A side effect ( NW ) is an effect (desired or undesired) that occurs in addition to the intended main effect of a drug . In addition, the term undesirable drug effects ( ADRs ), or just undesirable effects for short , is used. Sometimes the undesirable drug side effects are also referred to as harmful effects or disruptive effects .
"If it is claimed that a substance shows no side effects, then there is a strong suspicion that it has no main effect either."
In some cases, the effects that occur in addition to the main effect can also have a positive effect on an illness.
The pharmacodynamics investigates the effect and the mechanism of action .
Side effects can be divided into:
- Drug typical and dose- dependent side effects (mostly related to the main effect)
- Dose-independent adverse effects (such as hypersensitivity reactions ).
Depending on the severity of the disease, the doctor and the patient themselves must weigh up whether the risk of side effects can be outweighed by the benefits of the drug.
At times, side effects can have desirable effects. For example, the cell growth-inhibiting (anti- proliferative ) effect of the glucocorticoids is desired in patients with psoriasis , since dandruff formation is counteracted. In patients with endogenous eczema , this effect is undesirable because it leads to thinning ( atrophy ) of the skin.
In terms of pharmacovigilance , the classification in
- Unforeseen side effects : these have not been observed before and are therefore not described in the summary of product characteristics ( product information).
- Serious side effects : those that are fatal or life-threatening, necessitate inpatient treatment or prolongation of inpatient treatment, lead to permanent or serious disability or disability, or manifest themselves as a congenital malformation (congenital anomaly) or a birth defect. The term “ serious adverse event ” is also used in clinical trials .
They are subject to special documentation and reporting requirements across the EU in accordance with harmonized pharmaceutical law.
It is estimated that nearly 200,000 people die from drug side effects annually in the EU. The European Parliament therefore decided in 2010 to improve patient information (for example in the package insert ).
Frequency and description of side effects
Side effects must be listed in the product information (for doctors and pharmacists) and in the package insert (for patients). The frequency and description of the occurrence of side effects are standardized in terms of naming, structuring and frequency information ( terminology , organ class system and frequency definition according to MedDRA ).
The frequency of side effects is based on the following categories:
|Very often||> 10%||more than 1 patient in 10|
|Frequently||1 - 10%||1 to 10 patients in 100|
|Occasionally||0.1 - 1%||This affects 1 to 10 users in 1,000|
|Rare||0.01 - 0.1%||This affects 1 to 10 users in 10,000|
|Very rare||<0.01%||less than 1 patient in 10,000|
|Not known||Frequency cannot be estimated from the available data|
Rare and very rare side effects only become noticeable after a higher number of applications (duration of use, number of patients). For statistical reasons, for example, about six million applications have to be observed for side effects with a frequency of 1: 1 million. As a result, there is an increased risk of previously unknown side effects with new or less widely used drugs.
Pharmaceutical companies are obliged to collect and evaluate all known side effects of a drug, regardless of their causality , and, if necessary, to state them in the summary of the product characteristics (in Germany: product information ) and in the package insert. According to Medicines Act (AMG), the manufacturer is liable for all side effects not specified in this product information.
Situation in the European Union
According to the legal definition, side effects are harmful and unintentional reactions to the medicinal product , which in the case of veterinary medicinal products are, however, limited to those which occur when used as intended. The broader definition in human pharmaceutical law, on the other hand, also takes into account undesirable effects that occur after medication errors (e.g. overdose , incorrect type of application), off-label use or drug abuse - i.e. improper use: they too should be for reasons of Drug safety must be recorded and reported to the drug authorities . The presentation of the side effects in the package insert is limited to those observed after normal use.
Reporting suspected cases
If a patient notices unwanted changes after using a drug, he should inform his doctor or pharmacist. This reports the case to the responsible authorities (in Germany the drug commission or the responsible federal authority). It is also possible to report a suspected UAW case online, both for members of the medical professions and for citizens. The Drugs Commission of the German Medical Association (AKdÄ) publishes a report sheet on its website, which is also regularly printed in the Deutsches Ärzteblatt and which can also be used for reporting (in Germany). In other EU countries, too, an increasing number of suspected side effects can be reported directly by patients in various ways.
In the UK, however, patients can use the Yellow Card to report adverse side effects directly to the Medicines and Healthcare Products Regulatory Agency . In Switzerland there is a reporting system that is described on the website of the Swissmedic authority ; All professionals who are authorized to dispense, use or prescribe medicinal products and pharmaceutical companies that manufacture or sell medicinal products are required to report.
Research of suspected cases
The Federal Institute for Drugs and Medical Devices (BfArM) offered from April 2013, online access to its database of suspected adverse drug reaction. The internet offer gave doctors and patients the opportunity to find out more about drug risks. As of November 22, 2017, the German database was replaced by a European database of the European Medicines Agency . The database can be researched on a website created by the agency.
The spectrum of possible side effects of drugs ranges from relatively harmless side effects (e.g. tiredness) to effects whose damage exceeds the usefulness of the drug. A large number of the most serious adverse drug reactions occurred in the 1960s after taking the sleeping pill thalidomide ( Contergan ) during pregnancy, which caused severe physical malformations of the embryo and therefore had to be withdrawn from the market. Other cases of severe side effects that required the withdrawal, were under treatment with the rheumatism medium Coxigon (1982) and Vioxx (2004), in 1983 with the painkiller Zomax , the latter with five deaths in the US on. Apart from the rarity of side effects, factors such as different patient groups or risks, which only come into contact with the preparation when it is widely used, can also explain the observation of side effects.
In addition to a total ban on sales, possible measures to improve the benefit-risk ratio include, for example, restrictions on the areas of application, expansion of contraindications, the addition of warning notices and the establishment of precautionary measures.
In 2003, Jürgen C. Frölich , then head of pharmacology at the Hannover Medical School (MHH), reported that - if you transfer the data from a study from Norway to Germany - more than 50,000 people in Germany die every year from adverse drug reactions. The prospective Norwegian study at a clinic there had shown that more than 18% of the deaths that occurred there within two years were caused by adverse drug reactions and that without an autopsy just 8 out of 133 deaths caused by adverse drug effects and drug interactions were recognized as such . It is estimated that every second death from adverse drug reactions could be avoided. However, this number refers only to the " internal departments " and is therefore "a small part of all hospital admissions that take place" and still "a small part of all deaths that actually take place due to drugs", so Frölich among others in 2004 SWR documentary " Deadly Pills ".
According to EU calculations, the economic damage of a (accident) death is around one million euros. Petra Thürmann from the Chair of Clinical Pharmacology at the University of Witten / Herdecke presented an evaluation of 3,664 hospital admissions due to adverse drug reactions between 2000 and 2006. 530 of the ADRs were caused by insulins and their analogues, 446 by NSAIDs , 437 by phenprocoumon , 316 by digitalis (90% by digitoxin ), 285 by beta-blockers , 267 by oral anti-diabetic drugs and 262 by diuretics . 59% of the ADRs occurred in patients over 70 years of age.
In 2006, the statutory health insurance companies Y spent almost 125 million euros on the treatment of gastrointestinal side effects of NSAIDs. An estimated 1100 to 2200 people die each year in Germany from gastrointestinal complications. The number of unreported cases is likely to be significantly higher.
It is assumed that ADRs occur in about five percent of drug-treated patients and that ADRs are the cause of admission in about three to six percent of all patients admitted to internal medicine wards (estimated 50,000–300,000). About 2.3% of the admitted patients die as a direct effect of the ADR. Adverse effects were therefore responsible for the death of 0.15% of the patients treated in the hospital (0.1 to 0.2%). 49.6% of fatal ADRs were justified by incorrect use of the drugs.
In addition to the burden on patients due to ADRs, the economic burden on the supply system is also considerable: In a report by the German Advisory Council on the assessment of developments in the health care system from 2007, the costs for ADR-induced hospital treatments in Germany were estimated at € 350 to 400 million annually, costs can be five to nine percent of total hospital costs.
According to the results of a prospective observational study from 2004, every 16th inpatient treatment is the result of a drug side effect. This would result in costs of the equivalent of more than 700 million euros for the National Health Service (NHS) in Great Britain every year . A research team led by Munir Pirmohamed from the University of Liverpool evaluated the admission data of 18,820 patients over the age of 16 who were treated in two clinics over the course of six months. The authors tried to identify all cases where a drug side effect was the definitive, probable, or possible cause of hospital admission. This association was seen in 1225 patients, which corresponds to a prevalence of 6.5%. According to their presentation, corresponding results were also obtained from earlier studies on the same question.
The risk of ADRs is particularly high in older patients. For this reason, the American geriatrician Mark Beers compiled a list of drugs that should not be prescribed for patients over 65 years of age, the so-called Beers list .
Side effect becomes the main effect
Side effects can also become the main effect or indication . The drug sildenafil , for example, was originally developed to lower blood pressure , for which it turned out to be unsuitable. Instead, he showed "side" effects of a completely different nature, which became the new main effect: Sildenafil came onto the market in 1998 as Viagra, initially for the treatment of erectile dysfunction ( "sexual enhancer ") - the effect on blood pressure became an undesirable side effect. In 2005 it was approved as a Revatio for the treatment of abnormally high blood pressure in the pulmonary arteries ( pulmonary hypertension ).
- Regulatory Affairs
- Step-by-step plan procedure (Medicines Act)
- Vaccine Adverse Event Reporting System
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- For example regularly in the medicine telegram .
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- Directive 2001/83 / EC Article 1 (11); see e.g. Medicines Act (Germany), § 2b Medicines Act (Austria)
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