Treatment-emergent Adverse Drug Reactions Research Articles

Can quantitative monitoring of B cells evaluate the efficacy of Rituximab in primary CNS demyelinating disorders?

Abstract Introduction: Rituximab (RTX), initially approved for various blood cancers, is additionally used for the management of primary central nervous system (CNS) demyelinating disorders. This study aimed to quantify the % of B cells following RTX therapy in patients with primary CNS demyelinating disorders, so as to establish a correlation, if any, between the degree of B-cell depletion and clinical response(s). Materials and Methods: A prospective, observational study was conducted from February 2020 to August 2021 in 15 adults diagnosed with primary CNS demyelinating disorders. The % of B cells was quantified in terms of CD20 by flow cytometry, and clinical evaluation was by Expanded Disability Status Scale (EDSS) scores. Following the first dose of RTX, the %CD20 counts were measured 2 and 24 weeks later; subsequently, depending on the %CD20, RTX was administered. Accordingly, patients were divided into Group 1 (n = 7, %CD20 ≥ 1.5) and Group 2 (n = 8, %CD20 < 1.5) and followed up on the basis of CD counts till the completion of the study or until they were lost to follow-up. Safety was evaluated by recording of treatment-emergent adverse drug reactions (ADR). Results: In patients with CNS demyelinating disorders (n = 15), their median (interquartile range [IQR]) %CD20 and EDSS at baseline was 9.8 (5.6–18.8)% and 8.0 (7.5–8.0)%, respectively. In Group 1 (n = 7, %CD20 ≥ 1.5), there was a gradual decrease of %CD20 and EDSS, whereas in Group 2 (n = 8, %CD20 < 1.5), despite withholding RTX, patients remained asymptomatic, and their %CD20 remained <1.5 and EDSS showed a gradual decrease. 87% of patients experienced at least one ADR, the median (IQR) of ADRs per patient was 3 (0–3), and all 31 ADRs were infusion-related, with 100% recovery. Conclusion: RTX was relatively safe to use in these disorders, and monitoring its efficacy was adequately achieved using EDSS, with no additional benefits accrued by measuring %CD20 counts.

Multizonal observational study conducted by clinical practitioners on Repatha® use in patients with hyperlipidemia (ZERBINI): Colombian results

BackgroundCardiovascular disease (CVD) represents the primary cause of death and disability globally, with elevated cholesterol as one of the leading risk factors for CVD. We describe the clinical characteristics, treatment patterns, and effectiveness of evolocumab in treating hyperlipidemia. MethodsObservational study conducted through a chart review of patients with hyperlipidemia receiving evolocumab as part of clinical management in Colombia. ResultsThis study included 115 patients treated with evolocumab. A total of 101 patients (87.8%) had a history of CVD, 13 (11.3%) familial hypercholesterolemia (FH), and 23 (20%) type 2 diabetes. Thirty-nine patients reported intolerance to any statin (33.9%). The median value of LDL-C before initiation of evolocumab was 147mg/dL (IQR: 122.5–183.7mg/dL). Within the first 3 months of treatment, LDL-C value dropped to a median value of 53mg/dL (IQR: 34.0–95.5mg/dL), showing a reduction of 63.9%. The median LDL-C values remained below 45mg/dL until the end of follow-up. Among the patients with available data, up to 61% achieved an LDL-C level below 55mg/dL at the 10–12-month follow-up. A total of 72% of patients were persistent with treatment. Safety results showed a low frequency of hospitalizations (≤2%) and treatment-emergent adverse drug reactions (5.2%). No serious adverse events were reported. ConclusionsEvolocumab was associated with reductions in LDL-C levels, with a relative decrease of 63.9% within the first 3 months of treatment. Low rates of interruptions due to adverse events and adequate medication persistence was reported.

Vismodegib Efficacy in Advanced Basal Cell Carcinoma Maintained with 8-Week Dose Interruptions: A Model-Based Evaluation

Long-term use of vismodegib is associated with treatment-emergent adverse drug reactions in clinical trials of patients with locally advanced basal cell carcinoma (laBCC) and metastatic BCC (mBCC). Treatment interruptions have been recommended for management of adverse drug reactions, but there is no clear guidance on the duration of those interruptions. A model-based evaluation was conducted to assess the impact of treatment interruptions on vismodegib efficacy. A tumor growth-inhibition model was developed and model-based simulations were performed to assess the proportion of patients achieving ≥30% reduction from baseline in tumor size (ie, proportion of responders) for various dosing schedules. The most conservative simulated scenario compared an intermittent dosing schedule of 12 weeks of vismodegib treatment followed by 8-week dosing interruption (repeated four times for a total duration of 80 weeks) versus 80 weeks of continuous dosing, which predicted a decrease in responders of -4.7% from 90.7% in laBCC and -3.7% from 63.0% in mBCC. These results demonstrated maintenance of vismodegib efficacy with the intermittent dosing schedule and support the recently approved recommendations of treatment interruptions of up to 8 weeks to manage tolerability in laBCC or mBCC patients in the vismodegib US prescribing information.

2231. Safety of Nebulized Colistin as Adjunctive Treatment of Lower Respiratory Tract Infections

BackgroundSystemic antibiotics used in treatment of drug-resistant lower-respiratory tract infections (LRTI) may have poor lung penetration or narrow therapeutic indices. Nebulized administration of colistin allows direct instillation of active agent to maximize concentrations at the site of infection. Theoretically, local administration also avoids treatment-limiting toxicities and adverse drug reactions (ADR). Current literature supports efficacy of nebulized colistin as adjunctive treatment for LRTI. However, there is a paucity of data surrounding safety and tolerability of this administration technique.MethodsThe electronic medical record (EMR) was queried to identify patients treated with nebulized colistin between January 1, 2016 and December 31, 2018. The following data were collected from the EMR and hospital ADR reporting systems: demographics, treatment regimen, serum creatinine (SCr), concomitant nephrotoxins, infecting pathogen, treatment-emergent ADRs, and drug toxicities. The primary outcome was prevalence of renal (acute kidney injury [AKI]), neurologic (seizure, visual disturbance), or respiratory (bronchospasm) ADRs secondary to colistin nebulization therapy. AKI was defined according to the RIFLE criteria.ResultsThirty-two patients were administered nebulized colistin during the study period. Approximately 19% of patients had a baseline renal impairment. Cultures were positive in 29 patients of which 11 organisms were resistant to all tested antimicrobials. The most common infecting pathogen was A. baumanii (n = 15) followed by K. pneumoniae (n = 9). The median duration of therapy was 4.6 days. Seventeen patients (53.1%) were exposed to concomitant nephrotoxins. Three patients experienced AKI of which two received simultaneous furosemide and one had underlying renal dysfunction and received concomitant vancomycin. The one observed neurologic reaction, seizure, occurred in a patient with underlying epilepsy. No patients had documented visual disturbances or bronchospasm.ConclusionThe results of our study are consistent with the principle that localized administration of colistin results in a lower incidence of systemic adverse events. Nebulized colistin is a safe adjunct for managing LRTI. Renal, pulmonary, and neurologic reactions in this study were likely not treatment-related. Disclosures All authors: No reported disclosures.

Efficacy and safety of topical BAK-free travoprost 0.004% versus BAK-preserved travoprost 0.004% in the treatment of primary open angle glaucoma: a comparative study at a tertiary care hospital

Background: Prostaglandin analogues (PGAs) reduce intraocular pressure (IOP) in patients with primary open-angle glaucoma (POAG); however, these medications may affect the ocular surface and elicit ocular discomfort when preserved with benzalkonium chloride (BAK). Hence the above study was taken to evaluate the benefit of BAK-free formulations of travoprost. The objectives of the study were to compare the efficacy, safety of topical BAK-free travoprost 0.004% versus BAK-preserved travoprost 0.004% in patients with primary open angle glaucoma.Methods: 40 patients with POAG who fulfilled the inclusion /exclusion criteria were randomised into two groups of 20 each to receive BAK-free travoprost 0.004% or BAK-preserved travoprost once daily in the evening. Efficacy was measured in terms of reduction in IOP monitored at 4, 8 and 12 weeks from baseline. Ocular surface disease index (OSDI) questionnaire was used to assess the ocular surface symptoms. Safety was assessed by monitoring treatment emergent adverse drug reactions (ADRs).Results: Both the study medications were effective in reducing IOP when compared to baseline. Mean IOP reduction from baseline to week 12 was 11±3mmHg (p <0.001), 10.78±3.01mmHg, (p<0.001) in BAK-free travoprost and BAK-preserved travoprost groups respectively. Both produced equivalent reductions in IOP at the end of 4 (7.89±1.82 vs 7.63±2.83, p=0.72), 8 (9.94±2.75 vs10.05±2.75, p=0.90), and 12 weeks (11±3 vs10.78±3.01, p=0.82). BAK-free travoprost demonstrated significantly lower OSDI scores (15.10±3.60) compared to BAK- preserved travoprost (23.47±7.10) at 12 weeks (p <0.0001). There was no significant difference in occurrence of conjunctival hyperaemia between the study drugs (c2 = 0, df = 1, p = 1) and BAK-free travoprost was well tolerated.Conclusions: BAK-free and BAK-preserved travoprost significantly reduced IOP at 12 weeks. But, BAK- free travoprost produced significantly less ocular surface symptoms as compared to BAK- preserved travoprost. Hence it could be a favourable option in POAG patients with ocular surface disease symptoms.

Real-world evidence for the safety of ipragliflozin in elderly Japanese patients with type 2 diabetes mellitus (STELLA-ELDER): final results of a post-marketing surveillance study

ABSTRACTObjective: To investigate the real-world safety of ipragliflozin in elderly Japanese patients with type 2 diabetes mellitus (T2DM).Research design and methods: Japanese patients (≥65 years old) who were first prescribed ipragliflozin within 3 months after its launch in April 2014 were registered in this post-marketing surveillance (PMS). Final data collection was in July 2015. Survey items included demographics, treatments, adverse drug reactions (ADRs), vital signs, and laboratory variables.Results: The PMS included 8505 patients (4181 males/4324 females). The mean age and diabetes duration were 72.3 years and 10.6 years, respectively. In 84.3% of patients, ipragliflozin was prescribed at 50 mg/day, which was continued unchanged. Overall, 16.91% of patients experienced 1880 ADRs, and 165 ADRs were classified as serious in 127 patients (1.49%). ADRs of special interest included skin complications, volume depletion, polyuria/pollakiuria, genital infection, urinary tract infection, renal disorders, hypoglycemia, cerebrovascular disease, cardiovascular disease, malignant tumor, fracture, and ketone body-related events.Conclusions: This 1-year PMS revealed probable ADRs in elderly Japanese patients with T2DM prescribed ipragliflozin in real-world settings, with no new safety concerns. The risk factors for ADRs varied but could be rationalized. The results should help physicians to identify possible treatment-emergent ADRs in ipragliflozin-treated patients.

Incidence of bone pain in patients with breast cancer treated with lipegfilgrastim or pegfilgrastim: an integrated analysis from phase II and III studies

Lipegfilgrastim is a once-per-cycle, fixed-dose, glycoPEGylated recombinant granulocyte colony-stimulating factor (G-CSF) recently approved in Europe to reduce the duration of chemotherapy-induced neutropenia and incidence of febrile neutropenia in patients with cancer receiving chemotherapy. Bone pain-related (BPR) adverse events are commonly associated with G-CSF therapy. This post hoc analysis examined BPR treatment-emergent adverse events (TEAEs) in two comparative studies of lipegfilgrastim or pegfilgrastim in patients receiving chemotherapy. A post hoc analysis was conducted using integrated data from two double-blind randomized studies in patients with breast cancer receiving docetaxel and doxorubicin and treated prophylactically with subcutaneous lipegfilgrastim 6 mg or pegfilgrastim 6 mg once per cycle. BPR TEAEs were defined as arthralgia, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, noncardiac chest pain, and pain in extremity. Relationship of BPR TEAEs to study treatment or chemotherapy was also reported by the investigators. The analysis included 306 patients (lipegfilgrastim: n = 151; pegfilgrastim: n = 155). The proportion of patients experiencing BPR TEAEs was similar with lipegfilgrastim and pegfilgrastim (25.2 vs 21.9%, respectively), as was the proportion of patients experiencing BPR treatment-emergent adverse drug reactions (TEADRs) (18.5 vs 16.8%, respectively). No BPR TEADRs were serious, and none led to discontinuation. Nonsevere BPR TEAEs and TEADRs were observed in patients with breast cancer receiving chemotherapy and G-CSF; rates of BPR events were similar between lipegfilgrastim and pegfilgrastim. The similar BPR safety profile of lipegfilgrastim and pegfilgrastim provides support for use in patients with breast cancer receiving chemotherapy.

Adverse Effects of Antiepileptic Drugs in North Indian Pediatric Outpatients

The present study investigates the pattern and predictors of treatment-emergent adverse drug reactions (ADRs) in children diagnosed with epilepsy. We conducted prospective observational study in a tertiary care teaching hospital on 277 epileptic children. Antiepileptic drug (AED)-associated ADRs, demographic and clinical characteristics, AED regimen, and so on were recorded. Causality, severity, and preventability were performed by World Health Organization-Uppsala Monitoring Center scale, Hartwig's severity scale, and Schumock and Thornton questionnaire, respectively. Of the enrolled population, 53% children had symptomatic epilepsy, and 51% were in 5- to 10-year age group. More than two-thirds of children were on monotherapy, with phenytoin (n = 176, 63.5%) being the most common AED. Three hundred fifty-three AED-related ADRs were recorded in 175 children (63.2%). Poor scholastic performance (19%) was the most common ADR, followed by gum hypertrophy (13.3%), headache (10.2%), behavioral problems (5.7%), drowsiness (5.7%), and others. Two hundred sixteen ADRs were probable, and 126 ADRs were possible. Severe ADRs were noted in 6 children. Girls (odds ratio [OR], 1.93; 95% confidence interval [95% CI], 1.07-3.45; P = 0.03), children with secondary epilepsy (OR, 3.31; 95% CI, 1.76-6.23; P ≤ 0.001), children older than 5 years (5-10 years; OR, 6.28; 95% CI, 2.79-14.12; P ≤ 0.001), and those older than 10 years (OR, 9.04; 95% CI, 3.69-22.17; P ≤ 0.001) were found to be at higher risk of experiencing ADRs. Monotherapy was the preferred treatment. Phenytoin was the most common ADR causative agent. Female sex, symptomatic epilepsy, and older age (> 5 years) were found to be associated with higher probability of ADR development.

Evaluation of efficacy of oral pregabalin in reducing postoperative pain in patients undergoing total knee arthroplasty

Background:Optimal pain treatment with minimal side effects is essential for early mobility and recovery in patients undergoing total knee arthroplasty (TKA). We investigated the effect of pregabalin as an adjuvant for postoperative analgesia provided by opioid-based patient-controlled epidural analgesia (PCEA) in such patients.Materials and Methods:Forty patients undergoing unilateral primary TKA were randomly assigned to two equal groups, to receive either placebo or pregabalin 75 mg twice a day. The drug was administered orally starting before surgery and was continued for 2 days after surgery. Anesthetic technique was standardized. Postoperatively, static and dynamic pain was assessed by verbal rating score. Mean morphine consumption, PCEA usage, rescue analgesic requirement, and overall patient satisfaction were also assessed. Treatment emergent adverse drug reactions were recorded.Results:Mean morphine consumption was significantly reduced by pregabalin. Postoperative pain (both static and dynamic) and PCEA consumption too was significantly reduced in the pregabalin group during the first 48 h after surgery. This group needed fewer rescue analgesics and recorded higher overall patient satisfaction. Pregabalin-treated patients had fewer opioid-related adverse reactions like nausea, vomiting, and constipation. Dizziness was noted in two of the patients receiving pregabalin. There was no statically significant difference in the incidence of sedation in the two groups.Conclusions:Oral pregabalin 75 mg started preoperatively is a useful adjunct to epidural analgesia following TKA. It reduces opioid consumption, improves postoperative analgesia, and yields higher patient satisfaction levels.

Amisulpride Versus Olanzapine in the Treatment of Schizophrenia in Indian Patients: Randomized Controlled Trial

Atypical antipsychotics are increasingly drugs of first choice in schizophrenia. Amisulpride, a new atypical antipsychotic, is reported to be effective for both positive and negative symptoms of schizophrenia in Western countries but Indian experience is limited. The aim of the present study was therefore to conduct a trial of amisulpride versus olanzapine in Indian schizophrenia patients. Eighty adult patients of either sex were randomized to receive standard doses of the two drugs orally, in a single blind manner, for 12 weeks, with follow up at 4 and 8 weeks. Effectiveness was assessed by changes in scores on the Brief Psychiatric Rating Scale (BPRS), Scale for Assessment of Positive Symptoms (SAPS), Scale for Assessment of Negative Symptoms (SANS), and physician-administered Clinical Global Impression (CGI) scale. Tolerability was assessed by treatment-emergent adverse drug reactions (ADRs). Evaluable were 39 patients on amisulpride and 38 on olanzapine. The groups were comparable at baseline with respect to demographics, illness duration and rating scores. Final BPRS score was lower for olanzapine (33.2 +/- 9.44) than for amisulpride (37.7 +/- 9.67). SAPS and SANS scores and CGI rating improved individually in both arms but remained comparable between groups throughout the study period, but olanzapine reduced SAPS score to a greater extent. ADRs were encountered in 67.5% and 47.5% of patients (p = 0.113) on amisulpride and olanzapine, respectively. Tremor and insomnia were more frequent with amisulpride, while olanzapine caused more weight gain and sedation. No serious ADRs occurred. Amisulpride, although comparable to olanzapine on some measures, did not match the improvement seen with the latter drug in BPRS and SAPS scores. Despite differences in ADR profiles, overall tolerability was satisfactory for both drugs. In Indian patients, amisulpride should therefore be an alternative to olanzapine to a limited extent, such as when weight gain and sedation are undesirable.

Effects of Oral Ziprasidone and Oral Haloperidol on QTc Interval in Patients with Schizophrenia or Schizoaffective Disorder

To characterize the effect of oral ziprasidone and haloperidol on the corrected QT (QTc) interval under steady-state conditions. Design. Prospective, randomized, open-label, parallel-group study. Inpatient clinical research facility. Patients Fifty-nine adults (age range 25-59 yrs) with schizophrenia or schizoaffective disorder who had no clinically significant abnormality on electrocardiogram (ECG) at screening. Intervention. During period 1 (days -10 to -4), antipsychotic and anticholinergic drugs were tapered. On the first day (day -3) of period 2, the drugs were discontinued, and placebo was given for the next 3 days (days -2 to 0). On the last day (day 0) of period 2, serial baseline ECGs were collected. During period 3 (days 1-16), patients received escalating oral doses of ziprasidone and haloperidol to reach steady state. Period 4 (days 17-19) allowed for study drug washout and initiation of outpatient antipsychotic therapy; safety assessments were also performed during this period. At each steady-state dose level, three ECGs and a serum or plasma sample were collected at the predicted time of peak exposure to the administered drug. Point estimates and 95% confidence intervals (CIs) were determined for the mean QTc interval at baseline and for the mean change from baseline in QTc at each steady-state dose level. Mean changes from baseline in the QTc interval (msec) for ziprasidone were 4.5 (95% CI 1.9-7.1), 19.5 (95% CI 15.5-23.4), and 22.5 (95% CI 15.7- 29.4) for steady-state doses of 40, 160, and 320 mg/day, respectively; for haloperidol, -1.2 (95% CI -4.1-1.7), 6.6 (95% CI 1.6-11.7), and 7.2 (95% CI 1.4-13.1) for steady-state doses of 2.5, 15, and 30 mg/day. Although no patient in either treatment group experienced a QTc interval of 450 msec or greater, the QTc interval increased 30 msec or more in 11 and 17 ziprasidone-treated patients at 160 and 320 mg/day, respectively, and in 3 and 5 haloperidol-treated patients at 15 and 30 mg/day, respectively. Most treatment-emergent adverse drug reactions were mild in intensity, and none were severe. The QTc interval in ziprasidone- and haloperidol-treated patients increased with dose. Treatment with high doses of ziprasidone or haloperidol did not result in any patient experiencing a QTc interval of 450 msec or greater.