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Anadverse effect is an undesired harmful effect resulting from amedication or otherintervention, such assurgery.^[1] An adverse effect may be termed a "side effect", when judged to be secondary to a main ortherapeutic effect. The termcomplication is similar to adverse effect, but the latter is typically used in pharmacological contexts, or when the negative effect is expected or common. If the negative effect results from an unsuitable or incorrectdosage or procedure, this is called amedical error and not an adverse effect. Adverse effects are sometimes referred to as "iatrogenic" because they are generated by aphysician/treatment. Some adverse effects occur only when starting, increasing or discontinuing a treatment. Using a drug or other medical intervention which iscontraindicated may increase therisk of adverse effects. Adverse effects may cause complications of adisease or procedure and negatively affect itsprognosis. They may also lead tonon-compliance with a treatment regimen. Adverse effects of medical treatment resulted in 142,000 deaths in 2013 up from 94,000 deaths in 1990 globally.^[2]

The harmful outcome is usually indicated by some result such asmorbidity,mortality, alteration inbody weight, levels ofenzymes, loss of function, or as apathological change detected at the microscopic, macroscopic or physiological level. It may also be indicated bysymptoms reported by a patient. Adverse effects may cause a reversible or irreversible change, including an increase or decrease in the susceptibility of the individual to other chemicals,foods, or procedures, such asdrug interactions.

In terms of drugs, adverse events may be defined as: "Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment."^[3]

Inclinical trials, a distinctionis made between anadverse event and aserious adverse event. Generally, any event which causes death, permanent damage,birth defects, or requireshospitalization is considered a serious adverse event.^[4] The results of trials are often included in the labelling of the medication to provide information both for patients and the prescribing physicians.

The term "life-threatening" in the context of a serious adverse event refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe.^[3]

In many countries, adverse effects are required by law to be reported, researched inclinical trials and included into the patient information accompanyingmedical devices anddrugs for sale to the public. Investigators in human clinical trials are obligated to report these events inclinical study reports.^[5] Research suggests that these events are often inadequately reported in publicly available reports.^[6] Because of the lack of these data and uncertainty about methods for synthesising them, individuals conductingsystematic reviews and meta-analyses of therapeutic interventions often unknowingly overemphasise health benefit.^[7] To balance the overemphasis on benefit, scholars have called for more complete reporting of harm from clinical trials.^[8]

TheYellow Card Scheme is aUnited Kingdom initiative run by theMedicines and Healthcare products Regulatory Agency (MHRA) and theCommission on Human Medicines (CHM) to gather information on adverse effects tomedicines. This includes all licensed medicines, from medicines issued onprescription to medicines boughtover the counter from a supermarket. The scheme also includes allherbal supplements and unlicensed medicines found in cosmetic treatments. Adverse drug reactions (ADRs) can be reported by a number of health care professionals includingphysicians,pharmacists andnurses, as well aspatients.

In theUnited States several reporting systems have been built, such as theVaccine Adverse Event Reporting System (VAERS), the Manufacturer and User Facility Device Experience Database (MAUDE) and the Special Nutritionals Adverse Event Monitoring System.MedWatch is the main reporting center, operated by theFood and Drug Administration.

InAustralia, adverse effect reporting is administered by theAdverse Drug Reactions Advisory Committee (ADRAC), a subcommittee of theAustralian Drug Evaluation Committee (ADEC). Reporting is voluntary, and ADRAC requests healthcare professionals to report all adverse reactions to its current drugs of interest, and serious adverse reactions to any drug. ADRAC publishes the Australian Adverse Drug Reactions Bulletin every two months. The Government'sQuality Use of Medicines program is tasked with acting on this reporting to reduce and minimize the number of preventable adverse effects each year.

Adverse reaction reporting is an important component of New Zealand'spharmacovigilance activities. TheCentre for Adverse Reactions Monitoring (CARM) in Dunedin is New Zealand's national monitoring centre for adverse reactions. It collects and evaluates spontaneous reports of adverse reactions to medicines, vaccines, herbal products and dietary supplements from health professionals in New Zealand. Currently the CARM database holds over 80,000 reports and provides New Zealand-specific information on adverse reactions to these products, and serves to support clinical decision making when unusual symptoms are thought to be therapy related

In Canada, adverse reaction reporting is an important component of the surveillance of marketed health products conducted by the Health Products and Food Branch (HPFB) of Health Canada. Within HPFB, the Marketed Health Products Directorate leads the coordination and implementation of consistent monitoring practices with regards to assessment of signals and safety trends, and risk communications concerning regulated marketed health products.

MHPD also works closely with international organizations to facilitate the sharing of information. Adverse reaction reporting is mandatory for the industry and voluntary for consumers and health professionals.

In principle, medical professionals are required to report all adverse effects related to a specific form of therapy. In practice, it is at the discretion of the professional to determine whether a medical event is at all related to the therapy. As a result, routine adverse effects reporting often may not include long-term and subtle effects that may ultimately be attributed to a therapy.^[9]

Part of the difficulty is identifying the source of a complaint. A headache in a patient taking medication forinfluenza may be caused by the underlying disease or may be an adverse effect of the treatment. In patients with end-stagecancer, death is a very likely outcome and whether the drug is the cause or a bystander is often difficult to discern.^{[citation needed]}

Surgery may have a number of undesirable or harmful effects, such asinfection,hemorrhage,inflammation,scarring, loss of function, or changes in localblood flow. They can be reversible or irreversible, and a compromise must be found by the physician and the patient between the beneficial or life-saving consequences of surgery versus its adverse effects. For example, a limb may be lost toamputation in case of untreatablegangrene, but the patient's life is saved. Presently, one of the greatest advantages ofminimally invasive surgery, such aslaparoscopic surgery, is the reduction of adverse effects.

Other nonsurgical physical procedures, such as high-intensityradiation therapy, may causeburns and alterations in theskin. In general, these therapies try to avoid damage to healthytissues while maximizing the therapeutic effect.

Vaccination may have adverse effects due to the nature of its biological preparation, sometimes usingattenuatedpathogens andtoxins. Common adverse effects may befever,malaise and local reactions in the vaccination site. Very rarely, there is a serious adverse effect, such aseczema vaccinatum, a severe, sometimes fatal complication which may result in persons who haveeczema or atopicdermatitis.

Diagnostic procedures may also have adverse effects, depending much on whether they areinvasive,minimally invasive ornoninvasive. For example,allergic reactions toradiocontrast materials often occur, and acolonoscopy may cause the perforation of theintestinal wall.

Adverse effects can occur as a collateral or side effect of many interventions, but they are particularly important inpharmacology, due to its wider, and sometimes uncontrollable, use by way ofself-medication. Thus,responsible drug use becomes an important issue here. Adverse effects, liketherapeutic effects of drugs, are a function ofdosage or drug levels at the targetorgans, so they may be avoided or decreased by means of careful and precisepharmacokinetics, the change of drug levels in the organism in function of time after administration.

Adverse effects may also be caused bydrug interaction. This often occurs when patients fail to inform their physician and pharmacist of all the medications they are taking, including herbal and dietary supplements. The new medication may interact agonistically or antagonistically (potentiate or decrease the intended therapeutic effect), causing significantmorbidity and mortality around the world. Drug-drug and food-drug interactions may occur, and so-called "natural drugs" used inalternative medicine can have dangerous adverse effects. For example, extracts ofSt John's wort (Hypericum perforatum), aphytotherapic used for treating milddepression are known to cause an increase in thecytochrome P450enzymes responsible for themetabolism and elimination of many drugs, so patients taking it are likely to experience a reduction inblood levels of drugs they are taking for other purposes, such ascancerchemotherapeutic drugs,protease inhibitors forHIV andhormonal contraceptives.

The scientific field of activity associated with drug safety is increasingly government-regulated, and is of major concern for the public, as well as todrug manufacturers. The distinction between adverse and nonadverse effects is a major undertaking when a new drug is developed and tested beforemarketing it. This is done intoxicity studies to determine the nonadverse effect level (NOAEL). These studies are used to define the dosage to be used in human testing (phase I), as well as to calculate the maximum admissible daily intake. Imperfections in clinical trials, such as insufficient number of patients or short duration, sometimes lead topublic health disasters, such as those offenfluramine (the so-calledfen-phen episode),thalidomide and, more recently, ofcerivastatin (Baycol, Lipobay) androfecoxib (Vioxx), where drastic adverse effects were observed, such asteratogenesis,pulmonary hypertension,stroke,heart disease,neuropathy, and a significant number of deaths, causing the forced or voluntarywithdrawal of the drug from the market.

Most drugs have a large list of nonsevere or mild adverse effects which do not rule out continued usage. These effects, which have a widely variable incidence according to individual sensitivity, includenausea,dizziness,diarrhea,malaise,vomiting,headache,dermatitis, dry mouth, etc. These can be considered a form of pseudo-allergic reaction, as not all users experience these effects; many users experience none at all.

The Medication Appropriateness Tool for Comorbid Health Conditions in Dementia^[10] (MATCH-D) warns that people with dementia are more likely to experience adverse effects, and that they are less likely to be able to reliably report symptoms.^[11]

• Abortion,miscarriage oruterinehemorrhage associated withmisoprostol (Cytotec), a labor-inducing drug (this is a case where the adverse effect has been used legally and illegally for performing abortions)^[12]
• Addiction to manysedatives andanalgesics, such asdiazepam,morphine, etc.^[13]
• Birth defects associated withthalidomide
• Bleeding of theintestine associated withaspirin therapy^[14]
• Cardiovascular disease associated withCOX-2 inhibitors (i.e. Vioxx)^[15]
• Deafness andkidney failure associated withgentamicin (anantibiotic)^[16]
• Death, followingsedation, in children usingpropofol (Diprivan)^[17]
• Depression orhepatic injury caused byinterferon^[18]
• Diabetes caused byatypical antipsychotic medications (neurolepticpsychiatric drugs)^[19]
• Diarrhea caused by the use oforlistat (Xenical)^[20]
• Erectile dysfunction associated with many drugs, such asantidepressants^[21]
• Fever associated withvaccination^[22][23]
• Glaucoma associated withcorticosteroid-basedeye drops^[24]
• Hair loss andanemia may be caused bychemotherapy againstcancer,leukemia, etc.^[25]
• Headache followingspinal anaesthesia^[26]
• Hypertension inephedrine users, which prompted FDA to remove thedietary supplement status ofephedra extracts^[27]
• Insomnia caused by stimulants,methylphenidate (Ritalin),Adderall, etc.^[28]
• Lactic acidosis associated with the use ofstavudine (Zerit, forHIV therapy)^[29] ormetformin (for diabetes)^[30]
• Mania caused bycorticosteroids^[31]
• Liver damage fromparacetamol^[32]
• Melasma andthrombosis associated with use of estrogen-containinghormonal contraception, such as thecombined oral contraceptive pill^[33][34]
• Priapism associated with the use ofsildenafil^[35]
• Rhabdomyolysis associated withstatins (anticholesterol drugs)^[36]
• Seizures caused by withdrawal frombenzodiazepines^[37]
• Drowsiness or increase inappetite due toantihistamine use. Some antihistamines are used in sleep aids explicitly because they cause drowsiness.^[38]
• Stroke orheart attack associated withsildenafil (Viagra), when used withnitroglycerin
• Suicide, increased tendency associated to the use offluoxetine and otherselective serotonin reuptake inhibitor (SSRI) antidepressants
• Tardive dyskinesia associated with use ofmetoclopramide and manyantipsychotic medications^[39]

Sometimes, putative medical adverse effects are regarded as controversial and generate heated discussions in society andlawsuits against drug manufacturers. One example is the recent controversy as to whetherautism was linked to theMMR vaccine (or tothiomersal, amercury-based preservative used in somevaccines). No link has been found in several large studies, and despite removal of thimerosal from most early childhood vaccines beginning with those manufactured in 2003, the rate of autism has not decreased as would be expected if it had been the causative agent.^[40][41]

Another instance is the potential adverse effects ofsiliconebreast implants, which led to class actions brought by tens of thousands of plaintiffs against manufacturers of gel-based implants, due to allegations of damage to theimmune system which have not yet been conclusively proven.^[42] In 1998, Dow Corning settled its remaining suits for $3.2 Billion and went into bankruptcy.^[43]

Due to the exceedingly high impact on public health of widely used medications, such ashormonal contraception andhormone replacement therapy, which may affect millions of users, even marginal probabilities of adverse effects of a severe nature, such asbreast cancer, have led to public outcry and changes in medical therapy, although its benefits largely surpassed the statistical risks.

• Patient Safety Network – includes a glossary and articles on adverse effects, drug reactions, medical error, iatrogenesis, among others.
• Australian Adverse Drug Reactions Bulletin – published bimonthly
• MedEffect Canada (Health Canada)
• Medication Errors—from theU.S. Food and Drug Administration.
• Medical Product Safety Information – MedWatch lists safety alerts for drugs, biologics, devices and dietary supplements, recalls, market withdrawals, public health advisories and links
• Medical Devices Safety National Library of Medicine (Medline Plus, useful lists of conventional drug and medical device articles and websites)
• When Medicine Hurts Instead of Helps – June 1998 report by theAlliance for Aging Research.

• Medical terminology
• Clinical pharmacology
• Patient safety
• Effects of external causes
• Drug safety

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