Warfarin-associated bleeding events and concomitant use of potentially interacting medicines reported to the Norwegian spontaneous reporting system

AIMS

To study warfarin associated bleeding events reported to the Norwegian spontaneous reporting system and evaluate the differences in assessment of potentially interacting medicines between reporters and evaluators.

METHODS

Data on bleeding events on warfarin were retrieved from the Norwegian spontaneous reporting system database. Key measurements were time to bleeding, use of concomitant medications and the evaluation done by reporters.

RESULTS

In 289 case reports a total of 1261 medicines (median 4.0 per patient, range 1–17) was used. The evaluators (authors of this article) identified 546 medicines including warfarin (median 2.0 per patient, range 1–7) that could possibly cause bleeding alone or in combination. Reporters assessed 349 medicines (median 1.0 per patient, range 1–4) as suspect. Evaluators identified 156 pharmacokinetic and 101 pharmacodynamic interactions, compared with 19 pharmacokinetic and 56 pharmacodynamic interactions reported as suspected by the reporters. Time to bleeding was stated in 224 reports. Among the early bleeding events, the reports on warfarin without interacting medicines showed the highest INR (international normalized ratio). Heparin was used in 17/21 reported bleeding events during the first week on warfarin. Among the late bleeding events, reports with pharmacokinetic interacting medicines had the highest INR.

CONCLUSIONS

Concomitant use of potentially interacting medicines was involved in the majority of the warfarin-associated bleeding events reported to the Norwegian spontaneous reporting system. Reporters assessed mostly warfarin as the only contributor to bleeding. In particular, pharmacokinetically interacting medicines were not suspected as contributing to bleeding.     

The availability and age-appropriateness of medicines authorized for children in The Netherlands

AIM

To study the number of medicines and active chemical entities that are authorized and commercially available for children in the Netherlands and to evaluate the age-appropriateness of the available paediatric medicines.

METHODS

The availability of paediatric medicines and active chemical entities was studied with the help of a Dutch medicines database and the Summary of Product Characteristics. Medicines were categorized with respect to their route of administration, type of oral dosage form and therapeutic category. The age-appropriateness was assessed on three aspects: dose capability, suitability of the dosage form and inclusion of potentially harmful excipients.

RESULTS

Three thousand five hundred and forty-two paediatric medicines containing 703 different active chemical entities were identified. This equalled half of all the medicines and chemical entities available for human use. The percentage of paediatric medicines increased with age and varied for the route of administration from 22% (dermal) to 81% (inhalation) and for the therapeutic category from 11% (uro-genital, sex hormones) to 89% (anti-parasites). The appropriateness of the paediatric medicines with respect to their authorization status, dose capability and dosage form increased with age from 27–88%. Fifty-two percent of all oral paediatric liquid formulations contained a potentially harmful excipient.

CONCLUSION

This study confirms the limited availability of paediatric medicines for a broad range of therapeutic areas and shows that paediatric medicines may not be age-appropriate, even if authorized. While confirming the need for a legislative incentive, the results also provide baseline information for an estimation of the effect of the European Paediatric Regulation in the near future.     

Pharmacy Students' Ability to Identify Potential Drug-Drug Interactions

Objective

To evaluate the ability of third- and fourth-year pharmacy students to identify clinically significant drug-drug interactions (DDIs)

Methods

A questionnaire designed to measure DDI knowledge was disseminated to fourth-year pharmacy students in a school of pharmacy. A second questionnaire was distributed to third-year pharmacy students in 2 schools of pharmacy (schools A and B) and re-administered to students in 1 of the schools 1 year later.

Results

Class of 2005 fourth-year pharmacy students correctly categorized an average of 52% ± 13% DDI pairs on the first questionnaire. Third-year pharmacy students at schools A and B correctly categorized an average of 61% ± 18% and 66% ± 15% of DDI pairs, respectively. The average percentage of correct responses for fourth-year students from the class of 2007 was 65% (± 17%).

Conclusion

Pharmacy students'' ability to identify important DDIs is far from optimal, even after completing experiential requirements.     

Regulatory review time and post-market safety events for novel medicines approved by the EMA between 2001 and 2010: a cross-sectional study

Aims

Regulatory review time has been associated with post-market medication safety issues in the United States. Our objective was to evaluate whether regulatory review time and near deadline approval are associated with post-market safety events (PMSEs) for novel medicines approved by the European Medicines Agency (EMA).

Methods

We performed a cross-sectional analysis of all novel medicines approved by the EMA through the centralized authorization procedure between 2001 and 2010. PMSEs were defined as withdrawals and communications identified through Dear Healthcare Professional Communications (DHPCs). Regulatory review time was defined as the time that elapsed between the start of the assessment procedure and approval. Near regulatory deadline approval was defined as approval within the 30 days before the EMA’s 210 day regulatory deadline.

Results

Among 161 eligible medicines, PMSEs were identified for 49 (30.4%), 44 of which were DHPCs, five of which were withdrawals. Median regulatory review time was 337 days (IQR 276–406) and was not associated with PMSEs (P = 0.57). However, when categorized by regulatory review speed tertile, there were differences in risk of PMSEs, with higher rates among medicines in the middle tertile (25 of 55, 45.4%; P = 0.01). Finally, 26 medicines were approved near the 210 day regulatory deadline, but were not more likely to have PMSEs (38.5% vs. 28.7%; P = 0.32).

Conclusions

Neither faster EMA regulatory review speed nor approval near regulatory deadlines was associated with greater likelihood of PMSEs among recently approved novel medicines.     

The evolution of Reference Drug Lists and Clinical Practice Guidelines in the public health system of a middle-income country

Aims

The aims were to analyze the dynamics of the medicines formulary in a middle-income country and to analyze the concordance of the included medicines with the national Clinical Practices Guidelines (CPG).

Methods

Medicines and their indications of use included in the Mexican Reference Drug List (Mex-RDL) from 1996 to 2013 were analyzed. The top 10 indications with the highest number of medicines in 2013 were analyzed retrospectively until 1996 in order to identify the increase in the number of medicines to treat each one, as well as the progressive specificity of the indication according to the International statistical Classification of Diseases (ICD-10). The concordance between the CPG and medicines approved for the top 10 indications was studied.

Results

The number of medicines included in the Mex-RDL kept constantly growing from 454 drugs in 1996 to 811 in 2013. Up to 26.3% of these medicines were approved to treat only 10 indications (1.5% of all possible indications of use). Many of these new medicines had been approved for more and more specific indications, while the oldest ones had been approved for general indications. Up to 27.6% of the medicines approved for these top 10 indications do not appear in the updated recommendations of the specific CPG for those indications.

Conclusions

During the last 18 years, the new medicines and indications included in the Mex-RDL were redundant and concentrated into few similar clinical conditions. This is a factor that promotes an irrational use of these medicines and, thus, unnecessarily raises the price of health care, undermines the quality of the health system and probably increases the uncertainty of treatments.     

Factors influencing community pharmacist decision to dispense generic or branded medicines; Eastern Province,Alahsa, Saudi Arabia

Background

Rising costs of medicines have increased the interest of policy makers in generic medicines. However, consumers’ and health care providers’ perception and attitude towards generic medicine act as a main barrier to the promotion of generic medicines.

Objective

To explore the factors community pharmacists consider while dispensing branded or generic medicines to consumers.

Method

A qualitative study was planned; twenty community pharmacists (ten hospital affiliated pharmacies and ten non-hospital affiliated pharmacies) were approached using a convenient sampling method. Interviews were recorded and later were coded into themes.

Result

Overall, it is seen that generic medicine stock was available for antibiotics, pain killers, cough syrups, antihistaminics and antacids. Pharmacists working in hospital affiliated pharmacies were more concerned about the quality of drug before dispensing it to the consumer and they believe that what is prescribed is best for them and substitution or switching is unnecessary while for pharmacists in the non-hospital affiliated pharmacies, appearance of the client was found to be the main factor influencing them to dispense generic (low cost) or branded (expensive) medicines.

Conclusion

Physical appearance of the consumer is revealed to be one of the main factors affecting the pharmacist decision to dispense generic or branded medicine. Pharmacists practising in hospital affiliated pharmacies were found to be influenced by physicians’ recommendation, and prefer to dispense good quality medicines.     

Interpreting adverse drug reaction (ADR) reports as hospital patient safety incidents

AIM

In the UK, the National Patient Safety Agency (NPSA) includes adverse drug reactions as a reporting category, while the MHRA Yellow Card Scheme also collects data regarding adverse drug reactions (ADRs). In this study, we aimed to assess ADRs using NPSA criteria and discuss the resulting implications.

METHODS

ADRs identified in a 6-month prospective study of 3695 inpatient episodes were assessed according to their impact on the patient and on the organization, using tools developed by the NPSA.

RESULTS

Seven hundred and thirty-three (100%) ADRs were assessed. In terms of impact on the patient, 537 (73.3%) were categorized as ‘low’ (minor treatment), 181 (24.7%) as ‘moderate’ (moderate increase in treatment, no permanent harm), 14 (1.91%) as ‘severe’ (permanent harm) and 1 (0.14%) was categorized as ‘catastrophic’ (direct cause of death). In terms of impact on the organization, none was categorized as ‘no harm/ no risk’, 508 (69.3%) as ‘insignificant’, 188 (25.6%) as ‘minor’, 25 (3.4%) as ‘moderate’, 12 (1.6%) as ‘major’ and none was classed as ‘catastrophic’. Less than 2% of ADRs would be eligible for detailed analysis according to the NPSA guidance. The ADRs that cause incidents of greater significance relate to bleeding, renal impairment and Clostridium difficile infection.

CONCLUSIONS

Classification of ADRs according to NPSA guidance offers limited additional value over and above that offered by the Yellow Card System. A consistent message needs to be sent to prospective reporters of ADRs; the availability of more than one system is likely to confuse reporters and does not aid patient safety.     

A categorization scheme for assessing pharmacy students' levels of reflection during internships

Objective

To test the reliability, feasibility, and responsiveness of a categorization scheme for assessing pharmacy students'' levels of reflection during internships.

Methods

Pharmacy interns at Uppsala University were asked to write a reflective essay about patient counseling at the start and end of their internships. A modified version of Kember''s categorization scheme for assessing the level of reflection was used to evaluate these essays.

Results

Based on their essay scores, the students'' levels of reflection increased during the internship course (p < 0.001) The mean time for categorization was 3 minutes per essay. The interrater reliability of the 182 essays was κ = 0.63.

Conclusions

The evaluation of the categorization scheme showed that it has good interrater reliability, feasibility, and responsiveness. This scheme might be useful in pharmacy practice educational settings, but needs further validation.     

Access to orphan drugs despite poor quality of clinical evidence

AIM

We analysed the Belgian reimbursement decisions of orphan drugs as compared with those of innovative drugs for more common but equally severe diseases, with special emphasis on the quality of clinical evidence.

METHODS

Using the National Health Insurance Agency administrative database, we evaluated all submitted orphan drug files between 2002 and 2007. A quality analysis of the clinical evidence in the orphan reimbursement files was performed. The evaluation reports of the French ‘Haute Autorité de Santé’, including the five-point scale parameter ‘Service Médical Rendu (SMR), were examined to compare disease severity. Chi-squared tests (at P < 0.05 significance level) were used to compare the outcome of the reimbursement decisions between orphan and non-orphan innovative medicines.

RESULTS

Twenty-five files of orphan drugs and 117 files of non-orphan drugs were evaluated. Twenty-two of 25 (88%) submissions of orphan drugs were granted reimbursement as opposed to 74 of the 117 (63%) non-orphan innovative medicines (P = 0.02). Only 52% of the 25 orphan drug files included a randomized controlled trial as opposed to 84% in a random control sample of 25 non-orphan innovative submissions (P < 0.01). The duration of drug exposure was in most cases far too short in relation to the natural history of the disease.

CONCLUSIONS

Orphan drug designation predicts reimbursement despite poor quality of clinical evidence. The evidence gap at market authorization should be reduced by post-marketing programmes, in which the centralized regulatory and the local reimbursement authorities collaborate in an efficient way across the European Union member states.     

A systematic review of hospitalization resulting from medicine-related problems in adult patients

Aims

Medicine-related problems (MRPs) represent a major issue leading to hospitalization, especially in adult and elderly patients. The aims of this review are to investigate the prevalence, causes and major risk factors for MRPs leading to hospitalization in adult patients and to identify the main medicine classes involved.

Methods

Studies were identified through electronic searches of Medline, Embase, Scopus and International Pharmaceutical Abstracts between January 2000 and May 2013. A systematic review was conducted of both retrospective and prospective studies. Studies included were those involving hospitalization resulting from MRPs in adults (≥18 years old), whereas studies excluded were those investigating drug misuse and abuse and studies investigating MRPs in hospitalized patients. Data analysis was performed using SPSS version 20.

Results

Forty-five studies were identified, including 21 that investigated hospitalization resulting from adverse drug reactions, six studies that investigated hospitalization due to adverse drug events and 18 studies that investigated hospitalization due to MRPs. The median prevalence rates of hospitalization resulting from adverse drug reactions, adverse drug events and MRPs were 7% (interquartile range, 2.4–14.9%), 4.6% (interquartile range, 2.85–16.6%) and 12.1% (interquartile range, 6.43–22.2%), respectively. The major causes contributing to MRPs were adverse drug reactions and noncompliance. In addition, the major risk factors associated with MRPs were old age, polypharmacy and comorbidities. Moreover, the main classes of medicines implicated were medicines used to treat cardiovascular diseases and diabetes.

Conclusions

Hospitalization due to MRPs had a high prevalence, in the range of 4.6–12.1%. Most MRPs encountered were prevalent among adult patients taking medicines for cardiovascular diseases and diabetes.     

Monitoring of adverse drug reactions associated with antihypertensive medicines at a university teaching hospital in New Delhi

Aim

To monitor the adverse drug reactions (ADRs) caused by antihypertensive medicines prescribed in a university teaching hospital.

Methods

The present work was an open, non-comparative, observational study conducted on hypertensive patients attending the Medicine OPD of Majeedia Hospital, Jamia Hamdard, New Delhi, India by conducting patient interviews and recording the data on ADR monitoring form as recommended by Central Drugs Standard Control Organization (CDSCO), Government of India.

Results

A total of 21 adverse drug reactions were observed in 192 hypertensive patients. Incidence of adverse drug reactions was found to be higher in patients more than 40 years in age, and females experienced more ADRs (n = 14, 7.29%) than males, 7 (3.64%). Combination therapy was associated with more number of adverse drug reactions (66.7%) as against monotherapy (33.3%). Calcium channel blockers were found to be the most frequently associated drugs with adverse drug reactions (n = 7), followed by diuretics (n = 5), and β-blockers (n = 4). Among individual drugs, amlodipine was found to be the commonest drug associated with adverse drug reactions (n = 7), followed by torasemide (n = 3). Adverse drug reactions associated with central nervous system were found to be the most frequent (42.8%) followed by musculo-skeletal complaints (23.8%) and gastro-intestinal disorders (14.3%).

Conclusions

The present pharmacovigilance study represents the adverse drug reaction profile of the antihypertensive medicines prescribed in our university teaching hospital. The above findings would be useful for physicians in rational prescribing. Calcium channel blockers were found to be the most frequently associated drugs with adverse drug reactions.     

Prevalence of potentially hazardous drug interactions amongst Australian veterans

BACKGROUND

Up to 21% of adverse drug event-related hospital admissions are due to drug interactions. Clinical significance of drug interactions varies, and drug interactions defined ‘potentially hazardous’ are more likely to contribute to morbidity and mortality.

AIM

The aim of this study was to assess the prevalence of potentially hazardous drug interactions in an elderly Australian veteran population.

METHODS

This study assessed the prevalence of potentially hazardous drug interactions, where hazardous was defined in three or more international drug interaction references, using Repatriation Pharmaceutical Benefits Scheme pharmacy claims data. Analysis was limited to patients who received regular concurrent dispensings of potentially hazardous interacting medicines.

RESULTS

Of the 287 074 subjects included in the study, 1.5% were dispensed potentially hazardous interacting drug pairs. For patients dispensed cyclosporin, concomitant use of a statin was common (47%); as was statin use with those dispensed itraconazole (31%). Of those dispensed methotrexate, 24% also received a non-steroidal anti-inflammatory drug; of those on lithium, 18% also received an ACE inhibitor or angiotensin 2 receptor blocker; of those on warfarin, 7.2% and 5.9% were co-dispensed an non-steroidal anti-inflammatory drugs or antiplatelets respectively; for those on verapamil, 5.3% were co-dispensed a beta-blocker, while for those on amiodarone 6.2% were co-dispensed digoxin.

CONCLUSIONS

Overall prevalence of potentially serious drug interactions appears to be low in the Australian veteran population. However, patients taking cyclosporine, itraconazole, methotrexate, lithium, warfarin, verapamil and amiodarone appear to be most at risk and their medicine use should be regularly reviewed to prevent potentially hazardous drug interactions.     

Prospective observational study of adverse drug reactions to diclofenac in children

AIM

The aim of this study was to investigate the type of common (occurring in >1% of patients) adverse reactions caused by diclofenac when given to children for acute pain.

METHODS

A prospective observational study was undertaken on paediatric surgical patents aged ≤12 years at Great Ormond Street and University College London Hospitals. All adverse events were recorded, and causality assessment used to judge the likelihood of them being due to diclofenac. Prospective recruitment meant not all patients were prescribed diclofenac, allowing an analysis of utilization. Causality of all serious adverse events was reviewed by an expert panel.

RESULTS

Children prescribed diclofenac were significantly older, and stayed in hospital for shorter periods than those who were not. Diclofenac was not avoided in asthmatic patients. Data on 380 children showed they suffer similar types of nonserious adverse reactions to adults. The incidence (95% confidence interval) of rash was 0.8% (0.016, 2.3); minor central nervous system disturbance 0.5% (0.06, 1.9); rectal irritation with suppositories 0.3% (0.009, 1.9); and diarrhoea 0.3% (0.007, 1.5). No serious adverse event was judged to be caused by diclofenac, meaning the incidence of serious adverse reactions to diclofenac in children is <0.8%.

CONCLUSION

Children given diclofenac for acute pain appeared to suffer similar types of adverse reactions to adults; the incidence of serious adverse reaction is <0.8%.     

A computerized system for detecting signals due to drug–drug interactions in spontaneous reporting systems

AIMS

In spontaneous reporting systems (SRS), there is a growing need for the automated detection of adverse drug reactions (ADRs) resulting from drug–drug interactions. In addition, special attention is also needed for systems facilitating automated data preprocessing. In our study, we set up a computerized system to signal possible drug–drug interactions by which data acquisition and signal detection could be carried out automatically and the process of data preprocessing could also be facilitated.

METHODS

This system was developed with Microsoft Visual Basic 6.0 and Microsoft Access was used as the database. Crude ADR reports submitted to Shanghai SRS from January 2007 to December 2008 were included in this study. The logistic regression method, the Ω shrinkage measure method, an additive model and a multiplicative model were used for automatic detection of drug–drug interactions where two drugs were used concomitantly.

RESULTS

A total of 33 897 crude ADR reports were acquired from the SRS automatically. The 10 drug combinations most frequently reported were found and the 10 most suspicious drug–drug ADR combinations for each method were detected automatically after the performance of the system.

CONCLUSIONS

Since the detection of drug–drug interaction depends upon the skills and memory of the professionals involved, is time consuming and the number of reports is increasing, this system might be a promising tool for the automated detection of possible drug–drug interactions in SRS.     

An investigation into the effect of advice from the Scottish Medicines Consortium on the use of medicines in Scotland's Health Service

AIMS

The aims of the study were to determine the effect of advice from the Scottish Medicines Consortium (SMC) on the use of medicines within Scotland''s National Health Service (NHS) and generate hypotheses that may explain differences in the impact of advice on the use of individual medicines.

METHODS

A retrospective analysis of medicine advice issued between January 2002 and December 2005 was performed. The inclusion criterion was medicines with a ‘not recommended for use’ decision (NRD) from the SMC (57 out of 207 medicines submitted). The exclusion criteria were medicines used predominately in secondary care and medicines with multiple indications. In total, 20 medicines fulfilled these criteria. The volume of prescribing was measured by each medicine''s gross ingredient cost to the prescribing budget.

RESULTS

Before the SMC published advice there was use, though limited, of all 20 medicines. After an NRD, the pattern of use was variable, with the use of some medicines stabilizing or declining but others increasing. We identified factors to help explain unexpected use in some cases. These included delays between medicine launch and initial SMC advice, the publication of conflicting advice from different national bodies and failure to engage with relevant clinical experts early in the medicine review process.

CONCLUSIONS

This study demonstrates the complex relationship between advice following health technology assessment and change in clinical practice. When this study was done there were significant limitations in the collection of prescribing data within the NHS, which recent changes promise to improve.     

Adverse drug reactions in adult medical inpatients in a South African hospital serving a community with a high HIV/AIDS prevalence: prospective observational study

Aims

To describe the frequency, nature and preventability of community-acquired and hospital-acquired adverse drug reactions (ADRs) in a South African hospital serving a community with a high prevalence of human immunodeficiency virus (HIV)/ acquired immunodeficiency syndrome.

Methods

A 3-month prospective observational study of 665 adults admitted to two medical wards.

Results

Forty-one (6.3%) patients were admitted as a result of an ADR and 41 (6.3%) developed an ADR in hospital. Many of the ADRs (46.2%) were considered preventable, although less likely to be preventable in HIV-infected patients than in those with negative or unknown HIV status (community-acquired ADRs 2/24 vs. 35/42; P < 0.0001; hospital-acquired ADRs 3/25 vs. 14/26; P = 0.003). Patients admitted with ADRs were older than patients not admitted with an ADR (median 53 vs. 42 years, P = 0.003), but 60% of community-acquired ADRs at hospital admission were in patients <60 years old. Among patients <60 years old, those HIV infected were more likely to be admitted with an ADR [odds ratio (OR) 2.32, 95% confidence interval (CI) 1.17, 4.61; P = 0.017]. Among HIV-infected patients, those receiving antiretroviral therapy (ART) were more likely to be admitted with an ADR than those not receiving ART (OR 10.34, 95% CI 4.50, 23.77; P < 0.0001). No ART-related ADRs were fatal. Antibiotics and drugs used for opportunistic infections were implicated in two-thirds of hospital-acquired ADRs.

Conclusions

ADRs are an important, often preventable cause of hospitalizations and inpatient morbidity in South Africa, particularly among the elderly and HIV-infected. Although ART-related injury contributed to hospital admissions, many HIV-related admissions were among patients not receiving ART, and many ADRs were associated with medicines used for managing opportunistic infections.

What is already known about this subject

• Studies conducted primarily in developed countries have shown that adverse drug reactions (ADRs) are a significant cause of hospital admission, prolong hospital stay and consequently increase the cost of disease management in patients.
• Cardiovascular medicines, hypoglycaemic agents, nonsteroidal anti-inflammatory drugs and antibiotics are the most frequently implicated medicines in these studies.
• A large proportion of these ADRs have been shown to be preventable through improved drug prescribing, administration and monitoring for adverse effects.

What this paper adds

• This is the first Sub-Saharan African study in the HIV/AIDS era that describes the contribution of ADRs to patient morbidity, hospitalisation and mortality.
• Cardiovascular medicines and antiretroviral therapy contributed the most to community-acquired ADRs at the time of hospital admission while medicines used for opportunistic infections (such as antifungals, antibiotics and antituberculosis medicines were most frequently implicated in hospital acquired ADRs.
• ADRs in HIV-infected patients were less likely to be preventable.