Comparative safety profiles of intravitreal bevacizumab, ranibizumab and pegaptanib: the analysis of the WHO database of adverse drug reactions.

PURPOSE: The purpose of this study is to conduct a comparative analysis of the suspected adverse drug reactions (ADRs) associated with intravitreal bevacizumab, ranibizumab and pegaptanib in the WHO database in order to have a real-life information on these drugs, which now is only based on data coming from clinical trials. METHODS: ADR reports for intravitreal use of bevacizumab, ranibizumab and pegaptanib from January 2002 to December 2012 were selected from the WHO-VigiBase. Reporting odds ratio (ROR) with confidence interval of 95 % and p value was calculated. The analysis was performed for drug-reaction pairs. The Medical Dictionary for Regulatory Activities (MedDRA) terminology for ADRs was used. RESULTS: The analysis was performed on 3180 reports corresponding to 7753 drug-reaction pairs. Significant RORs for endophthalmitis and uveitis (1.90, 95 % confidence interval (CI) 1.48-2.43, and 10.62, 6.62-17.05, respectively) were retrieved for bevacizumab, and cerebrovascular accident and myocardial infarction produced significant ROR (1.54, 1.14-2.10 and 1.73, 1.18-2.53, respectively) for ranibizumab. Pegaptanib was significantly associated with visual impairment (1.98, 1.12-3.5, p = 0.02), nausea (3.29, 1.57-6.86, p < 0.001), vomiting (2.91, 1.2-7.07, p = 0.01) and drug hypersensitivity (8.75, 3.1-24.66, p < 0.001). CONCLUSIONS: Our data showed an elevated disproportionality for cardiovascular ADRs in patients treated with ranibizumab and for infective ocular reactions in those treated with bevacizumab. No relevant safety issues were identified for pegaptanib. These findings suggest bevacizumab as a suitable choice for AMD therapy due to its effectiveness similar to that of ranibizumab, its favourable safety profile and for its lower cost.

Three years of experience: the Italian registry and safety data update.

At the end of 2006, a pharmacovigilance program on natalizumab was settled by the Italian Pharmaceutical Agency, and on January 2007, multiple sclerosis patients poorly responding to the immunomodulating therapies or with an aggressive clinical form of disease from onset initiated to be registered and to receive the medication. On February 2010, almost 3,000 cases have been treated with natalizumab. The drop-out rate is 10%. Almost 800 cases received cycles of natalizumab for more than 18 months. One case of PML was reported and other adverse events are similar to those described in phase III studies. The majority of cases remained stable, while in 25% of cases, an improvement of disability was documented.

The pharmacovigilance program on natalizumab in Italy: 2 years of experience.

At the end of 2006 a country-based surveillance program on natalizumab therapy in multiple sclerosis was settled in Italy by a collaborative effort of the Italian Drug Agency (AIFA) and a group of experts and neurologists appointed by the National Society of Neurology (SIN). After 2 years, 1,818 patients are registered in the database. The majority of cases (88.6%) failed the therapy with beta interferon or glatiramer acetate and had relapses or accumulated disability during immunomodulating treatment, while 11.4% of patients enrolled in the surveillance study were not previously treated with immunomodulating therapies and had a rapidly evolving clinical course. Almost 10% of the patients treated with natalizumab interrupted, for various different reasons, the therapy. Treatment was well tolerated and side effects were similar to those reported in the registrative studies. The majority of treated cases are stable or ameliorated.

Use of anti-asthmatic drugs in Italy: analysis of prescriptions in general practice in the light of guidelines for asthma treatment.

UNLABELLED: Our aim was to analyse anti-asthmatic drug utilisation in primary health care in a Northern Italian region in the light of guidelines for asthma treatment. METHODS: We collected all prescriptions for anti-asthmatic agents reimbursed in 1998 in six local health authorities (overall population: 1,909,192 inhabitants) of Emilia Romagna (Northern Italy). The asthmatic cohort was defined as the population of subjects aged 20-44 years receiving at least one prescription of an anti-asthmatic agent devoid of indications for transient respiratory diseases. In order to include routine users, the asthmatic cohort was restricted to those subjects with at least one prescription in the first quarter of 1998. Anti-asthmatic agents were classified according to their therapeutic role as follows: maintenance therapy for mild-moderate asthma (Mm); maintenance therapy for severe asthma (Ms); quick relief for mild attack (Qm) and quick relief for severe attack (Qs). RESULTS: The asthmatic cohort included 11,518 subjects; of these, 47% received only one prescription in 1998. The most frequent regimens were Mm+Qm (25%) and Qm alone (23%). Some regimens appeared not to be in accordance with international recommendations. The main reasons were lack of drugs for quick relief (36%), use of long-term beta(2)-adrenoceptor agonists (Ms drugs) without quick-relief or anti-inflammatory agents (10% of the cohort and 56% of the recipients of Ms drugs) and presence of fixed-dose combinations (27%). In 76% of the patients treated with Mm drugs (mainly inhaled steroids), the total amount of drugs prescribed over the 1-year period covered less than 150 days. CONCLUSIONS: The use of anti-asthmatic drugs in general practice in Italy does not seem to comply with the international recommendations especially with regard to the use of quick-relief agents. Active interventions to implement guidelines and monitor the choice of drug regimens are warranted.

Organising evidence on QT prolongation and occurrence of Torsades de Pointes with non-antiarrhythmic drugs: a call for consensus.

BACKGROUND: The growing list of non-antiarrhythmic drugs associated with QT prolongation and the relevant regulatory interventions have generated concern for two reasons. First, QT prolongation is sometimes viewed as an intrinsic effect of a whole therapeutic class (for example, antihistamines), whereas, in many cases, it is displayed only by some compounds within a given class of non-antiarrhythmic drugs because of an effect on cardiac repolarisation. Second, drug-induced Torsades de Pointes are still considered idiosyncratic, totally unpredictable adverse drug reactions, whereas a number of risk factors for their occurrence is now recognised. OBJECTIVES: In order to increase awareness among prescribing physicians that many non-antiarrhythmic drugs can affect cardiac repolarisation, we would like to propose a comprehensive and updated list of QT-prolonging drugs that should be a starting point to maintain a "consensus list" to be periodically updated. METHODS: The drug list was generated by performing a Medline search, by using published lists as starting points to retrieve the relevant references quoted in each article and by considering the International Registry for Drug-induced Arrhythmias maintained by the Georgetown University and mainly based on the FDA approved labelling. RESULTS: The drug list presented in this paper: (1) includes virtually all non-antiarrhythmic drugs with QT-prolonging potential, (2) organises the available information on each drug at different levels of clinical relevance and (3) is as up-to-date as possible in order to provide a fast track for the clinical pharmacologist to retrieve the original publications. CONCLUSIONS: This list should be considered as a starting point to call for consensus on: (1) the criteria used to generate the list, (2) possible ways to implement the use of this list as a quick reference for clinicians, for instance by providing a "proarrhythmic score" for each drug, and (3) inclusion/exclusion of a given agent into the list on the basis of evidence that may not be available to us.

The therapeutic course as a measure complementary to defined daily doses when studying exposure to antibacterial agents.

OBJECTIVE: The defined daily dose (DDD) method may not provide accurate information about exposure to antibacterial agents, owing to their short-term use and the consequently high turnover of subjects. This study was addressed to evaluate whether the number of "therapeutic courses" could offer additional information. METHODS: Prescription data of antibacterial agents (ATC J01) in Ravenna, Italy (350,000 inhabitants), were studied in 1998. All the prescriptions issued within 10 days were considered as belonging to one therapeutic course (TC). The following measures were compared: DDD/1000 inhabitants/year, number of exposed subjects/1000 inhabitants/year and number of TC/1000 inhabitants/year. In order to compare the number of 10-day TCs with the number of DDDs, the latter was divided by 10 (DDD10). The intensity of drug treatment was also evaluated as the average number of DDDs per TC (therapeutic intensity). RESULTS: Sixty-one percent of the subjects received only one prescription in 1998. Among the second prescriptions, 69% were issued after a time interval greater than 21 days. The overall prevalence of use was 329 per 1000 inhabitants, the TCs were 525 per 1000 inhabitants and DDD10/1000 inhabitants/year were 470. The therapeutic intensity varied with the age classes (being lowest in the elderly) and with the individual antibiotics used. Two or more antibacterials were used within the same TC in 7% of the cases. CONCLUSION: The measures considered in this study provided different estimates of exposure to antimicrobial agents. The combined analysis of DDDs and TCs may offer a more reliable information about exposure to antimicrobial agents.

Pattern of antibiotic use in primary health care in Italy.

OBJECTIVE: The overuse and misuse of antibiotics have been related to the growing emergence of bacterial resistance. The aim of the present study was to assess the pattern of antibiotic use by Italian general practitioners (GPs) in the treatment of the most frequent infectious problems. METHODS: The study was performed with 131 GPs recruited on a voluntary basis from among the 181 GPs contacted in two Italian regions, Emilia Romagna and Umbria. GPs were requested to report all the infectious events encountered during six sample weeks on a special form, whether an antibiotic was administered or not. RESULTS: The GPs reported 7095 infectious cases, of which 5036 (77%) were respiratory-tract infections (RTIs) and 749 (11%) were urinary-tract infections (UTIs). Antibiotics were prescribed in 71% of the cases. The proportion of antibiotic-treated cases was highest in UTIs (97%), followed by lower respiratory-tract infections (LRTIs; 93%) and upper respiratory-tract infections (URTIs; 54%). Drugs belonging to 16 Anatomical Therapeutical Chemical groups (fourth level) were used. Wide-spectrum penicillins and macrolides ranked first (23%), followed by penicillins plus beta-lactamase inhibitors (15%), cephalosporins (15%) and fluoroquinolones (10%). The most prescribed antibiotics for the major disease groups were wide-spectrum penicillins for URTIs (36%), macrolides and cephalosporins for LRTIs (27% each) and fluoroquinolones for UTIs (46%). CONCLUSIONS: The present survey showed a high level of inappropriate use. In fact, a large number of infectious diseases, including infections commonly caused by viral agents, were treated with an anti-bacterial drug. Italian GPs had a tendency to preferentially prescribe wide-spectrum antibiotics and to use, in many cases, antibiotics that are rarely of choice in primary health care, such as cephalosporins and fluoroquinolones. In order to attain a more evidence-based prescription, local guidelines shared by specialists and GPs should be implemented.

Deviations from evidence-based prescribing of non-steroidal anti-inflammatory drugs in three European regions.

OBJECTIVE: We examined to what extent the evidence of the relative gastrointestinal toxicity with non-steroidal anti-inflammatory drugs (NSAIDs) was implemented in clinical practice in Bologna, Italy, Funen, Denmark, and Stockholm, Sweden, areas with accurate computerised information on prescriptions purchased by defined populations. METHODS: We ranked each NSAID by purchased volume in defined daily doses during September 1996 and compared it with the ranking of gastrointestinal complications from a meta-analysis of controlled epidemiological studies published between 1986 and 1994. We restricted our comparison to those NSAIDs that accounted for 90% of the use and within this DU90% segment we determined the proportion of "high risk" (azapropazone, ketoprofen, piroxicam) and "low risk" (ibuprofen, diclofenac) drugs with respect to gastrointestinal toxicity. RESULTS: In Funen, Denmark, we found the best NSAID profile (63% low risk/11% high risk) while Bologna, Italy, had the other extreme (26% low risk/38% high risk), with Stockholm, Sweden, in between (43% low risk/20% high risk). CONCLUSION: Our study suggests that factors other than evidence-based medicine had a dominating impact on the use of prescription NSAIDs in 1996.

QT-interval prolongation by non-cardiac drugs: lessons to be learned from recent experience.

BACKGROUND: Evidence has accrued that several non-cardiac drugs may prolong cardiac repolarisation (hence, the QT interval of the surface electrocardiogram) to such a degree that potentially life-threatening ventricular arrhythmias (e.g. torsades de pointes) may occur, especially in case of overdosage or pharmacokinetic interactions. DISCUSSION: This has fostered discussion on the molecular mechanisms underlying the class-III antiarrhythmic effect shared by apparently disparate classes of drugs, on the clinical relevance of this side effect and on possible guidelines to be followed by drug companies, ethics committees and regulatory agencies in the risk-benefit assessment of new and licensed drugs. This review provides an update on the different classes of non-cardiac drugs reported to prolong the QT interval (e.g. histamine H1-receptor antagonists, antipsychotics, antidepressants and macrolides), on the possible underlying molecular mechanisms and on the clinical relevance of the QT prolonging effect. Identification and widespread knowledge of risk factors that may precipitate prolongation of the QT interval into life-threatening arrhythmias becomes an important issue. Risk factors include congenital long QT syndrome, clinically significant bradycardia or heart disease, electrolyte imbalance (especially hypokalaemia, hypomagnesaemia), impaired hepatic/renal function and concomitant treatment with other drugs with known potential for pharmacokinetic/ pharmacodynamic interactions (e.g. azole antifungals, macrolide antibacterials and class-I or -III antiarrhythmic agents). Future perspectives for drug research and development are also briefly outlined.

Lack of adherence to lipid-lowering drug treatment. A comparison of utilization patterns in defined populations in Funen, Denmark and Bologna, Italy.

AIMS: The objective was to explore differences in lipid-lowering drug (LLD) prescribing in Italy and Denmark. METHODS: We used two geographical areas with computerized drug prescription records in defined populations, one in Funen, Denmark with 500 000 inhabitants, the other in Bologna, Italy with 400 000 inhabitants. Prescriptions for patients who had purchased a LLD from 1994 until 1996 were retrieved as well as coprescriptions of antidiabetic and cardiovascular drugs as markers for diabetes and cardiovascular disease. Only patients surviving and remaining in the area were included. Compliance was defined as percentage of DDDs purchased divided by the number of days within the time window. The limit between good and poor compliance was set at 82%. RESULTS: In Bologna, LLD consumption measured in DDD increased by 41% and in Funen by 129%. Annual prevalence increased from 36.9 to 46.3 users/1000 inhabitants from 1994 to 1996 and from 3.2 to 6.6 users/1000 inhabitants in Bologna and Funen, respectively. From 1995 to 1996, the incidence of use decreased slightly in Bologna from 19.3 to 18. 8/1000 inhabitants/year, whereas in Funen the incidence increased from 1.8 to 2.3/1000 inhabitants/year. In Bologna 48% and in Funen 91% of users persisted with treatment for 2 years or longer. In Bologna, 7% and in Funen 45% were good compliers. In Bologna, 61% and in Funen, 72% received other drugs indicating cardiovascular or diabetic comorbidity. CONCLUSIONS: Patterns of use differed substantially between the two areas. In contrast with Funen, where long-term use was common, Bologna LLD use was sporadic. Based on a higher rate of coprescription, LLDs seemed to be used for secondary prevention to a higher extent in Funen than in Bologna. In Funen it appeared that the correct patients, but an insufficient number of them, were being treated adequately according to guidelines. The higher discontinuation rate of lipid lowering drugs in the Bologna area indicates that a large proportion of patients use these drugs for too short a period of time to benefit from treatment. Since society's health care resources are limited it is difficult to justify public funding of these medications without at the same time giving appropriate attention to these problems.

Rescue of implantation potential in embryos with poor prognosis by assisted zona hatching.

The effect of the assisted zona hatching (AZH) procedure was investigated on 135 cycles with a poor prognosis of pregnancy due to: (i) maternal age > or = 38 years (45 cycles); (ii) three or more failed in-vitro fertilization (IVF) attempts (70 cycles), and (iii) patients possessing both inclusion criteria (20 cycles). The control groups (113 cycles) included patients possessing the same characteristics (42, 53 and 18 cycles respectively) and who did not undergo the AZH procedure. A total of 505 embryos was treated with AZH before transfer, resulting in: 14, 25 and 6 clinical pregnancies. The percentage of clinical pregnancies per cycle was significantly higher than controls for the first (31 vs 10% in control 1, P < 0.05) and second groups (36 vs 17% in control 2, P < 0.05). No significant difference in percentage of clinical pregnancies was found for the third group (30 vs 6%). Similarly, higher rates of implantation were obtained (11.5, 15 and 11%) compared to the respective controls (4%, P < 0.02; 6.3%, P < 0.01; and 1.5%). The rate of miscarriage in the AZH groups was similar to that obtained in the controls (22 vs 21%). Finally, the morphological analysis of the embryos transferred revealed that the poor prognosis condition is associated to a significantly slower rate of development and a higher rate of fragmentation. The present results indicate that AZH procedure improves pregnancy and implantation rates in patients with a poor prognosis of pregnancy by facilitating the hatching process in embryos which would otherwise be trapped inside the zona pellucida.

Will preimplantation genetic diagnosis assist patients with a poor prognosis to achieve pregnancy?

PGD (preimplantation genetic diagnosis) of aneuploidy for chromosomes X, Y, 13, 18 and 21 was carried out on 196 embryos from 36 infertile patients classified with a poor prognosis due to (i) maternal age, (ii) repeated in-vitro fertilization (IVF) failures and (iii) mosaic karyotype. The percentage of abnormal embryos was comparable in the three groups of patients: maternal age 63%, repeated IVF failure 57%, and mosaic karyotype 62%. The analysis of the overall data revealed an increased incidence of abnormal embryos in the older age categories (predominantly due to aneuploidy), even in embryos at the 7- to 8-cell stage. In addition, the percentage of chromosomally abnormal embryos was directly proportional to the number of IVF failures, where the increase in chromosomal abnormalities was not correlated to aneuploidy but to other aberrations such as mosaicism and polyploidy. Following PGD, 28 patients had at least one embryo transferred that appeared normal by fluorescent in-situ hybridization (FISH). Four clinical pregnancies resulted, with an implantation rate of 10% per normal embryo. In conclusion, the high rate of chromosomally abnormal embryos in poor prognosis patients may have been the cause of implantation failure in their previous IVF cycles. Therefore, the possibility of transferring embryos with a normal FISH complement could improve the chance of pregnancy in this category of patients.

Use of lipid-lowering drugs from 1990 to 1994: an international comparison among Australia, Finland, Italy (Emilia Romagna Region), Norway and Sweden.

OBJECTIVE: To compare the overall utilisation pattern of lipid-lowering drugs between 1990 and 1994 in Australia, Finland, Italy, Norway and Sweden as well as the pattern of use with respect to age and gender in Italy and Sweden. METHODS: Data were retrieved from regulatory authorities in each country for the 5-year period and analysed according to the ATC/DDD methodology (Anatomical Therapeutic Chemical classification/Defined Daily Doses). Utilisation was calculated as the DDDs for 1000 inhabitants per day for all drugs of the ATC category B04 (serum lipid-reducing agents). Data from Sweden and Italy were also compared with respect to gender and age. RESULTS: In 1994, Australia demonstrated the highest degree of utilisation (11.9 DDD) and the Nordic Countries the lowest (Sweden 5.6; Norway 4.9; Finland 4.0). In all countries except Italy, a steady increase was observed; in Italy, utilisation of these drugs reached a maximum in 1992 (11.5 DDD), but then underwent a reduction which was caused by restrictions in the reimbursement status in 1993 (10.4) and 1994 (6.7). Administration of statins increased in all countries, becoming the most used group of the B04 class. In 1988, the number of different drugs listed by each national health service ranged from 4 (Norway) to 16 (Italy); in 1994 it ranged from 6 (Norway) to 9 (Sweden). Analysis with respect to gender showed the opposite pattern in Sweden (males 4.6 and females 3.3 in 1992; 6.2 and 4.5, respectively, in 1994) than in Italy (males 10.8 and females 17.8 in 1992; 6.4 and 9.2, respectively, in 1994). Exposure was highest in people aged 60-69 years in both countries, followed by age group 50-59 in Sweden and 70-79 in Italy. CONCLUSIONS: Large variations in the utilisation of lipid-lowering drugs exist between countries, with Australia and Italy much higher than others. Of the drugs in the ATC category B04, the use of statins predominates in all countries, but to varying degrees. The large difference in the degree of drug utilisation with respect to age and gender between Italy and Sweden suggests major deviations from evidence-based medicine.

Prolonged sperm-oocyte exposure and high sperm concentration affect human embryo viability and pregnancy rate.

A reduced time interval of oocyte exposure to spermatozoa was investigated to assess whether it could enhance oocyte development and improve embryo viability, especially in cases of male factor infertility. A total of 167 patients were included in a prospective randomized study. They were randomly allocated to two major study groups, A (n = 85) and B (control group; n = 82). The oocytes from group A patients were exposed to spermatozoa for only 1 h; those from group B were exposed for 16 h. The two study groups were then subdivided according to semen quality for further analysis of the results. Significantly higher percentages were obtained in group A than in group B in terms of the fertilization rate (74 versus 68%, P < 0.025), cleavage rate (53 versus 41%, P < 0.005), pregnancy rate (27 versus 12%, P < 0.05) and implantation rate (11 versus 6%, P < 0.05). In addition, an increased fertilization rate was achieved in oocytes exposed to male factor spermatozoa for only 1 h compared with the conventional incubation period (78 versus 65%, P < 0.01). Advanced cellular stages (55 versus 41%, P < 0.02) and higher implantation rates (13 versus 4%, P < 0.05) were attained in the subgroup whose oocytes were exposed to normal spermatozoa for 1 h compared with the male factor spermatozoa with the standard culture interval. The higher fertilization rates, enhanced embryo development and viability achieved in group A indicate that prolonged exposure of oocytes to high concentrations of spermatozoa is detrimental, decreasing sperm-oocyte interaction and subsequent embryo implantation, particularly in male factor patients.

Relationship of timing of agonist administration in the cycle phase to the ovarian response to gonadotropins in the long down-regulation protocols for assisted reproductive technologies.

OBJECTIVE: To assess whether the ovarian response to exogenous gonadotropins and cycle performance is affected by different timing of an agonist administration in long down-regulation protocols. DESIGN: An agonist was administered irrespective of cycle phase, with exogenous gonadotropin beginning 15 days later. PATIENTS: Five hundred fifty-seven normovulatory infertile patients, aged < or = 38 years, were classified into seven study groups, depending on the phase of the cycle in which agonist was started. MAIN OUTCOME MEASURES: Endocrine profile, amount of exogenous stimulation, occurrence of ovarian cysts, mean number of oocytes recovered and embryos transferred, pregnancy rate, implantation rate, and live-birth rate of the seven groups. RESULTS: The ovarian response of the groups did not show any statistically significant differences in relation to the initiation of the agonist. The only effect was a different incidence of ovarian cyst formation, but this phenomenon did not affect cycle performance. The pregnancy, implantation, and live-birth rates showed differences that did not reach statistical significance. CONCLUSION: Agonists initiation can be programmed in advance irrespective of the phase of the cycle. This approach can be of help for the logistics of assisted reproduction programs.

Use of benzodiazepines in the Italian general population: prevalence, pattern of use and risk factors for use.

This study was conducted to determine the prevalence and profile of use of benzodiazepines in the Italian population and risk factors for use. Between November 1992 and February 1993, 62 general practitioners submitted a validated self-administered questionnaire on health status and drug use to a randomised sample of 3100 subjects ( > or = 18 years of age, stratified by sex and age), of whom 2803 responded (response, rate 90.4%). Main outcome measures were point estimate (past-week) of all the drugs taken by each individual, dosage and length of use and source of the prescription. The overall past-week prevalence of use of benzodiazepines was 8.6% (5.0% males and 11.8% females). In the elderly ( > or = 65 years) 18.8% reported current use (9.0% males and 24.7% females). Fifty-six per cent of the persons exposed to a benzodiazepine were chronic users (daily, for more than 6 months), and 70.1% in subjects > or = 65 years. The average daily dose taken was relatively low: 61% of short-term users and 51% of chronic users used less than half a defined daily dose (DDD). Female sex, older age, unemployment and retirement were independently associated with the use of benzodiazepines. Benzodiazepine use in Italy appeared to be relatively high (about 9% of subjects reported current use 57% of whom were chronic users). Women were prescribed a benzodiazepine twice as often as men and one out of four elderly women was on treatment. Although the average dosage used was rather low, the high prevalence and the elevated proportion of chronic users should encourage drug information campaigns and educational interventions to promote a more conservative use of these drugs especially in the elderly.