Veilig gebruik van contrastmiddelen

Initiatief: NVvR Aantal modules: 48

Definities van bijwerkingen

Definitions of Adverse Drug Reactions 


Disclaimer: This narrative supplement has been written by members of the Guideline Development Group so that non-specialized readers can follow the text more easily. It was not part of the actual guideline process with structured literature analyses. 


Adverse drug reaction (ADR), synonyms: Adverse reaction, Suspected adverse (drug) 

reaction, Adverse effect, Undesirable effect (CIOMS IX) 

A response to a medicinal product which is noxious and unintended. Response in this context means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility. Adverse reactions may arise from use of the product within or outside the terms of the marketing authorisation or from occupational exposure. Conditions of use outside the marketing authorization include off-label use, overdose, misuse, abuse, and medication errors (EMA, 2017). 

The terms “adverse reaction” and “adverse effect” are interchangeable, except that an adverse effect is seen from the point of view of the drug, whereas an adverse reaction is seen from the point of view of the patient (Edwards, 2000). 


Toxic effect 

A toxic effect is an effect that occurs as an exaggeration of the desired therapeutic effect, and which is not common at normal doses. It occurs by the same mechanism as the therapeutic effect and is always dose related. 


Side effect 

A side effect is any effect that is not the main aim of a therapy. Side effect include effects that may be beneficial rather than harmful. A side effect may or may not occur through the pharmacological action for which the drug is being used. 


Unexpected adverse reaction 

An adverse reaction, the nature or severity of which is not consistent with domestic labelling or market authorisation, or expected from characteristics of the drug 


Serious adverse effect 

Any untoward medical occurrence that at any dose results in death, requires hospital admission or prolongation of existing hospital stay, results in persistent or significant disability/incapacity, or is life 


  • Cancers and congenital anomalies or birth defects should be regarded as serious 
  • Medical events that would be regarded as serious if they had not responded to acute treatment should also be considered serious 
  • The term ‘severe’ is often used to describe the intensity (severity) of a medical event, as in the grading ‘mild’, ‘moderate’, and ‘severe’; thus, a severe skin reaction need not be serious 

Adverse event/adverse experience 

Any untoward occurrence that may present during treatment with a pharmaceutical product, but which does not necessarily have a causal relation to the treatment 


Drug hypersensitivity reaction (DHR) 

Drug hypersensitivity reactions (DHRs) are adverse effects of drugs that clinically resemble allergic reactions (‘pseudo-allergic’). DHR includes adverse reactions that are immune or nonimmune mediated. For general communication, when an allergic drug reaction is suspected DHR is the preferred term, because true drug allergy and nonallergic DHR may be difficult to differentiate based on the clinical presentation alone, especially in cases of acute severe DHR. 

Clinically, DHRs are commonly classified as immediate or nonimmediate/delayed depending on their onset during treatment. The discrimination between immediate and nonimmediate DHR has its limitations because other factors such as the route of administration, the role of drug metabolites, and the presence of co-factors or co-prescribed drugs may accelerate or slow down the onset or progression of a reaction. Although artificial, this classification into immediate and nonimmediate DHR is very important in clinical practice for workup planning. 


Non-immune drug hypersensitivity reaction 

Nonimmune hypersensitivity drug reactions are all adverse drug reactions whose symptomatology suggests an allergy but for which the immunologic nature of the reaction cannot be proved. 

Nonimmune drug hypersensitivity reactions assume most of the criteria listed under drug allergy. Numerous nonimmune hypersensitivity reactions occur and are caused by multiple aetiologies. Examples include: 

  • Include nonspecific histamine release (opiates, radiocontrast media, and vancomycin), 
  • An accumulation of bradykinin (angiotensin-converting enzyme inhibitors), 
  • Complement activation (radiocontrast media, protamine), 
  • An activation of leukotriene synthesis (aspirin and nonsteroidal anti-inflammatory drugs), 
  • Bronchospasm (by liberation of sulphur dioxide during treatments containing sulphites or by blockage of the b-adrenergic receptors, even when the drug is administered through the eyes). 
  • Nonimmediate drug hypersensitivity like reaction due to pharmacological interaction with immune receptor. P-i concept reactions are associated with specific HLA types. 

Immediate drug hypersensitivity reaction (IHR) 

Immediate DHRs are possibly induced by an IgE-mediated mechanism and occur within 1–6 h after the last drug administration. Typically, they occur within the first hour following the first administration of a new course of treatment. 

Immediate DHRs usually present with urticaria, angioedema, rhinitis, conjunctivitis, bronchospasm, gastrointestinal symptoms (nausea, vomiting, diarrhoea), or anaphylaxis, which can lead to cardiovascular collapse (anaphylactic shock) 


Non-immediate drug hypersensitivity reaction (NIHR) 

Nonimmediate DHRs may occur any time as from 1 h after the initial drug administration. They commonly occur after many days of treatment and are often associated with a delayed T-cell-dependent type of allergic mechanism. 

Nonimmediate DHRs often affect the skin with variable cutaneous symptoms such as late occurring or delayed urticaria, maculopapular eruptions, fixed drug eruptions (FDE), vasculitis, blistering diseases (such as TEN, SJS, and generalized bullous fixed drug eruptions), HSS, acute generalized exanthematous pustulosis (AGEP), and symmetrical drug-related intertriginous and flexural exanthemas (SDRIFE). Internal organs can be affected either alone or with cutaneous symptoms (HSS/DRESS/DiHS, vasculitis, SJS/TEN) and include hepatitis, renal failure, pneumonitis, anaemia, neutropenia, and thrombocytopenia. 


Drug allergy 

A drug allergy is always associated with an immune mechanism for which evidence can be shown of drug-specific antibodies or activated T lymphocytes. Drugs can induce all the types of immunologic reactions described by Gell and Coombs 

A drug allergy is characterized by the following criteria: 

  • The reaction is not an expected pharmacologic effect. 
  • A period of sensitization precedes the reaction. 
  • The reaction may occur at a dose much lower than that required for a pharmacologic effect. 
  • The clinical symptoms are characteristic of an allergic reaction. 
  • Resolution occurs within an expected interval, usually days, after discontinuation of the offending agent. 
  • Chemical cross-reactivity may occur 

Classification of Adverse Drug Reactions 


Type A adverse drug reaction 

Type A (augmented) reactions result from an exaggeration of a drug’s normal pharmacological actions when given at the usual therapeutic dose and are normally dose dependent. Examples include respiratory depression with opioids or bleeding with warfarin. Type A reactions also include those that are not directly related to the desired pharmacological action of the drug, for example dry mouth that is associated with tricyclic antidepressants 


Type B adverse drug reaction 

Type B (bizarre) reactions are novel responses that are not expected from the known pharmacological actions of the drug. These are less common, and so may only be discovered for the first time after a drug has already been made available for general use. 

Examples include anaphylaxis with penicillin or skin rashes with antibiotics. 

Type B ADR include adverse reactions that are dose-independent, unpredictable, noxious, and unintended response to a drug taken at a dose normally used in humans. However, some dose dependence has been shown repeatedly in DHRs (e.g., for nonsteroidal anti-inflammatory drugs (NSAIDs), antiepileptic drugs) and some are predictable due to the disease state (e.g., human immunodeficiency virus (HIV) infection/acquired immunodeficiency syndrome (AIDS), Epstein–Barr virus (EBV) infection) or a similar previous reaction to the same drug or drug class. Some are associated with specific HLA types 


Type C adverse drug reaction 

Type C (‘continuing’) reactions persist for a relatively long time. Examples are osteonecrosis of the jaw with bisphosphonates, Hypothalamic-pituitary-adrenal axis suppression by corticosteroids 


Type D adverse drug reaction 

Type D (‘delayed’) reactions become apparent sometime after the use of a drug. The timing of these may make them more difficult to detect. An example is leucopoenia, which can occur up to six weeks after a dose of lomustine. Teratogenic (e.g., vaginal adenocarcinoma with diethylstilbesterol) and carcinogenic reactions can also be type D reactions. 


Type E adverse drug reaction 

Type E (‘end-of-use’) reactions are associated with the withdrawal of a drug. An example is insomnia, anxiety and perceptual disturbances following the withdrawal of benzodiazepines. 


Type F adverse drug reaction 

Type F (failure) reactions are the result of unexpected failure of therapy. An example is inadequate dosage of an oral contraceptive, particularly when used with specific enzyme inducers (interaction). 


Causality assessment of suspected adverse drug reactions 



• A clinical event, including a laboratory test abnormality, which occurs in a plausible time relation to drug administration, and which cannot be explained by concurrent disease or other drugs or chemicals 

• The response to withdrawal of the drug (de-challenge) should be clinically plausible 

• The event must be definitive pharmacologically or phenomenologically, using a satisfactory rechallenge procedure if necessary 



• A clinical event, including a laboratory test abnormality, with a reasonable time relation to administration of the drug, unlikely to be attributed to concurrent disease or other drugs or chemicals, and which follows a clinically reasonable response on withdrawal (de-challenge) 

• Rechallenge information is not required to fulfil this definition 



• A clinical event, including a laboratory test abnormality, with a reasonable time relation to administration of the drug, but which could also be explained by concurrent disease or other drugs or chemicals 

• Information on drug withdrawal may be lacking or unclear 



• A clinical event, including a laboratory test abnormality, with a temporal relation to administration of the drug, which makes a causal relation improbable, and in which other drugs, chemicals, or underlying disease provide plausible explanations 



• A clinical event, including a laboratory test abnormality, reported as an adverse reaction, about which more data are essential for a proper assessment, or the additional data are being examined 


Not assessable/unclassifiable 

• A report suggesting an adverse reaction that cannot be judged, because information is insufficient or contradictory and cannot be supplemented or verified 


Literature For Further Reading 

Abrams EM, Khan DA. Diagnosing and managing drug allergy. CMAJ 2018; 190(17): E532-E538. 

CIOMS Cumulative Pharmacovigilance Glossary v1.1. Available at: [URL]. Accessed: 7 June 2022. 

Demoly P, Adkinson NF, Brockow K, Castells M, Chiriac AM, Greenberger PA, et al. International consensus on drug allergy. Allergy. 2014; 69(4): 420-437. 

Demoly P, Hillaire-Buys D. Classification and epidemiology of hypersensitivity drug reactions. Immunol Allergy Clin N Am 2004; 24: 345– 356. 

Edwards IR, Jeffrey K Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet 2000; 356: 1255–1259. 

European Medicines Agency. Guideline on good pharmacovigilance practices (GVP). Annex I – Definitions (rev 4, 2017). Available at: [URL]. Accessed: 7 June 2022. 

Gerth van Wijk R, Van Cauwenberge PB, Johansson SG. [Revised terminology for allergies and related conditions]. Ned Tijdschr Geneeskd. 2002; 146(48): 2289-2293. 

Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol. 2004; 113(5): 832-836. 

Lindquist M. The Need for Definitions in Pharmacovigilance. Drug Safety 2007; 30 (10): 825-830. 

Medicines and Healthcare Regulatory Agency. Guidance on adverse drug reactions Yellow Card. Available at: [URL]. Accessed: 7 June 2022. 

Autorisatiedatum en geldigheid

Laatst beoordeeld  : 28-11-2022

Laatst geautoriseerd  : 28-11-2022

Geplande herbeoordeling  :


The Radiological Society of the Netherlands (NVvR) will determine around 2027 if this guideline (per module) is still valid and applicable. If necessary, the scientific societies will form a new guideline group to revise the guideline. The validity of a guideline can be shorter than 5 years, if new scientific or healthcare structure developments arise, that could be a reason to commence revisions. The Radiological Society of the Netherlands is the owner of this guideline and thus primarily responsible for the actuality of the guideline. Other scientific societies that have participated in the guideline development share the responsibility to inform the primarily responsible scientific society about relevant developments in their field.

Initiatief en autorisatie

  • Nederlandse Vereniging voor Radiologie
Geautoriseerd door:
  • Nederlandse Internisten Vereniging
  • Nederlandse Vereniging van Maag-Darm-Leverartsen
  • Nederlandse Vereniging voor Cardiologie
  • Nederlandse Vereniging voor Heelkunde
  • Nederlandse Vereniging voor Neurologie
  • Nederlandse Vereniging voor Obstetrie en Gynaecologie
  • Nederlandse Vereniging voor Radiologie
  • Nederlandse Vereniging voor Klinische Chemie en Laboratoriumgeneeskunde
  • Patiëntenfederatie Nederland
  • Nederlandse Vereniging voor Allergologie en Klinische Immunologie
  • Nederlandse Vereniging voor Endocrinologie
  • Nederlandse Vereniging voor Vaatchirurgie

Algemene gegevens

General Information

The Kennisinstituut van de Federatie Medisch Specialisten ( assisted the guideline development group. The guideline was financed by Stichting Kwaliteitsgelden Medisch Specialisten (SKMS) which is a quality fund for medical specialists in The Netherlands.

Samenstelling werkgroep

Guideline development group (GDG)

A multidisciplinary guideline development group (GDG) was formed for the development of the guideline in 2020. The GDG consisted of representatives from all relevant medical specialization fields which were using intravascular contrast administration in their field.


All GDG members have been officially delegated for participation in the GDG by their scientific societies. The GDG has developed a guideline in the period from June 2020 until November 2022. The GDG is responsible for the complete text of this guideline.


Guideline development group

  • Dekkers I.A. (Ilona), clinical epidemiologist and radiologist, Leiden University Medical Center, Leiden
  • Geenen R.W.F. (Remy), radiologist, Noordwest Ziekenhuisgroep, Alkmaar
  • Kerstens M.N. (Michiel), internist-endocrinologist, University Medical Centre Groningen
  • Krabbe J.G. (Hans), clinical chemist-endocrinologist, Medisch Spectrum Twente, Enschede
  • Rossius M.J.P. (Mariska), radiologist, Erasmus Medical Centre, Rotterdam
  • Uyttenboogaart M. (Maarten), neurologist and neuro-interventionalist, University Medical Centre Groningen
  • van de Luijtgaarden K.M. (Koen), vascular surgeon, Maasstad Ziekenhuis, Rotterdam
  • van der Molen A.J. (Aart), chair guideline development group, radiologist, Leiden University Medical Center, Leiden
  • van der Wolk S.L. (Sabine), gynaecologist-obstetrician, Haga Ziekenhuis, Den Haag
  • van de Ven A.A.J.M. (Annick), internist-allergologist-immunologist, University Medical Centre Groningen (until 1.7.2022)
  • van der Houwen, T.B. (Tim), internist-allergologist-immunologist, Amsterdam University Medical Center (from 1.7.2022)

Invited experts

  • van Maaren M.S. (Maurits), internist-allergologist-immunologist, Erasmus MC, Rotterdam


Conflicts of interest

The GDG members have provided written statements about (financially supported) relations with commercial companies, organisations or institutions that were related to the subject matter of the guideline. Furthermore, inquiries have been made regarding personal financial interests, interests due to personal relationships, interests related to reputation management, interest related to externally financed research and interests related to knowledge valorisation. The statements on conflict of interest can be requested from the administrative office of Kennisinstituut van de Federatie Medisch Specialisten ( and were summarised below.


Last name


Other positions

Personal financial


Personal relations

Reputation management

Externally financed


Knowledge valorisation

Other interests



Dekkers IA

Radiologist, LUMC

Clinical Epidemiologist


Member of contrast media safety committee, European Society of Urogenital Radiology (no payment)


Member, Gadolinium Research and Education Committee, European Society of Magnetic Resonance in Medicine, and Biology (no







Received consultancy fees from Guerbet, 2019-


July 24th, 2020, Reaffirmed October 12th, 2022

No restrictions: received in part 3 of the guideline speaker fees, but this guideline does not mention specific medication, not of working mechanism, nor of side effects.

Geenen RWF

Radiologist, Noordwest ziekenhuisgroep

/Medisch specialisten


Member of contrast media safety

committee, European

Society of Urogenital

Radiology (no payment)







April 11th, 2020, Reaffirmed October 12th,


No restrictions

Houwen T, van der

Internist - Immunologist - Allergologist, Amsterdam UMC, also seconded allergologist in Huid Medisch









July 11th, 2022 Reaffirmed October 12th, 2022

No restrictions

Kerstens MN

Internist- endocrinologist, UMCG

Chairman Bijniernet (no payment)







July 1st, 2020, reaffirmed October 25th,


No restrictions

Krabbe JG

Clinical chemist, Medisch Spectrum Twente








September 1st, 2020,

Reaffirmed October 13th, 2022

No restrictions

Luijtgaarden KM, van de

Vascular surgeon, Maasland Ziekenhuis








August 1st, 2020,

reaffirmed October 26th, 2022

No restrictions

Molen AJ, van der

Radiologist LUMC

Member of contrast media safety committee, European Society of Urogenital Radiology (no



Member, Gadolinium Research and Education Committee, European Society of Magnetic Resonance in Medicine, and Biology (no







Received consultancy fees from Guerbet, 2019-


July, 24th, 2020 Reaffirmed October 12th, 2022

No restrictions: received in part 3 of the guideline speaker fees, but this guideline does not mention

Specific medication, not

of working mechanism, nor of side effects.

Rossius MJP

Radiologist Erasmus Medical Centre

Medical coordinator (no payment)







April 7th, 2020, Reaffirmed October 13th,


No restrictions

Uyttenboogaart M

Neurologist and neuro- interventionalist UMCG

Advisor International Federation of Orthopaedic Manipulative Physical Therapist / Nederlandse Vereniging Manuele Therapie



Subsidy Hart Stichting for CONTRAST

(Consortium of New Treatments in Acute Stroke): WP8 Stroke logistics and Epidemiology: financing of 2 PhD students by the Hart Stichting / PPS


Work package leader CONTRAST

(Consortium of New Treatments in Acute Stroke): WP8 Stroke logistics and Epidemiology



June 30th, 2020, reaffirmed October 26th, 2022

No restrictions: the CONTRAST

consortium wp8 is only about organisation and treatment of stroke.

Stroke is not in this guideline.

Ven AAJM, van de

Internist- allergologist- immunologist, UMCG

Education and research related to work as internist-








April 7th, 2020, Reaffirmed October 19th, 2022

No restrictions

Wolk S, van der

Gynaecologist- obstetrician, Haga Ziekenhuis








June 30th, 2021, reaffirmed October 25th,


No restrictions

Inbreng patiëntenperspectief

Input of patient’s perspective

The guideline does not address a specific adult patient group, but a diverse set of diagnoses. Therefore, it was decided to invite a broad spectrum of patient organisations for the stakeholder consultation. The stakeholder consultation was performed at the beginning of the process for feedbacking on the framework of subjects and clinical questions addressed in the guideline, and during the commentary phase to provide feedback on the concept guideline. The list of organisations which were invited for the stakeholder consultation can be requested from the Kennisinstituut van de Federatie Medisch Specialisten ( In addition, patient information on safe use of contrast media in pregnancy and lactation was developed for, a platform to inform patients about health and disease.



During different phases of guideline development, implementation and practical enforceability of the guideline were considered. The factors that could facilitate or hinder the introduction of the guideline in clinical practice have been explicitly considered. The implementation plan can be found in the ‘Appendices to modules’. Furthermore, quality indicators were developed to enhance the implementation of the guideline. The indicators can also be found in the ‘Appendices to modules’.




This guideline has been developed conforming to the requirements of the report of Guidelines for Medical Specialists 2.0 by the advisory committee of the Quality Counsel ( This report is based on the AGREE II instrument (Appraisal of Guidelines for Research & Evaluation II) (, a broadly accepted instrument in the international community and based on the national quality standards for guidelines: “Guidelines for guidelines” (


Identification of subject matter

During the initial phase of the guideline development, the GDG identified the relevant subject matter for the guideline. The framework is consisted of both new matters, which were not yet addressed in part 1 and 2 of the guideline, and an update of matters that were subject to modification (for example in case of new published literature). Furthermore, a stakeholder consultation was performed, where input on the framework was requested.


Clinical questions and outcomes

The outcome of the stakeholder consultation was discussed with the GDG, after which definitive clinical questions were formulated. Subsequently, the GDG formulated relevant outcome measures (both beneficial and harmful effects). The GDG rated the outcome measures as critical, important and of limited importance (GRADE method). Furthermore, where applicable, the GDG defined relevant clinical differences.


Search and select

For clinical questions, specific search strategies were formulated, and scientific articles published in several electronic databases were searched. First, the studies that potentially had the highest quality of research were reviewed. The GDG selected literature in pairs (independently of each other) based on the title and abstract. A second selection was performed by the methodological advisor based on full text. The databases used, selection criteria and number of included articles can be found in the modules, the search strategy in the appendix.


Quality assessment of individual studies

Individual studies were systematically assessed, based on methodological quality criteria that were determined prior to the search. For systematic reviews, a combination of the AMSTAR checklist and PRISMA checklist was used. For RCTs the Cochrane risk of bias tool and suggestions by the CLARITY Group at McMaster University were used, and for cohort studies/observational studies the risk of bias tool by the CLARITY Group at McMaster University was used. The risk of bias tables can be found in the separate document Appendices to modules.


Summary of literature

The relevant research findings of all selected articles were shown in evidence tables. The evidence tables can be found in the separate document Appendices to modules. The most important findings in literature were described in literature summaries. When there were enough similarities between studies, the study data were pooled.


Grading quality of evidence and strength of recommendations

The strength of the conclusions of the included studies was determined using the GRADE- method. GRADE stands for Grading Recommendations Assessment, Development and Evaluation (see (Atkins, 2004). GRADE defines four levels for the quality of scientific evidence: high, moderate, low, or very low. These levels provide information about the certainty level of the literature conclusions (


The evidence was summarized in the literature analysis, followed by one or more conclusions, drawn from the body of evidence. The level of evidence for the conclusions can be found above the conclusions. Aspects such as expertise of GDG members, local expertise, patient preferences, costs, availability of facilities and organisation of healthcare aspects are important to consider when formulating a recommendation. These aspects are discussed in the paragraph justifications. The recommendations provide an answer to the clinical question or help to increase awareness and were based on the available scientific evidence and the most relevant justifications.



Internal (meant for use by scientific society or its members) quality indicators were developed with the guideline and can be found in the separate document Appendices to modules. In most cases, indicators were not applicable. For most questions, additional scientific research on the subject is warranted. Therefore, the GDG formulated knowledge gaps to aid in future research, which can be found in the separate document Appendices to modules.


Commentary and authorisation phase

The concept guideline was subjected to commentaries by the involved scientific societies. The list of parties that participated in the commentary phase can be requested from the Kennisinstituut van de Federatie Medisch Specialisten ( The commentaries were collected and discussed with the GDG. The feedback was used to improve the guideline; afterwards the GDG made the guideline definitive. The final version of the guideline was offered to the involved scientific societies for authorization and was authorized.



Brouwers MC, Kho ME, Browman GP, et al. AGREE Next Steps Consortium. AGREE II: advancing guideline development, reporting and evaluation in health care. CMAJ. 2010; 182(18): E839-E842.

Medisch Specialistische Richtlijnen 2.0. Adviescommissie Richtlijnen van de Raad Kwaliteit, 2012. Available at: [URL].

Schünemann H, Brożek J, Guyatt G, et al. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. The GRADE Working Group, 2013. Available at: [URL].

Schünemann HJ, Oxman AD, Brozek J, et al. Grading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ. 2008;336(7653):1106- 1110. Erratum published in: BMJ 2008;336(7654).

Ontwikkeling van Medisch Specialistische Richtlijnen: stappenplan. Kennisinstituut van Medisch Specialisten, 2020.