Impact of Adverse Drug Reactions in Patients with End Stage Renal Disease in Greece.

Int J Environ Res Public Health. 2020 12 06;17(23):

Authors: Spanakis M, Roubedaki M, Tzanakis I, Zografakis-Sfakianakis M, Patelarou E, Patelarou A

Abstract
BACKGROUND: Patients with end-stage renal disease (ESRD) require specialized therapeutic interventions. The decreased renal function that modulates the physiology and presence of comorbidities is often associated with variations in the pharmacological response, thus increasing the risk of adverse drug events or reactions (ADE/ADRs) from co-administered drugs.
METHODS: A cross-sectional study to record comorbidities, drug-drug interactions (DDIs), ADE/ADRs in patients with chronic kidney disease of stage five in Greece. The study enrolled 60 patients of mean age 64.8 ± 12.9 years, undergoing hemodialysis three times a week. Demographic and social factors, comorbidities, laboratory test data, medication regimens, DDIs and the reporting of ADE/ADRs were analyzed.
RESULTS: Cardiovascular diseases and diabetes were the main comorbidities. In total, 50 different DDIs of various clinical significance were identified. CNS, GI-track, and musculoskeletal-system-related ADE/ADRs were most often reported by patients. ADE/ADRs as clinical outcome from DDIs were associated in 64% of the total identified DDIs. There was a positive trend between number of medications, ADE/ADRs report and DDIs.
CONCLUSIONS: The impact of ADE/ADRs in ESRD patients should be always considered. Guidelines as well as continuous training in the context of evidence-based clinical practice by healthcare personnel on therapy administration and prevention of adverse events are important.

PMID: 33291233 [PubMed - indexed for MEDLINE]

Body mass index and immune-related adverse events in patients on immune checkpoint inhibitor therapies: a systematic review and meta-analysis.

Cancer Immunol Immunother. 2021 Jan;70(1):89-100

Authors: Guzman-Prado Y, Ben Shimol J, Samson O

Abstract
BACKGROUND: As a result of the growing use of immune checkpoint inhibitors (ICIs) for treating malignancy, immune-related adverse events (irAEs) have been increasingly reported. Higher body mass index (BMI) has been highlighted as a potential risk factor for the development of irAEs. However, there are no meta-analyses summarizing the association between BMI and irAEs in patients on ICI therapies.
METHODS: PubMed, MEDLINE, EMBASE, Cochrane and grey literature were searched up to January 2020. Odds ratios (ORs) 95% and confidence intervals (CIs) were summarized using the random-effects model. Heterogeneity test, subgroup and sensitivity analyses were conducted. The protocol was registered on PROSPERO (number registration: CRD42020168790).
RESULTS: Five studies (n = 1937) met eligibility criteria for inclusion. Being overweight or obese was associated with an increased odds of developing irAEs (OR 2.62, 95% CI 1.70-4.03, P ≤ 0.00001, I2 = 53%). In subgroup analyses, higher BMI was associated with irAEs in patients using anti-CTLA-4 single agents or in combination with anti-PD-1/PD-L1 (OR 1.87, 95% CI 1.17-2.98, P = 0.009, I2 = 0%) and in patients using anti-PD-1/PD-L1 (OR 3.22, 95% CI 2.06-5.01, P = 0.00001, I2 = 32%) monotherapy. The increased odds of irAEs in patients with higher BMI was comparable (test for subgroup differences, P = 0.72, I2 = 0%) between studies with adjusted OR (OR 2.21, 95% CI 1.44-3.38, P = 0.0003, I2 = 4%) and unadjusted OR (OR 2.65, 95% CI 1.08-6.50, P = 0.03, I2 = 66%).
CONCLUSION: Our meta-analysis provides evidence of a relationship between higher BMI (overweight-obesity) and increased risk of irAEs in patients on ICI therapies. Further research is needed to strengthen this association.

PMID: 32648164 [PubMed - indexed for MEDLINE]

Meta-analysis examining overall survival in patients with pancreatic cancer treated with second-line 5-fluorouracil and oxaliplatin-based therapy after failing first-line gemcitabine-containing therapy: effect of performance status and comparison with other regimens.

BMC Cancer. 2020 Jul 08;20(1):633

Authors: Wainberg ZA, Feeney K, Lee MA, Muñoz A, Gracián AC, Lonardi S, Ryoo BY, Hung A, Lin Y, Bendell J, Hecht JR

Abstract
BACKGROUND: Pancreatic cancer has a poor prognosis and few choices of therapy. For patients with adequate performance status, FOLFIRINOX or gemcitabine plus nab-paclitaxel are preferred first-line treatment. 5-Fluorouracil (5-FU)-based therapy (e.g. FOLFIRI, OFF, or FOLFOX) are often used in patients who previously received gemcitabine-based regimens. A systematic review was conducted of the safety and efficacy of FOLFOX for metastatic pancreatic cancer following prior gemcitabine-based therapy. A Bayesian fixed-effect meta-analysis with adjustment of patient performance status (PS) was conducted to evaluate overall survival (OS) and compare outcomes with nanoliposomal irinotecan combination therapy.
METHODS: PubMed.gov , FDA.gov , ClinicalTrials.gov , congress abstracts, Cochrane.org library, and EMBASE database searches were conducted to identify randomized controlled trials of advanced/metastatic disease, prior gemcitabine-based therapy, and second-line treatment with 5-FU and oxaliplatin. The database search dates were January 1, 1990-June 30, 2019. Endpoints were OS and severe treatment-related adverse events (TRAEs). Trial-level PS scores were standardized by converting Karnofsky grade scores to Eastern Cooperative Oncology Group (ECOG) Grade, and overall study-weighted PS was calculated based on weighted average of all patients.
RESULTS: Of 282 studies identified, 11 randomized controlled trials (N = 454) were included in the meta-analysis. Baseline weighted PS scores predicted OS in 10 of the 11 studies, and calculated PS scores of 1.0 were associated with a median OS of 6.3 months (95% posterior interval, 5.4-7.4). After adjusting for baseline PS, FOLFOX had a similar treatment effect profile (median OS, range 2.6-6.7 months) as 5-FU/leucovorin plus nanoliposomal irinotecan therapy (median OS, 6.1 months; 95% confidence interval 4.8-8.9). Neutropenia and fatigue were the most commonly reported Grade 3-4 TRAEs associated with FOLFOX.
CONCLUSIONS: Baseline PS is a strong prognostic factor when interpreting the efficacy of 5-FU and oxaliplatin-based therapy of pancreatic cancer after progression on first-line gemcitabine-based regimens. When baseline PS is considered, FOLFOX has a similar treatment effect as 5-FU and nanoliposomal irinotecan therapy and a comparable safety profile. These findings suggest that 5-FU and oxaliplatin-based therapies remain an acceptable and alternative second-line treatment option for patients with pancreatic cancer and adequate PS (e.g. ECOG 0-1) following gemcitabine treatment.

PMID: 32641104 [PubMed - indexed for MEDLINE]

A rare case of therapy-associated acute megakaryoblastic leukemia.

Indian J Pathol Microbiol. 2020 Apr-Jun;63(2):339-341

Authors: Shekhar R, Rauthan A, Pai S

PMID: 32317554 [PubMed - indexed for MEDLINE]

Pazopanib-Induced Liver Toxicity in Patients With Metastatic Renal Cell Carcinoma: Effect of UGT1A1 Polymorphism on Pazopanib Dose Reduction, Safety, and Patient Outcomes.

Clin Genitourin Cancer. 2020 02;18(1):62-68.e2

Authors: Henriksen JN, Bøttger P, Hermansen CK, Ladefoged SA, Nissen PH, Hamilton-Dutoit S, Fink TL, Donskov F

Abstract
BACKGROUND: Pazopanib can induce liver toxicity in patients with metastatic renal cell carcinoma (mRCC). We assessed the effect of a TA repeat polymorphism in the UGT1A1 (uridine diphosphate glucuronosyltransferase 1A1) gene encoding uridine diphosphate glucuronosyltransferase 1A1 on liver toxicity, dose reductions, and patient outcomes.
PATIENTS AND METHODS: Patients with mRCC treated with first-line pazopanib developing liver toxicity underwent genotyping for the UGT1A1 polymorphism. Liver toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 4.0. Progression-free survival and overall survival were assessed using the Kaplan-Meier and log-rank methods.
RESULTS: Of 261 patients, 34 (13%) had developed liver toxicity after a median of 29 days (range, 5-155 days). Grade 4, 3, and 2 alanine aminotransferase or bilirubin had increased in 2 (6%), 17 (50%), and 8 (24%) patients, respectively. The UGT1A1 assessment demonstrated that 18 patients (53%) had TA6/TA7, 7 (21%) had TA7/TA7, and 9 (26%) had wild-type TA6/TA6. The UGT1A1 polymorphism was associated with improved median progression-free survival (TA6/TA6, 5.5 months; TA6/TA7, 34.2 months; TA7/TA7, 22.3 months; unknown UGT1A1 status, 9.2 months; UGT1A1 polymorphisms combined vs. unknown status, P = .021). UGT1A1 polymorphism was associated with improved median overall survival (TA6/TA6, 8.1 months, TA6/TA7 or TA7/TA7 not reached, unknown UGT1A1 status, 16.6 months; UGT1A1 polymorphisms combined vs. unknown status, P = .033). Patients with UGT1A1 polymorphism safely resumed pazopanib at ultra-low doses determined by the degree of liver toxicity and UGT1A1 polymorphism.
CONCLUSIONS: UGT1A1 polymorphisms were associated with improved outcomes, despite pazopanib interruption and dose reductions. UGT1A1 assessment could improve the management of pazopanib-induced liver toxicity in patients with mRCC.

PMID: 31640912 [PubMed - indexed for MEDLINE]

The burden of corticosteroid overload in severe and difficult to treat asthma: how to reduce this?

Curr Opin Pulm Med. 2020 01;26(1):90-96

Authors: Slisz T, Vasakova M

Abstract
PURPOSE OF REVIEW: Severe asthma is a serious condition that requires an individualized approach combining several treatment agents administered simultaneously in order to reach adequate control. Glucocorticosteroid treatment, as the cornerstone of asthma pharmacotherapy, has great disease-controlling capability, although it may induce a vast amount of severe adverse effects. This review describes our current knowledge of the monitoring and managing options of these adverse effects and possibilities to prevent them, including new therapeutic options.
RECENT FINDINGS: A large amount of new drugs is emerging, which may offer a better control of glucocorticosteroid-induced adverse effects. At the same time, major achievements in our understanding of the underlying mechanisms in severe asthma and in the field of biologic agents may help to substantially reduce the need of glucocorticosteroids in the first-line treatment.
SUMMARY: We discuss new insights and approaches to treatment strategy of severe asthma allowing less oral glucocorticosteroid use and hence, substantial less severe adverse effects of the treatment.

PMID: 31599753 [PubMed - indexed for MEDLINE]

Delayed Onset of Manic Symptoms in a Patient with Influenza A (H1N1) after administration of Oseltamivir (Tamiflu): A Case Report.

Clin Psychopharmacol Neurosci. 2021 Feb 28;19(1):166-169

Authors: Jhon M, Kim JW, Kang HJ, Kim SY, Lee JY, Kim SW, Shin IS, Kim JM

Abstract
Psychiatric side effects of oseltamivir can result in accident-proneness and suicide. Reportedly, such adverse psychiatric events are more common in children than in adults, but other risk factors are not known. We present a 13-year-old girl with influenza infection who developed manic symptoms after taking oseltamivir and receiving the human papillomavirus vaccination. While other research has found that psychiatric side effects associated with oseltamivir generally occur within 48 hours after beginning administration, in this case the manic symptoms developed on the fourth day after cessation of 5-day course of oseltamivir administration. Based on our review of this case, we recommend that clinicians should carry out vigilant monitoring of each patient's mental state when the patient is young, has a family history of psychiatric disorder, has drug sensitivity and has received medical treatments such as vaccination before or after taking oseltamivir. In addition, as side effects of oseltamivir may occur more than 48 hours after administration, it will be necessary to observe patients for several days after the prescription of oseltamivir.

PMID: 33508801 [PubMed - as supplied by publisher]

A phase 1b trial of the CXCR4 inhibitor mavorixafor and nivolumab in advanced renal cell carcinoma patients with no prior response to nivolumab monotherapy.

Invest New Drugs. 2021 Jan 28;:

Authors: Choueiri TK, Atkins MB, Rose TL, Alter RS, Ju Y, Niland K, Wang Y, Arbeit R, Parasuraman S, Gan L, McDermott DF

Abstract
Background The CXCR4 chemokine receptor promotes tumor survival through mechanisms that include suppressing antitumor immune responses. Mavorixafor (X4P-001) is an oral, selective, allosteric CXCR4 inhibitor that decreases the recruitment of immunosuppressive cells into the tumor microenvironment and increases activated cytotoxic Tcell infiltration. Methods Patients with metastatic clear cell renal cell carcinoma (ccRCC) unresponsive to nivolumab monotherapy received oral mavorixafor 400 mg daily plus 240 mg intravenous nivolumab every 2 weeks. Results Nine patients were enrolled, median age 65 years. At baseline 4 had progressive disease (PD) and 5 had stable disease (SD). One of 5 patients with SD at study entry on prior nivolumab monotherapy had a partial response (PR) on combination treatment; all 4 patients with PD at study entry had a best response of SD with the combination treatment (median duration: 6.7 months; range: 3.7-14.7). Four patients discontinued therapy due to treatment-related adverse events (AEs). Grade ≥ 3 drug-related AEs were elevated alanine and aspartate aminotransferase (2 patients each); and autoimmune hepatitis, chronic kidney disease, increased lipase, maculopapular rash, and mucosal inflammation (1 patient each). A robust increase in levels of chemokine (C-X-C motif) ligand 9 CXCL9 on mavorixafor appeared to correlate with clinical benefit. Conclusions The CXCR4 inhibition mediated by mavorixafor, in combination with PD-1 blockade to enhance antitumor immune responses in patients unresponsive to checkpoint inhibitor monotherapy, is worthy of further study. Mavorixafor and nivolumab combination therapy in patients with advanced ccRCC demonstrated potential antitumor activity and a manageable safety profile.Trial registration: ClinicalTrials.gov identifier: NCT02923531. Date of registration: October 04, 2016.

PMID: 33507454 [PubMed - as supplied by publisher]

Medication errors and adverse drug events in a UK hospital during the optimisation of electronic prescriptions: a prospective observational study.

Lancet Digit Health. 2019 12;1(8):e403-e412

Authors: Slight SP, Tolley CL, Bates DW, Fraser R, Bigirumurame T, Kasim A, Balaskonis K, Narrie S, Heed A, Orav EJ, Watson NW

Abstract
BACKGROUND: WHO's Third Global Patient Safety Challenge, Medication Without Harm, focused on reducing the substantial burden of iatrogenic harm associated with medications by 50% in the next 5 years. We aimed to assess whether the number and type of medication errors changed as an electronic prescribing system was optimised over time in a UK hospital.
METHODS: We did a prospective observational study at a tertiary-care teaching hospital. Eight senior clinical pharmacists reviewed patients' records and collected data across four adult wards (renal, cardiology, general medical, and orthopaedic surgical) over a 2-year period (from Sept 29, 2014, to June 9, 2016). All medication errors and potential and actual adverse drug events were documented and the number of medication errors measured over the course of four time periods 7-10 weeks long. Pharmacists also recorded instances where the electronic prescribing system contributed to an error (system-related errors). A negative-binomial model and a Poisson model were used to identify factors related to medication error rates.
FINDINGS: 5796 primary errors were recorded over the four time periods (period 1, 47 days [Sep 29-Dec 2, 2014]; period 2, 38 days [April 20-June 12, 2015, for the renal, medical, and surgical wards and April 20-June 15, 2015, for the cardiology ward]; period 3, 35 days [Sep 28-Nov 27, 2015] for the renal ward, 37 days [Sep 28-Nov 23, 2015] for the medical ward, and 40 days [Sep 28-Nov 20, 2015] for the cardiology and surgical wards; and period 4, 37 days [Feb 22-April 15, 2015] for the renal and medical wards and 39 days for the cardiology [April 13-June 7, 2015] and surgery [April 18-June 9, 2015] wards; unanticipated organisational factors prevented data collection on some days during each time period). There was no change in the rate of primary medication errors per admission over the observation periods: 1·53 medication errors in period 1, 1·44 medication errors in period 2, 1·70 medication errors in period 3, and 1·43 medication errors in period 4, per admission. By contrast, the overall rate of different types of medication errors decreased over the four periods. The most common types of error were medicine-reconciliation, dose, and avoidable delay-of-treatment errors. Some types of errors appeared to reduce over time (eg, dose errors [from 52 errors in period 1 to 19 errors in period 4, per 100 admissions]), whereas others increased (eg, inadequate follow-up of therapy [from 12 errors in period 1 to 24 errors in period 4, per 100 admissions]). We also found a reduction in the rates of potential adverse drug events between the first three periods and period 4. 436 system-related errors were recorded over the study period.
INTERPRETATION: Although the overall rates of primary medication errors per admission did not change, we found a reduction in some error types and a significant decrease in the rates of potential adverse drug events over a 2-year period, during which system optimisation occurred. Targeting some error types could have the added benefit of reducing others, which suggests that system optimisation could ultimately help improve patient safety and outcomes.
FUNDING: No funding.

PMID: 33323222 [PubMed - indexed for MEDLINE]

Safety and efficacy of prednisone versus placebo in short-term prevention of episodic cluster headache: a multicentre, double-blind, randomised controlled trial.

Lancet Neurol. 2021 01;20(1):29-37

Authors: Obermann M, Nägel S, Ose C, Sonuc N, Scherag A, Storch P, Gaul C, Böger A, Kraya T, Jansen JP, Straube A, Freilinger T, Kaube H, Jürgens TP, Diener HC, Katsarava Z, Kleinschnitz C, Holle D

Abstract
BACKGROUND: Prednisone is commonly used for initial short-term therapy of episodic cluster headaches before preventive medication such as verapamil becomes effective, but this strategy has not been tested in large randomised trials. We aimed to access the safety and efficacy of this treatment approach.
METHODS: This study was a multicentre, randomised, double-blind, placebo-controlled trial done in ten specialised headache centres in Germany. Patients with episodic cluster headaches who were aged between 18 and 65 years and within a current pain episode for not more than 30 days, received 100 mg oral prednisone for 5 days followed by tapering of 20 mg every 3 days, or matching placebo (17 days total exposure). All patients received oral verapamil for long-term prevention, starting with 40 mg three times daily and increasing to 120 mg three times daily by day 19; patients then continued with verapamil 120 mg throughout the study. Randomisation was computer-generated at a 1:1 ratio by use of an interactive web-response system, with stratification according to age, sex, and participating site. Participants, investigators, and those assessing outcomes were unaware of treatment allocation. The primary endpoint was the mean number of attacks within the first week of treatment with prednisone compared with placebo. An attack was defined as a unilateral headache with moderate-to-severe intensity of at least five on a numerical rating scale. All efficacy and safety analyses were done in the modified intention-to-treat (mITT) population, which consisted of all patients who had been randomly assigned to a trial group and received at least one dose of prednisone or placebo. The study was stopped early due to slow recruitment and expired funding. The study was registered with EudraCT (2011-006204-13) and with the German Clinical Trials Register (DRKS00004716).
FINDINGS: Between April 5, 2013, and Jan 11, 2018, 118 patients were enrolled in the study. Two patients dropped out immediately and 116 patients were randomly assigned (57 patients to prednisone and 59 patients to placebo); 109 patients were included in the mITT analysis (53 patients assigned to prednisone and 56 patients assigned to placebo). Participants in the prednisone group had a mean of 7·1 (SD 6·5) attacks within the first week compared with 9·5 (6·0) attacks in the placebo group (difference -2·4 attacks, 95% CI -4·8 to -0·03; p=0·002). Two serious adverse events occurred, both in the placebo group (inguinal hernia and severe deterioration of cluster headache). A total of 270 adverse events were observed: in the prednisone group, 37 (71%) of 52 patients reported 135 adverse events (most common were headache, palpitations, dizziness, and nausea) and in the placebo group, 39 (71%) of 55 patients had 135 adverse events (most common were nausea, dizziness, and headache).
INTERPRETATION: Oral prednisone was an effective short-term preventive therapy in our population of patients with episodic cluster headache. Our findings support the use of prednisone as a first-line treatment in parallel to the up-titration of verapamil, although the efficacy of prednisone alongside other long-term prevention requires additional investigation.
FUNDING: German Federal Ministry for Education and Research.

PMID: 33245858 [PubMed - indexed for MEDLINE]

Safety and efficacy of amantadine, modafinil, and methylphenidate for fatigue in multiple sclerosis: a randomised, placebo-controlled, crossover, double-blind trial.

Lancet Neurol. 2021 01;20(1):38-48

Authors: Nourbakhsh B, Revirajan N, Morris B, Cordano C, Creasman J, Manguinao M, Krysko K, Rutatangwa A, Auvray C, Aljarallah S, Jin C, Mowry E, McCulloch C, Waubant E

Abstract
BACKGROUND: Methylphenidate, modafinil, and amantadine are commonly prescribed medications for alleviating fatigue in multiple sclerosis; however, the evidence supporting their efficacy is sparse and conflicting. Our goal was to compare the efficacy of these three medications with each other and placebo in patients with multiple sclerosis fatigue.
METHODS: In this randomised, placebo-controlled, four-sequence, four-period, crossover, double-blind trial, patients with multiple sclerosis who reported fatigue and had a Modified Fatigue Impact Scale (MFIS) score of more than 33 were recruited at two academic multiple sclerosis centres in the USA. Participants received oral amantadine (up to 100 mg twice daily), modafinil (up to 100 mg twice daily), methylphenidate (up to 10 mg twice daily), or placebo, each given for up to 6 weeks. All patients were intended to receive all four study medications, in turn, in one of four different sequences with 2-week washout periods between medications. A biostatistician prepared a concealed allocation schedule, stratified by site, randomly assigning a sequence of medications in approximately a 1:1:1:1 ratio, in blocks of eight, to a consecutive series of numbers. The statistician and pharmacists had no role in assessing the participants or collecting data, and the participants, caregivers, and assessors were masked to allocation. The primary outcome measure was the MFIS measured while taking the highest tolerated dose at week 5 of each medication period, analysed by use of a linear mixed-effect regression model. This trial is registered with ClinicalTrials.gov, NCT03185065 and is closed.
FINDINGS: Between Oct 4, 2017, and Feb 27, 2019, of 169 patients screened, 141 patients were enrolled and randomly assigned to one of four medication administration sequences: 35 (25%) patients to the amantadine, placebo, modafinil, and methylphenidate sequence; 34 (24%) patients to the placebo, methylphenidate, amantadine, and modafinil sequence; 35 (25%) patients to the modafinil, amantadine, methylphenidate, and placebo sequence; and 37 (26%) patients to the methylphenidate, modafinil, placebo, and amantadine sequence. Data from 136 participants were available for the intention-to-treat analysis of the primary outcome. The estimated mean values of MFIS total scores at baseline and the maximal tolerated dose were as follows: 51·3 (95% CI 49·0-53·6) at baseline, 40·6 (38·2-43·1) with placebo, 41·3 (38·8-43·7) with amantadine, 39·0 (36·6-41·4) with modafinil, and 38·6 (36·2-41·0) with methylphenidate (p=0·20 for the overall medication effect in the linear mixed-effect regression model). As compared with placebo (38 [31%] of 124 patients), higher proportions of participants reported adverse events while taking amantadine (49 [39%] of 127 patients), modafinil (50 [40%] of 125 patients), and methylphenidate (51 [40%] of 129 patients). Three serious adverse events occurred during the study (pulmonary embolism and myocarditis while taking amantadine, and a multiple sclerosis exacerbation requiring hospital admission while taking modafinil).
INTERPRETATION: Amantadine, modafinil, and methylphenidate were not superior to placebo in improving multiple sclerosis fatigue and caused more frequent adverse events. The results of this study do not support an indiscriminate use of amantadine, modafinil, or methylphenidate for the treatment of fatigue in multiple sclerosis.
FUNDING: Patient-Centered Outcomes Research Institute.

PMID: 33242419 [PubMed - indexed for MEDLINE]

Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study.

Lancet Neurol. 2021 01;20(1):49-59

Authors: Adams D, Polydefkis M, González-Duarte A, Wixner J, Kristen AV, Schmidt HH, Berk JL, Losada López IA, Dispenzieri A, Quan D, Conceição IM, Slama MS, Gillmore JD, Kyriakides T, Ajroud-Driss S, Waddington-Cruz M, Mezei MM, Planté-Bordeneuve V, Attarian S, Mauricio E, Brannagan TH, Ueda M, Aldinc E, Wang JJ, White MT, Vest J, Berber E, Sweetser MT, Coelho T, patisiran Global OLE study group

Abstract
BACKGROUND: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy.
METHODS: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261.
FINDINGS: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4·0, 95 % CI -7·7 to -0·3; phase 2 OLE patisiran -4·7, -11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1·4, 95% CI -6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups.
INTERPRETATION: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran.
FUNDING: Alnylam Pharmaceuticals.

PMID: 33212063 [PubMed - indexed for MEDLINE]

Risk Factors for Safety of Allergen-Specific Sublingual Immunotherapy in Children with Allergic Rhinitis.

Int Arch Allergy Immunol. 2020;181(12):934-940

Authors: Liu W, Zeng Q, Yan S, Sun C, Tang Y, Luo R

Abstract
A good compliance often attributes to good efficacy and safety of sublingual immunotherapy (SLIT). However, few studies have been conducted on the safety of SLIT treatment in children. We aimed to confirm the pretreatment parameters to predict the safety in children who underwent SLIT. 601 children with allergic rhinitis (AR) treated with SLIT were enrolled in this study. Baseline clinical information and laboratory parameters were collected. The clinical response and adverse events (AEs) were recorded and evaluated. A multivariate logistic regression model was established to confirm the predictors for AEs. The AEs were reported in 75 children (13.8%). The serum-specific IgE (s-IgE) level was significantly correlated with the occurrence of AEs by multivariate logistic regression analysis. Our receiver operating characteristic (ROC) analysis of the serum s-IgE levels >21.6 IU/mL had the best sensitivity (83.7%) and specificity (76.7%) to predict safety. The serum s-IgE level was significantly correlated with safety of SLIT in children, which may be helpful for patient selection before SLIT.

PMID: 32937623 [PubMed - indexed for MEDLINE]

Prevention and management of adverse effects of disease modifying treatments in multiple sclerosis.

Curr Opin Neurol. 2020 06;33(3):286-294

Authors: Moiola L, Rommer PS, Zettl UK

Abstract
PURPOSE OF REVIEW: To summarize the currently known side effects of the approved therapies of multiple sclerosis and to suggest monitoring procedures.
RECENT FINDINGS: The progress in the treatment of multiple sclerosis with new very effective therapies is accompanied by a number of side effects. Some of these have already been described in the approval studies, but some only after approval in a real world situation. The reason for this is the short duration of the clinical studies, the very heterogeneous patient profile in the real world setting with a number of comorbidities, pretherapies, and wider age range. The side effects may occur during application of therapies or afterwards during the course of the treatment. The side effects may range from mild infections, mild laboratory abnormalities, secondary autoimmune diseases to life-threatening side effects such as progressive multifocal leukoencephalopathy.
SUMMARY: It has to be pointed out that these side effects are not to be considered as final and neurologists should be vigilant against new unknown side effects. The doctor should be aware of these undesirable effects, should weigh the benefits of the therapies against the risks, but at the same time she/he should keep in mind that multiple sclerosis can be a very disabling disease if not treated properly.

PMID: 32374570 [PubMed - indexed for MEDLINE]

Adverse Medication Events Related to Hospitalization in the United States: A Comparison Between Adults With Intellectual and Developmental Disabilities and Those Without.

Am J Intellect Dev Disabil. 2020 01;125(1):37-48

Authors: Erickson SR, Kamdar N, Wu CH

Abstract
This study examined the proportion of hospitalizations associated with adverse medication events (AMEs) for adults with intellectual and developmental disabilities (IDD) and adults from the general population in the United States using the 2013 National Inpatient Sample (NIS) dataset of the Healthcare Cost and Utilization Project (HCUP). Adults with IDD had greater odds of having a hospitalization associated with an AME than the general adult population. Unadjusted odds ratios (95% CI) for hospitalization due to any medication for IDD was 2.47 (2.31-2.65). In the multivariate logistic regression model, IDD was significantly associated, with an odds ratio of 1.28 (1.19-1.38). Adults who have IDD are at greater risk of having a hospital admission due to an AME.

PMID: 31877264 [PubMed - indexed for MEDLINE]

Diagnosis and Management of Autoimmune Hemolytic Anemia in Patients with Liver and Bowel Disorders.

J Clin Med. 2021 Jan 22;10(3):

Authors: Bianco C, Coluccio E, Prati D, Valenti L

Abstract
Anemia is a common feature of liver and bowel diseases. Although the main causes of anemia in these conditions are represented by gastrointestinal bleeding and iron deficiency, autoimmune hemolytic anemia should be considered in the differential diagnosis. Due to the epidemiological association, autoimmune hemolytic anemia should particularly be suspected in patients affected by inflammatory and autoimmune diseases, such as autoimmune or acute viral hepatitis, primary biliary cholangitis, and inflammatory bowel disease. In the presence of biochemical indices of hemolysis, the direct antiglobulin test can detect the presence of warm or cold reacting antibodies, allowing for a prompt treatment. Drug-induced, immune-mediated hemolytic anemia should be ruled out. On the other hand, the choice of treatment should consider possible adverse events related to the underlying conditions. Given the adverse impact of anemia on clinical outcomes, maintaining a high clinical suspicion to reach a prompt diagnosis is the key to establishing an adequate treatment.

PMID: 33499290 [PubMed]

Management of Crohn Disease: A Review.

JAMA. 2021 Jan 05;325(1):69-80

Authors: Cushing K, Higgins PDR

Abstract
Importance: Crohn disease, a chronic gastrointestinal inflammatory disease, is increasing in incidence and prevalence in many parts of the world. Uncontrolled inflammation leads to long-term complications, including fibrotic strictures, enteric fistulae, and intestinal neoplasia. Therefore, early and effective control of inflammation is of critical importance.
Observations: The optimal management approach for Crohn disease incorporates patient risk stratification, patient preference, and clinical factors in therapeutic decision-making. First-line therapy generally consists of steroids for rapid palliation of symptoms during initiation of anti-tumor necrosis factor α therapy. Other treatments may include monoclonal antibodies to IL-12/23 or integrin α4β7, immunomodulators, combination therapies, or surgery. Effective control of inflammation reduces the risk of penetrating complications (such as intra-abdominal abscesses and fistulae), although more than half of patients will develop complications that require surgery. Adverse reactions to therapy include antibody formation and infusion reactions, infections, and cancers associated with immune modulators and biologics and toxicity to the bone marrow and the liver. Both Crohn disease and corticosteroid use are associated with osteoporosis. Vaccinations to prevent infections, such as influenza, pneumonia, and herpes zoster, are important components of health maintenance for patients with Crohn disease, although live vaccines are contraindicated for patients receiving immune suppression therapy.
Conclusions and Relevance: The treatment of patients with Crohn disease depends on disease severity, patient risk stratification, patient preference, and clinical factors, including age of onset and penetrating complications, and includes treatment with steroids, monoclonal antibody therapies, immunomodulators, and surgery. Physicians should be familiar with the advantages and disadvantages of each therapy to best counsel their patients.

PMID: 33399844 [PubMed - indexed for MEDLINE]

Global Safety Database Summary of COVID-19-Related Drug Utilization-Safety Surveillance: A Sponsor's Perspective.

Drug Saf. 2021 01;44(1):95-105

Authors: Beyzarov E, Chen Y, Julg R, Naim K, Shah J, Gregory WW, Ayoub A, Caubel P

Abstract
INTRODUCTION: Evidence-based clinical data on coronavirus disease 2019 (COVID-19) pharmacotherapies are scarce.
OBJECTIVE: This study documented and characterized COVID-19 cases reported in individuals receiving treatment with Pfizer pharmaceutical products and cases that reported use of Pfizer pharmaceutical products for COVID-19 treatment.
METHODS: This retrospective observational review leveraged the Pfizer safety database containing adverse event data collected in association with use of Pfizer products between 1 October, 2019, and 25 June, 2020; the database includes worldwide adverse event data from various sources. Selected Medical Dictionary for Drug Regulatory Activities (MedDRA®) Preferred Terms and subsequent clinical review were used to characterize COVID-19 cases.
RESULTS: Over 1500 relevant cases were identified over an 8-month period. In cases that reported COVID-19, immunosuppressant/immunomodulating agents, followed by anticoagulant/antithrombic agents and corticosteroids, were the most frequently reported agents. The frequent reporting of immunosuppressant/immunomodulating agents among cases of COVID-19 suggests increased vulnerability to infection among treated patients, either because of immunosuppressive effects of certain agents or the nature of the underlying treated condition. In cases involving off-label pharmacotherapy use for the treatment of COVID-19-related conditions, the most frequently reported therapeutic classes included antibiotics, antimalarial agents, antivirals/antiretroviral agents, immunosuppressant/immunomodulating agents, corticosteroids, anticoagulants, and immunoglobulin/interferons. The most frequently reported pharmacotherapeutic agents were azithromycin and chloroquine/hydroxychloroquine, followed by lopinavir-ritonavir, ceftriaxone, and tofacitinib. The most frequently reported clinical adverse events associated with azithromycin (as sole therapy or combined with chloroquine/hydroxychloroquine) include electrocardiogram QT prolonged, drug interaction, hepatitis, diarrhea, and hepatitis acute. Regarding cardiac-related events, 19% (120/645) of azithromycin cases reported events associated with QT prolongation/torsade de pointes (which included seven fatal cardiac events). The most frequently reported clinical adverse events associated with other commonly used agents are also presented.
CONCLUSIONS: This pharmacovigilance surveillance study provides a unique characterization of cases in which a broad range of pharmaceutical products was reported in relation to COVID-19.

PMID: 33354753 [PubMed - indexed for MEDLINE]

An overview of acute gastrointestinal side effects of systemic anti-cancer therapy and their management.

Best Pract Res Clin Gastroenterol. 2020 Oct - Dec;48-49:101691

Authors: Smith P, Lavery A, Turkington RC

Abstract
Treatment-related acute gastrointestinal toxicities are a common and often debilitating hurdle encountered in the treatment of cancer patients. While the introduction of targeted therapies such as tyrosine kinase inhibitors has led to improvements in survival outcomes, their use has also been complicated by a high frequency of clinically important adverse effects. Gastrointestinal toxicities such as nausea, vomiting, diarrhoea and hepatotoxicity represent potentially serious adverse events that may necessitate dose reductions, treatment interruptions and cessation of treatment. An improved knowledge of the incidence, pathophysiology, management and prophylaxis of these toxicities is crucial in order to reduce patient morbidity and mortality. In this review, we discuss the main gastrointestinal toxicities associated with chemotherapy and targeted therapies in oncology, outlining their incidence, pathophysiology and expert management guidelines.

PMID: 33317796 [PubMed - indexed for MEDLINE]

How to Investigate a Serious Adverse Event Reported During a Clinical Trial for a COVID-19 Vaccine.

Drug Saf. 2021 01;44(1):1-5

Authors: Shakir S, Lane S, Davies M

PMID: 33219926 [PubMed - indexed for MEDLINE]