Paola Cutroneo

Clinical and economic burden of adverse drug reactions

Adverse drug reactions (ADRs) are unwanted drug effects that have considerable economic as well as clinical costs as they often lead to hospital admission, prolongation of hospital stay and emergency department visits. Randomized controlled trials (RCTs) are the main premarketing methods used to detect and quantify ADRs but these have several limitations, such as limited study sample size and limited heterogeneity due to the exclusion of the frailest patients. In addition, ADRs due to inappropriate medication use occur often in the real world of clinical practice but not in RCTs. Postmarketing drug safety monitoring through pharmacovigilance activities, including mining of spontaneous reporting and carrying out observational prospective cohort or retrospective database studies, allow longer follow-up periods of patients with a much wider range of characteristics, providing valuable means for ADR detection, quantification and where possible reduction, reducing healthcare costs in the process. Overall, pharmacovigilance is aimed at identifying drug safety signals as early as possible, thus minimizing potential clinical and economic consequences of ADRs. The goal of this review is to explore the epidemiology and the costs of ADRs in routine care.

Identifying Adverse Drug Reactions Associated with Drug-Drug Interactions: Data Mining of a Spontaneous Reporting Database in Italy

AbstractBackground: Drug-drug interactions (DDIs) are an important cause of adverse drug reactions (ADRs). Many studies have recently considered this issue, but most of them focus only on potential interactions and are often related to the hospital setting. A spontaneous reporting database could be a valuable resource for detection of ADRs associated with DDIs; however, data in the literature are limited. Objective: To detect those patients treated with potentially interacting drugs and the cases where reported adverse reactions are a possible consequence of DDIs, using an Italian spontaneous reporting database. Methods: The data were obtained from a database containing all reports of suspected ADRs from five Italian regions (January 1990 to December 2007) that are the main contributors to the Italian spontaneous reporting system. All reports containing at least two drugs, reported as being suspected of causing the ADR or as concomitant medication, were selected and a list of drug pairs was drawn up. We performed a search to verify which drug pairs are considered a potential DDI, using the Internet version of the DRUGDEX® system. For each report containing a potential DDI, we verified whether the description of the adverse reaction corresponded to the interaction effect. Results: The database contained 45 315 reports, of which 17 700 (39.1%) had at least two reported drugs. We identified 5345 (30.2%) reports with potential DDIs, and in 1159 (21.7%) of these reports a related ADR was reported. The percentage of reports with potential DDIs increased in relation to the number of concomitantly administered drugs, ranging from 9.8% for two drugs to 88.3% for eight or more drugs. The percentages of serious or fatal reports of ADRs associated with a DDI were significantly higher than other reports analysed. The mean age, percentage of male patients and the mean number of drugs were also significantly higher in reports with DDIs than in other reports. In 235 of 1159 reports (20.3%), both interacting drugs were recognized as suspect by the reporter. This percentage varies in relation to the drugs involved, ranging from 2% to about 65%. The most frequently reported interaction was digoxin and diuretics, but no fatal ADRs were reported with this combination. The combination of anticoagulant and antiplatelet agents was responsible for the greatest number of serious reactions and deaths. Conclusions: This study validates that spontaneous reporting, despite its limitations, can be an important resource for detecting ADRs associated with the concomitant use of interacting drugs. Moreover, our data confirm that DDIs could be a real problem in clinical practice, showing that more than one in five patients exposed to a potential DDI experienced a related ADR.

Allergic reactions to oral drugs : A case/non-case study from an Italian spontaneous reporting database (GIF)

Despite the wide number of studies investigating on drug-induced allergy, limited data focused on allergies associated with orally administered drugs are available. The aim of the study is to evaluate allergic drug reactions associated with oral drug use, using an Italian spontaneous reporting database of adverse drug reactions (ADRs). Spontaneous reports associated with oral drugs retrieved from seven Italian regions (GIF research group), collected from 1988 to 2006, were analysed. Association between drugs and allergic adverse reactions was assessed using the case/non-case method, calculating the ADR reporting odds ratio (ROR) as a measure of disproportionality. Overall, 27,175 reports of adverse reactions related to oral drug use were analysed; of these, 3143 (11.6%) were judged as allergy cases. Paediatric patients (<or=15 years) and inpatients (p<0.001) were more represented in cases than in non-cases. Antibiotics and Non-Steroidal Anti-inflammatory Drugs (NSAIDs) were the only two drug classes associated with a significant increase of ROR. Regarding antibiotics, cinoxacin (6.88; 95%CI 4.19-11.29) and moxifloxacin (4.20; 95% CI 3.19-5.55) were related to the highest ROR values, while propionic acid derivates (ROR 2.75; 95% CI 2.30-3.28), and in particular ibuprofen (4.20; 95% CI 3.13-5.63), have shown the highest ROR values among NSAIDs. The results of the present paper confirm the higher frequency of allergic reactions with oral antibiotics and NSAIDs, although more data are needed. Given the widespread use of these drug classes (some of them being purchased as over the counter drugs), awareness should be raised among patients and prescribers about these risks.

Adverse reactions induced by NSAIDs and antibacterials: analysis of spontaneous reports from the Sicilian regional database.

AbstractObjectives: To (i) evaluate the suspected adverse drug reactions (ADRs) related to NSAIDs and antibacterials that were reported to Sicilian local health officers by healthcare professionals; and (ii) to detect new or serious potential signals of alarm related to these two widely used drug categories. Methods: We selected all the spontaneous reports of ADRs sent between January 1998 and June 2004 and analysed those attributed to NSAIDs and systemic antibacterials, applying proportional reporting ratio (PRR) methodology. PRRs >2, χ2 >4 and >3 ADRs were regarded as signals. Results: During the period considered, 1585 reports of ADRs were received overall (42.6% serious), with an annual reporting rate of approximately 49.1 reports per million inhabitants on average; 351 referred to systemic antibacterials, and 179 to NSAIDs. There were 174 (49.6%) reports of serious ADRs associated with antimicrobials and 108 (60.3%) associated with NSAIDs. Disproportionality was observed, in particular for anaphylactic shock induced by ceftriaxone (all reports were associated with off-label use of the drug), photosensitivity reaction induced by lomefloxacin (administered in the summer), hepatitis induced by nimesulide (three cases leading to liver transplantation) and vasculitis induced by nimesulide. Conclusion: Our analysis highlighted several signals of alarm deserving further investigation or measures to influence prescribing. This study underlines the value of a regional centre in identifying local factors (such as prescribing patterns) that may increase the prevalence of serious ADRs.

Acute Cerebellar Ataxia Following Meningococcal Group C Conjugate Vaccination

Acute cerebellar ataxia is the most common cause of childhood ataxia, usually resulting from infections or vaccinations. Cases of acute cerebellar ataxia have been reported as a consequence of several viral and bacterial infections as well as immunizing agents, such as varicella, influenza, hepatitis B, and diphtheria-pertussis-tetanus vaccines. Although immunization with meningococcal group C conjugate vaccines has been associated with several neurological side effects, acute cerebellar ataxia has not been previously reported. The authors describe a case of a 12-year-old girl exhibiting acute cerebellar ataxia following meningococcal group C conjugate vaccination. In this patient, cerebellar symptoms started within 24 hours from the vaccination, and infective causes have been ruled out by serum and liquoral analyses. Magnetic resonance imaging findings were normal. Progressive clinical improvement was obtained after corticosteroid treatment. This case increases the small number of postvaccinal ataxias and contributes to further clarifying the complex pathogenesis of this disorder.

Overview of the Safety of Anti-VEGF Drugs: Analysis of the Italian Spontaneous Reporting System

IntroductionAnti-vascular endothelial growth factor (anti-VEGF) drugs are widely used for the treatment of several cancers and retinal diseases. The systemic use of anti-VEGF drugs has been associated with an increased risk of serious adverse reactions. Whether this risk is also related to intravitreal administration of anti-VEGF drugs is unclear.ObjectiveThe aim of this study was to provide an overview of the safety of anti-VEGF drugs in oncology and ophthalmology settings using the Italian Spontaneous Reporting System (SRS).MethodsWe selected all suspected adverse drug reaction (ADR) reports attributed to anti-VEGF drugs and conducted descriptive frequency analyses stratified by indication of use. As a measure of disproportionality, we calculated the proportional reporting ratio with 95% confidence intervals at the level of standardized Medical Dictionary for Regulatory Activities (MedDRA®) queries (SMQs).ResultsOf a total of 2472 anti-VEGF drug-related reports, 2173 (87.9%) and 299 (12.1%) were attributed to systemic and intravitreal use of these drugs, respectively. The frequency of serious ADRs reported was higher for intravitreal administration of anti-VEGF drugs than for systemic use in patients with cancer (58.9 vs. 34.1%) (p < 0.001) and were disproportionally associated with ischemic heart disease and thromboembolic and cerebrovascular events. Most serious ADRs related to anti-VEGF drugs in patients with cancer are known and clinically relevant (e.g., gastrointestinal and vascular disorders).ConclusionsThis study documented that serious ADRs and systemic toxicity may occur not only with systemic use of anti-VEGF drugs in patients with cancer but also with intravitreal administration. Close monitoring of cardio/cerebrovascular adverse events should be considered during treatment with all anti-VEGF drugs.

Effects of a computerized decision support system in improving pharmacological management in high-risk cardiovascular patients: A cluster-randomized open-label controlled trial.

This study was aimed to investigate the effects of computerized decision support system in improving the prescription of drugs for cardiovascular prevention. A total of 197 Italian general practitioners were randomly allocated to receive either the alerting computerized decision support system integrated into standard software (intervention arm) or the standard software alone (control arm). Data on 21230 patients with diabetes, 3956 with acute myocardial infarction, and 2158 with stroke were analysed. The proportion of patients prescribed with cardiovascular drugs and days of drug–drug interaction exposure were evaluated. Computerized decision support system significantly increased the proportion of patients with diabetes prescribed with antiplatelet drugs (intervention: +2.7% vs. control: +0.15%; p < 0.001) or lipidlowering drugs (+4.2% vs. +2.8%; p = 0.001). A statistically significant decrease in days of potential interactions has been observed only among patients with stroke (−1.2 vs. −0.5 days/person-year; p = 0.001). In conclusion, computerized decision support system significantly increased the use of recommended cardiovascular drugs in diabetic patients, but it did not influence the exposure to potential interactions

Long-term intravitreal ranibizumab as a potential additional risk factor for neurodegeneration in Parkinson’s disease: a case report

In November 2012, a 72-year old patient was diagnosed with left eye wet age-related macular degeneration. The patient received three monthly intravitreal injections of ranibizumab, with complete resolution of retinal hemorrhage and edema and reinstatement of visual acuity. In May 2015, symptomatic relapse was detected. The patient was again treated with intravitreal ranibizumab, with overall six injections till the end of February 2016. In May 2016, the patient complained of left hand resting tremor, bradykinesia, and postural rigidity of head and trunk. A diagnosis of clinically established PD was made based on new criteria of the Movement Disorders Society. Single Photon Emission Computerized Tomography of the Dopamine Transporter with (123I) ioflupane documented a low Dopamine Transporter (DAT) uptake mostly in the right striatum. Due to the documented protective role of vascular endothelial growth factor (VEGF) on the dopaminergic neurons, intensive intravitreal injections of the anti-VEGF agent ranibizumab may have played as an additional risk factor accelerating the neurodegeneration process related to PD and the onset of the related clinical signs and symptoms.

Adverse Drug Reactions in Hospitalized Patients: Results of the FORWARD (Facilitation of Reporting in Hospital Ward) Study

Background: Adverse drug reactions (ADRs) are an important public health problem, representing a major cause of morbidity and mortality. However, several countries have no recent studies available. Since 2014, a prospective active pharmacovigilance project, aimed to improve ADRs monitoring in hospital wards (FORWARD) was performed in Sicily. This study, as part of FORWARD project, was aimed to describe ADRs occurred during the hospital stay in Internal Medicine wards. ADRs related to hospital admission, characteristics and preventability of ADRs were also evaluated. Methods: Demographic, clinical, and pharmacological data on patients admitted to six wards of Internal Medicine, from 2014 to 2015, were collected by trained, qualified monitors, who screened all medical records. The rate of ADRs occurred during hospital stay and those leading to hospitalization were analyzed. A descriptive analysis of the reactions, suspected drugs, and associated factors was performed according to the setting analyzed. Results: During the study period, 4,802 admissions were recorded; in 3.2% of them ADRs occurred during hospital stay while in 6.2%, admission was due to ADRs. The duration of hospital stay was longer in patients who experienced ADRs during hospitalization, compared to patients without ADRs [median days 12 (Q1–Q3: 8–17) vs. 9 (6–13)]; p < 0.001). Females [OR1.39 (95% CI 1.03–1.93)] and patients taking ≥ 4 drugs [OR1.46 (95% CI 1.06–2.03)] were more likely to experience ADRs during hospital stay, as well as to be admitted because of ADRs [female: OR1.75 (95% CI 1.37–2.24); ≥ 4 drugs: OR2.14 (95% CI 1.67–2.74)]. The most frequent ADRs occurred during hospital stay were cutaneous (26.8%), general (13.4%), vascular (13.4%), and cardiac (11.5%) disorders and the drug classes mainly involved were anti-bacterials (38.2%) and antithrombotic agents (21.7%). ADRs were serious in 44.6% and probably preventable in 69.4%. Gastrointestinal (27.7%), hematological (26.5%), metabolic (18.1%), and nervous (16.1%) disorders were the main ADRs cause of hospitalization, primarily due to antithrombotic agents (39.0%) RAS-inhibitors (13.9%), NSAIDs (11.9%), and diuretics (9.0%). Only 12.9% of them was not preventable. Conclusion: Adverse drug reactions occurred during hospitalization or contributing to admission to Internal Medicine wards were considerable and most of them were preventable. Females and patients taking many medications were more likely to present ADRs both during hospital stay or as cause of admission.