Neuropsychiatric Adverse Drug Reactions Research Articles

Neuropsychiatric adverse drug reactions with oral tyrosine kinase inhibitors in metastatic colorectal cancer: an analysis from the FDA Adverse Event Reporting System.

New oral tyrosine kinase inhibitors (TKIs) are approved for metastatic colorectal cancer (mCRC). The aim of this study was to assess the neuropsychiatric adverse drug reactions (ADRs) of these drugs reported in the FDA Adverse Event Reporting System (FAERS) database. All reports with regorafenib (REG) and encorafenib (ENC) as the primary suspect, and reported in the FAERS between 2012 and 2022, were collected. A descriptive and disproportionality analyses were conducted. Out of 4,984 cases, 1,357 (30.2%) reported at least one neuropsychiatric ADR. New potential signals for REG included neuropathy peripheral (n = 265; reporting odds ratio, ROR = 19.48, 95% confidence interval, CI 95% = 17.52-22.47; information component, IC = 2.89, IC025-IC075=2.77-3.02), hyperesthesia (n = 18; ROR = 12.56, CI 95% = 7.90-19.96; IC = 2.25, IC025-IC075=1.79-2.72), taste disorder (n = 41; ROR = 9.91, CI 95% = 7.29-13.49; IC = 2.18, IC025-IC075=1.88-2.49), poor quality sleep (n = 18; ROR = 6.56, CI 95% = 4.13-10.42; IC = 1.74, IC025-IC075=1.27-2.20), altered state of consciousness (n = 15; ROR = 5.50, CI 95% = 3.31-9.14; IC = 1.57, IC025-IC075=1.06-2.07), depressed mood (n = 13; ROR = 1.85, CI 95% = 1.07-3.19; IC = 0.58, IC025-IC075=0.04-1.13) and insomnia (n = 63; ROR = 1.48, CI 95% = 1.15-1.89; IC = 0.38, IC025-IC075=0.13-0.63). For ENC comprised depressed mood (n = 4; ROR = 5.75, CI 95% = 2.15-15.39; IC = 1.74, IC025-IC075=0.76-2.73) and cognitive disorders (n = 3; ROR = 4.71, CI 95% = 1.51-14.66; IC = 1.54, IC025-IC075=0.41-2.68). This study identified new unknown potential neuropsychiatric ADRs. Further investigations are required to better define the neurotoxicity of TKIs in mCRC patients.

Association of depression and suicidal behaviour reporting with HIV integrase inhibitors: a global pharmacovigilance study.

Concerns have been raised regarding neuropsychiatric adverse drug reactions of integrase inhibitors (INSTIs) in patients living with HIV. The aim of this study was to assess the risk of depression and suicidality reporting with INSTIs based on a global pharmacovigilance database. Depression and suicidality cases in patients treated with INSTIs were identified within the WHO global database of individual case safety reports, VigiBase. Risk of depression and suicidality reporting with INSTIs compared with other ART was assessed using disproportionality analyses (case/non-case statistical approach). Of 19 991 410 reports over the study period, 124 184 reports concerned patients exposed to ART, including 22 661 patients exposed to an INSTI. Among patients treated with an INSTI, 547 cases of depression and 357 cases of suicidality were identified. Disproportionality analyses showed that depression [reporting OR (ROR) 3.6; 95% CI: 3.2-4.0] and suicidality (ROR 4.7; 95% CI: 4.1-5.4) were more reported with the use of INSTIs compared with other ART. Amongst INSTIs, depression reporting was significantly greater for bictegravir and dolutegravir, whereas suicidality reporting was significantly greater for dolutegravir only. Our findings suggest that depression and suicidality are adverse drug reactions of all INSTI agents, especially dolutegravir, which may occur within the first months of therapy.

Self‐reported neuropsychiatric adverse reactions in people receiving bictegravir combined with emtricitabine/tenofovir alafenamide

AbstractThe integrase‐inhibitor bictegravir combination antiretroviral therapy (ART) Biktarvy became available in Australia in October 2018. Neuropsychiatric adverse drug reactions (ADRs) are associated with bictegravir and may affect persistence and adherence to treatment. The aim of this study was to describe the type and frequency of reported neuropsychiatric reactions in people dispensed Biktarvy. Ethics approval was obtained from Alfred Hospital Ethics Committee (Project No. 541/20). Data were collected from records of people dispensed Biktarvy between October 2018 and May 2020 and who subsequently had a new neuropsychiatric reaction reported to the organisation's ADR Review Committee. Data were sourced from ADR reports, medical and dispensing records, and included demographics, medical history, and concurrent medicines with known psychiatric adverse reactions. Data were analysed descriptively. Biktarvy was dispensed to 1265 patients. Twenty‐two (1.7%, 95% confidence interval [CI] 1.0–2.5%) people reported 50 neuropsychiatric ADRs, including abnormal dreams (n = 13), sleep disorders (n = 5), and headaches (n = 5). The median time from initiation to reaction was 13 (interquartile range [IQR] 4–94) days. Eighteen patients discontinued Biktarvy (1.4%, 95% CI 0.85–2.24). There was no statistically significant difference in discontinuation of Biktarvy between people who did or did not have a pre‐existing psychiatric diagnosis (p = 0.58). Concurrent medicines with known psychiatric adverse reactions were used by 10 people. A low rate of reported neuropsychiatric ADRs lead to discontinuation of Biktarvy, similar to rates in Biktarvy trials. This study adds to the post‐marketing surveillance data of Biktarvy tolerance amongst people living with human immunodeficiency virus (HIV).

Clozapine Optimization: A Delphi Consensus Guideline From the Treatment Response and Resistance in Psychosis Working Group.

There is limited evidence to guide the approaches to clozapine treatment. Accordingly, an international initiative was undertaken with the aim of developing consensus recommendations for the optimization of clozapine monotherapy. We conducted an online Delphi survey among members of the Treatment Response and Resistance in Psychosis (TRRIP) working group comprising experts from twenty-nine countries. The threshold criterion for a consensus recommendation was ≥ 75% agreement ("agree" and "strongly agree" responses) on a question. Agreement of ≥ 50% but < 75% in a second or third Delphi round was deemed to provide guidance. Forty-nine (first round), 32 (second round), and 48 (third round) of the 91 current TRRIP members participated. Expert recommendations at ≥ 75% comprised second-line treatment with clozapine in cases of persistent positive symptoms with co-occurring extrapyramidal symptoms, tardive dyskinesia, or suicidality/aggression. There was considerable disagreement on myocarditis screening parameters. The management of somatic and neuropsychiatric adverse drug reactions warrants further research for more evidence-based recommendations. Rechallenge with clozapine was recommended for eosinophilia, sinus tachycardia and fever and guidance (agreement ≥ 50%) was reached for pneumonia and thrombocytopenia. Given the limited evidence available, this consensus-based series of recommendations and guidance statements supports clinical decision-making to optimize clozapine monotherapy and provides guidance for future research in treatment-resistant schizophrenia.

Neuropsychiatric Adverse Drug Reactions with Tyrosine Kinase Inhibitors in Gastrointestinal Stromal Tumors: An Analysis from the European Spontaneous Adverse Event Reporting System

Tyrosine kinase inhibitors (TKIs) are widely used in gastrointestinal stromal tumors (GISTs). The aim of this study is to evaluate the reporting frequency of neuropsychiatric adverse drug reactions (ADRs) for TKIs through the analysis of European individual case safety reports (ICSRs). All ICSRs collected in EudraVigilance up to 31 December 2021 with one TKI having GISTs as an indication (imatinib (IM), sunitinib (SU), avapritinib (AVA), regorafenib (REG), and ripretinib (RIP)) were included. A disproportionality analysis was performed to assess the frequency of reporting for each TKI compared to all other TKIs. The number of analyzed ICSRs was 8512, of which 57.9% were related to IM. Neuropsychiatric ADRs were reported at least once in 1511 ICSRs (17.8%). A higher reporting probability of neuropsychiatric ADRs was shown for AVA. Most neuropsychiatric ADRs were known, except for a higher frequency of lumbar spinal cord and nerve root disorders (reporting odds ratio, ROR 4.46; confidence interval, CI 95% 1.58-12.54), olfactory nerve disorders (8.02; 2.44-26.33), and hallucinations (22.96; 8.45-62.36) for AVA. The analyses of European ICSRs largely confirmed the safety profiles of TKIs in GISTs, but some ADRs are worthy of discussion. Further studies are needed to increase the knowledge of the neuropsychiatric disorders of newly approved TKIs.

Neuropsychiatric adverse drug reactions and associated factors in a cohort of individuals starting dolutegravir-based or efavirenz-based antiretroviral therapy in Belo Horizonte, Brazil

Objective To measure the incidence of neuropsychiatric adverse drug reactions (ADRs) in individuals living with HIV who initiated antiretroviral therapy (ART) with first-line regimens containing dolutegravir (DTG) or efavirenz (EFV) and associated factors. Methods Prospective cohort study with individuals living with HIV who started ART with DTG or EFV associated with tenofovir disoproxil and lamivudine in Belo Horizonte, Brazil. Sociodemographic, clinical, and laboratory data were collected from September/2015 to October/2018 in three specialized HIV care services through interviews, clinical records, and computerized systems. We analyzed the frequency of neuropsychiatric ADRs recorded in clinical records 12 months after starting antiretroviral use, and the associated factors were investigated using binary logistic regression. Results A total of 152 (35.1%) of the 433 individuals included had neuropsychiatric ADRs. The incidence density was 35.3/100 person-years. The subjects mainly had sleep disorders and disturbances (21.3%), neurological disorders (13.9%), headaches (8.1%), and anxiety disorders and symptoms (3.0%), more frequently in individuals using EFV. A lower likelihood of neuropsychiatric ADRs was associated with using a DTG-based antiretroviral regimen (OR = 0.24; 95% CI = 0.14-0.40) and anxiety or depression signs and symptoms at the onset of treatment (OR = 0.57; 95% CI = 0.37-0.89). Conclusion The incidence of neuropsychiatric ADRs was high in individuals starting ART with a lower likelihood of using a DTG-based regimen. The DTG-based regimen had a better safety profile for neuropsychiatric ADRs than the EFV-based regimen.

Cycloserine Induced Psychosis, Insomnia and Suicidal Attempts in a Young Female Patient with Pre-Extensively Drug Resistant Tuberculosis

The World Health Organization classifies cycloserine as a group four second line anti tubercular drug for the treatment of drug resistant tuberculosis. Neuropsychiatric adverse drug reactions associated with cycloserine need more attention as they may compromise treatment success. Here, we report a case of cycloserine induced psychosis, insomnia and suicidal attempts in a young female patient with pre-extensively drug resistant tuberculosis (pre-XDR-TB). A 20-year-old female patient was prescribed longer oral XDR-TB regimen (high dose of moxifloxacin, cycloserine, linezolid, clofazimine, bedaquiline and pyridoxine). After fifteen days of treatment, patient developed changes in behaviour with frequent episodes of spontaneous and excessive laughing or crying. She also developed insomnia, started to hear voices and made two attempts of suicide. Following this, cycloserine was discontinued. Clonazepam and clomipramine were prescribed to her. Patient gradually recovered over a period of one month. Extreme caution with regular and close monitoring should be exercised while administering cycloserine because psychiatric adverse drug reactions could be associated with increased risk of poor drug adherence in drug resistant tuberculosis.

Study of pattern and time-reaction sequence for adverse drug reactions reported to antiretroviral drugs

Background: Adverse drug reactions (ADRs) to antiretroviral drugs have a varied pattern and wide spectrum of severity from mild to very serious. The lack of a pre-established time-reaction sequence hampers the causality assessment of ADRs. Recognition of pattern of ADRs to antiretroviral drugs in a particular setup might sensitize the reporters to report ADRs, especially in setups dependent on spontaneous reporting. Aim and Objectives: The study of pattern and time-reaction sequence for ADRs reported to antiretroviral drugs. Materials and Methods: Retrospective study was conducted at a first-line antiretroviral therapy (ART) center after obtaining approval from the Institutional Ethics Committee. Pattern of ADRs associated with ART was done by analyzing the type of ADRs, severity, and outcome of ADRs reported to antiretroviral drugs. Mean duration of time lapse between administration of drug to onset of adverse drug reaction was calculated. Descriptive statistics was used for data analysis. Results: There were 73 adverse reactions reported. Most common type of adverse reaction was cutaneous (53.42%) followed by anemia (31%). Causality assessment of most ADRs was concluded as possible (60.27%). Most ADRs were of moderate severity and 12% were severe reactions. Reactions such as anemia and neuropsychiatric ADRs often occurred late, while maculopapular rash usually occurred within 30 days of drug administration. Conclusions: ADRs to ART include an array of reactions ranging from mild rash to psychosis or severe anemia. Most of these reactions are of moderate severity and have a favorable outcome. Many of these reactions actually occur almost a month after initiating a drug regime suggesting the need for intensive monitoring around this time.

The mechanisms underlying montelukast's neuropsychiatric effects - new insights from a combined metabolic and multiomics approach

AimsMontelukast (MTK) is an antagonist of the cysteinyl leukotrienes receptor 1 widely used to manage asthma symptoms among adults and children. However, it has been associated with an increasing number of neuropsychiatric adverse drug reactions (ADRs), particularly among children, including depression, sleep disturbance, and suicidal ideation. The aims of this work were to characterize MTK metabolism in vitro and in vivo and to identify its effects at the metabolome and proteome levels in order to explain its toxicity. Main methodsAn extensive study of montelukast metabolism was carried out using in vitro systems, an embryonic neuron-enriched cell model, and a mouse model. Metabolites were identified by high-resolution mass spectrometry, and a combined mass spectrometry-based metabolomics and proteomics approach was employed to assess the effect of MTK on mice and isolated chicken neurons. Key findingsEighteen new MTK metabolites were identified. MTK's ability to react with glutathione was confirmed. The multi-omics approach employed confirmed that montelukast interferes with the glutathione detoxification system in the brain. Moreover, montelukast is also able to dysregulate various neurotransmitter and neurosteroid pathways, particularly those involved in regulation of the hypothalamic–pituitary–adrenal axis, also interfering with mitochondrial function in neuronal cells. SignificanceResults clearly indicate that montelukast therapeutic effects are accompanied by a strong modulation of specific processes in the central nervous system that may explain the observed neuropsychiatric reactions. Moreover, the results also suggest that adverse drug reactions are more likely to occur in children, due to the early maturation stage of their brains.

Leukotrienes vs. Montelukast-Activity, Metabolism, and Toxicity Hints for Repurposing.

Increasing environmental distress is associated with a growing asthma incidence; no treatments are available but montelukast (MTK)—an antagonist of the cysteinyl leukotrienes receptor 1—is widely used in the management of symptoms among adults and children. Recently, new molecular targets have been identified and MTK has been proposed for repurposing in other therapeutic applications, with several ongoing clinical trials. The proposed applications include neuroinflammation control, which could be explored in some neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases (AD and PD). However, this drug has been associated with an increasing number of reported neuropsychiatric adverse drug reactions (ADRs). Besides, and despite being on the market since 1998, MTK metabolism is still poorly understood and the mechanisms underlying neuropsychiatric ADRs remain unknown. We review the role of MTK as a modulator of leukotriene pathways and systematize the current knowledge about MTK metabolism. Known toxic effects of MTK are discussed, and repurposing applications are presented comprehensively, with a focus on AD and PD.

Active Pharmacovigilance Project on the safety profile of Dolutegravir in Brazil

ABSTRACT A quantitative descriptive study based on Brazilian Active Pharmacovigilance of Dolutegravir (DTG) Project was performed to describe the adverse drug reactions (ADRs) to DTG reported and to evaluate the noncompleteness of data from DTG active pharmacovigilance in Brazil. ADRs and clinical and individual data were obtained from information from the Pharmacovigilance Questionnaire from April 2017 to August 2019. The reported ADRs were classified using the Medical Dictionary for Regulatory Activities (MedDRA). In the evaluated period, 249,066 individuals using DTG participated in the active pharmacovigilance of DTG, with 3472 (1.39%) reporting ADRs at least once. A total of 6312 ADRs were reported, of which 57.56% were persistent and 81.46% were not serious according to the individuals’ reports. Most of the reported ADRs were gastrointestinal, neurological and psychiatric. ADRs related to neural tube defects and serious neuropsychiatric ADRs have been reported. Completion of more than half of the fields in the Pharmacovigilance Questionnaire was excellent. The frequency of ADR was low in relation to the number of people living with HIV (PLHIV) using DTG in Brazil, which suggests good tolerability and safety of DTG. The DTG active pharmacovigilance database in Brazil showed good data completeness.

Neuropsychiatric adverse drug reactions associated with low dose methotrexate in rheumatoid arthritis patients

Background: Neuropsychiatric adverse drug reactions (NPADRs) are not commonly associated with low dose methotrexate (LDMTX) in patients with rheumatoid arthritis (RA). Research design and methods: In this case series assessment, we described the nature and frequency of NPADRs with LDMTX in the Dutch DREAM-RA registry, including causality of NPADRs, the impact on further LDMTX treatment and the impact on patient reported Health Related Quality of Life (HRQoL). Results: A total of 71 NPADRs (frequency 6.8%) associated with LDMTX were captured in the DREAM-RA registry. NPADRs were registered for 62 (5.9%) out of 1048 patients with 10.9 NPADRs per 1000 patient years. Headache, dizziness and depression were most frequently reported. The causality was considered probable for 67 NPADRs (94.4%) and definite for 1 NPADR (1.4%). NPADRs led to LDMTX withdrawal in 34 cases (47.9%) and was not restarted in 16 cases (47.1%). Median mental HRQoL was significantly decreased around the occurrence of the NPADR and remained significantly lower after the event. Median physical HRQoL was not significantly affected. Conclusions: Knowledge on the nature, frequency and impact of the demonstrated NPADRs during LDMTX therapy will enhance attention towards these potential ADRs allowing better risk assessment and communication to patients.

Adverse drug reactions of montelukast and pranlukast: Analysis of the Korea database.

Leukotriene receptor antagonists are recommended to treat asthma and allergic rhinitis. Although they had been used for a long time, recent studies have reported neuropsychiatric adverse drug reactions are associated with montelukast. This study analyzed the adverse drug reactions of montelukast and pranlukast, which are the two most frequently prescribed leukotriene receptor antagonists, respectively in Korea. This study retrospectively reviewed ADRs of 5,426 montelukast and 1,146 pranlukast reported in the Korea Adverse Event Reporting System between January 2014 and December 2018. When both drugs are classified by system organ class, the most adverse drug reactions were related to the gastro-intestinal system, followed by psychiatric events. The reported adverse drug reactions for both drugs were more common in women, and the ratio of adverse drug reactions to prescriptions was highest in the elderly. Women aged 19 to 64 years reported more than twice as many adverse drug reactions than men of the same age, and more than 5 times in insomnia. When prescribing montelukast and pranlukast, attention would need to digestive and sleep disorders, especially women aged 19 to 64. After prescribing montelukast, physicians would need to pay more attention to agitation (5/396378 vs 0/82475), bad or vivid dreams (6/396378 vs 0/82475), anxiety (11/396378 vs 0/82475), depression (14/396378 vs 1/82475), tremor (53/396378 vs 7/82475), irritability (5/396378 vs 1/82475), insomnia (159/396378 vs 25/82475), and headache (68/396378 vs 10/82475), compared to when prescribing pranlukast. Further prospective research needs to elucidate the relationship between neuropsychiatric events and montelukast.

Differences between paediatric and adult suspected neuropsychiatric adverse drug reactions of Melatonin reported to the European Medicines Agency

Melatonin has been approved as a sleep medication in Europe since 2007. The pharmacological dosages of this substance are much higher than the physiological ones, so it is no surprise that it has potential for many adverse effects. In children melatonin has been used for many years off-label, but in 2018 the Committee for Medicinal Products for Human Use (CHMP) granted paediatric-use marketing authorization for melatonin. We used the European Medicines Agency (EMA) database to compare the distribution of melatonin adverse drug reaction (ADRs) between the pediatric and the adult population. The results will serve as a basis for future research involving melatonin use in specific populations. All ADR reports received in EMA up to 23.03.2019 were analyzed for overall numbers, age and gender. The nature of the ADRs and the most frequently reported drug substances and drug event combinations were evaluated using MedDRA 21.0. As of 27th March 2019, EudraVigilance contained 1061 spontaneous reports. After excluding all the cases with other suspected or concomitant drugs, we are left with 177 cases. In children ADRs were generally associated with central nervous system (CNS) excitability, whereas in adults there was mainly inhibition. The present study focused on the ADR reports of melatonin in one of the largest databases. Future research of melatonin in the pediatric population is needed, because the current SmPCs lack such information, and in the cases of melatonin use in children are increasing in recent years.

PCSK9 Inhibitors and Neurocognitive Adverse Drug Reactions: Analysis of Individual Case Safety Reports from the Eudravigilance Database.

IntroductionProprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9Is) were associated with a risk of neurocognitive adverse drug reactions (ADRs).ObjectiveWe aimed to investigate the occurrence of neuropsychiatric ADRs related to PCSK9Is.MethodsWe analyzed Individual Case Safety Reports (ICSRs) sent through the European pharmacovigilance database that reported alirocumab or evolocumab as the suspected drug and at least one neurological or psychiatric ADR. The reporting odds ratio (ROR) was computed to compare the probability of reporting ICSRs with neuropsychiatric ADRs between alirocumab, evolocumab and statins.ResultsOverall, 2041 ICSRs with alirocumab and/or evolocumab as the suspected drug described the occurrence of neuropsychiatric ADRs. The most reported preferred terms for both drugs were headache, insomnia and depression. No difference between alirocumab and evolocumab was observed for the RORs of ICSRs with ADRs belonging to the System Organ Classes (SOCs) ‘Nervous system disorders’ or ‘Psychiatric disorders’ (ROR 1.02, 95% confidence interval 0.91–1.14; and 1.12, 95% CI 0.94–1.34, respectively), while evolocumab and alirocumab had a higher reporting probability of ICSRs with ADRs belonging to the SOC ‘Nervous system disorders’ compared with atorvastatin and fluvastatin. A lower reporting probability was instead found for ICSRs with ADRs belonging to the SOC ‘Psychiatric disorders’ for evolocumab and alirocumab versus simvastatin, pravastatin and rosuvastatin.ConclusionOur results demonstrated that 22.7% of all ICSRs reporting alirocumab or evolocumab as suspect drugs described the occurrence of neuropsychiatric ADRs. The ROR showed that evolocumab and alirocumab had a higher reporting probability of neurological ADRs compared with statins. Further data from real-life contexts are needed.Electronic supplementary materialThe online version of this article (10.1007/s40264-020-01021-3) contains supplementary material, which is available to authorized users.

Neuropsychiatric adverse drug reactions induced by montelukast impair the quality of life in children with asthma

Introduction Montelukast-induced neuropsychiatric adverse drug reactions (ADRs) have been reported in retrospective studies. This study aimed to reveal the neuropsychiatric ADRs triggered in patients taking montelukast due to asthma in real time, and to evaluate the effect of these ADRs on quality of life (QoL). Methods Patients, ages 3–18 years, taking montelukast for the first time and their parents were included. Ages 3–7 years were defined as the preschool and ages 8–18 years as the school-age group. At the beginning of the study and at the end of the second week of treatment, the neuropsychiatric complaint assessment questionnaire and the KINDL QoL scale were administered to patients and their parents. The effect of ADRs on the decrease in QoL was evaluated by multivariable logistic regression. Results Neuropsychiatric ADRs were reported in 78 (62.4%) of 125 patients, who recovered when the drug was discontinued. Temperamental behavior, nightmares and sleep disorders occurred significantly more often in both groups compared with pretreatment (p < 0.001 for each). In both groups, except in the child-reported family relationships subscale in the school-age group, significant decreases were found in both child and parent proxy-reported QoL total/sub-scores compared with pretreatment (p˂0.001 for each). It was found in the evaluation that the overall QoL of those experiencing ADRs in both age groups was more affected. (Child-reported QoL ORpreschool age=2.66, p = 0.048; ORschool-age=5.95, p = 0.027; parent-proxy QoL ORpreschool age =3.52, p = 0.010, ORschool-age=6.43, p = 0.027) Conclusions Montelukast-induced neuropsychiatric ADRs are more frequent than reported in the literature and negatively impact children’s QoL.

Adverse drug reactions in infants, children and adolescents exposed to antidepressants: a French pharmacovigilance study.

Despite their frequent use in children and adolescents, the evidence for efficacy and safety of antidepressants (ATDs) in this population is scarce and off-label prescribing common. The aim of this study was to describe reported adverse drug reactions (ADRs) associated to ATDs over a 30-year period using the French Pharmacovigilance Database (FPVD). We performed an analysis of ADRs registered in the FPVD from 1985 to 2016, occurred in children and adolescents receiving an ATD. Descriptive statistics were used to obtain an overview of ADRs types and characteristics, and data were stratified by age. Among the 45,070 pediatric cases reports registered into the FPVD, we identified 1366 reports (3.0%) in which ATDs were "suspected" as the cause of 2922 ADRs. ADRs were more frequently reported in female (n = 743; 55.5%) and adolescents (n = 627; 49.3%). Neuropsychiatric ADRs were the most reported, mainly sleepiness, agitation, and suicidal thinking and behavior, followed by gastrointestinal and hepatobiliary disorders, mainly vomiting, abdominal pain, hepatitis, nausea, and three unexpected ADRs of pancreatitis. There was an increase of annual reporting between 1986 and 2003, followed by a plateau state then a decrease from 2003 to 2012, and a rapid escalation until 2016, while an increase in the number of reporting of suicidal thinking and behavior was observed after 2003, highlighting a possible impact of black box warnings on reporting practices and ATD use. This pediatric pharmacovigilance study underscored the high prevalence of neuropsychiatric and gastrointestinal ADRs, including three unexpected cases of pancreatitis.

Safety Challenges of Using High Dose Baclofen for Alcohol Use Disorder: A Focused Review.

Since the early 2000s, the gamma-aminobutyric acid type B (GABA-B) receptor agonist baclofen has been extensively used for treating alcohol use disorder (AUD). In some countries, like France, Australia, or Germany, baclofen has been used at patient-tailored dose regimens, which can reach 300 mgpd or even more in some patients. The GABA-B-related pharmacology of baclofen expose patients to a specific profile of neuropsychiatric adverse drug reactions (ADRs), primarily some frequent sedative symptoms whose risk of occurrence and severity are both related to the absolute baclofen dosing and the kinetics of dose variations. Other frequent neuropsychiatric ADRs can occur, i.e., tinnitus, insomnia, or dizziness. More rarely, other serious ADRs have been reported, like seizures, manic symptoms, or sleep apnea. However, real-life AUD patients are also exposed to other sedative drugs, like alcohol of course, but also benzodiazepines, other drugs of abuse, or other sedative medications. Consequently, the occurrence of neuropsychiatric safety issues in these patients is essentially the result of a complex multifactorial exposure, in which baclofen causality is rarely obvious by itself. As a result, the decision of initiating baclofen, as well as the daily dose management should be patient-tailored, according the medical history but also the immediate clinical situation of the patient. The overall safety profile of baclofen, as well as the clinical context in which baclofen is used, have many similarities with the use of opiate substitution medications for opiate use disorder. This empirical statement has many implications on how baclofen should be managed and dosing should be adjusted. Moreover, this constant patient-tailored adjustment can be difficult to adapt in the design of clinical trials, which may explain inconsistent findings in baclofen-related literature on AUD.

Adverse drug reactions to integrase strand transfer inhibitors.

To describe and compare integrase strand transfer inhibitor (INSTI) adverse drug reactions (ADRs) for raltegravir, elvitegravir-cobicistat, and dolutegravir. Population-based, retrospective cohort. Antiretroviral-experienced and naive persons at least 19 years old were included if they received their first prescription for raltegravir, elvitegravir-cobicistat, or dolutegravir in British Columbia, Canada, in 2012-2014, and were followed for 2 years until 31 December 2016. The primary outcome was an ADR resulting in INSTI discontinuation. ADR rates and 95% confidence intervals (95% CIs) were calculated by Poisson method. Cox proportional-hazards regression estimated the hazard ratio for ADR-related INSTI discontinuation, adjusted for confounders. ADR symptoms were compared across INSTIs. There were 1344 persons contributing 1464 person-INSTI exposures. The cohort was predominantly male (79%) and antiretroviral therapy-experienced (85%). ADR events and unadjusted ADR rates (95% CI) per 100 person-years were raltegravir 24 of 551 (4.4%), 2.91 (1.95, 4.35); elvitegravir-cobicistat 38 of 394 (9.6%), 5.94 (4.32, 8.16); and dolutegravir 27 of 519 (5.2%), 2.96 (2.03, 4.31). The ADR rate for elvitegravir-cobicistat was double that of dolutegravir (adjusted hazard ratio 2.24, 95% CI 1.13, 4.44), but not significantly different for either dolutegravir or elvitegravir versus raltegravir. Elvitegravir-cobicistat-treated persons had a significantly higher proportion of gastrointestinal and general (fatigue, malaise) ADRs. Neuropsychiatric ADRs were more frequent with dolutegravir, but not significantly different between INSTIs. Among those switching between INSTIs, there was no apparent relationship between experiencing an ADR to one INSTI and subsequent intolerance to another. This study affirms INSTIs are well tolerated during routine clinical use. Consideration of differences in side effect profiles can inform antiretroviral therapy individualization.

Evolution of neuropsychiatric adverse events of enzalutamide and abiraterone acetate treatments reported in EudraVigilance in metastatic castration resistant prostate cancer patients.

343 Background: Abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ), oral hormonal treatment of metastatic castration resistant prostate cancer (mCRPC), can have neuropsychiatric impact. Methods: The Proportional Reporting Ratio (PRR) was used to analyze evolution of suspected adverse drug reactions (ADRs) reported in real world, in EudraVigilance from March to August 2017. Results: From the total ADRs of AAP and ENZ reported in Eudra from March to August 2017, 1,162 were related to AAP and 5,101 were related to ENZ. ADRs of ENZ reported in Eudra in August were higher than those reported in March 2017, in all the neuropsychiatry ADRs analyzed. In the case of AAP, 44% of the neuropsychiatric suspected ADRs analyzed did not show new cases reported and 56% of the ADRs shown an increase, although it was not higher than 15 new cases reported. Conclusions: In August 2017, the updated ADRs of AAP and ENZ from Eudra were consistent with those observed in March 2017 (Iznaola et al.). It confirms an increasing trend of reporting neuropsychiatric ADRs of ENZ in mCRPC. Suspected ADRs of AAP reported remained steady.[Table: see text]