Pharmacokinetic-Pharmacodynamic Assessment of the Hepatic and Bone Marrow Toxicities of the New Trypanoside Fexinidazole.

Fexinidazole is a novel oral treatment for human African trypanosomiasis caused by Trypanosoma brucei gambiense (g-HAT). Fexinidazole also has activity against T. cruzi, the causative agent of Chagas disease. During the course of a dose ranging assessment in patients with chronic indeterminate Chagas disease, delayed neutropenia and significant increases in hepatic transaminases were observed and clinical investigations were suspended. We retrospectively analyzed all available pharmacokinetic and pharmacodynamic data on fexinidazole in normal healthy volunteers and in patients with Chagas disease and g-HAT to assess the determinants of toxicity. A population pharmacokinetic model was fitted to plasma concentrations (n = 4,549) of the bioactive fexinidazole sulfone metabolite, accounting for the majority of the bioactive exposure, from three phase 1 studies, two g-HAT phase 2/3 field trials, and one Chagas disease phase 2 field trial (n = 462 individuals in total). Bayesian exposure-response models were then fitted to hematological and liver-related pharmacodynamic outcomes in Chagas disease patients. Neutropenia, reductions in platelet counts, and elevations in liver transaminases were all found to be exposure dependent and, thus, dose dependent in patients with Chagas disease. Clinically insignificant transient reductions in neutrophil and platelet counts consistent with these exposure-response relationships were observed in patients with g-HAT. In contrast, no evidence of hepatotoxicity was observed in patients with g-HAT. Fexinidazole treatment results in a dose-dependent liver toxicity and transient bone marrow suppression in Chagas disease patients. Regimens of shorter duration should be evaluated in clinical trials with patients with Chagas disease. The currently recommended regimen for sleeping sickness provides exposures within a satisfactory safety margin for bone marrow suppression and does not cause hepatotoxicity.

Cost-effectiveness of ceritinib in previously untreated anaplastic lymphoma kinase-positive metastatic non-small cell lung cancer in the United States.

AIMS: To assess the cost-effectiveness of first-line ceritinib vs crizotinib and platinum doublet chemotherapy for anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) from a US third-party payer's perspective. MATERIALS AND METHODS: A partitioned survival model with three health states (stable disease, progressive disease, death) was developed over a 20-year time horizon. Ceritinib's efficacy inputs (progression-free and overall survival) were estimated from ASCEND-4; parametric survival models extrapolated data beyond the trial period. The relative efficacy of ceritinib vs chemotherapy was obtained from ASCEND-4, the relative efficacy of ceritinib vs crizotinib was estimated using a matching-adjusted indirect comparison based on ASCEND-4 and PROFILE 1014. Drug acquisition, treatment administration, adverse event management, and medical costs were obtained from publicly available databases and the literature, and inflated to 2016 US dollars. Treatment-specific stable-state utilities were derived from trials and progressive-state utility from the literature. Incremental costs per quality-adjusted life year (QALY) were estimated for ceritinib vs each comparator. Cost-effectiveness was assessed based on US willingness-to-pay thresholds. Deterministic and probabilistic sensitivity analyses were performed to test model robustness. RESULTS: In the base case, first-line ceritinib was associated with total direct costs of $299,777 and 3.28 QALYs (from 4.61 life years gained [LYG]) over 20 years. First-line crizotinib and chemotherapy were associated with 2.73 and 2.41 QALYs, 3.92 and 3.53 LYG, and $263,172 and $228,184 total direct costs, respectively. The incremental cost per QALY gained was $66,064 for ceritinib vs crizotinib and $81,645 for ceritinib vs chemotherapy. In the first 2 years following treatment initiation, ceritinib dominated crizotinib by conferring greater health benefits at reduced total costs. Results were robust to deterministic and probabilistic sensitivity analyses. LIMITATIONS: In the absence of head-to-head trials, an indirect comparison method was used. CONCLUSIONS: Ceritinib is cost-effective compared to crizotinib and chemotherapy in the treatment of previously untreated ALK-positive metastatic NCSLC in the US.

NSAID-antihypertensive drug interactions: which outpatients are at risk for a rise in systolic blood pressure?

BACKGROUND: Management guidelines for drug-drug interactions between non-steroidal anti-inflammatory drugs (NSAIDs) and antihypertensives recommend blood pressure monitoring in hypertensive patients. We measured the short-term effect of initiating NSAIDs on systolic blood pressure (SBP) in users of antihypertensives, aiming to investigate which outpatients are at risk for an increase in SBP in daily clinical practice. DESIGN: A cohort study with a nested case-control design in Dutch community pharmacies. METHODS: Patients with a drug-drug interaction alert for a newly initiated NSAID and antihypertensive were interviewed and their SBP was measured at T0, after one week (T1) and after two weeks (T2). We evaluated risk factors for exceeding a predefined limit of change (PLoC) in SBP (≥ 10 mmHg to ≥ 140 mmHg) at T1 and T2 versus T0. RESULTS: For 112 patients the SBP at T0 was measured. Two patients were excluded (T0 SBP ≥ 180 mmHg). PLoC was exceeded in 10 patients (10.4%) at T1 and in seven patients (8.0%) at T2. Patients using etoricoxib (odds ratio (OR), 21.0; 95% confidence interval (CI), 3.7-120.6) and patients using >1 defined daily dose of an NSAID (OR, 3.3; 95% CI, 1.1-10.0) were at increased risk of a rise in SBP. CONCLUSIONS: A newly initiated NSAID has an immediate clinically relevant effect on SBP in some users of antihypertensives. Management guidelines for NSAID-antihypertensive drug-drug interactions should advise SBP monitoring before and after initiation of an NSAID or intensification of NSAID therapy. Monitoring is especially relevant in patients prescribed high dosages of NSAIDs. Etoricoxib should not be used in hypertensive patients.

The deception and fallacies of sponsored randomized prospective double-blinded clinical trials: the bisphosphonate research example.

The randomized prospective double-blinded clinical trial (RCT) is accepted as Level I evidence and is highly regarded. However, RCTs that gained FDA approval of drugs such as Vioxx, Fen-Phen, and oral and intravenous bisphosphonates have proven to generate misleading results and have not adequately identified serious adverse reactions. The development, research, and clinical marketing of the oral and intravenous bisphosphonates can serve as a representative example for the deteriorated value of many of today's RCTs. The expected high value of RCTs is jeopardized by: (1) sponsorship that incorporates bias; (2) randomization that can select out an expected improved result or eliminate higher-risk individuals; (3) experimental design that can avoid recognition of serious adverse reactions; (4) blinding that can easily become unblinded by the color, shape, odor, or administration requirements of a drug; (5) definitions that can define an observation as something other than what it actually represents, or fail to define it as an adverse reaction; (6) labeling of retrospective data as a prospective trial by using adjudicators prospectively to look at retrospective data; (7) change of the length of study to avoid the longer-term adverse reaction from accumulation of drug or treatment effects; (8) ghost writing, as when drug company physicians or a hired corporation either edit or write the entire protocol and/or manuscript for publication. Such corruption of the well-intended properly conducted RCT should be viewed with a sense of outrage by practitioners and requires a restructuring of the levels of evidence accepted today.

[Drug-related claims in the Norwegian system of compensation to patients]. / Legemiddelsaker i Norsk pasientskadeerstatning.

BACKGROUND: Patients subjected to drug-related injuries can, in accordance with Norwegian legislation, seek compensation from the Norwegian System of Patient Injury Compensation (NPE). The aim of this study was to examine what drugs and injuries instigate claims against NPE, and how these cases are resolved. MATERIAL AND METHODS: We have assessed anonymised summaries of 992 consecutive indemnity applications received and evaluated by NPE over the period 2003-2009. We recorded the age and gender of applicants, treatment diagnosis, drugs implicated, outcome, and NPE's decision in each case. RESULTS: A total of 964 claims were included. The most commonly implicated drugs were those affecting the nervous system (34.6%) and the musculoskeletal system (26.1%). Rofecoxib at 18.9% was the predominant single drug implicated. In two-thirds of the cases, adverse effects were given as the reason for the claim, whereas the last one-third consisted of claims for medication errors. The most common injuries were related to cardiovascular diseases (28.7%) or non-specific conditions (17.5%). 8.4% of the cases related to fatalities. In all, 26.3% of the claims resulted in compensations. INTERPRETATION: Few patients made use of the NPE. Most of the compensation claims in the years 2003-2009 involved rofecoxib and psychoactive drugs, and the majority of claims were rejected.

Sildenafil and ventriculo-arterial coupling in Fontan-palliated patients: a noninvasive echocardiographic assessment.

The fundamental role of pulmonary vascular resistance in the Fontan circulation is obvious. Medications decreasing this resistance may have an impact on the fate of this population. Hence, we assessed noninvasively the effect of oral sildenafil on the ventriculo-arterial coupling in patients with Fontan circulation. In a single-center, prospective case series study, 23 patients with fenestrated extracardiac total cavopulmonary connection age 12-31 years were enrolled in this study. Clinical characteristics and echocardiographic examination were performed before and after a 1 week course of sildenafil at 0.5 mg/kg every 8 h. Sildenafil had no effect on heart rate and blood pressure. However, oxygen saturation was significantly increased with sildenafil (87.6 ± 4.3 vs. 90.1 ± 3.6; P < 0.0001). The calculated noninvasive ventricular end-systolic elastance (Ees) was greater after sildenafil compared with the pre-sildenafil values (1.59 ± 0.17 vs. 1.72 ± 0.27 mm Hg/ml; P = 0.001). Moreover, significant decreases in arterial elastance (Ea) (1.62 ± 0.53 vs. 1.36 ± 0.43 mm Hg/ml; P < 0.0001), ventricular end-diastolic elastance (Eed) (0.05 ± 0.021 vs. 0.04 ± 0.013; P = 0.002), and, finally, ventriculo-arterial coupling index (0.99 ± 0.26 vs. 0.76 ± 0.15; P < 0.0001) were found after sildenafil administration. The intolerable side effects that led to stopping the sildenafil occurred only in one (4 %) patient. Sildenafil has increased ventricular systolic elastance and improved ventriculo-arterial coupling in patients palliated with Fontan circulation. Short-term sildenafil was well tolerated in most of the patients with only minor side effects.

Internet-ordered viagra (sildenafil citrate) is rarely genuine.

INTRODUCTION: Counterfeit medication is a growing problem. This study assessed the requirement for prescription, cost, origin, and content of medications sold via the Internet and purporting to be the phosphodiesterase type 5 inhibitor Viagra (sildenafil citrate). METHODS: Pfizer monitored top search results for the query "buy Viagra" on the two leading Internet search engines in March 2011. Orders were placed from 22 unique Web sites claiming to sell Viagra manufactured by Pfizer. Tablets received were assessed for chemical composition. RESULTS: No Web site examined required a prescription for purchase or a health screening survey; 90% offered illegal "generic Viagra." Cost per tablet ranged from $3.28-$33.00. Shipment origins of purchases were Hong Kong (N = 11), the United States (N = 6), and the United Kingdom (N = 2) as well as Canada, China, and India (N = 1 each). Notably, the four Internet pharmacies claiming to be Canadian did not ship medication from a Canadian address. Of 22 sample tablets examined, 17 (77%) were counterfeit, 4 (18%) were authentic, and 1 (5%) was an illegal generic. Counterfeit tablets were analyzed for sildenafil citrate, the active pharmaceutical ingredient (API) of Viagra, and contents varied between 30% and 50% of the label claim. Counterfeits lacked product information leaflets, including appropriate safety warnings, and genuine Viagra formulations. CONCLUSION: Internet sites claiming to sell authentic Viagra shipped counterfeit medication 77% of the time; counterfeits usually came from non-U.S. addresses and had 30% to 50% of the labeled API claim. Caution is warranted when purchasing Viagra via the Internet.

Comparison of fasting bioavailability among 100-mg commercial, 100-mg generic, and 50-mg chewable generic sildenafil tablets in healthy male Mexican volunteers: a single-dose, 3-period, crossover study.

BACKGROUND: Sildenafil citrate (SIL) was the first oral drug registered in Mexico for the treatment of erectile dysfunction. However, succinct pharmacokinetic data are available in the Mexican population. OBJECTIVE: The goals of the present work were: (1) to design a specific method to quantify SIL plasma levels by using UPLC-MS/MS; (2) to compare oral SIL bioavailability in Mexican men with pharmacokinetic data in other populations; (3) to fulfill local regulatory requests; and (4) to describe the relative tolerability of a new 50-mg chewable tablet. METHODS: This was a randomized, single-dose, 3-period, 6-sequence crossover study in healthy male volunteers. In each period, subjects received single oral doses of 100 mg of sildenafil (1 commercial [reference(⁎)], 1 generic [test 1(†)], or 2 chewable generic tablets [test 2(‡)]), with a 4-day washout period between each dose. Serial blood samples were collected for up to 24 hours. SIL was measured in heparinized plasma by using a validated UPLC-MS/MS method. Pharmacokinetic parameters included C(max), T(max), AUC(0-24), and AUC(0-∞). Bioequivalence was established if 90% CIs for mean test:reference ratios of log-transformed C(max) and AUC fell within the range of 0.80 to 1.25. Tolerability was assessed on the basis of a clinical interview with the subject and monitoring of vital signs. RESULTS: Demographic data showed a homogeneous population. Validation of analytical method proved to be linear within the range of 1 to 1000 ng/mL, with selectivity, accuracy, and precision. 90% CIs for test 1:reference ratios were 86.52 to 113.56, 94.75 to 108.84, and 94.97 to 108.82 for the logarithm parameters C(max), AUC(0-24), and AUC(0-∞), respectively. The 90% CIs for the test 2:reference ratios were 82.14 to 107.24, 98.26 to 112.56, and 99.19 to 113.34 for C(max), AUC(0-24), and AUC(0-∞). Regarding relative tolerability, slight cephalea was the most common adverse effect. CONCLUSIONS: The developed analytical method was validated in compliance with local requirements and was useful for sildenafil measurement. This single-dose study under fasting conditions suggests that both test products met the Mexican regulatory criteria for assuming bioequivalence in these healthy, male Mexican volunteers. The clinical data suggest that the chewable tablets were well tolerated by volunteers.

Concordance with guideline recommendations: previous and more recent nonsteroidal anti-inflammatory drug prescriptions in Quebec, Canada.

BACKGROUND: Clinical practice guidelines for appropriate nonsteroidal anti-inflammatory drug (NSAID) utilisation focus on preventing NSAID-related gastrointestinal (GI), cardiovascular (CV), congestive heart failure (CHF) and renal adverse events. We compared concordance of NSAID prescriptions with clinical practice guideline recommendations in Quebec, pre and post rofecoxib withdrawal from market. METHODS: Data were obtained from the Quebec Health Insurance Agency (RAMQ). All prescriptions for celecoxib and traditional NSAIDs (tNSAIDs) dispensed to patients ≥50 years of age were evaluated for concordance with clinical practice guidelines. Prescriptions were stratified by time period (pre and post rofecoxib withdrawal) and, GI, CV, CHF and renal risk factors at the dispensing date. Gastro-protective agent (GPA) co-prescriptions were also evaluated. RESULTS: We assessed 1,966,793 celecoxib and 1,743,481 tNSAIDs prescriptions. Of celecoxib prescriptions, 87.2% and 86.5% were appropriate in the post- and pre-periods, respectively, compared to 72.6% and 70.1% of tNSAIDs prescriptions, respectively. In logistic regression, 'appropriateness' of celecoxib prescriptions increased with age, rheumatoid arthritis and osteoarthritis (OA), and was higher in the post- versus pre-period (odds ratio 1.22, 95% confidence interval 1.18-1.26); it was lower in women and in patients with higher income. 'Appropriateness' of tNSAID prescriptions decreased in the post-period (0.92, 0.89-0.95), was lower in older persons and those with OA, and higher in women and in higher income patients. Of tNSAID prescriptions that should have received a GPA co-prescription, only 45.6% did. CONCLUSION: Concordance with guideline recommendations increased for celecoxib and decreased for tNSAIDs after rofecoxib withdrawal; GPA co-prescription with tNSAIDs remained suboptimal.

An assessment of the efficacy and safety of sildenafil administered to patients with erectile dysfunction referred for posterior urethroplasty: a single-center experience.

INTRODUCTION: Urethral trauma is often associated with erectile dysfunction (ED). Reconstructive surgery is complex and may impact negatively on sexual function. AIM: The aim of this article is to investigate ED in patients with pelvic fracture urethral distraction defects (PFUDD) who underwent urethroplasty, and efficacy of treatment with sildenafil citrate. MAIN OUTCOME MEASURES: A total of 41 patients with urethral stricture who suffered from PFUDD were assessed to exclude systemic diseases that may cause ED, such as hypertension, diabetes mellitus, heart disease, and chronic liver disease. The International Index of Erectile Function-5 was used as an evaluation tool. Assessments were made at three time points: the time of admission, two weeks after urethroplasty, and 3 months post-treatment with sildenafil. METHODS: Pharmacopenile duplex ultrasonography was used to examine blood flow of the cavernosum in order to distinguish arterial ED, venous ED, and nonvascular ED. All patients were treated with oral sildenafil, 100 mg once daily, three times a week, for 3 months. RESULTS: The incidence of ED following injury was 95.12%. There were no significant changes in scores following surgery. However, sildenafil had a success rate of approximately 81%, which appeared to be independent of age. Drug treatment seemed most effective for those with less severe ED at the outset. There was no significant difference in scores post-treatment between those who had vascular and nonvascular ED. Overall, the incidence of side effects due to sildenafil was 19.5%. CONCLUSIONS: Urethral trauma is frequently associated with ED. Sildenafil citrate is useful in the drug treatment of ED in these patients and appears to be well-tolerated.

Further assessment of the clinically effective dose range of etoricoxib: a randomized, double-blinded, placebo-controlled trial in rheumatoid arthritis.

OBJECTIVE: To further assess the clinically active dose range of etoricoxib, a COX-2 selective inhibitor, in rheumatoid arthritis (RA). METHODS: RA patients were randomized to etoricoxib 10, 30, 60, or 90 mg or placebo in a double-blind, 12-week study. DMARDs (methotrexate, biologics) or low-dose corticosteroids were allowed in stable doses. The primary endpoint was the proportion of patients completing the study and achieving an American College of Rheumatology 20% (ACR20) response. Secondary endpoints included individual components of the ACR index and Patient Global Assessment of Pain. Safety was assessed by physical exam and adverse experiences (AEs) occurrences. RESULTS: Etoricoxib 90 mg was the only dose to reach a statistically significant difference from placebo (p < 0.001) on the primary endpoint; etoricoxib 60 mg approached significance (p = 0.057). Significant pain improvement vs. placebo was observed with etoricoxib 90 mg (p < 0.001), 60 mg (p = 0.018), and 30 mg (p = 0.017). Despite the use of background biologics and corticosteroids, a dose response was still apparent. A higher proportion of etoricoxib 60 and 90 mg patients had renovascular AEs (i.e., edema and hypertension) compared with placebo, although discontinuations for renovascular AEs were rare. Etoricoxib 90 mg had a higher incidence of serious AEs (n = 5; 1 was considered drug-related) versus placebo (n = 0). LIMITATIONS: The present study was not powered to detect differences in cardiovascular or gastrointestinal safety by dose. Additionally, further research is needed to clarify the role of doses less than the etoricoxib 90 mg dose for pain management in RA patients. CONCLUSION: Etoricoxib 90 mg demonstrated statistically superior efficacy (ACR20) compared with placebo and numerical superiority over the other doses of etoricoxib studied. Etoricoxib 30 and 60 mg demonstrated significant pain improvement versus placebo, suggesting utility for some patients.

Phosphodiesterase type 5 inhibitor abuse: a critical review.

Abuse of sildenafil has been reported since its introduction in 1999 and commonly documented in combination with illicit drugs among men and women of all ages. Increased risks of sexually transmissible diseases including HIV have been associated with sildenafil use in men who have sex with men. Recognizing the abuse potential of phosphodiesterase type 5 inhibitors (PDE5), we aim to summarize the current knowledge of this abuse. An investigation of EMBASE, PubMed, the Food and Drug Administration (FDA) website, MedWatch, and search engines was performed to evaluate information regarding sildenafil, tadalafil, and vardenafil abuse. The EMBASE search provided 46 articles fitting the search criteria and evaluation led to 21 separate publications with specific information regarding PDE5 abuse. A PubMed search found 10 additional publications. MedWatch reported 44 separate warnings since 2000, most of which reported contamination of herbal products with active drug components. Few reports of abuse were among the 14,818 reports in the FDA AERS for sildenafil. A search for "internet drug store" revealed 6.4 million hits and of 7000 internet pharmacies identified by the Verified Internet Pharmacy Practice Sites Program (VIPPS) only 4% were in proper compliance. The role internet pharmacies play in counterfeit PDE5 or abuse is not well documented; however based on easy access, direct patient marketing, and low advertised cost it is likely this role is underreported. Currently the best recommendation for providers is to recognize the possibility of abuse and to educate patients on risks of this behavior.

The Vioxx pharmaceutical scandal: Peterson v Merke Sharpe & Dohme (Aust) Pty Ltd (2010) 184 FCR 1.

In early March 2010, Federal Court Justice Jessup in Peterson v Merke Sharpe & Dohme (Aust) Pty Ltd (2010) 184 FCR 1 ruled that Merke Sharpe & Dohme Pty Ltd had produced a defective product contrary to the Trade Practices Act 1974 (Cth), the anti-arthritic drug Vioxx. Promoted as relieving arthritic pain without the side effect of gastric ulceration, the drug also doubled the risk of heart attack in those prescribed it. The court also heard that the manufacturing company had engaged in misleading practices to promote the prescription and usage of Vioxx, including "fake" journals and guidelines to "drug reps" that minimised the adverse cardiovascular risks. The manufacturer had already settled a class action in the United States for more than US$7 billion for those harmed by the drug but this was the first such case to be decided in Australia. The court awarded the applicant, Graeme Peterson, A$300,000 in damages. This column examines this judgment and analyses evidence there presented that Merck may have misled the scientific community, the medical profession and Australia's drug regulation system to get Vioxx on the market and keep it there. It considers whether the case reveals the need for more rigorous post-marketing surveillance and other changes to Australia's drug regulatory system, including a replacement of self-regulation in pharmaceutical promotion with a United States-style system of rewarded informant-led criminal penalties and civil damages claims.

Noninvasive assessment of acute cardiopulmonary effects of an oral single dose of sildenafil in patients with idiopathic pulmonary hypertension.

We aimed to assess the acute cardiopulmonary effects of a 100-mg oral single dose of sildenafil in patients with idiopathic pulmonary hypertension (IPAH) using a well-validated but less-used noninvasive echocardiographic method for the measurement of both systolic and diastolic pulmonary artery pressure (PAP), by tricuspid regurgitation (TR) velocity curve analysis. We studied 12 consecutive patients with IPAH (10 patients with New York Heart Association functional class III, and 2 patients with functional class II). A 100-mg oral single dose of sildenafil was added to previous medications of all patients and its immediate effects were evaluated 1, 5, and 12 h after treatment. Using paired analysis, administration of a 100-mg oral single dose of sildenafil led to a significant reduction in mean PAP and a remarkable increase in pulmonary acceleration time (PAT) 1 h after treatment (P = 0.000; 95% confidence interval [CI] 18.99-26.00 and P = 0.005; 95% CI -12.89 to -2.95, respectively). In addition, although the right heart dimensions (right atrium and right ventricle) showed a trend toward improvement, the differences were not statistically significant (P = 0.13 and P = 0.08, respectively). Our results demonstrated that Doppler examination of TR alone can be easily used for the estimate of systolic and diastolic PAP in patients with IPAH. This study also shows that sildenafil is the only drug given orally that can evaluate the vasodilatory capacity of the pulmonary vascular bed in patients with IPAH, with promising effects on mPAP and PAT in these patients.

[The relation between publication bias and clinical trials funding]. / Publikationsbias in Abhängigkeit von der Art der Finanzierung bei klinischen Studien.

Publication bias describes the distortion of data in scientific journals resulting from the fact that studies with significant and positive results are more likely to be published than studies with negative or insignificant results. In studies funded by pharmaceutical companies publication bias has a considerable impact. It has been shown that more than half of the studies that are conducted as part of the drug approval process will remain unpublished. In addition, multiple publications of the same results, the selective use of data and the withholding of data relating to adverse drug reactions were also demonstrated. It is unclear, however, whether the probability of publication of studies funded by pharmaceutical companies is different from those not funded by pharmaceutical companies. Also, data vary as to the correlation between the type of funding of clinical studies and the length of time to publication. For the benefit of patients, everyone involved in clinical studies ought to take responsibility and facilitate access to all data.

A quantitative evaluation of the regulatory assessment of the benefits and risks of rofecoxib relative to naproxen: an application of the incremental net-benefit framework.

PURPOSE: To undertake a quantitative benefit-risk analysis of rofecoxib relative to naproxen using an incremental net-benefit (INB) analysis from the societal perspective, using the same data evaluated by the Health Canada and US FDA expert advisory panels. METHODS: We developed a discrete event simulation model to calculate the INB of rofecoxib relative to naproxen in arthritis patients over a 1-year time horizon. All outcomes were weighted using societal utilities for each health state which facilitated the use of quality-adjusted life years (QALYs) as the outcome. Probability distributions were incorporated for each model parameter to facilitate a probabilistic analysis using second-order Monte Carlo simulation. RESULTS: In the base case analysis, the mean INB (SD) of rofecoxib relative to naproxen was 0.0002 (0.415) QALYs per patient over 12 months of treatment, or 0.2 QALYs per 1000 patients treated. The probabilistic sensitivity analysis resulted in a mean INB of 0.0022 QALYs (95%CI -0.0005, 0.0051). Overall, the INB associated with rofecoxib relative to naproxen was ≥0 in 94% of the iterations of the model. CONCLUSIONS: This analysis illustrates the application of the incremental net-benefit framework to quantitative benefit-risk evaluation, and suggests that the potential benefits of rofecoxib outweigh the potential harms relative to naproxen over 1 year from the societal perspective under the assumptions of this model.