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Adverse drug reactions

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This article has a correction. Please see:

• Adverse drug reactions - November 12, 2018
• Robin E Ferner , honorary professor of clinical pharmacology 1 ,
• Patricia McGettigan , reader in clinical pharmacology and medical education 2
• 1 West Midlands Centre for Adverse Drug Reactions, City Hospital, Birmingham B18 7QH, UK
• 2 William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, UK
• Correspondence to: R E Ferner r.e.ferner{at}bham.ac.uk

What you need to know

Prescribers need to balance the possibility of causing harm against the probability of benefit

Some drugs cause characteristic adverse reactions, whereas others cause non-specific or bizarre effects

Some adverse drug reactions occur within minutes of administration, whereas others can present years after treatment

The dose of the drug, time since starting treatment, and potential susceptibility of the patient can help determine if adverse drug reactions enter the differential diagnosis

Report suspected serious or unusual adverse drug reactions to the national medicines regulator; you don’t have to be certain in order to report

No medicine is entirely safe, so the therapeutic benefit needs to be balanced against the risk of an adverse drug reaction. The pharmacovigilance environment has changed in the past two decades, with biological therapies, complex multidrug regimens, genetic testing, “big data,” and new regulation for drug safety. 1 In this clinical update we describe some principles that guide prevention, recognition, and response to adverse drug reactions.

Sources and selection criteria

We searched Medline for “exp drug-related side effects and adverse reactions/”, which gave 103 893 hits. We limited the search to 2008 onwards; to “exp drug-related side effects and adverse reactions/classification, diagnosis, diagnostic imaging, etiology, genetics, prevention, and control”; and to core medical journals, which gave 1236 titles to look through. We also used the UK Medicines and Healthcare products Regulatory Agency’s Drug Safety Update , the US Food and Drug Administration’s MedWatch alerts, the journal Reactions Weekly , Meyler’s Side Effects of Drugs Annual , and our own reference collections to identify relevant articles.

What is an adverse drug reaction?

Medicines have unintended side effects, and if any of these is harmful, the patient has an adverse drug reaction. 2 The European Medicines Agency (EMA) defines an adverse drug reaction as “a response to a medicinal product which is noxious and unintended.” 3 This definition now extends beyond …

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• Research article
• Open access
• Published: 06 January 2020

Adverse drug reactions in primary care: a scoping review

• H. Khalil   ORCID: orcid.org/0000-0002-3302-2009 1 , 2 &
• C. Huang 2  

BMC Health Services Research volume  20 , Article number:  5 ( 2020 ) Cite this article

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Medication-related adverse events, or adverse drug reactions (ADRs) are harmful events caused by medication. ADRs could have profound effects on the patients’ quality of life, as well as creating an increased burden on the healthcare system. ADRs are one of the rising causes of morbidity and mortality internationally, and will continue to be a significant public health issue with the increased complexity in medication, to treat various diseases in an aging society. This scoping review aims to provide a detailed map of the most common adverse drug reactions experienced in primary healthcare setting, the drug classes that are most commonly associated with different levels/types of adverse drug reactions, causes of ADRs, their prevalence and consequences of experiencing ADRs.

We systematically reviewed electronic databases Ovid MEDLINE, Embase, CINAHL Plus, Cochrane Central Register of Controlled Trials, PsycINFO and Scopus. In addition, the National Patient Safety Foundation Bibliography and the Agency for Health Care Research and Quality and Patient Safety Net Bibliography were searched. Studies published from 1990 onwards until December 7, 2018 were included as the incidence of reporting drug reactions were not prevalent before 1990. We only include studies published in English.

The final search yielded a total of 19 citations for inclusion published over a 15-year period that primarily focused on investigating the different types of adverse drug reactions in primary healthcare. The most causes of adverse events were related to drug related and allergies. Idiosyncratic adverse reactions were not very commonly reported. The most common adverse drug reactions reported in the studies included in this review were those that are associated with the central nervous system, gastrointestinal system and cardiovascular system. Several classes of medications were reported to be associated with adverse events.

This scoping review identified that the most causes of ADRs were drug related and due to allergies. Idiosyncratic adverse reactions were not very commonly reported in the literature. This is mainly because it is hard to predict and these reactions are not associated with drug doses or routes of administration. The most common ADRs reported in the studies included in this review were those that are associated with the central nervous system, gastrointestinal system and cardiovascular system. Several classes of medications were reported to be associated with ADRs.

Peer Review reports

Medication-related adverse events, or adverse drug reactions (ADRs) are harmful events caused by medication. Adverse drug reactions (ADRs) are defined by the World Health Organization (WHO) as “a response to a medication that is noxious and unintended used in man to treat” [ 1 ]. ADRs could be a result of a preventable medication error, resulting in a side-effect as a result of medication administration, or an unforeseen error such as an allergic reaction [ 2 , 3 ].

ADRs could have profound effects on the patients’ quality of life, as well as creating an increased burden on the healthcare system. ADRs are one of the rising causes of morbidity and mortality internationally, and will continue to be a significant public health issue with the increased complexity in medication, to treat various diseases in an aging society. A recent study showed that ADRs accounted for approximately 3.5% of hospital admission [ 4 , 5 ]. Furthermore, ADRs were the cause of ~ 197,000 deaths in Europe annually [ 1 ].

The causes and nature of adverse drug events are often complex and multifactorial. The types of adverse reactions are classified into the following categories: dose/drug related, allergic or idiosyncratic reactions. Dose-related and drug related adverse drug reactions are usually related to the dose of the medication and are usually predictable but sometimes unavoidable [ 6 , 7 , 8 , 9 ]. It is highly dependent on the patient’s sensitivity to the drug and combinations of medication used. It generally does not lead to severe ADR but is relatively common. An allergic drug reaction is when the patients develops an inappropriate reaction to the medication, which mostly could be avoided with a skin test prior to or through effective consultation and communication between primary care facilities and patients. An idiosyncratic adverse drug reaction is a type that is not widely understood and its severity is often quite unpredictable. This affects the fewer people and the reason for the adverse reaction may be genetically predetermined [ 9 ].

ADRs have become a significant problem in patients who are on multiple medications such as the elderly. A study has reported that as high as 75% of all aged care residents had medication discrepancies after the transition from hospital to primary care setting [ 6 ].

Most of the adverse medication events are associated with prescription errors in general practice [ 7 ]. Medication errors in general practice had a prevalence rate of 5% in England according to a large retrospective case review study [ 8 ]. With the incorporation of technology in healthcare system, the implementation of computerized prescribing systems also has a range of medication error rates that may lead to mild or severe adverse drug events [ 10 , 11 ].

Another cause of adverse events is the off -label use of uncommon medications in children and patients. Off label prescribing is the process of prescribing of medications to non-approved indications by organizations such the Therapeutic Goods Administration of Australia or the Food and Drug Administration agency in the United States. Medication error or dosage error can occur in these circumstances due to the lack of evidence to support their use in non-approved conditions [ 12 , 13 , 14 ].

To date, there is limited data and evidence on the epidemiology of ADRs. After a preliminary search of literature, (i.e. The Cochrane Library, JBI Database of Systematic Reviews and Implementation Reports, Ovid MEDLINE ) there are no systematic reviews, meta-analysis or scoping reviews that provide a comprehensive overview of the types of adverse events in primary care. Most of the studies available were relatively small, and often confined to individual units. Alternately, most of the current reviews focused on the occurrence of medication errors, specific interventions to reduce medication errors and medication management [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. While there are several reviews on medication programs focusing on the effect of medication errors and effectiveness of interventions, they do not describe the types of adverse events [ 21 , 22 ]. The review by Khalil et al., 2017 examined the effectiveness of various types of medication safety interventions to reduce mortality, emergency visits and hospital admissions. The authors found little evidence to support the benefits of organizational, professional and structural interventions addressing medication errors due to the heterogeneity of the included studies [ 21 ]. .Assiri et al., 2018 examined the prevalence of medications errors and adverse events associated with errors and risk factors associated with them. They found inconsistencies in the definitions of medications errors, methodologies used to detect adverse events and different outcome measures.

Therefore, this review sought to address the type of ADRs, the major drug classes associated with the reactions, causes of ADRs, their prevalence as well as consequences of experiencing ADRs to reduce the risk of adverse drug events in primary care. This will enable clinicians to be more informed of the adverse events and which class of drugs are associated with them. Targeted educational interventions addressing these gaps have the potential to improve patient safety. This scoping review will also be useful for researchers and healthcare providers as well as policy makers in the development of interventions to reduce adverse drug reactions in today’s primary care.

Inclusion criteria

Participants.

This review considered participants of any age and any condition treated and/or managed from any primary care services.

The concept of interest for the scoping review was the type of adverse drug reactions experienced by patients and the classes of medications associated with these adverse drug events.

The context of the review was the primary care setting. These include; primary health care organizations, general practitioner clinics, pharmacies, outpatient clinics and any other clinics that do not classify patients as inpatients. We only excluded hospital patients.

Types of studies

This scoping review considered quantitative study designs including experimental, descriptive and observational studies reporting any quantitative data that can be included in the review. Qualitative studies were not considered in this review as the data extracted were not eligible for inclusion as mentioned in the scoping protocol [ 23 ]. Due to time constraints, only data published in English were considered for the review. No gray literature was searched as we are interested in studies that are published in peer reviewed journals based on scientific methods that use evidence to develop conclusions.

Search strategy

The search strategy aimed to identify studies published from 1990 to 2018. A three-step search strategy was utilized in this review. An initial limited search of Ovid MEDLINE, JBI Database of Systematic Reviews and Implementation Reports and Cochrane Central Register of Controlled Trials was undertaken followed by analysis of the text words contained in the title and abstract and of the index terms used to describe the article. A second search using all identified keywords and index terms was undertaken across all included databases. The following databases were searched on December 7, 2018: Ovid MEDLINE, Embase, CINAHL Plus, Cochrane Central Register of Controlled Trials, PsycINFO and Scopus . The search strategy of all the databases followed the same strategy shown in Appendix I. In addition, the National Patient Safety Foundation Bibliography and the Agency for Health Care Research and Quality and Patient Safety Net Bibliography were searched. Studies published from 1990 onwards until December 7, 2018 were included as the incidence of reporting drug reactions were not prevalent before 1990. The reference list of all identified reports and articles were searched for additional studies. The following keywords were used: patient safety, adverse events, harmful incidents, primary care, aged care, ambulatory care, general practice and home healthcare. These were used along with a comprehensive list of variations of these key terms.

Data extraction

Relevant data were extracted from the included studies to address the review question using the methodology outlined by Peters et al. [ 24 , 25 ] The data extracted followed the template developed in the protocol [ 23 ]. .Please refer to the search strategy published in the protocol [ 23 ].

The data extracted included the following: author(s), year of publication, origin/country of origin (where the study was published or conducted), aims/purpose, study population, methodology/methods, context, types of adverse drug reactions experienced by patients and the classes of medications associated with them as shown in Tables  1 and 2 .

The database search yielded a total of 4462 citations after duplicates were removed. The titles and abstracts for these 4462 citations were screened and 4426 had irrelevant titles and abstracts and therefore excluded. The remaining 36 papers were selected for further assessment of the full-text assessment. Of these, 17 were excluded due to having: an irrelevant setting that is not primary care, irrelevant interventions that were only addressing medication errors instead of reporting on drug related adverse events and describing only qualitative aspects of medication safety. The final search yielded a total of 19 citations for inclusion in this review, with two abstracts and 17 full papers [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. A protocol detailing the methodology for the current review was followed [ 23 ]. A PRISMA flowchart showing the study selection at each stage is detailed in Fig. 1 . Tables 1 and 2 detail the study characteristics and the outcomes.

PRISMA flowchart of study selection and inclusion process

Studies characteristics

Authors and year of publication/country of origin.

The included studies were published between 2003 and 2018. Most of the studies included were undertaken in developed countries such as USA, Germany, Sweden. Details of the studies country of origin are presented in Table  1 .

Study population

The population size for the included studies ranged from 2842 to 33,891,339 patients from across databases searched for this study. The types of participants included elderly residents, cancer patients, epileptic patients, multidrug-resistant TB patients, pediatrics and general adult patients.

The types of studies included mainly observational cohort studies, retrospective case reviews and health record reviews.

All studies were conducted in primary care settings. Eleven were set in primary care centers, 12 were set in outpatient clinics, two were set in general practice clinics, one was set in a residential nursing facility, and one was set in home care.

Type of adverse drug reactions (context)

The types of ADRs are categorized into three groups: drug related, allergic reaction and idiosyncratic reactions. The majority of studies have addressed drug related adverse reactions followed by allergic reactions. Only four studies addressed idiosyncratic reactions [ 29 , 33 , 38 , 42 ]. ADRs were classified either by systems (Central nervous systems, cardiovascular events, etc. …) or by adverse reactions (ie. seizures, hearing loss, etc.). The frequency of ADRs reported were not included in all the studies. The most frequent ADR was related fatigue (55%) followed by dizziness (18.4%) and tremor (15.8%) [ 40 ]. The body system that was associated with the most ADRs reported was the central nervous system followed by gastrointestinal and cardiovascular systems [ 26 , 28 ].

Classes associated with ADRs (context)

A total of nine studies out of the 19 included studies addressed specific classes of medications such as; anti-tuberculosis drugs [ 29 ], anti-epileptics [ 31 , 40 ], antipsychotics, antidepressants and mood stabilisers [ 32 ], antibiotics [ 33 , 39 ], insulin and oral diabetic medications [ 35 ], biologicals [ 37 ], and anticholinergic drugs including dementia medications [ 44 ]. The remainder of the studies covered other classes of medications such as beta blockers, antiplatelets, analgesics, benzodiazepines, musculoskeletal drugs, stimulants, lipid modifying agents, selective serotonin reuptake inhibitors and skin preparations. The classes of drugs that were associated with the highest ADRs reported in the included studies were drugs used for the cardiovascular system (beta-adrenergic blocking agents, diuretics, ACE inhibitors) warfarin, antipsychotic agents and opioids analgesics [ 26 , 27 , 28 ].

ADRs incidences

There was no standardized reporting of the prevalence data in the included studies. Prevalence data varied from simple calculations of the frequency of ADR in the study populations to an estimated number of adverse events per 100 patients, 100 residents’ month, number of reactions per 1000 consultations [26. 28, 42]. Overall, the incidence of ADR reported in the studies ranged between 6% and up to 80% in some cases [ 29 , 44 ].

Causes of ADRs reported

The causes of ADR varied between the studies. However, the majority of the authors cited patient factors as the cause of ADRs such as advanced age, lack of patients’ education and patients’ comorbidities [ 4 , 26 , 28 , 29 , 30 , 31 , 34 , 35 , 36 , 37 , 38 , 40 , 42 ].

Some studies mentioned drug related causes such as prescribers’ errors, inconsistent consultation notes, incomplete physical examination, inappropriate follow up and monitoring errors as causes of ADRs [ 26 , 27 , 35 , 36 , 38 , 41 , 44 ].

Drug specific causes such as drug administration, dispensing errors, drug interactions and look alike medications were also mentioned by three studies [ 27 , 30 , 35 , 43 ].Allergic reactions were cited as the cause of ADRs in one study by Shehab et al. [ 39 ] Iatrogenic causes was also cited by one study amongst other causes [ 42 ]. Two studies did not specify any causes for the reported ADR [ 32 , 33 ].

Consequences of ADRs

The consequences of the ADRs reported in the included studies ranged from medication cessation to death in some cases. Hospitalizations were reported in seven studies [ 28 , 34 , 36 , 38 , 39 , 42 , 43 ]. Death was reported in six studies [ 26 , 27 , 34 , 35 , 37 , 43 ].

This scoping review identified that the most causes of ADRs were drug related and due to allergies. Idiosyncratic adverse reactions were not very commonly reported in the literature. This is mainly because it is hard to predict and these reactions are not associated with drug doses or routes of administration [ 45 ]. The most common ADRs reported in the studies included in this review were those that are associated with the central nervous system, gastrointestinal system and cardiovascular system. Several classes of medications were reported to be associated with ADRs.

The prevalence of ADRs varied significantly between the studies, reasons for this variation include study designs, characteristics of participants and setting of the study and study length. These results are consistent with a similar review of observational studies [ 46 ]. Studies addressing children are also underrepresented in this review. We only found one study that met our inclusion criteria where the authors investigated the rates and types of ADRs in a pediatric ambulatory setting [ 30 ].

The causes of ADRs in this review were found to be multifactorial. These included: patient related factors such as co-morbidities, drug interactions, older age, provider characteristics such as monitoring errors, administration errors, incorrect drug selection and drug specific such as allergies or idiosyncratic reactions. Therefore, it is reasonable to predict their occurrences in primary care settings. This is in line with other findings from similar reviews [ 47 ].

Hospitalization and mortality were reported in less than half the studies included. Hospitalizations due to ADRs ranged between 6 to 14% which is comparable to other systematic reviews [ 48 , 49 , 50 ]. Mortality rates ranged between 0.4 to 2.7% in the studies included in this review. Under reporting of adverse events have been cited in the literature [ 51 ]. This may have been due to several factors including barriers to reporting within each organization, clinicians’ reluctance to report to avoid punishment or blame [ 52 ]. Other barriers could be lack of knowledge about adverse events and whether they are related to the actual condition or the medications [ 51 , 52 ]. Complacency and other personal factors related to clinicians such as fear of being ridiculed of reporting merely suspected ADRs and fatigue were also reported [ 53 ].

Health care professionals are encouraged to be aware of the most commonly classes of drugs associated with ADRs such as cardiovascular drugs, antipsychotics and opioids as found in these studies. Targeted educational interventions to address underreporting of ADRs is essential to improve public health safety. There are many reasons for underreporting ADRs especially in children is paramount to improve patient safety. Our review highlighted the limited number of studies reporting ADRs in children.

Personal medicine is the approach where health professionals tailor specific treatments for individual patients to optimize outcome and reducing ADRs. As today’s society moves towards personalized medicine, by understanding the causes and nature of ADRs, healthcare providers can extend the benefits and limit adversity on a personal level. By understanding the population and the groups of medications that are particularly susceptible to ADRs, health professionals can make better medication selections and improved dosing for the specific populations [ 54 ]. Extensions into research of pharmacogenomics will also improve the understanding of ADRs. Understanding the impact of genetics on drug effects have the potential to predict ADRs.

Limitations of the review

This review has a few limitations. There was also limited data from the included studies in regard to the ADRs and classes of medications associated with them. Furthermore, most of the studies were undertaken in developed countries. Applying these results to other countries might not be relevant due to the various systems in reporting ADRs. This is in addition to the limitations in the included studies such as small sample sizes, heterogeneous populations, variations in outcome measures.

This scoping review identified that the most causes of ADRs were drug related and due to allergies. Idiosyncratic adverse reactions were not very commonly reported in the literature.

This is mainly because it is hard to predict and these reactions are not associated with drug doses or routes of administration. The most common ADRs reported in the studies included in this review were those that are associated with the central nervous system, gastrointestinal system and cardiovascular system. Several classes of medications were reported to be associated with ADRs.

Availability of data and materials

Not applicable.

Abbreviations

Adverse drug reactions

Angiotensin converting enzyme inhibitors

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

tuberculosis

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• Published: 13 March 2024

Prevalence of urgent hospitalizations caused by adverse drug reactions: a cross-sectional study

• Junpei Komagamine 1 , 2  

Scientific Reports volume  14 , Article number:  6058 ( 2024 ) Cite this article

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Adverse drug reactions account for a substantial portion of emergency hospital admissions. However, in the last decade, few studies have been conducted to determine the prevalence of hospitalization due to adverse drug reactions. Therefore, this cross-sectional study was conducted to determine the proportion of adverse drug reactions leading to emergency hospital admission and to evaluate the risk factors for these reactions. A total of 5707 consecutive patients aged > 18 years who were emergently hospitalized due to acute medical illnesses between June 2018 and May 2021 were included. Causality assessment for adverse drug reactions was performed by using the World Health Organization-Uppsala Monitoring Centre criteria. The median patient age was 78 years (IQR 63–87), and the proportion of women was 47.9%. Among all the hospitalizations, 287 (5.0%; 95% confidence interval (CI) 4.5–5.6%) were caused by 368 adverse drug reactions. The risk factors independently associated with hospitalization due to adverse drug reactions were polypharmacy (OR 2.66), age ≥ 65 years (OR 2.00), and ambulance use (OR 1.41). Given that the population is rapidly aging worldwide, further efforts are needed to minimize hospitalizations caused by adverse drug reactions.

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Introduction.

An adverse drug reaction (ADR) is defined as a harmful or uncomfortable event due to medication 1 . Older age and polypharmacy, which is defined as the use of more or five regular medications, are associated with an increased risk of ADRs 2 , 3 . Given the aging population worldwide, monitoring and minimizing the burden of ADRs are important.

The most frequent encounter for ADRs is ambulatory care 4 . According to ambulatory care-based studies 4 , 5 , approximately one in every eight outpatients have at least one ADR during no more than one year. However, monitoring ADRs in an ambulatory setting is laborious 5 , 6 , 7 . Therefore, monitoring emergency department (ED) visits or urgent hospitalizations due to ADRs is an alternative strategy 6 . Previous meta-analyses of observational studies 2 , 8 , 9 , 10 , 11 , 12 , 13 reported that 5–10% of hospital admissions were caused by ADRs. Moreover, approximately half of the hospitalizations due to ADRs were preventable 11 , 12 .

However, in the last decade, few studies have been conducted to determine the prevalence of hospitalization due to ADRs 14 , 15 , 16 . Moreover, passive surveillance systems reporting ADRs underestimate their prevalence because of underreporting and lack of awareness by clinicians 17 , 18 . Given that a substantial proportion of hospitalizations is caused by ADRs, it is important to establish the accurate prevalence of hospitalization due to ADRs. Therefore, a cross-sectional study was conducted to determine the prevalence of hospitalization due to ADRs and associated risk factors.

The baseline characteristics of the 5707 patients hospitalized for acute medical illnesses are shown in Table 1 . The median patient age was 78 years (interquartile range (IQR) 63–87), 2605 (45.6%) were women, 4123 (72.3%) were independent in activities of daily living (ADLs), and 3217 (56.4%) had used an ambulance. The median Charlson Comorbidity Index score was one (IQR 0–3), 1011 patients (17.7%) had chronic kidney disease, and 2743 (48.1%) took more or five regular medications at admission. The most common chief complaint was fever or chills (n = 1278, 22.4%), followed by dyspnea (n = 793, 13.9%), abdominal pain or discomfort (n = 394, 6.9%), and chest pain or discomfort (n = 351, 6.2%) (eTable 1 in the Supplemental file ). The most common final clinical diagnoses leading to hospitalization were acute heart failure (n = 623, 10.9%), followed by COVID-19 (n = 533, 9.7%), pneumonia or pneumonitis (n = 524, 9.2%), gastrointestinal bleeding (n = 361, 6.3%), acute coronary syndrome (n = 259, 4.5%), and stroke or transient ischemic attack (n = 239, 4.2%) (eTable 2 in the Supplemental file ).

A total of 494 medications contributed to adverse events at admission (Table 2 and eTable 3 in the Supplemental file ). Of those, 368 medications (74.5%) were judged to cause 287 hospitalizations due to ADRs. The most common categories of medications leading to hospitalization were cardiovascular agents (n = 83, 22.6%), musculoskeletal agents (n = 62, 16.8%), antithrombic agents (n = 49, 13.3%), psychotropic agents (n = 39, 10.6%), and antidiabetic agents (n = 37, 10.1%). Medications in these five categories accounted for more than 70% of all ADRs leading to hospitalization.

For the primary outcome, the proportion of patients who were hospitalized due to ADRs among all patients hospitalized for acute medical illnesses was 5.0% (95% CI 4.5–5.6%). According to our multivariable analysis, the risk factors independently associated with hospitalization due to adverse drug reactions were polypharmacy (odds ratio (OR) 2.66; 95% CI 2.00–3.54), age ≥ 65 years (OR 2.00; 95% CI 1.34–3.00), and ambulance use (OR 1.41; 95% CI 1.41–1.81) (Table 3 ). For the secondary outcome, the proportion of patients who had any ADRs at admission among all patients hospitalized for acute medical illnesses was 6.6% (95% CI 6.0–7.3%).

The post hoc analysis showed that the prevalence rates of hospital admissions due to ADRs during the pre-COVID-19 pandemic and COVID-19 pandemic periods were 6.1% and 3.8%, respectively (eTable 4 in the Supplemental file ). The prevalence of hospitalizations due to ADRs was significantly lower during the COVID-19 pandemic period than during the pre-COVID-19 pandemic period ( p  < 0.001).

The present study showed that approximately 5% of urgent hospital admissions were caused by ADRs. Our findings are consistent with those of past meta-analyses 10 , 13 of observational studies using data before 2012 showing that 5–10% of hospital admissions were caused by ADRs. This means that the prevalence of hospital admissions due to ADRs has not significantly improved during the last decade. However, compared with the findings of a previous recent study 19 using almost the same methods, the prevalence of hospital admissions due to ADRs in the present study was reduced by approximately half. In Japan, the “Proper Medication Guideline for Older Adults” was published for healthcare providers in May 2018 20 , and polypharmacy reduction incentives were initiated in 2016 21 and 2018 22 . A recent study reported that the prevalence of polypharmacy among elderly individuals subsequently decreased in Japan 23 . Therefore, it is possible that the national strategy for polypharmacy among elderly patients in Japan might have reduced hospital admissions due to ADRs. However, according to post hoc analysis, the prevalence of hospital admissions due to ADRs significantly decreased from the pre-COVID-19 pandemic period to the COVID-19 pandemic period. During the COVID-19 pandemic, the number of hospital visits in Japan substantially decreased 24 . Therefore, a reduction in hospital visits and increase in hospital admissions due to COVID-19 might have resulted in a decrease in the prevalence of hospital admissions due to ADRs. Nonetheless, additional studies are needed to confirm this hypothesis and monitor the prevalence of hospital admissions induced by ADRs since the COVID-19 pandemic.

In the present study, cardiovascular agents, nonsteroidal anti-inflammatory drugs (NSAIDs), antithrombic agents, psychotropic agents, and antidiabetic agents accounted for more than two-thirds of the medications leading to hospitalization. This finding is similar to that of past studies showing that the most common categories of medications leading to hospitalization included cardiovascular agents, antithrombic agents, psychotropic agents, NSAIDs, and antidiabetic agents 3 , 4 , 6 , 12 , 13 . Although the proportion of opioid use was lower in the present study than in past studies 13 , 25 , this difference might be attributed to the lower consumption of opioids in Japan than in European countries and the United States 26 . Previous 19 , 27 and recent studies showed that the proportion of psychotropic agents in medications causing hospitalization was greater than that in other countries 3 , 4 , 6 , 12 , 13 . Most of the patients included in the present study were 65 years or older. Given that psychotropic agents for elderly patients are considered potentially inappropriate medications in most cases 28 , 29 , further efforts to minimize the harmful effects of psychotropic agents are needed by implementing proper medication guidelines 20 , 30 . Moreover, in the present study, polypharmacy and age ≥ 65 years were independent risk factors associated with hospitalization due to ADRs. Our findings are consistent with those of a previous systematic review 13 regarding hospitalization due to ADRs. Therefore, deprescribing interventions for elderly patients with polypharmacy is also important.

In the present study, ambulance use was independently associated with an increased risk of hospitalization due to ADRs. This indicated that patients who were hospitalized due to ADRs had more severe symptoms that necessitated ambulance use than those who were not. To our knowledge, no studies have ever been conducted to investigate the association between ambulance use and hospitalization induced by ADRs 3 . Therefore, further studies are needed.

This study has several limitations. First, the present study was limited to patients hospitalized in the internal medicine ward of a single center. Second, a substantial proportion of patients were excluded due to insufficient information on documented medication history and medical history. Third, ADRs were screened based on information from electronic medical records documented in usual care. Therefore, some assessments of the causality of ADRs might have been inaccurate. Fourth, hindsight bias might have overestimated the prevalence of hospitalizations due to ADRs 31 . Fifth, ADRs were assessed by a single investigator. Therefore, the assessments of the causality of ADRs might have been inaccurate. Sixth, the preventability of ADRs was not assessed. Seventh, the inclusion of patients who were readmitted during the study period in the present study might overemphasize the characteristics of those patients. Finally, a medication list of trigger symptoms was not used to identify the medications that might have caused adverse events. Therefore, the prevalence of ADRs might have been underestimated.

In conclusion, one in every twenty emergency hospital admissions was caused by ADRs. Polypharmacy and old age were associated with an increased risk of hospitalization due to ADRs. Given the rapidly aging populations worldwide, efforts to mitigate hospitalizations due to ADRs are needed.

Study design and setting

A single-center retrospective cross-sectional study using chart reviews was conducted at NHO Tochigi Medical Center to determine the prevalence of hospitalization caused by ADRs among all emergency hospital admissions. NHO Tochigi Medical Center is a 350-bed general community hospital in Utsunomiya, Japan, and is one of the two largest acute care hospitals providing care for approximately 0.5 million people in this area. This research was approved and the requirement for individual informed consent was formally waived by the Medical Ethics Committee of NHO Tochigi Medical Center (No. 2019-2) because deidentified data were collected without contacting the patients. This research was conducted in accordance with the Ethical Guidelines for Epidemiological Research in Japan and the Declaration of Helsinki.

Inclusion and exclusion criteria

All consecutive patients aged > 18 years who were urgently hospitalized in the internal medicine ward of NHO Tochigi Medical Center due to acute medical illnesses from June 2018 to May 2021 were included. If the same patient was admitted two or more times during the study period, the admissions were evaluated separately. Patients who were planned to be hospitalized for diagnostic procedures, education, treatment, or short-term care were excluded. In this study, data collected in usual care were used. Therefore, patients with insufficient information on regular medications or medical history at admission documented in the electronic medical records were also excluded. During the study period, 7468 patients were hospitalized. A total of 5707 patients who met the inclusion criteria were included in the final analysis (eFigure 1 in the Supplemental file ).

Data collection and screening

Information on age, sex, medical history, medications, primary diagnosis at hospitalization, and prognosis was collected as deidentified data from electronic medical records. For the primary diagnosis, the documented diagnosis in the discharge summary was used. For information on prescribed medications, a comprehensive medication list documented by pharmacists as usual care was used. The type of medication was classified according to the World Health Organization Anatomical Therapeutic Chemical classification. Based on the medication list and the patients’ medical histories, physical findings, and laboratory test results from the electronic medical records, the medications that could cause ADRs were screened. During the study period, all patients who were hospitalized in the internal medicine ward of the hospital were screened within a few days after admission as routine care. All medications that the patients took were evaluated for whether they caused ADRs at hospital admission. If needed, the principal physicians were contacted regarding the possibility of ADRs due to specific medications. The patients were subsequently followed up until discharge by using the electronic medical records.

Outcome measures

The primary outcome was the proportion of patients who were hospitalized due to ADRs among hospitalized patients with acute medical illnesses. Based on a previous report 1 , ADRs were defined as harmful or unpleasant reactions resulting from an intervention related to the use of a medicinal product, which predicts risks from future administration and warrants prevention or specific treatment, alteration of the dosage regimen, or withdrawal of the product. Unpleasant reactions included any new symptoms or signs that were presumed to be caused by the medications. However, ADRs associated with treatment failure or withdrawal of medications were not included. Intentional drug abuse or unintentional medication overdose were not included as ADRs. The secondary outcome was the proportion of patients who had any ADRs at admission among hospitalized patients with acute medical illnesses.

The causality of ADRs was assessed according to the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) criteria 32 . The medication was judged to cause adverse events if both of the following criteria were met: (1) there was a “certain” or “probable” causal association between the medication and adverse events based on the WHO-UMC criteria 32 ; and (2) the medication was stopped or its dose was reduced by the principal physician caring for the patient during the index hospitalization. The contribution of the ADR to hospitalization was evaluated based on the Hallas criteria 33 . The patients for whom problems due to ADRs were “dominant” leading to hospitalization were judged to be hospitalized due to ADRs. These assessments were performed by a single investigator (J.K.).

Statistical analysis

Initially, approximately 10,000 patients were planned to be included. This sample size would provide a precision of 0.5% for calculation of the 95% confidence interval (CI) of the primary outcome, assuming that the proportion of patients who were hospitalized due to ADRs was 7%, which was based on previous Japanese studies 19 , 27 and systematic reviews 10 , 13 . However, the recent coronavirus disease 2019 (COVID-19) pandemic made it difficult to continue enrollment due to a shortage of healthcare providers. Therefore, the sample size of this study was reduced.

Descriptive statistics are used to report the baseline characteristics of the study population. For the primary outcome, the proportion of patients who were hospitalized due to ADRs among all the hospitalized patients was calculated. For the secondary outcome, the proportion of hospitalized patients who had any ADRs at admission among all hospitalized patients was calculated. The 95% CIs were calculated for these outcomes. Multivariate analysis using binary logistic regression was performed to determine the predictive factors associated with ADRs leading to hospitalization. We examined the associations between the primary outcome and age, sex, ambulance use, Charlson Comorbidity Index score, chronic kidney disease, and polypharmacy at admission. Polypharmacy was defined as the use of five or more medications 34 . The clinical features of patients who are transferred or not transferred by ambulance to the emergency department are different 35 . Therefore, ambulance use was chosen as one of the variables. The COVID-19 pandemic began during the study period. In the region of the hospital, the first hospital admissions of COVID-19 patients occurred in February 2020. Therefore, in a post hoc analysis, the proportion of patients who were hospitalized due to ADRs between the pre-COVID-19 pandemic period (June 2018 to January 2020) and the COVID-19 pandemic period (February 2020 to May 2021) was compared by using Fisher’s exact test. Excel statistical software version 4.04 (Bellcurve for Excel; Social Survey Research Information Co., Ltd., Tokyo, Japan) and Stata version 18.0 (StataCorp, USA) were used for these analyses. A p value < 0.05 indicated statistical significance.

Data availability

All data relevant to the study are included in the article or uploaded as supplementary information.

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Junpei Komagamine

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JK conceived and designed this study. JK collected and analyzed the data. JK wrote the initial draft and critically revised the manuscript. The author has read and approved the final version of the manuscript. JK assumes responsibility for the integrity and accuracy of the data.

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Research Article

Prevalence of adverse drug reactions in the primary care setting: A systematic review and meta-analysis

Roles Conceptualization, Data curation, Formal analysis, Methodology, Writing – original draft, Writing – review & editing

Affiliations Research Department of Practice and Policy, School of Pharmacy, University College London, London, United Kingdom, Department of Pharmacology and Clinical Pharmacy, Center of Excellence for Pharmaceutical Care Innovation, Padjadjaran University, Bandung, Indonesia

Roles Conceptualization, Methodology, Project administration, Supervision, Writing – review & editing

Affiliation Research Department of Practice and Policy, School of Pharmacy, University College London, London, United Kingdom

Roles Data curation, Formal analysis, Methodology, Validation, Writing – review & editing

Affiliations Research Department of Practice and Policy, School of Pharmacy, University College London, London, United Kingdom, Faculty of Medicine, Umm Al Qura University, Mecca, Saudi Arabia

Roles Methodology, Supervision, Writing – review & editing

Affiliations Research Department of Practice and Policy, School of Pharmacy, University College London, London, United Kingdom, Department of Pharmacology and Pharmacy, University of Hong Kong, Hong Kong, Hong Kong

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Affiliation Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom

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• Widya N. Insani, 
• Cate Whittlesea, 
• Hassan Alwafi, 
• Kenneth K. C. Man, 
• Sarah Chapman, 

• Published: May 26, 2021
• https://doi.org/10.1371/journal.pone.0252161
• Reader Comments

Adverse drug reactions (ADRs) represent a major cause of iatrogenic morbidity and mortality in patient care. While a substantial body of work has been undertaken to characterise ADRs in the hospital setting, the overall burden of ADRs in the primary care remains unclear.

To investigate the prevalence of ADRs in the primary care setting and factors affecting the heterogeneity of the estimates.

Studies were identified through searching of Medline, Embase, CINAHL and IPA databases. We included observational studies that reported information on the prevalence of ADRs in patients receiving primary care. Disease and treatment specific studies were excluded. Quality of the included studies were assessed using Smyth ADRs adapted scale. A random-effects model was used to calculate the pooled estimate. Potential source of heterogeneity, including age groups, ADRs definitions, ADRs detection methods, study setting, quality of the studies, and sample size, were investigated using sub-group analysis and meta-regression.

Thirty-three studies with a total study population of 1,568,164 individuals were included. The pooled prevalence of ADRs in the primary care setting was 8.32% (95% CI, 7.82, 8.83). The percentage of preventable ADRs ranged from 12.35–37.96%, with the pooled estimate of 22.96% (95% CI, 7.82, 38.09). Cardiovascular system drugs were the most commonly implicated medication class. Methods of ADRs detection, age group, setting, and sample size contributed significantly to the heterogeneity of the estimates.

ADRs constitute a significant health problem in the primary care setting. Further research should focus on examining whether ADRs affect subsequent clinical outcomes, particularly in high-risk therapeutic areas. This information may better inform strategies to reduce the burden of ADRs in the primary care setting.

Citation: Insani WN, Whittlesea C, Alwafi H, Man KKC, Chapman S, Wei L (2021) Prevalence of adverse drug reactions in the primary care setting: A systematic review and meta-analysis. PLoS ONE 16(5): e0252161. https://doi.org/10.1371/journal.pone.0252161

Editor: Mojtaba Vaismoradi, Nord University, NORWAY

Received: January 31, 2021; Accepted: May 11, 2021; Published: May 26, 2021

Copyright: © 2021 Insani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting information files.

Funding: WNI is funded by a scholarship from Indonesia Endowment Fund for Education (LPDP No. 201908223215121), Ministry of Finance, Republic of Indonesia. This funding body had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Adverse drug reactions (ADRs) represent a significant clinical problem in healthcare, owing to the increasing multimorbidity and complexity of medical treatment. ADRs are defined as "noxious and unintended responses to a medicinal product" [ 1 ]. Since 2010, this definition has included reactions not only from appropriate use of drugs at normal doses, but also those resulted from errors and the use outside the term of authorization [ 2 ]. Lazarou et al estimated from a meta-analysis, that ADRs represent the fourth leading causes of death in the United States (US) [ 3 ]. In England, Hospital Episode Statistic (HES) data showed that between 2008 and 2015, there were 541,416 hospital admissions caused by ADRs, representing 1.5% of total hospital episodes; over this period the number of ADRs-related hospital admissions increased by 53.4% [ 4 , 5 ].

While a substantial body of work had been undertaken to characterise ADRs that resulted in hospital admissions and occurred during hospital stay [ 6 – 11 ], much less is known about the overall burden of ADRs in the primary care setting, where most medications are prescribed and administered [ 12 ]. Identification of ADRs in the primary care setting is inherently challenging due to the intermittent nature of healthcare contacts and scattered information across multiple patient care providers [ 13 ]. As a gatekeeper, primary care provider has a critical role in signalling and recognising ADRs to minimise the subsequent impact of the reaction and ensure optimal individual pharmacotherapy [ 14 ].

Previous systematic reviews have been conducted in primary care setting, but these reviews focused on medication errors [ 15 ] and general safety incidents, e.g., diagnostic incidents, administrative and communication incidents, and medication management incidents [ 16 ]. Tache et al examined medication-related adverse events, but the review combined both primary and secondary care settings and included six ambulatory-based studies only up to 2011 [ 13 ]. Another review has been conducted by Khalil et al, however no meta-analysis, evaluation of study quality, heterogeneity analysis, and preventability assessment were performed [ 17 ]. Ascertaining the burden of ADRs in the community has significant public health implication, as this information may help in prioritising areas of improvement, and thus potentially decreasing patients’ risk of untoward therapeutic consequences. Therefore, this systematic review and meta-analysis were performed to investigate the prevalence of ADRs in the primary care setting, their preventability, and factors affecting the heterogeneity of the estimates.

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used to guide the reporting of the findings. A completed PRISMA checklist is provided as an additional file ( S1 Appendix ). The study protocol was registered in the International Prospective Register of Systematic Reviews database (PROSPERO: CRD 42020191159).

Search strategy

A systematic search was conducted within Medline, Embase, Cumulative Index of Nursing and Allied Health Literature (CINAHL), and International Pharmaceutical Abstracts (IPA) databases across all publication dates up to June 2020. The search strategies cover the terms related to ADRs and setting of interest ( S2 Appendix ). The reference lists of eligible studies were reviewed to identify potential relevant studies. The corresponding authors of the eligible articles were contacted when additional information was needed.

Eligibility criteria

• Study type: Observational studies that provided information on the prevalence, i.e., the rate of patients with ADR(s) within the observed period were included. Studies that reported the occurence of ADRs in relation to total consultations or total course of drug therapies without reporting the number of patients with ADR(s) and total number of patients included, were not eligible for inclusion to ensure comparability of outcome measure.
• Population and setting: Patients from all age groups receiving care from primary care facilities were included. Primary care is defined as the first point of contact with healthcare system, providing generalist care delivered outside inpatient setting [ 16 , 18 ]. This setting included general/family medicine, general internal medicine, general paediatrics, community pharmacy, and community health services such as long-term care facilities [ 16 ]. As primary care practitioners are commonly responsible for the provision of first-line health care to long-term care facilities residents [ 19 , 20 ], we included studies investigating ADRs in long-term care facilities. General internal medicine was included only when the studies specified that they provided primary care services for the patients, as typically observed in the context of US primary care health system [ 21 ].
• Types of outcome: The outcome of interest was ADRs, defined as "noxious and unintended responses to a medicinal product" [ 1 ]. For example, muscle symptoms/myopathy associated with statin, cough associated with angiotensin converting enzyme inhibitor (ACEI), and ankle oedema associated with calcium channel blocker (CCB). Since 2010, this definition has included reactions not only from appropriate use of drugs at normal doses, but also those resulted from errors at any medication process [ 2 ], e.g., myopathy in a statin user who was previously prescribed systemic azole antifungal and rash after admistration of flucloxacillin in a patient with a documented allergy to penicillin [ 22 , 23 ].

The eligible detection methods were one or a combination of the following [ 24 ];

• Spontaneous/solicited reporting by healthcare professionals, which involves active participation of clinicians to collect and notify any ADRs observed during primary care consultations to research investigators within a specified period of time [ 25 , 26 ].
• Medical record/notes/medication review, either using prospective or retrospective review. This method could be combined with patient survey [ 23 , 27 ]. We included studies using medical record review alone or combined record/medication review-patient survey.
• Trigger-based medical record review, which involves a two-step review process [ 28 , 29 ]. Firstly, a selection of patient record was screened using a set of pre-defined ADRs triggers, e.g., specific laboratory values, prescribing of antidote medication, specific phrases, or drug-event potentially indicative of ADRs. For example, on warfarin treatment and international normalised ratio (INR) > 5, on statin treatment and serum aspartate amino transferase (AST) > 150 U/L; and on diuretics treatment and serum potassium < 3.0 mmol/L [ 30 , 31 ]. Subsequently, the investigators performed thorough reviews of these flagged charts to determine whether the use of drug was associated with the event or ADRs had actually occurred [ 28 , 29 , 32 , 33 ].
• Administrative database screening to identify ADRs recorded by primary care providers during routine care. These reactions were typically recorded using specific designated codes for ADRs, e.g., International Classification of Primary Care (ICPC) Code A-85 or Read Code Chapter TJ [ 14 , 34 ].

Exclusion criteria

Studies investigating ADRs as causes of emergency department visits and/or hospital admission were excluded. Studies with combined setting that did not provide separate estimate of ADRs between primary and secondary/tertiary care setting were excluded. Studies that assessed ADRs using only public surveys without any further assessment by healthcare professional/research investigator were excluded to ensure comparability of outcome measure. Studies that examined ADRs associated with specific drug exposure were excluded as the samples were not generalizable of primary care population in general. Literature review, cases reports/series, and conference abstracts were excluded, as were articles written in languages other than English.

Screening and data extraction

Two investigators (WI and HA) independently screened the titles and abstracts generated from the databases using the predetermined criteria. Any discrepancies between the two reviewers were resolved through discussion. Following initial screening, the full-text of potentially relevant papers were further assessed to identify eligible studies. The process of study selection was presented using an adapted PRISMA diagram [ 35 ]. The process of data extraction was conducted using a standardized data collection form for all included studies. Data extracted included general characteristics of the studies, ADRs prevalence, and when reported: drugs implicated in the ADRs, preventability, severity, and risk factors of ADRs.

Appraisal of study quality

The quality of the included studies were examined using Smyth ADRs adapted scale [ 36 ]. This 10-item instrument was developed specifically for studies examining ADRs in clinical settings [ 37 , 38 ]. The following aspects were evaluated from each study; study design, data source, methods of ADRs detection, assessment of causality, preventability, and severity [ 36 ].

Data analysis

A random-effects model was used to calculate the pooled prevalence of ADRs and the percentage of preventable ADRs. Heterogeneity among the included studies was assessed using I 2 statistics. Sub-group analyses and meta-regression were performed to explore potential source of heterogeneity, i.e., age groups, ADRs detection methods, ADRs definitions, setting, study quality, and sample size. All analyses were performed in Stata version 15.

Literature search and selection process

A total of 10,407 citations were retrieved from the electronic databases and other sources. After removal of duplicates, 5944 records remained for evaluation. Title and abstract screening yielded 179 records eligible for full-text assessment. Finally, a total of 33 studies were included in this systematic review ( Fig 1 ) ( Table 1 ).

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Characteristics of included studies

Majority of the included studies were cross-sectional in design [ 14 , 25 , 26 , 30 , 31 , 39 – 46 , 48 – 53 , 55 – 64 ], with two retrospective cohort [ 47 , 56 ] and two prospective cohort studies [ 23 , 27 ]. Study periods spanned from 1992 to 2020. Almost half of the included studies were conducted in Europe (n = 16) [ 14 , 25 , 26 , 42 , 48 , 50 , 53 , 54 , 56 – 58 , 60 – 64 ], about one-third in North America (n = 12) [ 23 , 27 , 30 , 31 , 39 – 41 , 43 , 44 , 47 , 51 , 52 ] and five in Australia [ 45 , 46 , 49 , 55 , 59 ]. Majority of the studies (n = 22) focused on adult, with ten of them were performed among the elderly [ 39 – 42 , 46 , 47 , 51 , 53 , 54 , 56 ]. Nine studies were conducted among all age groups [ 14 , 27 , 31 , 59 – 64 ], while the remaining two studies examined ADRs in a paediatric population [ 26 , 58 ].

About one-third of the studies were performed in a general practice setting [ 14 , 25 , 42 , 48 , 49 , 52 , 55 , 56 , 59 , 61 ], while seven studies were conducted within primary care internal medicine [ 23 , 27 , 30 , 39 , 41 , 43 , 44 ]. The remaining studies were performed in the community pharmacy (n = 5) [ 53 , 57 , 60 , 62 , 63 ], long-term care facilities (n = 4) [ 40 , 47 , 51 , 54 ], paediatric practice (n = 2) [ 26 , 58 ], and home setting (n = 4) [ 45 , 46 , 50 , 64 ], where healthcare professionals performed domiciliary medication review.

Majority of the studies (n = 21) used medical record/notes/medication review to identify ADRs. Most of these studies combined this method with patient survey or direct patient assessment (n = 16), with two studies used telephone-based survey [ 23 , 27 ]. Three studies applied trigger-based medical record review, with one study combined it with spontaneous (voluntary) reporting by healthcare professionals [ 30 , 31 , 47 , 51 ]. Solicited reporting method were used in five studies, in which healthcare professionals were asked to notify ADRs within a specified period, ranging from a 1-week to a 3-month period [ 25 , 26 , 49 , 58 , 59 ]. The remaining five studies used administrative database screening to identify ADRs data recorded by primary care providers during routine care [ 14 , 42 , 48 , 52 , 61 ] ( Table 1 ).

Prevalence of ADRs

The pooled estimate of ADRs among 1,568,164 individuals was 8.32% (95% CI 7.82, 8.83) (I 2 = 99.7%) ( Fig 2 ). When only studies with low risk of bias were considered (scored ≥ 7 in the ADRs risk of bias assessment, n = 12), the estimate increased to 20.37% (95% CI 16.89, 23.85) but the heterogeneity remains high (I 2 = 99.5).

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Preventability of ADRs

The percentage of preventable ADRs in the primary care ranged from 12.35–37.96% [ 23 , 27 , 31 , 43 ], with the pooled estimate of 22.96% (95% CI, 7.82, 38.09). Three studies defined preventable ADRs as reactions which due to errors in any medication process [ 23 , 27 , 31 ]. For example, myopathy was detected in a statin user who was recently prescribed systemic azole antifungal. Errors in acknowledging this potentially harmful drug-drug interaction during the prescribing stage led to this reaction. Thus, this myopathy was considered preventable ADR [ 23 , 65 ]. One study defined preventable ADRs as reactions that occurred among patients who previously had a documented allergic reaction to the drug, and reactions which related to inadequate monitoring of the causative drug. For example, bleeding in warfarin users is considered preventable when adequate INR monitoring is not performed for patients starting warfarin [ 43 , 66 ] ( Fig 3 ). Examples of preventable and non-preventable ADRs are provided in Table 2 .

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Severity of ADRs

One-third of the included studies (n = 11) assessed the severity of the ADRs. The criteria used to classify severity varied between studies. Mild reactions were typically defined as reactions which did not require; i.) change in drug regimen, and ii.) specific antidote/treatment for the reactions. Moderate reactions are those requiring change in drug regimen and/or specific antidote/treatment to relieve ADRs; limits daily activities. Severe ADRs were potentially life-threatening reactions, require hospitalization, and result in significant disability [ 23 , 26 , 27 , 31 , 40 , 43 , 44 , 47 , 49 , 56 , 59 ]. Based on the included studies, the majority (76.0–96.3%) of ADRs in primary care were of mild-moderate severity, for example drug rash, easily bruising and bleeding related with aspirin which did not require hospitalization, indigestion/heartburn related with anti inflammatory and antirheumatic drug, dizziness/lightheadedness related with beta-blocker, sexual dysfunction related with selective serotonin reuptake inhibitor (SSRI) and beta-blocker, cough and orthostatic hypotension related with ACEI, muscle symptom related with statin, ankle swelling related with CCB, and throat pain related with oral bisphosphonate [ 23 , 26 , 27 , 31 , 40 , 43 , 44 , 47 , 49 , 56 , 59 ]. Up to 62.8% of the reactions required changes in drug regimen. About 1.35–9.1% of the reactions required visits to emergency department and/or hospital admission, for example bradycardia related with beta-blocker and hypoglycemic event related with sulfonylureas. Half of the patients with ADRs reported interferences with work, leisure, or daily activities; and anxiety/discomfort [ 23 , 26 , 27 , 31 , 40 , 43 , 44 , 47 , 49 , 56 , 59 ].

Subgroup analysis and meta-regression

We performed subgroup analysis to investigate how the prevalence estimate varied across different subgroup of studies and potential source of heterogeneity. The analysis was performed through stratification by age group, methods to identify ADRs, definition, setting, risk of bias, and sample size. We found that studies performed among the elderly (≥ 65 years) showed the highest prevalence of ADRs, with more than a quarter of these patients potentially having experienced ADRs (28.43%, 95% CI 18.65, 38.21). There was a significant heterogeneity in every age group (I 2 >99.2%), except studies among paediatric populations (I 2 = 71.8%) with moderate heterogeneity. High heterogeneity was still observed among studies that used the same methods to identify ADRs (I 2 >97.9%), as were studies using the same ADRs definition (I 2 >98.3%). Studies using combined medical record/notes/medication review and patient survey (n = 16) exhibited the highest prevalence (19.92%, 95% CI 16.11, 23.73). Studies which applied the WHO definition [ 1 ] (n = 9) had lower estimates compared to Bates et al definition [ 22 , 71 ] (n = 6) with the prevalence of 13.05% (95% CI, 9.37, 16.73). With regard to the study setting, the prevalence of ADRs in studies conducted in long-term care facilities were higher than other units, with 42.22% (95% CI 17.57, 66.88) of the residents potentially experiencing ADRs. A large difference was observed among studies involving different sample sizes (i.e., 0–1000, 1001–10,000, and >10,000), with studies having a larger sample size tending to have a lower prevalence of ADRs. Factors affecting heterogeneity of the prevalence were further assessed using meta-regression. There were significantly higher estimates of prevalence of ADRs in studies using different ADRs detection methods, age group, setting, and sample size (P<0.05) ( Table 3 ).

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Drugs associated with ADRs

Table 4 shows information on the most common drugs class implicated in ADRs in the primary care setting. The most frequent drug class involved in the ADRs among adults were cardiovascular drugs (median 27.3%; range: 18.1–71.9%), including antihypertensive, lipid-modifying, antithrombotic drugs; followed by nervous system drugs (median 13.4%; range: 3.5–39.6%), including antidepressants, antipsychotics, analgesics; and musculoskeletal system drugs (median 8.3%; range 3.8–13.4%), including NSAIDs, antirheumatic drugs, and drugs for bone structures and mineralisation (e.g., bisphosphonates). For all age groups, the most commonly involved drugs were cardiovascular drugs (median 38%; range:23.4–73.5%), nervous system drugs (median 16.5%; range: 9.9–23.2%), and anti infectives (median 14.5%; range:8.3–20.6%). The most commonly involved drugs in the ADRs among paediatric patients were anti infectives. (median 85%; range 70–100%) [ 23 , 26 , 31 , 39 , 40 , 42 , 45 , 47 , 49 , 51 , 58 , 61 , 63 ] ( Table 4 ).

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Risk factors of ADRs

Multimorbidity condition was found to be a strong predictor of ADRs in the primary care, as well as the higher number of referrals to different specialties [ 48 ]. Number of medication prescribed was consistently reported as a major determinant of ADRs [ 23 , 48 ]. Honigman et al showed that patients with ADRs were reported to take almost three times the number of drugs compared to those without ADRs [ 31 ]. Gandhi et al further demonstrated that the mean number of ADRs per patient was likely to be increased by 10% for one additional medication prescribed [ 23 ]. Other risk factors reported included the number of consultations to family physician, being female, off-label drug use, and exposure to several medication classes (i.e., antiinfectives and systemic hormonal preparation) [ 23 , 26 , 31 , 39 , 48 ] ( Table 5 ).

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Quality assessment

All of the included studies reported study design, methods to identify ADRs, and data sources. Individuals who identified ADRs, either researchers or clinicians, were described in all studies. The process of establishing causal relationship was reported in more than a third of the studies (n = 13) [ 23 , 25 – 27 , 31 , 39 – 41 , 43 , 44 , 47 , 50 , 58 ] with the majority having used a validated tool, i.e., Naranjo algorithm (n = 7) [ 27 , 31 , 39 , 40 , 43 , 44 , 47 ] or French causality method (n = 3) [ 25 , 26 , 58 ]. One study used criteria defined by the authors that considered three aspects; i) temporal relationship (timing) between the use of drug and the symptom; ii) whether the patient attributed the symptom to the drug; and iii) the strength of published data on the relationship between the symptom and the drug [ 23 ]. Four studies assessed the preventability [ 23 , 27 , 31 , 43 ] and a third of the studies (n = 11) assessed the severity of ADRs [ 23 , 26 , 27 , 31 , 40 , 43 , 44 , 47 , 49 , 56 , 59 ].

To the best of our knowledge, this is the first systematic review to provide comprehensive information on the overall burden of ADRs focusing on primary care with quantitative assessment and evaluation of the quality of included studies. The pooled prevalence of ADRs in the primary care setting was 8.32% (95% CI, 7.82, 8.83). The percentage of preventable ADRs in primary care ranged from 12.35–37.96%, with the pooled estimate of 22.96% (95% CI, 7.82, 38.09). The prevalence estimates varied significantly according to age group, method of ADRs detection, setting, and sample size.

The lack of other reviews investigating ADRs in primary care hinders comparison to previous evidence. A previous scoping review found that the most common ADRs observed in this setting were dose-related and allergic reactions, while idiosyncratic reactions were not common [ 17 ]. Our review significantly extends this finding through the use of a thorough search strategy, evaluation of study quality, preventability and severity; and detailed heterogeneity analysis. Our prevalence estimate was slightly lower than the estimate reported by Tache et al which included a subset of six ambulatory-based studies performed before 2008 (8.32% vs 12.80%) [ 13 ]. The difference might result from different ADRs detection methods as all studies used combined medical record review and patients survey. In our subgroup analysis, studies using this method (n = 16) exhibited the highest estimate, with the prevalence of 19.92%, 95 CI, 16.11, 23.72. Compared to the previous systematic reviews of ADRs as causes of hospital admission, our estimate is higher [ 72 , 73 ]. It has been estimated that the frequency of ADRs occurred in the primary care is likely to be higher due to inclusion of mild-moderate symptoms compared to the those requiring urgent medical care which possibly represents only the most severe reactions in the community [ 6 , 30 ].

Our review suggests that about one fifth of ADRs in primary care were preventable (22.96%, 95% CI, 7.82, 38.09). This finding was comparable with two earlier ambulatory-based reviews showing that 16.5–21% of ADRs in this setting were preventable [ 13 , 74 ]. The most frequently cited causes of preventable ADRs included failure to recognise previously documented allergic reaction to the causative drug, drug-drug interactions overlooked, and inappropriate selection of medication and/or dosage for patients’ clinical condition (e.g., comorbidity, age) [ 23 , 27 , 31 , 43 ]. Several initiatives have been performed to potentially reduce preventable medication harm in the primary care setting, including pharmacists-led medication review [ 75 – 78 ], clinical decision support (CDS) embedded in information system [ 79 , 80 ], educational intervention [ 81 , 82 ], and nurse-led medication monitoring, particularly in long-term care facilities [ 83 – 85 ].

Inadequate monitoring was also reported as one of the major contributing factors in preventable ADRs [ 23 , 27 , 31 , 43 ]. Nevertheless, such monitoring is often inadequate in the primary care [ 86 ]. A recent study undertaken in the UK primary care on ACEIs and ARBs users found that only one-tenth of these patients had guideline-recommended creatinine monitoring [ 87 ]. Another study involving 27,355 patients with hypertension, further demonstrated that those who received routine potassium monitoring were less-likely to experience serious hyperkalemia associated with spironolactone and ACEIs/ARBs [ 88 ]. Thus, strengthening drug monitoring is likely to generate tangible clinical benefits for patients.

Despite considerable variation on how each study defined severity, this review found that majority (76.0–96.3%) of ADRs occurred in the primary care setting were of moderate-low severity [ 23 , 26 , 27 , 31 , 40 , 43 , 44 , 47 , 49 , 56 , 59 ]. Nevertheless, it is worth noting that these reactions might not be minor for patients, as these reactions might affect their quality of life, medication adherence, and subsequent health service utilization [ 43 , 89 , 90 ]. In addition, changes in the treatment regimen were required in over half of the ADRs [ 23 , 26 , 27 , 31 , 43 , 44 , 49 , 56 , 59 ]. Patients with ADRs may be at increased risk of suboptimal therapeutic outcome due to prolonged discontinuation, limited treatment options, and potentially impaired adherence [ 91 , 92 ], yet there is little clarity on further impact of ADRs on clinical outcomes. Further studies should investigate the consequences of ADRs on treatment pattern changes and their outcomes, as this information may help inform clinicians on the most appropriate intervention strategies following the reaction and provide thorough understanding on the burden of ADRs for patients and the health system.

It is not surprising that in our subgroup analysis, studies focusing on the elderly population (≥65 years) showed a higher prevalence of ADRs compared to other age groups (28.43%, 95% CI 18.65, 38.21; n = 10). Altered pharmacokinetics due to physiological impairment is largely unavoidable in this population, putting them at particularly higher risks of developing such reactions [ 93 ]. In addition, up to 44% of the elderly were exposed to polypharmacy (the use ≥ 5 medications) [ 94 ]. Onder et al showed that about a quarter of people living in the nursing homes (mean age 83,5 ± 9.3) used ≥ 10 medications (i.e., excessive polypharmacy) to manage their medical conditions [ 95 ]. We found 42.22% (95% CI 17.57, 66.88) of residents (age ≥ 65 years) in this setting potentially having experienced ADRs. As the world’s population is ageing, mitigation of ADRs among the elderly will become increasingly important.

Studies combining medical record/notes/medication review and patient survey resulted in the highest proportion of ADRs compared to other approaches (19.92%, 95% CI 16.11, 23.73). Medical record review alone might have limitation, owing to inadequate documentation [ 43 , 44 , 96 ]. Due to intermittent nature of health care contacts in primary care, it is possible that ADRs were not adequately recognised and/or communicated, thus, additional information received from patients might identify more ADRs than those captured in the medical record [ 41 , 43 , 49 , 56 , 59 ]. Jordan et al showed that nurse-led patient monitoring has been shown to be effective to improve recognition of ADRs. Timely identification of ADRs is important to further prevent a deterioration of patients’ condition which may result in unnecessary healthcare utilization [ 83 – 85 ].

Trigger-based record review has been increasingly used in various settings to facilitate more targeted and efficient identification of ADRs [ 29 , 33 , 97 ]. In this review, it generated comparable, but slightly lower estimates compared to manual chart review. Nevertheless, our result was derived from only limited studies (n = 3) that used the former method [ 30 , 31 ]. In this approach, only records containing specific trigger indicators were further assessed, possibly limiting the capture of ADRs not associated with the pre-defined triggers. Several ADRs triggers with high-moderate positive predictive values (PPV) in primary care included INR >5, creatinine >2.5 mg/dL, thyroid stimulating hormone (TSH) <0.03 mLU/L for thyroxine, serum theophylline >20 microgram/mL, medication discontinued, and new order for ARBs [ 28 , 30 – 32 ].

We found five studies using general practice database screening to identify readily-available ADRs data recorded by primary care providers during routine care [ 14 , 42 , 48 , 61 ]. This approach reflects how primary care physicians recognise and document ADRs in a real-world setting, thus, the Hawthorne effect (i.e., observer effect) was likely to be minimal compared to a solicited reporting method [ 26 , 58 ]. Nevertheless, differences in recording practice might hinder precise estimation [ 98 ]. Miguel et al demonstrated that a smaller prevalence of ADRs identified by administrative databases screening compared to manual chart review (2.4% versus 9.0%) was not a limitation, considering high PPV obtained (87.6%) and the reduced resource utilised (two person-hours versus 35 person-hours) [ 24 ].

There was considerable variation with regard to the risk factors of ADRs among the studies. Multimorbidity and referrals to different specialties were reported as significant predictors of ADRs [ 48 ]. A different result was observed by Tsang et al which showed that having one or more referrals was protective against adverse events [ 99 ]. Lack of coordination at different levels of care might put patients, particularly those with multimorbidity, at a higher risk of ADRs, due to the increased risk of potentially harmful drug-drug and/or drug-disease interactions, and non-adherence [ 100 , 101 ].

Our finding showed that the most commonly implicated drugs in the ADRs in the primary care setting were cardiovascular drugs [ 23 , 26 , 31 , 39 , 40 , 42 , 45 , 47 , 49 , 51 , 58 , 61 , 63 ]. This is consistent with the existing evidence [ 13 , 72 ]. Cardiovascular drugs, particularly RAAS agents, CCBs, lipid-modifying agents, and aspirin were found to be among the most frequently prescribed medications in primary care in the UK, US, and the Netherlands [ 102 – 105 ]. Thus, it is imperative for primary healthcare professionals to be vigilant in managing ADRs for this particular medication class [ 106 – 108 ].

Patient-provider awareness of relevant ADRs associated with patients’ medications and adequate patient-provider communication were important aspects in the management of ADRs in less-controlled healthcare environment such as primary care [ 14 ]. However, only about one-third of patients in the community had received information on ADRs [ 109 , 110 ]. Healthcare professionals are often hesitant in giving information about important ADRs due to potential nocebo effects (i.e., perceived adverse effects as the result of negative expectancies) [ 111 ], nevertheless, a previous study showed the opposite, i.e, not receiving information on potential side effects from healthcare professional was associated with increased risk of self-reported ADRs and decreased satisfaction [ 43 ]. It is possible that patients who receive such information will better manage the drug reactions and become less worried [ 43 , 112 ]. In specific therapeutic areas such as diabetes management, previous studies found that up to 48% patients were often uninformed about drug-induced hypoglycemia risk and thus unable to recognise this reaction [ 109 , 110 , 113 ]. This highlights the need for better education strategies by their primary care providers as the majority of patients with chronic diseases were routinely managed in the primary care setting [ 114 ].

Implementation for practice and research

ADRs constitute a significant health problem in primary care, with about a fifth of ADRs identified as preventable. This indicates potential areas for improvement, particularly targeting errors in prescribing (contraindication, drug interactions, inappropriate selection of dosage/frequency for patients’ condition, previously documented drug allergy) and inadequate monitoring, particularly for patients with multimorbidity, advanced age, and concomitant use of medications. There is also a need to improve patient-provider communication of ADRs to prevent further iatrogenic complication and unnecessary healthcare utilisation. Weingart et al showed that an electronic patient-centered portal, enabled patients to ask question and report problem about their prescribed medication, was effective in improving communication about medication problems and was able to identify ADRs in the primary care setting [ 115 , 116 ]. In addition, further educational support for both patient and provider may be beneficial to increase general awareness on the safe use of medicines and improve safety culture [ 23 , 117 , 118 ].

Current knowledge of ADRs has focused on the frequency, with only limited studies reflecting how ADRs impact patient’ health status. Although most of the ADRs in the primary care setting are not likely to pose life-threatening condition for patients, the consequences on health-related outcomes might be significant. It could interfere with patient treatments and result in suboptimal therapeutic outcomes, yet there is little clarity about the impact of ADRs on treatment pattern changes and its associated outcomes, particularly for high-risk therapeutic area [ 91 , 92 ]. Such information would allow identification of appropriate strategies following the ADRs which best fit patients’ circumstances and provide thorough understanding on the burden of ADRs for patients and the health system.

The main strength of this review is that this is the first systematic review with quantitative assessment and heterogeneity analysis on the burden of ADRs in the primary care with evaluation of the quality of the studies. We presents detailed information on factors contributing to heterogeneity, preventability, medication class frequently implicated, severity, and risk factors of ADRs. In addition, the risk of bias of included studies were assessed using the specific assessment instrument for ADRs studies.

Limitations

The finding of this review should be interpreted in light of its limitations. Firstly, there was a substantial heterogeneity in the reported prevalence between studies. Previous systematic review showed that high statistical heterogeneity is more frequent in meta-analyses of prevalence compared to binary outcome [ 115 , 119 ]. We performed subgroup analysis and meta-regression to allow better identification of potential source of variability, showing that different ADRs detection methods, age group, setting, and sample size affected the estimates. Secondly, there was no uniformity with regard to description of medications associated with ADRs. Some studies described the medication in Anatomical Therapeutic Chemical (ATC) level and others in specific drug class/active substances level, making the comparison challenging. Thirdly, all eligible studies were performed in the context of European, North America, and Australian healthcare systems, which limit the generalisability of the results. Nevertheless, the finding of this review might serves as basis estimate for other countries, where the prevalence of overall ADRs in primary care have yet to be characterised.

ADRs constitute a significant health problem in the primary care setting. Cardiovascular system drugs were the most commonly implicated medication class. Further research should focus on examining whether ADRs affect subsequent clinical outcomes, particularly in high-risk therapeutic areas. Such understanding might better inform strategies to reduce the burden of ADRs in the primary care setting.

Supporting information

S1 appendix. prisma 2009 checklist..

https://doi.org/10.1371/journal.pone.0252161.s001

S2 Appendix. Search strategy.

https://doi.org/10.1371/journal.pone.0252161.s002

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Adverse drug reactions

Affiliations.

• 1 Servicio de Farmacología Clínica, Hospital Universitari Germans Trias i Pujol, Barcelona, España; Departamento de Farmacología, Terapéutica y Toxicología, Universitat Autònoma de Barcelona, Barcelona, España. Electronic address: [email protected].
• 2 Servicio de Medicina Interna, Hospital Universitari Germans Trias i Pujol, Barcelona, España; Departamento de Medicina, Universitat Autònoma de Barcelona, Barcelona, España.
• PMID: 31771857
• DOI: 10.1016/j.medcli.2019.08.007

An adverse drug reaction (ADR) is defined as a response to a medicinal product which is noxious and unintended. ADRs are an important cause of morbidity and mortality and increase health costs. The pharmacovigilance systems allow the identification and prevention of the risks associated with use of a drug, especially of recently marketed drugs; they detect signals from data of the global ADR register and also support decisions taken by regulatory agencies in different countries. Only a few drugs are withdrawn from the market, mainly due to hepatotoxicity. Spontaneous notification of ADR is the cheapest, simplest and most used method to recognize new safety drug problems, under-reporting being its main limitation. The future of pharmacovigilance and ADRs will include a higher involvement of patients, doctors, health authorities and pharmaceutical companies, and the use of new technologies.

Keywords: Adverse drug reaction; Drug safety; Efecto adverso; Farmacovigilancia; Pharmacovigilance; Reacción adversa a medicamento; Seguridad del medicamento; Side effect.

Copyright © 2019 Elsevier España, S.L.U. All rights reserved.

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• Published: 23 March 2020

Adverse drug reactions in older adults: a retrospective comparative analysis of spontaneous reports to the German Federal Institute for Drugs and Medical Devices

• Diana Dubrall   ORCID: orcid.org/0000-0002-8763-051X 1 , 2 ,
• Katja S. Just 3 ,
• Matthias Schmid 1 ,
• Julia C. Stingl 3 &
• Bernhardt Sachs 2 , 4  

BMC Pharmacology and Toxicology volume  21 , Article number:  25 ( 2020 ) Cite this article

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Metrics details

Older adults are more prone to develop adverse drug reactions (ADRs) since they exhibit numerous risk factors. The first aim was to analyse the number of spontaneous ADR reports regarding older adults (> 65) in the ADR database of the German Federal Institute for Drugs and Medical Devices (BfArM) and to set them in relation to i) the number of ADR reports concerning younger adults (19–65), and ii) the number of inhabitants and assumed drug-exposed inhabitants. The second aim was to analyse, if reported characteristics occurred more often in older vs. younger adults.

All spontaneous ADR reports involving older or younger adults within the period 01/01/2000–10/31/2017 were identified in the ADR database. Ratios concerning the number of ADR reports/number of inhabitants and ADR reports/drug-exposed inhabitants were calculated. The reports for older ( n  = 69,914) and younger adults ( n  = 111,463) were compared using descriptive and inferential statistics.

The absolute number of ADR reports involving older adults increased from 1615 (2000) up to 5367 ADR reports (2016). The age groups 76–84 and 70–79 had the highest number of ADR reports with 25 ADR reports per 100,000 inhabitants and 27 ADR reports per 100,000 assumed drug-exposed inhabitants. For both ratios, the number of reports was higher for males (26 and 28 ADR reports) than for females (24 and 26 ADR reports). Fatal outcome was reported almost three times more often in older vs. younger adults. Six out of ten drug substances most frequently suspected were antithrombotics (vs. 1/10 in younger adults). For some drug substances (e.g. rivaroxaban) the ADRs reported most frequently differed between older (epistaxis) and younger adults (menorrhagia).

Conclusions

There is a need to further investigate ADRs in older adults since they occurred more frequently in older vs. younger adults and will likely increase in future. Physicians should be aware of different ADRs being attributed to the same drug substances which may be more prominent in older adults. Regular monitoring of older adults taking antithrombotics is recommended.

Peer Review reports

Older adults usually present with many risk factors promoting the occurrence of adverse drug reactions (ADRs) [ 1 ] like e.g. multimorbidity which can lead to polypharmacy [ 2 ]. In Germany, up to 58% of older adults suffer from at least one chronic disease [ 3 ], and around 50% in the age group of 70–79 years exhibit polypharmacy [ 4 ]. Further risk factors for ADRs in older adults include changes in renal and hepatic clearance, distribution and metabolism leading to prolonged half-lives or higher plasma concentrations if not taken into consideration [ 5 ].

With regard to spontaneously reported ADRs roughly three times more ADR reports per million inhabitants per year are reported for older adults aged 65–74 years compared to younger adults aged 5–19 years for high-income countries [ 6 ]. Since ADRs are an important cause for morbidity and death [ 7 ], they have a significant impact on healthcare systems, especially in older adults [ 8 ]. For example, ADR-related hospital admissions are more common in older than younger adults in two German observational studies [ 9 , 10 ]. Concerning ADRs resulting in death, the highest number of reported fatal ADRs is reported for the older adults aged 71–80 years in a Swedish study [ 11 ].

Since the proportion of older adults within the German population is steadily increasing [ 12 ] (in 2060 roughly every third person will be ≥65 years [ 13 ]) the impact and significance of ADRs in older adults is supposed to gain further medical and economic relevance in the future.

In general, ADRs in older adults may be difficult to recognise as they often present with unspecific symptoms or are attributed to underlying diseases. Therefore, the causal association with drug treatment is difficult to assess [ 10 , 14 ] and the prevalence of ADRs in older adults might even be higher. With regard to the reporting of ADRs, some (older) studies found that ADRs in older adults are less often reported [ 15 , 16 ] whereas a recent study describes the opposite [ 17 ].

Since some drugs were found to be associated more often with ADRs in older adults, lists of potentially inappropriate medications (PIMs) for older adults (e.g. PRISCUS list, international Beers Criteria) have been published [ 18 , 19 , 20 ]. Irrespective of these lists of PIMs, in spontaneous reports from Italy and Sweden the drug classes reported most frequently to be associated with ADRs in older adults are cardiovascular drugs and drugs acting on the blood and blood forming organs [ 17 , 21 ].

The present study is the first retrospective analysis of spontaneous ADR reports (specified as “ADR reports” in the following) concerning older adults (> 65 years) performed in the large ADR database of the Federal Institute for Drugs and Medical Devices (BfArM) [ 22 ]. The first aim of the study was to determine the number of ADR reports regarding older adults (> 65 years) and to set these reports in relation to i) the number of spontaneous ADR reports regarding younger adults (19–65), and ii) the number of inhabitants [ 23 ] and assumed drug-exposed inhabitants [ 4 ], and to oppose the ADR reports to the number of defined daily doses (DDD) used per insured person [ 24 ]. The second aim was to analyse, if some of the reported characteristics are more often described in the ADR reports of older adults compared to younger adults.

Reporting channels

Physicians in Germany are obliged by their professional code of conduct to report ADRs to their professional councils which forward these reports to either BfArM (responsible for chemically defined drugs) or Paul-Ehrlich-Institut (PEI) (responsible for monoclonal antibodies, vaccines etc.) as described elsewhere [ 25 ]. BfArM and PEI are independent federal higher authorities within the portfolio of the Federal Ministry of Health (so called competent authorities) [ 26 ].

Both, Health Care Professionals (HCPs) and Non-Health Care Professionals (non-HCPs, e.g. consumer) may also directly report to one of these two competent authorities, or to the respective marketing authorization holders.

ADRs can be reported online [ 27 , 28 ] or by using standardized reporting forms. Alternatively a reporting by fax, scan, or postal mail, or directly (without a form) by postal mail, fax, or email is also possible. However, the online platforms are explicitly recommended for ADR reporting as all relevant information is specifically queried there.

Until 22 November 2017 [ 29 ] marketing authorization holders forwarded the ADR reports to the aforementioned competent authorities. After the changes to the pharmaceutical legislation in 2012 marketing authorization holders had to report transitionally to BfArM or PEI, and additionally to the European Medicines Agency (EMA). However, this transitional period ended on 22 November 2017 and BfArM’s ADR database was closed. From that date onwards marketing authorization holders, BfArM, and PEI now forward serious and non-serious ADRs directly to the EMA.

The public access to the restricted set of data elements of BfArM’s ADR database is no longer available since the closure of the database [ 29 ]. Due to data privacy requirements, it is not possible to make the individual case reports available to the readership. Nevertheless, researchers and/or readers who are interested can perform the same analysis in the ADR database EudraVigilance of the EMA [ 30 ]. However, different levels of access are granted for different stakeholders [ 31 ].

BfArM’s ADR database

BfArM’s ADR database contains about 555,000 ADR reports from Germany up to the data lock point November 22, 2017. The majority of these ADR reports (69.8%) were reported spontaneously (voluntary reporting), whereas 28.2% were reported in studies. In 2.0% it was unknown whether the ADR report originated from spontaneous reporting or from a study [ 25 ]. We restricted the present analysis to spontaneous reports for consistency and to avoid any bias through stimulated reporting. In the vast majority of these spontaneous reports a HCP (82.5%) was involved in the reporting of the ADR. In contrast, in 15.6% of the spontaneous reports a non-HCP reported (in 4.5% both, a HCP and a non-HCP reported, and in 6.4% the reporter was unknown).

In the database, drugs are coded according to the WHO Drug Dictionary [ 32 ] and the Anatomical Therapeutic Chemical (ATC) classification system [ 33 ]. ADRs are coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology [ 34 ]. Both terminologies include five different hierarchical levels for coding and, thus for the analysis of the reported drug substances and ADRs, respectively. The five hierarchical levels represent different levels of analysis with regard to granularity and specificity. In both the highest level of the terminology represents the analysis level of aggregated data (coarse-grained data) with lowest specificity. In contrast, the lowest level of the terminology represents the finer-grained analysis level with highest specificity.

According to the legal definition an ADR is a noxious and unintended reaction caused by a medicinal product [ 35 ]. In 2012 the definition of an ADR was extended to the use outside the marketing authorisation including off-label use, overdose, misuse, abuse, and medication errors [ 36 ]. A more detailed description of the changes to the legal reporting obligation in the time period from 1987 to 2016 is published elsewhere [ 25 ]. The defined time period of our analysis covers both, the new and the old legal definition. For consistency, we restricted our analysis to ADRs associated with the intended use of a drug.

Identification of cases and reference group

We identified all spontaneous reports of ADRs referring to patients > 65 years (“ older adults ” aligned with the most frequently applied definition for older adult in developed countries [ 37 ]), registered between 01/01/2000–10/31/2017, from Germany ( n  = 74,950) in which drugs were designated as “suspected/interacting” (Fig.  1 ). All ADR reports coded as medication errors, intentional suicide/self-injury, or drug abuse were excluded by application of respective standardised MedDRA queries [ 25 , 34 ] ( n  = 71,412). Subsequently, 1355 cases with an unknown primary source were excluded (resulting in n  = 70,057). In order to analyse i) if more ADR reports of older adults are contained in BfArM’s ADR database, and ii) if some of the reported characteristics are more often reported in ADR reports of older adults a reference group with patients aged 19–65 years (“ younger adults ”) was generated. For this reference group the same inclusion and exclusion criteria were used ( n  = 111,606). We excluded 143 cases contained in both datasets. Finally, the dataset older adults consisted of 69,914 reports whereas the dataset of younger adults included 111,463 reports.

Flowchart: identification of ADR reports for older adults and younger adults

Assessment of ADR reports with regard to quality of documentation and causal association

Due to the large sample size in our analysis ( n  = 69,914 reports) it was not possible to assess each case individually. Instead, we assessed a random sample of 250 ADR reports of older adults . This random sample was drawn by using the sample function in R [ 38 ]. First, 15 of the randomly selected cases were assessed together by the three evaluators KJ (physician), BS (physician), and DD (pharmacist) in order to harmonise the application of the VigiGrade completeness score [ 39 ] and the WHO criteria [ 40 ]. VigiGrade evaluates the documentation quality of the ADR reports. A report with a completeness score higher than 0.8 is considered as well documented [ 39 ]. The WHO criteria were applied to assess the causal relationship between administration of the suspected drug substances and the ADR. After 50 cases had been assessed we calculated the mean completeness score and its standard deviation (SD). Based on this result we estimated how many cases we would have to evaluate to achieve a completeness score of 0.8. According to this calculation a random sample of 250 cases was necessary. Therefore, we set the case number to 250 for our assessment of quality of documentation and causal association.

The calculation of the completeness score (VigiGrade, [ 39 ]) was, however, modified as it was not computed for every reported drug-ADR pair (in case more than one ADR had been reported) and then aggregated to an average, to yield an overall score for the corresponding report. Instead, the score was only calculated for the leading ADR [ 41 ].

Finally, the completeness score of our 250 randomly selected cases was 0.75 (95% CI = [0.69–0.81]) with the upper limit of the confidence interval including 0.8. “Time to onset” was the most imprecise criterion (40.4% of reports) due to the fact that it was not documented exactly (19.2%) or was even missing (21.2%).

The assessment of the causal relationship based on the WHO criteria [ 40 ] was chosen since it is an internationally used method and due to already existing experiences of the study team regarding its application. In 199/250 reports (79.6%) the causal relationship was considered to be “at least possible” (i.e. 1.6% (4/250) certain plus 22.0% (55/250) probable plus 56.0% possible (140/250)). Hence, if the random sample was representative for the whole dataset, one could expect a dataset of well-documented cases in which about 80% of the reported ADRs have an “at least possible” causal relationship.

Strategy of analysis

For each group we analysed the number of reports per year, demographic parameters, reported history, seriousness criteria, administration route of the applied drugs, the drugs most frequently reported as suspected together with their most frequently reported ADRs, and the 20 ADRs which were reported most often (irrespective of the drug concerned). Additionally, age-stratified analyses (age intervals: 66–75, 76–85, 86+) were performed in older adults .

In order to analyse the reported history, suitable hierarchy levels of the MedDRA terminology [ 34 ] were selected. According to the legal definition, an ADR was considered serious if it led to death, was life-threatening, required or prolonged hospitalisation, resulted in persistent or significant disabilities, and/or was a congenital anomaly/birth defect [ 42 ]. Hence, this classification of seriousness of the ADR report may differ from the clinical severity of the perceived ADR.

For an overview on drugs classes frequently suspected to cause an ADR, we performed the analysis on the second level of the ATC-code [ 32 , 33 ] which is a more aggregated level (with lower specificity). Additionally, the drug substance level was selected for a more specific analysis. The ADRs reported most frequently overall and the ADRs associated with the most frequently reported drug classes and drug substances were analysed in both, older and younger adults on the preferred term (PT) level of the MedDRA terminology [ 34 ].

With regard to PIMS we analysed the number of respective ADR reports separately for older adults . For this purpose the PRISCUS list [ 18 ] was applied as it was the recommendation used presumably most often by physicians in Germany with regard to drug prescribing in older adults. However, the PRISCUS list was lastly revised in 2011. Hence, we also discuss (see discussion) the 10 drug classes and drug substances most frequently reported as suspected in older adults with regard to the recommendations of the Beers Criteria [ 19 ].

In general, in older adults 88,968 suspected drug substances and 206,666 ADRs (PT-level) were coded compared to 136,791 suspected drug substances and 338,046 ADRs (PT-level) in younger adults . Only 3.2% and 1.7% of the ADR reports for the older adults and younger adults were explicitly designated as “interacting”. Hence, these ADR reports were not separately analysed in the context of this study.

The study was designed as a retrospective ADR database analysis which was linked to population-related data about inhabitants [ 23 ], assumed drug-exposed inhabitants [ 4 ], and DDD per insured person [ 24 ], and which incorporates a comparative analysis of ADR reports of older adults and younger adults .

Number of DDD per insured person

In order to describe the prescribing behaviours in Germany with rising age we extracted the number of defined daily doses (DDD) per insured person per age group for each of the years 2000–2016 in the German drug prescription reports [ 24 ]. Averages (+/−SD) of the mean number of DDD per insured person were calculated for the 16 years per age group. The average number of DDD per insured person of the 16 years per age group was divided by 365 days to calculate the mean number of DDD used per day per insured person per age group.

The drug prescription reports contain all outpatient drug prescriptions of statutory insured patients [ 24 ]. Hence, the drug prescription report covers about 80–90% of the German population. The number of prescribed drugs is not patient-related and is available in DDD only. Further limitations refer to missing data on privately insured patients, over-the-counter (OTC) drug use, and inpatient treatments. There is also no exact data referring to the DDD per insured males/females.

Number of inhabitants and assumed number of drug-exposed inhabitants

The exact number of drug-exposed inhabitants and drug-exposed males/females in Germany is unknown as already described in the previous section [ 24 ]. Hence, data about the German population distributed by age and gender for each of the years 2000–2016 (since data of 2017 were limited to October) was extracted from the GENESIS database of the Federal Statistical Office [ 23 ] to calculate reporting rates. First, averages (+/−SD) were calculated for the number of ADR reports divided by the number of inhabitants identified for the 16 years for i) each age group, and ii) each of the reported seriousness criteria in the age and gender-stratified analysis. The results are presented as the number of ADR reports per 100,000 inhabitants. However, not all inhabitants are exposed to medication and the proportion of drug exposure may vary between age and gender. Therefore, we estimated the number of assumed drug-exposed inhabitants and drug-exposed males/females based on the number of German inhabitants and German males/females per age group for each year multiplied by the proportion of drug-exposed patients published by a study about the medication use of German adults (DEGS1) [ 4 ]. In order to match the conditions of that study, the analysis was adapted to the period of the aforementioned study (2008–2011). Averages (+/−SD) were calculated for the number of ADR reports divided by the number of assumed drug-exposed inhabitants identified for each age group for each of the 4 years. The results are presented as the number of ADR reports per 100,000 assumed drug-exposed inhabitants. Both calculations were based on the date of the ADR report and not of the ADR. However, any inaccuracy would apply to all years, thus diminishing any effects.

Statistical analysis

Means and medians were calculated for the patients’ age, the annual increase of ADR reports, and frequency distributions for all other results. The chi-squared test was applied to assess differences between the frequency distributions of the datasets for older adults and younger adults . P -values below 0.05 were considered statistically significant. Odds ratios with Bonferroni adjusted confidence intervals (CI) to account for multiple testing were calculated for demographic parameters, comorbidities, the drug classes and drug substances reported most often and their respective ADRs reported most frequently, and for the 20 ADRs reported most frequently, irrespective of the drug concerned.

To analyse if the number of reports for older adults have increased proportionally to the number of reports for younger adults a ratio ( older adults / younger adults ) was calculated for each year.

Regression slopes for the number of ADR reports per 100,000 older adults and younger adults per year were estimated using linear regression analysis. In order to model the differences in the yearly increase of the slopes for ADR reports per 100,000 older adults vs. younger adults, an interaction effect between the number of ADR reports per 100,000 younger adults and years was included. Differences in the variances of the two groups were taken into account by weighting the observations in the linear model by inverse residuals.

Wilcoxon-Mann-Whitney test was used to detect differences in the medians of the number of ADR reports per 100,000 German males/females for each age group.

All analyses were performed using R, version 3.3.3. The study was approved by the local ethics committee of the Medical Faculty of Bonn (009/17).

Characteristics of the reports

Overall age groups more ADR reports referred to females than to males (absolute numbers, without any relation to inhabitants and drug-exposed inhabitants) (Table  1 ). The relative proportion was slightly higher in younger adults than in older adults (60.3% vs. 55.9%, OR 0.8 [0.8–0.9]), and increased with rising age within older adults .

The reports of older adults were more often designated as “serious” (83.9% vs. 78.9%; p  < 0.001) or “required or prolonged hospitalisation” (40.2% vs. 32.7%; < 0.001), and were even 3 times more often designated as “fatal” (9.1% vs. 3.4%; < 0.001) compared to the reports of younger adults .

More comorbidities were reported in older adults compared to younger adults . For instance, pre-existing vascular hypertensive disorders and renal disorders were mentioned in 24.5 and 8.9% of the reports from older adults compared to 9.2 and 2.8% of the reports from younger adults (OR 3.2 [3.1–3.3], OR 3.4 [3.2–3.6]) (Table 1 ). There were no substantial differences regarding either the oral or intravenous route of administration between older adults and younger adults .

Annual number of ADR reports (absolute numbers)

The number of ADR reports contained in the ADR database (absolute numbers, without any relation to inhabitants and assumed drug-exposed inhabitants) increased from 2000 to 2016 for younger adults and older adults with an annual mean increase of 177 and 165 ADR reports, respectively. The calculated ratio of ADR reports for older adults / younger adults slightly increased from 0.4 in the year 2000 to 0.7 in the year 2017 (mean ratio for the time period 2000–2017: 0.6; range: 0.4–0.8). The age-stratified mean increase of the number of ADR reports per year for the age groups 66–75 years and 76–85 years was approximately the same (both 66 reports/year), while it was notably lower for the age group 86+ years (15 reports/year) (see Supplementary Figure 1 and Supplementary Table 1, Additional file  1 ).

Number of reports in relation to inhabitants, assumed drug-exposed inhabitants, and DDD per insured person

The annual number of ADR reports for older adults and younger adults per 100,000 inhabitants increased from 2000 (12.7 and 6.9) to 2016 (32.6 and 15.8) (Fig.  2 ). Analysis of the regression slopes revealed a significantly larger increase in older adults ( p -value for interaction effect < 0.001). Across eight age groups the average number of ADR reports/100,000 inhabitants was highest for the age groups 66–75, 76–84, and 85+ (Fig.  3 ). This finding remained stable if the number of reports was related to the assumed proportion of drug-exposed inhabitants in the respective age group (see Supplementary Document 1, Additional file  2 ). Notably, the average number of DDD per insured person per age group increased from the youngest age group (25–34) to the age group 75–84 (Fig.  4 ). The youngest age group (25–34) used on average 0.3 DDD per insured person per day in contrast to 3.8 DDD per insured person for the age group 75–84.

Number of ADR reports per 100,000 younger/older German inhabitants per year. *interaction test of the slopes: p < 0.001; slope older adults: 1.3 [0.9-1.7]; slope younger adults: 0.5 [0.5-0.6]. Figure  2 shows the number of ADR reports for younger adults per 100,000 German inhabitants (19–65) and the number of ADR reports for older adults per 100,000 German inhabitants (> 65) [ 23 ] per year. The increases in the number of ADR reports for older adults and younger adults are presented as weighted linear regression slopes. There was a significant higher increase of the slope for the number of reports per 100,000 older adults than per 100,000 younger adults ( p  < 0.001). The obvious higher number of ADR reports for older adults in 2007 is mainly due to reports for rofecoxib (withdrawn in 2004). Roughly 30.0% of these ADR reports in 2007 referred to rofecoxib as suspected drug substance compared to 5.2% of the reports for younger adults . About 98.7% of the reports concerning rofecoxib in 2007 were reported by lawyers. Hence, the delayed increase of the number of ADR reports referring to rofecoxib may likely be due to lawsuit after its withdrawal. The limitations of both data sources have to be considered [ 23 , 25 ]

Average number of ADR reports per 100,000 German inhabitants distributed by age and gender. *Wilcoxon-Mann-Whitney test < 0.05. The Fig. 3 shows the average number (+/− SD) of ADR reports per 100,000 German inhabitants distributed by age and gender [ 23 ]. The age groups were adapted for this analysis since inhabitants older than 85 years could not be stratified further in the database queried. All ADR reports (male, female and unknown gender) were considered for the calculation of the total average number of spontaneous reports per 100,000 inhabitants (grey bars). Thus, the grey bars possibly do not lie exactly in the middle between the blue and red bars for males and females

Average number of DDD per insured person. Figure  4 shows the average (+/− SD) of DDD per insured person per age group per year [ 24 ]. The mean DDD per day was inserted at the bottom of the bars for each age group. The data stemmed from the German drug prescription reports for the years 2001–2017. The defined age groups of the drug prescription reports were adapted for this analysis since they did not match the defined age groups of the ADR database analysis. Defined daily dose (DDD): The DDD is based on the amount of active substances or medicinal product that should typically be used for the main indication per day. The DDD does not necessarily reflect the recommended or actual administered dose of a drug substance or medicinal product. It mainly provides a technical means of measurement and comparison [ 24 ]

If the number of ADR reports was set in context to inhabitants and exposure more reports referred to males for the age groups > 65 years per 100,000 inhabitants and for the age group > 70 years per 100,000 drug-exposed inhabitants (see Fig. 3 and Supplementary Document 1 Additional file 2 ). In relation to the number of inhabitants, slightly more ADR reports for all of the reported seriousness criteria were observed for males (Table  2 ).

Most frequently suspected drug classes and drug substances

The analysis of the drug classes reported most often as suspected (second level ATC-code) (Table 3 ) yielded that antithrombotics were reported almost 5 times more often in older adults compared to younger adults (1st rank; 19.8% of older adults ; OR 4.6 [4.3–4.9]). Likewise, among the ten drug substances most often suspected in older adults , there were six antithrombotics (acetylsalicylic acid was mostly used as an anti-platelet agent, Table 4 ). Three of the ten drug classes (Table 3 ) are used for the treatment of nervous system disorders (6th rank psychoanaleptics, 7th rank psycholeptics, and 10th rank analgesics). Antineoplastic agents ranked 2nd, and antiphlogistics and antirheumatics ranked 3rd.

In contrast, psycholeptics were the drug class most frequently reported in younger adults (10.0% of the reports; OR 0.4 [0.4–0.5], Table 3 ). Likewise, four of the ten drug substances most frequently suspected within the reports for younger adults were antipsychotics (only one being an antithrombotic; rivaroxaban ranking 10th) (Table 4 ).

Only 3611 (4.1% of 88,968) suspected drug substances reported in older adults were PIMs according to the PRISCUS list. Olanzapine was the most often reported PIM in older adults (45th rank in older adults with 0.5% of older adults reports) (see Supplementary Table 2, Additional file  3 ). In contrast, olanzapine ranked fourth in the reports of younger adults (Table 4 ).

Most frequently reported ADRs

There is broad consistency along with some differences concerning the 20 ADRs reported most frequently in older adults and younger adults irrespective of the suspected drug substance (see Supplementary Table 3, Additional file  4 ). In the top ranks of both, mainly unspecific ADRs (“nausea”, “dizziness”, “dyspnoea”, “diarrhoea”, “pruritus”, “vomiting”, “rash”, “headache”) are listed. Interestingly, those mainly unspecific ADRs were less often reported in patients older than 86 years (see Supplementary Table 3, Additional file 4 ). The highest odds ratios (and thus more frequently reported in older adults compared to younger adults ) were observed for “gastrointestinal haemorrhage” (15th rank; OR 5.1 [4.2–6.1]), “death” (9th rank; OR 3.8 [3.3–4.4]), “fall” (18th rank; OR 3.0 [2.6–3.6]), and “cerebrovascular accident” (19th rank; OR 3.0 [2.6–3.6]). Conversely, for younger adults the lowest odds ratios compared to older adults (and thus being more reported in younger adults ) were found for “urticaria” (12th rank; OR 0.5 [0.4–0.5]), “paraesthesia” (19th rank; OR 0.5 [0.4–0.6]), and “hepatic enzyme increased” (18th rank; OR 0.6 [0.5–0.7]). The calculated odds ratios for “death”, “gastrointestinal haemorrhage”, “fall”, “cerebrovascular accident”, “cerebral infarction”, “syncope”, “cerebral haemorrhage”, and “haemoglobin decreased” increased with rising age. It should be noted though, that “death” itself is not an ADR but an outcome coded by MedDRA terminology [ 25 ].

Drug classes reported as suspected most frequently and their ADRs

The ADRs reported most frequently differed for some drug classes between older adults and younger adults . This becomes obvious with antithrombotics, psychoanaleptics, and psycholeptics (Table 3 ). For instance, for antithrombotics, “gastrointestinal and cerebral haemorrhage” were the ADRs reported most frequently for older adults . In contrast “thrombocytopenia” and “pulmonary embolism” were the ADRs reported most frequently for younger adults (possibly suggesting ineffectiveness of the drug). Similarly, “hyponatraemia” was the ADR reported most frequently for psychoanaleptics in older adults but ranked only 29th in the respective reports of younger adults .

Different drug substances belonging to the same respective drug class (Table 3 ) may account for the discrepancies in ADRs between older adults and younger adults (further description see legend Table 3 ).

Drug substances reported as suspected most frequently and their ADRs

Likewise, Table 4 shows that for some drug substances the most frequently reported ADRs between older adults and younger adults differed. The ADRs most frequently reported for rivaroxaban were “epistaxis” (OR 2.2 [1.3–3.9]), and “cerebral haemorrhage” (OR 3.6 [1.7–7.3]) in older adults vs. “menorrhagia” (OR 0.0 [0.0–0.1]), and “deep vein thrombosis” (OR 0.3 [0.2–0.5]) in younger adults . Further analysis with regard to rivaroxaban revealed that the indications most often reported differed between older adults and younger adults (see Supplementary Table 5, Additional file  6 ). Hence, not only the drug substance itself but the difference in the indications (i.e. the underlying diseases) could have affected the ADR profile. Among the other antithrombotic agents (acetylsalicylic acid (3rd rank), phenprocoumon (4th rank), and apixaban (5th rank)) differences concerning the ADRs most frequently reported were less striking (see Supplementary Table 6, Additional file  7 ). However, “gastrointestinal haemorrhage” (OR 1.9 [1.1–3.2]) related to phenprocoumon, “cerebral haemorrhage” (OR 2.3 [0.8–7.2]) related to apixaban, “gastrointestinal haemorrhage” related to dabigatran (OR 2.0 [0.7–5.5]) and clopidogrel (OR 2.1 [1.0–4.7]), respectively, were reported more often in older adults than younger adults . Further differences were observed with regard to the ADRs most frequently reported for risperidone and olanzapine. “Falls” were reported about 10 times more often for risperidone and “parkinsonism” was reported about 4 times more often for olanzapine in older adults compared to younger adults.

This study is the first retrospective analysis of ADR reports referring to older adults in the national ADR database of the competent authority BfArM in Germany. In order to strengthen the significance of the ADR database analysis, parallel analysis with other external data sources providing complementary data about the number of inhabitants [ 23 ], the medication use (prescription-only medicine and OTC) [ 4 ], and drug prescriptions [ 24 ] were also conducted. Furthermore, the ADR reports of older adults were compared to ADR reports of younger adults in order to identify differences among both patient populations. We saw a significant higher increase of ADR reports in older adults per 100,000 inhabitants vs. younger adults per 100,000 inhabitants in the last years, underlining the importance of ADRs in older adults. Interestingly, the ADRs reported the most frequently differed for some drug classes and drug substances between older vs. younger adults .

An increase of the absolute number of ADR reports with rising age up to the age group 66–70 years was already shown in our previous descriptive analysis of all ADR reports contained in BfArM’s ADR database [ 25 ]. In the present study, however, the number of ADR reports was set in relation to the number of inhabitants and assumed drug-exposed inhabitants distributed by age and gender [ 4 , 23 ]. We found an increase in the number of ADR reports per 100,000 inhabitants and assumed drug-exposed inhabitants with rising age up to the age groups 76–84 years and 70–79 years, respectively. Our finding may reflect the increase of older inhabitants in the same time frame in Germany [ 23 ] which may have led to an increase of drug-exposed inhabitants and, thus, more patients with ADRs.

In an analysis of the global ADR database Vigibase the highest mean number of ADR reports per million inhabitants for high-income countries has been observed for the age group 65–74 years [ 6 ]. The slight shift compared to our age strata may be explained by differences of the underlying data. Our analysis was restricted to Germany only, whereas the analysis in Vigibase included several high-income countries.

The rising frequency of ADRs with older age per inhabitants has also been described in ADR database analysis of other countries [ 21 , 43 , 44 ]. A higher proportion of ADRs in inpatients older than 65 years compared to younger inpatients has been reported in two medical record studies performed in German hospitals as well [ 10 , 45 ]. Various factors may account for this finding, e.g. a higher proportion of multi-morbid persons and a higher proportion of drug-exposed and polymedicated patients, which has been described in two German surveys [ 3 , 4 ]. Polypharmacy and comorbidities have been assumed to correlate with the seriousness of spontaneously reported ADRs in a study from Italy [ 21 ]. This may also explain the increase of serious ADRs with rising age in our analysis (see below).

ADRs itself and ADR related hospital admissions are associated with costs for the Health Care System [ 46 ] which are estimated to be even higher for patients older than 65 years [ 9 ]. Assuming that the number of ADR reports will further increase in the future, we would expect almost a doubling of ADR reports per 100,000 older inhabitants (78.9 [62.1–95.7] ADR reports) in the year 2050 based on the linear trend displayed in Fig. 2 . If so, a further increase of health care costs can be expected in the future. However, this prediction is associated with considerable uncertainty due to the distance of the year 2050 to the analysed time period (2000–2016) and possible unknown variables (e.g. legislative changes) that may occur in the future and could impact on this scenario.

Known risks for ADRs in older patients are age-related changes in pharmacodynamics and pharmacokinetics, e.g. reduced kidney and liver function leading to a higher variability in drug response [ 5 , 47 ]. Likewise, we also found a higher proportion of patients with one of the queried comorbidities (e.g. cardiac disorders) with rising age, except for hepatobiliary disorders. The higher number of patients with hepatobiliary disorders in younger adults compared to older adults could be due to a reduced life expectancy of patients with severe - and thus possibly also more often reported - hepatobiliary disorders. Compared to a German survey [ 3 ] the proportion of individuals older than 65 years with hypertension was much lower in our analysis (50% vs. 24.5%). This discrepancy could be due to incomplete or missing data in the ADR reports or differences in the recording of diseases inherent to the different study designs.

In the present study an ADR was considered serious if it led to death, and/or hospitalisation or prolonged hospitalisation, and/or congenital anomalies or was life-threatening [ 42 ]. A higher proportion of “serious” ADRs and ADRs “leading to/or prolonging hospitalisation” with increasing age has been seen in spontaneously reported ADRs from Italy and Sweden as well [ 11 , 21 ]. Likewise, in a German cohort study an increase of ADR related hospital admissions has been reported with increasing age [ 9 ]. However, differences regarding the study designs have to be considered.

Like the Swedish study which focussed on fatal ADR reports [ 11 ] we observed an increase of ADR reports informing about a fatal outcome with rising age, as well. However, it should be noted that we did not specifically assess fatal ADR reports with regard to their causal relationship. Hence, we cannot elucidate the number of cases in which the fatal outcome was due to other causes like underlying comorbidities or natural death.

As also observed in other ADR database analysis [ 17 , 48 , 49 ] we found a higher absolute number of ADR reports referring to older females with rising age. This finding may be explained by (i) sex differences in pharmacokinetics and pharmacodynamics [ 50 ], (ii) differences in reporting behaviours (females tend to report ADRs more often than males [ 48 , 51 ]), (iii) the higher number of female inhabitants in the older German population [ 23 , 52 ], and (iiii) more older females in the German population taking drugs and having comorbidities compared to older males [ 3 , 4 ].

Unexpectedly, slightly more ADR reports referred to older males than females when related to either 100,000 inhabitants or assumed drug-exposed inhabitants in our analysis. With regard to gender related differences concerning ADRs in older adults there is conflicting data in literature [ 15 , 17 , 44 , 53 , 54 , 55 ]. Different study designs (e.g. observational studies versus analysis of ADR reports) and different denominators (e.g. drug prescriptions versus inhabitants) may account for these differences. For instance, female gender as a risk factor for ADRs has been reported in a prospective multicentre cohort study involving three German hospitals and one hospital in Jerusalem overall and for females older than 65 years even after adjusting for age, body mass index and the number of prescribed drugs [ 53 ]. In a Swedish study the number of ADR reports for females related to the number of drug prescriptions in DDD was similar or only slightly lower in the age groups 75–84 years and ≥ 85 years but significantly higher in the age group 65–74 years compared to males [ 17 ]. In an older study from West Germany Hopf et al. [ 15 ] found more ADR reports per 1,000,000 million inhabitants for males from the age group 60–69 years onwards. However, this was only observed before adjusting for drug exposure in DDD [ 15 ]. Our results that more ADR reports referred to older males for both denominators (inhabitants and drug exposed-inhabitants) are thus in line with the first but not the second finding (different denominators) from Hopf et al. [ 15 ].

In some database analyses a higher proportion of “serious” ADR reports and/or ADR reports with fatal outcome were found in older males [ 11 , 17 , 49 ]. In our study, a slightly higher number of ADR reports for all seriousness criteria in all stratified age groups was only observed when related to 100,000 inhabitants (not for all age groups in absolute numbers). In a French analysis, a preponderance of male gender for serious ADRs in relation to inhabitants has been observed for the age group 60–69 years only [ 54 ]. Possibly the higher number of ADR reports per 100,000 older male inhabitants in our analysis may be due to serious ADRs which are more often reported by German physicians [ 56 ]. However, as a conclusion from our findings, female gender should not be considered as a risk factor for all age groups. Especially in older adults more emphasis should be put on the occurrence of ADRs and serious ADRs in older males.

In the last few years the number of drug prescriptions for antithrombotics (especially for rivaroxaban) increased enormously [ 24 ] and drug-exposure in terms of DDD increased with rising age [ 24 ]. Likewise, in our analysis almost one fifth (19.8%) of all ADR reports of older adults reported an antithrombotic agent as “suspected/interacting” drug (and the number of these reports has increased over the last years). However, we cannot elucidate whether antithrombotics actually cause more ADRs or if these are only reported more frequently, due to the huge number of drug prescriptions. Nevertheless, antithrombotics were identified as the top ranking drugs responsible for ADR in older adults in ADR database studies from Italy and France [ 21 , 57 ] and in medical record studies from Germany and US [ 10 , 58 ]. In contrast, psycholeptics ranked first in younger adults in our analysis accounting for 10.0% of all reports in younger adults (4.5% of all reports in older adults ). This finding is in line with studies showing that ADRs associated with drugs acting on the nervous system were more often reported for younger adults [ 17 , 21 ] vs. older adults [ 59 ].

Interestingly, for some drug substances and drug classes the ADRs reported most often differed between older adults and younger adults . This was striking for rivaroxaban. Differences regarding the reported indications for rivaroxaban between younger and older adults and, thus, a more common chronic use (e.g. atrial fibrillation) in older adults may account for this finding. A cohort study has shown that the risk for bleeding, especially gastrointestinal bleeding, inherently increases with rising age [ 60 ], it may then be potentiated by antithrombotics. In this respect, higher numbers of ADR reports with regard to gastrointestinal and nervous system haemorrhages associated with direct oral anticoagulants have been seen in patients aged 60 years or older compared to younger patients in a study performed in two large ADR databases from USA and Japan [ 61 ]. Haemorrhages were the cause of death reported most often in the Swedish study of fatal ADR reports [ 11 ]. Within these reports, antithrombotics were most frequently suspected. Hence, our data in conjunction with the data from literature underline the recommendation to monitor older patients taking antithrombotics.

Likewise to the increase of prescription-only drugs, the use of OTC drugs increases with rising age [ 4 ]. Two out of the 10 most frequently reported drug substances in older adults are also available as OTC drugs in Germany (acetylsalicylic acid (3rd) and diclofenac (7th)). In our analysis we cannot differentiate, if acetylsalicylic acid or diclofenac had been prescribed or taken as an OTC drug. However, since OTC drugs may also cause ADRs or interact with prescribed therapy [ 62 ] the importance of taking a full medical history inclusive OTC drugs and food supplements still remains.

In our study, “parkinsonism” was reported as an ADR for psycholeptic drugs and olanzapine 1.8 times and 4 times more often in older adults compared to younger adults , respectively. In general, the prevalence of Parkinson disease increases with rising age [ 63 ]. However, “parkinsonism” as an example for an ADR may be difficult to distinguish from the onset of the disease itself, the progression of the disease or signs of aging, which illustrates the challenge of ADR recognition in older adults. Hence, in order to avoid prescription cascades new symptoms should be critically examined and their aetiology clarified.

The exact exposure of older adults with PIM in the German population is unknown. In our analysis PIMs according to PRISCUS [ 18 ] were not very frequently reported as suspected in older adults . One explanation for this observation could be that non-PIM related ADRs are more frequently in our analysis due to the higher number of drug prescriptions for non-PIMs. This may lead to an underrepresentation of ADRs related to PIMs. In a prospective medical record study performed in Germany the prevalence of ADRs associated with a PIM was rather low [ 45 ]. Likewise, more ADR reports related to non-PIMs than to PIMs according to the Laroche list have also been reported in a study conducted in a French Pharmacovigilance database [ 57 ]. However, differences in PIM lists and PIM prescription behaviours between Germany and France complicate the comparability of this study with our study. In addition, an underreporting of PIMs e.g. due to fear of legal consequences cannot be excluded. This limitation, however, would probably also apply to the French study.

In our analysis, risperidone and mirtazapine were the psycholeptic and psychoanaleptic drug substances reported most frequently in older adults . Both are recommended in the PRISCUS list [ 18 ] to be prescribed instead of other psycholeptics and psychoanaleptics. Conversely, the international Beers Criteria [ 19 ] advises caution when using both drug substances in older adults and recommend a close monitoring of sodium levels when prescribing mirtazapine and psychoanaleptics. In our analysis “hyponatraemia” was infact about 7 times more often reported for the drug class psychoanaleptics in older adults than in younger adults .

In the Beers Criteria [ 19 ] the chronic use of diclofenac is discouraged in older adults due to an increased risk of gastrointestinal (GI) bleeding. In contrast, diclofenac is not reported as inappropriate drug for older adults in the PRISCUS list [ 18 ]. In our analysis, “GI haemorrhage” associated with diclofenac (7th rank) was roughly three times more often reported in older adults compared to younger adults . It should be noted that diclofenac is also available as an OTC drug in Germany. Hence, diclofenac intake will even be higher, and subsequently may impact on the number of ADR reports referring to diclofenac. In summary, our findings with regard to risperidone, mirtazapine, and diclofenac are consistent with the recommendation of the Beers Criteria.

The seven ADRs reported most frequently for older adults and younger adults are rather unspecific and may be co-reported to the main ADR triggering the report [ 25 ]. Among the 20 ADRs reported most often for older adults , were “gastrointestinal haemorrhage”, “death”, “fall”, and “cerebrovascular accident” (see Supplementary File 4, Supplementary Table  3 ) . An increase in the frequency of these four ADRs was observed with rising age in our dataset and is also reported in literature [ 11 , 58 ]. This observation may reflect the increase of serious ADRs with rising age as discussed above.

Falls in general, as well as ADRs which may favour falls like syncope or confusional states (also more often reported with rising ages in our analysis) are associated with a higher mortality, morbidity and immobility [ 64 , 65 ]. These may lead to more intense need of care in older adults, resulting in an enormous increase of health care costs [ 64 ]. Hence, physicians should critically examine the current and intended drugs taken with respect to their potential to favour falls.

The monitoring of drugs used in older adults remains of major importance since data about efficacy and safety in older adults are still underrepresented in initial drug approval documents [ 66 ]. Despite its limitations the spontaneous reporting system has proved to be a useful tool to recognize ADRs after marketing approval [ 25 ]. Its strengths are based on a large population coverage including real world data as well as vulnerable patient populations (e.g. older adults, comorbid patients), a long-term data collection, and the inclusion of all types of drugs like OTC drugs [ 25 ].

One of its major limitations is the unknown amount of underreporting [ 67 ], which may depend on the type of ADR and drugs taken, or the recognition of the symptoms as an ADR, especially in older adults [ 56 ]. Another limitation is the lack of matching exact exposure data. As a consequence of these both limitations, exact incidences and prevalences cannot be calculated, which also applies to our results. To address this limitation, we set the number of ADR reports in relation to the number of inhabitants and assumed drug-exposed patients. This allows for an estimation of the dimension but should not be misunderstood as exact prevalences and/or incidences.

The distribution of ADR reports originating from physicians, pharmacists and patients was equal in older and younger adults . Hence, published differences in reporting behaviours among these three reporter types [ 25 , 56 , 68 , 69 ] are not assumed to play a role for the detected differences between younger and older adults in our analysis.

We could not account for any impact of the medical speciality of the reporter since respective data is only rarely available. The chronological age and biological age may differ individually, as well as the degree of frailty, which also could have an impact that cannot be accounted for in our analysis.

Finally, a full case validation with regard to the causal relationship and the quality and completeness of the reports was not possible due to the large sample sizes. However, we would like to point out that all ADR reports have been submitted to BfArM because the reporter assumed an underlying causal association. However, if an equal distribution of cases with poor documentation quality and lack of causal relationship is expected, the same tendency of the results would be observed with a smaller number of cases.

In summary, our analysis underlines the need to further investigate ADRs in older adults since these reports are expected to significantly increase in the future. Also, more attention should be payed to the occurrence of ADRs in older males. Moreover, physicians should be aware of different ADRs being associated with the same drug depending on age. Our findings may also be helpful for the regular update of PIMs lists. Physicians should continue their caution and monitoring when prescribing antithrombotics to older adults. Finally, HCPs should report ADRs, particularly in older adults, as this gives regulators and researches the possibility to further investigate ADRs in older adults and to develop strategies to prevent them.

Availability of data and materials

The datasets generated and/or analysed during the current study are not publicly available due data privacy requirements. Researchers and/or readers who are interested can perform the same analysis in the ADR database EudraVigilance of the EMA (public access: http://www.adrreports.eu/en/index.html ). However, different levels of access are granted for different stakeholders [ 22 ].

Abbreviations

Adverse drug reaction

Anatomical Therapeutic Chemical classification

Drug prescription reports (Arzneiverordnungs-Reporte)

Federal Institute for Drugs and Medical Devices

Confidence interval

Defined daily doses

European Medicines Agency

Health Care Professionals

Medical Dictionary for Regulatory Activities

Non-Health Care Professionals

Over-the-counter drugs

Paul-Ehrlich-Institut

Potentially inappropriate medications

Preferred term

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Acknowledgements

The authors would like to thank the ADR database research team of BfArM’s pharmacovigilance division for their excellent support and Catharina Scholl for critically reading the manuscript.

The information and views set out in this manuscript are those of the authors and do not necessarily reflect the official opinion of the Federal Institute for Drugs and Medical Devices.

This project received funding from the Federal Institute for Drugs and Medical Devices (BfArM) own resources and the Institute for Medical Biometry, Informatics, and Epidemiology (IMBIE), University Hospital of Bonn (V-16703/68502/2016–2020).

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Contributions

DD and BS designed the research strategy. DD performed the analysis in BfArM’s ADR database and in R. Assessment of causality and documentation quality of ADR reports was conducted by DD, BS and KJ. Statistical analysis was performed by DD and MS. DD, BS and KJ wrote the manuscript. MS and JS were involved in revising the manuscript. All authors read and approved the manuscript.

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Correspondence to Diana Dubrall .

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Supplementary information

Additional file 1 supplementary figure 1.

. The number of ADR reports per year for younger adults, older adults, patients aged 66-75 years, patients aged 76-85 years, patients aged ≥ 86 years (absolute numbers). Supplementary Table 1 . The calculated ratio “number of ADR reports for older adults/number of ADR reports for younger adults” per year.

Additional file 2 Supplementary Document 1

. The average number of ADR reports per 100,000 inhabitants/males/females and estimation of the number of ADR reports per 100,000 assumed drug-exposed inhabitants/males/females per age group.

Additional file 3 Supplementary Table 2

. The number of ADR reports of the potentially inappropriate medications (PIMs) contained in the PRISCUS list in older adults (> 65 years).

Additional file 4 Supplementary Table 3

. The 20 ADRs reported most frequently in the ADR reports of younger adults , older adults and stratified age groups.

Additional file 5 Supplementary Table 4

. The three drug substances most frequently suspected for the three most frequently reported ADRs in the ADR reports of antithrombotic agents of younger adults and older adults .

Additional file 6 Supplementary Table 5

. Characteristics, drug indications, and ADRs in the ADR reports of younger adults and older adults in which rivaroxaban was suspected before and after extension of the indication (01/13/2012).

Additional file 7 Supplementary Table 6

. The five most frequently reported ADRs of younger adults in which phenprocoumon, acytylsalicyclic acid, and apixaban were reported as suspected drug substance.

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Dubrall, D., Just, K.S., Schmid, M. et al. Adverse drug reactions in older adults: a retrospective comparative analysis of spontaneous reports to the German Federal Institute for Drugs and Medical Devices. BMC Pharmacol Toxicol 21 , 25 (2020). https://doi.org/10.1186/s40360-020-0392-9

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Adverse drug reactions reporting: Five years analysis from a teaching hospital

Thakare, Vaishali; Patil, Anant; Jain, Mukta; Rai, Vivek; Langade, Deepak

Department of Pharmacology, Dr. DY Patil Medical College, Navi Mumbai, Maharashtra, India

Address for correspondence: Dr. Vaishali Thakare, Associate Professor, Department of Pharmacology, Dr. DY Patil Medical College, Navi Mumbai, Maharashtra, India. E-mail: [email protected]

This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 4.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background: 

Adverse drug reactions (ADRs) are important cause of morbidity and mortality. Despite its known importance, rate and quality (completeness score) of ADR reporting is not satisfactory. The objective of this study was to analyze pattern and completeness score of ADRs during past five-years.

Material and Methods: 

In this retrospective study, ADRs reported between 2017 to 2021 were analyzed according to year, gender, age-group, pharmacological class and department. The completeness score of ADRs was calculated. The number of sensitization programs conducted over 5 years and its impact on the completeness score was also evaluated.

Results: 

A total of 104 ADRs were reported among 61 (58.6%) female and 43 (41.4%) male patients. Adults (18-65 years) comprised the most affected age group, accounting for 82 (79%) patients. Out of all, 35.5% ADRs were reported in 2018, whereas 27% were reported during 2021. Except during 2017, percentage of females with ADRs was more. Department of pulmonary medicine and dermatology contributed to maximum extent in ADR reporting. Antibiotics [23 (22.11%)], antitubercular drugs (AKT) [21 (20.19%)], and vaccines [13 (12.4%)] represented the most common agents with which ADRs were reported. ADR reporting was very low in 2017 (4/104). Percentage improvement in completeness score in 2021 vs. 2018 was 11.95% ( P < 0.05). Positive trend in the improvement of average completeness score with number of sensitization programs was observed.

Conclusion: 

Incidence of ADRs was more common in females. AKT and antimicrobials are commonly implicated in ADRs. Increase in awareness of ADR reporting through sensitization programs can help to improve rate and quality of reporting.

Introduction

Adverse drug reactions (ADRs) are a major cause of morbidity and mortality across the world. ADR-related hospitalizations contribute substantially to the economic burden in both developing countries and developed countries.[ 1 ] In India, 52810 ADRs were reported between April 2020 to March 2021, of which 28.10% were serious events as per the annual report released in pharmacovigilance program of India (PvPI).[ 2 ] As ADRs are an inevitable part of treatment, healthcare professionals (HCPs) are encouraged to identify and spontaneously report individual case safety reports (ISCRs) using a predesigned suspected ADR reporting form.[ 3 ] These ISCRs should be reported to the nearest adverse drug reaction monitoring centers (AMC). There are over 300 AMCs spread across the country.[ 4 , 5 ] These centers receive the adverse events, review them for completeness, perform causality assessments and report to National Coordination Centre (NCC) via online software, Vigiflow for quality and signal review. With gradual increase in number of activities and spread of its work, PvPI has collaborated with several national health programmes and research institutions.

Although pharmacovigilance programs are becoming successful in improving drug use patterns, under-reporting of ADRs is still a major problem.[ 6 ] ADR reporting is affected by many factors, including lack of awareness, ambiguity about who should report, difficulties with reporting procedures, lack of feedback on submitted reports, rapid resolution of adverse events and fear of backlash as it may highlight medication errors.[ 7 - 9 ] There is a need to increase HCPs awareness on prevention, identification, and reporting of ADRs. The sensitization and awareness programs at various tertiary hospitals across India have shown appreciable impact on the pharmacovigilance and ADR reporting.[ 10 , 11 ]

D Y Patil Medical College and Hospital Navi, Mumbai, one of the recognized AMCs works in close coordination with all the clinical and respective paramedical departments for prompt detection, assessment and reporting of the ADRs. After receiving AMC status, there has been considerable progress and improvement in pharmacovigilance activities at our center for smooth functioning and regular reporting. Team of pharmacovigilance unit supported by pharmacovigilance committee and clinicians play a vital role in ADR reporting. Further, formation of causality assessment committee (CAC) in September 2021 as per the guidelines from NCC-PVPI has helped to improvement of ADR analysis. This study was aimed to perform analysis of ADRs reported in the institute during the previous five-year period. We also analyzed the effect of sensitization programs on ADR reporting rate and completeness score.

Material and Methods

In this retrospective study, ADRs reported to the pharmacovigilance unit of tertiary care teaching hospital, Navi Mumbai by HCPs between 2017 to 2021 were analyzed after taking the approval from IECBH and IEC Ref. No: DYP/IECBH/2021/279. Frequency and percentage of ADRs according to years, gender and age-group is presented. Analysis of ADRs was done based on the age group less than one year, one to five-years, five to 12-years, 12–18 years, 18–65 years and more than 65 years.

Analysis of department wise reporting, pharmacological group of medication implicated in the ADR and common suspected drugs for ADR is also presented.

The completeness score of each reported ADR was calculated based on the data reported for the four essential and major components of the form, that is, patient details, suspected ADR details, suspected medication details and reporter details. Each of these large sections were given 10 points.[ 12 , 13 ] Total score out of 40 was calculated by adding available information from the four mandatory sections [ Table 1 ]. The total completeness score was calculated as average out of ten. The number of sensitization programs conducted over last 5 years and its impact on the completeness score is reported.

Statistical analysis

In the present study, categorical data are presented as frequency and percentage. The results are presented for overall results and subgroups based on the year, gender, age group and department. Wilcoxon test was used for comparison of completeness scores. Mean (95% Confidence Interval) of completeness score is provided. P value of less than 0.05 was considered statistically significant.

A total of 104 ADR forms were analyzed in this study. As shown in Figure 1 , ADR reporting during 2017–2021 showed oscillatory trend. Very low reporting was seen in 2017 followed by marked improvement in 2018. ADR reporting again reduced in 2019-20 followed by rise in 2021.

Overall, the study population consisted of 61 (58.6%) females and 43 (41.4%) male patients. Adults (18 years – 65 years) comprised the most affected age group accounting for 82 (79%) patients.

Details of year-wise ADRs based on the gender and age of the patient are summarized in Table 2 . Out of all, 35.5% ADRs were reported in 2018 whereas 27% were reported during 2021. Except during 2017, percentage of females with ADRs was more than males.

As shown in [ Table 3 ], department of pulmonary medicine and dermatology contributed to maximum extent in ADR reporting.

Antibiotics [23 (22.11%)], AKT [21 (20.19%)] and vaccines [13 (12.4%)] represented the most common group of drugs with which ADRs were reported. Other classes of drugs implicated in the ADR reporting are shown in [ Figure 2 ]. Lithium 1 (16.7%), sulfasalazine 1 (16.7%), lignocaine 1 (16.7%), atracurium 1 (16.7%), Magnesium sulfate 1 (16.7%), and remdesivir 1 (16.7%) were amongst the miscellaneous group.

Among other antimicrobials ceftriaxone, ciprofloxacin and amoxycillin were commonly responsible for ADRs. Among the vaccines, ADRs were most reported with pentavalent vaccine [ Figure 3 ].

As shown in Table 4 , positive trend in completeness score was seen from 2018 onwards in various sections. 2017 has shown higher mean completeness score 9.37 (8,94, 9.80), but number of ADR reports was quite low (4/104). Percentage improvement in mean completeness score of 2021 vs. 2018 was 11.95% [Mean (95% C.I.) 9.84 (9.66, 10.02) and 8.79 (8.61, 8.98), respectively] ( P < 0.05).

Completeness score was highest and same throughout the study period in drug details section (10/10).

As shown in [ Figure 4 ], initial high value of mean completeness score was seen in drug detail and reporters detail section in 2017 followed by gradual improvement from 2018 onwards.

With increase in number of sensitization programs from 2017–2021, positive trend in improvement of average completeness score was observed [ Figure 5 ].

In this study, we analyzed the pattern of ADR reporting in a tertiary care hospital along with impact of sensitization programs on reporting rate and completeness score.

Trend of ADR reporting

Oscillatory trend was seen in ADR reporting from 2017–2021. Positive trend in number of ADR reporting observed 2018 onward could be the effect of sensitization program. Reduction in ADR reporting during 2019–20, may due to more focus of clinicians on the management of coronavirus disease (COVID-19) pandemic and unprecedented rise in work pressure.

ADR reporting based on demographic parameters

Overall, rate of ADRs in female patients was found to be higher than male patients. This is in accordance with a study by Meda Venkatasubbaiah, et al .[ 14 ] It has been reported that female patients have a 1.5- to 1.7-fold greater risk of developing an ADR, compared with male patients.[ 15 ] The exact cause of this increased risk is not entirely clear but may be related to gender-related differences in pharmacokinetical, immunological, and hormonal factors as well as differences in the use of medications by women as compared with men.[ 15 ] In our study, adult patients, that is, the wage-earner group was most widely affected age group. This observation is in line with a recently published study by Megha Sharma, et al . (2021).[ 16 ]

Amongst all departments, pulmonary medicine and dermatology contributed large number of ADRs. This could be partly explained by the nature of patients presenting to these departments. Pulmonary department caters to the patients with tuberculosis among others to whom multiple drugs are prescribed. The nature of drugs, condition of patients and polypharmacy may be the factors contributing to these ADRs. Similarly, cutaneous ADRs are common in the dermatology department. Moreover, this is in line with the studies conducted by Kishor A Bansod, et al . (2020).[ 17 ] and Sameer Uz Zaman, et al . (2021).[ 18 ]

ADR reporting based on drug categories

In the present study, antibiotics and antitubercular drugs represented two most common categories of agents contributing to ADRs followed by vaccines. Ceftriaxone from antibiotic group and pentavalent vaccine from vaccine group were common examples of drug/vaccine associated with ADRs. This observation is also in accordance with a study by Megha Sharma, et al . (2021).[ 16 ]

Completeness score

In the present study, analysis of ADR reporting showed positive trend in the average completeness score 2018 onwards. This positive impact could be possibly an outcome of the pharmacovigilance sensitization activities in the form of workshops, lectures, induction program, and other activities organized for the clinicians, postgraduate students, paramedical staff including nursing staff. Similar reports are available.[ 19 ]

As per our analysis, the lowest average score was seen in the reporter’s detail. This study was conducted in a tertiary care teaching hospital, where most of the ADRs are reported by postgraduate students, registrars, consultants, and nurses. In terms of low completeness score, our results are in agreement with a study by Vishal R. Tandon et al . (2015).[ 20 ] This could be attributed to lack of awareness about—importance of PV and ADR reporting. Attitude toward reporting like indifference, ignorance, lack of monitory incentives, fear of legal issues like litigation or further enquiry and wish to publish personal case reports are important predictors of low reporting. Postgraduate students are busy with academic activities including seminars, journal clubs, thesis and synopsis submission which influences quality and quantity of ADR reporting.[ 20 ]

The higher completeness score noted in reporter’s detail section in 2017 could be the result of very small number of self-motivated clinicians (4 out of 104) who may have filled this section completely voluntarily. Improvement in mean completeness score in this section from 2018 onwards could be due to sensitization programs.

Overall, results of our study provide several insights about the pattern of ADR reporting and positive influence of sensitization activities on rate of reporting and completeness score. More efforts are essential to increase ADR reporting rates by HCPs.

Small number of ADRs, retrospective study and no formal statistical analysis to evaluate the impact of sensitization programs on rate of ADR reporting and completeness score are limitations of our study. Larger studies from other academic/teaching institutes may help to find similarities and differences with our observations.

According to the results of our study, incidence of ADRs is more common in females as compared to male population. Anti-tuberculosis drugs and antimicrobial agents are commonly implicated agents in ADRs. Our results also suggest, increase in awareness of reporting through sensitization programs can help to improve quantity and quality of ADR reporting.

Ethics committee approval

This study was approved by the institutional ethics committee for biomedical and health research, Dr DY Patil Medical College and Research Center, Navi Mumbai.

It was a retrospective study, so patient consents were waived.

Financial support and sponsorship

Conflicts of interest.

There are no conflicts of interest.

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Adverse drug reactions and drug-related problems with supportive care medications among the oncological population

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• Batoul Barari Tajani   ORCID: orcid.org/0009-0006-7340-5086 1 ,
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The current study emphasizes the impact of adverse drug reactions (ADRs) and Drug-Related Problems (DRPs) caused by supportive care medications administered with chemotherapy.

This is a longitudinal observational study carried out at the Ramaiah Medical College Hospital in Bengaluru, Karnataka, India, at the Department of Oncology. The data was recorded using a specifically created data collecting form. Based on the PCNE (Pharmaceutical Care Network Europe), DRPs are identified. The WHO probability scale, Modified Hartwig and Siegel for ADR severity assessment, Naranjo's algorithm for causality assessment, Rawlins and Thompson for predictability assessment, and Modified Shumock and Thornton for preventability assessment were all utilized. The OncPal guideline was considered in terms of the precision of supportive care medications regarding the reduction of ADRs in cancer patients.

We enrolled 302 patients,166 (55%) female and 136 (45%) male (SD 14.378) (mean 49.97), patients with one comorbidity 59(19.6%) and multimorbidity (two or more) 45(14.9%), the DRPs identified were found to be 153 (50.6%); only P2 (safeties of drug therapy PCNE) were considered in this study. ADRs which are identified 175(57.9%) contributed/caused by the supportive care medications. WHO probability scale: 97 (32.1%) possible and 60 (19.9%) unlikely; Naranjo’s algorithm: 97 (32.1%) unlikely and 69 (22.8%) possible; ADR severity assessment scale (Modified Hartwig and Siegel): 95 (31.5%) mild and 63 (20.9%) moderates; Rawlins and Thompson for determining predictability of an ADR: 33 (10.9%) predictable and 137 (45.5%) non-predictable; and Modified Shumock and Thornton for determining preventability of an ADR: 81 (26.8%) probably preventable and 90 (29.8%) non-preventable. The statistical comparison through preforming t-test and measuring Chi-Square between group with ADRs and without ADRs shows in some variables, significantly (Alcohol consumption status, P  = .019) and Easter Cooperative Oncology Group (ECOG) performance status P  < 0.001.

Comprehensive assessment of supportive medications in cancer patients would enhance the patient management and therapeutic outcome. The potential adverse drug reactions (ADRs) caused by supportive care medications can contribute to longer hospital stays and interact with the systemic anti-cancer treatment. The health care professionals should be informed to monitor the patients clinically administered with supportive medications.

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1 Introduction

Any incident or situation pertaining to drug therapy that modifies (actually/potentially) the intended health outcome is classified as a drug-related issue under the PCNE classification [ 1 ]. DRPs have a great deal of unintended consequences, including significant rates of death, morbidity, and prolonged hospital stays and admissions. As a result, the families and the healthcare system bear a heavy financial burden. Therefore, improving patients’ safety status is the goal, and DRP prevention might help achieve this. Drug-Drug Interactions (DDIs) and Adverse Drug Events (ADEs) will rise due to complicated medication regimens and a variety of pharmacological agents, which might make patient care challenging [ 2 ].

Pharmacy practice is a systematic program that helps hospital pharmacists get the optimum medication therapy by analyzing clinical data and performing appropriate patient evaluations, it really plays a significant role in enhancing drug efficacy and safety. In order to identify and trace the DRPs, this would be carried out in coordination with other healthcare professionals. Numerous variables, including possible drug-drug interactions and ineffectiveness, might lead to drug-related issues and impede treatment outcomes [ 3 ]. DRPs rise in oncology ward as a result of adverse drug reactions (DDIs) brought on by complicated cancer medications, which worsen morbidity and death [ 4 ]. In order to determine the optimal course of treatment and reduce the financial burden associated with hospital stays and further emergency room visits, it is imperative that DRPs must be detected and evaluated [ 5 ]. Studies have shown constantly, adverse reactions in cancer patients significantly influenced by factors such as patient quality of life [ 6 , 7 , 8 ], stage and type of the illness[ 9 ], specificity of the therapeutic course, age, gender, diet and comorbidities[ 10 , 11 , 12 ,- 13 ]. Given the importance of identifying any cause that might result in ADR, it is particularly vital to consider DRPs, especially in susceptible groups like cancer patients [ 14 , 15 ]. These individuals, due to their weakened health state and issues stemming from chemotherapy and their illness, are highly susceptible to the adverse effects of ADR. Therefore, it is essential to be mindful of the potential causes of ADR, including DRPs, when working with vulnerable populations like cancer patients [ 16 , 17 ].

Pharmaceutical care provides the right strategy and ensures that patients receive the best treatment from several areas such as dosage, frequency, route of administration, etc., in order to meet therapeutic objectives and an appropriate patient's quality of life [ 18 ]. The most important factor affecting cancer patients, especially the elderly population, is polypharmacy, which raises the prevalence of DRP [ 19 , 20 , 21 ,-  22 ]. Such a disease might be brought on by DRPs, which would impact the treatment strategy [ 23 , 24 ].

DRPs could happen in different parts of the prescription process, from treatment, which is given during hospital admission, to discharge medications [ 25 ]. When the treatment doesn’t go according to the plan, then ADRs will be the result. A study shows that about 17% of hospital admissions occur due to the presence of ADRs, which can cause complications and even death [ 26 ]. To prevent such an event, it is crucial to identify and trace all the DRPs so patients will face less burden and complications in their treatment process.

While it is difficult to stop every DRP incident, pharmacy practice may play a significant role in preventing DRPs through patient evaluation. By studying and tracking DRPs early on, however, treatment outcomes can be enhanced [ 27 ]. Patients who are more vulnerable to DRPs, such as those with cancer, must be carefully assessed and closely monitored, in order to ensure that any consequences resulting from the existence of DRPs are addressed. Currently available causation tools are insufficient for DRP detection. In addition, a cohesive team of various healthcare providers who are willing to work together should be established in order for them to make a substantial contribution to the patient. This study focused on the occurrence of ADRs and DRPs caused by supportive medications among patients administered with chemotherapy. The goal is to create alertness on potential drug interactions occurring with supportive medications during chemotherapy treatment, which would undoubtedly have an impact on the patients’ ability to get through their therapeutic course.

2 Materials and methods

The study was conducted amongst cancer patients ≥ 18 years and admitted in the Department of Medical Oncology for a duration of 14 months from December 2022 to January 2024. The protocol was approved by institutional Ethics Committee of Ramaiah Medical College, Bangalore, India with the reference number ECR/215/Inst/KA/2013/RR-22. The data was collected from patients in a suitable data collection form after obtaining informed consent from the patients or the care takers. The consent form was translated into local language Kannada before obtaining consent. The data was collected from the patient medical records, laboratory reports and by interaction with the patients and care takers.

ADRs identified by oncologists were documented in addition to the data collection. criteria for determining preventability of an ADR (modified Shumock and Thornton) [ 28 ], The WHO probability scale [ 29 ], Naranjo's algorithm [ 30 ], ADR severity assessment scale (modified Hartwig and Siegel) [ 31 ], criteria for determining predictability of an ADR (Rawlins and Thompson) [ 32 ], were among the causality assessment criteria used to evaluate the ADR pattern.

The DRPs detection has been done by PCNE classification since this is an observational study; thus, (I) and (A) are not used; only (P) domain (P2) is used in this study. The detected DRPs were classified according to the PCNE Classification for Drug-Related Problems V9.1. It includes five domains: problem (P), cause (C), planned interventions (I), intervention acceptance (A), and outcome of DRP (O), and for DDIs, Stockley’s drug interaction text book and Drug Interactions Checker by Medscape are used as a reference sources.

2.1 Inclusion and exclusion criteria

All adult patients aged ≥ 18 who were admitted to the Medical Oncology Ward and had or did not have comorbidities were included in this study. Patients who underwent radiotherapy without chemotherapy (during the time of study) and those who did not sign the consent form were excluded.

2.2 Statistical analysis

Descriptive statistics of the demographic data, Baseline characteristics and ADR pattern was described and analyzed in terms of percentages. Kolmogorov Smirnov test, graphical methods and range of variation was used to test to normality of the data. Independent sample T test was used to compare the continuous data between patients with ADR and without ADR. Chi square test was used to compare the categorical data between two groups. the SPSS version 23 was used to analyze the data that was transferred from the collection form to an excel sheet. P value which is < 0.05 was considered as statistically significant.

3.1 Baseline demographic

The sample consisted of 302 adult patients, 166 (or 55% of the total) were female, and 136 (or 45%) were male. The participants' average age is 49.97. Additional patient details were noted, including nutrition, level of education (which PUC refers to Pre-University Course, UG refers to Under Graduate and PG is Post Graduate), marital status and so on (Table  1 ) presents baseline characteristics.

3.2 Prevalence of cancer and comorbidity

Gastrointestinal cancer was diagnosed at 68 (22.5%), followed by head and neck cancer at 34 (11.3%), lymphoid cancer at 29 (9.6%), cervical cancer at 27 (8.6%), leukemia at 21 (7%), lung cancer at 17 (5.6%), ovarian cancer at 9.0%, brain cancer at 7.3%, and other cancer types like testis, elbow, skin, urinary bladder, renal, and others 39 (17.6%). Gastrointestinal cancer is the most common type of cancer. Of the patients, 96 (31.8%) are taking less than five drugs, while 197 (65.2%) are taking five or more. 107 (35.4%) of the comorbidities include hypertension 34 (11%), type 2 diabetes mellitus 16 (5.3%) and other conditions. 14 (4.6%) people have type 2 diabetes mellitus and hypertension; 9 (3%), hypothyroidism; respiratory disorders such as asthma; and other diseases 6 (2.0%), type 2 diabetes mellitus, and disorders of the cardiovascular system, including deep vein thrombosis and ischemic heart disease, 4 (1.3%), HIV (human immunodeficiency viruses) with the incident of 3 (1%), acute renal illness, and two (0.7%) cases of hepatitis B surface antigen positive (Table  2 ).

3.3 Adverse events

When the patient was being examined by the oncologist during follow up (while patient admitted in the Medical Oncology Ward), all ADRs found were noted and categorized according to organ systems and then we evaluated drug suspected, of course some of the identified ADRs are disease related and some of them are blood product related for hematologic cancer population. Peripheral neuropathy is the most common cause of ADRs in the central nervous system (CNS), accounting for 48 incidents (27.3%), of which anticonvulsant, antimicrobial, and psychotropic drugs might also participate in ADR occurrence along with SACTs. fever (10.7%) which could be due to antimicrobials. Another ADR that has been identified is in gastrointestinal (GI) system, vomiting accounting for the largest percentage at 25 (14.2%), other common ADRs are diarrhea (10.7%), nausea (5.8%) which might be related to antiemetics and opioids, acute gastritis (5.8%), in that order. The hematologic ADR pattern comprises of three types of febrile neutropenia (10.7%) which antimicrobials could participate in the occurrences, thrombocytopenia (3.7%), and non-febrile (3.4%) which are disease related. there is oral mucositis with an incident rate of 17 (9.7%), oral mucositis grade (3), with a frequency of 2 (1.1%) which is due to SACTs, Acute liver damage (0.3%) which antimicrobial such as trimethoprim and sulfamethoxazole could be drug suspected, transaminitis (1.1%) could occur by NSAIDs (non-steroidal anti-inflammatory drugs) and antifungals.

3.4 ADR causality, severity, predictability, and preventability

As mentioned in Fig.  1 WHO UMC, Scale World Health Organization-Uppsala Monitoring Center, 97 (32.1%) are possible, 60 (19.9%) are unlikely, and Naranjo’s algorithm is 97 (32.1%) unlikely, 69 (22.8%) possible. Hartwig & Seigel: 95 (31.5%) mild, 63 (20.9%) moderate, Rawlins & Thompson: 33 (10.9%) predictable, 137 (45.4%) non-predictable, Shumock & Thornton: 81 (26.8%) probably preventable, and 90 (29.8%) non-preventable.

Causality Assessment: a WHO-UMC probability scale b NARANJO’S algorithm c ADR severity assessment scale Modified Hartwig and Siegel d Predictability of an ADR Rawlins and Thompson e Preventability of an ADR Modified Shumock and Thornton

3.5 Statistical comparison on patient’s demographic characteristics based on ADR occurrences

In addition to analyzing demographics in the population of study, statistical measurements were made in both the group with ADR and the group without ADR, as depicted in Table  4 , all demographic characteristics were statistically analyzed in both groups and some variables such as alcohol consumption status (P = 0.019) with a Chi-Square value of 7.877), and Eastern Cooperative Oncology Group (ECOG) performance status (P = 0.000), showed statistically significant results. However, statistical analysis reveals no significant difference between patients with and without ADR in variables such as polypharmacy and cancer type (P  > 0.05).

4 Discussion

The reported ADRs which is identified by medical oncologist were assessed to determine the potential extent of their relationship with the DRPs. Only (P2) which is evaluating the drugs to see if there are any drug interactions, even in a potential status that the patient may or may not suffer from, are taken into consideration in this study. The primary goal of this study is to raise vigilance in the implementation of drug precision in supportive care medication, which will have an influence on patient treatment in terms of ADR incidence and consequences at the medical oncology ward. In terms of SACTs the adverse drug reactions bring tremendous burden for patient and healthcare provider to manage, due to its potent complex therapy, in this study we would like to highlight the fact that how to minimize this burden as much as possible, one of the crucial factor is to focus on drug precision in supportive care medication, for so many years this topic is studied, yet the problem exists and patients are facing incredible amount of pain and suffering whereas for some would not be possible to get through their chemotherapy.

As it shown in Table  3 the types of the ADRs which could have a strong connection with supportive drugs are mentioned, for example in case of nausea, vomiting and diarrhea which causes by SACTs also due to antiemetics and opioids as well. Due to ondansetron metabolism by CYP2D6 (the isoenzyme that forms an active tramadol metabolite), tramadol and ondansetron have a pharmacodynamic interaction (P450 CYT2D6). Most racemic tramadol forms undergo significant metabolism through distinct mechanisms, such as oxidation mediated by CYP2D6 to produce O-desmethyltramadol, which is 200 times more compatible with mu opioid receptors than the parent drug dosage [ 33 , 34 ]. Because noradrenaline is a poor metabolizer of CYP2D6, it exhibits a much lower median value for area under concentration–time curves for the active metabolite after a dose of tramadol. Therefore, ( +)- o -desmethyltramadol is the mediator factor for opioid receptor-mediated analgesia. On the other hand, ( +) and (−) tramadol contribute to analgesia through inhibition reuptake of neurotransmitter serotonin and noradrenaline [ 35 , 36 ]. Though serotonin (5-HT) is known to influence pain responses through presynaptic 5-HT3 receptors in the spina dorsal horn, it is theoretically expected that ondansetron, an antagonist of 5-HT3 receptors, will create antagonistic effects with the medications that inhibit pain transmission. This phenomenon also applies to tramadol, an opioid that is not pure and functions by amplifying the effects of noradrenaline (norepinephrine) and serotonin. It appears that ondansetron and tramadol can interact to provide tramadol effectiveness when ondansetron is prescribed concurrently. This interaction has been allowed in the clinical sector. The recommended outcome, which is decreased control pain, may be reached by increasing the dosage; however, this increase exacerbates nausea and vomiting, which ondansetron cannot adequately compensate for. In summary, ondansetron should not be used as an antiemetic in combination with tramadol [ 37 ]. Tramadol and ondansetron combine to produce serotonin syndrome, which manifests as a wide range of symptoms, including autonomic instability (autonomic dysfunction), which includes symptoms including nausea, vomiting, and diarrhea [ 38 ].

Emmanuel Andres et al. [ 39 ] implicated non-chemotherapy drugs that induce febrile neutropenia, such as antibiotics like amoxicillin + clavulanic acid, piperacillin, ceftriaxone, levofloxacin, and other molecules like acyclovir. According to Emmanuel Andres et al., all healthcare providers should be aware of their practice in terms of potential adverse reactions and apply it to their daily routine programs. Particular attention should be paid to these drugs especially in oncological population because febrile neutropenia occurs in most of the case due to SACTS and disease related and also due to antimicrobials as it is shown in Table  3 , since it is highly prescribed in patients with hematological cancer either for empirical administration or prophylaxis.

Concurrent use of two or more CNS depressants (such as tramadol, morphine, pregabalin, and gabapentin) produces an addictive respiratory depressant and sedative effect [ 40 ]. the combination of these drugs as we know exacerbates ADRs such as lethargy, dizziness, constipation and blurred vision. Also, the bioavailability of gabapentin can be increased by morphine, and consequently, the analgesic efficacy would be enhanced. Gabapentin also induces the analgesic effect of morphine and other opioids.

Electrolyte imbalance is a very crucial aspect for patient management, for example, hypokalemia and hypokalemia induce nausea and vomiting, hypokalemia could increase ADRs such as muscle weakness, fatigue, tingling sensations which occurs in oncological population a lot. That being said, considering laxative which is prescribed highly due to constipation that most of cancer patients are facing and in a long term if this drug dose not monitored it would cause so many complications.

Peripheral neuropathy with the highest incident ADR occurrences which induce by SACTs and non-cancer specific medications such as antimicrobials, anticonvulsants and psychotropics as well, the intensity of peripheral neuropathy would increase if drug precision doesn’t consider regarding supportive care medications, the occurrence of ADRs such as tingling sensation, numbness, general weakness, fatigue, constipation, diarrhea and blurred vision could worsen patient’s condition. According to Table  3 , other ADRs are mentioned such as gum bleeding, acute gastritis, epigastric burning sensation and transaminitis which shown with the drug suspected. our main focus is to reduce the high incident occurrences ADRs which impact on patient mostly. Even though the majority of non- specific cancer medications may not be prescribed for an extended period of time, it has been observed that some patients take these medications for a longer duration and frequency due to disease related problems. Therefore, knowledge of these medications may greatly enhance therapeutic precision thus any DDIs should be acknowledged and take to the consideration as a drug safety [ 41 ] and this is more significant in an oncological population.

Julian Lindsay et al. [ 42 ] mentioned in their study regarding the developing oncological palliative care guideline OncPal [ 42 ], the list of the drugs which are not benefit in patient, although this guideline is about palliative care patient with the short life expectancy, we considered in our study for determining the drugs could increase the ADRs in Medical Oncology Ward. Our aim is to highlights the correlation of supportive care medication in ADR occurrences while considering the majority of ADRs in cancer patients are due to potent chemotherapy. Our primary focus was on addressing ADRs that were associated with supportive medications. Specifically, we excluded adverse effects resulting from chemotherapy, such as Carboplatin hypersensitivity, extravasation, Bendamustine-induced rash, and chemotherapy-induced oral mucositis.

Cancer patients, particularly those who are undergoing watch-and-wait management in case of relapse, require precise medication and supportive drugs due to their susceptibility, resulting from disease progression and long-term therapy. This is crucial to prevent any additional complications [ 43 , 44 , 45 ].

According to Table  4 patients with higher ECOG scores were found to experience more ADRs. As a result, it is essential to closely monitor patients based on their supportive drug therapy, as disease progression can cause a variety of issues in all aspects of treatment.

Table 4 , was shown the participation of patient’s background and ADR occurrences, although it was not statistically significant in most of the variable ( P  > 0.05), except ECOG ( P  < 0.001) and alcoholic consumption status with the P value of (0 0.019), the percentage of patient who had ADRs in most of the variable is higher, for example, the DRP = 134(44.37%) showing 83(61.9%) had ADRs compare to 51(38.1%) without ADRs ( P  = 0.209).

According to a study conducted by Amanda et al. [ 46 ], the extent of admissions in cancer patients due to ADRs was examined, as well as the role of chemotherapy- and non-chemotherapy-induced ADRs. The study revealed that the percentage of ADRs caused by supportive drugs is similar to that caused by SACTs, highlighting the importance of awareness and monitoring of non-chemotherapy drugs. In our study, patients with drug-related problems exhibited a higher percentage of ADRs and experienced issues that resulted in delays in chemotherapy, discontinuation, and extended hospital stays.

Conducting a comprehensive assessment is important, especially for geriatric oncology patients, who are particularly vulnerable to experiencing adverse drug reactions (ADRs) due to their age-related frailty. This vulnerability can lead to a range of issues [ 47 ] The feasibility of assessment in geriatric oncology and its potential benefits for enhancing patient management and treatment outcomes have been demonstrated [ 48 ]. The American Society of Clinical Oncology (ASCO) advises conducting a special assessment for geriatric oncology patients aged 65 or more who are undergoing chemotherapy. The intention of this assessment is to recognize drug-related issues contributed by supportive care medications that could have been overlooked by the oncologist to acknowledged [ 49 ] Our study supports this approach, and we strongly recommend its application not just for geriatric oncology but also for adult patients under the age of 65 who are admitted in Medical Oncology Ward, as we have done in this study.

5 Conclusion

DRPs are present in the Medical Oncology Ward as a result of comorbid and disease-related problems. Therefore, it may be possible to significantly influence the severity of ADR occurrences and, consequently, patient care by recognizing and tracking DRPs. The unforeseen difficulties caused by DRPs can have an effect on patients' health and create a significant number of issues, which magnifies notably during chemotherapy.

Data availability

The data used to support the finding of this study are included within the manuscript.

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Acknowledgements

Authors express their deepest gratitude to the Faculty of Pharmacy, M S Ramaiah University of Applied Science, all the nursing staff and resident doctors of M S Ramaiah Medical College Hospital for their incredible cooperation.

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Batoul Barari Tajani & E. Maheswari

Department of Medical Oncology, M S Ramaiah Medical College Hospital, Bengaluru, Karnataka, India

Vinayak V. Maka

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BBT, EM, VVM contributed to the study conception and design, material preparation, data collection. Data analysis was performed by ASN. VVM performed project administration. BBT contributed writing the manuscription, EM supervised the study and reviewed the manuscription. All authors read and approved the manuscription.

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Correspondence to Batoul Barari Tajani .

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The study was authorized by the Ethics Committee of the M. S. Ramaiah Medical College Hospital (MSRMCH), Bengaluru, Karnataka, India, before to its start in December 2022. Prior to the start of the data collection procedure, the collecting form was accompanied with the consent form which was translated into Kannada language was signed by patient or family member. Ethics Committee, MS Ramaiah Medical College Hospital, Bangaluru, Karnataka, India is registered under DCGI (Drugs Controller General India) and Department of Health Services and works in accordance with the Declaration of Helsinki.

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Tajani, B.B., Maheswari, E., Maka, V.V. et al. Adverse drug reactions and drug-related problems with supportive care medications among the oncological population. Discov Onc 15 , 416 (2024). https://doi.org/10.1007/s12672-024-01300-w

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Adverse drug reactions reporting: Five years analysis from a teaching hospital

Vaishali thakare.

Department of Pharmacology, Dr. DY Patil Medical College, Navi Mumbai, Maharashtra, India

Anant Patil

Deepak langade, background:.

Adverse drug reactions (ADRs) are important cause of morbidity and mortality. Despite its known importance, rate and quality (completeness score) of ADR reporting is not satisfactory. The objective of this study was to analyze pattern and completeness score of ADRs during past five-years.

Material and Methods:

In this retrospective study, ADRs reported between 2017 to 2021 were analyzed according to year, gender, age-group, pharmacological class and department. The completeness score of ADRs was calculated. The number of sensitization programs conducted over 5 years and its impact on the completeness score was also evaluated.

A total of 104 ADRs were reported among 61 (58.6%) female and 43 (41.4%) male patients. Adults (18-65 years) comprised the most affected age group, accounting for 82 (79%) patients. Out of all, 35.5% ADRs were reported in 2018, whereas 27% were reported during 2021. Except during 2017, percentage of females with ADRs was more. Department of pulmonary medicine and dermatology contributed to maximum extent in ADR reporting. Antibiotics [23 (22.11%)], antitubercular drugs (AKT) [21 (20.19%)], and vaccines [13 (12.4%)] represented the most common agents with which ADRs were reported. ADR reporting was very low in 2017 (4/104). Percentage improvement in completeness score in 2021 vs. 2018 was 11.95% ( P < 0.05). Positive trend in the improvement of average completeness score with number of sensitization programs was observed.

Conclusion:

Incidence of ADRs was more common in females. AKT and antimicrobials are commonly implicated in ADRs. Increase in awareness of ADR reporting through sensitization programs can help to improve rate and quality of reporting.

Introduction

Adverse drug reactions (ADRs) are a major cause of morbidity and mortality across the world. ADR-related hospitalizations contribute substantially to the economic burden in both developing countries and developed countries.[ 1 ] In India, 52810 ADRs were reported between April 2020 to March 2021, of which 28.10% were serious events as per the annual report released in pharmacovigilance program of India (PvPI).[ 2 ] As ADRs are an inevitable part of treatment, healthcare professionals (HCPs) are encouraged to identify and spontaneously report individual case safety reports (ISCRs) using a predesigned suspected ADR reporting form.[ 3 ] These ISCRs should be reported to the nearest adverse drug reaction monitoring centers (AMC). There are over 300 AMCs spread across the country.[ 4 , 5 ] These centers receive the adverse events, review them for completeness, perform causality assessments and report to National Coordination Centre (NCC) via online software, Vigiflow for quality and signal review. With gradual increase in number of activities and spread of its work, PvPI has collaborated with several national health programmes and research institutions.

Although pharmacovigilance programs are becoming successful in improving drug use patterns, under-reporting of ADRs is still a major problem.[ 6 ] ADR reporting is affected by many factors, including lack of awareness, ambiguity about who should report, difficulties with reporting procedures, lack of feedback on submitted reports, rapid resolution of adverse events and fear of backlash as it may highlight medication errors.[ 7 , 8 , 9 ] There is a need to increase HCPs awareness on prevention, identification, and reporting of ADRs. The sensitization and awareness programs at various tertiary hospitals across India have shown appreciable impact on the pharmacovigilance and ADR reporting.[ 10 , 11 ]

D Y Patil Medical College and Hospital Navi, Mumbai, one of the recognized AMCs works in close coordination with all the clinical and respective paramedical departments for prompt detection, assessment and reporting of the ADRs. After receiving AMC status, there has been considerable progress and improvement in pharmacovigilance activities at our center for smooth functioning and regular reporting. Team of pharmacovigilance unit supported by pharmacovigilance committee and clinicians play a vital role in ADR reporting. Further, formation of causality assessment committee (CAC) in September 2021 as per the guidelines from NCC-PVPI has helped to improvement of ADR analysis. This study was aimed to perform analysis of ADRs reported in the institute during the previous five-year period. We also analyzed the effect of sensitization programs on ADR reporting rate and completeness score.

Material and Methods

In this retrospective study, ADRs reported to the pharmacovigilance unit of tertiary care teaching hospital, Navi Mumbai by HCPs between 2017 to 2021 were analyzed after taking the approval from IECBH and IEC Ref. No: DYP/IECBH/2021/279. Frequency and percentage of ADRs according to years, gender and age-group is presented. Analysis of ADRs was done based on the age group less than one year, one to five-years, five to 12-years, 12–18 years, 18–65 years and more than 65 years.

Analysis of department wise reporting, pharmacological group of medication implicated in the ADR and common suspected drugs for ADR is also presented.

The completeness score of each reported ADR was calculated based on the data reported for the four essential and major components of the form, that is, patient details, suspected ADR details, suspected medication details and reporter details. Each of these large sections were given 10 points.[ 12 , 13 ] Total score out of 40 was calculated by adding available information from the four mandatory sections [ Table 1 ]. The total completeness score was calculated as average out of ten. The number of sensitization programs conducted over last 5 years and its impact on the completeness score is reported.

Calculation of completeness score of ADR[ 12 , 13 ]

Statistical analysis

In the present study, categorical data are presented as frequency and percentage. The results are presented for overall results and subgroups based on the year, gender, age group and department. Wilcoxon test was used for comparison of completeness scores. Mean (95% Confidence Interval) of completeness score is provided. P value of less than 0.05 was considered statistically significant.

A total of 104 ADR forms were analyzed in this study. As shown in Figure 1 , ADR reporting during 2017–2021 showed oscillatory trend. Very low reporting was seen in 2017 followed by marked improvement in 2018. ADR reporting again reduced in 2019-20 followed by rise in 2021.

Year-wise numbers of reported adverse drug reactions

Overall, the study population consisted of 61 (58.6%) females and 43 (41.4%) male patients. Adults (18 years – 65 years) comprised the most affected age group accounting for 82 (79%) patients.

Details of year-wise ADRs based on the gender and age of the patient are summarized in Table 2 . Out of all, 35.5% ADRs were reported in 2018 whereas 27% were reported during 2021. Except during 2017, percentage of females with ADRs was more than males.

Distribution of year-wise adverse drugs reactions based on gender and age

As shown in [ Table 3 ], department of pulmonary medicine and dermatology contributed to maximum extent in ADR reporting.

Department-wise distribution of reported adverse drug reactions

Antibiotics [23 (22.11%)], AKT [21 (20.19%)] and vaccines [13 (12.4%)] represented the most common group of drugs with which ADRs were reported. Other classes of drugs implicated in the ADR reporting are shown in [ Figure 2 ]. Lithium 1 (16.7%), sulfasalazine 1 (16.7%), lignocaine 1 (16.7%), atracurium 1 (16.7%), Magnesium sulfate 1 (16.7%), and remdesivir 1 (16.7%) were amongst the miscellaneous group.

Distribution of adverse drug reactions based on pharmacological class of medicine (n = 104). AKT: antitubercular drugs

Among other antimicrobials ceftriaxone, ciprofloxacin and amoxycillin were commonly responsible for ADRs. Among the vaccines, ADRs were most reported with pentavalent vaccine [ Figure 3 ].

Drugs from the most common three categories (antibiotics, antituberculosis and vaccines) of medicines implicated in adverse drug reactions

As shown in Table 4 , positive trend in completeness score was seen from 2018 onwards in various sections. 2017 has shown higher mean completeness score 9.37 (8,94, 9.80), but number of ADR reports was quite low (4/104). Percentage improvement in mean completeness score of 2021 vs. 2018 was 11.95% [Mean (95% C.I.) 9.84 (9.66, 10.02) and 8.79 (8.61, 8.98), respectively] ( P < 0.05).

Mean (95% C.I.) values for completeness scores

Completeness score was highest and same throughout the study period in drug details section (10/10).

As shown in [ Figure 4 ], initial high value of mean completeness score was seen in drug detail and reporters detail section in 2017 followed by gradual improvement from 2018 onwards.

Mean Completeness score of reported adverse drug reactions

With increase in number of sensitization programs from 2017–2021, positive trend in improvement of average completeness score was observed [ Figure 5 ].

Impact of sensitization program on completeness score of adverse drug reactions

In this study, we analyzed the pattern of ADR reporting in a tertiary care hospital along with impact of sensitization programs on reporting rate and completeness score.

Trend of ADR reporting

Oscillatory trend was seen in ADR reporting from 2017–2021. Positive trend in number of ADR reporting observed 2018 onward could be the effect of sensitization program. Reduction in ADR reporting during 2019–20, may due to more focus of clinicians on the management of coronavirus disease (COVID-19) pandemic and unprecedented rise in work pressure.

ADR reporting based on demographic parameters

Overall, rate of ADRs in female patients was found to be higher than male patients. This is in accordance with a study by Meda Venkatasubbaiah, et al .[ 14 ] It has been reported that female patients have a 1.5- to 1.7-fold greater risk of developing an ADR, compared with male patients.[ 15 ] The exact cause of this increased risk is not entirely clear but may be related to gender-related differences in pharmacokinetical, immunological, and hormonal factors as well as differences in the use of medications by women as compared with men.[ 15 ] In our study, adult patients, that is, the wage-earner group was most widely affected age group. This observation is in line with a recently published study by Megha Sharma, et al . (2021).[ 16 ]

Amongst all departments, pulmonary medicine and dermatology contributed large number of ADRs. This could be partly explained by the nature of patients presenting to these departments. Pulmonary department caters to the patients with tuberculosis among others to whom multiple drugs are prescribed. The nature of drugs, condition of patients and polypharmacy may be the factors contributing to these ADRs. Similarly, cutaneous ADRs are common in the dermatology department. Moreover, this is in line with the studies conducted by Kishor A Bansod, et al . (2020).[ 17 ] and Sameer Uz Zaman, et al . (2021).[ 18 ]

ADR reporting based on drug categories

In the present study, antibiotics and antitubercular drugs represented two most common categories of agents contributing to ADRs followed by vaccines. Ceftriaxone from antibiotic group and pentavalent vaccine from vaccine group were common examples of drug/vaccine associated with ADRs. This observation is also in accordance with a study by Megha Sharma, et al . (2021).[ 16 ]

Completeness score

In the present study, analysis of ADR reporting showed positive trend in the average completeness score 2018 onwards. This positive impact could be possibly an outcome of the pharmacovigilance sensitization activities in the form of workshops, lectures, induction program, and other activities organized for the clinicians, postgraduate students, paramedical staff including nursing staff. Similar reports are available.[ 19 ]

As per our analysis, the lowest average score was seen in the reporter’s detail. This study was conducted in a tertiary care teaching hospital, where most of the ADRs are reported by postgraduate students, registrars, consultants, and nurses. In terms of low completeness score, our results are in agreement with a study by Vishal R. Tandon et al . (2015).[ 20 ] This could be attributed to lack of awareness about—importance of PV and ADR reporting. Attitude toward reporting like indifference, ignorance, lack of monitory incentives, fear of legal issues like litigation or further enquiry and wish to publish personal case reports are important predictors of low reporting. Postgraduate students are busy with academic activities including seminars, journal clubs, thesis and synopsis submission which influences quality and quantity of ADR reporting.[ 20 ]

The higher completeness score noted in reporter’s detail section in 2017 could be the result of very small number of self-motivated clinicians (4 out of 104) who may have filled this section completely voluntarily. Improvement in mean completeness score in this section from 2018 onwards could be due to sensitization programs.

Overall, results of our study provide several insights about the pattern of ADR reporting and positive influence of sensitization activities on rate of reporting and completeness score. More efforts are essential to increase ADR reporting rates by HCPs.

Small number of ADRs, retrospective study and no formal statistical analysis to evaluate the impact of sensitization programs on rate of ADR reporting and completeness score are limitations of our study. Larger studies from other academic/teaching institutes may help to find similarities and differences with our observations.

According to the results of our study, incidence of ADRs is more common in females as compared to male population. Anti-tuberculosis drugs and antimicrobial agents are commonly implicated agents in ADRs. Our results also suggest, increase in awareness of reporting through sensitization programs can help to improve quantity and quality of ADR reporting.

Ethics committee approval

This study was approved by the institutional ethics committee for biomedical and health research, Dr DY Patil Medical College and Research Center, Navi Mumbai.

It was a retrospective study, so patient consents were waived.

Financial support and sponsorship

Conflicts of interest.

There are no conflicts of interest.