The efficacy and cost-impact of rasburicase 3†mg versus 6†mg for the management of tumor lysis syndrome: A multicenter analysis.

Purpose: Hyperuricemia is a complication arising from tumor lysis syndrome (TLS). Literature has shown that a single 3 mg dose was just as efficacious as a single 6 mg dose when the uric acid (UA) levels were ≤12 mg/dL. Here, we present a multi-center analysis rasburicase utilization and its effect on healthcare costs. Methods: This is a multi-center, retrospective analysis of adult cancer patients who were admitted to Methodist Le Bonheur Healthcare hospitals and received rasburicase from February 2020 to February 2021. The primary endpoint was to test whether rasburicase 3 mg had similar rates of uric acid normalization (defined as uric acid ≤7.5 mg/dL) within 24 h as a dose of 6 mg. Results: Seventy-nine patients were included in the study. While the baseline uric acid was lower in the 3 mg arm compared to the 6 mg arms, there was no difference in the uric acid normalization at 24 h between the 3 mg arm (95%) and 6 mg arm (82%) (p = 0.134). A cost-savings of over $300,000 annually can be achieved with the proposed protocol. Conclusion: A single, fixed rasburicase dose of 3 mg was effective in normalizing uric acid levels within 24 h, and is associated with significant cost-savings.

Cardiovascular risk of urate-lowering drugs: A study using the National Database of Health Insurance Claims and Specific Health Checkups of Japan.

In the present study, we aimed to investigate the association between urate-lowering drugs and cardiovascular events, primarily focusing on the risk of febuxostat and topiroxostat when compared with allopurinol in Japan. We conducted an observational study with a cohort design using the National Database of Health Insurance Claims and Specific Health Checkups of Japan, including new urate-lowering drugs users between August 1, 2010, and March 31, 2018. Exposure and control groups were defined based on the first prescription of urate-lowering drugs as follows: febuxostat or topiroxostat for exposure groups, allopurinol for the control group, and benzbromarone for the secondary control group. The primary outcome was cardiovascular events, defined as a composite of acute coronary syndrome, cerebral infarction, and cerebral hemorrhage. Hazard ratios were estimated using a Cox proportional hazards model. The number of patients in each exposure and control group was 1,357,671 in the febuxostat group, 83,683 in the topiroxostat group, 1,273,211 in the allopurinol group, and 258,786 in the benzbromarone group. The adjusted hazard ratios for the cardiovascular risk were 0.97 (95% confidence interval [CI]: 0.95-0.98) for febuxostat and 0.84 (95% CI: 0.78-0.90) for topiroxostat groups. The benzbromarone group exhibited similar results. No increased cardiovascular risk was observed with febuxostat or topiroxostat when compared with allopurinol in patients with hyperuricemia in Japan. These results provide real-world evidence regarding the cardiovascular risk associated with urate-lowering drugs, indicating that no additional safety-related regulatory actions are warranted in Japan.

Cost-Effectiveness of Colchicine Prophylaxis for Gout Flares When Commencing Allopurinol.

OBJECTIVE: Colchicine prophylaxis to prevent gout flares when commencing urate-lowering therapy is recommended by international rheumatology society guidelines. Whether this is a cost-effective intervention is currently unknown. Our objective was to perform a cost-effectiveness analysis using both a US cost input model and an Australian cost input model. METHODS: This cost-effectiveness analysis was completed from the point of view of the third-party payer. We used a 2-arm decision tree with 1 arm commencing allopurinol with no colchicine prophylaxis and the other with colchicine prophylaxis. Model inputs were drawn from published literature where available. We completed a univariate and probabilistic sensitivity analysis to confirm the robust nature of the modeling. The time frame for the model was 6 months. RESULTS: The colchicine prophylaxis arm resulted in a cost of $1,276 and 0.49 quality-adjusted life-years (QALYs), while in the placebo arm the cost was $516 and 0.47 QALYs, with an incremental cost-effectiveness ratio of $34,004 per QALY gained. In Australia, where cost of colchicine was much lower, the colchicine arm dominated the placebo ($208 [Australian] in the colchicine arm versus $415 [Australian] in the placebo). Univariate and probability sensitivity analysis demonstrated that results were robust to changes in input parameters. In the probabilistic sensitivity analysis, the probability of colchicine prophylaxis being the most cost-effective option was 93% in the US and 100% in the Australian setting. CONCLUSION: Colchicine prophylaxis to prevent gout flares while commencing allopurinol in gout is very cost-effective.

Prescription of Colchicine with Other Dangerous Concomitant Medications: A Nation-Wide Survey Using the Japanese Claims Database.

The anti-inflammatory agent colchicine may cause toxic effects such as rhabdomyolysis, pancytopenia, and acute respiratory distress syndrome in cases of overdose and when patients have renal or liver impairment. As colchicine is a substrate for CYP3A4 and P-glycoprotein (P-gp), drug-drug interactions are important factors that cause fatal colchicine-related side effects. Thus, we conducted a nation-wide survey to determine the status of inappropriate colchicine prescriptions in Japan. Patients prescribed the regular use of colchicine from April 2014 to March 2017 were identified using the Japanese large health insurance claims database. As the primary endpoint, we evaluated the concomitant prescription proportions of strong CYP3A4 and/or P-gp inhibitors classified as "contraindications for co-administration" with colchicine in patients with renal or liver impairment. We defined these cases as "inappropriate colchicine prescriptions." Additionally, factors affecting inappropriate colchicine prescriptions were analyzed. Among the 3302 enrolled patients, 43 (1.30%) were inappropriately prescribed colchicine. Of these 43 patients, 11 had baseline renal and/or liver impairment. By multiple regression analysis, the primary diseases "gout" and "Behçet's disease" were extracted as independent factors for inappropriate colchicine prescriptions with odds ratios of 0.40 (95% confidence interval: 0.19-0.84) and 4.93 (95% confidence interval: 2.12-11.5), respectively. We found that approximately 1% of patients had important colchicine interactions. Particularly, Behçet's disease was a risk factor for inappropriate prescriptions, with approximately 25% of patients showing renal and/or liver impairment (classified as "contraindications for co-administration"). These findings may be useful for medical professionals who prescribe colchicine therapy.

Allopurinol-induced severe cutaneous adverse drug reactions: Risk minimization measures in Malaysia.

PURPOSE: To describe risk minimization measures (RMMs) implemented in Malaysia for allopurinol-induced severe cutaneous adverse drug reactions (SCARs) and examine their impact using real-world data on allopurinol usage and adverse drug reaction (ADR) reports associated with allopurinol. METHODS: Data on allopurinol ADR reports (2000-2018) were extracted from the Malaysian ADR database. We identified RMMs implemented between 2000 and 2018 from the minutes of relevant meetings and the national pharmacovigilance newsletter. We obtained allopurinol utilization data (2004-2018) from the Pharmaceutical Services Programme. To determine the impact of RMMs on ADR reporting, we considered ADR reports received within 1 year of RMM implementation. We used the Pearson χ2 test to examine the relation between the implementation of RMMs and allopurinol ADR reports. RESULTS: The 16 RMMs for allopurinol-related SCARs implemented in Malaysia involved nine risk communications, four prescriber or patient educational material, and three health system innovations. Allopurinol utilization decreased by 21.5% from 2004 to 2018. ADR reporting rates for all drugs (n = 144 507) and allopurinol (n = 1747) increased. ADR reports involving off-label use decreased by 6% from 2011. SCARs cases remained between 20% and 50%. RMMs implemented showed statistically significant reduction in ADR reports involving off-label use for August 2014 [χ2(1, N = 258) = 5.32, P = .021] and October 2016 [χ2(1, N = 349) = 3.85, P = .0499]. CONCLUSIONS: RMMs to promote the appropriate use of allopurinol and prescriber education have a positive impact. We need further measures to reduce the incidence and severity of allopurinol-induced SCARs, such as patient education and more research into pharmacogenetic screening.

In older adults, new use of allopurinol or febuxostat was linked to hypersensitivity reactions versus colchicine.

SOURCE CITATION: Singh JA, Cleveland JD. Hypersensitivity reactions with allopurinol and febuxostat: a study using the Medicare claims data. Ann Rheum Dis. 2020;79:529-35. 32024648.

Association between long-term prescription of febuxostat and the progression of heart failure with preserved ejection fraction in patients with hypertension and asymptomatic hyperuricemia.

Both hypertension and hyperuricemia are closely associated with the morbidity and mortality of heart failure. This study was designed to evaluate the influences of long-term xanthine oxidase inhibitor (febuxostat) prescription on left ventricular hypertrophy (LVH), left ventricular (LV) diastolic function, and new-onset heart failure with preserved ejection fraction (HFpEF) in these patients. Using a propensity score matching of 1:2 ratio, this retrospective claims database study compared febuxosatat prescription (n = 96) and non-urate-lowering therapy (n = 192) in patients with hypertensive left ventricular hypertrophy (LVH) and asymptomatic hyperuricemia. With a follow-up of 36 months, febuxostat significantly decreased the level of serum uric acid as well as generated more prominent improvement in LVH and LV diastolic function. Besides, the new-onset symptomatic HFpEF occurred in 2 of 96 patients in febuxostat group and 13 of 192 patients in non-urate-lowering group (P = 0.091). No increased risk for major adverse cardiovascular events in patients prescribed with febuxostat was noted. In conclusion, long-term febuxostat exposure was associated with protective effects in terms of LVH or LV diastolic dysfunction in patients with hypertensive LVH and asymptomatic hyperuricemia. Febuxostat also displayed a trend for reduced risk of new-onset HFpEF in this population.

Cost-effectiveness of sequential urate lowering therapies for the management of gout in Singapore.

Aims: Allopurinol is the most common urate lowering therapy (ULT) used to treat gout but may cause life-threatening severe cutaneous adverse reactions (SCAR) in a small number of patients. Risk of SCAR is increased for patients with the HLA-B*58:01 genotype. When alternative ULT is required, febuxostat or probenecid are recommended. The aim of this study was to conduct a cost-utility analysis of sequential ULT treatment strategies for gout, including strategies with and without HLA-B*58:01 genotyping prior to treatment initiation, with a view to inform optimal gout management in Singapore.Materials and methods: A Markov model was developed from the Singapore healthcare payer perspective. Reflecting local practice, 12 different treatment strategies containing at least one ULT (allopurinol, febuxostat, probenecid) were evaluated in adults with gout. Response rates (SUA < 6mg/dL) were derived from an in-house network meta-analysis and from published literature. Incremental cost-effectiveness ratios (ICERs) were calculated over a 30-year time horizon, with costs and benefits discounted at 3% per annum. Sensitivity analyses were conducted to explore uncertainties.Results: Sequential treatment of allopurinol 300 mg/day-allopurinol 600 mg/day-probenecid ("standard of care") was cost-effective compared to no ULT, with an ICER of SGD1,584/QALY. Allopurinol300-allopurinol600-probenecid-febuxostat sequence compared to allopurinol300-allopurinol600-probenecid had an ICER of SGD11,400/QALY. All other treatment strategies were dominated by preceding strategies. Treatment strategies incorporating HLA-B*58:01 genotyping before ULT use were dominated by the corresponding non-genotyping strategy.Conclusions: Current standard of care (allopurinol300-allopurinol 600-probenecid) for gout is cost-effective compared with no ULT in the local context. Febuxostat is unlikely to be cost-effective in Singapore at current prices unless it is used last-line.

Hypersensitivity reactions with allopurinol and febuxostat: a study using the Medicare claims data.

OBJECTIVE: To assess the risk of hypersensitivity reactions (HSRs) with allopurinol and febuxostat in a population-based study. METHODS: We used the 5% Medicare beneficiary sample (≥65 years) from 2006 to 2012 to identify people with a newly filled prescription for allopurinol, febuxostat or colchicine. We used multivariable-adjusted Cox regression analyses to compare the hazard ratio (HR) of incident HSRs with allopurinol or febuxostat use versus colchicine use; separate analyses were done in people exposed to allopurinol. Propensity-matched analyses (5:1) compared hazards with allopurinol versus febuxostat. RESULTS: Crude incidence rates of HSRs were as follows: allopurinol, 23.7; febuxostat, 30.7; and colchicine, 25.6 per 1000 person-years. Compared with colchicine, allopurinol, febuxostat and febuxostat+colchicine were associated with significantly higher HRs of HSRs, 1.32 (95% CI: 1.10 to 1.60) and 1.54 (95% CI: 1.12 to 2.12) and 2.17 (95% CI: 1.18 to 3.99), respectively. In propensity-matched analyses, febuxostat did not significantly differ from allopurinol; HR for HSRs was 1.25 (95% CI: 0.93 to 1.67). Compared with allopurinol start dose <200 mg/day, allopurinol start dose ≥300 mg/day, diabetes and female sex were associated with significantly higher hazard of HSRs, 1.27 (95% CI: 1.12 to 1.44), 1.21 (95% CI: 1.00 to 1.45) and 1.32 (95% CI: 1.17 to 1.48), respectively. The majority (69%) of HSRs occurred in the outpatient setting. CONCLUSIONS: Compared with colchicine, allopurinol and febuxostat similarly increased the risk of HSRs. Allopurinol and febuxostat did not differ from each other. In allopurinol users, starting dose, female sex and diabetes increased this risk, findings that need further study.

Clinical profile of cutaneous adverse drug reactions: a retrospective study of 1883 hospitalized patients from 2007 to 2016 in Shanghai, China.

BACKGROUND: Cutaneous adverse drug reactions (CADRs) are drug-induced skin reactions with or without systemic involvement, ranging from mild maculopapular exanthema (MPE) to life-threatening severe CADRs (S-CADRs). Due to their unpredictability and severity, early recognition of suspected causative drugs is highly recommended. However, the profile of CADRs remains unknown in China. OBJECTIVES: To assess the clinical profile, predominant causative drugs, and cost associated with CADRs in Shanghai, China. MATERIALS AND METHODS: Clinical records of inpatients admitted with a diagnosis of CADRs to the dermatology ward of Huashan Hospital from January 2007 to December 2016 were retrospectively studied. RESULTS: A total of 1,883 patients (1,231 female and 652 male), admitted with a diagnosis of CADR, were investigated. S-CADRs made up 21.99% of all cases (n=414), and urticaria (27.19%) was the most frequent reaction. Of the patients, 53.43% suffered from multiple drug-induced drug eruptions and the rest (45.83%) from single drug-induced drug eruptions. Overall, antimicrobials (28.85%) was the main drug group involved, and for S-CADRs, this was antiepileptic drugs (36.15%). The total cost for CADRs was RMB23,718,788.83 ($3,588,319.04). Both age and sex were related to admission cost (p=0.005 and p=7.84E-8, respectively). Antimicrobials were the most common treatment causing CADRs. CONCLUSION: The management of CADRs requires considerable medical cost. CADRs are not only a health problem but also a significant financial burden for affected individuals.

Cost-Effectiveness of Panel Tests for Multiple Pharmacogenes Associated With Adverse Drug Reactions: An Evaluation Framework.

The cost-effectiveness of testing for multiple genes implicated in adverse drug reactions requires the simultaneous assessment of all actionable information, including future prescribing decisions based on incidental findings. We developed methodology for determining the value of pharmacogenetic panel tests, illustrated with a multigene panel, including HLA-A*31:01, HLA-B*15:02, HLA-B*57:01, HLA-B*58:01, HLA-B (158T), and HLA-DQB1 (126Q). If the findings for all alleles are acted upon, regardless of their individual cost-effectiveness, the HLA panel resulted in cost savings of £378 (US $491), and a quality-adjusted life year gain of 0.0069. Based on a stratified analysis and compared with no testing, initial use of the panel was cost-effective in patients eligible for abacavir (HLA-B*57:01), carbamazepine (HLA-A*31:01), and clozapine (HLA-B (158T) and HLA-DQB1 (126Q)), but not for carbamazepine (HLA-B*15:02) or allopurinol (HLA-B*58:01). The methods presented allow for the assessment of the cost-effectiveness of multiple-gene panels.

Cost-effectiveness of an adherence-enhancing intervention for gout based on real-world data.

AIM: Medication non-adherence influences outcomes of therapies for chronic diseases. Allopurinol is a cornerstone therapy for patients with gout; however, non-adherence to allopurinol is prevalent in Singapore and limits its effectiveness. Between 2008-2010, an adherence-enhancing program was implemented at the rheumatology division of a public tertiary hospital. The cost-effectiveness of this program has not been fully evaluated. With healthcare resources being finite, the value of investing in adherence-enhancing interventions should be ascertained. This study aims to evaluate the cost-effectiveness of this adherence-enhancing program to inform optimal resource allocation toward better gout management. METHOD: Adopting a real-world data approach, we utilized patient clinical and financial records generated in their course of routine care. Intervention and control groups were identified in a standing database and matched on nine risk factors through propensity score matching. Cost and effect data were followed through 1-2 years. A decision tree was developed in TreeAge using a societal perspective. Deterministic and probabilistic sensitivity analyses were performed to assess parameter uncertainty. RESULTS: At an assumed willingness-to-pay threshold of $50 000 USD ($70 000 SGD) per quality-adjusted life year (QALY), the intervention had an 85% probability of being cost-effective compared to routine care. The incremental cost-effectiveness ratio was $12 866 USD per QALY for the base case and ranged from $4 139 to $21 593 USD per QALY in sensitivity analyses. CONCLUSION: The intervention is cost-effective in the short-term, although its long-term cost-effectiveness remains to be evaluated.

Comparison of fixed versus traditional weight-based dosing of rasburicase in a pediatric population.

BACKGROUND: The American Society of Clinical Oncology guidelines recommend rasburicase for the treatment of pediatric patients with hyperuricemia at risk of tumor lysis syndrome (TLS) using a weight-based dose of 0.1-0.2 mg/kg once daily for 1-7 days. However, there has been a trend in practice due to recent data showing benefit using a fixed-dose approach. The purpose of this study was to evaluate the efficacy and safety between fixed and weight-based dosing of rasburicase in a pediatric population. PROCEDURE: This was a retrospective chart review of 48 patients from January 1, 2007 to August 31, 2016 at Children's National Health System. Patients less than 18 years old with a documented diagnosis of a malignancy and baseline uric acid level were included; patients less than 30 kg at the time of rasburicase administration were excluded. RESULTS: The primary endpoint of this study was the treatment success of normalization of uric acid level (<5 mg/dl) within 24 hr of rasburicase administration. Eighty-three percent of patients had success with normalization of uric acid post rasburicase dose. Eighty-five percent of patients had success in the weight-based group compared to eighty-one percent in the fixed-dose group (P = 0.715). Mean percent reduction of uric acid at 24 hr was relatively similar between both groups (94% vs. 89%). CONCLUSION: Our results suggest that a fixed-dose strategy of rasburicase is both safe and effective in reducing uric acid levels in the pediatric patient population. A fixed dose of rasburicase 6 mg is a cost-effective treatment option for TLS.

Design and Rationale for the Veterans Affairs "Cooperative Study Program 594 Comparative Effectiveness in Gout: Allopurinol vs. Febuxostat" Trial.

BACKGROUND: Gout patients do not routinely achieve optimal outcomes related in part to suboptimal administration of urate lowering therapy (ULT) including first-line xanthine oxidase inhibitors allopurinol or febuxostat. Studies leading to the approval of febuxostat compared this agent to allopurinol in inappropriately low, fixed doses. We will compare allopurinol with febuxostat in gout using appropriately titrated doses of both agents and a "treat-to-target" strategy congruent with specialty guidelines. METHODS: We have planned and initiated the Veterans Affairs (VA) Cooperative Study Program (CSP) 594, Comparative Effectiveness in Gout: Allopurinol vs Febuxostat study. This large double-blind, non-inferiority trial will enroll 950 gout patients randomized to receive allopurinol or febuxostat. Patients will be followed for a total of 72 weeks encompassing 3 distinct 24-week study phases. During Phase I (0-24 weeks), participants will undergo gradual dose titration of ULT until achievement of serum uric acid (sUA) <6.0 mg/dL or <5.0 mg/dL if tophi are present. Dose escalation will not be allowed during final three study visits of Phase 2 (24-48 weeks) and during Phase 3 (48-72 weeks). The primary study outcome is the proportion of participants experiencing at least one gout flare during Phase 3. Subsequent to the 72-week study, participants will be followed passively for up to 10 years after the study to assess long-term health outcomes. CONCLUSION: With its completion, the VA Comparative Effectiveness in Gout: Allopurinol vs Febuxostat study will demonstrate the central role of gradual ULT dose escalation and a treat-to-target strategy in gout management.