Evaluation of Potential Complications of Interstitial Lung Disease Associated With Antiandrogens Using Data From Databases Reporting Spontaneous Adverse Effects

From 2002 to 2018, the number of patients with prostate cancer significantly increased from 679,023 to 1276,106 worldwide. Total prostatectomy (including robot-assisted prostatectomy), radiation therapy, and pharmacological treatment are commonly used to treat prostate cancer. The Chief of the Pharmaceutical Safety Division, that is, the Federation of Pharmaceutical Manufacturers’ Associations of Japan (FPMAJ), recently called for the revision of package inserts for ethical drugs. However, the pathogenesis of interstitial lung disease (ILD), a serious drug-induced adverse effect, remains unclear. Moreover, there have been no large-scale evaluations of potential complications associated with currently used antiandrogens, which are commonly employed to treat prostate cancer. Hence, ILD, as an adverse event, remains poorly understood. Therefore, we conducted a survey of reports in the Japanese Adverse Drug Event Report (JADER) database to investigate the potential association between the reporting of ILD and antiandrogen drug use in clinical practice. The occurrence of ILD was investigated by evaluating the relationship between antiandrogen drug use and ILD. Adverse event signals were detected with reporting odds ratios (RORs), using data from the JADER and FDA Adverse Event Reporting System (FAERS) databases, for the analysis of post-marketing adverse event reports. The JADER was used to examine the time profile of adverse event occurrence for each drug, whereas the FAERS was used to screen cases of unknown adverse events and analyze their trends of occurrence. The analysis of data from both databases revealed the 95% confidence interval lower limits of ROR for bicalutamide and flutamide to be > 1, and adverse event signals were detected following the use of either drug. While caution should be exercised for drugs that are new to the market, we conclude that drugs with similar therapeutic effects that have been in use for a long period should also be re-examined for potential adverse events.

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Immune-related adverse events for different age groups using the FDA Adverse Event Reporting System.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14256 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14256-e14256

Author(s):

Zin Myint ◽

Ayman Qasrawi ◽

Richard O'Neal ◽

Chris Z Thomas ◽

Susanne M. Arnold ◽

...

Keyword(s):

Adverse Event ◽

Interstitial Lung Disease ◽

Adverse Events ◽

Lung Disease ◽

Reporting System ◽

Adverse Event Reporting System ◽

Age Groups ◽

Adverse Event Reporting ◽

Age Group ◽

Event Reporting

e14256 Background: Understanding immune-related adverse events (irAEs) for different age groups is crucial in the era of immunotherapy. The aim of our study is to assess the irAE profiles in different age groups (≤65 and > 65 years) for drugs that target PD1/PDL1, CTLA4, and their combination. Methods: Data were obtained from the FDA Adverse Event Reporting System database from Jan 2014 to Sep 2018. We extracted the data based on reported irAEs and reviewed 30 different irAEs including, but not limited to colitis, pneumonitis, interstitial lung disease (ILD), myocarditis and pneumonitis. Cases with missing data, another drug reported with the PD1/PDL1 or CTLA4 combinations, and duplicate cases were excluded. We calculated the reporting odds ratio (ROR) for irAE associated with the use of PD1/PDL1, CTLA4 and combination, respectively. Results: A total of 6197 reported irAEs cases were included: 3140 cases from patients ≤65 years and 3057 from > 65 years old. Colitis was the most common irAEs in both groups. The RORs (95% CI) in patients using CTLA4 alone, PD1/PDL1 alone or the combination were 4.17 (3.47-5.02), 0.6 (0.5-0.72), 1.98 (1.64-2.39) for colitis; 0.21 (0.09-0.52), 2.94 (1.97-4.38), 2.2 (1.46-3.3) for diabetic ketoacidosis; 0.29 (0.09-0.92), 16.5 (6.54-41.9), 0.18 (0.04-0.73) for rheumatoid arthritis in ≤65 age group. In > 65 age group, the RORs (95% CI) in patients using CTLA4 alone, PD1/PDL1 alone or the combination were 4.79 (3.49-6.58), 0.56 (0.4-0.78), 2.84 (2.06-4) for hypophysitis; 0.12 (0.06-0.24), 28.53 (18.5-44), 0.17 (0.1-0.29) for interstitial lung disease (ILD); 0.38 (0.19-0.78), 2.87 (2.01-4.1), 2.41 (1.64-3.54) for myocarditis. When we compared all the studied irAEs between age groups (≤65 and > 65) by ROR, the only statistically significant irAE was ILD. The RORs (95%CI) for ILD associated with PD1/PDL1 in age≤65 and > 65 were 11.3 (7.65-16.8) & 28.53 (18.49-44.02). Conclusions: There was no significant difference between irAEs in different age groups except with ILD, which is more commonly seen in the > 65 age group. The ROR combination irAE profiles provide hypothesis generating information regarding association between irAEs and the use of various immune therapies.

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Safety and tolerability of nintedanib in patients with systemic sclerosis-associated interstitial lung disease: data from the SENSCIS trial

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-217331 ◽

2020 ◽

Vol 79 (11) ◽

pp. 1478-1484

Author(s):

James R Seibold ◽

Toby M Maher ◽

Kristin B Highland ◽

Shervin Assassi ◽

Arata Azuma ◽

...

Keyword(s):

Adverse Event ◽

Systemic Sclerosis ◽

Interstitial Lung Disease ◽

Adverse Events ◽

Lung Disease ◽

Treatment Interruption ◽

Common Adverse Event ◽

Tolerability Profile ◽

Trial Drug ◽

The Impact

ObjectivesTo characterise the safety and tolerability of nintedanib and the dose adjustments used to manage adverse events in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD).MethodsIn the SENSCIS trial, patients with SSc-ILD were randomised to receive nintedanib 150 mg two times per day or placebo. To manage adverse events, treatment could be interrupted or the dose reduced to 100 mg two times per day. We assessed adverse events and dose adjustments over 52 weeks.ResultsA total of 576 patients received nintedanib (n=288) or placebo (n=288). The most common adverse event was diarrhoea, reported in 75.7% of patients in the nintedanib group and 31.6% in the placebo group; diarrhoea led to permanent treatment discontinuation in 6.9% and 0.3% of patients in the nintedanib and placebo groups, respectively. In the nintedanib and placebo groups, respectively, 48.3% and 12.2% of patients had ≥1 dose reduction and/or treatment interruption, and adverse events led to permanent discontinuation of the trial drug in 16.0% and 8.7% of patients. The adverse events associated with nintedanib were similar across subgroups defined by age, sex, race and weight. The rate of decline in forced vital capacity in patients treated with nintedanib was similar irrespective of dose adjustments.ConclusionsThe adverse event profile of nintedanib in patients with SSc-ILD is consistent with its established safety and tolerability profile in patients with idiopathic pulmonary fibrosis. Dose adjustment is important to minimise the impact of adverse events and help patients remain on therapy.

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POS0645 RITUXIMAB THERAPY IN THE INTERSTITIAL LUNG DISEASE OF RHEUMATOID ARTHRITIS: A SYSTEMATIC REVIEW

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.4192 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 560.3-561

Author(s):

E. F. Vicente-Rabaneda ◽

J. De la Macorra ◽

J. P. Baldivieso ◽

F. Gutiérrez-Rodríguez ◽

A. García-Vadillo ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Interstitial Lung Disease ◽

Lung Function ◽

Adverse Events ◽

Lung Disease ◽

Statistical Significance ◽

Connective Tissue Diseases ◽

Case Series ◽

Original Research ◽

Case Control Studies

Background:Interstitial lung disease (ILD) is a severe manifestation of rheumatoid arthritis (RA), linked to increased mortality. There is still no consensus on the best therapeutic strategy as there aren’t yet randomized controlled trials.Objectives:To analyze the available scientific evidence on the efficacy and safety of rituximab (RTX) treatment of interstitial lung disease (ILD) associated with rheumatoid arthritis (RA).Methods:A systematic search was carried out in PubMed until April 2020 following the PRISMA recommendations. Studies were selected according to the following inclusion criteria: (1) original research, including case series, case/control studies, cohort studies, and clinical trials; (2) population with RA and associated ILD, either monographically or together with other connective tissue diseases (CTD), provided that individualized data on patients with RA were provided; (3) patients treated with RTX; (4) objective and quantifiable results on the evolution of ILD after treatment with available data of FVC, DLCO and/or HRCT.Results:Of the 64 papers identified, 9 articles were selected. The studies showed great heterogeneity in design, both in the sample selection criteria and in the objectives of the analysis. Most were observational, retrospective (n = 6) or prospective (n = 2) studies, with only one open prospective experimental study. Those focused on RA predominated, but 3 of them also included patients with other CTDs. The mean age of the patients in the different studies ranged between 52 and 70 years, predominantly women. 40-79% had a history of smoking and were mostly positive for rheumatoid factor (83-100%) and anti-CCP (82-100%). The most frequent radiological patterns were NSIP, UIP and undefined. The outcome measures were diverse: changes in respiratory function tests (LTF) and HRCT, incidence of pulmonary dysfunction, mortality rates, effect on glucocorticoid deprivation, delay in inclusion in the lung transplant list and/or serious adverse events. The initiation of RTX was motivated by pulmonary and/or joint pathology, in patients with failure to other synthetic or biological DMARDs. A total of 393 treatment cycles were collected in 114 patients, with a mean of 3.45 cycles per patient. The RTX regimen was 2 infusions of 1g 2 weeks apart in all patients, except for 1 who received the lymphoma-like regimen. With regard to the efficacy of the treatment with RTX, improvement and especially stabilization of HRCT and LFT predominated, with numerically greater improvement for DLCO than for FVC. There was also a favorable trend in the evolution of patients treated with RTX compared to controls, although it did not reach statistical significance, and a lower risk of deterioration of lung function in patients treated with RTX versus those who had received other DMARDs. The mortality rate found at 5 years was lower than that previously described for the disease and half for the patients treated with RTX compared to those treated with anti-TNF. The adverse events described in the studies did not show additional safety alerts to those already described for RTX.Conclusion:RTX seems to be postulated as a promising therapy for patients with ILD associated with RA, showing a stabilizing effect on the lung function, with an acceptable safety profile. However, further research of higher methodological quality prospective studies is needed to confirm these favorable preliminary results.Disclosure of Interests:None declared

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Abstract 16180: Cardiovascular Adverse Events Associated With Androgen Receptor-targeted Therapy Used in the Treatment of Prostate Cancer

Circulation ◽

10.1161/circ.142.suppl_3.16180 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Bishesh Shrestha ◽

Sugam Gouli ◽

Asis Shrestha

Keyword(s):

Prostate Cancer ◽

Heart Failure ◽

Atrial Fibrillation ◽

Adverse Event ◽

Androgen Receptor ◽

Targeted Therapy ◽

Coronary Artery ◽

Adverse Events ◽

Cardiogenic Shock ◽

Cardiovascular Adverse Event

Introduction: Prostate cancer is the second most common cancer in males. Its risk increases with age. So does the risk for cardiovascular disease. Androgen receptor-targeted therapy is now recommended to be added to androgen-deprivation therapy in the treatment of prostate cancer. We present common cardiovascular adverse events seen with the use of anti-androgens medication: abiraterone, enzalutamide, apalutamide, and darolutamide. Methods: We conducted a meta-analysis of 13 multinational randomized phase III clinical trials looking for cardiovascular adverse events in groups that received abiraterone, enzalutamide, apalutamide and darolutamide for treatment of prostate cancer. We analyzed a cohort of 9867 patients in these trials. Results: In the abiraterone usage group (n= 3492), most common cardiovascular adverse event was hypertension reported in 16.03%. Atrial fibrillation was reported in 0.97% and other cardiovascular events (IHD, MI, SVT, VT, and heart failure) were seen in 9.56%. In the enzalutamide usage group (n=4094) hypertension was seen in 10.6%, IHD in 1.88%, and atrial fibrillation was seen in 0.39%. Other unspecified cardiovascular adverse events were reported in 5.98%. In the apalutamide usage group (n=1327) hypertension was seen in 22%. Other cardiovascular adverse events (atrial fibrillation, MI, cardiogenic shock) were seen in 0.96%. In the darolutamide usage group (n=954) hypertension was seen in 6.6%, coronary artery disorders (coronary artery disease, coronary artery occlusion and stenosis) in 3.24%, and heart failure in 1.88%. Conclusions: The most common cardiovascular adverse event with use of anti-androgen medication seen in this large cohort analysis was hypertension with highest incidence seen in apalutamide group. Other cardiovascular side-effects noted were atrial fibrillation, SVT, VT, ischemic heart disease, MI, heart failure, and cardiogenic shock. Abiraterone and enzalutamide are the drugs that have been used in most trials. FDA adverse reaction reporting system (FAERS) shows hypertension as the most commonly reported cardiovascular adverse event with abiraterone and enzalutamide use. More prospective studies are needed to further access cardiovascular risk with use of anti-androgen therapy.

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DRUG-INDUCED INTERSTITIAL LUNG DISEASE DURING COMBINED ANDROGEN BLOCKADE WITH BICALUTAMIDE AND LEUPRORELIN ACETATE FOR PROSTATE CANCER

The Japanese Journal of Urology ◽

10.5980/jpnjurol.110.36 ◽

2019 ◽

Vol 110 (1) ◽

pp. 36-40 ◽

Cited By ~ 1

Author(s):

Koki Maeda ◽

Takashi Osafune ◽

Yoshikata Masuda ◽

Takayuki Takeda ◽

Susumu Kageyama ◽

...

Keyword(s):

Prostate Cancer ◽

Interstitial Lung Disease ◽

Lung Disease ◽

Drug Induced ◽

Leuprorelin Acetate ◽

Combined Androgen Blockade ◽

Androgen Blockade

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Study design of a randomised, placebo-controlled trial of nintedanib in children and adolescents with fibrosing interstitial lung disease

ERJ Open Research ◽

10.1183/23120541.00805-2020 ◽

2021 ◽

pp. 00805-2020

Author(s):

Robin Deterding ◽

Matthias Griese ◽

Gail Deutsch ◽

David Warburton ◽

Emily M. DeBoer ◽

...

Keyword(s):

Interstitial Lung Disease ◽

Adverse Events ◽

Lung Disease ◽

Children And Adolescents ◽

Controlled Trial ◽

Controlled Clinical Trial ◽

Life Questionnaire ◽

Long Term Effects ◽

Double Blind ◽

Clinically Significant

IntroductionChildhood interstitial lung disease (chILD) comprises >200 rare respiratory disorders, with no currently approved therapies and variable prognosis. Nintedanib reduces the rate of forced vital capacity (FVC) decline in adults with progressive fibrosing ILDs. We present the design of a multicentre, prospective, double-blind, randomised, placebo-controlled clinical trial of nintedanib in patients with fibrosing chILD (1199-0337 or InPedILD™; ClinicalTrials.gov: NCT04093024).Methods and analysisMale or female children and adolescents aged 6–17 years (≥30; including ≥20 adolescents aged 12–17 years) with clinically significant fibrosing ILD will be randomised 2:1 to receive oral nintedanib or placebo on top of standard of care for 24 weeks (double-blind), followed by variable duration nintedanib (open-label). Nintedanib dosing will be based on body weight-dependent allometric scaling, with single-step dose reductions permitted to manage adverse events. Eligible patients will have evidence of fibrosis on high-resolution computed tomography (within 12 months of their first screening visit), FVC ≥25% predicted, and clinically significant disease (Fan score of ≥3 or evidence of clinical progression over time). Patients with underlying chronic liver disease, significant pulmonary arterial hypertension, cardiovascular disease, or increased bleeding risk are ineligible. The primary endpoints are pharmacokinetics and the proportion of patients with treatment-emergent adverse events at Week 24. Secondary endpoints include change in FVC% predicted from baseline, Pediatric Quality of Life Questionnaire™, oxygen saturation, and 6-minute walk distance at Weeks 24 and 52. Additional efficacy and safety endpoints will be collected to explore long-term effects. #PedILD. #InPedILD.

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Successful treatment of anti-MDA5 antibody-positive refractory interstitial lung disease with plasma exchange therapy

Rheumatology ◽

10.1093/rheumatology/kez357 ◽

2019 ◽

Vol 59 (4) ◽

pp. 767-771 ◽

Cited By ~ 5

Author(s):

Yoshiyuki Abe ◽

Makio Kusaoi ◽

Kurisu Tada ◽

Ken Yamaji ◽

Naoto Tamura

Keyword(s):

Survival Rate ◽

Interstitial Lung Disease ◽

Adverse Events ◽

Lung Disease ◽

Plasma Exchange ◽

Immunosuppressive Therapy ◽

Fresh Frozen Plasma ◽

Fresh Frozen ◽

Frozen Plasma ◽

Intensive Immunosuppressive Therapy

Abstract Objectives We examined the effectiveness of plasma exchange (PE) therapy to reduce the mortality of rapidly progressive interstitial lung disease (RP-ILD) in patients positive for anti-melanoma differentiation-associated gene 5 (MDA5) antibodies. Methods Among 142 patients newly diagnosed with PM/DM or clinically amyopathic DM from 2008 to 2019 at our hospital, 10 were diagnosed with refractory RP-ILD and were positive for anti-MDA5 antibodies. PE was used as an adjunct to standard therapy and consisted of fresh frozen plasma as replacement solution. The primary outcome was non-disease-specific mortality. Results Anti-MDA5 antibodies were detected in 28 patients, of whom 21 were diagnosed with RP-ILD and 10 were refractory to intensive immunosuppressive therapy. Six patients received PE (PE group) and four did not (non-PE group). The 1-year survival rate of the PE group was higher than that of the non-PE group (100% and 25%, respectively, P = 0.033). Regarding adverse events associated with PE, two patients had anaphylactic shock, one had high fever due to fresh frozen plasma allergy and one had a catheter infection. All adverse events resolved with appropriate treatment. Conclusion We evaluated the association between 1-year survival rate and PE for refractory RP-ILD in patients positive for anti-MDA5 antibodies. Intensive immunosuppressive therapy improved the survival rate in RP-ILD patients with anti-MDA5 antibodies, but 20–30% of cases were still fatal. PE could be administered to patients with active infectious disease who were immunocompromised by intensive immunosuppressive therapy. PE may be considered in refractory RP-ILD patients positive for anti-MDA5 antibodies.

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Incidence and outcome of interstitial lung disease (ILD) with everolimus treatment for metastatic renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.6_suppl.427 ◽

2013 ◽

Vol 31 (6_suppl) ◽

pp. 427-427

Author(s):

Fumiya Hongo ◽

Masakatsu Oishi ◽

Takashi Ueda ◽

Yasunori Kimura ◽

Terukazu Nakamura ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Interstitial Lung Disease ◽

Adverse Events ◽

Lung Disease ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Progression Free Survival ◽

Intermediate Risk ◽

Free Survival

427 Background: Interstitial lung disease (ILD) is known as one of the adverse events during treatment with everolimus for metastatic renal cell carcinoma (mRCC). Methods: We retrospectively assessed the incidence and outcome of ILD in mRCC patients treated with everolimus. From April 2010 to August 2012, 25 cases were treated with everolimus after failure of one or two TKIs in our institute. All adverse events were graded in accordance with NCI CTCAE, version 3.0. Results: A total of 25 patients received treatment with everolimus. They included 18 male and 7 female patients ranging in age from 21 to 84 years (median 62). According to MSKCC risk criteria, 6 cases were at favorable risk, 16 cases were at intermediate risk, and 3 cases were at poor risk. Median treatment term was 4 months (range 2-17 months). SD was in 19 cases and PD was in 6 cases. Progression free survival was 3.5 months and overall survival was 12 months. ILD was found in 7 cases (28%). 1 was G1, 5 were G2 and 1 was G3. Corticosteroid therapy was initiated in 3 cases. In 5 of 7 ILD cases, everolimus was re-challenged. In our series, patients with ILD showed significantly better progression free survival than those without ILD (PFS was 8 months vs. 3 months. Log-rank, p < 0.001). There were no significant different between the 2 groups in over all survival (12 months in patients with ILD vs. 10 months in patients without ILD. Log-rank, NS). Conclusions: Everolimus appears to be effective and well-tolerated in our institute. Re-challenge of everolimus was feasible after improving of everolimus-induced ILD in cases of grade 1-2.

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