A Post-Authorization Safety Surveillance Study to Report Clinical Experience with Purified Factor IX Concentrate in Pediatric Patients with Hemophilia B.

Introduction: Purified factor IX (FIX) concentrate (IMMUNINE®, Takeda Manufacturing Austria AG, Vienna, Austria) is indicated for the treatment and prophylaxis of bleeding episodes in patients with congenital hemophilia B. Data on the use of purified FIX concentrate in patients ≤6 years old with congenital hemophilia B are limited. Aim: Document real-world clinical experience with purified FIX concentrate in routine practice for pediatric patients with hemophilia B. Methods: This prospective post-authorization safety surveillance study enrolled patients ≤6 years old with moderate or severe hemophilia B (baseline FIX ≤5%) who were prescribed purified FIX concentrate, as determined by the treating physician. The planned observation period for each patient was either 12 months or ≥50 exposure days, whichever occurred first. The primary endpoints were the occurrence of treatment-related adverse events (AEs) and serious AEs (SAEs), and inhibitor development. Results: Thirteen male patients (mean ± standard deviation age, 3.80 ± 1.76 years) enrolled and received ≥1 treatment with purified FIX concentrate. Thirty-two AEs were reported in 6 patients; 4 were SAEs. No AEs were considered related to purified FIX concentrate. No patients developed inhibitory antibodies. Inhibitor testing was not conducted in 2 patients. Eighteen bleeding episodes were treated with purified FIX concentrate in 6 patients. Hemostatic efficacy was rated as either "excellent" or "good" in all patients with an available rating. Conclusion: No treatment-related AEs were reported, and purified FIX concentrate was shown to be effective in treating and preventing bleeding episodes in pediatric patients ≤6 years old with hemophilia B.

Real-world long-term safety and effectiveness of turoctocog alfa in the treatment of haemophilia A in Japan: results from a multicentre, non-interventional, post-marketing study.

OBJECTIVES: To assess the safety and effectiveness of turoctocog alfa in previously treated patients (PTPs) and previously untreated patients (PUPs) with haemophilia A in a real-world setting in Japan. METHODS: This multicentre, non-interventional, post-marketing study recruited patients with haemophilia A who initiated treatment with turoctocog alfa from 18 sites (08/2014-12/2018). The primary endpoint was adverse events (AEs) during the 2-year study period. RESULTS: The safety and effectiveness analysis set included 39 patients. In total, 13 (33.3%) patients reported ≥1 AE; incidence rate was 60.4 events/100 patient-years of exposure (PYE). Treatment was withdrawn in two cases: pruritus in a PTP and factor VIII inhibitor development in a PUP. Inhibitor development occurred in 2.6% of all patients, with an incidence rate of 3.8 events/100 PYE. The rate of inhibitor development was 0%, 25% and 20% in PTPs, PUPs and PUPs with severe type, respectively. The haemostatic success rate was 91.4% for 383 bleeding episodes and 85.7% for 14 surgeries. The negative binomial annualised bleeding rate for the prophylaxis regimen was 6.19 episodes/year (95% CI, 3.69-10.38). The mean (SD) total consumption of turoctocog alfa (n = 34; excluding FVIII inhibitors) was 5,382.6 (7,180.1) IU/kg/year/patient; consumption was 4,133.1 (1,452.4) IU/kg/year/patient for prophylaxis. DISCUSSION: The effectiveness and safety profiles were comparable to those observed in other turoctocog alfa trials; effectiveness analysis and consumption were not affected by treatment regimens. CONCLUSION: Long-term use of turoctocog alfa therapy in clinical practice posed no newly identified safety issues and was effective for prophylaxis and treatment of bleeds in patients with haemophilia A in Japan.

Safety of recombinant activated factor VII for treatment of breakthrough bleeds in patients with congenital haemophilia A and inhibitors receiving emicizumab prophylaxis: Review of the real-world evidence.

BACKGROUND: Emicizumab is used as a subcutaneous prophylaxis for prevention of bleeding episodes in patients with haemophilia A (HA) with and without inhibitors. While low bleeding rates were observed in clinical trials, patients still experience breakthrough bleeds (BTBs) with emicizumab in the real-world. Current guidelines recommend use of recombinant activated factor VII (rFVIIa) for treatment of BTBs in patients with inhibitors. Due to thrombotic events observed in the HAVEN 1 study, activated prothrombin complex concentrate (aPCC) should be used with caution. OBJECTIVES: The objective of this review is to identify and discuss real-world data on the frequency of BTBs and the safety of concomitant rFVIIa use in patients with inhibitors on emicizumab prophylaxis. METHODS: A search of the following databases was conducted on 15 July 2022: BIOSIS Previews® , Current Contents Search® , Embase® , MEDLINE® . Search terms included 'real world', 'haemophilia A', and 'emicizumab'. RESULTS AND CONCLUSIONS: Eleven relevant publications were identified (seven original research articles and four congress abstracts). The frequency of BTBs specifically for HA patients with inhibitors was described in three publications with 5%-56% patients on emicizumab reporting ≥1 bleeding episode. Treatment of these BTBs appeared to be managed according to relevant guidelines. Importantly, no thrombotic complications occurred during concomitant rFVIIa use. Due to the nature of real-world studies, direct comparison of the results between studies is limited. However, real-world data show that BTBs in inhibitor patients during emicizumab prophylaxis can be safely treated with rFVIIa.

Cases of less-than-expected FVIII activity in previously treated patients during post-marketing surveillance of N8-GP.

INTRODUCTION: Turoctocog alfa pegol (N8-GP) is a glycoPEGylated, extended half-life (EHL), human recombinant factor VIII (FVIII) approved for the treatment and prevention of bleeding episodes in patients with haemophilia A. Since its launch in August 2019, > 800 patients have been treated worldwide. AIM: To present data from identified post-marketing cases of less-than-expected FVIII activity in previously treated patients (PTPs) without inhibitors after switching to N8-GP. METHODS: The post-marketing safety database was searched using keywords such as 'coagulation FVIII level decreased'. Identified cases reported prior to 13 October 2021 were included in this report. Cases in which patients had FVIII inhibitors were excluded. RESULTS: Here we report 14 cases of less-than-expected FVIII activity. Details varied greatly amongst the cases. At presentation, FVIII activity ranged from 1% (15 min post-dose) to 51% (2 days post-dose). Seven patients experienced bleeding episodes after switching to N8-GP with heterogeneity in bleeding presentations. Six out of seven patients who were tested for anti-PEG IgG and/or IgM antibodies were positive. In all known cases, FVIII activity returned to the expected range when switched to an alternative FVIII replacement product. CONCLUSION: In conclusion, the 14 reported cases of less-than-expected FVIII activity, without presence of detectable FVIII inhibitors, presented with heterogenous characteristics, and wide variations in FVIII activity and anti-PEG antibody titre. FVIII activity returned to the expected range after switching to alternative FVIII products. In line with WFH guidelines, monitoring of FVIII activity can ensure FVIII activity in the expected range. The safety surveillance of N8-GP continues.

The safety profile of nivolumab plus ipilimumab combination therapy in Japanese patients with renal cell carcinoma: results from post-marketing surveillance.

BACKGROUND: Nivolumab and ipilimumab combination therapy is approved in Japan for unresectable or metastatic renal cell carcinoma. Because the clinical trials supporting the approval of nivolumab and ipilimumab combination therapy included relatively few Japanese patients, post-marketing surveillance was implemented to collate further safety data for nivolumab and ipilimumab combination therapy. METHODS: Patients with unresectable or metastatic renal cell carcinoma who started nivolumab and ipilimumab combination therapy between September 2018 and December 2019 were registered in this post-marketing surveillance. The observation period was 13 weeks. Safety data included treatment-related adverse events with a particular emphasis on the gastrointestinal-related (colitis, enteritis, diarrhoea and gastrointestinal perforation) and liver-related (hepatic failure, hepatic function abnormal, hepatitis and cholangitis sclerosing) treatment-related adverse events that are listed in the risk management plan for nivolumab and ipilimumab combination therapy. RESULTS: Of the 203 patients registered, safety data were available for 159 (119 males/40 females) with a median age of 67 years (range 22-88). Seventy-one patients received nivolumab and ipilimumab combination therapy four times per usual clinical therapy, and 33 continued nivolumab monotherapy thereafter. Any-grade treatment-related adverse events were reported in 102 (64.2%) patients and grade ≥ 3 in 63 (39.6%). Hepatic function abnormalities (13.2%), rash (8.8%) and interstitial lung disease (7.5%) were the most common treatment-related adverse events. Five patients died following treatment-related adverse events. Gastrointestinal-related and liver-related treatment-related adverse events occurred in 10 (6.3%; four with grade ≥ 3 treatment-related adverse events) and 27 (17.0%; 19 with grade ≥ 3 treatment-related adverse events) patients, respectively. CONCLUSIONS: This post-marketing surveillance in patients with unresectable or metastatic renal cell carcinoma revealed a safety profile for nivolumab and ipilimumab combination therapy consistent with CheckMate 214. Furthermore, no new safety concerns were identified including gastrointestinal-related and liver-related treatment-related adverse events.

A Pharmacovigilance Study of Adverse Drug Reactions Reported for Cardiovascular Disease Medications Approved Between 2012 and 2017 in the United States Food and Drug Administration Adverse Event Reporting System (FAERS) Database.

PURPOSE: Between 2012 and 2017, the FDA approved 29 therapies for a cardiovascular disease (CVD) indication. Due to the limited literature on patient safety outcomes for recently approved CVD medications, this study investigated adverse drug reports (ADRs) reported in the FDA Adverse Event Reporting System (FAERS). METHODS: A disproportionality analysis of spontaneously reported ADR was conducted. Reports in FAERS from Quarter 1, 2012, through Quarter 1, 2019, were compiled, allowing a 2-year buffer following drug approval in 2017. Top 10 reported ADRs and reporting odds ratios (ROR; confidence interval (CI)), a measure of disproportionality, were analyzed and compared to drugs available prior to 2012 as appropriate. RESULTS: Of 7,952,147 ADR reports, 95,016 (1.19%) consisted of reports for newly approved CVD medications. For oral anticoagulants, apixaban had significantly lower reports for anemia and renal failure compared to dabigatran and rivaroxaban but greater reports for neurological signs/symptoms, and arrhythmias. Evaluating heart failure drugs, sacubitril/valsartan had greater reports for acute kidney injury, coughing, potassium imbalances, and renal impairment but notably, lower for angioedema compared to lisinopril. Assessing familial hypercholesterolemia drugs, alirocumab had greater reports for joint-related-signs/symptoms compared to other agents in this category. A newer pulmonary arterial hypertension treatment, selexipag, had greater reports of reporting for bone/joint-related-signs/symptoms but riociguat had greater reports for hemorrhages and vascular hypotension. CONCLUSION: Pharmacovigilance studies allow an essential opportunity to evaluate the safety profile of CVD medications in clinical practice. Additional research is needed to evaluate these reported safety concerns for recently approved CVD medications.

Long-term safety and effectiveness of mycophenolate mofetil in adults with lupus nephritis: a real-world study in Japan.

OBJECTIVES: To assess the safety and effectiveness of mycophenolate mofetil (MMF) in Japanese adults with lupus nephritis (LN) in real-world clinical practice. METHODS: This multicentre, prospective, post-marketing surveillance study investigated the effectiveness and safety of MMF, as induction or maintenance therapy, in LN patients. Primary endpoints were adverse drug reactions (ADRs), changes in renal function from baseline, and relapse rate (RR) after 6 months in the maintenance group, estimated using the Kaplan-Meier method. Complete remission (CR) and partial remission (PR) were estimated by renal measurements. RESULTS: Overall, 112 patients were enrolled in the induction group and 340 in the maintenance group. Of these 452 patients, 418 were evaluable for safety and 396 for effectiveness. Eighty-three patients (19.85%) experienced ADRs, most commonly herpes zoster (3.34%) and diarrhoea (3.11%). Serious ADRs occurring in more than three patients were cytomegalovirus infections (1.43%), acute pyelonephritis (0.71%), and herpes zoster (0.71%). One patient died from herpes zoster disseminated. CR and PR were 19.54% and 44.82%, respectively, in the induction group, and 40.62% and 66.16%, respectively, in the maintenance group. RR in the maintenance group was 0.70%. CONCLUSIONS: The tolerability of MMF is in line with that reported in other studies. Since the average dose of MMF was <1.5 g/day, research into the optimal dose for achieving effectiveness is required.

Adverse events following immunization of elderly with COVID-19 inactivated virus vaccine (CoronaVac) in Southeastern Brazil: an active surveillance study

ABSTRACT Healthcare workers, the elderly and other vulnerable populations were the first to receive COVID-19 vaccines in public health programs. There were few vaccine safety data available on the elderly. This observational study aimed to evaluate the inactivated vaccine (CoronaVac) safety in the elderly, at the beginning of the vaccination program, in Sao Paulo city, Brazil. The elderly people that received CoronaVac at the Reference Center for Special Immunobiologicals (CRIE) or at home, administered by the Interdisciplinary Home Care Team (NADI) of the Hospital das Clinicas were invited to participate in this phase 4 observational study. The vaccination schedule included two CoronaVac doses 28 days apart. The information on solicited and unsolicited adverse events following immunization were collected by phone calls on days 4 and 8 after each vaccine dose. We enrolled 158 adults aged 65 to 101 years (mean of 84.1 years); 63.9% were females and 95.6% had chronic conditions, 21.5% had moderate or severe impairment in daily living activities; 34.2% were pre-frail and 19.6% were frail. We were able to contact 95.6% and 91.6% of the vaccinated people, after the first and second doses, respectively; 31.8% and 23.4% of the contacted participants reported some adverse events (AE) following the first and second doses, respectively. Pain at the injection site, fatigue, myalgia and headaches were the most frequent solicited AE. Most AE were mild to moderate. There were eight severe adverse events, but none of them were considered related to the vaccine. The CoronaVac was safe and well tolerated by these adults of advanced age with frailty and comorbidities.

Final Results of the Prospective ADVATE® Immune Tolerance Induction Registry (PAIR) Study with Plasma- and Albumin-Free Recombinant Factor VIII.

INTRODUCTION: Neutralizing antibodies to coagulation factor VIII (FVIII) remain a major complication associated with FVIII replacement therapy. AIM: To assess safety and efficacy of immune tolerance induction (ITI) therapy with ADVATE® (antihemophilic factor [recombinant] [rAHF]) in patients who participated in the Prospective ADVATE Immune Tolerance Induction Registry (PAIR) study. METHODS: The PAIR study was an international, multicenter, open-label, prospective, observational study in patients with hemophilia A and inhibitors, prescribed rAHF ITI therapy in clinical practice. The primary endpoint was adverse event (AE) reporting; the secondary endpoints included incidence of central venous access device-related complications and success rates of ITI therapy. Maintenance of immune tolerance was monitored for 12 months post-ITI therapy. RESULTS: Of 44 patients, 36 completed ITI therapy, including 31 completing the 12-month follow-up. Most patients received rAHF 90-130 IU/kg/day (59.1%) and a mean of 6.0 doses/week; the median duration of rAHF ITI therapy during the PAIR study was 600 days. Overall, 284 AEs were reported; 56 AEs were serious, of which none were considered rAHF-related. Of 228 nonserious AEs, 14 (in six patients) were deemed rAHF-related: increase of FVIII inhibitors titer due to anamnestic response, nausea, catheter site pain, pyrexia, urticaria, upper respiratory tract infection, arthralgia, and hemarthrosis. None were severe or led to ITI discontinuation. Eighteen patients experienced ≥1 central venous access device-related complication, and 21 of 36 completers achieved a negative inhibitor titer. The Kaplan-Meier estimate of success for achievement of first negative titer at 18 months of ITI therapy was 68.3% (95% confidence interval 51.8-83.6%) among completers. Of patients with partial or complete success post-ITI, 87% (20/23) maintained immune tolerance at 12-month follow-up. CONCLUSION: Data suggest that rAHF ITI therapy in the PAIR study was effective, with no unexpected safety signals reported.

Safety of Tacrolimus in Autoimmune Disease: Results From Post-marketing Surveillance in South Korea.

Objective: Tacrolimus, a macrolide immunosuppressant, is approved in Korea for the treatment of rheumatoid arthritis (RA), lupus nephritis (LN) and myasthenia gravis (MG) We report three prospective post-marketing surveillance studies of tacrolimus conducted in South Korea in these indications. Methods: Studies were conducted according to South Korean Ministry of Food and Drug Safety requirements Patients were followed up for the duration of the study (up to 4 years) or until treatment discontinuation Occurrence and likely relationship with tacrolimus of adverse events (AEs), adverse drug reactions (ADRs; defined as AEs where causal relationship to tacrolimus could not be excluded) and serious AEs were recorded Association of AEs with demographic and medical factors was evaluated by multivariable analysis. Results: The studies included 740 (RA), 307 (LN) and 104 (MG) patients The incidence of AEs was 127% in RA (642% of AEs potentially related to tacrolimus), 209% (378% potentially related) in LN and 298% (568% potentially related) in MG The incidence of ADRs was 84%, 98% and 202%, respectively Serious AEs were reported in 07%, 72% and 87%, respectively The most common AEs were abdominal pain (RA), pharyngitis (LN) and diarrhea (MG) Unexpected AEs occurred in 35% of patients with RA, 29% in LN and 87% in MG; no pattern of unexpected AEs was apparent Multivariable analysis demonstrated that patients with comorbidity had higher probability of experiencing an AE in RA and MG studies. Conclusion: The incidence of AEs and the safety profile of tacrolimus in each indication was consistent with previous reports.

Patterns and correlates of prescribed and non-prescribed pregabalin use among a sample of people who inject drugs in Australia.

INTRODUCTION AND AIMS: Pregabalin is a gamma-aminobutyric acid analogue registered and subsidised for the treatment of neuropathic pain in Australia. Despite pre-clinical evidence of low abuse potential, there are increasing reports of extramedical use and overdose deaths involving pregabalin. This study aimed to describe patterns of pregabalin use among an Australian sample of people who inject drugs (PWID) and identify sociodemographic, substance use and mental/physical health correlates of prescribed and non-prescribed use. DESIGN AND METHODS: Data were obtained from the 2018 Illicit Drug Reporting System, comprising a cross-sectional sample of 905 PWID recruited from Australian capital cities. Multinomial logistic regression was used to identify correlates of past 6-month prescribed and non-prescribed pregabalin use. RESULTS: One-quarter (25%) of participants reported any past 6-month pregabalin use, with 10% reporting prescribed use and 15% non-prescribed use. Past 6-month use of prescribed benzodiazepines and non-prescribed pharmaceutical opioids were associated with both prescribed and non-prescribed pregabalin use compared to no recent pregabalin use. Pain/discomfort on the day of interview was significantly associated with prescribed pregabalin use. Recent use of non-prescribed benzodiazepines and illicit stimulants and past year non-fatal overdose were significantly associated with non-prescribed pregabalin use (compared to no recent pregabalin use). DISCUSSION AND CONCLUSIONS: Pregabalin use was relatively common among an Australian sample of PWID. Benzodiazepine and pharmaceutical opioid use were positively correlated with both prescribed and non-prescribed pregabalin use, suggesting that education campaigns regarding the risks of harm associated with concomitant use of these substances are warranted (targeting both health professionals and consumers).

Safety and effectiveness of a biosimilar biphasic insulin in the management of diabetes mellitus during routine clinical practice in Asian patients

@#Introduction: Biosimilar insulins have the potential to increase access to treatment among patients with diabetes mellitus (DM), reduce treatment costs, and expand market competition. There are no published studies evaluating the performance of biosimilar insulins in routine clinical practice in Asia. This study assessed the safety and effectiveness of biphasic isophane insulin injection in Malaysian DM patients. Materials and Methods: In this open label, single-arm, observational, post marketing study, patients received biphasic isophane insulin injection as per the Prescribing Information; and were assessed for safety (adverse events including hypoglycaemia), effectiveness (glycosylated haemoglobin [HbA1c]; fasting blood sugar, [FBS]; and patient’s condition by patient and physician) over a period of 24 weeks. Results: Adult male and female diabetes patients (N=119; type 2 DM, n=117) with a mean (SD) diabetes duration of 13 years were included. No new safety signals have been identified. Significant reduction in HbA1c was observed at weeks 12 and 24 (mean [SD] - baseline: 9.6% [1.9]; Week 12: 9.0% [1.7] and at Week 24: 9.1% [1.7]; p < 0.001). There were 10 serious and 9 non-serious adverse events reported in the study. Expected mild events included hypoglycaemia and injection site pruritus. However, the majority of the adverse events were non-study drug related events. No deaths were reported during the study. Discussion: Biphasic isophane insulin injection was well tolerated with no new safety concerns. It was found effective in post- marketing studies conducted in routine clinical settings when administered in DM patients in this study.

Interim results of a real-world observational study of eribulin in soft tissue sarcoma including rare subtypes.

BACKGROUND: Although eribulin is used to treat soft tissue sarcomas (STSs), treatment data for rare subtypes are limited. We conducted a post-marketing surveillance study to assess safety and efficacy of eribulin in STS patients stratified by subtype. METHODS: Japanese patients (n = 256) with advanced or metastatic STS receiving eribulin treatment were monitored for treatment status, adverse events, diagnostic imaging, and clinical outcomes at 3 months and 1 year. Interim analysis was performed. Patients will be monitored up to 2 years. RESULTS: Interim analysis included 3-month (n = 255), imaging (n = 226), and 1-year (n = 105) data. STS subtype distribution was normal. Median number of eribulin cycles was 3.0 (range: 1-17 cycles). Among patients with imaging data, best overall tumor response (12 weeks) was partial response, 7.5% (n = 17); stable disease, 34.5% (n = 78); and stable disease ≥11 weeks, 10.2% (n = 23). Overall response rate (ORR), disease control rate (DCR), and clinical benefit rate (CBR) for all patients were 7.5%, 42.0% and 17.7%, respectively. ORR, DCR, and CBR were 10.3%, 32.0% and 16.5%, respectively, for patients with STS subtypes other than liposarcoma and leiomyosarcoma and included responses from patients with rare STS subtypes. Adverse drug reactions (ADRs) occurred in 211 (82.7%) patients (42 [16.5%] patients had serious ADRs), and none led to death. ADRs leading to drug withdrawal and dose reduction occurred in 27 (10.6%) and 55 (21.6%) patients, respectively. CONCLUSION: Eribulin was generally well tolerated and showed antitumor activity against STSs, including rare subtypes that currently have few treatment options. CLINICAL TRIAL NUMBER: NCT03058406 (ClinicalTrials.gov).

Diversion and injection of buprenorphine-naloxone film two years post-introduction in Australia.

INTRODUCTION AND AIMS: We report 2 years of post-marketing surveillance of the diversion and injection of buprenorphine-naloxone (BNX) film following its introduction in 2011. DESIGN AND METHODS: Interviews were conducted with people who inject drugs regularly (PWID) (2004-2013), opioid substitution therapy clients (2013, n = 492) and key experts (n = 44). Key outcomes were unsanctioned removal of supervised doses, diversion, injection and street price. Prevalence of past 6-month injection among PWID was adjusted for background availability of opioid substitution therapy medications using sales data. RESULTS: Among out-of-treatment PWID, the levels of regular (weekly+) BNX film injection were comparable to methadone and BNX tablets, and lower than mono-buprenorphine, adjusting for background availability. Fewer BNX film clients [3%; 95% (CI) 1-5] regularly injected their medication than mono-buprenorphine clients (25%; 95% CI 11-39), but at levels equivalent to those among methadone (3%; 95% CI 1-6) and BNX tablet clients (2%; 95% CI 0-6). Key experts perceived BNX film needed less supervised dosing time as it dissolved rapidly and was harder to remove from the mouth than sublingual tablets; however, removal of supervised doses was higher among BNX film clients (15%; 95% CI: 10-20) than methadone clients (3%; 95% CI 1-6), and not significantly different from BNX tablet (11%; 95% CI 2-21) and mono-buprenorphine clients (31%; 95% CI 16-46). DISCUSSION AND CONCLUSIONS: Two years post-introduction, levels of BNX film diversion and injection remained comparable with those for methadone and BNX tablets, and lower than mono-buprenorphine. We found no evidence that BNX film has lower non-adherence and diversion than the tablet formulation. [Larance B, Mattick R, Ali R, Lintzeris N, Jenkinson R, White N, Kihas I, Cassidy R, Degenhardt L. Diversion and injection of buprenorphine-naloxone film two years post-introduction in Australia. Drug Alcohol Rev 2015].

Description of Important Potential Risks of Japanese Risk Management Plan on Each Package Insert / 医薬品情報学

<b>Objective: </b>The Japanese risk management plan (RMP) contains the risk minimization action plans for important potential risks of drugs.  One of the basic risk minimization action plans is reminding on package insert; however, we found that some potential risks were not described in package inserts.  In this study, we investigated the description of potential risks on package inserts.<br><b>Design: </b>Document analysis.<br><b>Methods: </b>We collected all posted RMP documents and the package inserts of corresponding products from the Pharmaceutical and Medical Devices Agency website on January 31, 2015 and investigated the risk minimization action plans of important potential risk items and whether the items had been described in each package insert.<br><b>Results: </b>Of 268 important potential risk items in 81 products, 56 items were not described on package insert.  The major reason for not including the risk items on the package insert was “causality was not indicated sufficiently” and some items had no written reason.<br><b>Conclusion: </b>About 20% of important potential risks are not described in package inserts.  Because most post-marketing pharmacovigilance plans depend on spontaneous reporting by healthcare personnel, description on package insert, the most frequently referred drug information resource, should be considered.

A typology of people who tamper with pharmaceutical opioids: responses to introduction of a tamper-resistant formulation of controlled-release oxycodone.

PURPOSE: In April 2014, a tamper-resistant controlled-release oxycodone formulation was released in Australia. We aimed to determine whether there are latent classes of people who tamper with pharmaceutical opioids based on frequency of opioid and illicit drug use, the demographic and clinical profiles of these groups, and if there were changes in use and harms following the introduction. METHODS: A prospective cohort of 606 people who regularly tamper with pharmaceutical opioids was interviewed January to March 2014 (Wave 1) and May to August 2014 (Wave 2). Latent class analysis identified groups based on non-prescribed opioid, illicit drug and prescribed opioid substitution therapy (OST) use at Wave 1. Regression models examined whether group membership predicted use and harms at Wave 2. RESULTS: Four groups were identified: frequent OST group (39%), mixed OST/heroin group (7%), infrequent pharmaceutical opioid and heroin group (44%) and frequent oxycodone group (25%). Compared with the frequent OST group, the infrequent pharmaceutical opioid/heroin group was more likely to report non-everyday pain and risky alcohol use, and the frequent oxycodone group had higher odds of homelessness. At Wave 2, oxycodone use decreased across groups (odds ratios (OR) ≤ 0.18, p < 0.001, particularly for the frequent oxycodone group: OR ≤ 0.05, p < 0.001), with reductions in days of use (g ≥ 0.35, p < 0.050). Non-prescribed pharmaceutical opioid use, illicit drug use and harms remained stable or decreased. CONCLUSIONS: Despite heterogeneity among people who tamper with pharmaceutical opioids, the tamper-resistant formulation was followed by reductions in oxycodone tampering among high-frequency and low-frequency users. There was no evidence of increased use of other opioids or illicit drugs.

Ambrisentan for the treatment of adults with pulmonary arterial hypertension: a review.

OBJECTIVE: To provide an overview of the drug profile of the orally active, selective endothelin A receptor antagonist ambrisentan, and its efficacy and safety in the treatment of patients with pulmonary arterial hypertension (PAH). RESEARCH DESIGN AND METHODS: Medical literature on the use of ambrisentan in PAH was identified using MEDLINE and EMBASE. Additional references were identified from the reference lists of published articles and from the authors' own bibliographies. RESULTS: Significant improvements in exercise capacity were observed with approved dosages of ambrisentan (5 or 10 mg once daily) in the AMB-220 dose-ranging study and the pivotal ARIES-1 and ARIES-2 trials, with sustained effects up to 2 years observed in ARIES-E. Improvements in cardiopulmonary hemodynamic variables were reported in AMB-220 and ARIES-E (subset analysis). Ambrisentan had little or no effect on hepatic transporters in in vitro studies and displayed a low risk of potential drug-drug interactions, including those with other PAH therapies. Results from the VOLT post-marketing program confirmed the safety profile of ambrisentan observed in the ARIES studies, including the low incidence of liver function test abnormalities. Peripheral edema and anemia were common side effects of endothelin receptor antagonist therapies, including ambrisentan. In the recently completed AMBITION study (ClinicalTrials.gov Identifier: NCT01178073), upfront initial combination therapy with ambrisentan and tadalafil significantly reduced the risk of clinical failure (primary endpoint) by 50% compared with the pooled monotherapy groups. CONCLUSIONS: The long-term efficacy and safety profile of ambrisentan in patients with PAH is supported by data from a comprehensive clinical trial program and real-life, post-marketing observations.

The biosimilar road in inflammatory bowel disease: the right way?

The biologicals have led to dramatic changes in the management of immune-mediated diseases, and the subsequent development of their biosimilars may reduce the high costs of these agents. However, there remain concerns about the true equivalence of a biosimilar and its reference product, as well as around immunogenicity of these agents in IBD, although studies on rheumatoid arthritis support the similarity of biosimilars and their originators. Many of the biologicals are approved for multiple indications, but it is not always possible to extrapolate across indications for the corresponding biosimilars. For both reference agents and biosimilars, rare adverse events and long-term efficacy and safety can only be assessed through post marketing surveillance; therefore, particular emphasis should be placed on the traceability of these agents in clinical practice. Lastly, based on current data, biosimilars cannot be considered simple substitutes of reference products in IBD, unless demonstrated by well-designed randomized controlled trials.

Notificação de eventos adversos em vigilância sanitária: incompletitude das variáveis do NOTIVISA em 2007 E 2008. / Notification of adverse events in Sanitary Surveillance: variables incompleteness in Notivisa from 2007 to 2008.

A informação é instrumento fundamental para o processo decisório na vigilância póscomercialização/ uso, que tem por finalidade promover a identificação precoce de eventos adversos (EAs) relacionados com o uso de produtos sob vigilância sanitária. Este estudo avaliou aqualidade da informação, utilizando o indicador incompletitude das variáveis dos formulários das notificações de EA de uso de sangue e componentes (10), vacinas e imunoglobulinas (39), equipamentos (31) e artigos (30) médico-hospitalares recebidos pelo Notivisa em 2007 e2008. Trata-se de estudo transversal e descritivo. No ano de 2007, apenas 3 (30,0%); 6 (15,4%); 6 (19,4%) e 6 (20%) variáveis apresentaram taxa de incompletitude com classificação bom ouexcelente, respectivamente. Já em 2008, foram 4 (40,0%); 7 (17,9%); 7 (22,9%) e 7 (23,3%), porém as variáveis não foram as mesmas. Os resultados indicam que houve elevada incompletitude para a maior parte das variáveis estudadas. A instrumentalização para subsidiara vigilância pós-comercialização/uso está em construção no âmbito do Sistema Nacional de Vigilância Sanitária. Estratégias com melhoria do preenchimento das variáveis devem ser implementadas para contribuir com informações robustas na tomada decisão.

Information is essential to support the decision making process in post marketing surveillance. It aims to promote the early identification of adverse events (AE) related to the use of products under surveillance. This study aimed to evaluate information quality, using variables incompleteness of the notification forms of AE related to blood and its components use (10), vaccines and immunoglobulin (39), health care equipments (31) and medical devices (30) received by Notivisain 2007 and 2008. This is a transversal and descriptive study. In the year of 2007, only 3 (30%); 6 (15.4%); 6 (19.4%) and 6 (20%) variables presented incompleteness ratio with good or excellent classification, respectively. In 2008, there were 4 (40%), 7 (17.9%), 7 (22.9%) and 7 (23.3%), although the variables were not the same. The results indicate that the incompleteness for most of the studied variables increased. The instrumentation to subside the post marketing surveillance is still being constructed under the Sistema Nacional de Vigilância Sanitária (Brazilian national sanitary surveillance system). Strategies to improve the data s filling out must be implemented in order to provide relevant information to decision makers.