Definitions of Adverse Drug Reactions 

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 

threatening 

• 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 

Certain 

• 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 

Probable/likely 

• 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 

Possible 

• 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 

Unlikely 

• 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 

Conditional/unclassified 

• 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.}