single-group study design and classification tree analysis (CTA) to model PED (lasting ≥90 days after stopping 5α-RI). Covariates included subject attributes, diseases, and drug exposures associated with sexual dysfunction.SettingOur data source was the electronic medical record data repository for Northwestern Medicine.SubjectsThe analysis cohorts comprised all men exposed to finasteride or dutasteride or combination products containing one of these drugs, and the subgroup of men 16–42 years old and exposed to finasteride ≤1.25 mg/day.Main outcome and measuresOur main outcome measure was diagnosis of PED beginning after first 5α-RI exposure, continuing for at least 90 days after stopping 5α-RI, and with contemporaneous treatment with a phosphodiesterase-5 inhibitor (PDE5I). Other outcome measures were erectile dysfunction (ED) and low libido. PED was determined by manual review of medical narratives for all subjects with ED. Risk of an adverse effect was expressed as number needed to harm (NNH).ResultsAmong men with 5α-RI exposure, 167 of 11,909 (1.4%) developed PED (persistence median 1,348 days after stopping 5α-RI, interquartile range (IQR) 631.5–2320.5 days); the multivariable model predicting PED had four variables: prostate disease, duration of 5α-RI exposure, age, and nonsteroidal anti-inflammatory drug (NSAID) use. Of 530 men with new ED, 167 (31.5%) had new PED. Men without prostate disease who combined NSAID use with >208.5 days of 5α-RI exposure had 4.8-fold higher risk of PED than men with shorter exposure (NNH 59.8, allp< 0.002). Among men 16–42 years old and exposed to finasteride ≤1.25 mg/day, 34 of 4,284 (0.8%) developed PED (persistence median 1,534 days, IQR 651–2,351 days); the multivariable model predicting PED had one variable: duration of 5α-RI exposure. Of 103 young men with new ED, 34 (33%) had new PED. Young men with >205 days of finasteride exposure had 4.9-fold higher risk of PED (NNH 108.2,p< 0.004) than men with shorter exposure.Conclusion and relevanceRisk of PED was higher in men with longer exposure to 5α-RIs. Among young men, longer exposure to finasteride posed a greater risk of PED than all other assessed risk factors.

Background: Due to the lack of properly tested medicines for children, there is little available information with regards to indications and dosing of medications in children. Aim: To collect data on sources where hospital based pediatricians obtain prescribing information when treating children and the extent of collaboration with the hospital pharmacist. METHOD: Two hundred and fifty pediatricians in different hospitals within different cities in Jordan were asked to fill in a structured questionnaire regarding information sources used when prescribing for children. Results: Questionnaires were collected from 162 (64.8%) hospital based pediatricians, who have completed the questionnaire by the designated date. Most (75.5%) reported that the Lexi Comp's Drug Information Handbook was the source that they most frequently used for drug information when prescribing for in children. The BNF and the BNFc (British National Formulary for children) were found to be the most sources that contain sufficient information that aids pediatricians when prescribing for children. A minority (22%) claimed to consult with the hospital pharmacist when they face difficulties when prescribing for children. Conclusions: Pediatricians rely on different information sources when they prescribe for children. Those sources vary in their reliability in aiding pediatrician when prescribing. Further work should be done in the provision of useful information on pediatric drug therapy to pediatricians. More steps should be taking place to activate collaboration and interaction between pediatricians and pharmacists as well.