Dose adjustment in patients with liver cirrhosis: impact on adverse drug reactions and hospitalizations

Aim and background

To assess drug-related problems in patients with liver cirrhosis by investigating the prevalence of inadequately dosed drugs and their association with adverse drug reactions (ADRs) and hospitalizations.

Methods

This was a cross-sectional retrospective study assessing the dose adequacy of drug treatment of 400 cirrhotic patients at hospital admission based on the authors’ own previous studies and standard literature. The prevalence of total and preventable ADRs and of hospitalizations due to preventable ADRs was determined.

Results

Of all 1653 drugs prescribed (median 4 per patient), 336 (20 %) drugs were inadequately dosed in 184 patients. Overall, 210 ADRs (78 % preventable) occurred in 120 patients. Sixty-nine ADRs (33 % of all ADRs) were associated with inadequate drug dosing in 46 patients, of which 68 % were preventable. Nonsteroidal anti-inflammatory drugs and psycholeptics in particular frequently caused preventable ADRs associated with inadequate drug dosing. Inadequate drug dosing was more frequently associated with ADRs than adequate drug dosing, and patients receiving inadequately dosed drugs were more frequently admitted to the hospital due to ADRs. Hospitalization of patients receiving inadequately dosed drugs that caused preventable ADRs resulted in 94 additional hospital days.

Conclusion

In this retrospective study, inadequate drug dosing was associated with an increased frequency of ADRs, hospital admissions and hospital days in cirrhotic patients. We therefore conclude that the careful dosing of critical drugs is important in patients with liver cirrhosis.     

Use of administrative hospital database to identify adverse drug reactions in a Pediatric University Hospital

Purpose

The aim of the study was to detect adverse drug reactions (ADRs) in pediatric inpatients using the medical administrative database “Programme de Médicalisation des Systèmes d′Information” (PMSI) and to compare these cases ADRs with those spontaneously reported to a regional PharmacoVigilance (PV) Centre.

Methods

The study was conducted from January 2008 to December 2011 in the Children University Hospital of Toulouse (Midi-Pyrénées, South-west France). From PMSI database, all discharge summaries including selected ICD-10 codes (10th International Classification of Diseases) were analyzed. All ADRs spontaneously reported by the Children Hospital of Toulouse and registered in the French PV Database (FPVDB) were included. The capture–recapture method was applied to estimate the incidence of ADRs.

Results

During the study period, we identified 60 reports from the PMSI database and 200 from the FPVDB. The rate of “serious” ADRs was higher in PMSI reports (74.6 % vs 38.9 %, p?Conclusions Use of PMSI database improves from around 30 % detection of ADRs in children. In comparison with classical pharmacovigilance database, it also allows to detect different ADRs and drugs, thus enhancing safe medicine use for pediatric patients.     

Spontaneous reporting of serious cutaneous reactions with protein kinase inhibitors

Purpose

Our aim was to describe all serious cutaneous adverse drug reactions (ADRs) spontaneously reported in France for all oral protein kinase inhibitors, their characteristics and whether they were labeled (reported in the Summary of Product Characteristics) or not.

Methods

We performed a retrospective observational study in the French PharmacoVigilance Database, selecting for analysis serious cutaneous reactions of patients due to treatment with oral protein kinase inhibitors (erlotinib, gefitinib, imatinib, nilotinib, dasatinib, sunitinib, sorafenib, pazopanib, lapatinib, everolimus) between 1 January 2008 and 31 December 31 2010.

Results

Ninety-four patients suffered from 115 serious cutaneous reactions due to oral protein kinase inhibitors. Serious cutaneous reactions more frequently reported were maculo-papular rash (mostly with imatinib), followed by hand–foot syndrome (specifically with sorafenib) and papulopustular rash (particularly with erlotinib). Patients were mostly males (63 %) with a mean age of 62.6?±?15.4 years. Drug withdrawal was observed in 73.1 % of cases because of these cutaneous reactions. Delay of occurrence of the ADR varied from 11.5 to 58.5 days. Unlabeled serious reactions were found (17.4 %), including skin ulceration, vasculitis or purpura with sorafenib or sunitinib and drug rash with eosinophilia and systemic symptoms with imatinib.

Conclusion

Some of the serious ADRs spontaneously reported with oral protein kinase inhibitors are labeled and commonly reported in the literature, but others occur only rarely and unlabeled. In our study, most serious ADRs occurred in males within the 2 first months of treatment and were responsible for the withdrawal of therapy with protein kinase inhibitors.     

Evaluation of adverse drug reactions in medical intensive care units

Purpose

Patterns of adverse drug reactions (ADRs) in the medical intensive care unit (MICU) were analysed, and signals for detecting ADRs were developed from the analysis.

Method

A retrospective study was conducted in MICU wards at a tertiary care teaching hospital in Seoul, Korea. The areas included one general MICU and one cancer centre MICU. Two pharmacists evaluated ADRs in terms of length of stay, causality, severity, preventability, types, related organs, and incidence. Differences in ADR perception rates between physicians and pharmacists were also evaluated. ADR cases detected through the evaluation were reviewed to develop specific alerting signals for ICU ADRs.

Results

The study group included 346 patients admitted to the ICU over 4 months. The overall incidence of ADRs was 32%. ICU length of stay is closely related to ADRs (p?=?0.014). Most ADR cases were mild, temporary, and harmful to the patient. Twenty percent of ADRs were preventable, and 74% were type A. Of the ADRs, 70% were noted by physicians; 80% required intervention. The most commonly implicated drug was amphotericin B, and the clinical presentation was a haematologic reaction. Data on the time required for pharmacists to identify ADRs indicated that they were not slower than physicians. Six signals for early detection of the ADRs were developed.

Conclusions

The overall ADR incidence in the MICU was about one-third, and the length of stay of the ADR group was longer than that of those without this experience. Automated signal generation was developed. It seemed to be a valuable tool for faster and more efficient patient management, and possibly prevention of ADRs. A future study should scientifically evaluate the clinical relevance of this tool.     

Comparative epidemiology of hospital-acquired adverse drug reactions in adults and children and their impact on cost and hospital stay – a systematic review

Purpose

To study and analyze the comparative impact of hospital-acquired adverse drug reactions (ADRs) in adult and pediatric patients in terms of the economic implications, (length of) hospital stay, and salient features in relation to the incidence rate, severity, morbidity, mortality, and preventability of the ADRs.

Methods

A systematic search to identify and retrieve relevant articles/studies in the PubMed, Medline, Scopus, MEDPAR, and Cochrane databases and by the Google search engine was performed for the study period 2000 to April 2013. In total, 51 studies were identified on patients hospitalized for ADRs, and these were included in the study. The incidence rate of ADRs, their severity, mortality, morbidity, preventability, cost, and association with extended hospital stay due to ADRs were extracted and scrutinized.

Results

Hospital-acquired ADRs are more widely studied in adults than in children, and the incidence rate is higher in the former. However, a wide variation in the incidence rate worldwide is observed in both groups. Irrespective of the ages of patients, ADRs are among the most frequent causes of morbidity and mortality. Interestingly, preventable ADRs are more frequently observed in patients at the younger and older ends of the age spectrum. Hospital-acquired ADRs place an immense economic burden on healthcare systems, with the overall cost for a hospitalized patient with an ADR reported to be $2,401 per patient, which is equivalent to a 19.86 % additional increase in the total cost of care and an increase in average length of hospital stay of 8.25 %.

Conclusion

Based on the findings of this review, we suggest that excellent assertive measures of pharmacovigilance with the aim to diminish the incidence rate of hospital-acquired ADRs and support the development of interventions are needed to promote vital facets of drug safety with an overall objective to avert potential ADRs.     

Adverse drug reactions in an emergency medical dispatching centre

Purpose

The purpose of this study is to assess the incidence of adverse drug reactions (ADR) leading to call an emergency medical dispatching centre.

Methods

A prospective, observational, monocentric clinical study performed over a 2-year period (2011–2012) in a French prehospital emergency dispatching centre, the Service d'Aide Médicale Urgente (SAMU) covering 1,156,000 inhabitants. All adult patients (age?≥?18) who called for any cause were included. We created an electronic trigger ‘iatrogenic event’ implemented by the dispatching physician for each suspected case of ADR, then we completed the analyses of all the cases with a chief complain represented in more than 1 % of the triggered cases. The primary outcome variable was the occurrence of any possible ADR. We then used the French method of causal relationship assessment.

Results

The SAMU dispatched 339,915 calls during the study. In total, 1,467 ADRs were identified, representing 0.95 % (CI 95 % 0.90–1.00 %) of cases. ADRs were as serious (SADR) in 51.06 % (CI 95 % 48.45–53.67 %) of cases. The major ADR observed was haemorrhage, (42.81 % (CI 95 % 40.62–45.00 %), n?=?628) followed by allergy, hypoglycaemia, vomiting, dizziness and drowsiness. The class of drugs most frequently involved was antithrombotic (43.69 % (CI 95 % 41.45–45.93 %), n?=?641), followed by insulin (17.98 % (CI 95 %:17.06–18.90 %), n?=?264).

Conclusions

Emergency calls concerning ADRs were estimated as 9/1,000, and one out of two is serious.     

Therapeutic drug monitoring of once daily aminoglycoside dosing: comparison of two methods and investigation of the optimal blood sampling strategy

Purpose

Therapeutic drug monitoring of patients receiving once daily aminoglycoside therapy can be performed using pharmacokinetic (PK) formulas or Bayesian calculations. While these methods produced comparable results, their performance has never been checked against full PK profiles. We performed a PK study in order to compare both methods and to determine the best time-points to estimate AUC_0-24 and peak concentrations (C _max).

Methods

We obtained full PK profiles in 14 patients receiving a once daily aminoglycoside therapy. PK parameters were calculated with PKSolver using non-compartmental methods. The calculated PK parameters were then compared with parameters estimated using an algorithm based on two serum concentrations (two-point method) or the software TCIWorks (Bayesian method).

Results

For tobramycin and gentamicin, AUC_0-24 and C _max could be reliably estimated using a first serum concentration obtained at 1 h and a second one between 8 and 10 h after start of the infusion. The two-point and the Bayesian method produced similar results. For amikacin, AUC_0-24 could reliably be estimated by both methods. C _max was underestimated by 10–20 % by the two-point method and by up to 30 % with a large variation by the Bayesian method.

Conclusions

The ideal time-points for therapeutic drug monitoring of once daily administered aminoglycosides are 1 h after start of a 30-min infusion for the first time-point and 8–10 h after start of the infusion for the second time-point. Duration of the infusion and accurate registration of the time-points of blood drawing are essential for obtaining precise predictions.     

Bevacizumab-induced serious side-effects: a review of the French pharmacovigilance database

Purpose

Bevacizumab, a recombinant humanized monoclonal antibody to vascular endothelial growth factor, is widely used in association with standard chemotherapy in metastatic cancer. Well tolerated, bevacizumab is sometimes associated with serious adverse drug reactions (ADRs). The objective of this study is to describe the profile of ADRs related to bevacizumab and reported to the French Pharmacovigilance system.

Method

All serious cases of ADRs associated with bevacizumab recorded in the French Pharmacovigilance database up to November 31, 2010 were identified and analyzed, focusing on patient information, drug exposure, and characteristics of the ADRs. Categorical variables were compared using the chi-square test when appropriate.

Results

A total of 351 serious cases involving 626 ADRs were recorded in the database during the study interval. The most frequent ADRs reported involved the gastrointestinal system (21.9%). The most frequent ADRs included gastrointestinal perforation (4.8%), thromboembolic events (4.0%), pulmonary embolism (3.2%), hypertension (2.7%), gastrointestinal hemorrhage (2.7%), and cerebral hemorrhage or vascular accident (2.6%). The median duration of bevacizumab exposure was four cycles (range 1–30) when ADRs occurred. In 18 cases of death directly caused by ADRs, 50% occurred after only one cycle. In cases of disability, 40% of ADRs were neurologic: neuropathy, paralysis, and paresis.

Conclusion

To the best of our knowledge, this is the first analysis of bevacizumab safety profile using data collected in a national pharmacovigilance database. Our study confirms the frequency and seriousness of gastrointestinal, thromboembolic, and hemorrhage events with bevacizumab use and provides a picture of the bevacizumab safety profile in daily medical practice, despite intrinsic limitations.     

Underreporting in pharmacovigilance: an intervention for Italian GPs (Emilia–Romagna region)

Purpose

Underreporting is a major limitation of spontaneous reporting systems for suspected adverse drug reactions (ADRs). Several interventions to increase the ADR reporting rate have been proposed, but their efficacy remains poorly investigated.

Methods

This was a questionnaire study aimed at assessing the knowledge, attitudes, and behavior of general practitioners (GPs) regarding ADR reporting and at evaluating whether a monthly e-mail-based newsletter on drug safety could affect the rate and the quality of the ADR reports submitted by these GPs. Three local health authorities (LHAs) of the Emilia–Romagna region were chosen on the basis of their ADR reporting rate during the period preceding the study: Rimini (high), Ferrara (average), and Piacenza (low reporting rate). All GPs (n?=?737) associated with these three LHAs were recruited. The pooled number of ADR reports sent by GPs in the remaining seven LHAs of the region was used as controls. The study covered a period of 3 years and was divided into: (1) identification of the reasons leading to underreporting through a questionnaire (Phase I); (2) the intervention, i.e., sending a newsletter for a 10-month period (Phase II); (3) evaluation of the intervention outcomes during the 10 months following the period in which the newsletter had been received (Phase III).

Results

Among GPs involved, 22.8 % returned the questionnaire. Over 94 % of the respondents considered the spontaneous reporting of suspected ADRs to be part of their professional obligations, but only 6.5 % had submitted at least one report in the previous 6 months. Following the completion of Phase II, the overall number of reports coming from the LHAs subjected to the intervention rose by 49.2 % compared to 2009, while the number of reports coming from the control LHAs increased by 8.8 %. Rimini and Piacenza showed a 200 % increase in the number of ADR reports submitted by GPs, while the number of ADR reported submitted by the control group decreased by 25.5 %. In 2011, the number of overall ADRs reports from the LHAs subjected to the intervention decreased by 6.8 %; this decrease reached 50.0 % of the GPs. Control HLAs showed an overall decline of 4.3 %, while the total number of ADRs from GPs increased by 63.3 %. Ferrara was excluded from the analysis due to confounding factors.

Conclusions

The periodic e-mail update on the safety of drugs represents an effective and inexpensive way to raise the awareness of GPs on the importance of spontaneous ADR reporting. Since the outcome of the intervention seemed to disappear after the intervention was stopped, there appears to be a need to adopt a policy of regular updates and educational strategies for health professionals.     

A qualitative study to explore how patients identify and assess symptoms as adverse drug reactions

Purpose

To explore how Thai patients assess symptoms as adverse drug reactions (ADRs).

Methods

Out-patients at two hospitals in Thailand previously reporting suspected ADRs to statins were purposively selected to cover factors relevant to the accuracy of ADR reports. Semi-structured interviews explored the mechanisms participants used to work out whether their symptoms were related to their statin. All interviews were audio-recorded, transcribed and independently thematically analyzed by two researchers.

Results

One hundred interviews were suitable for analysis; 52 were male, age range was 36 to 77 years (mean?±?S.D.: 59.83?±?9.14) and most (92) were taking other medicines in addition to statins. Patient assessment of symptoms as ADRs fell into two major themes: medicine-related factors and external factors. Timing relationships were mentioned most frequently (74), followed by information received (55), seeing similar symptoms in others (7) and diagnosis through blood tests (4). Use of multiple medicines, consideration of the medicine versus diseases, symptoms occurring with more than one medicine or relieved through treatment reduced confidence in ADR attribution. Many participants proposed alternative explanations for symptoms, including old age. Lack of information and knowledge were obstacles to the assessment process.

Conclusions

Patients assessed possible ADRs most often by considering timing relationships. While they also used medicine information, Thai patients received inadequate information to help them assess their symptoms. Patients expressed uncertainty and difficulties in deciding attribution when concomitant medicines and diseases were involved. The findings could support the development of a patient-friendly systematic tool for identifying and assessing possible ADRs.     

Large scale implementation of clinical medication reviews in Dutch community pharmacies: drug-related problems and interventions

Background

Research on the benefits of clinical medication reviews (CMRs) performed by pharmacists has been conducted mostly in controlled settings and has been widely published. Less is known of the effects after large scale implementation in community pharmacies. An online CMR tool enabled the systematic registration of drug-related problems (DRPs) and implemented interventions derived from CMRs in daily practice.

Objective

To describe the effects of CMRs on pharmacy practice after large-scale implementation in the Netherlands.

Setting

268 community pharmacies. Pharmacists were trained on CMRs with a patient centred approach.

Method

Retrospective analyses of DRPs, pharmacists’ proposals and implemented interventions recorded between January 1st and September 1st 2012.

Main outcome measure

Frequencies of DRPs, intervention proposals, implemented interventions, and drugs involved.

Results

4,579 CMRs were analysed. On average 2.9 (SD 2.1) DRPs per review were identified. 4,123 (31 %) of the DRPs led to medication changes. Stopping a drug (16 %) was more frequent than starting a drug (8.1 %). Drugs related to cardiovascular risk management, diabetes and osteoporosis were most frequently involved.

Conclusion

This study is the largest analysis of pharmacists-initiated CMRs in the Netherlands to date. The findings demonstrate the potential to reduce medication-related errors through pharmacist involvements in complex pharmacotherapy and the positive impact on the quality of drug therapy through making necessary medication changes. The data also support the need for large-scale implementation of pharmacists-initiated CMRs in the presence of proper training programmes.     

Association between initial morphine intake and body weight change,acoustic startle reflex and drug seeking in rats

Rationale

Although chronic use of opiates can induce physical dependence and addiction, individual differences contributing to these symptoms are largely unknown.

Objectives

Using intravenous morphine self-administration (MSA), we investigated whether individual differences in drug intake are associated with weight change, acoustic startle reflex (ASR), pre-pulse inhibition (PPI), and drug seeking during spontaneous withdrawal.

Methods

Male Sprague-Dawley rats self-administered morphine (0.5 mg/kg/infusion) or saline for 3 weeks (4–6 h/day, 5 days/week) and drug intake and body weight were monitored daily. The ASR and the PPI (baseline, 1 day and 1 week) and drug seeking (1 week) were measured during spontaneous withdrawal.

Results

Morphine animals did not gain weight (101 %?±?0.69), while the control animals did (115 %?±?1.06) after 3 weeks of self-administration. The ASR and the PPI were not significantly different between morphine and saline animals in 1-day or 1-week withdrawal. However, individual differences in initial (first 10 min), but not total (4–6 h), morphine intake of the daily sessions were positively correlated with weight change (r?=?0.437, p?=?0.037) and drug seeking (r?=?0.424, p?=?0.035) while inversely correlated with the ASR (r?=??0.544, p?=?0.005) in 1-week withdrawal from chronic morphine.

Conclusions

A subgroup of animals that self-administered a larger amount of morphine at the beginning of the daily sessions exhibited subsequent weight gain, reduced ASR, and enhanced drug seeking in morphine withdrawal. Thus, individual differences in initial morphine intake may reveal a novel behavioral phenotype in opioid addiction.     

A nationwide prospective study on prescribing pattern of antidepressant drugs in Italian primary care

Purpose

Our purpose was to explore antidepressant drug (AD) prescribing patterns in Italian primary care.

Methods

Overall, 276 Italian general practitioners (GPs) participated in this prospective study, recruiting patients >18 years who started AD therapy during the enrolment period (January 2007 to June 2008). During visits at baseline and 3, 6, and 12 months, data about patients’ characteristics and AD treatments were collected by the GPs. Discontinuation rate among new users of AD classes [i.e., selective serotonin reuptake inhibitors (SSRI); tricyclics (TCAs); other ADs) were compared. Logistic regression analyses were performed to identify predictors of AD discontinuation.

Results

SSRIs were the most frequently prescribed ADs (N?=?1,037; 75.3 %), especially paroxetine and escitalopram. SSRIs were more likely to be prescribed because of depressive disorders (80 %), and by GPs (51.1 %) rather than psychiatrists (31.8 %). Overall, 27.5 % (N?=?378) of AD users discontinued therapy during the first year, mostly in the first 3 months (N?=?242; 17.6 %), whereas 185 (13.4 %) were lost to follow-up. SSRI users showed the highest discontinuation rate (29 %). In patients with depressive disorders, younger age, psychiatrist-based diagnosis, and treatment started by GPs were independent predictors of SSRI discontinuation.

Conclusions

In Italy, ADs—especially SSRIs—are widely prescribed by GPs because of depressive/anxiety disorders. Active monitoring of AD users in general practice might reduce the AD discontinuation rate.     

Drug-induced adverse reactions via breastfeeding: a descriptive study in the French Pharmacovigilance Database

Purpose

Most drugs are excreted in maternal milk and may therefore be ingested by children during breastfeeding. Data concerning the safety of the use of drugs by breastfeeding women are patchy, and almost nothing is known about this issue for many drugs.

Methods

The aim of this study was to describe the adverse drug reactions of drugs transmitted in breast milk on the basis of the data collected in the French Pharmacovigilance Database. All spontaneous reports of adverse drug reactions (ADRs) in breastfed infants recorded in the National Pharmacovigilance Database by the 31 French regional pharmacovigilance centres between 1984 and June 2011 were investigated.

Results

Between January 1985 and June 2011, 276 adverse drug reactions in 174 breastfed children were notified to the French Pharmacovigilance Network. The most frequently reported adverse drug reactions were neurological (28.6 %) and gastrointestinal (20.3 %). Sixty-five of the adverse drug reactions recorded were considered to be serious (37.4 %). The results of our study confirm that certain drugs were frequently implicated in serious adverse drug reactions. Two cases of ADRs (1.1 %) had a ‘certain’ causality score (I4) and 13 (7.5 %) a ‘likely’ score (I3). The suspected drugs include antiepileptic drugs, opiate analgesics and benzodiazepines. These results also demonstrate that some drugs that were thought to be anodyne or for which no data were available, such as ketoprofen and hydroxyzine, may be implicated in adverse effects. Finally, these data show that certain drugs, like pseudoephedrine, which should not be used during breastfeeding, were nevertheless implicated in several of the adverse drug reactions recorded.

Conclusion

This study shows that ADR via breastfeeding are rarely reported due to low awareness or low occurrence of ADR via breast milk. These results highlight the need for additional pharmacokinetic, clinical and epidemiological studies, given the paucity of published data. They also demonstrate the need to improve information for the general public about drugs and self-medication during breastfeeding.     

Use of the recommended drug combination for secondary prevention after a first occurrence of acute coronary syndrome in France

Purpose

The recommended pharmacotherapy for secondary prevention of acute coronary syndrome (ACS) is long-term treatment with a combination of four therapeutic classes: beta-blockers, antiplatelet agents (including aspirin), statins or other lipid-lowering agents, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. The aim of this study was to describe use and persistence of the recommended drug combination after the first occurrence of ACS in France.

Methods

This was a database cohort study of patients with first registration for ACS between 2004 and 2007 in a representative sample of the French healthcare insurance database (Echantillon Généraliste de Bénéficiaires, EGB). The drugs of interest were those recommended. Persistence was assessed for patients dispensed three or all four drug classes within 2 months following ACS. Discontinuation was defined by a gap of more than 6 weeks between two dispensations. The follow-up period was 24 months after ACS occurrence.

Results

Of 2,057 patients with incident ACS, 872 (42.4 %) had at least one dispensation of each of the four recommended drug classes, and 684 (33.3 %) had three of the four classes. Persistence to treatment at 24 months was 57.4 % (95 % CI [54.0-60.6]) for patients with four classes, and 55.5 % (95 % CI [51.6-59.1]) with three classes. Discontinuation of initial combination was higher in patients aged ?≥?65 years at ACS occurrence, those with associated ongoing chronic disease, and in those who did not suffer myocardial infarction.

Conclusions

Post-ACS secondary prevention in France is not optimal, especially in patients who did not have myocardial infarction.