Postmarketing Surveillance Data Research Articles

A prospective registry of European haemophilia B patients receiving nonacog alfa, recombinant human factor IX, for usual use

Nonacog alfa, a recombinant factor IX (FIX) used for the treatment of haemophilia B, was approved in Europe in 1998. In accordance with European Medicines Agency requirements, a registry study was conducted from 2002 to 2009. A reformulated iso-osmotic version was approved for European use in 2007. This study was conducted to evaluate the safety of nonacog alfa in a usual care setting, and provide clinical trial and postmarketing surveillance data support. This open-label, non-interventional, prospective observational cohort study (registry) comprised 52 sites in nine European countries. Patients with haemophilia B receiving nonacog alfa in either formulation for prevention or treatment were followed on a usual care schedule. A total of 218 patients were enrolled, of whom 66 (30.3%) were <18 years of age. Haemophilia severity was evenly distributed, with baseline FIX activity of <1%, 1-5% and >5% in 33.3%, 36.6% and 30.1% of patients, respectively. One hundred thirty-eight patients received the original formulation alone; 80 switched to or received only the new formulation. There was a low incidence of events of special interest (ESIs), with less-than-expected therapeutic effect in five patients (2.2%), inhibitor development in two (0.9%), thrombosis in one (0.5%) and allergic events in eight (3.7%). These accounted for the majority of the 15 serious AEs reported in six patients. Six patients discontinued because of AEs, primarily related to hypersensitivity. Nonacog alfa was shown to be safe for the treatment of haemophilia B, with a low incidence of serious AEs and ESIs.

Safety of Gadobutrol, a New Generation of Contrast Agents

To assess the clinical safety and tolerability of the macrocyclic contrast agent gadobutrol (Gadovist/Gadavist) overall and in specific patient populations based on clinical trials and postmarketing experience. In total, 5545 patients enrolled in 34 prospective clinical studies were evaluated in an integrated analysis of safety. Of all enrolled patients, 4549 received gadobutrol at a dose of ≤ 0.09 mmol/kg body weight to a maximum of 0.51 mmol/kg body weight, with most patients (53.5%) receiving the recommended dose of >0.09 to 0.11 mmol/kg body weight. Data include comparisons with other extracellular contrast agents and subgroup analyses in pediatric patients, and patients with allergic disposition, renal impairment, hepatic impairment, or cardiovascular disease. Furthermore, worldwide postmarketing safety surveillance results, including nephrogenic systemic fibrosis reports, based on more than 5.7 million estimated applications are described. One or more adverse events (AEs) assessed as related to the administration of gadobutrol were reported by 182 (4.0%) of the 4549 patients who participated in clinical trials. This is comparable to the incidence observed with the comparator contrast agents (74/1844 patients, 4.0%). The most common AEs, independent of drug relationship, were headache, nausea, feeling hot, and dysgeusia. The favorable safety profile of gadobutrol was also demonstrated in the following specific subpopulations in whom similar incidence rates were seen: pediatric patients aged 2 to 17 years (8/138 patients, 5.8%), patients with severe or moderate renal impairment (9/366 patients, 2.5%), patients with severe or moderate hepatic impairment (9/214 patients, 4.2%), and patients with cardiovascular disorders (42/1506 patients, 2.8%). Having been established in controlled clinical trials, this safety profile was also confirmed by postmarketing surveillance data. With more than 5.7 million estimated administrations of gadobutrol, a total of 1175 (0.02%) suspected adverse drug reactions have been reported. The most serious adverse reactions seen in postmarketing surveillance included rare reports of cardiac arrest, respiratory arrest, anaphylactoid shock, and nephrogenic systemic fibrosis. Incidence and type of AEs from postmarketing surveillance were consistent with the established safety profile. The comprehensive analysis of safety data obtained from 34 clinical studies demonstrates that gadobutrol has an excellent safety profile and a positive benefit risk profile when used in patients in need of contrast-enhanced magnetic resonance imaging. Gadobutrol was well tolerated by adults, by children, by patients with impaired liver or kidney function, and by patients with cardiovascular disease. The favorable safety profile is confirmed by the available postmarketing surveillance data and is compared with that of other gadolinium-based contrast agents.

Safety and effectiveness of adalimumab in Japanese rheumatoid arthritis patients: postmarketing surveillance report of the first 3,000 patients

This interim analysis of postmarketing surveillance data for adalimumab-treated rheumatoid arthritis (RA) patients summarizes safety and effectiveness during the first 24weeks of therapy for the first 3,000 patients treated in Japan (June 2008-December 2009). Patient eligibility for antitumor necrosis factor therapy was based on the Japanese College of Rheumatology treatment guidelines and Japanese labeling. All patients were screened for tuberculosis. Approximately 50% of the population was biologic naïve, 66% received concomitant methotrexate (MTX), and 72% received concomitant glucocorticoids. The overall incidence rate of adverse events was 31% (5.5% serious) and that of adverse drug reactions (ADRs) was 27% (4.1% serious). Incidence rates of ADRs and serious ADRs were similar regardless of prior biologic therapy or concomitant MTX use but were significantly higher in patients receiving glucocorticoids compared with those not receiving glucocorticoids. Bacterial/bronchial pneumonia occurred in 1.2% of patients; interstitial pneumonia, 0.6%; Pneumocystis jirovecii pneumonia, 0.3%; tuberculosis, 0.13%; and administration-site reactions, 6.1%. Mean 28-joint Disease Activity Scores decreased significantly after 24weeks from 5.29 to 3.91. All subgroups showed significant improvement, particularly the biologic-naïve patients receiving concomitant MTX. No new safety concerns were identified. ADR Incidence rates were similar to those of other biologic agents approved for RA.

Clarification of clinical features of interstitial lung disease induced by irinotecan based on postmarketing surveillance data and spontaneous reports

Irinotecan-induced interstitial lung disease (ILD) requires accurate diagnosis, followed by prompt and appropriate treatment. This study was conducted to compile information and imaging data to define the characteristics of irinotecan-induced ILD. Searches were performed on information collected for a drug reexamination application and on data from spontaneous safety reports submitted to Daiichi Sankyo Company, Limited. These database searches revealed 153 cases of serious ILD that occurred in association with irinotecan therapy, and which were reported as adverse drug reactions. Computed tomographic findings obtained after the onset of ILD were categorized based on four typical patterns. A total of 66 patients (including 15 for whom a relationship between death and serious ILD could not be excluded; incidence of serious ILD: 0.74%; death rate of ILD: 0.17%) were detected during the postmarketing surveillance along with 87 patients (22 deaths) that were identified from spontaneous reports. Within 16 weeks of starting treatment, 80.7% of the patients developed ILD. A total of 61.3% of the cases treated using steroids responded to the steroid therapy. These results indicate that there is no specific clinical or imaging feature associated with ILD related to irinotecan and that the prognosis of ILD related to irinotecan was poor in patients with preexisting ILD. The relative risk calculated for the association between preexisting ILD and death was 2.25 (P=0.29). During irinotecan treatments, patients need to be carefully observed for symptoms, especially at 16 weeks after starting treatment. In addition, when patients are receiving this type of therapy, they also need to undergo chest imaging studies.

Pharmacology of Dipeptidyl Peptidase-4 Inhibitors

The dipeptidyl peptidase (DPP)-4 inhibitors, which enhance glucose-dependent insulin secretion from pancreatic β cells by preventing DPP-4-mediated degradation of endogenously released incretin hormones, represent a new therapeutic approach to the management of type 2 diabetes mellitus. The 'first-in-class' DPP-4 inhibitor, sitagliptin, was approved in 2006; it was followed by vildagliptin (available in the EU and many other countries since 2007, although approval in the US is still pending), saxagliptin (in 2009), alogliptin (in 2010, presently only in Japan) and linagliptin, which was approved in the US in May 2011 and is undergoing regulatory review in Japan and the EU. As the number of DPP-4 inhibitors on the market increases, potential differences among the different members of the class become important when deciding which agent is best suited for an individual patient. The aim of this review is to provide a comprehensive and updated comparison of the pharmacodynamic and pharmacokinetic properties of DPP-4 inhibitors, and to pinpoint pharmacological differences of potential interest for their use in therapy. Despite their common mechanism of action, these agents show significant structural heterogeneity that could translate into different pharmacological properties. At the pharmacokinetic level, DPP-4 inhibitors have important differences, including half-life, systemic exposure, bioavailability, protein binding, metabolism, presence of active metabolites and excretion routes. These differences could be relevant, especially in patients with renal or hepatic impairment, and when considering combination therapy. At the pharmacodynamic level, the data available so far indicate a similar glucose-lowering efficacy of DPP-4 inhibitors, either as monotherapy or in combination with other hypoglycaemic drugs, a similar weight-neutral effect, and a comparable safety and tolerability profile. Data on nonglycaemic parameters are scant at present and do not allow a comparison among DPP-4 inhibitors. Several phase III trials of DPP-4 inhibitors are currently ongoing; these trials, along with post-marketing surveillance data, will hopefully increase our knowledge about the long-term efficacy and safety of DPP-4 inhibitor therapy, the effect on pancreatic cell function and peripheral glucose metabolism, and the effect on cardiovascular outcomes in patients with type 2 diabetes.

Efficacy of continuing medical education to reduce the risk of buprenorphine diversion

As office-based opioid dependence treatment (OBOT) has grown in the United States, postmarketing surveillance data reveal increased reports of buprenorphine misuse and diversion. It is important that doctors understand buprenorphine clinical pharmacology and engage in practices to decrease risk of misuse, diversion, and other adverse events. This study evaluated the efficacy of continuing medical education (CME) in two U.S. regions with surveillance signals of buprenorphine misuse/diversion. Four surveys (before, on-site, and 1 and 3 months post CME) evaluated physician characteristics, practice behaviors, and buprenorphine pharmacology and legislative knowledge. The results show that physicians had limited addictions training. Knowledge and practice behaviors significantly improved after the CME, which should enhance the quality of OBOT and may decrease risk of buprenorphine misuse and diversion from their practices. Mandatory CME targeting OBOT-certified physicians could have a positive impact on patient and public health outcomes.

Safety and effectiveness responses to etanercept for rheumatoid arthritis in Japan: a sub-analysis of a post-marketing surveillance study focusing on the duration of rheumatoid arthritis

The aim is to investigate the relationship of duration of rheumatoid arthritis (RA) with safety and effectiveness of etanercept (ETN) in Japan. Post-marketing surveillance data for 7,099 patients treated with ETN were analyzed. Baseline characteristics, treatment effectiveness, incidence of adverse events (AEs), and serious AEs (SAEs) in relation to duration of RA were studied. At baseline, patients with RA for longer duration were older, weighed less, had more comorbidities, allergies, and corticosteroid use, but smoked less and had less morning stiffness. By 2–5 years with RA, more than half of the patients had advanced to Steinbrocker radiographic stage III or IV. Methotrexate (MTX) was the most commonly used pre-treatment disease-modifying antirheumatic drug; however, concomitant MTX use and its dose were lower among patients with longer duration of RA. Remission rates (26.6%) were greatest among patients having RA for <2 years. Less AEs and SAEs were observed among patients with shorter duration of RA. These results suggest that RA treatment in Japan in the era pre-biologics may not have been adequate to control disease activity and prevent joint destruction. Patients with shorter duration of RA may have better physical status which allows the opportunity to treat more intensively putting a higher percentage of patients in remission and possibly decreasing exposure to SAEs.

The Clinical Assessment and Treatment of Nicotine Dependence

In the United States and around the world, nicotine dependence is a leading cause of preventable death. Smoking cessation results in immediate and enduring health benefits. A wide range of clinical interventions have been shown to facilitate smoking cessation and to have a favorable cost-benefit profile. Practice guidelines and national reports have issued calls to action and have made smoking cessation resources readily available. Yet utilization of smoking cessation interventions and resources is lagging. Health care systems and providers have a shared responsibility to ensure that all smokers are offered appropriate interventions. This article summarizes the epidemiology and pathophysiology of nicotine dependence as a background for reviewing the central components of clinical evidence-based smoking cessation interventions: screening, assessment, advice, assistance, and follow-up. Specific patient populations are discussed, as well as emerging strategies to address nicotine dependence.

Spotlight on Pentavalent Rotavirus Vaccine (RotaTeq®) in the Prevention of Rotavirus Gastroenteritis in Europe†

In Europe, rotavirus gastroenteritis is associated with a significant health, economic, and social burden, as it is responsible for large numbers of hospitalizations and other healthcare encounters among infants and children, as well as numerous days of work lost by parents and caregivers. RotaTeq is a three-dose, orally administered, live, pentavalent human-bovine reassortant rotavirus vaccine used for the active immunization of infants for prevention of rotavirus gastroenteritis. The protective efficacy of RotaTeq has been evaluated in terms of its effects on the incidence of rotavirus gastroenteritis and on healthcare resource use. Clinical trial data from REST (a randomized, double-blind, placebo-controlled, multinational study in ≈70 000 healthy infants aged 6-12 weeks) and various subgroup analyses, including a large European cohort, have shown that RotaTeq may be administered at the same time as various other routine vaccines, has high and sustained efficacy covering the main period of risk for rotavirus gastroenteritis, has early protective efficacy after the first and second doses, reduces rotavirus gastroenteritis-associated hospitalization and emergency department and physician visits, and is generally well tolerated. Moreover, RotaTeq has demonstrated efficacy against the five most prevalent serotypes of rotavirus in Europe (G1-G4, G9), in terms of reductions in associated healthcare resource use. There is also evidence that the widespread use of RotaTeq may provide herd immunity, as it appears to have indirect benefits in older, unvaccinated children. Reports on the 'real world' effectiveness of RotaTeq in Europe are just emerging, but data from the US have shown a rapid and marked reduction in rotavirus burden nationwide during the ≈2-year period following the introduction of RotaTeq and the subsequent availability of official recommendations advocating universal use of the vaccine as part of routine childhood immunization. Postmarketing surveillance data from the US have not identified any concerns, such as an association with intussusception or Kawasaki disease, related to the safety of RotaTeq. In conclusion, RotaTeq is a generally well tolerated vaccine that has efficacy against the five most prevalent serotypes of rotavirus in Europe and provides sustained efficacy over the main risk period for rotavirus gastroenteritis in infants and children, reducing hospitalizations and emergency department visits by decreasing the incidence and severity of illness.

Natalizumab Use in Patients with Crohnʼs Disease and Relapsing Multiple Sclerosis: Updated Utilization and Safety Results from the TOUCH,TM Prescribing Program, the Pregnancy Registry, and the INFORM and TYGRIS Studies

Purpose: To report the most recent data on natalizumab utilization and safety in patients with Crohn's disease (CD) and relapsing multiple sclerosis (MS). Methods: Natalizumab was approved by the FDA for use in CD in 2008. The TYSABRI Outreach: Unified Commitment to Health (TOUCHTM) Prescribing Program, CD INFORM: Investigating Natalizumab through Further Observational Research and Monitoring, TYSABRI Global ObseRvation Program In Safety (TYGRIS), and pregnancy registry are ongoing risk management programs or studies designed to further evaluate the safety of natalizumab. TOUCHTM is a mandatory prescribing program for all patients, physicians, and infusion centers in the United States that ensures appropriate and informed use of natalizumab. The purpose of TOUCHTM is to monitor patients for serious opportunistic infections (OIs), including progressive multifocal leukoencephalopathy (PML). CD INFORM is a voluntary study in the United States collecting patient history, efficacy as assessed by the Harvey Bradshaw Index (HBI), Health Related Quality of Life outcomes, and serious adverse events (SAE) in CD patients. TYGRIS is a voluntary global observational study evaluating the long-term safety of natalizumab in MS. Post-marketing surveillance data from countries that do not participate in TOUCHTM or TYGRIS are also collected. This abstract provides updates on natalizumab utilization and safety data from these programs in both indications. Results: As of the end of March 2010, ˜67,700 patients have been exposed to natalizumab in the post-marketing setting, predominately for MS. As of 6 May 2010, 49 confirmed cases of PML had been reported in the post-marketing setting (all in MS patients). There were 11 deaths; 38 of the 49 (78%) natalizumab-treated patients who developed PML have survived and exhibit varying levels of disability. CD INFORM has enrolled 84 patients with an average HBI at time of entry of 8.3 as of 23 May 2010. Of the 51 CD patients with an HBI assessment following 6 months of natalizumab therapy, the average score was 4.7, a mean decrease of 2.8 points from baseline. The overall SAE incidence in CD INFORM was 16.7% (n=14), though only 2.4% (n=2) was considered treatment related. As of 23 February 2010, there were 198 women (including 1 woman with CD) enrolled prospectively in the pregnancy registry where the outcome of the pregnancy was unknown at time of enrollment. Follow-up was ongoing in 51 cases and 151 outcomes have been reported (4 patients with twins resulted in 2 outcomes for each pregnancy). The most current exposure and safety data from patients receiving natalizumab worldwide will be presented. Conclusion: Cumulative data from both indications suggest a safety profile consistent with the product labeling of natalizumab. Disclosure: Drs Anthony Pepio and Lori Taylor are employees of Elan Pharmaceuticals, Inc. Drs Mariska Kooijmans, Lynda M. Cristiano, and Carmen Bozic are employees of Biogen Idec, Inc. Dr Grainne Quinn is an employee of Elan Pharma International Ltd.

The Japanese experience with biologic therapies for rheumatoid arthritis

The unique genetic, environmental and medical backgrounds of people in Japan might influence the effectiveness and safety of biologic agents in patients with rheumatoid arthritis (RA). Indeed, clinical trials revealed higher response rates to some biologic agents (including infliximab, etanercept and tocilizumab) in patients with RA in Japan than patients treated with the same agents in Western countries, although response rates to adalimumab were comparable in both populations. The reasons why response rates to some biologic agents differ in Japanese individuals is currently under investigation. Post-marketing surveillance data have been collected for all patients with RA who were treated with biologic agents in Japan to monitor drug safety. These data clearly demonstrated that only ∼5% of these patients experienced adverse drug reactions to biologic agents, which were well tolerated. Pneumonia, tuberculosis, Pneumocystis jirovecii pneumonia and interstitial pneumonitis are considered important severe adverse reactions and risk factors for these adverse effects have been identified. Adverse drug reactions could exaggerate the risks associated with biologic therapy in Japanese patients with RA. Attempts have, therefore, been made to predict clinical response and adverse effects to enable personalized therapy with biologic agents and to optimize the outcomes of these patients.

Incidence of tuberculosis infection in psoriatic patients on anti‐TNF therapy: report of a case series with 144 patients

Worldwide clinical trials and post-marketing surveillance data have demonstrated an increased incidence of tuberculosis (TB) disease associated with antitumour necrosis factor (anti-TNF) agents. The majority of these cases are presumed to result from a reactivation of latent disease, while the rate of new infections is unknown. A study was performed to evaluate th incidence of latent tuberculosis infection (LTBI) in psoriatic patients screened for biological therapy in a high-incidence area, such as Madrid, Spain. One hundred and forty-four patients with moderate-to-severe psoriasis treated with anti-TNF agents were recruited. All of them were screened for active TB or LTBI before therapy. The screening included a detailed medical study, physical examination, chest X-ray, tuberculin skin test (TST) with purified protein derivative and re-TST. A total of 42 (29%) patients were diagnosed with LTBI based on a positive TST or re-TST, and/or signs of past TB in the chest X-ray. All of them received chemoprophylaxis with isoniazide. One patient developed a primary active lymphnode TB. This is the first study to underscore the incidence of LTBI in patients with psoriasis treated with anti-TNF therapy in the Spanish population. We support that the use of TST is still reliable and an effective diagnostic method for the detection of LTBI in anti-TNF therapy.

Pentavalent Rotavirus Vaccine (RotaTeq®)

In Europe, rotavirus gastroenteritis is associated with a significant health, economic and social burden, as it is responsible for large numbers of hospitalizations and other healthcare encounters among infants and children, as well as numerous days of work lost by parents and caregivers. RotaTeq is a three-dose, orally administered, live, pentavalent human-bovine reassortant rotavirus vaccine used for the active immunization of infants for prevention of rotavirus gastroenteritis. The protective efficacy of RotaTeq has been evaluated in terms of its effects on the incidence of rotavirus gastroenteritis and on healthcare resource use. Clinical trial data from REST (a randomized, double-blind, placebo-controlled, multinational study in approximately 70,000 healthy infants aged 6-12 weeks) and various subgroup analyses, including a large European cohort, have shown that RotaTeq may be administered at the same time as various other routine vaccines, has high and sustained efficacy covering the main period of risk for rotavirus gastroenteritis, has early protective efficacy after the first and second doses, reduces rotavirus gastroenteritis-associated hospitalization and emergency department and physician visits, and is generally well tolerated. Moreover, RotaTeq has demonstrated efficacy against the five most prevalent serotypes of rotavirus in Europe (G1-G4, G9), in terms of reductions in associated healthcare resource use. There is also evidence that the widespread use of RotaTeq may provide herd immunity, as it appears to have indirect benefits in older, unvaccinated children. Reports on the 'real world' effectiveness of RotaTeq in Europe are just emerging, but data from the US have shown a rapid and marked reduction in rotavirus burden nationwide during the approximately 2-year period following the introduction of RotaTeq and the subsequent availability of official recommendations advocating universal use of the vaccine as part of routine childhood immunization. Similar benefits have also been demonstrated in Australia after the introduction of a publicly funded rotavirus vaccination programme. Postmarketing surveillance data from the US have not identified any concerns, such as an association with intussusception or Kawasaki disease, related to the safety of RotaTeq. In conclusion, RotaTeq is a generally well tolerated vaccine that has efficacy against the five most prevalent serotypes of rotavirus in Europe and provides sustained efficacy over the main risk period for rotavirus gastroenteritis in infants and children, reducing hospitalizations and emergency department visits by decreasing the incidence and severity of illness.

Evidence Report: The efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis [RETIRED

The chemotherapeutic agent mitoxantrone was approved for use in multiple sclerosis (MS) in 2000. After a review of all the available evidence, the original report of the Therapeutics and Technology Assessment Subcommittee in 2003 concluded that mitoxantrone probably reduced clinical attack rates, MRI activity, and disease progression. Subsequent reports of decreased systolic function, heart failure, and leukemia prompted the US Food and Drug Administration to institute a "black box" warning in 2005. This review was undertaken to examine the available literature on the efficacy and safety of mitoxantrone use in patients with MS since the initial report. Relevant articles were obtained through a review of the medical literature and the strength of the available evidence was graded according to the American Academy of Neurology evidence classification scheme. The accumulated Class III and IV evidence suggests an increased incidence of systolic dysfunction and therapy-related acute leukemia (TRAL) with mitoxantrone therapy. Systolic dysfunction occurs in approximately 12% of patients with MS treated with mitoxantrone, congestive heart failure occurs in approximately 0.4%, and leukemia occurs in approximately 0.8%. The number needed to harm is 8 for systolic dysfunction and 123 for TRAL. There is no new efficacy evidence that would change the recommendation from the previous report. The risk of systolic dysfunction and leukemia in patients treated with mitoxantrone is higher than suggested at the time of the previous report, although comprehensive postmarketing surveillance data are lacking.

Review: Optimizing outcomes with alosetron hydrochloride in severe diarrhea-predominant irritable bowel syndrome

Irritable bowel syndrome (IBS) is a highly prevalent functional gastrointestinal disorder that causes a range of symptoms. Currently, alosetron hydrochloride (Lotronex®), a selective serotonin type 3 receptor antagonist, is the only medication approved for the treatment of severe diarrhea-predominant irritable bowel syndrome (IBS-D) in women who have inadequately responded to conventional therapy. Alosetron has demonstrated efficacy compared with placebo in clinical trials and has been shown to improve overall health-related quality of life (HRQoL). However, rare instances of ischemic colitis and severe complications of constipation have been reported. As a result, in 2000 alosetron was voluntarily withdrawn from the market but was reintroduced in 2002 with a more restricted indication and a requirement that clinicians and patients follow a prescribing program. Although the efficacy and benefit of alosetron has been clearly demonstrated, it has been used sparingly since its reintroduction. This brief review describes the history of alosetron, efficacy of alosetron in the treatment of IBS, the impact of severe IBS on HRQoL, safety considerations, the risk evaluation and mitigation strategy program under which alosetron is now prescribed, and an update on postmarketing surveillance data.

Pilsicainide

Pilsicainide is a class Ic antiarrhythmic agent used for the treatment of supraventricular and ventricular tachycardia. The pharmacodynamic effects of pilsicainide are achieved via selective sodium channel blockade. In randomized, multicentre trials in patients with atrial fibrillation, restoration of sinus rhythm was achieved in significantly more patients treated with a single oral dose of pilsicainide than those who received placebo, and in a numerically higher proportion of oral pilsicainide than intravenous disopyramide recipients. In another well designed trial in patients with persistent atrial fibrillation, the proportion of patients whose arrhythmia converted to normal sinus rhythm was significantly higher among those randomized to receive 2 weeks of oral pilsicainide therapy than among patients who received placebo. Over a 1-year period, both pilsicainide and cibenzoline (another class Ic agent) were effective in preventing recurrence of atrial fibrillation in a substantial proportion of patients in a single-centre crossover trial. There were no between-group differences in the subgroup of patients with shorter-duration atrial fibrillation, but actuarial results over 1 year significantly favoured cibenzoline over pilsicainide in patients with longer-duration atrial fibrillation. Both oral and intravenous pilsicainide have demonstrated efficacy in ventricular tachyarrhythmias, including ventricular extrasystole. Clinical trial and postmarketing surveillance data indicate that pilsicainide is generally well tolerated in most patients.

A Pharmacologic Study on Risk Factors of Hyperkalaemia or Increased Blood Potassium Associated with ACE-Inhibitor Therapy

Objective: To investigate quantitatively the risk factors of hyperkalaemia or increased blood potassium associated with ACE-inhibitor therapyDesign: Nested case-control studyMethods: We used the antihypertensive drug database(72,379 subjects)developed by the RAD-AR Council, Japan and the Institute of Statistical Mathematics based on the post-marketing surveillance(PMS) data of pharmaceutical companies. Of 37,372 subjects taking ACE-inhibitors, the case group was composed of 64 patients who experienced hyperkalaemia or blood potassium increase while taking ACE-inhibitors, and the control group was composed of 1,280 patients(20 patients per case)randomly selected from patients who did not experience hyperkalaemia or blood potassium increase while taking ACE-inhibitors. The relevant factors that can be extracted from the database were the followings: age, WHO classification of hypertension, complications, antihypertensive drugs used before the PMS survey, and concomitant drugs.Results: Among the subjects taking antihypertensive agents, 65 patients experienced hyperkalaemia orincreased blood potassium, 64(98.5%)of whom were taking ACE-inhibitors. The factors that were significantly different between two groups(p<0.05)by univariate analysis were WHO classification of hypertension(p=0.005), complications of nephritis/nephrosis(p<0.001), other disorder of urinary system(p<0.001), unclear symptom or diagnosis(p=0.005), taking diuretics as antihypertensive drugs before study(p=0.032), and concomitant treatment with diuretics(p=0.004), vasodilators(p<0.001), and antigout agents(p=0.001). Conditional multivariate logistic analysis of these factors yielded adjusted odds ratio of 21.31 for complications of nephritis/nephrosis(p<0.001), 6.83 for other disorder of urinary system(p<0.001), and 2.30 for concomitant therapy with diuretics(p=0.049).Conclusion: The risk factors of hyperkalaemia or blood potassium increase associated with taking ACE-inhibitors were nephritis/nephrosis, other disorder of urinary system and concomitant therapy with diuretics.

Review of 8 years of experience with Infanrix hexa™ (DTPa–HBV–IPV/Hib hexavalent vaccine)

Combination vaccines that include multiple antigens within one formulation are now widely accepted as an effective means of eliciting protection against several diseases at the same time. Owing to improvements in quality and convenient modes of administration, they have become part of routine pediatric practice. Hexavalent vaccines, including diphtheria, tetanus, pertussis, hepatitis B, polio and Haemophilus influenzae type b antigens represent the latest advance in the development of combination vaccines. Over 8 years since its first licensure, this review looks at the immunogenicity, efficacy and safety profile of the only hexavalent pediatric vaccine currently in use – Infanrix hexa™ (diphtheria, tetanus, acellular pertusis–hepatitis B virus–inactivated poliovirus vaccine/Haemophilus influenzae type b vaccine [DTPa–HBV–IPV/Hib]; GlaxoSmithKline Biologicals, Rixensart, Belgium) – through published clinical trials and postmarketing surveillance data. These data show DTPa–HBV–IPV/Hib to be highly immunogenic and well tolerated across a range of different primary and booster vaccination schedules, as well as when administered concomitantly with other licensed vaccines (e.g., pneumococcal conjugate vaccine). Additional issues surrounding the use of hexavalent vaccines are also reviewed.

Abatacept therapy and safety management

Objectives To elaborate a how-to-use abatacept material intended to help physicians in the management of patients with inflammatory diseases treated with this drug in routine practice. Methods 1) Selection of the relevant domains by a rheumatologists’ panel; 2) Search for published evidence in each domain; 3) Elaboration of the clinical tool guide with a 3-level gradation of evidence (evidence-based medicine EBM, official recommendations and expert's opinion). The experts were 11 academic rheumatologists with a large experience in prescribing abatacept and in managing rheumatoid arthritis. They were all members of the CRI (Club Rhumatismes et Inflammation), a section of the French Rheumatology Society dedicated to the inflammatory rheumatic diseases. Each fact sheet was reviewed by two other experts; 4) Regular updating based on medical literature and postmarketing surveillance data. Results Four domains were considered relevant: abatacept contraindications, management of side effects or associated diseases appearing during abatacept treatment, management of “practical situations” such as surgery or pregnancy, physician and patient information. After the literature analysis and discussion during an experts’ meeting, a consensus was reached on: – a pre-treatment checklist aimed at searching abatacept contraindications; – a what-to-do document when facing side effects or associated diseases (autoimmune pathology, bacterial or viral infections, cardiovascular diseases, intolerance to abatacept, solid or haematological malignancy) or “practical situations” (surgery, pregnancy, vaccination, travel, drug-drug interactions); – an example of standard information letter to be addressed to the attending physician (rheumatologist and general practitioner); – an example of standard information letter to be addressed to the patient. Conclusion Based on both an EBM approach and an expert's opinion approach, this abatacept clinical tool guide should provide assistance to all physicians attending patients treated with abatacept. For a better implementation in clinical practice, this tool guide will be available online at www.cri-net.com and regularly updated.

Hallucinatory Side Effects of ADHD Drugs

Clinical trial and postmarketing surveillance data for drugs used in treatment of attention deficit hyperactivity disorder were analyzed to determine the frequency of hallucinations and other psychotic side effects, in a study at the US Food and Drug Administration, and Department of Health and Human Services, Maryland.