Adherence with regulatory resolutions on prevention of NSAIDS-related gastrointestinal injury in Italy.

Background The rate of gastrointestinal (GI) complications with non-steroidal antiinflammatory drugs (NSAIDs) or low-dose aspirin (LD-ASA) varies according to risk factors. For at risk patients, the Italian regulatory resolution enforce prophylaxis with proton pump inhibitors (PPIs) or misoprostol. Objective This study evaluated the consistency with such resolution in patients receiving NSAIDs or LD-ASA and assessed whether patients continued to receive GI protection with PPIs for an adequate time following NSAID discontinuation. Setting An observational retrospective study was conducted using data from Health District of Pisa. Methods The analysis was performed on patients receiving prescription of NSAIDs or LD-ASA, with or without concomitant PPIs or misoprostol, accordingly with the presence of risk factors (2008-2010). Prescription data were retrieved from the database of reimbursement claims for dispensed drugs, while history of past GI diseases was obtained from primary or secondary discharge diagnosis. Main outcome measure The consistency rates of PPI and misoprostol prescriptions with Italian regulatory rules in patients receiving chronic NSAIDs or LD-ASA. Results 6869 patients, receiving NSAIDs or LD-ASA during the observation period, were eligible for the analysis. For NSAIDs or LD-ASA, gastroprotection rates in patients without risk factors were: 8 and 6 % in 2008; 10 and 8 % in 2009; 9 and 6 % in 2010; while the proportions of patients with one or more risk factors not receiving gastroprotection were: 12 and 17 % in 2008; 25 and 22 % in 2009; 15 and 17 % in 2010. In patients discontinuing chronic NSAIDs, 62 % were maintained on protection with PPIs, but only 28 % continued the PPI treatment for an adequate time (60 ± 7 days). Conclusions The present analysis, although restricted to prescription patterns in a single health district, suggests scarce levels of consistency with Italian regulatory resolution on the prophylaxis of GI adverse events associated with chronic NSAIDs or LDASA.

Safety Profile of Certolizumab Pegol in Patients with Immune-Mediated Inflammatory Diseases: A Systematic Review and Meta-Analysis.

INTRODUCTION: Certolizumab pegol (CZP), an anti-tumor necrosis factor PEGylated Fab' fragment of a humanized monoclonal antibody, is currently approved for treatment of some immune-mediated inflammatory diseases (IMIDs). To our knowledge, no systematic review and meta-analysis evaluating the overall safety profile of CZP has been performed. OBJECTIVE: The objective of this systematic review was to assess the adverse event (AE) patterns of CZP versus a control in patients with IMIDs. METHODS: A systematic literature search was performed using PubMed/MEDLINE, EMBASE, the Cochrane Library, and the FDA database for clinical trials up to March 2014. Eligible studies were those that compared the safety profile of CZP to a control group in patients with IMIDs. The following data were extracted: number of patients experiencing AEs, serious AEs (SAEs), adverse drug reactions (ADRs), withdrawals due to AEs, fatal AEs, infectious AEs and SAEs, upper respiratory tract infections, injection-site reactions, neoplasms, and tuberculosis. RESULTS: A total of 2023 references were identified and 18 randomized controlled trials were included. The main pooled risk ratios of CZP-treated versus control patients were as follows: AEs 1.09 (95% confidence interval, CI 1.04-1.14), SAEs 1.50 (95% CI 1.21-1.86), ADRs 1.20 (95% CI 1.03-1.39), infectious AEs 1.28 (95% CI 1.13-1.45), infectious SAEs 2.17 (95% CI 1.36-3.47), and upper respiratory tract infections 1.34 (95% CI 1.15-1.57). CONCLUSION: Safety data on CZP suggest an overall favorable tolerability profile, with infections being the most common AE. However, CZP-treated patients had a twofold higher risk of infectious SAEs than control patients. Large observational studies and data from national registries are needed to detect rare AEs, which might occur after long-term exposures to CZP.

Adverse reactions to oncologic drugs: spontaneous reporting and signal detection.

Oncology is one of the areas of medicine with the most active research being conducted on new drugs. New pharmacological entities frequently enter the clinical arena, and therefore, the safety profile of anticancer products deserves continuous monitoring. However, only very severe and (unusual) suspected adverse drug reactions (ADRs) are usually reported, since cancer patients develop ADRs very frequently and some practical selectivity must be used. Notably, a recent study was able to identify 76 serious ADRs reported in updated drug labels of oncologic drugs and 50% of them (n = 38) were potentially fatal. Of these, 49 and 58%, respectively, were not described in initial drug labels. The aims of this article are to provide an overview about spontaneous reporting of ADRs of oncologic drugs and to discuss the available methods to analyze the safety of anticancer drugs using databases of spontaneous ADR reporting.

Neuropsychiatric adverse events associated with statins: epidemiology, pathophysiology, prevention and management.

Statins, or 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors, such as lovastatin, atorvastatin, simvastatin, pravastatin, fluvastatin, rosuvastatin and pitavastatin, are cholesterol-lowering drugs used in clinical practice to prevent coronary heart disease. These drugs are generally well tolerated and have been rarely associated with severe adverse effects (e.g. rhabdomyolysis). Over the years, case series and data from national registries of spontaneous adverse drug reaction reports have demonstrated the occurrence of neuropsychiatric reactions associated with statin treatment. They include behavioural alterations (severe irritability, homicidal impulses, threats to others, road rage, depression and violence, paranoia, alienation, antisocial behaviour); cognitive and memory impairments; sleep disturbance (frequent awakenings, shorter sleep duration, early morning awakenings, nightmares, sleepwalking, night terrors); and sexual dysfunction (impotence and decreased libido). Studies designed to investigate specific neuropsychiatric endpoints have yielded conflicting results. Several mechanisms, mainly related to inhibition of cholesterol biosynthesis, have been proposed to explain the detrimental effects of statins on the central nervous system. Approaches to prevent and manage such adverse effects may include drug discontinuation and introduction of dietary restrictions; maintenance of statin treatment for some weeks with close patient monitoring; switching to a different statin; dose reduction; use of ω-3 fatty acids or coenzyme Q10 supplements; and treatment with psychotropic drugs. The available information suggests that neuropsychiatric effects associated with statins are rare events that likely occur in sensitive patients. Additional data are required, and further clinical studies are needed.

Acute portal vein thrombosis precipitated by indomethacin in a HCV-positive elderly patient.

BACKGROUND: An increased risk of venous thromboembolism has been reported in patients treated with non-steroidal anti-inflammatory drugs (NSAIDs). We describe a case of acute portal vein thrombosis (PVT) in a hepatitis C virus (HCV)-positive elderly patient following administration of indomethacin. CASE PRESENTATION: A 79-year-old HCV-positive man was hospitalized for severe abdominal pain, nausea and vomiting, 15 days after starting indomethacin for back pain. Clinical signs and imaging evaluations disclosed a picture of PVT. Indomethacin was discontinued, and the patient was started on fondaparinux and antithrombin. He was discharged 15 days later due to improvement of his clinical conditions. Thirty days later, a follow-up ultrasound did not show appreciable signs of PVT. The time elapsing between the start of analgesic therapy and PVT onset suggests a role of indomethacin as the triggering agent. Indomethacin could have precipitated PVT by a combination of at least two detrimental mechanisms: 1) direct action on liver vascular endothelium by inhibition of prostacyclin biosynthesis; 2) damage to the intestinal mucosa, followed by inflammatory and pro-coagulant activation of portal endothelium upon exposure to bacterial endotoxins. CONCLUSIONS: This case can be of interest to physicians, who should exert caution when prescribing NSAIDs for inflammatory pain in patients with background inflammatory dysfunctions of the portal vein endothelium.

Autoimmune hemolytic anemia following MF59-adjuvanted influenza vaccine administration: a report of two cases.

OBJECTIVE: To describe 2 cases of autoimmune hemolytic anemia (AIHA) following the administration of MF59-adjuvanted influenza vaccine. CASE SUMMARY: An 83-year-old white woman developed persistent hyperpyrexia, polyarthralgia, and lower limb hypostenia about 2 days after receiving influenza vaccine. Clinical signs and laboratory evaluations suggested AIHA. The patient was treated with high-dose corticosteroids and immunoglobulins, and her clinical condition improved. A 74-year-old white woman developed severe abdominal pain and asthenia 3 days after the administration of influenza vaccine. Clinical signs and laboratory evaluations disclosed AIHA. She was treated with corticosteroids, rehydration, and blood transfusion; however, she died about 48 hours after hospitalization. DISCUSSION: AIHA has been rarely described following influenza vaccine administration. In the cases described here, the causal relationship between influenza vaccination and the occurrence of AIHA, assessed by means of World Health Organization criteria, was scored as probable. It has been proposed that the mechanism whereby vaccines induce autoimmune responses can be molecular mimicry, although a possible role of other vaccine constituents, with particular regard for adjuvants, such as MF59, can not be excluded. Squalene, a constituent of MF59, has been suggested as a causative agent of autoimmune reactions. However, it is not clear how and under what conditions squalene can cause immune responses. CONCLUSIONS: Influenza vaccination may rarely trigger severe AIHA, shortly after vaccine administration. A mechanism of molecular mimicry is probably involved in the development of these reactions, although the possible role of adjuvants can not be excluded. Patients should be instructed to report signs and symptoms of autoimmune disorders occurring in the first weeks after administration of influenza vaccine.

Inclusion of rituximab in treatment protocols for non-Hodgkin's lymphomas and risk for progressive multifocal leukoencephalopathy.

Objectives. Rituximab is an anti-CD20 monoclonal antibody that promotes better treatment outcomes in patients with non-Hodgkin's lymphoma (NHL). Case series of progressive multifocal leukoencephalopathy (PML) in patients receiving rituximab within polychemotherapy regimens have led to the introduction of a black box warning, but no risk estimation has ever been provided. Methods. We performed a retrospective, monocentric cohort study on 976 NHL patients diagnosed in 1994-2008, including 517 patients who received at least one dose of rituximab. Results. Inclusion of rituximab into standard chemotherapy regimens for NHL caused a significantly higher incidence of PML cases (rate difference, 2.2 every 1,000 patient-years; 95% confidence interval, 0.1-4.3). Interpretation. Based on this finding, clinical surveillance of PML-related symptoms is recommended in NHL patients exposed to rituximab.

Use of selective serotonin reuptake inhibitors during pregnancy and risk of major and cardiovascular malformations: an update.

General consensus exists about the need to avoid drug intake as much as possible during pregnancy due to the lack of thorough evidence about the safety of pharmacologic treatments during gestation for both mothers and fetuses. In this respect, the overall safety profile of selective serotonin reuptake inhibitors (SSRIs) in pregnancy remains unclear. This article reviews current evidence about the safety of each SSRI during pregnancy in order to describe their specific teratogenic potential, with a particular focus on major and cardiovascular malformations, and to verify whether such toxicity can be considered as a class effect. The literature review included controlled studies and meta-analyses (retrieved using PsychINFO, EMBASE, and Medline from January 1966 to May 2010) from which the risk of major and/or cardiovascular malformations associated with a specific SSRI (ie, fluoxetine, paroxetine, sertraline, citalopram, escitalopram, and fluvoxamine) could be estimated. Although there is evidence to support the association between birth defects and first-trimester exposure to paroxetine, findings from the studies reviewed suggest a teratogenic potential of the whole SSRI class, consistent with preclinical evidence. These teratogenic effects are mainly in the heart region, and they are often described as septal defects. It may be suggested that the higher frequency of teratogenic effects reported for paroxetine might depend on specific pharmacologic features of this drug compared with other SSRIs, although it is difficult to test this hypothesis. It is noteworthy that current evidence on SSRI teratogenicity stems from studies affected by several methodological weaknesses (ie, lack of investigations using control groups of untreated depressed mothers, confounding by indication, and recall bias). Accordingly, we are not yet able to rule out the possibility that positive associations, as determined in some studies, result from analyses of poor quality.

Transient acute liver failure complicating transurethral resection syndrome.

Transurethral resection (TUR) syndrome, resulting from dilutional hyponatraemia for excessive absorption of irrigating fluid, represents the most relevant complication of transurethral resection of prostate (TURP). Ethanol is used as a tracer in the irrigant solution to monitor fluid absorption with a breathalyser. An unusual case of transient acute liver failure complicating TUR syndrome is reported. A 54-year-old male patient, without risk factors for the development of toxic hepatitis, was subjected to TURP for treatment of benign prostatic hyperplasia. Fluid absorption (2275 ml), estimated by breathalyser, exceeded maximum allowed absorption (2000 ml) only at the end of the surgical intervention. No signs of possible toxicity were evident in the few hours following the intervention. About 10 h after the end of TURP, the patient developed sweating, vomiting and diarrhoea. Laboratory analysis revealed severe hyponatraemia (116 meq/l) with signs of severe liver impairment (total bilirubin 5.8 mg/dl, alanine aminotransferase 56,500 U/l, aspartate aminotransferase 32,700 U/l), kidney failure (serum creatinine 1.93 mg/dl) and serum ethanol levels of 219 mg/dl (0.2%). The patient was treated with acetylcysteine 150 mg/kg i.v. and furosemide 50 mg i.v. Liver and renal functions improved in few days and recovered completely within 30 days. The TUR syndrome observed in this case was probably extravascular in nature, and could have been identified and prevented by measuring ethanol levels 10 min after ending the surgical procedure. The performance of such a test should be strongly recommended to all surgeons. The clinicians attributed the development of liver impairment in this case to ethanol toxicity. However, further studies are warranted to confirm whether hepatic injury can represent a possible complication of TUR syndrome when ethanol solution is used as irrigant fluid.

Safety concerns associated with the use of serotonin reuptake inhibitors and other serotonergic/noradrenergic antidepressants during pregnancy: a review.

BACKGROUND: There is ongoing debate about the safety of selective serotonin reuptake inhibitors (SSRIs) and other serotonergic/noradrenergic antidepressants when used during pregnancy. OBJECTIVE: This article reviews the available literature on the main safety concerns associated with the use of SSRIs and other serotonergic/noradrenergic antidepressants (serotonin-norepinephrine reuptake inhibitors, norepinephrine reuptake inhibitors, noradrenergic and specific serotonergic antidepressants) during pregnancy. METHODS: English-language reports of analytical and descriptive studies, including case reports, case series, and meta-analyses, were identified through searches of MEDLINE, EMBASE, and PsycINFO (1966-April 2009). The search terms were fluoxetine, paroxetine, sertraline, Citalopram, escitalopram, fluvoxamine, venlafaxine, mirtazapine, reboxetine, duloxetine, SSRI, SNRI, NaSSA, and NRI in association with depression, pregnancy, prenatal exposure, miscarriage, spontaneous abortion, malformation, in utero exposure, and neonatal complications. RESULTS: Paroxetine has been associated with significant risks of major malformation, particularly cardiac defects, when used during pregnancy. Significant associations between maternal exposure to SSRIs and both persistent pulmonary hypertension of the newborn and a self-limiting neonatal behavioral syndrome have been reported in a number of recent original studies and meta-analyses. Some studies have suggested a relationship between the use of SSRIs or other serotonergic/noradrenergic antidepressants and the occurrence of miscarriage, although these studies had methodologic limitations that affected the strength of the data. Evidence for a possible association between in utero exposure to SSRIs or other serotonergic/noradrenergic antidepressants and alterations in neurobehavioral development, bleeding, and QTc-interval prolongation is currently weak. CONCLUSION: The available evidence suggests that SSRIs and other serotonergic/noradrenergic antidepressants should be used with caution during pregnancy, with careful follow-up of infants exposed to these agents in utero.