Positioning of tofacitinib in treatment of ulcerative colitis: a global perspective.

INTRODUCTION: Tofacitinib has emerged as a useful drug for the treatment of ulcerative colitis (UC). AREAS COVERED: There is an unmet need for cost-effective, non-immunogenic drugs with a safe adverse effect profile to treat patients with ulcerative colitis. In the present review, we evaluate the available literature to inform the appropriate positioning of tofacitinib in the current drug landscape and identify subsets where its use should be done with caution. EXPERT OPINION: Tofacitinib is helpful in the treatment of patients where the standard conventional or biological therapies have failed or were not tolerated. With lower costs of the generic drug than the biologicals (or biosimilars), it could be an important therapy in low- to middle-income countries. The risk of infections, especially Herpes Zoster and tuberculosis, needs to be addressed before initiation. Tofacitinib should be avoided in patients with venous thromboembolism and cardiovascular disease risk factors. Due to limited evidence, the use is not recommended in pregnancy, while it should be used with caution in elderly citizens. Future trials should look into the head-to-head comparison of tofacitinib with biologicals. The role of tofacitinib in acute severe colitis needs evaluation with comparative trials with current standards of care.

Sunitinib-Induced Congestive Heart Failure in a Patient with Gastrointestinal Stromal Tumor.

Common cardiovascular toxicities of sunitinib mainly include hypertension, QT prolongation, left ventricular dysfunction (LVD) and less frequently, congestive heart failure (CHF). Here, we report the case of a 67-year-old woman who developed heart failure after 24 months of sunitinib. Our case highlights the importance of strict and regular cardiovascular monitoring during sunitinib. It also shows that the reintroduction of sunitinib with maintaining heart failure treatment can be safe. The exact mechanisms of this cardiotoxicity have not been understood. There is no protective therapy available. Therefore, further investigations are needed in these areas. Medical specialists who prescribe and treat patients with sunitinib should be aware of the possible occurrence of these conditions and perform regular checkup of sunitinib-treated patients.

Real-world evidence of the effectiveness and safety of generic tofacitinib in rheumatoid arthritis patients: a retrospective, single-centre analysis from Western India.

Generic tofacitinib has been available in India for more than a year and is widely used in rheumatoid arthritis (RA) therapy. There is scarce real-world data on its effectiveness and safety from India, especially given infection endemicity. We retrospectively analysed records (demographic and clinical information, haematology and biochemistry, adverse events) of patients prescribed generic tofacitinib from a single centre in Mumbai, India. Disease activity was calculated using the disease activity score-28 and erythrocyte sedimentation rate (DAS28-ESR) and other tools, and we used paired T-tests for significant response. We defined clinical tofacitinib failure as a composite outcome, including clinician's decision to change to an alternative disease-modifying anti-rheumatic drug (DMARD) or flare after self-withdrawal. We performed logistic regression and survival analysis for determinants of clinical failure. We reviewed records of 102 patients (92 female; median age: 53 years) with mean RA duration of 146 months. Thirteen had prior treatment with innovator tofacitinib. There was significant improvement in disease activity parameters at a mean duration of 186 days. No serious adverse events were reported; 4 patients had tuberculosis and 19 patients had mild COVID-19 while on treatment. Clinical failure was seen in 25 patients, and mean time to failure on survival analysis was 357 days. No baseline characteristic predicted clinical failure. Generic tofacitinib showed good effectiveness and a tolerable adverse effect profile, despite tuberculosis endemicity and COVID-19. Setting up registries would be valuable in gaining more data on generic tofacitinib. Key Points • There is scarce data from India regarding the use of tofacitinib in rheumatoid arthritis, despite widespread use. • In this retrospective analysis of 102 patients at a single centre, we found tofacitinib monotherapy was efficacious and tolerable. • Tuberculosis was detected in four and nineteen patients had mild covid.

Time trends for drug specific adverse events in patients on sunitinib; implications for remote monitoring.

INTRODUCTION: Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor used to treat metastatic renal cell carcinoma (mRCC). Patients on sunitinib do require regular in-person appointments to monitor for adverse events (AEs). Given the Covid-19 pandemic, regular in-person visits expose patients to an increased risk of infection in addition to potentially preventable travel costs. This study investigated the feasibility of implementing a remote monitoring strategy for patients being treated with sunitinib for mRCC by examining the time trends of AEs. MATERIALS AND METHODS: In this retrospective chart review of patients with a diagnosis of mRCC, 167 patients received sunitinib during their treatment. The time between initiation of treatment and the first AE was recorded. The AEs were categorized according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5. Survival analysis was used to calculate the time-to-AE. RESULTS: Of the 167 patients identified, 145 experienced an AE (86.8%). Hypertension was the most common AE with 80% of AEs were ≤ Grade 2. Incidence of AE dropped by 91% after 3 months follow up and a further 36% after 6 months. The cumulative incidence of AEs were 87.8%, 94.6% and 98.0%, at 3, 6 and 9 months respectively. The severity of AEs observed were 39.3%, 38.6%, 20.7%, 1.4%,0% of Grade 1-5 events respectively. A trend of grade migration to less severe grades was also shown over time, with percentage of Grade ≥ 3 toxicity dropping from 22% between 0-3 months to 14% beyond 6 months follow up. CONCLUSIONS: The role of remote monitoring for mRCC patients on sunitinib remains relevant now with new waves of the Covid-19 pandemic, triggered by novel variants. The majority of AEs observed were of low severity ≤ Grade 2, with a trend of reduced AE frequency and severity most prevalent beyond 3 months of follow up. This data appears to support the implementation of a remote monitoring strategy 3 months after initiation of treatment.

Atogepant for the Preventive Treatment of Migraine.

BACKGROUND: Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist that is being investigated for the preventive treatment of migraine. METHODS: In a phase 3, double-blind trial, we randomly assigned adults with 4 to 14 migraine days per month in a 1:1:1:1 ratio to receive a once-daily dose of oral atogepant (10 mg, 30 mg, or 60 mg) or placebo for 12 weeks. The primary end point was the change from baseline in the mean number of migraine days per month across the 12 weeks. Secondary end points included headache days per month, a reduction from baseline of at least 50% in the 3-month average of migraine days per month, quality of life, and scores on the Activity Impairment in Migraine-Diary (AIM-D). RESULTS: A total of 2270 participants were screened, 910 were enrolled, and 873 were included in the efficacy analysis; 214 were assigned to the 10-mg atogepant group, 223 to the 30-mg atogepant group, 222 to the 60-mg atogepant group, and 214 to the placebo group. The mean number of migraine days per month at baseline ranged from 7.5 to 7.9 in the four groups. The changes from baseline across 12 weeks were -3.7 days with 10-mg atogepant, -3.9 days with 30-mg atogepant, -4.2 days with 60-mg atogepant, and -2.5 days with placebo. The mean differences from placebo in the change from baseline were -1.2 days with 10-mg atogepant (95% confidence interval [CI], -1.8 to -0.6), -1.4 days with 30-mg atogepant (95% CI, -1.9 to -0.8), and -1.7 days with 60-mg atogepant (95% CI, -2.3 to -1.2) (P<0.001 for all comparisons with placebo). Results for the secondary end points favored atogepant over placebo with the exceptions of the AIM-D Performance of Daily Activities score and the AIM-D Physical Impairment score for the 10-mg dose. The most common adverse events were constipation (6.9 to 7.7% across atogepant doses) and nausea (4.4 to 6.1% across atogepant doses). Serious adverse events included one case each of asthma and optic neuritis in the 10-mg atogepant group. CONCLUSIONS: Oral atogepant once daily was effective in reducing the number of migraine days and headache days over a period of 12 weeks. Adverse events included constipation and nausea. Longer and larger trials are needed to determine the effect and safety of atogepant for migraine prevention. (Funded by Allergan; ADVANCE ClinicalTrials.gov number, NCT03777059.).

Removal of Remdesivir's Metabolite GS-441524 by Hemodialysis in a Double Lung Transplant Recipient with COVID-19.

Remdesivir has reported efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro and in vivo Drug-drug interactions limit therapeutic options in transplant patients. Remdesivir and its metabolite GS-441524 are excreted principally in urine. In intensive care unit (ICU) settings, in which multiple-organ dysfunctions can occur rapidly, hemodialysis may be a viable option for maintaining remdesivir treatment, while improving tolerance, by removing both remdesivir's metabolite (GS-441524) and sulfobutylether ß-cyclodextrin sodium (SEBCD). Additional studies may prove informative, particularly in the evaluations of therapeutic options for coronavirus disease 2019 (COVID-19).