Impact Of Concomitant Medications Research Articles

Real-world analysis of levetiracetam-associated rhabdomyolysis: insights from the FDA adverse event reporting system

ABSTRACT Background Levetiracetam, a widely prescribed antiseizure medication, is recognized for its broad-spectrum efficacy, good tolerability, and minimal drug interactions. This study examines the association between levetiracetam and rhabdomyolysis, utilizing real-world data from the FDA Adverse Event Reporting System (FAERS) database to further elucidate its safety profile. Methods This study extracted adverse events related to levetiracetam from the FAERS database (Q1 2013 to Q1 2024). Four types of disproportionality analysis identified rhabdomyolysis as a significant adverse event. Logistic regression assessed risk factors, including gender, age, and severity. A Gaussian Mixture Model analyzed the time-to-onset distribution of rhabdomyolysis, while the impact of concomitant medications on its risk was evaluated using Reporting Odds Ratio (ROR). Results Levetiracetam significantly increased rhabdomyolysis risk (ROR = 13.5). Males showed a higher incidence (OR = 2.60). Most adverse events occurred within the first 30 days, with a bimodal onset distribution. Co-administration of antibiotics, antipsychotics, and PPIs elevated the risk while other antiseizure medications did not. Conclusion This study found a significant association between levetiracetam and the risk of rhabdomyolysis, highlighting the need for increased clinical vigilance in this patient population. Future research should focus on elucidating the underlying mechanisms and optimizing clinical guidelines.

No Impact of Concomitant Medications on Efficacy and Safety of Biologics and Small Molecules for Ulcerative Colitis

While participants with inflammatory bowel diseases (IBD) in clinical trials of biologics and small molecule drugs (henceforth, advanced therapies) frequently receive several medications concomitantly, it is unclear how they modify treatment effect. Through an individual patient data pooled analysis of ten clinical trials of advanced therapies for moderate-to-severe ulcerative colitis (UC), we assessed whether concomitant exposure to corticosteroids, immunomodulators, 5-aminosalicylates, proton pump inhibitors (PPIs), histamine receptor antagonists (H2RA), opiates, antidepressants, and antibiotics modified the effect of the intervention on treatment efficacy and safety outcomes, using modified Poisson regression model. Of 6044 patients (4280 receiving intervention, 1764 receiving placebo), several received concomitant corticosteroids (47%), immunomodulators (28%), 5-aminosalicylates (68%), PPIs (14%), H2RAs (2%), opiates (7%), antidepressants (6%), and/or antibiotics (5%). After adjusting for confounders and examining treatment efficacy of intervention vs. placebo, we observed no impact of concomitant exposure to corticosteroids (ratio of relative risk of drug vs. placebo with vs. without concomitant exposure: RRR, 0.81 [95% CI,0.63-1.06], 5-aminosalicylates (RRR, 1.04[0.78-1.39]), PPIs (RRR, 0.87 [0.61-1.22]), H2RAs (RRR, 1.72[0.97-14.29]), opiates (RRR, 0.90[0.54-1.49]), antidepressants (RRR, 1.02[0.57-1.83]), and antibiotics (RRR, 0.72[0.44-1.16]) on likelihood of clinical remission. Concomitant exposure to immunomodulators was associated with lower likelihood of achieving clinical remission (RRR, 0.73[0.55-0.97]), particularly with non-TNF antagonists. In clinical trials of advanced therapies for UC, baseline concomitant exposure to multiple commonly used class of medications does not impact treatment efficacy or safety. These findings directly inform design of regulatory clinical trials with respect to managing concomitant medications at baseline.

PPIs therapy has a negative impact on the clinical outcomes of advanced SCLC patients treated with PD-L1 inhibitors

BackgroundProgrammed death-ligand 1 (PD-L1) inhibitors has emerged as a first-line therapeutic strategy for advanced small cell lung cancer (SCLC), which can stimulate T-cell activation, thereby preventing tumor avoidance of immunologic surveillance, whereas, proton pump inhibitors (PPIs) can play an important role in regulating immune function. This study assessed whether the concomitantly use of PPIs affected outcomes of immunotherapy in advanced SCLC.MethodsData from advanced SCLC patients who firstly treated with PD-L1 inhibitors between July 2018 and February 2021 was retrospectively analyzed. The impact of concomitant medications (especially PPIs) on objective response rate, progression-free survival (PFS) and overall survival (OS) were evaluated.ResultsOf 208 patients, 101 received immunotherapy concomitant PPIs. The median PFS of patients receiving PPIs (6.6 months) were significantly shorter than those without PPIs (10.6 months), and so was OS. There was associated with a 74.9% increased risk of progression and 58.3% increased risk of death. Both first-line and post-first-line immunotherapy, patients treated PPIs had poorer PFS.ConclusionPPIs therapy has a negative impact on the clinical outcomes of advanced SCLC patients treated with PD-L1 inhibitors.

Methotrexate-related adverse events and impact of concomitant treatment with folic acid and tumor necrosis factor-alpha inhibitors: An assessment using the FDA adverse event reporting system.

Methotrexate (MTX) is an essential anti-rheumatic drug used to treat rheumatoid arthritis (RA). Prevention or management of adverse reactions, including interstitial lung disease (ILD), hepatotoxicity, myelosuppression, and infection, remains fundamental for safe MTX therapy. Using the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) (JAPIC AERS), we performed disproportionality analyses of adverse events related to MTX use and the impact of concomitant medications. Upon analyzing all reported cases in FAERS between 1997 and 2019, the crude reporting odds ratios (cRORs; 95% confidence intervals) for ILD, hepatotoxicity, myelosuppression, and tuberculosis (TB) in relation to MTX use were 4.00 (3.83-4.17), 1.99 (1.96-2.02), 3.66 (3.58-3.74), and 7.97 (7.65-8.3), respectively. Combining MTX with folic acid (FA) or tumor necrosis factor-alpha inhibitors (TNFis) tended to reduce cRORs for these adverse events (except for TB). Multiple logistic regression analysis in patients with RA was conducted to calculate adjusted reporting odds ratios (aRORs) for age, sex, and MTX treatment patterns (MTX alone and combined with FA and TNFi). Higher age (except for hepatotoxicity) and male sex were significantly associated with adverse events. Combining FA or TNFi with MTX reduced aRORs for MTX-related hepatotoxicity and myelosuppression; in contrast, the effect of FA was not obvious in ILD or TB. Although studies assessing spontaneous reporting systems have limitations such as reporting bias, data from our logistic regression analysis demonstrated that adding FA to MTX-based therapy could help reduce the dose-dependent adverse events of MTX, thereby providing clinical evidence that supports the beneficial effect of FA. This study also demonstrated the usefulness of FAERS in comparing adverse events based on treatment patterns.

Abstract 13467: Using Data Analytics Toward Precision Warfarin Dosing in Children With Heart Disease

Introduction: Warfarin is the most common anticoagulant used in children with heart disease. Multiple factors make initial warfarin dose selection and management subjective and variable in children. This variability increases hospital length of stay and impacts efficacy and safety. We sought to develop a data-driven tool to optimize time to warfarin goal dose in children with heart disease. Methods: We collected all demographic and clinical data for all patients <18 years who received warfarin at our institution. We developed a warfarin sensitivity metric (Δ International Normalized Ratio (INR)/mg warfarin) to assess individual medication processing and characterize influential factors. Each inpatient interaction with warfarin was analyzed to assess the impact of concomitant medications, hepatic impairment, and procedure type on dosing, sensitivity, and resultant INR. A linear regression model was formulated to predict ending warfarin dose based on these influential factors. Results: A total of 714 patients were identified; 334 patients met inclusion criteria, and 447 unique encounters with warfarin were analyzed. Warfarin sensitivity was 94.3% higher in patients receiving major anticoagulation enhancing drugs and 13.6% higher in patients with minor liver injury. Patients undergoing a Fontan procedure had increased warfarin sensitivity compared to other procedures; 60% and 66% increase from ventricular assist device and valve replacement, respectively. A linear regression model was used to predict a patient’s warfarin ed dose based on age, baseline INR, other medications, liver injury, and Fontan procedure status. The Fontan binary indicator and age were the most impactful in predicting end dose with an adjusted R 2 of 0.1792. Conclusions: We have identified multiple factors that could affect individualized warfarin. Further analysis will refine our warfarin sensitivity metric and finalize and validate our tool to allow accurate and efficient warfarin dose prediction.

Impact of concomitant medication on clinical outcomes in patients with advanced non-small cell lung cancer treated with immune checkpoint inhibitors: A retrospective study.

BackgroundIt has recently been suggested that concomitant medication may affect the clinical outcome of patients treated with immune checkpoint inhibitors (ICIs). However, only a few studies on the impact of concomitant medication on immune‐related adverse events (irAEs) have previously been reported. Here, we aimed to determine the impact of concomitant medication on the efficacy and safety of ICIs.MethodsWe retrospectively analyzed the data of 300 patients treated with nivolumab or pembrolizumab for advanced non‐small cell lung cancer (NSCLC) between January 2016 and July 2018. Multivariate logistic regression analysis was used to assess the effect of concomitant medication on treatment response or irAEs. A multivariate Cox proportional hazards model was used to evaluate concomitant medication‐related factors associated with time‐to‐treatment failure or overall survival (OS).ResultsA total of 70 patients responded to treatment and 137 experienced irAEs. The response rate and incidence of irAEs in patients treated with ICIs were not significantly associated with concomitant medication. Multivariate analysis showed that the use of opioids was an independent factor (time‐to‐treatment failure: hazard ratio 1.39, p = 0.021, OS: hazard ratio 1.54, p = 0.007).ConclusionsThe efficacy and safety of nivolumab or pembrolizumab in the treatment of patients with advanced NSCLC were not significantly influenced by concomitant medication. However, opioid usage might be associated with shorter OS in patients treated with these ICIs. Further mechanistic investigations should explore whether these associations are purely prognostic or contribute to ICI resistance.

Impact of Concomitant Medications on Biochemical Outcome in Localised Prostate Cancer Treated with Radiotherapy and Androgen Deprivation Therapy

AimsSeveral classes of concomitant medications have been shown to affect oncological outcomes in patients with prostate cancer (PCa). We assessed the association between the use of commonly prescribed concomitant medications and biochemical relapse-free survival (bRFS) in patients with localised PCa treated with radiotherapy and androgen deprivation therapy (ADT). Materials and methodsA secondary pooled analysis of two phase III randomised trials was carried out. In the first trial, patients with localised PCa with clinical stage T1b-T3, prostate-specific antigen <30 ng/ml and Gleason score ≤7 were treated with radical radiotherapy and 6 months of ADT starting 4 months before or concomitantly with radiotherapy. In the second trial, patients with high-risk PCa were treated with radical radiotherapy and 36 months of ADT with randomisation to three-dimensional conformal or intensity-modulated radiotherapy. Information on concomitant medications was collected from the medical record. Univariable and multivariable Cox regression was used to identify factors associated with bRFS. ResultsOverall, 486 patients were evaluable. The median follow-up was 125 months; 10-year bRFS was 83.7%. On univariable analysis, receipt of metformin was significantly associated with worse bRFS. Ten-year bRFS was 73% and 85% for patients with and without concomitant metformin (adjusted hazard ratio 2.11, 95% confidence interval 1.03–4.33). Similar evidence of an association was observed with sulfonamide-based α1-receptor blockers (adjusted hazard ratio 2.72, 95% confidence interval 1.31–5.66). However, no such association was seen with receipt of quinazoline-based α1-receptor blockers (adjusted hazard ratio 1.09, 95% confidence interval 0.42–2.82). There was no significant association between bRFS and receipt of all other medication classes considered. ConclusionsIn this population of patients with localised PCa treated with radiotherapy and ADT, receipt of concomitant metformin and sulfonamide-based α1-receptor blockers was associated with inferior biochemical outcome. Randomised trials are required to assess the true effect of these medications on oncological outcomes in localised PCa.

549P - Impact of concomitant medications on disease free survival (DFS) and overall survival (OS) in patients from the PETACC8 study

BackgroundImpact of comedications and comorbidities upon OS isn’t well described in cancer patients (pts). We aimed to evaluate their impacts on DFS and OS on pts resected from a stage III colon cancer and treated by adjuvant FOLFOX-4 +/- cetuximab in the PETACC8 study. MethodsTreatments (trts) categories were defined according to the WHO ATC classification system. We focused on 4 medication classes: anticoagulant, cardiovascular, antidiarrheal and antidiabetic trts. We classified the 2559 pts in each category if they took trt at baseline or during study whatever the duration was. Kaplan-Meier method and Cox model were used to compare survival curves. Multivariate analyses were performed on the overall population and according to trt arm. ResultsOnly 1% of pts had no comedications. Comedications with anticoagulant, cardiovascular, antidiarrheal and antidiabetic trts were observed respectively in 18%, 40%, 30% and 9% of the cases. Patients with antidiabetic or cardiovascular trts had more comorbidities. For each other comedication categories, baseline characteristics were balanced between pts treated or not. All comedication categories, except antidiarrheals, were associated with a significant decrease of DFS and OS (Table). Dose-intensity was balanced and may not explain survival differences. For pts treated with at least one cardiac, diabetic or anticoagulant trts, severe events were more frequently reported, including 9 early deaths. The use of antidiarrheals is maybe associated to a better exposure to chemotherapy as reflected by a higher rate of grade ≥3 adverse events but also a potential better efficacy. Table. Comedications impact on DFS and OS.Table549PTableOverall analysisDFSOSHR [95%CI]pHR [95%CI]pAnticoagulantsIntake vs no1.33 [1.10–1.62].0031.34 [1.07–1.67].01AntidiarrhealsIntake vs no0.87 [0.73–1.04].120.78 [0.63–0.96].02Cardiovascular trtsIntake vs no1.20 [1.03–1.41].021.28 [1.07–1.54].01AntidiabeticsIntake vs no1.37 [1.07–1.76].011.45 [1.09–1.92].01 ConclusionsComorbidities related to analyzed ATC classes negatively impact OS and DFS in PETACC8 pts, except antidiarrheal agents which positively impact OS and DFS. Clinical trial identificationPETACC8; 2005-003463-23. Legal entity responsible for the studyFédération Francophone de Cancérologie Digestive, Dijon. FundingMerck and Sanofi. DisclosureJ. Taieb: Advisory / Consultancy: Merck; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Roche Genentech; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Amgen. All other authors have declared no conflicts of interest.

23 Impact of Concomitant Medications on Outcome in Patients with Localized Prostate Cancer Treated with Dose-Escalated External Beam Radiotherapy and Androgen Deprivation Therapy: A Pooled Analysis of Two Prospective Trials

23 Impact of Concomitant Medications on Outcome in Patients with Localized Prostate Cancer Treated with Dose-Escalated External Beam Radiotherapy and Androgen Deprivation Therapy: A Pooled Analysis of Two Prospective Trials

Impact of Concomitant Medications on Outcome in Patients with Localized Prostate Cancer Treated with Dose-Escalated External Beam Radiotherapy and Androgen Suppression: A Pooled Analysis of Two Prospective Trials

Impact of Concomitant Medications on Outcome in Patients with Localized Prostate Cancer Treated with Dose-Escalated External Beam Radiotherapy and Androgen Suppression: A Pooled Analysis of Two Prospective Trials

Impact of concomitant medications on obstructive sleep apnoea

Obstructive sleep apnoea (OSA) is characterized by repeated episodes of apnoea and hypopnoea during sleep. Little is known about the potential impact of therapy drugs on the underlying respiratory disorder. Any influence should be taken into account and appropriate action taken, including drug withdrawal if necessary. Here, we review drugs in terms of their possible impact on OSA; drugs which (1) may worsen OSA; (2) are unlikely to have an impact on OSA; (3) those for which data are scarce or contradictory; and (4) drugs with a potentially improving effect. The level of evidence is ranked according to three grades: A - randomized controlled trials (RCTs) with high statistical power; B - RCTs with lower power, non-randomized comparative studies and observational studies; C - retrospective studies and case reports. Our review enabled us to propose clinical recommendations. Briefly, agents worsening OSA or inducing weight gain, that must be avoided, are clearly identified. Drugs such as 'Z drugs' and sodium oxybate should be used with caution as the literature contains conflicting results. Finally, larger trials are needed to clarify the potential positive impact of certain drugs on OSA. In the meantime, some, such as diuretics or other antihypertensive medications, are helpful in reducing OSA-associated cardiovascular morbidity.

Medium Increased Risk for Central Sleep Apnea but Not Obstructive Sleep Apnea in Long-Term Opioid Users: A Systematic Review and Meta-Analysis.

Opioids are associated with higher risk for ataxic breathing and sleep apnea. We conducted a systematic literature review and meta-analysis to assess the influence of long-term opioid use on the apnea-hypopnea and central apnea indices (AHI and CAI, respectively). A systematic review protocol (Cochrane Handbook guidelines) was developed for the search and analysis. We searched Embase, Medline, ACP Journal Club, and Cochrane Database up to November 2014 for three topics: (1) narcotics, (2) sleep apnea, and (3) apnea-hypopnea index. The outcome of interest was the variation in AHI and CAI in opioid users versus non-users. Two reviewers performed the data search and extraction, and disagreements were resolved by discussion. Results were combined by standardized mean difference using a random effect model, and heterogeneity was tested by χ(2) and presented as I(2) statistics. Seven studies met the inclusion criteria, for a total of 803 patients with obstructive sleep apnea (OSA). We compared 2 outcomes: AHI (320 opioid users and 483 non-users) and 790 patients with CAI (315 opioid users and 475 non-users). The absolute effect size for opioid use was a small increased in apnea measured by AHI = 0.25 (95% CI: 0.02-0.49) and a medium for CAI = 0.45 (95% CI: 0.27-0.63). Effect consistency across studies was calculated, showing moderate heterogeneity at I(2) = 59% and 29% for AHI and CAI, respectively. The meta-analysis results suggest that long-term opioid use in OSA patients has a medium effect on central sleep apnea.

Incidence of Congenital Malformations in Infants Born to Patients with Epilepsy: A Comparison of Pregnancy Registries and Cohort Study Data (S56.003)

Objective: To compare rates of major congenital malformations (MCM) and ventricular septal defects (VSD) within the UCB AED Pregnancy Registry (UCB Registry) to rates from other sources. Background The UCB Registry is a study designed to monitor pregnant women exposed primarily to levetiracetam (Keppra®) and their offspring. Design/Methods: MCM and VSD rates were calculated from the UCB Registry (interim data from 2004 through February 2011) and compared to published rates from a general population surveillance system (MACDP) and epilepsy patient registries: EURAP, UK registry, and NAAED. Results: MCM rates among levetiracetam monotherapy exposures were 7.7% (UCB Registry), 1.6% (EURAP), 2.1% (NAAED) and 0% (UK registry). An overall MCM rate for other AED monotherapies of 5.5% was reported by EURAP. MCM rates for individual monotherapy exposures in the first trimester were reported by NAAED: 9.5% valproate, 5.6% phenobarbital, 3.4% topiramate, 3.0% phenytoin, 2.9% carbamazepine, and 1.9% lamotrigine. MCM rates among levetiracetam polytherapy exposures were 12.5% (UCB Registry), 6.9% (EURAP), and 3.3% (UK). EURAP reported an overall MCM rate for other AED polytherapies of 9.2%. In an independent review of 59 published studies (Meador et al, Neurology 2008;71:1109-1117), the MCM rate was 7.1% in epilepsy patients and 2.3% in healthy women. The MACDP MCM rate was 2.8% and the VSD rate was 0.4%. VSD rates in the UCB Registry ranged from 0.8%–1.2% (n=5). Among epilepsy registries, VSD data was only available from EURAP in which one VSD was identified. Conclusions: Among the various registries, differences in observed MCM and VSD rates, as well as differences in the presence and impact of concomitant medications with a higher risk of birth defects, might be attributed to variations in study design. When an internal comparator was available, the rates of MCM and VSD were no greater in levetiracetam-exposed patients than in those treated with other AEDs. Supported by: UCB Pharma. Disclosure: Dr. Montouris has received personal compensation for activities with UCB Pharma, Eisai, Lundbeck, Meridian, and Sunovion. Dr. Montouris has received person compensation in an editorial capacity for Epilepsia. Dr. Harden has received personal compensation for activities with UCB Pharma, Pfizer, and GlaxoSmithKline as a speaker. Dr. Harden has received research support from Forest Pharmaceuticals. Dr. Albano has received personal compensation for activities with UCB Pharma. Dr. Leppik has received personal compensation for activities with Caremark R11 and UCB Pharma, Inc. as a consultantDr. Leppik has received research support from UCB Pharmaceuticals. Dr. Miller has received personal compensation for activities with UCB Pharma as an employee.

Interethnic differences in Cyp3A4 inhibition by ketoconazole on docetaxel pharmacokinetics (PK) and pharmacodynamics (PD)

2526 Background: Use of concomitant medications that inhibit drug metabolizing enzymes such as Cyp3A4 is common and may affect chemotherapy PK/PD. We studied the effects of Cyp3A4 inhibition with ketoconazole on docetaxel PK/PD in 3 Asian ethnic groups. Methods: Two cohorts of chemonaive breast cancer patients were compared. The first cohort comprised of 95 patients (62 Chinese, 26 Malay, 7 Indian) treated with 75mg/m2 docetaxel unmodulated by ketoconazole, while the second cohort comprised of 31 patients (14 Chinese, 14 Malay, 3 Indian) treated with docetaxel 70mg flat dose modulated by oral ketoconazole, a regimen we previously reported to result in comparable docetaxel AUC as 75mg/m2 docetaxel. Plasma docetaxel concentrations were obtained at 0, 0.5, 1, 2, 5, 7 and 24 hours, and blood counts monitored on days 8 and 15 of cycle 1. Results: No significant differences in docetaxel PK or neutropenia between the races were observed in response to 75mg/m2 docetaxel unmodulated by ketoconazole (docetaxel clearance 36.4±16.9, 34.3±12.5, 44.2±27.7L/h, p=0.702; docetaxel AUC 3.6±2.7, 3.5±1.2, 2.9±1.3mg/L h, p=0.418; day 8 neutrophil count 0.5±0.6, 0.8±0.8, 0.4±0.3x109/L, p=0.138; grade 4 neutropenia 66%, 50%, 86%, p=0.157). In contrast, when docetaxel was administered with ketoconazole to inhibit Cyp3A4, inter-ethnic differences in docetaxel PK/PD were observed, with Chinese having the lowest docetaxel clearance and highest docetaxel AUC, followed by Malays and Indians (docetaxel clearance 18.6±5.7, 23.7±9.3, 30.6±6.7L/h, p=0.048; p=0.017 trend test; docetaxel AUC 4.2±1.4, 4.1±3.9, 2.4±0.5 mg/L h, p=0.048, p=0.017 trend test), although there were no statistically significant differences in body weight or surface area between the races. In concordance, Chinese patients experienced greatest degree of myelosuppression, followed by Malays and Indians (day 8 neutrophil count 0.8±0.8, 1.5±1.1, 1.7±1.1x109/L, p=0.046, p=0.013 trend test), and were more likely to develop grade 4 neutropenia (57%, 14%, 0%, p=0.024) from docetaxel + ketoconazole. Conclusions: Inter-ethnic differences in CYP3A inhibition by ketoconazole exist, and are important when evaluating the impact of concomitant medications with chemotherapy that may inhibit Cyp3A4. No significant financial relationships to disclose.