Safety of cenobamate as adjunctive therapy in adults with uncontrolled focal seizures: Time to onset, duration, and severity of the most common adverse events

Background Monoclonal antibodies blocking the programmed cell death-1 (PD-1) or its ligand (PD-L1) are a group of immune checkpoints inhibitors (ICIs) with proven antitumor efficacy. However, their use is complicated by immune-related adverse events (irAEs), including endocrine adverse events (eAEs). Purpose We review the incidence, time to onset and resolution rate of dysthyroidism induced by PD-1/PD-L1 Ab, and the clinical, biological and radiological findings. We aim to discuss the potential mechanisms of PD-1/PD-L1 Ab-induced dysthyroidism, and to propose a management algorithm. Methods We performed a literature search of available clinical trials regarding PD-1/PD-L1 Ab in the PubMed database. We selected all English language clinical trials that included at least 100 patients. We also present selected case series or reports, retrospective studies and reviews related to this issue. Findings In patients treated with PD-1 Ab, hypothyroidism occurred in 2–10.1% and hyperthyroidism occurred in 0.9–7.8%. When thyroiditis was reported separately, it occurred in 0.34–2.6%. Higher rates were reported when PD-1 Ab were associated with other ICI or chemotherapy. The median time to onset of hyperthyroidism and hypothyroidism after PD-1 Ab initiation was 23–45 days and 2–3.5 months, respectively. Regarding PD-L1 Ab, hypothyroidism occurred in 0–10% and hyperthyroidism in 0.5–2% of treated patients. The average time to onset of dysthyroidism after PD-L1 Ab was variable and ranged from 1 day after treatment initiation to 31 months. Conclusion Dysthyroidism occurs in up to 10% of patients treated with PD-1/PD-L1 Ab. Hypothyroidism and reversible destructive thyroiditis are the most frequent endocrine adverse events (eAE) in PD-1/PD-L1 treated patients. Immune and non-immune mechanisms are potentially involved, independently of the presence of thyroid antibodies.

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Comprehensive Analysis of Bortezomib-Induced Adverse Events Using the Japanese Real-World Database

Oncology ◽

10.1159/000521448 ◽

2021 ◽

Author(s):

Aya Satoki ◽

Mayako Uchida ◽

Masaki Fujiwara ◽

Yoshihiro Uesawa ◽

Tadashi Shimizu

Keyword(s):

Peripheral Neuropathy ◽

Adverse Events ◽

Cardiac Failure ◽

Tumor Lysis Syndrome ◽

Adverse Event Reporting System ◽

Japanese Patients ◽

Comprehensive Analysis ◽

Drug Event ◽

Lung Disorder ◽

Time To Onset

Background: Bortezomib is used as first-line therapy for multiple myeloma. Observational studies based on the FDA Adverse Event Reporting System (FAERS) database analysis and systematic reviews indicate that the incidence of peripheral neuropathy and tumor lysis syndrome (TLS) tends to be higher with bortezomib than that of other drugs. In a comprehensive analysis assessing drugs that cause peripheral neuropathy in Japanese patients, the incidence of bortezomib-induced adverse events (AEs) was reportedly high. However, a comprehensive assessment of bortezomib is lacking. Objectives: The purpose of this study was to determine the frequency of bortezomib AEs in Japanese patients and to determine the incidence, time to onset, and post hoc outcomes of unique AEs using the Japanese Adverse Drug Event Report (JADER) database. Method: To investigate the association between bortezomib and AEs, we analyzed the JADER database, which contains spontaneous AE reports submitted to the Pharmaceuticals and Medical Devices Agency from April 2004 to December 2020. Criteria indicating the presence of an AE signal were met when the following requirements were fulfilled: proportional reporting ratios (PRR) ≥ 2 and χ2 ≥ 4. Time to onset and post-event outcomes were analyzed for characteristic AEs. Results: Among 26 extracted AEs, 13 presented AE signals. The post-exposure outcomes of 12 AEs showed fatal outcomes at rates exceeding 10%, including cardiac failure (30%), lung disorder (24%), pneumonia (18%), and TLS (10%). Furthermore, a histogram of time to onset revealed that the 12 AEs were concentrated from the beginning to approximately one month after bortezomib administration. The median onset times for cardiac failure, lung disorder, pneumonia, and TLS were 28, 13, 42, and 5 days, respectively. Conclusions: Cardiac failure, lung disorder, pneumonia, and TLS had a higher rate of fatal clinical outcomes after onset than other AEs. These AEs exhibited a greater onset tendency in the early post-dose period. This study suggests that there is a need to monitor signs of cardiac failure, lung disorder, pneumonia, and TLS, potentially resulting in serious outcomes.

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Safety and Tolerability of Adjunctive Eslicarbazepine Acetate in Pediatric Patients (Aged 4-17 Years) With Focal Seizures

Journal of Child Neurology ◽

10.1177/0883073819890997 ◽

2019 ◽

Vol 35 (4) ◽

pp. 265-273 ◽

Cited By ~ 4

Author(s):

Mark Mintz ◽

Jesus E. Pina-Garza ◽

Steven M. Wolf ◽

Patricia E. McGoldrick ◽

Sergiusz Józwiak ◽

...

Keyword(s):

Adverse Events ◽

Pediatric Patients ◽

Safety Data ◽

Adjunctive Treatment ◽

Eslicarbazepine Acetate ◽

Serious Adverse Events ◽

Double Blind ◽

Focal Seizures ◽

Clear Dose Response ◽

Cluster Seizures

Objective: To evaluate the safety and tolerability of adjunctive eslicarbazepine acetate (ESL) in pediatric patients (aged 4-17 years) with refractory focal seizures. Methods: Pooled safety data from patients aged 4-17 years in Study 208 (NCT01527513) and Study 305 (NCT00988156) were analyzed. Both were randomized, double-blind, placebo-controlled studies of ESL as adjunctive treatment in pediatric patients with refractory focal seizures receiving 1 or 2 antiepileptic drugs. Incidences of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), TEAEs leading to discontinuation, and TEAEs of special interest were evaluated. Results: The safety population comprised 362 patients (placebo, n = 160; ESL, n = 202). The overall incidence of TEAEs was similar between the ESL (67.8%) and placebo groups (65.6%), with no clear dose-response relationship. The most frequently reported TEAEs with ESL were headache, somnolence, vomiting, and diplopia. Overall incidences of SAEs and TEAEs leading to discontinuation were higher with ESL versus placebo (9.9% vs 5.0% and 5.9% vs 2.5%, respectively). The majority of SAEs with ESL occurred in Study 305. Two deaths were reported, 1 with ESL (0.5%) due to cluster seizures (resulting in herniation of the cerebellar tonsils) and 1 with placebo (0.6%) due to asphyxia. TEAEs related to allergic reaction, hyponatremia, hypothyroidism, cytopenia, seizure exacerbation, cognitive dysfunction, psychiatric disorders, or suicide occurred infrequently (<9%). Conclusion: Adjunctive ESL was generally well tolerated in children aged 4-17 years with focal seizures. The safety profile of ESL in children was comparable to that observed in adults.

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Perampanel in the treatment of partial seizures: Time to onset and duration of most common adverse events from pooled Phase III and extension studies

Epilepsy & Behavior ◽

10.1016/j.yebeh.2015.05.020 ◽

2015 ◽

Vol 48 ◽

pp. 45-52 ◽

Cited By ~ 19

Author(s):

David Ko ◽

Haichen Yang ◽

Betsy Williams ◽

Dongyuan Xing ◽

Antonio Laurenza

Keyword(s):

Adverse Events ◽

Phase Iii ◽

Partial Seizures ◽

Time To Onset

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Late immune-related adverse events in long-term responders to PD-1/PD-L1 checkpoint inhibitors: a multicentre study

10.1101/2020.04.09.20054031 ◽

2020 ◽

Author(s):

Olga Nigro ◽

Graziella Pinotti ◽

Federica De Galitiis ◽

Francesca Romana Di Pietro ◽

Raffaele Giusti ◽

...

Keyword(s):

Adverse Events ◽

Disease Progression ◽

Median Time ◽

Checkpoint Inhibitors ◽

Cumulative Risk ◽

Adjusted Risk ◽

Risk Of Death ◽

Risk Of Disease ◽

Time To Onset

AbstractData on spectrum and grade of immune-related adverse events (irAEs) in long-term responders to immune checkpoint inhibitors (ICI) are lacking.We performed a retrospective multicenter study to characterized irAEs occurring after a 12-months minimum treatment period with PD-(L)1 ICIs in advanced cancer patients. IrAEs were categorized into “early” (≤12 months) and “late” (>12 months).From September 2013 to October 2019, 436 consecutive patients were evaluated. 223 experienced any grade early-irAEs (51.1%), while 132 experienced any grade late-irAEs (30.3%) (p < 0.0001). Among the latter, 29 (22%) experienced a recurrence of an early-irAEs, while 103 (78%) experienced de novo late-irAEs involving different system/organ. Among patients with late-irAEs, 21 experienced G3/G4 irAEs (4.8%). Median time to onset of early-irAEs was 3.4 months (95%CI: 2.8-4.2), while the median time to onset of late-irAEs was 16.6 months (95%CI: 15.8-17.6). Cumulative time-adjusted risk of disease progression according to both the early-irAEs (HR = 0.63 [95%CI: 0.30-1.29], p = 0.204) and late-irAEs occurrence revealed no statistically significant differences (HR = 0.75 [95%CI: 0.37-1.56], p = 0.452). Also the time-adjusted cumulative risk of death according to both early-irAEs (HR = 0.79 [95%CI: 0.34-1.86], p = 0.598) and late-irAEs (HR = 0.92 [95%CI: 0.49-1.74], p = 0.811) did not show statistically significant differences.Although less frequent than early-irAEs, late-irAEs are quite common in long responders to PD-(L)1 ICIs, and are different in terms of spectrum and grade. Time-adjusted analysis revealed that the cumulative risk of disease progression and death were not significantly reduced in patients who experienced late-irAEs.

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An Open-Label, 8-Week Study of Safety and Efficacy of Pimavanserin Treatment in Adults with Parkinson’s Disease and Depression

Journal of Parkinson s Disease ◽

10.3233/jpd-202058 ◽

2020 ◽

Vol 10 (4) ◽

pp. 1751-1761

Author(s):

Daryl DeKarske ◽

Gustavo Alva ◽

Jason L. Aldred ◽

Bruce Coate ◽

Marc Cantillon ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Adverse Events ◽

Reuptake Inhibitor ◽

Adjunctive Therapy ◽

Rating Scale ◽

Depression Scale ◽

System Organ Class ◽

Hamilton Depression Scale ◽

Open Label

Background: Many patients with Parkinson’s disease (PD) experience depression. Objective: Evaluate pimavanserin treatment for depression in patients with PD. Methods: Pimavanserin was administered as monotherapy or adjunctive therapy to a selective serotonin reuptake inhibitor or serotonin/noradrenaline reuptake inhibitor in this 8-week, single-arm, open-label phase 2 study (NCT03482882). The primary endpoint was change from baseline to week 8 in Hamilton Depression Scale–17-item version (HAMD-17) score. Safety, including collection of adverse events and the Mini-Mental State Examination (MMSE) and Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale Part III (MDS-UPDRS III) scores, was assessed in patients who received ≥1 pimavanserin dose. Results: Efficacy was evaluated in 45 patients (21 monotherapy, 24 adjunctive therapy). Mean (SE) baseline HAMD-17 was 19.2 (3.1). Change from baseline to week 8 (least squares [LS] mean [SE]) in the HAMD-17 was –10.8 (0.63) (95% CI, –12.0 to –9.5; p < 0.0001) with significant improvement seen at week 2 (p < 0.0001) and for both monotherapy (week 8, –11.2 [0.99]) and adjunctive therapy (week 8,–10.2 [0.78]). Most patients (60.0%) had ≥50% improvement at week 8, and 44.4% of patients reached remission (HAMD-17 score ≤7). Twenty-one of 47 patients experienced 42 treatment-emergent adverse events; the most common by system organ class were gastrointestinal (n = 7; 14.9%) and psychiatric (n = 7; 14.9%). No negative effects were observed on MMSE or MDS-UPDRS Part III. Conclusion: In this 8-week, single-arm, open-label study, pimavanserin as monotherapy or adjunctive therapy was well tolerated and associated with early and sustained improvement of depressive symptoms in patients with PD.

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Safety, tolerability, and efficacy of brivaracetam as adjunctive therapy in patients with focal seizures, generalized onset seizures, or Unverricht–Lundborg disease: An open-label, long-term follow-up trial

Epilepsy Research ◽

10.1016/j.eplepsyres.2020.106526 ◽

2020 ◽

pp. 106526

Author(s):

Elinor Ben-Menachem ◽

Michel Baulac ◽

Seung Bong Hong ◽

Jody M. Cleveland ◽

Christoph Reichel ◽

...

Keyword(s):

Adjunctive Therapy ◽

Open Label ◽

Focal Seizures ◽

Long Term Follow Up

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Temporal characteristics of treatment-emergent adverse events and dose modifications with tivozanib and sorafenib in the phase 3 TIVO-3 study of relapsed or refractory mRCC.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4567 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4567-4567

Author(s):

Sumanta K. Pal ◽

David F. McDermott ◽

Bernard Escudier ◽

Thomas E. Hutson ◽

Camillo Porta ◽

...

Keyword(s):

Adverse Events ◽

Dose Reduction ◽

Phase 3 ◽

Temporal Characteristics ◽

Dose Modifications ◽

Time To Onset ◽

Improve Patient ◽

Insight Into ◽

Dose Reductions ◽

Clinical Trial Information

4567 Background: The randomized phase 3 TIVO-3 study met the primary endpoint of improved PFS with tivozanib (TIVO) vs sorafenib (SOR) in patients with relapsed/refractory mRCC with fewer dose reductions, interruptions and discontinuations despite a longer time on therapy. Greater insight into temporal characteristics of treatment-emergent adverse events (TEAEs) may enable proactive supportive care strategies and improve patient experience. Methods: Updated safety from the previously reported TIVO-3 study with a data cutoff August 15, 2019, was analyzed by treatment arm for time-to-onset (TTO, days [d]) of the most commonly reported TEAEs, and TTO of first dose reduction, interruption, and discontinuation occurring with TIVO and SOR. Duration of TEAE (median d and IQ range), and rate of dose reduction, interruption, or discontinuation due to the TEAE was calculated for each arm. Results: Patients in the safety analysis randomly assigned to TIVO (n = 173) or SOR (n = 170) received 11.9 and 6.7 cycles, or 336 and 192 mean days of treatment exposure, respectively. Incidence of any Gr, Gr >3, and TTO of any Gr TEAE of special interest occurring with >20% frequency in either arm is shown in Table 1. While TIVO was associated with less Gr>3 diarrhea, rash and PPE and more HTN than SOR, there were few differences in the TTO or duration of these TEAEs. Overall, dose reductions, interruptions, and discontinuations due to TEAEs were less frequent with TIVO than SOR, and TTO of first dose reduction (85 vs 45 d), interruption (81 vs 50 d), and discontinuation (114 vs 49 d) was longer for TIVO than SOR. Among those experiencing the same TEAE in either arm, resulting dose modifications were less frequent with TIVO than SOR. Conclusions: TIVO-3 demonstrated improved PFS with TIVO compared to SOR in mRCC, with longer duration of TIVO exposure, but fewer all Gr and Gr >3 TEAEs. Temporal characteristics of TEAEs were similar, but time to dose modifications was longer with TIVO than SOR. Among those with the same TEAEs, unmodified treatment was continued more often with TIVO than SOR. Clinical trial information: NCT02627963. [Table: see text]

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Abatacept as Adjunctive Therapy in Refractory Polymyalgia Rheumatica

The Journal of Rheumatology ◽

10.3899/jrheum.210455 ◽

2021 ◽

pp. jrheum.210455

Author(s):

Eric Toussirot ◽

Martin Michaud ◽

Daniel Wendling ◽

Valérie Devauchelle

Keyword(s):

Adverse Events ◽

Polymyalgia Rheumatica ◽

Adjunctive Therapy ◽

Substantial Proportion

Glucocorticoids (GCs) are the mainstay of treatment for patients with polymyalgia rheumatica (PMR).1 Despite their efficacy, GCs are associated with well-known adverse events and a substantial proportion of patients with PMR do not respond adequately, or are refractory, to initial GC treatment. GC-sparing agents in PMR are limited to methotrexate (MTX).1

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