Course Of Adverse Events Research Articles

Time course of adverse events in primary advanced or recurrent endometrial cancer treated with dostarlimab plus chemotherapy in the ENGOT-EN-6-NSGO/GOG-3031/RUBY trial.

Time course of adverse events in primary advanced or recurrent endometrial cancer treated with dostarlimab plus chemotherapy in the ENGOT-EN-6-NSGO/GOG-3031/RUBY trial.

Abstract 16245: Prevalence and Time Course of Adverse Events After a Biopsy Diagnosis of Antibody-Mediated Rejection in Pediatric Heart Transplant Recipients

Background: Antibody-mediated rejection (AMR) is of great relevance when assessing therapies to improve survival for pediatric heart transplant (HT). Biopsy (EMB) is the most specific means for diagnosing AMR. This study explores the impact on survival and adverse events after treated rejection (TRej) in children with AMR on EMB (any pAMR 1h or i, 2, or 3) vs acute cellular rejection (ACR). Methods: Children in the Pediatric HT Study transplanted between 1/2015-6/2022 who survived ≥2 weeks and had at least 1 TRej with EMB data were included. Survival was compared after 1st TRej with any AMR to pure ACR. Secondary outcomes of infection, malignancy, and cardiac allograft vasculopathy (CAV) after 1st TRej were assessed. Risk factors for mortality after AMR were identified using Cox proportional hazard modeling. Results: Among 3172 HT recipients, 906 (29%) had at least 1 TRej. Of these, 697 (77%) had EMB data to determine the presence of AMR. At the 1st TRej episode, 261 (37%) children had features of AMR. Median time to 1st Trej was earlier in those with AMR vs ACR, 0.11 vs 0.29 yrs. p=0.001. Survival after 1st TRej with AMR was worse than ACR in the 1st yr post HT (A); however, survival was similar when 1st TRej occurred after year 1 (B) (Figure 1 A, B). The AMR group had higher panel reactive antibody at HT, more congenital heart disease (CHD), and more had ABO incompatible HT (all p<0.05). There was no difference in time to 1st infection, malignancy, or CAV between those with treated AMR vs ACR. Multivariate predictors of graft loss after AMR were younger age, CHD, and ECMO at HT, and hemodynamic compromise at TRej (all p<0.048). Neither AMR grade nor concomitant ACR was associated with graft loss after AMR. Conclusion: This is the largest analysis of contemporary outcomes of EMB-confirmed AMR in pediatric HT. Findings underscore the impact of early AMR on graft loss and the need for tailored therapies. Similar time to infection after AMR vs ACR is notable since immune targets of therapy often differ.

Timelines of adverse event journeys of LVAD patients.

The INTERMACS Events data set contains an expansive collection of temporal evidence of the course of adverse events (AEs) of >15 000 patients that have received a left ventricular assist device (LVAD). The chronology of AEs may contain insightful information of the "AE journeys" of LVAD patients. The purpose of this study is to investigate the timelines of AEs within the INTERMACS database. Descriptive statistics were applied to 86 912 recorded AEs of 15 820 patients with a continuous flow-LVAD between 2008 to 2016, extracted from INTERMACS registry. The characteristics of the timelines of AE journeys were investigated by posing six descriptive research questions. The analysis revealed several time-related characteristics and patterns of the AE journey after LVAD including the most common time of occurrences of AEs after surgery, duration of AEs journeys, the time of first and last AEs, and the time gaps between AEs. The INTERMACS Event dataset is a valuable resource for research about the timeline of AE journeys of patients who received an LVAD. It is necessary for future studies to first explore and consider the time-related characteristics of the data set such as diversity and sparsity to effectively choose an appropriate scope of time and time granularity and to acknowledge potential challenges.

In search of similarity in adverse events journeys of patients with left ventricular assist devices

ObjectiveThe Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) Event data set contains an expansive collection of longitudinal evidence of the course of adverse events (AEs) of >15,000 patients who have received a left ventricular assist device (LVAD). Buried in the huge Event data set is knowledge that can provide a deeper understanding of the patterns of the “AE journey” of patients with LVAD. Thus, the goal of this study was to examine the Event data set from a comprehensive perspective to identify unique relationships and patterns of AEs, alert potential challenges, and suggest future research directions. MethodsA sequential pattern mining algorithm called SPADE (ie, Sequential PAttern Discovery using Equivalence classes) was applied to 86,912 recorded AEs of 15,820 patients with a continuous-flow LVAD between 2008 and 2016, extracted from the publicly accessible INTERMACS registry. The patterns of AE journey were investigated by posing 5 descriptive research questions about most common types of AE, concomitant AEs, AE sequences, AE subsequences, and interesting relations between AEs. ResultsThe analysis revealed several characteristics of patterns of the AE journey of patients who received an LVAD that accounts for the types and temporal ordering of successive AEs, combinations of AEs, and their timing after surgery. ConclusionsThe high diversity and sparsity of the types and timing of AE occurrences make the AE journeys of patients dissimilar from each other, impeding the discovery of highly-patterned AE journeys among the patients. This study suggests 2 salient directions for future studies to tackle this issue using cluster analysis to cluster patients into more similar groups and translate these results into a practical clinical tool to forecast the next AE based on the history of previous AEs.

Longitudinal Course of Adverse Events With Esketamine Nasal Spray: A Post Hoc Analysis of Pooled Data From Phase 3 Trials in Patients With Treatment-Resistant Depression.

Objective: To describe the tolerability of esketamine nasal spray based on the adverse event profile observed during treatment sessions occurring early and later over the course of treatment.Methods: In 2 long-term, phase 3 studies (NCT02493868, October 1, 2015-February 16, 2018; NCT02497287, September 30, 2015-October 28, 2017), patients with treatment-resistant major depressive disorder (per DSM-5) and nonresponse to ≥ 2 oral antidepressants received esketamine nasal spray (56 or 84 mg) twice weekly during a 4-week induction phase, weekly for weeks 5-8, and weekly or every 2 weeks thereafter as maintenance treatment, in conjunction with a new oral antidepressant. A post hoc analysis using descriptive statistics evaluated occurrence (incidence, frequency, severity) and recurrence (incidence and severity) of events of specific interest.Results: In patients treated with esketamine nasal spray plus a newly initiated oral antidepressant (n = 928), spontaneously reported adverse events of dizziness, nausea, sedation, vertigo, and increased blood pressure were more likely to recur after the first week of treatment if they occurred more frequently (twice > once > none) during the first week. The same pattern was observed when these events were assessed by structured instruments. Incidences of dizziness, dissociation, increased blood pressure, nausea, vertigo, and sedation were highest in week 1 of treatment (20.6%, 16.7%, 4.3%, 14.0%, 12.1%, and 3.8%, respectively) and decreased thereafter. Initial occurrences and subsequent recurrences of events were mostly mild or moderate in severity.Conclusions: Adverse events during treatment with esketamine nasal spray plus an oral antidepressant generally become less frequent with ongoing treatment, and the majority are mild or moderate in severity.Trial Registration: ClinicalTrials.gov identifiers: NCT02493868; NCT02497287.

1360MO Quality of life and patient-relevant endpoints with darolutamide in the phase III ARASENS study

In ARASENS, darolutamide (DARO) + androgen-deprivation therapy (ADT) + docetaxel significantly reduced risk of death by 32.5% vs placebo (PBO) + ADT + docetaxel (HR 0.68, 95% CI 0.57–0.80) in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC). Given the potentially long treatment duration, the impact of DARO + ADT + docetaxel on pt-relevant endpoints is important to assess. Pts were randomized 1:1 to DARO 600 mg twice daily or PBO + ADT + docetaxel. Pt-relevant endpoints were all-cause and prostate cancer related death; time course of adverse events (AEs) of special interest; and quality of life (QoL) based on time to worsening (TTW) of disease-related physical symptoms. In the safety analysis set (n=1302), the DARO + ADT + docetaxel arm (n=652) had fewer all-cause deaths (35.1% vs 46.8%) and prostate cancer related deaths (26.1% vs 36.0%) vs the PBO + ADT + docetaxel arm (n=650). Despite longer treatment exposure with DARO vs PBO (median 41.0 vs 16.7 months), overall AE incidence was similar in the 2 arms. Fatigue (DARO 33.1%, PBO 32.9%) and rash (16.6%, 13.5%) appeared predominantly in treatment months 1–3 and incidence decreased rapidly thereafter. Cumulative incidences of falls, fractures, and mental impairment were low (<10%) and similar between arms. The incidence of cardiac disorders was constant over time and similar between arms (DARO 10.9%, PBO 11.7%). Incidence of hypertension was 13.7% vs 9.2%, with similar distribution over time. Most pts had high baseline QoL scores that were maintained over time, with comparable TTW in both arms.Table: 1360MOPopulationEvents, n/N* (%)HR95% CI†DAROPBOOverall351/651 (53.9)308/654 (47.1)1.040.89, 1.22ALP ≥ULN176/361 (48.8)154/363 (42.4)0.980.79, 1.22Bone metastases275/517 (53.2)248/520 (47.7)1.020.86, 1.21Visceral metastases59/111 (53.2)54/118 (45.8)1.040.72, 1.51Baseline pain score >0183/374 (48.9)153/360 (42.5)1.000.80, 1.24 Open table in a new tab Early treatment intensification with DARO + ADT + docetaxel improved pt-relevant endpoints, with reduced all-cause and prostate cancer related deaths and similar incidences and time course for most AEs of special interest vs PBO + ADT + docetaxel, notably with no increase in cardiac disorders. QoL was maintained over time, and DARO had no adverse impact on QoL, including in pts with poor prognosis.

Profile analysis of adverse events after boron neutron capture therapy for head and neck cancer: a sub-analysis of the JHN002 study.

The purpose of this study was to outline the course and profile of adverse events specific to boron neutron capture therapy (BNCT) for head and neck cancer. This was a sub-analysis of the phase II JHN002 trial. Patients received 400 mg/kg borofalan(10B), followed by neutron irradiation. The course of adverse events after BNCT was documented in the JHN002 Look Up study. Patients were grouped into face/front (FF), face/lateral (FL) and neck (N) beam groups according to the point of skin incidence of the epithermal neutron beam axis, and the profile of adverse events dependent on beam incidence position was examined. The courses of adverse events in eight recurrent squamous cell carcinoma (R-SCC) and 13 recurrent or locally advanced non-SCC cases were analyzed. Median interval to complete recovery was 23 days (interquartile range (IQR), 14–48 days) for oral mucositis, 40 days (IQR, 24–56 days) for dermatitis, 58 days (IQR, 53–80 days) for dysgeusia and 156 days (IQR, 82–163 days) for alopecia. In the FF beam group, parotitis (P = 0.007) was less frequent, while oral mucositis (P = 0.032), fatigue (P = 0.002), conjunctivitis (P = 0.001), epistaxis (P = 0.001) and abdominal discomfort (P = 0.029) tended to be more frequent than in the FL and N beam groups. Courses and irradiation site-specific profiles of adverse events in BNCT for head and neck cancer were identified. This profile may be useful for considering interventions to prevent exacerbation of treatment-related adverse events on BNCT.

Time course of adverse events – descriptive data analysis of a schizophrenia relapse prevention trial of cariprazine

Time course of adverse events – descriptive data analysis of a schizophrenia relapse prevention trial of cariprazine

630P Time course profile of adverse events of interest and serious adverse events with darolutamide in the ARAMIS trial

Men with nonmetastatic castration-resistant prostate cancer (nmCRPC) are generally asymptomatic and may receive prolonged treatment with androgen receptor inhibitors (ARIs). Understanding the burden and time course of adverse events (AEs) commonly associated with ARIs that may impact patients’ daily life will help inform optimal treatment selection for men with nmCRPC. We present analyses of time to AEs of interest associated with some ARIs (fatigue, falls, fracture, hypertension, mental impairment, and rash) and the cumulative incidence of these AEs, grade 3/4 AEs, and serious AEs from ARAMIS.

1137P Incidence and time course of adverse events (AEs) with atezolizumab (A) in combination with vemurafenib (V) and cobimetinib (C) in the phase III IMspire150 study

The phase III IMspire150 study (NCT02908672) demonstrated improved progression-free survival with first-line A vs placebo (P) combined with V+C in patients (pts) with BRAFV600 mutation–positive advanced melanoma. Safety profiles of A and V+C partially overlap. Here we report incidence, time course, and outcomes of select AEs of special interest (AESIs) in IMspire150. 514 pts were randomized 1:1 to A+V+C or P+V+C. Pts received V+C from cycle 1; A or P was added from cycle 2 onward. Incidence (overall and by cycle), time to onset/resolution, and recurrence of select AESIs were evaluated in the safety population (A+V+C, n=230; P+V+C, n=281). Rash and hepatitis were analyzed as overall combined medical concepts. Median follow-up was 18.9 mo. AESI rates were numerically higher with A+V+C vs P+V+C (rash, 81% vs 77%; elevated creatine phosphokinase [eCPK], 53% vs 47%; pyrexia, 49% vs 35%; and hepatitis [clinical diagnosis and asymptomatic lab abnormalities], 53% vs 38%), excepting diarrhea (50% vs 56%). Incidences of diarrhea, rash, and eCPK were highest in cycle 1 and decreased thereafter. Incidences of pyrexia and hepatitis peaked in cycle 2 after addition of A in the A+V+C arm then similarly declined. Median time to onset was similar with A+V+C vs P+V+C for diarrhea (0.4 vs 0.4 mo) and rash (0.5 vs 0.4 mo), but was numerically longer with A+V+C for eCPK (1.4 vs 0.7 mo), pyrexia (1.2 vs 0.7 mo), and hepatitis (1.6 vs 1.2 mo). Median time to resolution was similar between arms (diarrhea, 0.3 vs 0.2 mo; rash, 0.8 vs 0.8 mo; eCPK, 0.5 vs 0.5 mo; pyrexia, 0.1 vs 0.1 mo; hepatitis, 0.7 vs 0.7 mo). In pts who had first occurrence of an AESI with A+V+C vs P+V+C, incidences of recurrent AESIs were diarrhea (58/115 vs 64/157), rash (65/187 vs 62/215), eCPK (62/121 vs 61/133), pyrexia (53/112 vs 29/98), and hepatitis (38/122 vs 25/107). Recurrent AESIs were generally grade 1/2 with median times to recurrence of 0.8-1.5 mo. These data indicate that key AESIs with A+V+C occur early during treatment; are manageable, with resolution times similar to those with V+C; and have low to moderate risk of recurrence. Recurrent AESIs are generally mild to moderate in severity with no evidence of cumulative effect.

Course of Adverse Events during Short Treatment Regimen in Patients with Rifampicin-Resistant Tuberculosis in Burundi.

The introduction of the nine-month short-treatment regimen (STR) has drastically improved outcomes of rifampicin-resistant tuberculosis (RR-TB) treatment. Adverse events (AE) commonly occur, including injectable-induced hearing loss. In Burundi we retrospectively assessed the frequency of adverse events and treatment modifications in all patients who initiated the STR between 2013–2017. Among 225 included patients, 93% were successfully treated without relapse, 5% died, 1% was lost-to-follow-up, 0.4% had treatment failure and 0.4% relapsed after completion. AE were reported in 53%, with grade 3 or 4 AE in 4% of patients. AE occurred after a median of two months. Hepatotoxicity (31%), gastro-intestinal toxicity (22%) and ototoxicity (10%) were most commonly reported. One patient suffered severe hearing loss. Following AE, 7% of patients had a dose reduction and 1% a drug interruption. Kanamycin-induced ototoxicity led to 94% of modifications. All 18 patients with a modified regimen were cured relapse-free. In this exhaustive national RR-TB cohort, RR-TB was treated successfully with the STR. Adverse events were infrequent. To replace the present STR, all-oral regimens should be at least as effective and also less toxic. During and after transition, monitoring, management, and documentation of AE will remain essential.

Everolimus plus exemestane in hormone-receptor-positive, HER2-negative locally advanced or metastatic breast cancer: incidence and time course of adverse events in the phase IIIb BALLET population

The addition of everolimus to exemestane therapy significantly improves progression-free survival in postmenopausal patients with hormone-receptor (HR)-positive HER2-negative endocrine-resistant breast cancer. However, the safety profile of this schedule still might be optimized. Patients included in the BALLET trial were assessed. The objectives of this analysis were to provide additional information on the safety profile of this schedule depending on prior anticancer therapies and to characterize the time course of adverse events (AEs) and serious AEs (SAEs) of clinical interest throughout the study period. Non-infectious pneumonitis (NIP), stomatitis, asthenia and weight loss were selected as AEs of clinical interest. The safety population of this analysis comprised 2131 patients. There were similar incidences of AEs and SAEs of clinical interest regardless of previous anticancer therapies. Most stomatitis and asthenia events occurred within the first three months. Incidence of weight loss appeared to plateau except in the case of grade 3-4 events, which occurred rarely. The incidence of any grade NIP (between 2 to 6%) and grade 3-4 NIP (between 0 to 1%) was low across the study, but steady. Everolimus plus exemestane is a well-known therapeutic option for aromatase inhibitor pretreated advanced breast cancer patients, and its toxicity profile is similar to that described in previous studies. Close monitoring, especially within the first three months, early intervention with preventive measures and patient education to help recognize the first signs and symptoms of AEs, will help to reduce their incidence and severity.

PD-0030 - Time Course of Adverse Events in the Velour Trial

1 and 2 adverse events (AEs); including diarrhea (50%), fatigue (40%), nausea (20%), pyrexia (20%), anemia (20%), constipation (10%), pain (10%), and dyspnea (10%). No infusion reaction AEs were reported. 3 patients reported grade 3 AEs; including abdominal abscess (10%), anemia (10%), hyponatremia (10%), increased gamma-glutamyltransferase (10%), increased white blood cell count (10%), and intestinal obstruction (10%). No grade 4 AEs have been reported; 3 patients reported unrelated SAEs consisting of intestinal obstruction (n = 1), convulsion (n = 1), and pyrexia (n = 1, occurred twice). Preliminary PK data show that MLN0264 exposure appears greater at increased dose levels. Conclusion: These preliminary data indicate that MLN0264 appears to be generally well tolerated and not associated with infusion reactions within the five dose-escalation

Time course of regorafenib-associated adverse events in the phase III CORRECT study.

467 Background: Regorafenib (REG) is an oral multikinase inhibitor that has recently demonstrated significant overall survival benefit vs placebo in the randomized phase III CORRECT study. We examined the time course of adverse events (AEs) in the CORRECT study. Methods: Regorafenib (REG) is an oral multikinase inhibitor that has recently demonstrated significant overall survival benefit vs placebo in the randomized phase III CORRECT study. We examined the time course of adverse events (AEs) in the CORRECT study. Results: The safety population comprised 753 patients (pts): REG n=500; placebo n=253. The mean treatment duration was 12.1 ± 9.7 weeks in the REG group and 7.8 ± 5.2 weeks in the placebo group. Treatment-emergent AEs occurred at any grade in 99.6% of REG pts and 96.8% of placebo pts, at grade 1/2 in 21.6% and 47.8%, respectively, at grade 3 in 56.0% and 26.5%, respectively, and at grade 4/5 in 22.0% and 22.5%, respectively. AEs occurring in ≥10% more REG than placebo pts were fatigue, hand–foot skin reaction (HFSR), anorexia, diarrhea, weight loss, voice changes, hypertension, rash/desquamation, oral mucositis, fever, hyperbilirubinemia, low platelet count. The most frequent AEs deemed to be regorafenib related were HFSR, fatigue, diarrhea, hypertension, and rash/desquamation. The frequency of these AEs over time is shown in the Table. The incidence of HFSR, fatigue, hypertension, and rash/desquamation peaked in cycle 1 and tapered to a relatively stable lower incidence over later cycles. The incidence of diarrhea remained relatively constant throughout treatment. AEs led to dose modification in 66.6% of pts in the REG group and 22.5% in the placebo group. Data on dose intensity across treatment cycles will be presented. Conclusions: In the CORRECT trial, the incidences of the most common AEs in the REG group peaked early during treatment. There appeared to be no evidence for cumulative toxicity of REG. Clinical trial information: NCT01103323. [Table: see text]

Adverse Events Associated with Azathioprine Treatment in Korean Pediatric Inflammatory Bowel Disease Patients

PurposeThis study was aimed to evaluate the frequency and course of adverse events associated with azathioprine treatment in Korean pediatric patients with inflammatory bowel disease.MethodsTotal of 174 pediatric patients (age range, 1 to 19 years) with inflammatory bowel disease who received azathioprine in order to maintain remission at Samsung Medical Center (Seoul, Korea) from January 2002 through December 2012 were included in this study. Medical records of these subjects were retrospectively reviewed regarding the development of adverse events associated with azathioprine treatment.ResultsNinety-eight patients (56.3%) of 174 patients experienced 136 episodes of adverse events, requiring dose reduction in 31 patients (17.8%), and discontinuation in 18 patients (10.3%). The mean dose of azathioprine that had been initially administered was 1.32±0.42 mg/kg/day. Among the adverse reactions, bone marrow suppression developed in 47 patients (27.0%), requiring dose reduction in 22 patients (12.6%) and discontinuation in 8 patients (4.6%). Other adverse events that occurred were gastrointestinal disturbance (15.5%), hair loss (12.1%), pancreatitis (7.5%), arthralgia (6.9%), hepatotoxicity (2.9%), skin rash/allergic reactions (2.9%), headache/dizziness (2.3%), sepsis (0.6%), and oral mucositis (0.6%).ConclusionBone marrow suppression, especially leukopenia was most commonly associated with azathioprine treatment in Korean pediatric inflammatory bowel disease patients. Close observation for possible adverse events is required in this population with inflammatory bowel diseases who are under treatment with azathioprine.

Risk Management in the Treatment of Malignant Gliomas with BCNU Wafer Implants

Implantation of BCNU wafers (Gliadel®) into the resection cavity has demonstrated a survival benefit for patients with newly diagnosed malignant gliomas. The follow-up of two phase III trails has further shown that the number of long-term survivors was significantly increased by BCNU wafer treatment. BCNU wafer implantation may be integrated into current multimodal first line strategies. In the setting of recurrent disease BCNU wafer implantation has also shown a survival benefit and now extends the treatment options in a patient population that typically has undergone extensive pretreatment. An analysis of the literature has helped to clearly identify the risks associated with topic BCNU treatment. Here we summarize the incidence and time course of adverse events associated with local chemotherapy and propose solutions. The growing body of experience with BCNU wafer implantation may serve as a basis to develop adequate risk management strategies with regard to patient selection, surgical techniques, and follow-up schedules.

Time course of adverse events most commonly associated with topiramate for migraine prevention

The efficacy, safety and tolerability of topiramate has been demonstrated in three large multicenter, randomized, double-blind, placebo-controlled trials. To characterize the time course of adverse events (AEs) that led to treatment discontinuation in >/=2% of patients who received topiramate 100 mg/day during three pivotal, multicenter, randomized, double-blind, placebo-controlled, and 26-week trials. The pooled population comprised all randomized patients who reported safety data during the double-blind phase (topiramate 100 mg/day, n = 386; placebo n = 372), which consisted of a 4-week titration period and a 22-week maintenance period. Incidence, time to onset, and cumulative mean rate of AEs were assessed. Overall, AEs led to treatment discontinuation in 24.9% of patients receiving topiramate 100 mg/day and 11.0% receiving placebo (P < 0.001). AEs leading to discontinuation during the double-blind phase in > or =2% of patients included paresthesia (8.0% discontinued), any cognitive symptoms (7.3% discontinued), fatigue (4.7% discontinued), insomnia (3.4% discontinued), nausea (2.3% discontinued), loss of appetite, anxiety, and dizziness (2.1% discontinued because each AE). Most AEs began during the titration period. Paresthesia, any cognitive symptoms, nausea, and loss of appetite occurred at a higher rate in the topiramate group than in the placebo group (P < 0.01). AEs leading to discontinuation of topiramate are probably to occur during dose titration. If a patient has not experienced one of these AEs within the first 6 weeks of initiating topiramate 100 mg/day, these AEs are unlikely to occur.

What Happens With Adverse Events During 6 Months of Treatment With Selective Serotonin Reuptake Inhibitors?

Although adverse events are a key factor in compliance, their evolution during treatment with antidepressants is poorly documented. Therefore, the time course of adverse events during 6 months of antidepressant treatment was investigated. 85 psychiatric outpatients with a DSM-IV diagnosis of major depressive disorder (with the exclusion of other DSM-IV Axis I disorders) were enrolled between September 2002 and March 2003 in a multicenter, randomized, double-blind trial with selective serotonin reup-take inhibitors (fluoxetine [N = 42] and paroxetine [N = 43]). At each visit, the presence and severity of treatment-emergent adverse events were assessed systematically using the UKU Side Effect Rating Scale (UKU). General linear mixed modeling was used to investigate the predictors of the time course of adverse events. Overall, the number of at least moderately severe adverse events decreased with time. More severely depressed patients reported overall more (at least moderately severe) adverse events than less severely depressed patients (p = .0002), but the decrease in reported adverse events was comparable over time. Men (N = 30) and women (N = 55) reported initially the same number of at least moderately severe adverse events, but the habituation was more rapid in men (p < .0001). Completers (N = 58) and dropouts (N = 27) did not differ initially, but completers' habituation was more rapid (p = .014). The habituation of adverse events was also more rapid in recurrent than in first-episode patients but only in men (p = .0025). The time course of adverse events varies with the severity of depression, sex, completer or dropout status, and recurrent versus first-episode depression.

Time Course of Adverse Events in Patients with Localization‐related Epilepsy Receiving Topiramate Added to Carbamazepine

To explore the time course of treatment-emergent adverse events (AEs) during topiramate (TPM) adjunctive therapy. Post hoc analyses were performed by using data from a large (264 subjects) multicenter, double-blind, placebo-controlled trial in which 200 mg/day TPM was added to carbamazepine (CBZ) with or without another antiepileptic drug (AED) in adults with treatment-resistant partial-onset seizures. The daily incidence and mean duration of the most common (> or =5% incidence) AEs were calculated for patients completing the 12-week study. The daily incidence of somnolence, headache, loss of appetite, nervousness, fatigue, dizziness, upper respiratory tract infection, and vertigo peaked during titration and declined to rates similar to that of placebo after the target TPM dose had been reached. In contrast, the daily incidence of paresthesia increased during titration and was maintained for the study duration. Relatively few patients had cognitive symptoms (9% with TPM, 5% with placebo), but these were the most common AEs associated with treatment discontinuation. Patient/investigator reports of weight loss increased gradually over the course of the trial, corresponding with the pattern of change in weight measured at study visits. This study demonstrates that most of the more common AEs with TPM adjunctive therapy are transient. Patients can be counseled that most AEs emerging when TPM is initially added to CBZ can be expected to diminish with continued therapy.