Alessandra Pugi

Safety profile of the fluoroquinolones: analysis of adverse drug reactions in relation to prescription data using four regional pharmacovigilance databases in Italy.

AbstractBackground: Fluoroquinolones are widely used both in primary care and in hospital settings. Since the last comparison performed in Italy on the safety profiles of different fluoroquinolones, a new molecule, prulifloxacin, has been introduced into the market and several warnings concerning this class of drugs have been released. The aim of this study was to reassess the safety profiles of fluoroquinolones using the database of the Italian Interregional Group of Pharmacovigilance (IGP) and the administrative data of fluoroquinolone prescriptions. Methods: All adverse drug reactions (ADRs) reported in four Italian regions (Lombardy, Veneto, Emilia Romagna and Tuscany) were retrieved from the IGP database. Consumption data (defined daily dose [DDD]/1000 inhabitants/ day) were used as denominators. Both single reports and all ADRs (classified by System Organ Classes and MedDRA® Preferred Term [PT]) due to fluoroquinolones were considered as numerators of each analysis, comparing two periods (2005 vs 2006). All fluoroquinolones with at least ten reports per year were included in the analysis. Results: On the basis of 272 reports (532 single ADRs or PTs), patients did not show any statistically significant differences between 2005 and 2006 in terms of sex, age and number of concurrent medications. After adjustment for drug consumption, moxifloxacin showed the highest reporting rate (84.6 reports/ DDD/1000 inhabitants/day; 15.4 serious reports/DDD/1000 inhabitants/day) followed by prulifloxacin (72.2; 22.2 serious) and levofloxacin (55.3; 30.6 serious) in 2005. An increment of ADR/report rates was observed over the 2 years for all fluoroquinolones except prulifloxacin, which had the lowest ADR reporting rate in 2006 (25.0; 12.5 serious). In 2006, the rate of serious ADRs associated with prulifloxacin was lower than with ciprofloxacin, while in 2005 serious events were almost equal for both compounds (55.6 vs 47.6 serious ADRs/DDD/1000 inhabitants/day). Ciprofloxacin showed the highest proportion of cutaneous PTs (e.g. rash, exanthema). Tendinopathies were mainly due to levofloxacin. Conclusions: These data suggest that different fluoroquinolones are characterized by different rates and types of ADRs. Among them, prulifloxacin was associated with more ADRs than other fluoroquinolones in 2005 but with fewer ADRs in 2006, when its consumption increased. Although these findings may represent an encouraging perspective towards a more appropriate use of fluoroquinolones because of their individual safety profiles, further pharmacoepidemiological studies must be performed to substantiate these results.

Efficacy of ketamine in refractory convulsive status epilepticus in children: a protocol for a sequential design, multicentre, randomised, controlled, open-label, non-profit trial (KETASER01).

Introduction Status epilepticus (SE) is a life-threatening neurological emergency. SE lasting longer than 120 min and not responding to first-line and second-line antiepileptic drugs is defined as ‘refractory’ (RCSE) and requires intensive care unit treatment. There is currently neither evidence nor consensus to guide either the optimal choice of therapy or treatment goals for RCSE, which is generally treated with coma induction using conventional anaesthetics (high dose midazolam, thiopental and/or propofol). Increasing evidence indicates that ketamine (KE), a strong N-methyl-d-aspartate glutamate receptor antagonist, may be effective in treating RCSE. We hypothesised that intravenous KE is more efficacious and safer than conventional anaesthetics in treating RCSE. Methods and analysis A multicentre, randomised, controlled, open-label, non-profit, sequentially designed study will be conducted to assess the efficacy of KE compared with conventional anaesthetics in the treatment of RCSE in children. 10 Italian centres/hospitals are involved in enrolling 57 patients aged 1 month to 18 years with RCSE. Primary outcome is the resolution of SE up to 24 hours after withdrawal of therapy and is updated for each patient treated according to the sequential method. Ethics and dissemination The study received ethical approval from the Tuscan Paediatric Ethics Committee (12/2015). The results of this study will be published in peer-reviewed journals and presented at international conferences. Trial registration number NCT02431663; Pre-results.

Complementary and Alternative Drugs Use among Preoperative Patients: A Cross-Sectional Study in Italy

Complementary and alternative drugs (CADs) are widely used in preoperative patients and may lead to potential interactions and adverse reactions. The aim of our study is to evaluate the prevalence and the predictors of CADs use among preoperative patients using data from an Italian survey. This cross-sectional study, which enrolled 478 patients (response rate: 83.5%), was carried out in three Tuscany hospitals (Italy). The prevalence of CADs use was 49.8%: 233 out of 238 participants used herbal products and/or dietary supplements. Valeriana officinalis was the most reported product (19.4%). According to univariate analysis, users were commonly identified among middle-aged or older patients; unadjusted ORs were 2.1 (95% CI: 1.3–3.3) for patients aged 48–69 years, and 3.0 (95% CI: 1.9–4.7) for those of 70–95 years, when compared with individuals aged 18–47 years. Except for education and gender, adjusted estimates showed consistent results with univariate analyses: direct association was observed with higher education, and—although not significantly—with female gender. The high prevalence of CAD use in preoperative period could be suggestive of a certain risk of adverse effects due to CADs interactions. A careful medical history of CADs consumption should be ascertained before surgery.

Consensus conference on the appropriateness of palivizumab prophylaxis in respiratory syncytial virus disease

Respiratory syncytial virus infection represents a clinical burden among young children under 24 months. Palivizumab is the only drug licensed in Italy for the prevention of serious lower respiratory tract disease requiring hospitalization caused by respiratory syncytial virus in children at high risk.

Safety profile of antiviral medications: A pharmacovigilance study using the Italian spontaneous-reporting database

PURPOSE The results of an analysis of suspected antiviral-associated adverse drug reactions (ADRs) in Italy over a 22-year period are presented. METHODS A case/non-case analysis was conducted using ADR reports compiled in the nationwide spontaneous-reporting database through September 2010. All reported events included in the analysis were evaluated and coded by drug safety experts; causality assessments were performed according to the algorithm of Naranjo et al. The association between an adverse reaction and antiviral use was assessed by estimating the reporting odds ratio (ROR), with 95% confidence interval (CI), as a measure of disproportionality. RESULTS Overall, 863 reports of suspected ADRs involving antivirals and 42,430 reports of adverse reactions to other drugs were identified; of those events, 3.3% and 64.3% were determined to be definite or probable ADRs, respectively, and an additional 32.4% were deemed possibly drug related. Several ADRs were disproportionately associated with antivirals relative to other drugs: renal colic (ROR, 25.5; 95% CI, 13.3-49.0), lactic acidosis (ROR, 18.6; 95% CI, 9.2-37.7), depression (ROR, 18.0; 95% CI, 11.6-27.9), anemia (ROR, 15.9; 95% CI, 12.3-20.4), hallucination (ROR, 4.3; 95% CI, 2.7-7.1), neutropenia (ROR, 4.1; 95% CI, 2.9-5.8), acute renal failure (ROR, 3.9; 95% CI, 2.3-6.4), fever (ROR, 3.8; 95% CI, 2.8-5.1), hyperpyrexia (ROR, 2.9; 95% CI, 1.7-4.9), and asthenia (ROR, 1.8; 95% CI, 1.2-2.8). CONCLUSION Analysis of data from a large Italian database showed that, among antiviral agents, the ribavirin-interferon combination, acyclovir, valacyclovir, indinavir, and zidovudine accounted for the most serious hematologic, neuropsychiatric, and renal ADRs.

Comparative efficacy of antiepileptic drugs in children and adolescents: A network meta-analysis

To estimate the comparative efficacy among antiepileptic drugs in the pediatric population (0‐18 years).

Anaphylaxis during the first course of high-dose methotrexate: a case report and literature review

What is known and Objective:  Methotrexate (MTX) is widely used in the management of paediatric cancer with a generally favourable benefit/risk profile. We report an unusual adverse drug reaction with the first course of high‐dose MTX in a paediatric patient and review the literature for similar cases.

Anything to declare? Possible risks for patients' health resulting from undeclared plants in herbal supplements

Problems due to poor quality of herbal products continue to be a major international problem. Of particular concern is the deliberate or accidental addition of other plant species or synthetic drugs leading to adverse reactions (AR). As a result, labelling of herbal products may sometimes not accurately reflect their contents, leading to adverse events or interactions attributed to specific herbs, when in fact they are actually due to misidentified plants, mislabelling and/or adulteration. Since producers may include or omit safety information on product labels at their own discretion, labels themselves may lack clinically pertinent information. In this frame, the interpretation of specific ARs to herbal products might also be difficult [1]. During the last 3 years, Florence University Pharmacovigilance system received several reports from patients referring to the unexpected effectiveness of ‘Olivis’, a dietary supplement marketed in Italy by the company Ser-Vis as an adjunct to hypertension therapy. The declared components of this liquid preparation were extracts of leaves and buds of olive (Olea europea L.), leaves, flowers, fruits of hawthorn (Crataegus oxyacantha L.), flowers of fumitory (Fumaria officinalis L.) and shepherds purse (Capsella bursa pastoris L.). Furthermore an AR report was present in the National Institute of Health phytovigilance database concerning a female patient affected by hypertension, admitted to the hospital after an episode of hypotension and bradycardia. The patient had spontaneously replaced her antihypertensive therapy with 25 Olivis drops day−1. After an episode of hypotension, the dose was reduced to 8 drops day−1, maintaining good blood pressure control. One month later, she suspended the treatment and soon after faced a hypertensive crisis. The patient re-assumed 15 Olivis drops day−1, resulting in good blood pressure control and eventually in the reported AR. The reported AR raised suspicion as the available data on the ingredients of Olivis did not indicate significant hypotensive effects for olive and hawthorn and several studies on shepherds purse have shown both lowering and elevation of blood pressure [2]. Therefore the product was analyzed at Florence University Mass Spectrometry Centre and Department of Pharmaceutical Sciences Laboratory, by means of HPLC-ESI-ITMS and NMR, to assess the possible presence of synthetic drugs (ACE inhibitors, β-adrenoceptor blockers, angiotensin II receptor antagonists, calcium channel antagonists, α-adrenoceptor antagonists), as well as undeclared natural compounds with hypotensive activity. No synthetic drugs were found in the preparation, but analyses showed the presence of indole alkaloids, principally ajmaline and reserpine. The concentration of reserpine in the sample was 1.57 µg ml−1, corresponding to a suggested dose of 3.5–12.0 µg day−1, while the concentration of ajmaline was 861.8 µg ml−1, corresponding to a suggested dose of 1.8–6.5 mg day−1. Since both compounds are absent in label-declared herbal ingredients, addition of an extract from an undeclared Rauwolfia species was suspected [3]. In this case the significant effect observed on blood pressure raised suspicions of possible adulteration of Olivis with synthetic antihypertensive drugs. However, further laboratory investigation revealed that a reserpine/ajmaline containing plant species had been used in the product. Neither of these alkaloids is permitted in food supplements according to Italian regulations. Whilst both of them are effective in lowering blood pressure, only reserpine was present at an active concentration. Ajmaline is a well-known cardioactive drug with an anti-arrhythmic profile and the potential of induction of bradycardia and hypotension, but its side effects have been reported only after rapid intravenous injection of doses significantly higher than in the present case [4]. Reserpine, while being an authorized drug, is rarely prescribed nowadays due to its poor tolerability and unfavourable safety profile. We concluded therefore that the reported side effects were mainly due to reserpine present in the undeclared plant species. Information was transmitted to the Italian Ministry of Health, and it arranged for the withdrawal of the product from the market. After some months a new product with a similar composition was marketed by the same producer. A subsequent analysis conducted by us showed no undeclared Rauwolfia species in the new product. This case highlights the potentially serious health risks posed by the lack of effective controls on the quality of herbal products [5]. Clinicians should be aware of the potential for such cases to arise and the need to take a detailed history of herbal products used by patients. Where ARs to herbal products report significant pharmacological effects which are not expected with the declared herbal ingredients, then undeclared active ingredients are possible and should be fully investigated.

Propranolol 0.1% eye micro-drops in newborns with retinopathy of prematurity: a pilot clinical trial.

Background:Oral propranolol reduces retinopathy of prematurity (ROP) progression, although not safely. This study evaluated safety and efficacy of propranolol eye micro-drops in preterm newborns with ROP.Methods:A multicenter open-label trial, planned according to the Simon optimal two-stage design, was performed to analyze safety and efficacy of propranolol micro-drops in newborns with stage 2 ROP. To this end, hemodynamic and respiratory parameters were monitored, and blood samples were collected weekly, for 3 wk. Propranolol plasma levels were also monitored. The progression of the disease was evaluated with serial ophthalmologic examinations.Results:Twenty-three newborns were enrolled. Since the fourth of the first 19 newborns enrolled in the first stage of the study showed a progression to stage 2 or 3 with plus, the second stage was prematurely discontinued. Even though the objective to complete the second stage was not achieved, the percentage of ROP progression (26%) was similar to that obtained previously with oral propranolol administration. However, no adverse effects were observed and propranolol plasma levels were significantly lower than those measured after oral administration.Conclusion:Propranolol 0.1% eye micro-drops are well tolerated, but not sufficiently effective. Further studies are required to identify the optimal dose and administration schedule.

A severe case of warfarin–canrenoate interaction: a role for genetic predisposition?

The interindividual variability in warfarin response is generally attributed to dietary vitamin K intake, drug interactions, demographic and genetic factors (D’Andrea et al, 2008). Many drugs are known to modify international normalized ratio (INR) values in warfarin-treated patients both for pharmacodynamic and pharmacokinetic interactions. We report an unusual case of interaction between potassium canrenoate (PC) and warfarin in a 77-year-old Caucasian female with atrial fibrillation, heart failure (New York Heart Association class II) and hypertension. During the previous 5 years, the patient had been effectively anticoagulated with warfarin 35Æ0 mg/week with a very stable INR (Fig 1); in the last 10 months drug therapy also included furosemide, bisoprolol and ramipril. Two weeks after PC addition (50 mg/d) to control a slight hypokalaemia, she suddenly developed an extensive facial and neck haematoma after a mild lesion of the internal jowl, followed by analogous limb lesions as consequences of mild traumas. Blood examinations revealed a marked INR increase (10Æ8), requiring warfarin discontinuation and vitamin K administration. Warfarin treatment was suspended until INR reached 1Æ0; subsequent titrations after warfarin reintroduction eventually resulted in a stable INR within the therapeutic range (2Æ0–3Æ0) with a final regimen of 22Æ5 mg/week (about 66% of the previous dose); PC was never withdrawn. Any other possible factor able to interfere with warfarin therapy was excluded, including: recent illness, changes in dietary vitamin K intake, over-the-counter products, fruit-juices, herbal products, alcohol, tobacco. The patient and her relatives confirmed adherence to drug therapy. Warfarin inhibits the synthesis of vitamin K-dependent clotting factors via inhibition of the vitamin K epoxide reductase complex 1 (vkorc1) and is primarily metabolized via cytochrome P450 2C9 (cyp2c9). The patient was genotypized for three warfarin-related SNPs, CYP2C9*2, CYP2C9*3 and VKORC1 -1639G>A (rs9923231, minor allele frequency 0Æ432 in Caucasian population) (D’Andrea et al, 2008). The Taqman Drug Metabolism Genotyping Assay (Applied Biosystems, Foster City, CA) was used. The patient was found to be homozygous wild-type for both CYP2C9 loci and homozygous -1639AA (low dose required) for VKORC1. Both PC and warfarin are highly bound to human serum albumin (HSA), and PC was previously shown to competitively displace warfarin from HSA to a significantly higher extent than spironolactone (the latter was, on the contrary, reported to decrease the anticoagulant effect of warfarin by means of clotting factors concentration) (O’Reilly, 1980; Takamura et al, 1997). This interaction may increase warfarin bioavailability, taking also into account that both R-Warfarin and PC undergo extensive hepatic metabolism via CYP3A (Cook et al, 1993; D’Andrea et al, 2008). To date, this is the first clinically relevant interaction between warfarin and PC. Its imputability was graded as ‘probable’ according to the objective causality assessment performed by our Pharmacovigilance Unit. As the combination of warfarin and PC might be quite common in cardiovascular therapy (e.g. 2042 out of 58 831 – 3Æ5% – warfarin users have at least a coexistent prescription of PC within a time window of 1–3 months according to recent prescription data of Tuscany), we hypothesize that the increase in warfarin serum concentration afforded by PC pharmacokinetic interactions may lead to a clinically relevant bleeding syndrome only in subjects with a warfarin-sensitive genotype (e.g. VKORC1 -1639AA as in the present case). (A)