Oral antineoplastic agents: assessment of safety and dose adjustments in clinical practice

Objectives: Although the safety profile of oral antineoplastic agents (OAAs) is better than that of classic chemotherapy, the rate of severe adverse events (AEs) is high. The objective was to assess the reasons for adjustments to treatment with OAAs during the first 100 days of treatment.

Methods: The authors performed a prospective observational study of cancer outpatients who initiated OAAs between November 2015 and October 2017. Dose reductions and treatment interruptions were closely followed-up during the first 100 days after the beginning of treatment with an OAA. The authors described the different safety profile of different OAA classes.

Results: The authors included 443 patients (31 different OAA assessed), of whom 53.0% required their OAA to be adjusted during the first 100 days of treatment. A total of 151 patients required dose reductions and/or interruptions of OAAs owing to AEs. The authors identified 203 AEs in these patients. Treatment with sorafenib, lower ECOG performance status, and first-line treatment were associated with a higher proportion of treatment adjustments due to AEs.

Conclusion: These results in clinical practice could be a first approach to help healthcare professionals to design patient monitoring programs by identifying priority patients and drugs, and remarks the importance of pharmacovigilance in OAAs.     

Factors that facilitate reporting of adverse drug reactions by pharmacists in Saudi Arabia

Objectives: Adverse drug reactions (ADRs) are a pervasive global problem, and its management is integral to patient safety and healthcare quality. Pharmacists play a pivotal role in monitoring and reporting ADRs, which has a direct impact on patient care. The aim of this study was to identify potential factors that facilitate pharmacists in community and hospital settings to report ADRs.

Methods: A cross-sectional, online survey using a validated questionnaire was administered to pharmacists working in community and hospital pharmacies in Saudi Arabia.

Results: 1,717 community and 153 hospital pharmacists participated in this study. Only 10.2% and 26.8% of community and hospital pharmacists, respectively, admitted ever reporting an ADR. The most reported factors that may facilitate ADRs reporting have included ongoing improvements in therapeutic knowledge about ADRs, attending educational programs with continuous medical education credits, the seriousness of the experienced ADRs and accessibility to patients’ medical profile. The impact of peers by seeing colleagues reporting ADRs and ADRs due to herbal or traditional medicine were the least important factors reported by pharmacists.

Conclusion: The study identified factors that can effectively address the under-reporting of ADRs by pharmacists. A multi-stakeholder, multi-pronged approach of ADR reporting is needed to develop greater awareness of this issue among pharmacists.     

Development of a list of high-risk perioperative medications for the elderly: a Delphi method

Objectives: There is a lack of direct evidence for the management of perioperative medications in elderly patients. Therefore, the authors aimed to develop a list of high-risk medications for the elderly population in China to provide indicators for clinicians to identify medication-related factors contributing to potential adverse events during the perioperative period.

Methods: The initial list of high-risk perioperative medications was developed by studying all the publications that described specific high-risk medications and their risk profiles in the elderly. Delphi consultations were performed to form a consensus among the group of experts and the list was finalized.

Results: The expert panel consisted of 36 experts from 29 tertiary hospitals and 18 provinces or municipalities. The consensus was reached after two Delphi rounds. Finally, a total of 86 medications of 13 medication classes and 120 screening items were included in the final list, along with perioperative risk profiles and risk aversion recommendations for each drug.

Conclusion: This is the first study to establish a high-risk perioperative medication list in China, which can be used as a reference for intervention and evaluation of perioperative medications for the elderly population.     

Zolpidem high-dose abuse: what about the liver? Results from a series of 107 patients

Objectives: Z-Drugs (ZDs) have been developed to limit benzodiazepines (BZDs) abuse for sleep disorders. Data on the liver toxicity of zolpidem (ZLM) are lacking or anecdotal. The authors evaluated the presence of drug-induced liver injury (DILI) among a cohort of high-dose ZLM abusers.

Methods: Retrospective study analyzing clinical records of 1112 consecutive patients admitted for BZDs detoxification from 2003 to 2018. Inclusion criteria: age >18 y.o.; ZLM abuse/dependence; high-dose ZDs abuse. Exclusion criteria: missing lab data; lack of informed consent. Main outcome was the presence of DILI measured as elevation of ALT/AST levels >250 U/l.

Results: A total of 107 patients met the eligibility criteria. Liver enzymes alterations were present in 9.3% (95% CI 4.6–16.5%); one patient (0.9%, 95% CI 0.0–2.8%) showed DILI criteria. BMI significantly influenced transaminases levels. No correlations between duration nor doses of ZLM abuse and transaminases levels were found.

Conclusion: The present study shows a very low prevalence of DILI among high-dose ZLM abusers. The prevalence of hypertransaminasemia was in line with general population. On one hand ZLM has a substantially safe liver profile but on the other hand ZLM abuse and dependence, especially at very high doses, represents an emerging problem.     

Systemic thromboembolic adverse events in patients treated with intravitreal anti-VEGF drugs for neovascular age-related macular degeneration: an update

Introduction: Intravitreal anti-VEGF is the most effective therapy for wet AMD, although systemic effects on the endothelium cannot be excluded.

Areas covered: The purpose of this review was to evaluate risk of thromboembolic events associated with intravitreal anti-VEGF.

Expert opinion: Current data are insufficient to confirm the safety of these compounds, due to the paucity of specific studies. Thus, pharmacovigilance for all anti-VEGF should be improved to verify the true role of anti-VEGF in the occurrence of systemic adverse events.     

Antibiotic-related adverse events in paediatrics: unique characteristics

Introduction: Antibiotics have saved and are still saving countless human lives from the burden of infectious diseases. However, as with all other drugs, they can cause adverse events. Generally, these are uncommon, mild and spontaneously resolving. However, in some cases, they can cause relevant clinical problems. Compared with adults, children, particularly in the first years of life, have a higher risk of antibiotic-related adverse events for several reasons.

Areas covered: In this paper, the conditions that can contribute to the elevated risk of antibiotic-related adverse events in children are discussed.

Expert opinion: Antibiotic stewardship can be a solution to limit antibiotic abuse and misuse and consequently the incidence of antibiotic-related adverse events in children. Moreover, most of the antibiotic-associated adverse events can be avoided with more extensive pre-marketing medicine investigations, improved postmarket safety surveillance system, increased transparency throughout the clinical research enterprise, increased training of clinical pharmacologists and paediatric researchers, expanded pool of paediatric patients, and providing additional funding and incentives for paediatric drug development.     

The safety of treatment options for acute bacterial skin and skin structure infections

Introduction: Acute bacterial skin and skin-structure infections (ABSSSI) may develop in both in-patients and out-patients, possibly with a severe clinical presentation. Since most phase 3 randomized clinical trials have shown non-inferiority in efficacy across different agents, considerations regarding their different safety profiles inevitably play a crucial role in the everyday choice about which of them should be employed for the treatment of ABSSSI.

Areas covered: In this review, the authors discuss the safety profile of different treatment options for ABSSSI.

Expert opinion: The spread of methicillin-resistant Staphylococcus aureus (MRSA) in the last decades has inevitably influenced the therapeutic approach to ABSSSI. Adequate knowledge of the peculiar toxicity profile of each drug active against MRSA is essential for guiding, monitoring and managing adverse events, in turn reducing any unfavorable impact of toxicity on patients’ outcomes. In the next five years, potential toxicity will play a critical role in establishing the best available therapy for each specific patient, together with consideration regarding the possibility of avoiding hospitalization or allowing a switch from intravenous to oral therapy and early discharge.     

Safety profile of non-vitamin K oral anticoagulants (NOACs) from a patient perspective: a web-based cohort event monitoring study

Objectives: Non-vitamin K oral anticoagulants (NOACs) are a relatively new group of anticoagulants. Characteristics of adverse drug reactions (ADRs) as experienced by patients in everyday use have not yet been fully clarified. The aim was to gain insight into the safety profile of NOACs from a patient’s perspective.

Methods: This was a prospective, observational web-based cohort event monitoring study among first-time users of NOACs. Patients were recruited between July 2012 and April 2017. They were invited to complete four web-based questionnaires 2 weeks, 5 weeks, 3 months and 6 months after starting treatment. Information was collected about patient characteristics, drug use, and characteristics of ADRs.

Results: 1748 NOAC users were included. 661 (38%) experienced at least one ADR. The reported ADRs were comparable with the information described in the Summary of Product Characteristics and generally occurred within 1 week after the start. In 59% of ADRs the patients recovered. These ADRs had no impact on the use and dosage of the NOAC in 68%. In total, 9% of the patients discontinued the NOAC because of ADRs.

Conclusion: Overall NOACs were well tolerated by the participants. Most reported ADRs occurred within 1 week after the start. Patients recovered from most ADRs without changes to the use of the NOAC.     

A drug safety evaluation of abiraterone acetate in the treatment of prostate cancer

Introduction: To evaluate the safety profile characteristics of abiraterone acetate (AA) in the treatment of metastatic prostate cancer (mPCa).

Areas covered: In this literature review the authors evaluate safety data from phase III trials investigating the combination of abiraterone acetate plus prednisone (AAP) in patients with metastatic prostate cancer. In particular, the aim was to clarify its toxicity profile, long-term exposure impact, and the correlation with general health-related quality of life (HRQoL).

Expert opinion: Based on the studies reviewed, it appears that abiraterone acetate has favourable outcomes, is effective and well tolerated, mostly in asymptomatic or slightly symptomatic patients, and has recognised toxicity profile characteristics. Incidence of adverse events (AEs), such as mineralocorticoid- and corticosteroid-releated AEs, and hepatotoxicity is well known and widely described. Understanding the toxicity profile of AA could assist decision-making in clinical practice.     

Comparison of common side effects from mood stabilizers and antipsychotics between pediatric and adult patients with bipolar disorder: a systematic review of randomized,double-blind,placebo-controlled trials

Introduction: To compare common side effects of mood stabilizers (MSs) and antipsychotics in pediatric and adult bipolar disorder (BD).

Area covered: MEDLINE, EMBASE, PsycINFO was searched for randomized, double-blind, placebo-controlled trials (RCTs) in the treatment of pediatric and adult BD. Twelve RCTs for pediatric patients and 30 for adult patients were included. The risk for the discontinuation due to adverse events, ≥7% weight gain, somnolence, akathisia, nausea and vomiting from a medication relative to placebo was estimated with absolute risk increase and the number needed to harm. The relative risk of these measures in pediatric and adult patients was compared.

Expert opinion: Overall, the relative risk for ≥7% weight gain, somnolence, nausea, or vomiting was higher, and akathisia was lower in pediatric patients than in adults. The magnitude of difference among MSs and antipsychotics and between pediatrics and adults varied widely. The risk for pediatric patients could be underestimated because in most pediatric studies, doses of studied medications were lower and flexibly dosed, and titration speeds were slower than in adult studies. Clinicians should pay attention to differences in study designs to understand the risk for common side effects when prescribing a medication for BD.     

An update on the safety and efficacy of oral antidiabetic drugs: DPP-4 inhibitors and SGLT-2 inhibitors

Introduction: Oral antidiabetic medications are important in many type 2 diabetes care plans

Areas covered: The article summarizes the cardiovascular and renal safety data for DPP-4 inhibitors and SGLT-2 inhibitors and specific safety data particular to each class.

Expert opinion: DPP-4 and SGLT-2 inhibitors provide unique anti-hyperglycemic mechanisms. The cardiovascular safety profiles of DPP-4 inhibitors are promising, but do not show the strong CV risk reduction of empagliflozin and canagliflozin. The heart failure signal associated with DPP-4 inhibitor use is unclear with differing agents, demonstrating increased risk or maybe even protective effects. The risk reduction in cardiovascular disease associated with SGLT-2 inhibitors has translated to recommendations to consider these therapies early in the treatment pathway. Both classes have potential safety concerns that necessitate appropriate patient selection and thorough education on potential side-effects. DPP-4 inhibitors are considered to have neutral or in some studies beneficial renoprotective effects. SGLT-2 inhibitor safety effects on the kidney are more complex. There are reports of acute kidney injury occurring soon after initiating SGLT-2 inhibitor therapy. However, there are large recent studies that have demonstrated the beneficial effect of SGLT-2 inhibitors in slowing the progression of established chronic kidney disease.     

Comparison of post-marketing surveillance approaches regarding infections related to tumor necrosis factor inhibitors (TNFi’s) used in treatment of autoimmune diseases

Objectives: To examine agreement between the FDA Adverse Event Reporting System (FAERS) and observational studies in common infections for tumor necrosis factor inhibitors (TNFi’s).

Methods: Using MedDRA® preferred terms, all infection cases in FAERS with each TNFi were retrieved using Evidex^TM. Observational studies reporting TNFi-related infections were identified from PubMed (OS-PM) and ClinicalTrials.gov (OS-CT). Infections with a reporting rate of ≥2% (based on percentage of total number of infections) from each data source were compiled. Fleiss’s kappa and Cohen’s kappa (κ) were calculated to determine agreement across all three sources and between each two sources.

Results: A total of 163,789 FAERS infection cases, 53 OS-PM studies and 52 OS-CT studies were identified. The Fleiss’ kappa that comparing all 3 data sources demonstrated lack of agreement. Significant moderate agreements were found between FAERS and OS-CT for etanercept and adalimumab, respectively (κ = 0.53, p = 0.02; κ = 0.56, p = 0.02), but no agreements (κ < 0) when comparing FAERS vs. OS-PM or OS-CT vs. OS-PM.

Conclusion: For common TNFi-related infections, passive (FAERS) and active (observational studies) pharmacovigilance results are similar between FAERS vs. OS-CT for etanercept and adalimumab but dissimilar across the 3 sources. Our findings suggest incorporating both active and passive pharmacovigilance methods in post-marketing drug safety assessment.     

Human organotypic bioconstructs from organ-on-chip devices for human-predictive biological insights on drug candidates

Introduction: Historically, drug development and marketing failures have been experienced by pharma organizations largely from insufficient human-predictability of biological data.

Areas covered: Organs-on-chips (OOCs) are emerging, cutting edge microphysiology systems for in vitro production of microengineered three-dimensional, miniature organotypic constructs obtained by cultivating small amounts of human primary, or induced pluripotent stem, cells in native-like microhabitats. These preparations circumvent experimental limitations inherent to animal assays and two-dimensional monolayers, the mainstay core biological assays of traditional drug research. This report reviews the fundamental tenets, key components (chip plate, biomaterials, cell differentiation approaches, and monitoring sensors) and issues concerning OOC systems (engineered top-down and bottom-up strategies for tissue/organ assembly, public aids to OOC development, regulatory validation, advantages, limitations, prospective and perspective of OOCs, ethics). Examples of OOC platforms (cancer-, lung-, blood-brain barrier-, heart-, intestine-, kidney-, liver-, pharmacokinetics-, placenta- and vessel-on-chip) and their importance for drug research and development are presented.

Expert opinion: OOC device-generated bioconstructs hold great promise as experimental human tissue and organ platforms for generating human-pertinent knowledge on drug candidates for clinical assessment and reducing reliance on animal models. MPS technologies currently enable ready-to-assemble tissue patches and, hopefully, in coming decades, full-size, patient-personalized organs for regenerative medical interventions.     

Safety of neoadjuvant chemotherapy for the treatment of breast cancer

Introduction: Preoperative systemic therapy (PST) including neoadjuvant chemotherapy (NAC) in breast cancer (BC) is used nowadays on a large scale especially in aggressive BC subtypes. The use of NAC in BC may be associated with some safety issues and hazards including possible increased rate of locoregional recurrence, inadequate staging with subsequent over or under-treatment, and surgical complications.

Areas covered: This review article aims to discuss these concerns and to clarify the adequate steps and procedures needed to increase safety and alleviate the possible drawbacks of NAC. The author will discuss the adequate and meticulous technical procedures needed to stage and localize the breast tumor, detect any affected axillary lymph node, improve the accuracy and safety of doing sentinel lymph node biopsy (SLNB) after NAC, estimate the tumor response to NAC to determine the extent of surgery, and enhance the precise documentation of pCR.

Expert opinion: The use of breast MRI, image-detectable clips in the tumor bed, dual technique during SLNB, and target axillary dissection are among the required steps to maintain safety. In the future, ongoing prospective trials will allow us to select patients who can safely avoid breast and/or axillary surgery after systemic therapy.     

Safety considerations in the psychopharmacology of pediatric bipolar disorder

Introduction: The standard of treatment of pediatric bipolar disorder (BPD) often requires life-long psychopharmacological management. Several pharmacological agents are approved by the US FDA for the treatment of pediatric BPD. However, each medication may cause adverse events (AEs). Provider awareness of AE profiles of common pharmacologic agents would serve to better inform patients and families in evaluating and selecting between treatment options.

Areas covered: This review focuses on medications that, in our clinical experience, are commonly prescribed for youth with BPD and were evaluated in prospective clinical trials for the treatment of pediatric BPD. This paper highlights acute and long-term AEs described in these studies.

Expert opinion: Most medications increase risk of AEs in youth with BPD. Treatment with lithium may lead to thyrotropin elevations, but generally does not cause significant weight gain. Divalproex may lead to weight gain; however, this finding was not consistent in comparison studies with lithium. Olanzapine, risperidone, quetiapine, and asenapine are associated with metabolic abnormalities and weight gain. Studies of ziprasidone, aripiprazole and lurasidone do not suggest significant metabolic AEs. More studies are needed to assess efficacy and safety of medications in managing pediatric BPD. Special focus on long-term maintenance trials is required to further identify long-term AEs in this population.     

An update on the problem of osteoporosis in people with epilepsy taking antiepileptic drugs

Introduction: Antiepileptic drugs (AEDs) have been associated with a negative impact on bone health. Comorbid disorders in patients with epilepsy may require drugs exerting a pro-osteoporotic effect, so a possibility of untoward interactions with AEDs is probable.

Areas covered: This review discusses evidence related to the deteriorating influence of AEDs on bone, demonstrating generally stronger negative effects of conventional AEDs. Lamotrigine seems to be a safer AED in this regard. Further, literature data indicate that generally AEDs can lower the serum concentration of vitamin D. Importantly, pediatric patients are of greater risk of bone problems during therapy with AEDs, which is probably due to their effects on bone-forming processes.

Expert opinion: Supplementation with vitamin D and calcium is frequently recommended in patients taking AEDs chronically. Whether to add a bisphosphonate remains an open question due to the limited data on this issue. A possibility of negative interactions exists between AEDs and other pro-osteoporotic drugs: glucocorticoids, proton pump inhibitors and aromatase inhibitors. Depression is a frequent comorbidity in patients with epilepsy. Clinical data indicate that antidepressant drugs may also increase the risk of fractures. Again, patients with epilepsy and depression may be exposed to a greater risk of osteoporosis.     

Safety of fertility treatments in women with systemic autoimmune diseases (SADs)

Introduction: Systemic Autoimmune Diseases (SADs) include systemic lupus erythematosus, antiphospholipid antibody syndrome, rheumatoid arthritis, systemic sclerosis, Sjogren’s syndrome, mixed connective tissue disease, idiopathic inflammatory myopathies and vasculitis. SADs often occur in women of childbearing age and can affect fertility. Both infertility treatments and fertility preservation techniques are thus often indicated.

Areas covered: The literature regarding the safety of fertility-related drugs for both fertility preservation and infertility treatment in patients affected by SADs was reviewed. Based on current knowledge, all the options for fertility preservation should be contemplated in patients with SADs who are at risk for fertility loss, including GnRH analogue administration, oocyte/embryo vitrification and ovarian tissue cryopreservation. Similarly, if pregnancy is not contraindicated in a patient with a SAD, neither should be any fertility treatment.

Expert opinion: Women with SADs should postpone conception until a stable disease has been achieved for at least 6 months. When infertility treatments are needed, women with antiphospholipid antibodies should receive concomitant anticoagulation. If in vitro fertilization/intra-cytoplasmic sperm injection and embryo transfer is required, ovarian hyperstimulation and the inherent risk of thrombosis should be eliminated by GnRH-agonist trigger and cycle segmentation. Counselling about adherence to anti-rheumatic therapy to prevent disease exacerbations is also critical.     

Evidence of bioequivalence and positive patient user handling of a tocilizumab autoinjector

Background: The anti–interleukin-6 receptor antibody tocilizumab is approved for subcutaneous injection using a prefilled syringe (PFS). We report results from a bioequivalence study in healthy subjects and a user-handling study in patients with rheumatoid arthritis (RA) using an autoinjector (AI) for tocilizumab.

Methods: A randomized crossover study in healthy subjects (N = 161) examined the bioequivalence, safety, and tolerability of tocilizumab after a single subcutaneous injection by AI versus PFS. A nonrandomized observational, real-life human factors study in RA patients (N = 54) assessed user (RA patients, caregivers, health care providers) ability to administer tocilizumab effectively by AI.

Results: Bioequivalence criteria for tocilizumab AI versus PFS were met for key pharmacokinetic parameters. Safety was comparable between devices and consistent with the established tocilizumab profile. In the real-life human factors study, the proportion of users who successfully performed all essential tasks required to operate the AI to deliver the full dose was 92.3% at first assessment and 98.1% at second assessment, with no safety concerns.

Conclusions: Tocilizumab administration by AI was bioequivalent to administration by PFS. Intended users were successful in performing the tasks required to administer tocilizumab by AI. No new safety signals were observed in either study.

Clinical Trial Registration: NCT02678988, NCT02682823     

Efficacy of istradefylline for gait disorders with freezing of gait in Parkinson’s disease: A single-arm,open-label,prospective, multicenter study

Background: Gait disorders are common in Parkinson’s disease patients who respond poorly to dopaminergic treatment. Blockade of adenosine A_2A receptors is expected to improve gait disorders. Istradefylline is a first-in-class selective adenosine A_2A receptor antagonist with benefits for motor complications associated with Parkinson’s disease.

Research design and methods: This multicenter, open-label, single-group, prospective interventional study evaluated changes in total gait-related scores of the Part II/III Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and Freezing of Gait Questionnaire (FOG-Q) in 31 Parkinson’s disease patients treated with istradefylline. Gait analysis by portable gait rhythmogram was performed.

Results: MDS-UPDRS Part III gait-related total scores significantly decreased at Weeks 4–12 from baseline with significant improvements in gait, freezing of gait, and postural stability. Significant decreases in MDS-UPDRS Part II total scores and individual item scores at Week 12 indicated improved daily living activities. At Week 12, there were significant improvements in FOG-Q, new FOG-Q, and overall movement per 48 h measured by portable gait rhythmogram. Adverse events occurred in 7/31 patients.

Conclusions: Istradefylline improved gait disorders in Parkinson’s disease patients complicated with freezing of gait, improving their quality of life. No unexpected adverse drug reactions were identified.

Trial registration: UMIN-CTR (UMIN000020288).