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Sicurezza e segnalazione degli eventi avversi: antibiotici, antinfiammatori, antidolorifici, stati febbrili. Effetto Nocebo del farmaco Achille P. Caputi.

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Presentazione sul tema: "Sicurezza e segnalazione degli eventi avversi: antibiotici, antinfiammatori, antidolorifici, stati febbrili. Effetto Nocebo del farmaco Achille P. Caputi."— Transcript della presentazione:

1 Sicurezza e segnalazione degli eventi avversi: antibiotici, antinfiammatori, antidolorifici, stati febbrili. Effetto Nocebo del farmaco Achille P. Caputi Direttore UOSD di Farmacologia Clinica Azienda Universitaria Policlinico G. Martino Messina

2 Disclosure I have received consultant and speaker fees from: AstraZeneca, Bayer, BMS, Chiesi, DOC-generici, Eli Lilly, GFK, Grunenthal, MSD, NovoNordisk, Otsuka, Pfizer, Rathiopharm, Rottapharm, Sanofi-Aventis, Schering-Plough, Servier, Theva. Assogenerici, ANIFA, IMS I have received grant support for investigator-initiated research from: AIFA European Commission, FP6 and FP7 Programmes SIMG-HSD Roche Novartis

3 My talk today Sicurezza dei farmaci Segnalazione di eventi avversi (EA) antibiotici, antinfiammatori, antidolorifici, stati febbrili. Effetto Nocebo del farmaco

4 RCT I RCT rappresentano lo standard sperimentale per valutare l'efficacia dei trattamenti grazie alla loro capacità di minimizzare i bias rispetto ad altri disegni sperimentali Nellambito delle linee-guida rappresentano la prova più rilevante, necessaria a produrre una raccomandazione terapeutica da implementare nella pratica clinica.

5 International Conference of Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH E2E: Pharmacovigilance Planning. 2004; (accessed 1/12/2009) The decision to approve a drug is based on having a satisfactory balance of benefits and risks within the conditions specified in the product labeling. This decision is based on the information available at the time of approval.. The knowledge related to the safety profile of the product can change over time through expanded use in terms of patient characteristics and the number of patients exposed.. In particular, during the early post-marketing period, the product might be used in settings different from clinical trials and a much larger population might be exposed in a relatively short timeframe. Benefits and risk

6 Once the product is marketed, new information will be generated, which can have an impact on the benefits or risks of the product; evaluation of this information should be a continuing process, in consultation with regulatory authorities. It is essential that pharmacovigilance be conducted throughout each products lifecycle. Pharmacovigilance should include collecting and evaluating safety data from all available international sources. Benefits and risk (2) Fruijtier A. Pharmaceutical postmarketing and compliance with the marketing authorisation. In Fundamentals of EU Regulatory Affairs Michor S, Rowl K (eds). RAPS Regulatory Affairs Professionals Society: Rockville (MA), 2006; 137–144. EMEA/CHMP/BMWP/42832/05. Committee for medicinal productsfor human use. Guideline on Similar Biological Medicinal Products containing Biotechnology-Derived Proteins as Active Substance: Non-Clinical and Clinical Issues. 2006; [accessed 1/12/2009].http://www.emea.europa.eu CHMP/437/04. Committee for medicinal products for human use. Guideline on Similar Biological Medicinal Products. 2005; [accessed 1 /12/2009].

7 Reazione avversa a un farmaco (Adverse Drug Reaction, ADR) Una reazione dannosa o significativamente spiacevole che si sospetta causata da un farmaco in dosi terapeutiche (o profilattiche, o diagnostiche), che richiede una riduzione di dose o la sospensione del farmaco, e/o fa prevedere un rischio per una futura somministrazione. ( Edwards IR, Aronson JK. Lancet 2000; 356: ) Obiettivi della FV: Riconoscere, il più rapidamente possibile, nuove ADR Migliorare ed allargare le informazioni su ADR sospette o già note Valutare i vantaggi (o gli svantaggi) di un farmaco su altri o su altri tipi di terapia Comunicare linformazione in modo da migliorare la pratica terapeutica (EDUCAZIONE CONTINUA) (Edwards, Eur J Clin Pharmacol, 1997) Evitare che altri possano andare incontro allo stesso evento indesiderato. (PREVENZIONE) (Leape et al., NEJM 2002)

8 Härmark L, van Grootheest AC. Eur J Clin Pharmacol 2008; 64: Dal segnale allazione regolatoria

9 Current Drug Safety, 2007,2, Farmaci ritirati dal commercio per motivi di sicurezza in USA dal 1993 al 2006 N = 20 principi attivi media di ritiri per anno: 1,5 farmaci

10 Dronedarone: grave epatotossicità Indicazione: fibrillazione atriale (anche non permanente) in corso, per prevenire una recidiva o per diminuire la frequenza ventricolare

11 OConnor NR. FDA Boxed Warnings: How to Prescribe Drugs Safely. Am Fam Physician 2010; 81: , 304. Common Drug Classes with Boxed Warnings

12 Giezen, T. J. et al. JAMA 2008; 300: Un totale di 174 biologici sono stati approvati nel periodo Gennaio Giugno 2007 (136 in USA and 105 in EU, di cui 67 approvati in entrambi). 82 azioni regolatorie di sicurezza sono state eseguite per 41 dei 174 biologici (23,6%) tra il gennaio 1995 ed il giugno 2008 La probabilità di una prima azione regolatoria di sicurezza è risultata del 14%, 3 anni dopo lapprovazione e del 29%, 10 anni dopo lapprovazione.

13 Lasser KE et al. JAMA 2002;287: 2215– new chemical entities were approved from of these, 56 (10.2%) drugs acquired a new black box warning or were withdrawn from the market. 42 drugs (8.2%) acquired 1 or more black box warnings that were not present when the drug was approved InKaplan-Meier analyses, the estimated probability of a new drug acquiring black box warnings or being withdrawn from the market over 25 years was 20%. 1 6 drugs (2.9%) approved between 1975 and 2000 were withdrawn from the market between 1975 and had acquired a black box warning prior to withdrawal In Kaplan-Meier analyses, new drugs had a 4% probability of being withdrawn from the market over the study period. Half of withdrawals occurred within 2 years following the drugs introduction.

14 Some post-marketing withdrawals for ADRs RCTs (some with thousands patients) had failed to detect ADRs; Safety profile of some drugs was reported = that of placebo Mibefradil Circulation 1998; 98:31 Troglitazone JAMA 2000; 283:2228 Cisapride JAMA 2000; 283:2228 Rofecoxib NEJM 2000; 343:1520 Alosetron Lancet 2001; 357:1544 Cerivastatina BMJ 2001; 323:359 Rosiglitazone NEJM 2007; 356:2457

15 I trial clinici pre-marketing sono capaci di prevedere che un farmaco, al momento dell AIC abbia un profilo rischio beneficio accettabile? NO

16 Safety e RCT cosa bisogna sapere RCT non disegnati per valutare la safety Selezione dei pazienti Grandezza del campione inadeguata Co-prescrizioni assenti o stabilite dal protocollo Co-morbifità assenti o stabilite dal protocollo Durata della somminsitrazione stabilita a priori Assenza del placebo EA insorti non sempre imputati al farmaco Practololo Vigabatrina Incompletezza dei dati di safety in RCT Lincidenza di disturbi muscolari osservati durante i trial clinici con statine non è stata significativamente diversa da quella osservata con il placebo. (Gotto AM. Safety and statin therapy. Arch Intern Med 2003; 163: )

17 Trial clinico: obiettivi Lobiettivo principale della maggior parte dei trial clinici è quello di dimostrare lefficacia del farmaco. La valutazione della safety è un obiettivo secondario senza una ipotesi da sperimentare Efficacia e sicurezza: cosa misurare Efficacia: provare qualcosa di positivo (il farmaco ha effetti benefici sulla malattia in questione) si raccolgono e valutano particolari parametri relativi a quella particolare malattia. Sicurezza: provare qualcosa di negativo (il farmaco non ha effetti indesiderati inaccettabili) tutti i dati possono essere rilevanti, indipendentemente dalla malattia da trattare e dalla efficacia del prodotto per quella indicazione.

18 Requiring that drugs on the market be completely safe is an impossible goal. The real question is whether the drugs dangers are in some acceptable proportion to the good it does. Jerry Avorn No drug is 100% safe for all people in all circumstances (Organizzazione Mondiale della Sanità)

19 The rapidly widespread and often prolonged use of drugs could mean that even a small increase in the risk of a serious adverse event could be very significant in population health terms Every new drug should enter the population of patients in a slow, monitored, and importantly an aselect and noninterventional way, maximising the accumulation of experience and minimising risk exposure. Meyboom RHB, Edwards IR. Lancet 2004; 364:

20 Brody H, Light DW. Am J Public Health. 2011;101: 399–404. The inverse benet law, inspired by Harts inverse care law, states that the ratio of benets to harms among patients taking new drugs tends to vary inversely with how extensively the drugs are marketed.

21 Brody H, Light DW. Am J Public Health. 2011;101: 399–404. The law is manifested through 6 basic marketing strategies: 1.reducing thresholds for diagnosing disease, 2.relying on surrogate endpoints, 3.exaggerating safety claims, 4.exaggerating efcacy claims, 5.creating new diseases, 6.encouraging unapproved uses.

22 Brody H, Light DW. Am J Public Health. 2011;101: 399–404.

23 Prescrire Int 2010; 19: 44 Evaluation of treatment risks: taking clinical data, pharmacology and patient characteristics into account

24 My talk today Sicurezza dei farmaci Segnalazione di eventi avversi (EA) antibiotici, antinfiammatori, antidolorifici, stati febbrili. Effetto Nocebo del farmaco

25 Metodiche in relazione alla frequenza di ADR (Meyboom et al. Drug Safety 1997) Metodo >1/1 0 1/10 1/100 1/1000 1/5000 1/ /50000 >1/ Segnalazione spontanea a livello nazionale Segnalazione spontanea a livello internazionale Studi coorte Caso-controllo Record-linkage Trial clinici Frequenza reazione avversa

26 SEGNALE (I) IPOTESI VERIFICA Segnalazione La descrizione di un evento clinico non previsto e/o non desiderato che il segnalatore ritiene che possa essere collegato al(i) farmaco(i) che il paziente assume DECISIONE Ritiro del farmaco Modifica Foglietto Illustrativo Dear Doctor Letter Non si fa niente

27 A. P. Jonville-Bera AP et al. Are incorrectly used drugs more frequently involved in adverse drug reactions? A prospective study. EJCP 2005; 61:231-6 During the 5-month study period, 198 ADRs in 182 patients were reported following the administration of 642 drugs to the Regional Pharmacovigilance Centre of Tours (France)

28 ricovero ospedaliero per una reazione avversa da farmaco (ADR) E per il paziente una perdita sia di salute che di qualit à di vita e per lo stesso e/o per la comunit à uno spreco di denaro. La prevenzione delle ADR si pone come strumento non solo di salute, ma anche di risparmio economico.

29 Pirmohamed M & al. Adverse drug reactions [ADR] as cause of admission to hospital: prospective analysis of patients. BMJ 2004; 329: Admissions: ADR/total 1225/18.820=6.5%* (16% drug interactions) ADR admissions caused by: NSAIDs 29.6 % Diuretics 27.3 % Warfarin 10.5 % Deaths: ADR/total 28/1225 = 2.2% ADR deaths caused by: NSAIDs 19/28, 67.8% Warfarin ± NSAIDs 3/28, 10.7%

30 Adverse drug events in emergency department population: a prospective Italian study (Trifirò G et al. Pharmacoepidemiol Drug Saf 2005) Admissions to hospital: ADR/total 93/4.467 = 4,3% ADR admissions caused by: NSAIDS: 18,1% (35 casi); Antibiotics: 17,1% (33); Analgesics: 10,9% (21). Deaths: ADR/total 1/93 = 1,08% Death caused by: low dosage aspirin acarbose tizanidine (hypoglycaemic crisis in a patient with diabetes, hypertension and deep venous thrombosis)

31 National Electronic Injury Surveillance System – Cooperative Adverse Drug Event Surveillance Project (NEISS-AIP) A partire dal ospedali degli USA ADR che inducono accesso ai dipartimenti di emergenza ed eventuale successivo ricovero Budnitz DS et al. JAMA 2006;296: Budnitz DS et al. Ann Inter Med 2007; 147: Cohen AL. et al. J Pediatr 2008; 152: 416 – 21 Schaefer MK et al, Pediatrics 2008;121;783-7; BudnitzDS et l, NEJM 2011;365:

32 National estimates of the numbers, population rates, and severity (measured by hospitalization) of individuals with ADEs treated in ED Active surveillance ( ) through the National Electronic Injury Surveillance System – Cooperative Adverse Drug Event Surveillance project (63 EDs) ED visit per ADEs = 21,298 annual estimate: 701,547 individuals ( ) 2.4 ( ) individuals per 1000 population, >65y: annual estimate, 4.9 vs 2.0 per 1000; RR= 2.4 ( ) ADEs induced hospitalization = 3,487 individuals annual estimate: 117,318 [16.7% ( 13.1%-20.3% )]. >65y: annual estimate, 1.6 vs 0.23 per 1000; RR= 6.8 ( ). Budnitz DS et al. JAMA 2006;296:

33 Budnitz DS et al. National Surveillance of Emergency Department Visits for Outpatient Adverse Drug Events JAMA, 296: ; 2006 warfarin, insulina, e digossina, con basso indice terapeutico ed alto rischio di tossicità sono causa di circa 1/3 delle ADE nei pazienti > 65 anni: dato importante per la prevenzione

34 Parte generale Parte sistematica basata su sospetto clinico e diagnosi differenziale … strumento per lappropriatezza

35 Il volo durerà due ore e 17 minuti. Ho il piacere di comunicarti che hai il 97% di probabilità di raggiungere la tua destinazione senza che vi siano significativi incidenti durante il volo e che le nostre probabilità di commettere un errore grave sono solo del 6,73%. Per favore allacciati la cintura di sicurezza e godeti il volo. A Edimburgo il tempo è bello e la temperatura intorno ai 16 gradi. D. M. Berwick in BMJ 1999; 318: Caro piccolino, benvenuto a bordo del volo n° 743 delle linee aeree Sterling, per Edimburgo. E il tuo comandante che ti parla.

36 ho il piacere di comunicarti che hai: l X % di probabilità di avere un evento avverso da farmaco e che le probabilità che il tuo medico abbia commesso un errore di prescrizione è solo del X %. Se però appartieni alla ètà più tenera le percentuali di cui sopra si innalzano dell X% Per favore accomodati e lasciati curare. Errori in medicina ed eventi avversi Caro piccolino, benvenuto a bordo del volo n° 743 delle linee aeree Sterling, per Edimburgo. E il tuo farmaologo che ti parla.

37 to reduce the risk of drug therapy

38 PHARMACOVIGILANCE IN PAEDIATRY

39 Aagaard L et al.Drug Saf 2010; 33: To characterize ADRs in children reported in Denmark over a period of one decade. Analysis of ADRs reported to the Danish Medicines Agency from 1998 to 2007 for individuals aged from birth to 17 years. Data were analysed with respect to time, age and sex, category of ADR, seriousness, suspected medicines and type of reporter ADR reports corresponding to 4500 ADRs were analysed. On average, 234 ADR reports were submitted annually, corresponding to approximately two ADRs per report. From 2003 to 2005, an increasing number of ADRs submitted per report were observed, but after 2005 the reporting rate decreased.

40 No. of ADR reports and ADRs reported annually (1998–2007) Aagaard L et al.Drug Saf 2010; 33:

41 ADRs by age group and number of serious ADRs (1998-–2007). Aagaard L et al.Drug Saf 2010; 33: One-half of ADRs were reported for infants from birth to 2 years of age. Similar total numbers of ADRs were reported for boys and girls

42 ADRs distributed by System Organ Class and age group (no. of serious ADRs in parentheses) Aagaard L et al.Drug Saf 2010; 33:

43 Reports encompassed medicines from: ATC group J: vaccines and antiinfectives for systemic use (65%); ATC group N: nervous system (17%). On average, 42% of ADRs were classified as serious (28 deaths). ATC group N had the highest proportion of ADRs that were classified as serious. Although physicians reported approximately 90% of the ADRs, a relatively large proportion of serious ADRs were reported by other sources.

44 This study investigated perceived ADRs among non-institutionalized children in Germany. All medicines used in the last 7 days before the medical interview were recorded among the children aged 0–17 years who participated in the 2003–06 German Health Interview and Examination Survey for Children and Adolescents (KiGGS). Perceived ADRs were reported by the childrens parents and confirmed by trained medical professionals during the medical interview. Knopf H, Du Y. BJCP 2010; 70:

45 157 medicines were involved in the occurrence of 198 perceived ADRs in 153 patients. This corresponded to 1.1% of total used drugs, 0.9% (95% CI 0.7, 1.1%) of all children, and 1.7% (1.4, 2.1%) of children treated with medications. About 40% of all perceived ADRs involved gastrointestinal disorders and 16% involved skin tissue disorders. Perceived ADRs were most frequently reported in relation to drugs acting on the nervous system (25.8%), followed by systemic anti-infectives (18.7%) and drugs acting on the respiratory system (16.2%). Risk factors for perceived ADRs included older age groups, polypharmacy (2) and a poor health status. Knopf H, Du Y. BJCP 2010; 70:

46 Wallerstedt S et al. Drug Saf 2011; 34: To determine the extent of the spontaneous reporting of ADRs in children with a focus on drugs not used as labelled; this involved investigations of reporting rates of individual case safety reports (ICSRs) per 1000 treated individuals for drugs reported in children, to compare these between drugs labelled and not labelled for use in children, and to compare the rates for children with those of adults. ICSRs (extracted from the Swedish ADR database) and number of treated individuals (extracted from the Swedish Prescribed Drug Register) were analyzed for a 2-year period (2006–7).

47 Wallerstedt S et al. Drug Saf 2011; 34: A total of 255 (children) and 1402 (adults) ICSRs concerning 94 drugs were included in the analysis. Seventy-four (29%) and 711 (51%) ICSRs in children and adults, respectively, were registered as serious (p < ). For drugs reported in three or more ICSRs regarding children, the rates of ICSRs per 1000 treated individuals varied between (range) 0.01–6.45 (children) and 0.01–6.39 (adults). For 17 of the drugs (18%) the rates of ICSRs per treated individual were significantly higher for children than for adults, and for 2 of the drugs (2%) the result was the opposite. The overall comparison of aggregated ICSRs per 1000 treated children revealed a higher reporting rate for drugs not labelled than for drugs labelled for children: rate ratio 3.44 (95% CI 2.67, 4.43); p < The corresponding result for adults was 1.52 (95% CI 1.37, 1.68); p < The overall reporting rate of aggregated ICSRs per 1000 treated individuals was higher in children than adults for drugs not labelled for children: rate ratio 2.01 (95% CI 1.61, 2.51); p <

48 Adverse Events From Cough and Cold Medications After a Market Withdrawal of Products Labeled for Infants Nadine Shehab N et al., Pediatrics 2010;126; National Electronic Injury Surveillance System Cooperative Adverse Drug Event Surveillance (NIESS-CADES) project: 63 hospitals in USA Surveillance cases: - any incident ED visit by a patient 12 years of age because of a condition that was attributed to a cough and cold medications in the ED medical record that occurred - 14-month (July 22, 2006, to October 11, 2007): period before market withdrawal of orally administered drugs for cough or cold -14-month (October 12, 2007, to December 31, 2008): period after withdrawal. Drugs analyzed decongestant, antihistamine, antitussive, and/or expectorant combinations, as well as single-ingredient decongestants and antitussive agents / expectorants

49 Nadine Shehab N et al., Pediatrics 2010;126; Numbers of cases and national estimates of AEs from cough and cold drugs among children <12y treated in EDs before and after withdrawal In the 14-month period after announcementof the withdrawal number and proportion of estimated ED visits for AEs involving children 12y remained unchanged

50 Nadine Shehab N et al., Pediatrics 2010;126; National estimates of cough and cold drug-related AEs among children <12 y treated in EDs before and after withdrawal the types of ingestions leading to ED visits for AEs remained relatively unchanged in the prewithdrawal and postwithdrawal periods < 2 y, unsupervised ingestions 59.5% pre- and 52.2% postwithdrawal. among 2-5 y, unsupervised ingestions 83.1% pre and 76.7% postwithdrawal

51 Nadine Shehab N et al., Pediatrics 2010;126; National estimates and difference in proprortion of cough and cold drug-related AEs among children <12 y treated in EDs before and after withdrawal a Estimate with coefficient of variation of The contribution of cough and cold medicine to the ED visit burden for all medication-related AEs was significantly reduced (2.1%) for children <2yin the postwithdrawal period, relative to the prewithdrawal period, but remained statistically unchanged (1.1%)for children 2 to 11y

52 Star K et al. Drug Saf 2011; 34: To characterize and contrast child reports against adult reports in an overall drug and adverse reaction review. To highlight increases in reporting of specific adverse reactions during recent years subdivided by age group. This was an exploratory study of internationally compiled individual case safety reports (ICSRs). Reports were extracted from the WHO global ICSR database, VigiBase, up until 5 February 2010.

53 Star K et al. Drug Saf 2011; 34:

54

55 Proportion of reports by drug group in child and adult groups

56 Star K et al. Drug Saf 2011; 34: Proportion of reports by MedDRA System Organ Class (SOC) in child and adult groups

57 Star K et al. Drug Saf 2011; 34: Reports in VigiBase received internationally for more than 40 years reflect real concerns for children taking medicines. The study highlights adverse reactions with an increased reporting during recent years, particularly those connected to the introduction of ADHD medicines in the child population. To enhance patient safety, medication errors indicating administration and dosing difficulties of drugs, especially in the younger age groups, require further attention.

58 Objective To describe the national scope and magnitude of outpatient adverse drug events (ADEs) that lead to emergency department (ED) visits in children and adolescents. Study design To conduct an active surveillance of patients 18 years of age or younger who came to EDs with ADEs, through a nationally representative, stratified probability sample of 63 US hospitals with EDs. Period Jan 1, Dec 31, 2005 The main outcome measures were national estimates of the number, type, patient demographics, and clinical characteristics of ADEs. National Surveillance of Emergency Department Visits for Outpatient Adverse Drug Events in Children and Adolescents (Cohen AL. et al. J Pediatr 2008; 152: 416–21)

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62 Association Between Second-Generation Antipsychotics and Changes in Body Mass Index in Adolescents Ghate SR et al, Journal of Adolescent Health 2013; 52: Purpose: To assess the association of second generation antipsychotics (SGAs) with changes in BMI) among adolescents compared with a matched untreated comparison group. Methods: A retrospective cohort study was conducted using an electronic medical record database between January 2004 and July Adolescents (12e19 years old), newly initiated on SGAs formed the exposure group and untreated adolescents formed the comparison group matched (3:1) to the antipsychotic group based on age, gender, and month of index SGA. Both the exposure and comparison groups were followed for slightly more than a year (395 days). Baseline and follow up BMI were evaluated for both groups and percentage change from baseline BMI to follow up BMI was calculated. Multivariate linear regression was conducted to assess the impact of SGAs on percent change in follow up BMI from baseline controlling for demographic characteristics, baseline medications, comorbidities, and other covariates.

63 Association Between Second-Generation Antipsychotics and Changes in Body Mass Index in Adolescents Ghate SR et al, Journal of Adolescent Health 2013; 52: Schematic of study design.

64 Ghate SR et al, Journal of Adolescent Health 2013; 52: Summary statistics for baseline and follow up BMI values among exposed and comparison group adolescents,

65 Ghate SR et al, Journal of Adolescent Health 2013; 52: Adjusted linear regression coefficients for percentage change in baseline to maximum follow-up BMI in adolescents,

66 Association Between Second-Generation Antipsychotics and Changes in Body Mass Index in Adolescents Ghate SR et al, Journal of Adolescent Health 2013; 52: Results: The mean percentage increase in follow up BMI from baseline for antipsychotic group was significantly higher than the comparison group (p< 0.01). After adjusting for covariates, adolescents on olanzapine had the highest percentage increase in follow up BMI from baseline [5.84%, ( )] followed by aripiprazole [4.36%( )], risperidone [3.65% ( )], and quetiapine [1.53% ( ) compared with the comparison group. Conclusion: This study further validates a growing concern of increased BMI in adolescents on SGA therapy.

67 My talk today Sicurezza dei farmaci Segnalazione di eventi avversi (EA) antibiotici, antinfiammatori, antidolorifici, stati febbrili. Effetto Nocebo del farmaco

68 My talk today Sicurezza dei farmaci Segnalazione di eventi avversi (EA) antibiotici, antinfiammatori, antidolorifici, stati febbrili. Effetto Nocebo del farmaco

69 Emergency Department Visits for Antibiotic-Associated AE Shehab N, Patel PR, Srinivasan A, Budnitz DS. Clin Infec Dis 2008; 47:735–43. Background. Drug-related AE are an underappreciated consequence of antibiotic use, and the national magnitude and scope of these events have not been studied. Our objective was to estimate and compare the numbers and rates of emergency department (ED) visits for drug-related adverse events associated with systemic antibiotics in the United States by drug class, individual drug, and event type. Methods. We analyzed drug-related adverse events from the National Electronic Injury Surveillance System– Cooperative Adverse Drug Event Surveillance project (2004– 2006) and outpatient prescriptions from national sample surveys of ambulatory care practices, the National Ambulatory Medical Care Survey and the NationalHospital Ambulatory Medical Care Survey (2004–2005).

70 Emergency Department Visits for Antibiotic-Associated AE Shehab N, Patel PR, Srinivasan A, Budnitz DS. Clin Infec Dis 2008; 47:735–43. On the basis of 6614 cases, an estimated 142,505 (116,506–168,504 visits) visits annually were made to US EDs for drug-related AE attributable to systemic antibiotics. Antibiotics were implicated in 19.3% of all ED visits for drug-related AE Most ED visits for antibiotic-associated AE were for allergic reactions [78.7% (75.3–82.1)] Estimated ED visits: 36.9% (34.7–39.2) attributable to penicillins 12.2% (10.9–13.5) attributable to cephalosporins

71 Clin Infec Dis 2008; 47:735–43. Number of cases and national estimates of ED) visits for AE due to systemic antibiotics, by patient and case characteristics- US

72 Clin Infec Dis 2008; 47:735–43. Number of cases and national estimates of ED visits for AE associated with systemic antibiotics, by drugUnited States, 2004–2006 (1).

73 Clin Infec Dis 2008; 47:735–43. Number of cases and national estimates of ED visits for AE associated with systemic antibiotics, by drugUnited States, 2004–2006 (2).

74 Number of cases and national estimates of the rate of emergency department (ED) visits for adverse events associated with a single systemic antibiotic class, by adverse event conditionUnited States, 2004–2006. Clin Infec Dis 2008; 47:735–43.

75 Emergency Department Visits for Antibiotic-Associated AE Shehab N, Patel PR, Srinivasan A, Budnitz DS. Clin Infec Dis 2008; 47:735–43. Conclusions Antibiotic-associated adverse events lead to many ED visits, and allergic reactions are the most common events. Minimizing unnecessary antibiotic use by even a small percentage could significantly reduce the immediate and direct risks of drug-related adverse events in individual patients

76 Antibiotic Exposure and IBD Development Among Children: A Population-Based Cohort Study Kronman MP et al Pediatrics 2012;130:e794–e803 OBJECTIVE: To determine whether childhood antianaerobic antibiotic (penicillin, amoxicillin, ampicillin, penicillin/b-lactamase inhibitor combinations, tetracyclines, clindamycin, metronidazole, cefoxitin, carbapenems, and oral vancomycin) exposure is associated with the development of inflammatory bowel disease (IBD). METHODS: This retrospective cohort study employed data from 464 UK ambulatory practices participating in The Health Improvement Network. All children with >2 years of follow-up from 1994 to 2009 were followed between practice enrollment and IBD development, practice deregistration, 19 years of age, or death; those with previous IBD were excluded. All antibiotic prescriptions were captured.

77 Antibiotic Exposure and IBD Development Among Children: A Population-Based Cohort Study Kronman MP et al Pediatrics 2012;130:e794–e803 RESULTS: A total of subjects contributed 6.6 million person-years of follow-up; 748 developed IBD. IBD incidence rates among: - antianaerobic antibiotic unexposed = 0.83 / person-year -exposed subjects were and 1.52/ person-years, - 84% relative risk increase. Exposure throughout childhood was associated with developing IBD, but this relationship decreased with increasing age at exposure. Exposure before 1 year of age had an adjusted hazard ratio of 5.51 (95% confidence interval [CI]: 1.66–18.28) but decreased to 2.62 (95% CI: 1.61–4.25) and 1.57 (95% CI: 1.35–1.84) by 5 and 15 years, respectively. Each antibiotic course increased the IBD hazard by 6% (4%–8%). A dose-response effect existed, with receipt of.2 antibiotic courses more highly associated with IBD development than receipt of 1 to 2 courses, with adjusted hazard ratios of 4.77 (95% CI: 2.13–10.68) versus 3.33 (95% CI: 1.69–6.58).

78 Antibiotic Exposure and IBD Development Among Children: A Population-Based Cohort Study Kronman MP et al Pediatrics 2012;130:e794– e803 Antibiotic Exposures According to Class

79 Antibiotic Exposure and IBD Development Among Children: A Population-Based Cohort Study Kronman MP et al Pediatrics 2012;130:e794–e e803 Multivariable Model for the Association Between Antianaerobic Antibiotic Exposure andIBD Development (a)

80 A, Proportion of subjects developing IBD according to age and antianaerobic antibiotic exposure status.P,.001 for the difference between groups by using the log-rank test. B, proportion of subjects developing IBD according to age and antianaerobic antibiotic exposure level. P,.001 for the difference among groups by using the log-rank test. Antibiotic Exposure and IBD Development Among Children: A Population-Based Cohort Study Kronman MP et al Pediatrics 2012;130:e794–e e803

81 Hazard of developing IBD if ever previously exposed to antianaerobic antibiotics, according to age Antibiotic Exposure and IBD Development Among Children: A Population-Based Cohort Study Kronman MP et al Pediatrics 2012;130:e794–e e803

82 Summary of Adjusted Multivariate Associations Between Antibiotic Exposure and IBD Development According to Antibiotic Class and Exposure Measure Antibiotic Exposure and IBD Development Among Children: A Population-Based Cohort Study Kronman MP et al Pediatrics 2012;130:e794–e e803

83 Summary of Adjusted Multivariate Associations Between Antibiotic Exposure and IBD Development According to Antibiotic Class and Exposure Measure Antibiotic Exposure and IBD Development Among Children: A Population-Based Cohort Study Kronman MP et al Pediatrics 2012;130:e794–e e803

84 Adjusted Association Between Antianaerobic Antibiotic Exposure and IBD Development According to IBD Type and Exposure Measure Antibiotic Exposure and IBD Development Among Children: A Population-Based Cohort Study Kronman MP et al Pediatrics 2012;130:e794–e e803

85 Antibiotic Exposure and IBD Development Among Children: A Population-Based Cohort Study Kronman MP et al Pediatrics 2012;130:e794–e803 CONCLUSIONS: Exposure to antianaerobic antibiotics during childhood was associated with development of the lifelong autoimmune condition IBD. This study suggests that reduction in childhood antianaerobic antibiotic use may have the potential to help curb the rising incidence of childhood IBD.

86 Ciprofloxacin safety in paediatrics: a systematic review AdefurinA et al; Arch Dis Child 2011;96:874–880. Objective To determine the safety of ciprofl oxacin in paediatric patients in relation to arthropathy, any other adverse events (AEs) and drug interactions. Methods A systematic search of MEDLINE, EMBASE, CINAHL, CENTRAL and bibliographies of relevant articles was carried out for all published articles, regardless of design, that involved the use of ciprofl oxacin in any paediatric age group 17 years. Only articles that reported on safety were included.

87 Ciprofloxacin safety in paediatrics: a systematic review AdefurinA et al; Arch Dis Child 2011;96:874– 880. Summary of reported adverse events (AEs) from 68 studies

88 Ciprofloxacin safety in paediatrics: a systematic review AdefurinA et al; Arch Dis Child 2011;96:874–880. Summary of serious adverse events necessitating withdrawal and/or discontinuation of therapy

89 Ciprofloxacin safety in paediatrics: a systematic review AdefurinA et al; Arch Dis Child 2011;96:874–880. Summary of reported musculoskeletal events from 32 studies

90 Ciprofloxacin safety in paediatrics: a systematic review AdefurinA et al; Arch Dis Child 2011;96:874–880. Results 105 articles met the inclusion criteria and involved paediatric patients. There were 1065 reported AEs (risk 7%, 95% CI 3.2% to 14.0%). The most frequent AEs were musculoskeletal AEs, abnormal liver function tests, nausea, changes in white blood cell counts and vomiting. Arthralgia accounted for 50% of these. The age of occurrence of arthropathy ranged from 7 months to 17 years (median 10 years). All cases of arthropathy resolved or improved with management. One prospective controlled study estimated the risk of arthropathy as 9.3 (OR 95% CI 1.2 to 195). Pooled safety data of controlled trials in this review estimated the risk of arthropathy as 1.57 (OR 95% CI 1.26 to 1.97). Conclusions Musculoskeletal AEs occur due to ciprofl oxacin use. The musculoskeletal events are reversible with management.

91 My talk today Sicurezza dei farmaci Segnalazione di eventi avversi (EA) antibiotici, antinfiammatori, antidolorifici, stati febbrili. Effetto Nocebo del farmaco

92 FANS nei bambini Eventi avverdi associati a FANS nei bambini sono IR, acidosi metabolica, ipocalcemia, dolore acuto al fianco e nefrite intestiziale (Van Biljon G Reversible renal failure associated with ibuprofen in a child: a case report. S Afr Med J 1989; 76: Challers S, Kaplan BS. Acute nonoliguric renal failure in children associated with nonsteroidal antiinflammatory agents. Pediatr Emerg Care1998; 14: Simcker AM et al., Ketorolac-induced irreversible renal failure in sickle cell disease: a case report. Pediatr Nephrol 1999; 13: Kim J et al. Acute renal insufficiency in ibuprofen overdose. Pediatr Emerg Care 1995; 11: 107-8) Insufficienza renale rara nei bambini esposti a FANS e reversibile alla interruzione Mcntire SC et al Acute flank pain and reversible renal dysfunction associated with NSAID use. Pediatrics 1993; 92 :

93 FANS e nefrotossicità in pediatria

94 Selected risk factors for NSAIDs-induced acute nephrotoxicity in pediatric age. Musu M et al., Acute nephrotoxicity of NSAID from the foetus to the adult. Eur Rev Med Pharmcol Sci 2011; 15: , Dehydration Hypovolemia Haemorrhage Congestive heart failure Liver failure Pre-existing renal problems Urinary tract malformations Recurrent urinary tract infections NSAIDs multitherapy Concomitant drugs (beta-blockers, ACE inhibitors, diuretics, aminoglycosides) Alcohol consumption Cystic fibrosis

95 Nonsteroidal Anti-Inflammatory Drugs Are an Important Cause of Acute Kidney Injury in Children Misurac JM et al, J Pediatr 2013 Objective To characterize nonsteroidal anti-inflammatory drug (NSAID)-associated acute kidney injury (AKI) in children. Study design A retrospective chart review of children diagnosed with AKI through the use of International Classification of Diseases, Ninth Revision diagnosis code or from January 1999 to June Medical records were reviewed to confirm the diagnosis of AKI and to quantify NSAID administration. Pediatric RIFLE criteria were used to codify AKI. Patients were not classified as having NSAID-associated AKI if they had a diagnosis explaining AKI or comorbid clinical conditions predisposing to AKI development.

96 Demographic and clinical characteristics of patients with NSAID- associated AKI (n = 27/ 1015) Misurac JM et al, J Pediatr 2013

97 Comparing course and characteristics by age (n = 27/ 1015) Misurac JM et al, J Pediatr 2013

98 Nonsteroidal Anti-Inflammatory Drugs Are an Important Cause of Acute Kidney Injury in Children Misurac JM et al, J Pediatr 2013 Results 1015 pts identified (International Classification of Diseases, 9° revision screening. 21 children had clinical, laboratory, and radiographic studies suggesting NSAIDassociated acute tubular necrosis 6 children had findings suggesting NSAID-associated acute interstitial nephritis, representing 2.7% (27 of 1015) of the total cohort with AKI and 6.6% when excluding complex patients with multifactorial AKI. Median (range) age of children with NSAID-associated AKI = 14.7 years ( ); 15% were <5 years old. 15 of 20 children (75%) for whom dosing data were available received NSAIDs within recommended dosing limits. Patients <5 years old were more likely to require dialysis (100% vs 0%, P <.001), intensive care unit admission (75% vs 9%, P =.013), and a longer length of stay(median 10 vs 7 days, P =.037). Conclusions 1.NSAID-associated AKI accounted for 2.7% of AKI in this pediatric population. 2.AKI typically occurred after the administration of correctly dosed NSAIDs. 3.Young children with NSAID-associated AKI may have increased disease severity.

99 My talk today Sicurezza dei farmaci Segnalazione di eventi avversi (EA) antibiotici, antinfiammatori, antidolorifici, stati febbrili. Effetto Nocebo del farmaco

100 Emergency Department Visits for Overdoses of Acetaminophen- Containing Products Budnitz DS et al., Am J Prev Med 2011;40:585–92 Purpose: To estimate the frequency of and characterize risks for emergency department visits foracetaminophen overdoses that were not related to abuse in the U.S. Methods: Data were collected from two components of the National Electronic Injury Surveillance System from January 1, 2006, through December 31, 2007, and analyzed from 2009 to 2010 to estimate the annual number of emergency department visits for: a)non-abuse-related acetaminophen b)overdose by patient demographics, c)treatments, d)and type and amount of acetaminophen-containing product ingested.

101 Emergency Department Visits for Overdoses of Acetaminophen-Containing Products Budnitz DS et al., Am J Prev Med 2011;40:585–92 Estimated rates of emergency department visits or overdoses involving acetaminophen-containing products, by age category and intentU.S., 2006–2007

102 Emergency Department Visits for Overdoses of Acetaminophen-Containing Products Budnitz DS et al., Am J Prev Med 2011;40:585–92 The population rate of emergency department visits for unsupervised ingestions among children aged 6 years was second to only the rate of emergency department visits for self-directed violence by those aged 15–24 years, and nearly one third of unsupervised ingestions were treated with NAC or gastrointestinal decontamination. Most of these unsuperunsupervised ingestions were by children aged 6 years, and slightly more than half of emergency department visits for unsupervised ingestions of acetaminophen were attributed to ingestion of pills. Unsupervised Ingestion

103 Emergency Department Visits for Overdoses of Acetaminophen-Containing Products Budnitz DS et al., Am J Prev Med 2011;40:585–92 Therapeutic misadventures accounted for 16.7% of emergency department visits for acetaminophen overdoses, and most therapeutic misadventures (56.1%) involved overuse of an acetaminophen product for a medicinal effect. Previous studies of patient knowledge and practices have found that oftentimes, individuals are not aware of the potential harm from taking or administering acetaminophen improperly. Among adolescents and young adults, overuse of an acetaminophen product for more potent medicinal effects was documented in three fourths of emergency department visits attributed to therapeutic misadventures, and three fourths of therapeutic misadventures involved OTC formulations. On the other hand, among older adults, more than four fıfths of therapeutic misadventures involved acetaminophen– opioid combination products. Thus, these data sugges that to reduce the incidence of emergency department visits for therapeutic misadventures, interventions should target safe practices in the use of OTC medications by adolescents and young adults and safe use of acetaminophen– opioid combination products by older adults. Therapeutic Misadventure

104 Emergency Department Visits for Overdoses of Acetaminophen- Containing Products Budnitz DS et al., Am J Prev Med 2011;40:585–92 Results: Estimated 78,414 emergency department visits (95% CI63655, 93172) annually for non-abuse-related overdoses of acetaminophen-containing products. Most emergency department visits for acetaminophen overdose were for self-directed violence (69.8%, 95% CI66.4%, 73.2%), with the highest rate among patients aged 15–24 years (46.4 per 100,000 individuals per year). Unsupervised ingestions by children aged 6 years accounted for 13.4% (95% CI11.0%, 15.9%) of visits for acetaminophen overdoses (42.5 per 100,000 individuals per year) Therapeutic misadventures accounted for 16.7% (95% CI14.0%, 19.5%) of visits and most involved overuse for medicinal effects (56.1%, 95% CI50.6%, 61.6%) rather than use of multiple acetaminophen-containing products or dose confusion. Conclusions: Non-abuse-related overdoses of acetaminophen products lead to many emergency department visits each year, particularly emergency department visits for self-directed violence. Acetaminophen overdose prevention efforts will likely need to be multidimensional..

105 Prevalenza dellasma pediatrica Between 1980 and 2003, the prevalence of pediatric asthma in the US increased from 3.6% to 5.8%, and similar increases were observed throughout the world. Asthma prevalence leveled off in the 1990s at a time in which acetaminophen had already become the most commonly used analgesic/antipyretic for children. Although other changes in the environment have been suggested that might explain an increase in childhood asthma, including the hygiene hypothesis, none so easily explains the rapid increase in asthma in the 1980s and the subsequent leveling off of asthma prevalence over the last 15 years. (Eder W, Ege MJ, von Mutius E. The asthma epidemic. N Engl J Med. 2006;355: 2226 –35) Furthermore, the prevalence of childhood wheezing in 36 countries around the world is predicted by each countrys per-capita sales of acetaminophen. (Newson RB et al; Paracetamol sales and atopic disease in children and adults: an ecological analysis. Eur Respir J. 2000;16:817– 23)

106 Acetaminofene / Paracetamolo e asma

107 ISAAC Phase Three Study Group. Acetaminophen (AC) use and risk of asthma, rhinoconjunctivitis, and eczema in adolescents (1) Beasley RW et al; Am J Respir Crit Care Med. 2011;183:171–8 122 centers in 54 countries, each study site enrolled at least 1000 children. The investigators rigorously identified children with wheezing and asthma symptoms and also collected data on AC exposure and other environmental factors that potentially contribute to the pathogenesis or severity of asthma. Data available children aged 6 to 7 years children aged 13 to 14 years. (Nearly 30% reported t aking AC at least once per month) In both age groups there was AC dose-dependent increase in the prevalence and severity of asthma. For 6- to 7-year-olds, the risk of current asthma was increased fold ( ) for those who took AC more than once per year but less than once per month fold (2.91–3.60) for those who took AC at least once per month. For 13- to 14-year-olds the risks of current asthma was increased 1.43 (95% CI: 1.33–1.53) for those who took AC more than once per year but less than once per month 2.51 (95% CI: 2.33–2.70 for those who took AC at least once per month Studi epidemiologici

108 ISAAC Phase Three Study Group. Acetaminophen (AC) use and risk of asthma, rhinoconjunctivitis, and eczema in adolescents (2) Beasley RW et al; Am J Respir Crit Care Med. 2011;183:171–8 For each age cohort, the investigators calculated a population-attributable risk (PAR) for AC exposure. This parameter estimates the reduction in incidence of asthma or asthma symptoms that would occur in the entire population if exposure to AC were eliminated, assuming that AC does exacerbate asthma. For 6- to 7-year-olds the PAR for severe asthma symptoms = 38%; For 13- to 14-year-olds, the PAR for current wheeze = 41% The PAR for severe asthma symptoms = 43%. Studi epidemiologici

109 ACETAMINOPHEN (AC): EPIDEMIOLOGIC STUDIES IN CHILDREN in Ethiopia and New Zealand An Ethiopian population-based cohort study revealed that a high rate of AC use among 1- and 3-year-olds (36% and 42%, respectively) and an association between AC use and wheeze are not limited to urban/industrial environments. (Amberbir A et al., The role of acetaminophen and geohelminth infection on the incidence of wheeze and eczema: a longitudinal birth- cohort study. Am J Respir Crit Care Med. 2011;183:165–170) In a group of 5- to 6-year-old children in New Zealand, use of 10 doses of AC per year was associated with an increased risk of current asthma (OR: 2.83 [1.63– 4.88]) Wickens K et al; New Zealand Asthma and Allergy Cohort Study Group. The effects of early and late paracetamol exposure on asthma and atopy: a birth cohort. Clin Exp Allergy. 2011;41: 399–406 Studi epidemiologici

110 Acetaminophen use and the risk of asthma in children and adults: a systematic review and meta-analysis. Etminan M et al; Chest. 2009; 136:1316 –1323 Meta-analysis of 6 other epidemiologic studies in children (27000 subjects) calculated a pooled odds ratio for wheezing in the previous year of 1.97 (95% CI: 1.51– 2.56) related to acetaminophen use Studi epidemiologici

111 Asthma morbidity after the short-term use of ibuprofen in children. Lesko SM et al Pediatrics. 2002; 109(2). Available at: cgi/content/full/109/2/e20 Between 1991 and 1993 the Boston University Fever Study randomly assigned nearly febrile children aged 6 months to 12 years to receive, as necessary, low-dose ibuprofen, high-dose ibuprofen, or acetaminophen (12 mg/kg per dose) in a double blind fashion. Of these children, 1879 with preexisting asthma were nearly evenly assigned among the 3 groups. For asthmatic children with a respiratory infection, the subsequent need for an outpatient asthma visit was 2.3 times higher in those treated with acetaminophen (95% CI: 1.26–4.16), and the risk was dose-dependent. Because there was no placebo control, it is theoretically possible that this outcome was a result of a protective action of ibuprofen, but the acetaminophen dose dependence, the lack of dose dependence for ibuprofen, and the availability of other evidence that acetaminophen exacerbates asthma make this explanation unlikely PROSPECTIVE TRIALS

112 Prospective study of acetaminophen use and newly diagnosed asthma among women Barr et al; Am J Respir Crit Care Med. 2004; 169:836–41 In 1990 and 1992, female nurses who were enrolled in the Nurses Health Study were asked about their use of acetaminophen and similar medications as well as known diagnoses. By 1996, 346 women who did not report a diagnosis of asthma at enrollment had a new physician diagnosis of asthma. There was a dose dependent increase in the risk of developing asthma among women exposed to acetaminophen and little relationship to aspirin or NSAIDs. Women who took acetaminophen14 days/month, were 1.63 (1.11–2.39) times as likely to have developed asthma as those who did not take acetaminophen. PROSPECTIVE TRIALS

113 The Association of Acetaminophen and Asthma Prevalence and Severity McBride JT, Pediatrics 2011;128: The epidemiologic association between acetaminophen use and asthma prevalence and severity in children and adults is well established and seggested by the: 1.strength of the association; 2.consistency of the association across age, geography, and culture; 3.dose-response relationship; 4.timing of increased acetaminophen use and the asthma epidemic; 5.the relationship between per-capita sales of acetaminophen and asthma prevalence across countries; 6.results of a double-blind trial of ibuprofen and acetaminophen for treatment of fever in asthmatic children; 7.biologically plausible mechanism of glutathione depletion in airway mucosa. Children with asthma or at risk for asthma should avoid the use of acetaminophen.

114 My talk today Sicurezza dei farmaci Segnalazione di eventi avversi (EA) antibiotici, antinfiammatori, antidolorifici, stati febbrili. Effetto Nocebo del farmaco

115 Il fenomeno Nocebo dei generici Poichè di solito i farmaci generici costano meno dei farmaci branded, molte persone credono erroneamente che i generici siano inferiori rispetto ai branded Doug Sporn Director of FDA s Office of Generic Drugs

116 La percezione del generico There is an extensive publicity suggesting that generic prescribing is potentially problematic. A patient knowing that a generic is being prescribed might view this in a very negative way and might have an increased tendency to attribute any adverse event to the change. If a recent switch to a generic has been made, the patient might even be more likely to call on the emergency services because of increased anxiety. This is the negative placebo or nocebo effect, the opposite of a placebo effect Generic antiepileptic drugs and increased health care utilization. Fact or myth? Besag FMC. Neurology 2010; 74:

117 La percezione del valore di un farmaco (placebo/nocebo) This nocebo effect, is the opposite of a placebo effect. Instead of the patient thinking that the medication might do good, the patient thinks that the medication or, in this case, switch to the medication, might do harm. Any negative change is consequently likely to be attributed to the generic. Generic antiepileptic drugs and increased health care utilization. Fact or myth? Besag FMC. Neurology 2010; 74:

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