Mauro Venegoni

Cohort study of hepatotoxicity associated with nimesulide and other non-steroidal anti-inflammatory drugs

Abstract Objective To estimate the risk of acute hepatotoxicity associated with nimesulide compared with other non-steroidal anti-inflammatory drugs. Design Retrospective cohort and nested case-control study. Setting Umbria region, Italy. Participants 400 000 current, recent, and past users (almost 2 million prescriptions) of non-steroidal anti-inflammatory drugs between 1 January 1997 and 31 December 2001. Main outcome measures Admissions to hospital for acute non-viral hepatitis and incidence of all hepatopathies and liver injury among users of nimesulide and other non-steroidal anti-inflammatory drugs. Results Current use of non-steroidal anti-inflammatory drugs was associated with a 1.4 (95% confidence interval 1.0 to 2.1) increased risk of hepatopathy compared with past use. In current users of nimesulide the rate ratio for all hepatopathies and more severe liver injury was 1.3 (0.7 to 2.3) and 1.9 (1.1 to 3.8), respectively. Conclusion The risk of liver injury in patients taking nimesulide and other non-steroidal anti-inflammatory drugs is small.

Adverse drug reactions related to the use of fluoroquinolone antimicrobials: an analysis of spontaneous reports and fluoroquinolone consumption data from three italian regions.

AbstractObjective: To analyse and compare with one another and with other antibacterial drugs the adverse drug reactions (ADRs) of the different fluoroquinolones currently used in Italy, spontaneously reported from doctors in three northern Italian regions. Methods: The data on fluoroquinolones and other antibacterials were obtained from the spontaneous reporting system database of Emilia Romagna, Lombardy and the Veneto, which are the principal contributors to the Italian spontaneous surveillance system. The fluoroquinolone ADRs with a causality assessment of certain, probable or possible (according to WHO criteria), reported between January 1999 and December 2001, were selected and toxicity profiles of individual drugs were described and compared with one another. The reports were also correlated with sex and age of patients and with regional prescription data to estimate individual fluoroquinolone reporting rate of adverse events. Results: During the study period, 10 011 reports were received by the system (a mean annual reporting rate of approximately 185 per million inhabitants): 1920 referred to systemic antimicrobials, of which 432 (22.5%) involved fluoroquinolones.Pefloxacin was associated with the highest reporting rate (982 reports/daily defined dose/1000 inhabitants/day), followed by moxifloxacin (356), rufloxacin (221) and lomefloxacin (196). The most frequently reported reactions to fluoroquinolones involved the skin, but their percentage (25%) was significantly lower (p < 0.01) than those of other systemic antimicrobials (58.5%), whereas the percentages of reactions involving the central nervous (12.2 vs 3.6%), musculoskeletal (14.7 vs 0.3%) and psychiatric systems (9.3 vs 1.8%) were significantly higher (p < 0.01). We found some significant differences in the safety profiles of individual fluoroquinolones: ciprofloxacin was more frequently associated with skin reactions (p < 0.01), levofloxacin and pefloxacin with musculoskeletal (p < 0.01), and rufloxacin with psychiatric disorders (p < 0.05). Levofloxacin was the fluoroquinolone associated with the highest rate of serious tendon disorders; phototoxic reactions were more frequent with lomefloxacin, and toxic epidermal necrolysis and Stevens-Johnson syndrome were seen only with ciprofloxacin. Conclusions: The differences in the safety profiles should be taken into account when prescribing a fluoroquinolone to individual patients.

Evidence of tendinitis provoked by fluoroquinolone treatment: a case-control study.

AbstractObjective: To investigate the association between the use of fluoroquinolone agents and the risk of tendinitis in a large population-based case-control study. Methods: The study was performed by linking automated health databases from the Region of Lombardia, Italy. Cases were patients aged ≥18 years who had a hospital discharge diagnosis of non-traumatic tendinitis in 2002–3. For each case, up to five controls were randomly selected among those eligible for inclusion in the study. A conditional logistic regression model was used to estimate the odds ratio of tendinitis associated with the current, recent and past use of fluoroquinolones. Odds ratios were adjusted for exposure to other antibacterials and other drugs. Results: 22 194 cases and 104 906 controls met the inclusion criteria. Current use of fluoroquinolones significantly increased the risk of tendon disorders as a whole (odds ratio [OR] = 1.7; 95% CI 1.4, 2.0), tendon rupture (OR = 1.3; 95% CI 1.0, 1.8) and rupture of the Achilles’ tendon (OR = 4.1; 95% CI 1.8, 9.6). Concomitant use of corticosteroids and fluoroquinolones increased the risk of both tendon rupture (OR = 3.1; 95% CI 1.5, 6.3) and rupture of the Achilles’ tendon (OR = 43.2; 95% CI 5.5, 341.1). Discussion: Evidence that exposure to fluoroquinolones is associated with the sudden occurrence of tendinitis is supported by this large population-based study. We can estimate that a single case of rupture of the Achilles’ tendon would occur for every 5958 persons treated with fluoroquinolones (95% CI 2148, 23 085). The corresponding number needed to harm is 979 (95% CI 122, 9172) for patients who concomitantly use corticosteroids and 1638 (95% CI 351, 8843) for those aged >60 years. Conclusion: Clinicians should be aware of this adverse effect, and the increased risk for fluoroquinolone-associated tendinitis in elderly patients with corticosteroid use must be considered when these agents are prescribed.

Drug-induced anaphylaxis : case/non-case study based on an italian pharmacovigilance database.

AbstractObjective: To identify the number of cases of anaphylaxis reported in association with different classes of drugs and compare it with other reports contained in the same database. Methods: The data were obtained from a database containing all of the spontaneous reports of adverse drug reactions (ADRs) coming from the Italian regions of Emilia Romagna, Lombardy and the Veneto, which are the main contributors to the Italian spontaneous surveillance system. The ADRs reported between January 1990 and December 2003 with a causality assessment of certainly, probably or possibly drug related (according to the WHO criteria) were analysed using a case/non-case design. The cases were defined as the reactions already coded by the WHO preferred terms of ‘anaphylactic shock’ or ‘anaphylactoid reaction’ (this last term also included anaphylactic reaction) and those with a time of event onset that suggested an allergic reaction and involved at least two of the skin, respiratory, gastrointestinal, CNS or cardiovascular systems; the non-cases were all of the other ADR reports. The frequency of the association between anaphylaxis and the suspected drug in comparison with the frequency of anaphylaxis associated to all of the other drugs was calculated using the ADR reporting odds ratio (ROR) as a measure of disproportionality. Results: Our database contained 744 cases (including 307 cases of anaphylactic shock with 10 deaths) and 27 512 non-cases. The percentage of anaphylaxis cases reported in inpatients was higher than that among outpatients (59.1% vs 40.9%). This distribution is significantly different from that of the other ADR reports that mainly refer to outpatients. After intravenous drug administrations, anaphylactic shock cases were more frequent than anaphylactoid reactions or other ADRs, but more than one-third of these reactions were caused by an oral drug. Blood substitutes and radiology contrast agents had the highest RORs. Among the systemic antibacterial agents, anaphylaxis was disproportionally reported more often for penicillins, quinolones, cephalosporins and glycopeptides, but diclofenac was the only NSAID with a significant ROR. As a category, vaccines had a significantly lower ROR, thus indicating that anaphylaxis is reported proportionally less than other ADRs. Conclusions: Anaphylaxis is a severe ADR that may also occur with commonly used drugs. It represents 2.7% of all of the ADRs reported in an Italian spontaneous reporting database.

Drug-related deaths: an analysis of the Italian spontaneous reporting database.

AbstractBackground: Adverse drug reactions (ADRs) represent a major public health concern, with death as the ultimate adverse drug outcome. Despite the relevance of this, the frequency of fatal ADRs (FADRs) is to a large extent unknown. Although spontaneous reporting data cannot give an exact estimate of the magnitude of drug-related mortality, it may highlight the importance and large dimensions of this public health problem. Objective: To describe the types and pattern of reported FADRs by analysing data from the national spontaneous reporting system in Italy. Methods: The Italian Medicines Agency (AIFA) runs a pharmacovigilance database where all the individual case safety reports (since January 2001) are stored. We selected and then analysed in detail all the case reports (to the end of December 2006) in which death was reported as the outcome. We included in the study only FADR case reports with a probable or possible causality assessment, according to the criteria established by the WHO. In line with the Italian reporting form, we divided FADR reports into two groups: (i) suspected ADRs that caused death; and (ii) suspected ADRs that contributed to death. Results: In the AIFA database 38 507 suspected ADR case reports were collected, of which 641 (1.66%) had a fatal outcome. We analysed 450 case reports (1.17% of total reports), 159 (35.33%) of them causing the patient’s death and 291 (64.67%) contributing to death. The annual percentage of FADR reports followed a constant trend during the 6-year period. The majority of fatal reports (79%) were sent by hospital doctors. In total, 222 different drugs were suspected as causes of FADRs. ‘Systemic anti-infective drugs’ was the drug category associated with the highest percentage of FADRs (21.9%), followed by antineoplastic and immunomodulating agents (18.8%), and then by nervous system drugs (14.8%). Other drug categories involved in the fatal case reports were antithrombotic agents, NSAIDs and contrast media. Conclusions: The drugs most frequently involved in FADRs were drugs of wide usage with a narrow therapeutic range or those that caused serious skin or systemic allergic reactions. Ceftriaxone, ticlopidine and nimesulide were associated with the highest number of fatal case reports; the related FADRs were already known and recognized for each of these drugs. We highlight some cases reflecting probable inappropriate drug use by Italian physicians. This suggests a need for continued clinical pharmacology training and that many FADRs might be preventable through better medical and prescribing practice.

Evaluation of safety of A/H1N1 pandemic vaccination during pregnancy: cohort study.

Objective To assess the risk of maternal, fetal, and neonatal outcomes associated with the administration of an MF59 adjuvanted A/H1N1 vaccine during pregnancy. Design Historical cohort study. Setting Singleton pregnancies of the resident population of the Lombardy region of Italy. Participants All deliveries between 1 October 2009 and 30 September 2010. Data on exposure to A/H1N1 pandemic vaccine, pregnancy, and birth outcomes were retrieved from regional databases. Vaccinated and non-vaccinated women were compared in a propensity score matched analysis to estimate risks of adverse outcomes. Main outcome measures Main maternal outcomes included type of delivery, admission to intensive care unit, eclampsia, and gestational diabetes; fetal and neonatal outcomes included perinatal deaths, small for gestational age births, and congenital malformations. Results Among the 86 171 eligible pregnancies, 6246 women were vaccinated (3615 (57.9%) in the third trimester and 2557 (40.9%) in the second trimester). No difference was observed in terms of spontaneous deliveries (adjusted odds ratio 1.02, 95% confidence interval 0.96 to 1.08) or admissions to intensive care units (0.95, 0.47 to 1.88), whereas a limited increase in the prevalence of gestational diabetes (1.26, 1.04 to 1.53) and eclampsia (1.19, 1.04 to 1.39) was seen in vaccinated women. Rates of fetal and neonatal outcomes were similar in vaccinated and non-vaccinated women. A slight increase in congenital malformations, although not statistically significant, was present in the exposed cohort (1.14, 0.99 to 1.31). Conclusions Our findings add relevant information about the safety of the MF59 adjuvanted A/H1N1 vaccine in pregnancy. Residual confounding may partly explain the increased risk of some maternal outcomes. Meta-analysis of published studies should be conducted to further clarify the risk of infrequent outcomes, such as specific congenital malformations.

Hepatotoxicity related to agomelatine and other new antidepressants: a case/noncase approach with information from the Portuguese, French, Spanish, and Italian pharmacovigilance systems.

Abstract Antidepressants have been associated with a low incidence of idiosyncratic hepatic injury. Some of them, nefazodone or amineptine, were observed to induce severe hepatic injury and withdrawn from the market. Recently, some cases of this severe condition have been reported in association with agomelatine use. Therefore, the objective of this study is to learn the risk of hepatic damage with agomelatine as compared with other new antidepressants. We took data from the Spanish, French, Italian, and Portuguese pharmacovigilance system databases. A case/noncase approach to assess the strength of the association between whichever antidepressant and hepatotoxicity was performed; cases were defined as reports of hepatotoxicity; noncases were reports of all reactions other than hepatotoxicity. Exposure was the recording of a new antidepressant in a report, whether or not it was suspected of causing the reaction. During the period surveyed, 3300 cases of hepatotoxicity were collected for the antidepressants assessed. They represent 10.3% of all cases collected for these drugs; the corresponding figure for all drugs was 6.0%. Meanwhile, 63 cases of hepatotoxicity associated with agomelatine were collected since its introduction until the end of the period studied; they account for a percentage of 14.6. Agomelatine was statistically associated with hepatotoxicity in Spain [reporting odds ratio (ROR), 4.9 (95% confidence interval [CI], 2.4–9.7)], France (ROR, 2.4 [95% CI, 1.5–3.7]), and Italy (ROR, 5.1 [95% CI, 1.7–14.0]). Current results support the idea of agomelatine to be related to a higher hepatotoxicity risk. Physicians should consider early discontinuation if the condition is suspected; health authorities should promptly explore the best regulatory actions to be taken.

Antipsychotic drug exposure and risk of pulmonary embolism: a population-based, nested case–control study

BackgroundOnly three observational studies investigated whether exposure to antipsychotics is associated with an increased risk of pulmonary embolism, with conflicting results. This study was therefore carried out to establish the risk of pulmonary embolism associated with antipsychotic drugs, and to ascertain the risk associated with first- and second-generation antipsychotic drugs, and with exposure to individual drugs.MethodsWe identified 84,253 adult individuals who began antipsychotic treatment in a large Italian health care system. Cases were all cohort members who were hospitalized for non-fatal or fatal pulmonary embolism during follow-up. Up to 20 controls for each case were extracted from the study cohort using incidence density sampling and matched by age at cohort entry and gender. Each individual was classified as current, recent or past antipsychotic user. The occurrence non-fatal or fatal pulmonary embolism was the outcome of interest.ResultsCompared to past use, current antipsychotic use more than double the risk of pulmonary embolism (odds ratio 2.31, 95% confidence interval 1.16 to 4.59), while recent use did not increase the risk. Both conventional and atypical antipsychotic exposure was associated with an increase in risk, and the concomitant use of both classes increased the risk of four times (odds ratio 4.21, 95% confidence interval 1.53 to 11.59).ConclusionsAdding the results of this case–control study to a recent meta-analysis of three observational studies substantially changed the overall estimate, which now indicates that antipsychotic exposure significantly increases the risk of pulmonary embolism.

Seriousness, preventability, and burden impact of reported adverse drug reactions in Lombardy emergency departments: a retrospective 2-year characterization

Objective The purpose of this study was to determine the prevalence of adverse drug reactions (ADRs) reported in emergency departments (EDs) and carry out a thorough characterization of these to assess preventability, seriousness that required hospitalization, subsequent 30-day mortality, and economic burden. Methods This was a retrospective cohort study of data from an active pharmacovigilance project at 32 EDs in the Lombardy region collected between January 1, 2010 and December 31, 2011. Demographic, clinical, and pharmacological data on patients admitted to EDs were collected by trained and qualified monitors, and deterministic record linkage was performed to estimate hospitalizations. Pharmacoeconomic analyses were based on Diagnosis-Related Group reimbursement. Results 8,862 ADRs collected with an overall prevalence rate of 3.5 per 1,000 visits. Of all ADRs, 42% were probably/definitely preventable and 46.4% were serious, 15% required hospitalization, and 1.5% resulted in death. The System Organ Classes most frequently associated with ADRs were: skin and subcutaneous tissue, gastrointestinal, respiratory thoracic and mediastinal, and nervous system disorders. The most common Anatomical Therapeutic Chemical classes involved in admissions were J (anti-infectives and immunomodulating agents), B (blood and blood-forming organs), and N (nervous system). Older age, yellow and red triage, higher number of concomitantly taken drugs, and previous attendance in ED for the same ADR were significantly associated with an increased risk of hospitalization. The total cost associated with ADR management was €5,184,270, with a mean cost per patient of €585. Fifty-eight percent of the economic burden was defined as probably/definitely preventable. Conclusion ADRs are a serious health/economic issue in EDs. This assessment provides a thorough estimation of their seriousness, preventability, and burden impact in a large population from a representative European region.

Intentional Rechallenge: Does the Benefit Outweigh the Risk?

Rechallenge is defined as the readministration of a medication suspected of being a possible cause of an adverse reaction and which has been discontinued as result. It may be unintentional when the appearance of a reaction was initially not attributed to the medication. A rechallenge may be intentional when a prescriber decides that the benefit of rechallenge will outweigh its risk. When considering intentional rechallenge, one should take into account the benefit/risk balance of the suspected causative medication, and the benefit/risk balance of the best available alternative treatment or no treatment. Clinical knowledge is essential in benefit/risk assessment but there is currently no suitable tool to guide the decision on rechallenge. This article aims to propose points to consider in the creation of reaction-specific algorithms for risk assessment and management in the case of drug rechallenge.