Brodalumab: 5-Year US Pharmacovigilance Report.

INTRODUCTION: Brodalumab is a human interleukin-17 receptor A antagonist indicated for the treatment of moderate-to-severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy and have failed to respond or have lost response to other systemic therapies. Although the US prescribing information for brodalumab includes a boxed warning regarding suicidal ideation and behavior, no causal association has been demonstrated. Here, we summarize 5 years of pharmacovigilance data, from August 15, 2017, through August 14, 2022, reported to Ortho Dermatologics by US patients and healthcare providers. METHODS: Prevalence of the most common adverse events (AEs) listed in the brodalumab package insert (incidence ≥ 1%) and AEs of special interest are described. Brodalumab exposure was estimated as the time from the first to last prescription-dispensing authorization dates. Data were collected from 4744 patients in the USA, with an estimated exposure of 5815 patient-years. RESULTS: Over 5 years, 11 cases of adjudicated major adverse cardiovascular events were reported (0.23 events/100 patients), a rate lower than that experienced by patients in the international Psoriasis Longitudinal Assessment and Registry. There were 106 serious infections. No serious fungal infections were reported. There were 40 confirmed and 2 suspected COVID-19 cases, with no new COVID-19-related deaths. Of 49 reported malignancies among 42 patients, 3 were deemed possibly related to brodalumab. No completed suicides and no new suicidal attempts were reported. CONCLUSION: Five-year pharmacovigilance data are consistent with the established safety profile reported in long-term clinical trials and previous pharmacovigilance reports, with no new safety signals.

Brodalumab is an injectable treatment approved for moderate-to-severe plaque psoriasis in adults who lacked response to previous treatments. In the USA, brodalumab is only available under a Risk Evaluation and Mitigation Strategy for increased suicidality risks; however, findings from 5 years of real-world safety data have demonstrated a lack of association. In this report, we discuss safety findings reported by US patients and healthcare providers for 4744 patients treated with brodalumab over 5 years. Joint pain (known as arthralgia) was the most common safety finding, with 122 cases reported over 5 years. Other safety findings of interest across 5 years included 106 serious infections (defined as prolonged infections or infections requiring treatment), 54 cases of depression, 49 cases of cancer (in 42 patients), 40 confirmed cases of COVID-19, and 11 cases of major cardiovascular events (such as stroke or heart attack). No completed suicides occurred throughout 5 years, and no new suicidal attempts were reported in year 5. In indirect comparisons with safety data from patients with psoriasis receiving or eligible to receive similar treatments, brodalumab was not associated with an increased risk of serious infection, cancer, major cardiovascular events, or inflammatory bowel disease. Taken together, these data are consistent with safety findings from long-term clinical trials and previous safety reports of brodalumab.

Outcomes Associated with Dronedarone Use in Patients with Atrial Fibrillation.

The antiarrhythmic drug dronedarone was designed to reduce the extra-cardiac adverse effects associated with amiodarone use in treatment of patients with atrial fibrillation / atrial flutter (AF/AFL). This epidemiological study used a retrospective cohort design to compare risk of cardiovascular-related hospitalizations and death in AF/AFL patients treated with dronedarone versus other antiarrhythmic drugs (AADs). AF/AFL patients with incident dronedarone fills were matched by propensity score (PS) to incident users of other AADs. The primary study outcome was hospitalization for cardiovascular (CV) causes within 24 months after the first study drug fill. A secondary composite outcome comprised hospitalization for CV causes or all-cause mortality during follow-up. In the AF/AFL patient cohort meeting eligibility criteria, 6,964 incident users of dronedarone and 25 607 incident users of other AADs were identified. The PS-matched cohort comprised 6,349 Dronedarone users (91.2% of all eligible) and 12,698 other AAD users. Dronedarone patients had a significantly lower risk of hospitalization for a CV event compared to Other AAD users (hazard ratio = 0.87; 95% confidence interval = 0.79 to 0.96). This was consistent with results for the composite outcome (hazard ratio=0.86; 95% confidence interval = 0.78 to 0.95). In conclusion, AF/AFL patients initiated on dronedarone versus other AADs had significantly lower risk of CV hospitalizations as well as the composite CV hospitalization / death from any cause.

Modafinil and the risk of cardiovascular events: Findings from three US claims databases.

PURPOSE: This study examined the potential risk of cardiovascular (CV) events associated with modafinil and the consistency of the risk estimates across databases. METHODS: A retrospective, inception cohort design of patients who initiated treatment with modafinil between 2006 and 2008 was used in three US health care claims databases. Modafinil users were matched with nonusers. Patients were further divided into two cohorts of obstructive sleep apnea (OSA) and non-OSA (NOSA) cohorts. Endpoints of interest, including myocardial infarction (MI), stroke, CV hospitalizations, and all-cause death, were assessed using incidence rates and Cox proportional hazard ratios (HRs), adjusted for potential confounding factors. RESULTS: The cohorts included a total of 175 524 patients in MarketScan CM; 77 266-in IMS LifeLink; and 8174-in MarketScan Medicaid. No increased risk for MI in the OSA and NOSA cohorts was observed across all three databases. The risks of CV hospitalization in the OSA and NOSA cohorts were not different between the modafinil users and nonusers, except for IMS LifeLink database where the HR was lower than one in the modafinil users compared with the nonusers (HR, 0.69; 95% confidence interval [CI], 0.54 to 0.87). For OSA patients with prior stroke, an adjusted HR of 1.96 (95% CI, 1.02 to 3.76) was observed for stroke among modafinil users compared with nonusers. Among the NOSA, the HRs for all-cause death in the OSA were inconsistent across databases. CONCLUSIONS: Except for few CV outcomes, applying one common protocol generated consistent risk estimates of CV events following modafinil use across cohorts and databases.

Hospitalized cardiovascular events in patients with diabetic macular edema.

BACKGROUND: Microvascular and macrovascular complications in diabetes stem from chronic hyperglycemia and are thought to have overlapping pathophysiology. The aim of this study was to investigate the incidence rate of hospitalized myocardial infarctions (MI) and cerebrovascular accidents (CVA) in patients with diabetic macular edema (DME) compared with diabetic patients without retinal diseases. METHODS: This was a retrospective cohort study of a commercially insured population in an administrative claims database. DME subjects (n = 3519) and diabetes controls without retinal disease (n = 10557) were matched by age and gender. Healthcare claims were analyzed for the study period from 1 January 2002 to 31 December 2005. Incidence and adjusted rate ratios of hospitalized MI and CVA events were then calculated. RESULTS: The adjusted rate ratio for MI was 2.50 (95% CI: 1.83-3.41, p < 0.001) for DME versus diabetes controls. Predictors of MI events were heart disease, history of acute MI, and prior use of antiplatelet or anticoagulant drugs. The adjusted rate ratio for CVA was 1.98 (95% CI: 1.39-2.83, p < 0.001) for DME versus diabetes controls. Predictors of CVA events were cardiac arrhythmia, Charlson comorbidity scores, history of CVA, hyperlipidemia, and other cerebrovascular diseases. CONCLUSION: Event rates of MI or CVA were higher in patients with DME than in diabetes controls. This study is one of few with sufficient sample size to accurately estimate the relationship between DME and cardiovascular outcomes.

Risk of significant infection in rheumatoid arthritis patients switching anti-tumor necrosis factor-α drugs.

OBJECTIVES: To describe rates of first significant infection of rheumatoid arthritis patients who switch between anti-tumor necrosis factor (aTNF) drugs. METHODS: Subjects with rheumatoid arthritis who received only aTNF drugs were observed in an insurance claims database from January 2001 to December 2007. Nonswitchers (NS) remained on one aTNF throughout the study period (date of the first aTNF claim was the index date); switchers (S) received at least one other aTNF (claim date for the 2nd agent was the index date). Significant infections included those that required intravenous antibiotics or hospitalization. Two attributable risk periods were used: (1) an infection occurring ≤90 days following a claim for an aTNF (90-day) and (2) an infection occurring after the index date (ever-treated). Follow-up was censored at the first occurrence of a significant infection event, end of eligibility, or end of study period. Data were analyzed using Cox regression. RESULTS: In 13,752 NS and 2293 S patients, time-stratified rates declined 2- to 3-fold between the first year versus ≥2 years. Risk of significant infection was not different for either attribution model [90-day hazard ratio (HR) = 0.93, 95CI: 0.74 to 1.17, P = 0.55; ever treated HR = 0.94, 95CI: 0.78 to 1.15, P = 0.57]. First and second year rates were similar. Predictors included age ≥50 years; history of significant or opportunistic infection, diabetes, respiratory disease; Charlson score ≥2; or prior hospitalizations. CONCLUSIONS: The risk of a significant infection was not different between NS and S patients. Regardless of switching status, the rate of infection was greater in the first year. This study was limited by the lack of clinical data to determine the reason for switching.

Validation of a claims-based diagnostic code for Stevens-Johnson syndrome in a commercially insured population.

PURPOSE: To validate the administrative claims identification of a diagnosis of Stevens-Johnson syndrome (SJS) using medical records as the "gold standard" in a large, commercially insured US population. METHODS: Patients with >1 medical claim with the International Classification of Diseases, Ninth Revision, Clinical Modification code 695.1x between 1 July 2000 and 31 May 2007 were queried in the HealthCore Integrated Research Database(SM) , which contains administrative claims data for 14 commercial health insurance plans. Trained nurses and pharmacists abstracted pertinent information from the identified patients' medical records, which were then reviewed by two independent dermatologists to identify criteria to determine SJS diagnosis. Positive predictive values (PPVs) based on the claims and chart data were computed for all the cases. RESULTS: Medical charts for 200 claims-identified cases, with the International Classification of Diseases, Ninth Revision, Clinical Modification code 695.1x, were abstracted and reviewed by the dermatologists. A total of five cases (PPV = 2.50%, 95%CI = 0.8%-5.7%) were determined to be SJS with clinical certainty. PPVs varied with data stratification: PPV for inpatient claims only (PPV = 2.00%, 95%CI = 0.24%-7.04%), inpatient claims with 695.1x in first diagnosis field (PPV = 4.11%, 95%CI = 0.86%-11.54%), and final decisions of either clinical certainty or probable cases of SJS (PPV = 6.00%, 95%CI = 3.14%-10.25%). CONCLUSION: These findings demonstrate the difficulties associated with identifying rare disorders, which lack specific diagnostic criteria, within administrative claims databases. They underscore the challenges of using claims data to monitor ill-defined clinical conditions as well as the need to validate claims-identified cases with information from other sources, such as medical charts. Copyright © 2012 John Wiley & Sons, Ltd.

Epidemiology and healthcare utilization of neurogenic bladder patients in a US claims database.

AIMS: To characterize the patient profile, medication utilization, and healthcare encounters of patients with neurogenic bladder dysfunction related to incontinence. METHODS: Medical and pharmacy claims were retrospectively analyzed from April 1, 2002 to March 31, 2007 to characterize neurogenic bladder patients. There were 46,271 patients in the Neurogenic bladder cohort, and 9,315 and 4,168 patients in Multiple Sclerosis (MS) and Spinal Cord Injury (SCI) subcohorts, respectively. Demographic data, concomitant diseases, use of overactive bladder (OAB) oral drug, and healthcare encounters were summarized using descriptive statistics. RESULTS: The mean age of neurogenic bladder patients was 62.5 (standard deviation 19.6) years. A high frequency of lower urinary tract infections (UTIs; 29%-36%), obstructive uropathies (6%-11%), and urinary retention (9%-14%), was observed. Overall, 33,100 (71.5%) patients were taking an OAB oral drug; 10,110 (30.5%) patients discontinued and did not restart. During the one-year follow-up period, 39.0% (8,034) of neurogenic bladder patients had a urology visit, 31.7% (14,679) had a neurology visit, 33.3% (15,415) were hospitalized, and 14.4% (6,646) were in a nursing home (highest rates observed in SCI subcohort). UTI diagnoses comprised over 20% of all hospitalizations one-year post-index. Annually, neurogenic bladder patients averaged 16 office and 0.5 emergency room visits. CONCLUSIONS: This is the largest observational study conducted to address the epidemiology of the neurogenic bladder population, including healthcare utilization. These data suggest that patients with neurogenic bladder may have suboptimal management, indicated by high incidences of urinary tract complications and hospitalizations.

Prevalence of pediatric dyslipidemia: comparison of a population-based claims database to national surveys.

OBJECTIVE: To determine the prevalence of pediatric dyslipidemia in a large US medical insurance claims database and to compare the resulting estimate to the prevalence from the National Health and Nutrition Examination Survey (NHANES). PATIENTS AND METHODS: Children 10-18 years old who had laboratory-defined dyslipidemia were identified from the Integrated Healthcare Information Services (IHCIS) database 2003-2006. For comparison purposes, the corresponding prevalence among the US children of same age was estimated from the NHANES 1999-2004 data. RESULTS: Among the 273 064 children with at least one laboratory lipid value in the IHCIS database, 22.9% (n = 62 451) had laboratory-defined dyslipidemia. This prevalence was the same as the NHANES estimate (23.9%, 95%CI: 21.6-26.3). Elevated triglyceride (TG) was the most common type of dyslipidemia, detected among 13.2% of the IHCIS children and 14.2% of the US children, followed by elevated total cholesterol (TC), 7.7 and 9.6%, respectively. Among IHCIS dyslipidemic children, older teenage boys had higher rates than younger boys for high-density lipoprotein cholesterol (HDL-C) abnormality, but lower rates for elevated TC and low-density lipoprotein cholesterol (LDL-C). These age-related trends were also seen among NHANES dyslipidemic children. CONCLUSIONS: Analyses of a population-based claims database revealed the same prevalence of pediatric dyslipidemia as that among the US children assessed in the NHANES data. Among dyslipidemic children in the claims database, the occurrence of specific dyslipidemias appeared to vary by age and gender, a trend that was also seen among the dyslipidemic children in the US.

Longitudinal study on pediatric dyslipidemia in population-based claims database.

PURPOSE: To examine the rate of lipid testing among children from a large US medical insurance claims database, describe the characteristics of pediatric dyslipidemia, and assess the sensitivity of the International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) codes for identifying dyslipidemic children. METHODS: This retrospective cohort study used the claims data from the Integrated Healthcare Information Services (IHCIS), for the years 2003-2006. Two study cohorts consisted of children with laboratory-defined and diagnosis/treatment-defined dyslipidemia, respectively. They were compared to age- and gender-matched children without dyslipidemia, with respect to co-morbidities during the 6-month prior to and 12-month after the first dyslipidemic laboratory value or diagnosis/treatment. RESULTS: Seven per cent of the children who had laboratory values available in the database had a cholesterol test during the study period. Only 15% of laboratory-defined children (n = 23,475) had a dyslipidemia diagnosis. Cholesterol-modifying medications were rarely prescribed. Substantially more laboratory-defined children than their comparators were obese (8 times), had diabetes mellitus (10 times), or had hypertension (5 times). These co-morbidities were even higher among diagnosis/treatment-defined children. CONCLUSIONS: The rate of lipid testing among children was low. The ICD-9-CM diagnostic codes showed low sensitivity against laboratory definitions. Though only a small proportion of dyslipidemic children were diagnosed or treated with a medication, co-morbidities associated with dyslipidemia were common.

Hospitalized cardiovascular diseases in neovascular age-related macular degeneration.

OBJECTIVE: To compare the incidence rate of hospitalized myocardial infarctions (MIs) and cerebrovascular accidents (CVAs) in subjects with and without neovascular age-related macular degeneration (AMD). METHODS: A retrospective database cohort study was performed in subjects with neovascular AMD and controls matched for age, sex, geography, and enrollment duration. Healthcare claims for the study period from January 1, 2002, to June 30, 2005, were used to identify subjects and outcomes. Incidence of hospitalized MI and CVA events and rate ratios adjusted for 11 risk factors were calculated. RESULTS: In 7203 subjects with neovascular AMD and 20,208 controls, the rate of MI was 16.2 events per 1000 subjects with neovascular AMD and 23.1 events per 1000 controls. The adjusted rate ratio for MI was 0.58 (95% confidence interval, 0.48-0.72; P < .001) for subjects with neovascular AMD vs controls. The rate of CVA was 14.3 events per 1000 subjects with neovascular AMD and 22.1 events per 1000 controls. The adjusted rate ratio for CVA was 0.56 (95% confidence interval, 0.45-0.70; P < .001). CONCLUSIONS: Rates of MI or CVA were significantly lower in subjects with neovascular AMD than in controls. These findings could not be explained by systematic differences in case selection, health care use, or comorbidities, although other possible biases cannot be ruled out.

Epidemiologic study of smell disturbance in 2 medical insurance claims populations.

OBJECTIVE: To report the rates of medical claims for sense of smell disturbance (SD) and their association with diseases and medications in a managed care population. DESIGN: Descriptive determination of demographics, prevalence, and incidence of SD and case-control analysis of risk factors. Preselected drug and disease groups were entered into a stepwise regression model to determine risk factors for SD. SETTING: Managed care organizations in the United States. PATIENTS: Patients identified through medical claims within IMS Health's LifeLink: Integrated Claims Solution (IMS) and i3 Magnifi Private Managed Care Organizations (MCO) medical insurance databases for 3-year observation periods. MAIN OUTCOME MEASURES: Prevalence and incidence of smell disturbance; adjusted odds ratios and 95% confidence intervals (CIs) of associated conditions and medications. RESULTS: The mean annual prevalence rate of SD was 26.2 per 100 000 for IMS (95% CI, 23.1-29.6) and 17.2 per 100 000 for MCO (95% CI, 15.6-18.7). The mean annual incidence per 100 000 was 26.3 for IMS (95% CI, 23.1-29.8) and 15.9 for MCO (95% CI, 14.5-17.5). The 5 strongest risk factors for SD were chronic sinusitis, oropharyngeal inflammatory disorders, other upper respiratory tract disease excluding sinusitis, cerebrovascular disease, and systemic viral disease. The regression model also retained 3 drug groups (corticosteroids, calcium channel blockers, and nasal and/or sinus products) among the significant risk factors for the presence of SD. CONCLUSIONS: The annual prevalence and incidence rates of SD are lower than prior estimates partly owing to reliance on specific medical claims. A number of conditions preceding the diagnosis of SD were significantly associated with the condition. Uses of certain medications were also risk factors for SD compared with controls.