Adverse drug reaction

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Adverse Drug Reaction
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An adverse drug reaction (ADR) can be defined as a response to a drug which is noxious and unintended. Adverse reactions may arise from use of the product within or outside the terms of the marketing authorization or from occupational exposure. Use outside the marketing authorization includes off-label use, overdose, misuse, abuse and medication errors. [1] Generally the causality of adverse drug reactions is uncertain, making it more accurate to refer to ‘suspected ADRs’. However, not all unwanted clinical phenomena encountered in practice are related to use of drugs and it is therefore important to differentiate between ADRs and adverse events (AEs) that are defined as untoward occurrences that may be present during treatment with a drug but which do not necessarily have a causal relationship with this treatment. [2]

Contents

Definitions of ADR, AE and related terms

Adverse Event

  • The World Health Organization (WHO) through the Program for International Drug Monitoring (PIDM) Uppsala Monitoring Center (UMC) defines Adverse Event (AE) as "Any negative or harmful occurrence that takes place during treatment, that may or may not be associated with a medicine. Note. A fall could be such an event that may– or may not – have any association with a medicine". [3]
  • The definition of Adverse Event (AE), is seen in the WHO´s and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for human use (ICH) Guidelines for Good Clinical Practice (GCP) for trials on Pharmaceutical Products glossary, as "untoward medical occurrence in a patient or clinical investigation, subject, administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can, therefore, be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational)".[4][5]
  • The FDA defined an AE as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related. [6]

Epidemiology

Adverse drug reactions caused by immune and nonimmune mechanisms are a major cause of morbidity and mortality worldwide. They are the most common iatrogenic illness, complicating 5 to 15 percent of therapeutic drug courses. In the United States, more than 100,000 deaths are attributed annually to serious adverse drug reactions. Three to 6 percent of all hospital admissions are because of adverse drug reactions, and 6 to 15 percent of hospitalized patients (2.2 million persons in the United States in 1994) experience a serious adverse drug reaction. Epidemiologic data support the existence of specific factors that increase the risk of general adverse drug reactions, such as female gender, or infection with human immunodeficiency virus (HIV), or herpes Factors associated with an increased risk for hypersensitivity drug reactions include asthma, systemic lupus erythematosus, or use of beta blockers. Although atopic patients do not have a higher rate of sensitization to drugs, they are at increased risk for serious allergic reactions.

  [7]

Serious Adverse Event

The FDA defined a Serious Adverse Event as an untoward medical occurrence in a patient/participant administered a medicinal product, which does not necessarily have a causal relationship with this treatment, and that at any dose results in:

  • Death - If there is reasonable suspicion that death was an outcome of the AE, it should be reported with the date included, if known.
  • Is life-threatening i.e. the subject is at risk of death at time of event - A life-threatening AE is defined as any adverse experience that places the subject, in the view of the investigator, at immediate risk of death from the reaction as it occurred or it is suspected that the use or continued use of the product would result in the patient’s death. If there is reasonable suspicion that the patient was at substantial risk of dying at the time of the AE, or use or continued use of the device or other medical product might have resulted in the death of the patient, or the use of drug/device that led to temporary or permanent disability, or prolongation of hospitalization or teratogenicity, hemorrhaging and internal bleeding with rapid drop in blood pressure, loss of consciousness from increase in pressure on the brain, then it should be reported. The term "life-threatening" in the definition of "serious" 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.
  • Results in persistent or significant disability/incapacity - Disability is defined as a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions. Examples include loss of speech; fatigue so great the subject cannot get out of bed at all; loss of memory; and paralysis.
  • Requires in-patient hospitalization or prolongs a current hospitalization - Hospitalization is defined as admission to the hospital for longer than 24 hours or prolongation of a hospital stay due to an AE. If admission to the hospital or prolongation of hospitalization was a result of the adverse event, it should be reported. Emergency room visits that do not result in admission to the hospital should be evaluated for one of the other serious outcomes (e.g., life-threatening; required intervention to prevent permanent impairment or damage; other serious medically important events). [8]
  • Congenital Anomaly - If there is reasonable suspicion that exposure to a medical product prior to conception or during pregnancy may have resulted in an adverse outcome in the child or children, it should be reported. Thalidomide is the best example of a drug causing congenital anomalies with babies born with deformed arms and legs. [9][10][11]
  • Important medical events jeopardizing the patient or subject - Events that may require medical or surgical intervention to prevent one of the outcomes listed in this definition, based upon appropriate medical judgment, even when they may not result in death, be life-threatening, or require hospitalization. Examples of such medical events include blood dyscrasias or convulsions that do not result in inpatient hospitalization, allergic bronchospasm requiring intensive treatment in an emergency room or at home, or the development of drug dependency or drug abuse. [12]

Adverse Drug Reaction (ADR)

  • An ADR is defined by the World Health Organization (WHO) as the response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function. [13] 
  • Adverse Drug Reaction (ADR) is the opposite response caused by taking a medicine. Numerous Adverse Drug Reactions speak to a mind-boggling symptom of the medication's helpful impacts and are because of the organization of single dosage or delayed utilization of medication. These responses are caused by a solitary medication or mix of various medications.
  • ADR is also defined as any noxious and unintended responses to the medicinal product related to any dose. [14]
  • Terms often used to mean ADR are: Suspected ADR, Drug Side Effects, Undesirable Drug Effects, Undesirable Side Effects. However, these terms may not be accurate to describe ADRs. [15]

Adverse effect

  • Adverse effects can hamper the treatment, lead to a complication or combine with the pre-existing disease and form a totally new disorder which is difficult to treat. One must be careful while using the term side-effect as it refers to a reaction which is known and expected by the physician whereas if one uses the term adverse effect then it implies that the reaction was a totally unexpected one and needs immediate medical attention to correct it. [16]
  • An adverse drug reaction is defined by The Lancet as “an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product.” [17]
  • The terms ‘ADR’ and ‘Adverse Effect’ are interchangeable, except that an adverse reaction is seen from the point of view of the patient and adverse effect is seen from the point of view of the drug. However, both terms must be distinguished from ‘adverse event’. [18]

Adverse Device Effect

Adverse Device Effect (ADE) : adverse event related to the use of an investigational medical device. This includes any adverse event resulting from insufficiencies or inadequacies in the instructions for use, the deployment, the implantation, the installation, the operation, or any malfunction of the investigational medical device. This includes any event that is a result of a use error or intentional misuse. In an instance if a patient is using blood glucose monitoring meter and the strip used to monitor the blood glucose is giving allergic reaction to the user is an Adverse Device Effect. Above explained scenario is an In Vitro device reaction. Devices that inserted into a human body is called In Vivo devices (Implantable Devices). In current pharmaceutical market many hormonal implants were used as long-term contraceptive. If the implant is broken inside the body and causes blood clotting then it is identified as Adverse Event. In the worst case, implants were move from the implanted location to another location and a surgery needed to remove it from body. This is called as serious device adverse reaction. [19] [20]

Serious Adverse Device Effect

Serious Adverse Device Effect is ADE that has resulted in any of the consequences characteristic of a serious adverse event that:

  • Led to death
  • Led to a serious deterioration in health that either:
  • Resulted in a life-threatening illness or injury or
  • Resulted in a permanent impairment of a body structure or a body function or
  • Required in-patient hospitalization or prolongation of existing hospitalization or
  • Resulted required in medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or a body function
  • Led to fetal distress, fetal death or a congenital abnormality or birth defect.

This includes device deficiencies that might have led to a serious adverse event if:

  1. suitable action had not been taken or
  2. intervention had not been made or
  3. if circumstances had been less fortunate.

These are handled under the SAE reporting system. A planned hospitalization for a pre-existing condition, or a procedure required by the Clinical Investigation Plan, without a serious deterioration in health, is not considered to be a serious adverse event. [21]

Product Quality Complaint

Main article: Product quality complaint

A Product Quality Complaint (PCQ) includes any written, electronic or oral communication that alleges deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or performance of a drug, combination product, or device after it is released for distribution to market or clinic. This includes all components distributed with the drug such as packaging, drug containers, delivery system, labeling, inserts, etc. Examples include:

  • Device that is damaged or broken
  • Bent or dull needles
  • Missing or illegible labeling
  • wrong label
  • incorrect batch number
  • Inability of a customer to administer the product
  • Product with an unexpected color, appearance, or particles is defined as any written.
  • Product shotages
  • Product mismatches [22]

Suspected ADR

  • The suspected ADR is any AE for which there is a reasonable possibility that the drug caused the adverse event. "Reasonable possibility" means there is evidence to suggest "A causal relationship between the drug and adverse event". [23]

Unexpected ADR

  • The WHO defined unexpected ADR as an ADR which nature or severity is not consistent with the applicable product information (e.g. Investigator's Brochure for an unapproved investigational medicinal product) or characteristics of the drug. [24][25]

Side Effects

  • ADR/AEs and drug side effects are completely different terms and are incorrectly used interchangeably, while they mean separate things. Drug side effects can be defined as a secondary unwanted (but proven) effects that have a high possibility to occur due to drug therapy regardless the dose. Side effects are tracked and investigated extensively during clinical trials and foreseen by the physician and usually, the patient knows them well before starting using the drug, while ADRs are not expected either by the physician nor the patient. The WHO defined side effects as "Any unintended effect of a pharmaceutical product occurring at a dose normally used in man, which is related to the pharmacological properties of the drug." [26]
  •  A side effect is an undesired effect that occurs when the medication is administered regardless of the dose. Unlike adverse events, side effects are mostly foreseen by the physician and the patient is told to be aware of the effects that could happen while on the therapy. Side effects differ from adverse events and later resolve on their own with time after taking the medication for several weeks. Some medications are even utilized due to their side effects, one example being mirtazapine used in anorexic patients due to the medications potential to cause weight gain. Side effects are tracked and investigated extensively during clinical trials before entering the market. [27]

Medication Error

Main article: Medication Error

  • A medication error is an unintended failure in the drug treatment process that leads to or has the potential to lead to, harm to the patient. Mistakes in the prescribing, dispensing, storing, preparation and administration of a medicine are the most common preventable cause of undesired adverse events in medication practice and present a major public health burden. Such events may be related to professional practice, healthcare products, procedures, and systems, including prescribing, order communication, product labeling, packaging, and nomenclature, compounding, dispensing, distribution, administration, education, monitoring, and use. [28]
  • Medication Errors can occur in:
  • Choosing a medicine—irrational, inappropriate, and ineffective prescribing, underprescribing and overprescribing
  • writing the prescription—prescription errors, including illegibility
  • Manufacturing the formulation to be used—wrong strength, contaminants or adulterants, wrong or misleading packaging
  • Dispensing the formulation—wrong drug, wrong formulation, wrong label
  • Administering or taking the drug—wrong dose, wrong route, wrong frequency, wrong duration
  • Monitoring therapy—failing to alter therapy when required, erroneous alteration [29]
  • The term ‘failure’ in the definition implies that certain standards should be set, against which failure can be judged. All those who deal with medicines should establish or be familiar with such standards. They should institute or observe measures to ensure that failure to meet the standards does not occur or is unlikely. Everybody involved in the treatment process is responsible for their part of the process.
  • National Coordinating Council for Medication Error Reporting and Prevention (NCCMERP) defined medication error as any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the healthcare professional, patient, or consumer. Such events may be related to professional practice, healthcare products, procedures, and systems, including prescribing; order communication; product labeling, packaging, and nomenclature, compounding, dispensing, distribution, administration, education, monitoring, and use." [30]
  • Bates et al. defined medication error as an error in the process of ordering or delivering a medication, regardless of whether an injury occurred or the potential for injury was present. [31]

Designated medical event

  • Designated medical event (DME) is an adverse event which is considered rare, serious, and associated with a high drug-attributable risk and which constitutes an alarm with as few as 1 to 3 reports. [32] As a help to prioritize the review of reports of suspected Adverse Drug Reactions (ADRs) in the framework of the day to day pharmacovigilance activities the European Medicines Agency has developed the Designated Medical Event (DME) list which is used by the European Medicines Agency, as well as the EEA Member States, to identify reports of suspected ADRs that deserve special attention, irrespective of statistical criteria used to prioritize safety reviews. [33]

ADR Case Report

ADR case report is a notification relating to a patient with an adverse effect or laboratory test abnormality suspected to be induced by a medicinal product. [34]

Identification of ADRs

In both the inpatient and outpatient setting, a patient’s new or worsening symptom may be the first sign of an ADR.

Outpatient setting

In a community pharmacy, patients often seek advice from the pharmacist to treat various symptoms at home. This can be an opportunity for the pharmacist to inquire about the patient’s symptoms to determine whether they might have been caused by an ADR. For example, if a patient asks the pharmacist for a recommendation to treat diarrhea, the pharmacist could inquire about other medications the patient is taking to determine whether diarrhea is a known ADR associated with the drug therapy, such as with antibiotics. An over-the-counter (OTC) medication may not be needed, and diarrhea may resolve on completion of the antibiotic therapy.

Inpatient setting

Patient interview

In the inpatient setting, patients may tell their nurse or physician about the new symptom they are having, which may result in a telephone call to the pharmacist. Asking detailed questions about the patient’s symptoms, rather than immediately providing a treatment recommendation, could uncover an ADR and prevent unnecessary drug therapy or further ADR symptoms. Noticing that an atypical laboratory or diagnostic procedure has been ordered may indicate that an ADR has occurred.

Laboratory tests

Common laboratory tests can also assist in identifying an ADR. A new order for a serum drug level may alert the practitioner to investigate whether an ADR caused by drug toxicity or treatment failure is occurring. Laboratory monitoring can help determine improvement or decline after a change in therapy. Laboratory values can also establish baseline organ function and help confirm or rule out alternative diagnoses. When initiating a new drug therapy, it may be helpful to obtain baseline laboratory values in anticipation of an ADR.Adverse drug reactions can be minimized including the patient as one pillar of the therapeutic plan and providing more patient counseling, which will improve drug safety. For example, baseline liver function tests are obtained before initiating therapy with a statin in anticipation that the therapy may cause an increase in these laboratory values, potentially warranting discontinuation. Abnormalities in laboratory results do not mean that an ADR has definitely occurred, but that the practitioner should take a close look at the patient to assess whether an ADR is a potential culprit.

Druge use monitoring

Often, an ADR can be detected by noticing an abrupt, unexpected discontinuation of a drug or a substantial dosage increase or reduction. Orders for new medications may occasionally alert the pharmacist that an ADR has occurred. Medication orders such as naloxone, flumazenil, diphenhydramine, antiemetics, vitamin K, sodium polystyrene sulfonate, corticosteroids, or antidiarrheals may be a sign that a practitioner is treating an ADR.

Reading patients records

Another way to identify an ADR is by reading the daily multidisciplinary notes in a patient’s chart. Notes pertaining to oversedation, lethargy, and falls may be the sign of an ADR caused by an analgesic, a sedative, or a muscle relaxant. Reports of a rash in a patient’s progress notes may be indicative of an ADR and should be investigated for a drug-related cause, such as an allergic reaction or yeast infection caused by the overuse of antibiotics. Some electronic medical record systems can compile reports for predetermined threshold changes in laboratory values. For example, if the health system determines that an increase or decrease in serum potassium values of 1 mEq/L in a 24-hour period is significant, a patient whose serum potassium falls from 4 mEq/L to 3 mEq/L will be included in the report. The pharmacist or other health care provider can then examine the medication profile to determine whether the drop in the potassium occurred because of an ADR (e.g., a diuretic in this case).

When an ADR occurs

Often, when an ADR occurs, a patient may require transfer to a higher level of care, such as from a general surgery ward to an intensive care unit. If an unexpected change in a patient’s clinical condition warrants transfer to a higher level of care, ADRs should always be included in the differential. Pharmacists should assess each medication that has been administered to the patient to identify whether an ADR could have occurred. Although several triggers aid in identifying potential ADRs, determining whether a patient’s symptoms or abnormal laboratory results are caused by a medication or by another underlying condition can be difficult. A causality assessment, performed for each potential ADR, can help determine future drug therapy options. [35]

Drug interaction

Drug interactions are changes in a drug’s effects due to recent or concurrent use of another drug or drugs (drug-drug interactions), ingestion of food (drug-nutrient interactions), or ingestion of dietary supplements (dietary supplement-drug interactions). [36] The probability of interactions increases with the number of drugs taken. The high rate of prescribed drugs in elderly patients (65-year-old patients take an average of 5 drugs) increases the likelihood of drug interactions and thus the risk that drugs themselves can be the cause of hospitalization. Potential interactions can arise at any age in life, but the frequency of polypharmacy in older life increases the risk substantially.[37]

Types of Drug Interactions

In general, drug interactions involve pharmacodynamics and pharmacokinetics.

  • In pharmacodynamic interactions, one drug alters the sensitivity or responsiveness of tissues to another drug by having the same (agonistic) or a blocking (antagonistic) effect. These effects usually occur at the receptor level but may occur intracellularly.
  • In pharmacokinetic interactions, a drug usually alters the absorption, distribution, protein binding, metabolism, or excretion of another drug. Thus, the amount and persistence of available drug at receptor sites change. Pharmacokinetic interactions alter magnitude and duration, not type, of effect. They are often predicted based on knowledge of the individual drugs or detected by monitoring drug concentrations or clinical signs.[36] Pharmacokinetic interactions occur at the levels of absorption (e.g., levothyroxine and neutralizing antacids), elimination (e.g., digoxin and macrolides), metabolism- competition for cytochrome P450 enzymes (e.g., SSRIs and certain beta-blockers). [38]
  • Drug-drug interactions occur when one drug interact or interfere with another drug. For example, Aspirin + Warfarin = excessive bleeding , decongestants + anti-hypertensive drug = increase blood pressure, clavulanic acid + amoxicillin = increase effect of antibiotic, codeine + paracetamol = increase analgesic effect;
  • Drug-nutrient interactions result from drugs reacting with foods or beverages. For example, alcohol + paracetamol = severe liver damage, tetracycline + food that contain calcium = interfere by decrease absorbing of tetracycline, MAOI + tyramine contain food = severe headache;
  • Drug-dietary supplement interactions may occur when herbs, vitamins, and other dietary supplements augment or antagonize the actions of prescription and nonprescription drugs. St. John's wort is the supplement that has the most documented interactions with drugs. As with many drug-drug interactions, the information for many dietary supplements is deficient and sometimes supported only by case reports. Deleterious effects are most pronounced with anticoagulants, cardiovascular medications, oral hypoglycemics, and antiretrovirals. [39]
  • Drug-condition interactions may occur when an existing medical condition makes certain drugs potentially harmful. For example, NSAID + Asthma = Airway obstruct, Metformin + Heart Failure = increase lactate level. [40][41]

Drug interaction mechanisms

There are several mechanisms by which drugs interact with other drugs, food, and other substances. An interaction can result when there is an increase or decrease in:

  • the absorption of a drug into the body;
  • distribution of the drug within the body;
  • alterations made to the drug by the body (metabolism); and
  • elimination of the drug from the body.

Most of the important drug interactions result from a change in the absorption, metabolism, or elimination of a drug. Drug interactions also may occur when two drugs that have similar (additive) effects or opposite (canceling) effects on the body are administered together. [42]

Preventing Drug Interactions

It is impossible to remember all of the drug interactions that can occur. It is therefore important to develop a stepwise approach to preventing adverse reactions due to drug interactions.

  1. First, taking a good medication history is essential. The "AVOID Mistakes" mnemonic presented on the next slide can help health care practitioners to develop good habits when performing this task.
  2. Second, it is essential that physicians develop an understanding of which patients are at risk for drug interactions. Of course, any patient taking 2 medications is at some risk. Studies show that the rate of adverse drug reactions increases exponentially in patients taking 4 or more medications.1 Importantly, some categories of drugs are especially at high risk for interactions. These categories include anticonvulsants, antibiotics, and certain cardiac drugs such as digoxin, warfarin, and amiodarone.
  3. Third, any time a patient is taking multiple drugs, we recommend that the first step be to check a readily available pocket reference, recognizing that the interaction may not be listed and more complete search may be required.
  4. Fourth, consult other members of the healthcare team. Depending upon the practice setting, this may be a clinical pharmacologist, a hospital pharmacist, a specially trained office staff nurse, or the nearby pharmacist in community practice.
  5. Fifth, use one of the computerized databases available. Up-to-date databases are maintained by gsm.com and epocrates.com, and others.* The latter can be placed on a hand-held computer (e.g. Palm Pilot) and can be configured to automatically update each time you synchronize with the desktop computer. The Medical Letter Drug Interaction Program is inexpensive and updated quarterly. [43]

Adverse Drug Reactions Monitoring

Adverse Drug Reactions monitoring is a process of continuously monitoring of undesirable effect suspected to be associated with the use of medicinal products. It facilitates the collection of unbiased safety data observed during clinical practice in ‘real life’ circumstances. The guidelines have been developed to assist healthcare professionals in understanding the importance of ADRs monitoring, procedures for reporting an ADR and the four essential components of an ADRs case report to improve drug safety. The essential components include information about the patient, description of the adverse drug reactions, the suspected drug(s) and the reporter. [44]

WHO - VigiBase

An international system for monitoring adverse reactions to drugs (ADRs) using information derived from the Member States was established in 1971. WHO Headquarters is responsible for policy issues while the operational responsibility for the programme rests with the WHO Collaborating Centre for International Drug Monitoring, Uppsala Monitoring Centre, (UMC), in Sweden. The system started with 10 countries that had already established national systems for spontaneous adverse reaction reporting and who agreed to contribute data for an effective international system to become operative, a common reporting form was developed, agreed guidelines for entering information formulated, common terminologies and classifications prepared and compatible systems for transmitting, storing and retrieving and disseminating data were created. The ADRs database in Uppsala currently contains over eight  million reports of suspected ADRs.[45] The database of adverse drug reactions (ADRs) held by the Uppsala Monitoring Centre on behalf of the 47 countries of the World Health Organization (WHO) Collaborating Programme for International Drug Monitoring is the largest database of this sort in the world, and about 35 000 new reports are added quarterly.

In 1978, this database, now known as VigiBase, moved to Uppsala in Sweden. Since then it has been managed by UMC. As of May 2017, 156 countries are Members of the WHO Programme for International Drug Monitoring (PIDM), with 127 countries submitting reports of adverse reactions associated with medicinal products to the WHO global database: VigiBase.[46]

FDA - MedWatch

MedWatch, the FDA's Safety Information and Adverse Event Reporting Program was launched in 1993 at the direction of the FDA Commissioner David Kessler, a physician who recognized that the identification and evaluation of serious adverse events and product quality issues related to the use of drugs and devices could not be done solely by the FDA without active support and collaboration with the nation's doctors, nurses, and pharmacists. Now that the voluntary reporting process is well established, the FDA receives over 40,000 adverse event reports directly from doctors, other clinicians, and their patients. Many hundreds of thousands of similar reports sent from clinicians to manufacturers are received indirectly by the FDA. [47] Using MedWatch form they need to report adverse events for human medical products that they observed or suspected, including serious drug side effects, medication errors/product use errors, product quality problems, and therapeutic failures for: 

  • Prescription or over-the-counter medicines, as well as medicines administered to hospital patients or at outpatient infusion centers
  • Biologics (including blood components, blood and plasma derivatives, allergenic, human cells, tissues, and cellular and tissue-based products (HCT/Ps))
  • Medical devices (including in vitro diagnostic products)
  • Combination products
  • Special nutritional products (infant formulas, and medical foods such as meal replacements or foods specifically intended for diabetic patients)
  • Cosmetics
  • Foods/beverages (including reports of serious allergic reactions). [48]

Events which should not be reported to FDA MedWatch are:

  • Tobacco: Tobacco product problems should be reported to the Safety Reporting Portal.
  • Vaccines: Report vaccine events to [the Vaccine Adverse Event Reporting System (VAERS) online https://vaers.hhs.gov/esub/index]
  • Investigational (study) drugs: Report investigational (study) drug adverse events as required in the study protocol and send to the address and contact person listed in the study protocol.
  • Mandatory reporting by regulated industry:
  • * Drugs and Biologics
  • * Applicable Regulations
  • * Devices
  • Reporting on Dietary Supplements
  • Reporting on Veterinary Medicine Products
  • Reports FDA does not handle (e.g. CPSC, FTC, State Health Departments) and where to send them.[49]

The Institute for Safe Medication Practices

Other private, non–government-initiated systems and agencies in the United States assist in the detection and reporting of ADRs, ADEs, and medication errors. The Institute for Safe Medication Practices (ISMP) is a national patient safety organization with a confidential medication error–reporting program (MERP). Reporting to the ISMP MERP is most appropriate for known or suspected medication errors. Alerts and medication safety information are distributed to health care providers every other week by a series of newsletters. The ISMP accepts reports from healthcare professionals and patients regarding ADEs and hazards in medication delivery and management. Reports can be submitted online or by telephone, mail, or fax. Staff from ISMP often contact the reporter to elicit additional details about the submission. After analyzing the reports, ISMP works with drug manufacturers and the FDA to ensure that safe medication practices are maintained. [50]

The Joint Commission

Sentinel events are those that result in an unanticipated death or major permanent loss of function, not related to the natural course of a disease state. Sentinel events should be reported to The Joint Commission (TJC), which implemented a sentinel event reporting system in 1996. The Joint Commission facilitates identification and learning among healthcare organizations of sentinel events and strategies for prevention. Any accredited healthcare organization may submit a report to TJC, which will then request a root-cause analysis and action plan from the facility. Reporting is voluntary, but if a report is submitted, the root-cause analysis is required. The organization’s action plan is monitored by TJC, similar to the monitoring of corrective actions observed during an accreditation survey. National Patient Safety Goals are often a result of information obtained in the sentinel event reporting process. The Joint Commission periodically chooses a reported event type and develops a sentinel event alert that describes the events, causes, and prevention strategies. [51]

Rationale for ADRs Monitoring

Information on safety and efficacy of a pharmaceutical product once it is marketed is limited to pre-marketing evaluation, clinical trials (phase I, II and III), animal tests and other factors in the product development process.

1. Phase I trial – Single dose studies in healthy volunteers, using low doses of the drug. Subsequently, larger doses and multiple sequences, the pharmacological and pharmacokinetics properties of a drug are evaluated.

2. Phase II trial – Efficacy is the primary objective of this phase, but safety is also continuously monitored and evaluated.

3. Phase III trial – Evaluation of safety in a group of patients with the disease.

Each phase involves increasing number of patients and by the end of full pre-marketing clinical trial about 5,000 patients would have taken the drug.

However, there is a problem of whether clinical trial involving 5,000 people provides enough information to extrapolate the safety of new drug to millions of people.

Some drugs typically have barely noticeable side effects when dosed properly. For example, Warfarin (Coumadin, Jantoven), used to prevent blood clots, is usually well tolerated, but serious internal bleeding can occur. Side effects may only occur when certain drugs are mixed with certain other things. These might also be considered drug interactions. Drinking alcohol with narcotic painkillers has caused an alarming increase in accidental overdose deaths. Drinking grapefruit juice can affect the blood levels of several drugs, including some blood pressure and cholesterol medicines. To find more about a drug's side effects, information about them is available on the label of over-the-counter drug products and on package inserts or printed materials dispensed with prescription drugs. Because the inserts include such a long list of possible bad effects, it is very helpful to also talk to your pharmacist or doctor if you have any questions regarding a drug's side effects.

It is also very important to know that the clinical trial was only performed to the innovator formulation. But after that Generic company starts manufacturing of that drug with new formualtion which has no clinical trial, f2 comparison or even imcomplete understanding about impurities profile. So the chance of ADRs in patient increase with a very high level of possibilities with the generic drugs.

Adverse effects may be local, i.e. limited to a certain location, or systemic, where a medication has caused adverse effects throughout the systemic circulation.

For instance, some ocular anti-hypertensives cause systemic effects, although they are administered locally as eye drops, since a fraction escapes to the systemic circulation..

Limitations of most clinical trials in highlighting a drug’s safety:[52]

  • Homogeneous sample populations: most trials assess relatively healthy patients with only one disease and mostly exclude specific groups such as pregnant women, children and elderly people.
  • Sample size: small sample size (up to 1,000 patients) reduces the chance of finding rare adverse effects.
  • Limited duration: trials of short duration preclude the discovery of long-term consequences such as cancer.
  • Inability to predict the real world: drug interactions can be substantial in a population as patients may take drugs concomitantly, a situation that can almost never be predicted from clinical trials.

=== Examples of therapeutic side effects ===

  1. Bevacizumab (Avastin), [53]used to slow the growth of blood vessels, has been used against wet age-related macular degeneration, as well as macular edema from diseases such as diabetic retinopathy and central retinal vein occlusion.mainly used as a cancer medicine.
  2. Buprenorphine [54]has been shown experimentally to be effective against severe, refractory depression.
  3. Bupropion[55] is an antidepressant medication used to treat major depressive disorder and seasonal affective disorder. The Zyban brand of bupropion is used to help people stop smoking by reducing cravings and other withdrawal effects.
  4. Carbamazepine[56] is an approved treatment for bipolar disorder and epileptic seizures, but it has side effects useful in treating attention-deficit hyperactivity disorder (ADHD), schizophrenia, phantom limb syndrome, paroxysmal extreme pain disorder, neuromyotonia, and post-traumatic stress disorder.
  5. Dexamethasone and Betamethasone[57] in premature labour, to enhance pulmonary maturation of the fetus.
  6. Doxepin[58] has been used to treat angiodema and severe allergic reactions due to its strong antihistamine properties.
  7. Gabapentin[59], approved for treatment of seizures and postherpetic neuralgia in adults, has side-effects which are useful in treating bipolar disorder, Drug and alcohol withdrawal seizures Diabetic neuropathy,Attention deficit disorder.Restless legs syndrome,migraine , neuropathic pain syndromes, and Periodic limb movement disorder of sleep.
  8. Hydroxyzine[60], an antihistamine, is also used as a sedative to treat anxiety and tension.
  9. Magnesium sulfate[61] in obstetrics for premature labor and preeclampsia.
  10. Methotrexate (MTX)[62],  approved for the treatment of choriocarcinoma, is frequently used for the medical treatment of an unruptured ectopic pregnancy.
  11. The SSRI medication sertraline[62] is approved as an antidepressant but delays conjugal climax in men, and thus may be supplied to those in which climax is premature.
  12. Sildenafil[63] was originally intended for pulmonary hypertension; subsequently, it was discovered that it also produces erections, for which it was later marketed.
  13. Terazosin[64], an α1-adrenergic antagonist approved to treat benign prostatic hyperplasia (enlarged prostate) and hypertension, is (one of several drugs) used off-label to treat drug induced diaphoresis and hyperhidrosis (excessive sweating).

Examples of undesirable/unwanted side effects

  • Echinacea [65]– more than 20 different types of reactions have been reported, including asthma attacks, loss of pregnancy, hives, swelling, aching muscles and gastrointestinal upsets.
  • Feverfew – pregnant women should avoid using this herb, as it can trigger uterine contractions. In animal experiments, the use of feverfew was found to trigger spontaneous abortions (miscarriages).
  • Asteraceae plants – which include feverfew, echinacea, dandelion and chamomile. Side effects include allergic dermatitis and hay fever.
.

Adverse Drug Reactions Etiology

Most adverse drug reactions are dose-related; others are allergic or idiosyncratic. Dose-related ADRs are usually predictable; ADRs unrelated to dose are usually unpredictable.

  • Dose-related ADRs are particularly a concern when drugs have a narrow therapeutic index (eg, hemorrhage with oral anticoagulants). ADRs may result from decreased drug clearance in patients with impaired renal or hepatic function or from drug-drug interactions.
  • Allergic ADRs are not dose-related and require prior exposure. Allergies develop when a drug acts as an antigen or allergen. After a patient is sensitized, subsequent exposure to the drug produces one of several different types of allergic reaction. Clinical history and appropriate skin tests can sometimes help predict allergic ADRs.
  • Idiosyncratic ADRs are unexpected ADRs that are not dose-related or allergic. They occur in a small percentage of patients given a drug. Idiosyncrasy is an imprecise term that has been defined as a genetically determined abnormal response to a drug, but not all idiosyncratic reactions have a pharmacogenetic cause. The term may become obsolete as specific mechanisms of ADRs become known.[66]

Classification of ADRs

Adverse drug reactions may be separated into two groups, Type A and Type B.

Type A reactions: are expected exaggerations of the drugs known effect. These are usually dose dependent and predictable and account for the majority of ADRs. Characteristics Type A reactions include: higher than normal dose administered, impaired metabolism or excretion, or very sensitive individuals. These reactions are often found in the FDA approved product labeling. Type A reactions include medication errors. Therefore, there may be some difficultly in deciding the correct reporting procedure. If the reaction is caused by a prescribing, administering or monitoring error, a medication error has occurred and medication error report should be completed. If the patient develops an ADR when the prescribing, administering and monitoring are appropriately carried out, an adverse drug reaction report form should be completed.

Type B reactions: are idiosyncratic and usually unrelated to the drug's known pharmacology. Normally they are not related to the dose, are unpredictable, uncommon, and usually more serious than Type A. The reactions that has been reported were teratogen and carcinogen, meaning it is harmful to the body.

Two further types of reactions were eventually added: chronic reactions, which relates to both dose and time (type C), and delayed reactions (type D). Withdrawal later became the fifth category (type E), and most recently, unexpected failure of therapy became the sixth (type F).

An extended version of this classification system is as follows:

1. Type A (Augmented) reactions: Maximum it is the dose dependent and predictable, Related to pharmacological action of drug. Extensions of the principal pharmacological action of the drug. Toxic reactions linked to excess dose or impaired excretion, or to both .These are three types Predictable, Common, Dose-dependent. Predictable is relatively easily predicted by preclinical and clinical pharmacological studies. Common Type A reactions is not serious and it is usually dose dependent. The toxicity of Drug overdose caused by excessive dosing.[67].

2. Type B (Bizarre) reactions: dose independent and unpredictable and Drug Intolerance, Lower threshold to normal pharmacological action of a drug, Undesirable pharmacological effect at recommended doses and single average dose of aspirin. Immune mediated response to a drug agent in sensitized patient eg. Anaphylaxis with penicillin. Idiosyncratic drug reactions are uncommon response to drug.

3. Type C (Chronic) reactions : biological characteristics can be rationalized from chemical structure and associated with long-term drug therapy. It is well known and can be anticipated.

4. Type D (Delayed) reactions: carcinogenic and teratogenic effects.

5. Type E (End-of-use) reactions: these reactions appear when the drug is abruptly discontinued, for example abstinence syndrome before stopping the use of narcotics, or adrenal failure when steroid therapy is discontinued abruptly.

6. Type F (Failure of Therapy) reactions: simply the loss of eficacy of the drug, or when it does not achieve the goal it was prescribed for. For example, when an analgesic does not dimish pain.

I. Classification with mnemonics.

This classification is shown in the table with examples of ADRs in each category and notes on their management. It is not always possible to classify an ADRs into one of these categories, but that is in the nature of classification. [68]

[69]

Type of reaction Mnemonic Features Examples Management
A: Dose-related Augmented
  • Common
  • Related to a pharmacological action of the drug
  • Predictable
  • Low Mortality
  • Toxic effects:

Digoxin toxicity; serotonin syndrome with SSRI (selective-serotonin reuptake inhibitors)

  • Side effects:

Anticholinergic effects of tricyclic antidepressants

  • Reduce dose or withhold
  • Consider effects of concomitant therapy
B: Non-dose-related Bizarre
  • Uncommon
  • Not related to a pharmacological action of the drug
  • Unpredictable
  • High mortality
  • Immunological reactions:

Penicillin hypersensitivity

  • Idiosyncratic reactions:

Acute porphyria, Malignant hyperthermia, Pseudoallergy (e.g., ampicillin rash)

  • Withhold and avoid in future
C: Dose-related and time-related Chronic
  • Uncommon
  • Related to the cumulative dose
  • Hypothalamic-pituitary-adrenal axis suppression by corticosteroids
  • Reduce dose or withhold; gradual withdraul
D: Time-related Delayed
  • Uncommon
  • Usually dose-related
  • Occurs or becomes apparent some time after the use of the drug
  • Teratogenesis (e.g., vaginal adenocarcinoma with diethylstilbestrol)
  • Carcinogenesis
  • Tardive dyskinesia
  • Interstitial pulmonary disease and corneal opacities caused by Amiodarone.
  • Often intractable
E: Withdrawal End of use
  • Uncommon
  • Occurs soon after withdrawal of the drug
  • Opiate withdrawal syndrome
  • Myocardial ischemia (ß-blocker withdrawal)
  • Reintroduce and withdraw slowly
F: Unexpected failure of therapy Failure
  • Common
  • Dose-related
  • Often caused by drug interactions
  • Inadequate dosage of an oral contraceptive, particularly when used with specific enzyme inducers
  • Increase dosage
  • Consider effects of concomitant therapy
G: Idiosyncratic  Genetically determined abnormal response
  • Not related to dose
  • Non allergic
  • Occur in small percentage of patients
  • Unusual behavior, mannerism or reaction of a person
  • Discontinuation of drug if necessary
  • Switching to a different drug
H: Allergic Hypersensitivity
  • Dose-related
  • Require prior exposure
  • Pulmonary effects
  • Serum sickness
  • Hemolytic anemia
  • DRESS (drug rash with eosinophilia and systemic symptoms)
  • Renal effects
  • Other autoimmune phenomena
  • Modification of dosage
  • Discontinuation of drug if necessary Switching to a different drug

II. Three-dimensional approach classification (DoTS)

In this system adverse reactions are classified according to the dose at which they usually occur, the time-course over which they occur, and the susceptibility factors that make them more likely. [70]

A new classification system for adverse drug reactions based on time, course and susceptibility as well as dose responsiveness should improve drug development and management of adverse reactions [71]

A. Dose-relatedness

All drug effects, beneficial or adverse, are dose related. ADRs are classified into three types according to dose-relatedness:

  • ADRs that occur at supra-therapeutic doses (toxic effects);
  • ADRs that occur at standard therapeutic doses (collateral effects). The term collateral effects is used for reactions that occur at standard therapeutic doses because the term side effects is often colloquially used to refer to all adverse effects. Collateral effects include those that occur due to a different pharmacological effect from the therapeutic action and those that occur through the therapeutic pharmacological effect but in another tissue;
  • ADRs that occur at sub-therapeutic doses in susceptible patients (hyper-susceptibility reactions).

Examples of immunological reactions that are clearly dose dependent include hay fever in response to high pollen counts; the immunogenic response to hepatitis B vaccine; desensitization by the use of increasing doses of antigen (for example, cephalosporins; and type IV hypersensitivity skin reactions.[72]

Traditionally, immunological and certain other adverse drug reactions have been considered not to be dose related. However, effects of drugs involve interactions between chemical entities and are therefore subject to the law of mass action. This implies that all drug effects, beneficial or adverse, are dose related. Examples of immunological reactions that are clearly dose dependent include hay fever in response to high pollen counts; the immunogenic response to hepatitis B vaccine; desensitisation by the use of increasing doses of antigen (for example, cephalosporins); and type IV hypersensitivity skin reactions.It is therefore misleading to suggest that type B adverse drug reactions are not dose dependent. In fact, it is clearer to divide adverse drug reactions into reactions that occur at supratherapeutic doses (toxic effects); reactions that occur at standard therapeutic doses (collateral effects); and reactions that occur at subtherapeutic doses in susceptible patients (hypersusceptibility reactions).

We use the term collateral effects for reactions that occur at standard therapeutic doses because the term side effects is often colloquially used to refer to all adverse effects. Collateral effects include those that occur due to a different pharmacological effect from the therapeutic action and those that occur through the therapeutic pharmacological effect but in another tissue.

B. Time relatedness

Many pharmacological effects depend on both the concentration of the drug at the site of action and the time course of its appearance there. We distinguish two patterns of time courses of ADRs: time-dependent, and time-independent. [73]

(i) Time-dependent reactions - the time from administration to the occurrence of an adverse reaction can be characteristic.

There are six sub-types of time dependent reactions:

  • Rapid reactions occur only when a drug is administered too rapidly. Examples include ‘red man syndrome’ due to histamine release caused by the rapid administration of vancomycin.
  • First-dose reactions occur after the first dose of a course of a drug. Examples include ‘first-dose hypotension’ with angiotensin converting enzyme inhibitors (ACE-I), and type I hypersensitivity reactions, such as anaphylaxis to penicillin. The severity of type I hypersensitivity reactions can increase with subsequent exposure.
  • Early reactions occur early in the course of treatment and then abate. Examples include reactions to which patients develop tolerance, such as a nitrate-induced headache.
  • Intermediate reactions occur after a delay, but if they have not occurred after a certain time, it is unlikely that they will occur later. These ADRs include delayed-type immunological reactions such as Stevens-Johnson syndrome (SJS) with carbamazepine.
  • Late reactions are reactions whose risk increases with continued or repeated exposure to a drug. Examples include many of the adverse effects of corticosteroids. Withdrawal reactions, such as agitation and seizures on withdrawal of long-term benzodiazepine treatment, are typical examples of late reactions.
  • Delayed reactions are those which occur some time after exposure, even after the drug has been withdrawn. A well-known example is of exposure of the fetus to thalidomide in the first trimester of pregnancy, causing phocomelia, a limb reduction deformity.

(ii) Time-independent reactions - can occur at any time during treatment and are independent of the duration of the course. For example, the risk of bleeding with warfarin depends on the degree of anticoagulation, which can vary during the course of the therapy. [74]

C. Susceptibility

The risk of an ADR differs among members of an exposed population. In some cases, the risk of an adverse reaction will be present in susceptible subjects and absent in others. In other cases susceptibility follows a continuous distribution—for example, increasing susceptibility with increasing impairment of renal function. Although reasons for hypersusceptibility may be unknown, several types are recognized. These include genetic variation, age, sex, physiological variation, exogenous factors, and disease. More than one susceptibility factor can be present.

Sources of altered susceptibility to adverse drug reactions [75]
Source of susceptibility Examples Implications
Genetic Porphyria Screen for abnormalities;

avoid specific drugs

Succinylcholine sensitivity
Malignant hyperthermia
CYP isozyme polymorphisms
Age Neonates (chloramphenicol) Adjust doses according to age
Elderly people (hypnotics)
Sex Alcohol intoxication Use different doses in

men and women

Mefloquine, neuropsychiatric effects
Angiotensin converting enzyme inhibitors, cough
Procainamide, Lupus-like syndrome
Physiology altered Phenytoin in pregnancy Alter dose or avoid
Exogenous factors Drug interactions (Warfarin plus Ciprofloxacin) Alter dose or avoid

co-administration

Interactions with food (eg grapefruit juice with drugs cleared by CYP3A4)
Disease Renal insufficiency (eg lithium) Screen for abnormalities; avoid

specific drugs; use reduced doses

Hepatic cirrhosis (eg morphine)

Examples of DoTS (dose-time-susceptibility) classification

  • Osteoporosis due to corticosteroids:

Do—collateral effect; T—late; S—age, sex.

  • Anaphylaxis due to penicillin:

Do—hypersusceptilbility; T—first dose; S—not understood; requires previous sensitization.

  • Hepatotoxicity due to isoniazid:

Do—collateral effect; T—intermediate; S—genetic (drug metabolism), age, exogenous (alcohol), disease (malnutrition).[76]

III. Classification according to Severity (Hartwig’s Severity Assessment Scale)

ADRs can also be classified according to severity. The most used classification scale is Hartwig’s Severity Assessment Scale which classifies the severity of ADR as mild, moderate or severe with various levels according to factors like the requirement for change in treatment, duration of hospital stay, and the disability produced by the adverse drug reaction. [77]

Hartwig’s Severity Assessment Scale
Level 1 An ADR occurred but required no change in treatment with the suspected drug Mild
Level 2 The ADR required that treatment with the suspected drug be held, discontinued, or otherwise changed. No antidote or other treatment requirement was required. No increase in length of stay (LOS)
Level 3 The ADR required that treatment with the suspected drug be held, discontinued, or otherwise changed

AND/OR
An antidote or other treatment was required. No increase in length of stay (LOS)

Moderate
Level 4 Any level 3 ADR which increases length of stay by at least 1 day

OR
The ADR was the reason for the admission

Level 5 Any level 4 ADR which requires intensive medical care Severe
Level 6 The adverse reaction caused permanent harm to the patient
Level 7 The adverse reaction either directly or indirectly led to the death of the patient

Severity is a point on an arbitrary scale of intensity of the adverse event in question. The terms "severe" and "serious" when applied to adverse events are technically very different. They are easily confused but can not be used interchangeably, requiring care in usage. A headache is severe, if it causes intense pain. There are scales like "visual analog scale" that help clinicians assess the severity. On the other hand, a headache is not usually serious (but may be in case of subarachnoid haemorrhage, subdural bleed, even a migraine may temporally fit criteria), unless it also satisfies the criteria for seriousness listed.

[78]

Classification of Adverse Events

There are five main levels of adverse events:

  • Adverse Events (AEs)are any unfavorable and unintended signs, including abnormal laboratory results, symptoms or a disease associated with treatment. These must always be recorded on a Case Report Form (CRF) and in the patient's medical notes unless the protocol states otherwise.
  • Adverse Reactions (ARs) are adverse events but causally related to investigational medicinal products. An adverse reaction is a response to a medicinal product which is noxious and unintended. This includes adverse reactions which arise from:
  1. use of a medicinal product within the terms of the marketing authorisation;
  2. use outside the terms of the marketing authorisation, including overdose, misuse, abuse and medication errors;
  3. occupational exposure.
  • Serious Adverse Events (SAEs) are defined as any untoward medical occurrence(s) that at any dose results in death, hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, causes malignancy, causes a relevant organ toxicity or a congenital anomaly or birth defect, . These events must be reported immediately to the sponsor. Serious Adverse Reactions (SARs) are serious adverse events but causally related to investigational medicinal products.
  • Suspected Serious Adverse reactions (SSARs) are any ARs considered consistent with information available about an Investigational Medicinal Product (IMP). They must be reviewed at regular intervals to see if the profile of any IMP has changed and a record made of this.
  • Suspected Unexpected Serious Adverse Reactions (SUSARs) are any events suspected to be caused by an IMP, but which are not consistent with information about the IMP (these are the most serious of events and are subject to expedited reporting procedures) [79]

ADRs can be mild, where no antidote or treatment is required (a headache, constipation), moderate (change in treatment or specific treatment is required), and severe, potentially life-threatening conditions that require inpatient hospitalization or prolongation of existing hospitalization, which results in persistent or significant disability or incapacity or congenital anomaly/birth defect. [80][81]

  • Suspected death or events resulting in death
  • Side effect related to drug effect or drug delivery system — even if it is a known side effect already listed on the approved label
  • Aggravation or worsening of a pre-existing condition
  • Lack of drug effect
  • Illnesses leading to hospitalizations or surgeries — whether or not they're related to the product or the disorder they are treating
  • Listed or not listed on the approved label
  • Related or not related to the use of a pharmaceutical product [82]
  • Reports of overdose, abuse, off-label use, misuse, medication error, occupational exposure, or falsified medicinal product [83]

Types of AEs

Another classification of AE say that the event can either be a type A reaction or a type B reaction. Type A reactions are predictable AEs which are commonly dose-dependent and can be mild, moderate or severe. Type B reactions are completely unpredictable and have nothing to do with dosage.

They occur less often and are influenced by patient-specific susceptibility factors such as drug allergies and intolerance. A patient may experience an AE due to the healthcare provider’s lack of knowledge of the drug and the medication's complete mechanism. The AE is not expected by either the doctor or the patient and the effects can be reduced by lowering the dose or just stopping the medication altogether. The severity of the AE will determine whether a change in dosage or stopping the medication altogether is best for the patient. [84]

Immunologic and Nonimmunologic Drug Reactions[85]

Drug reactions can be classified into immunologic and nonimmunologic etiologies. The majority (75% to 80%) of adverse drug reactions are caused by predictable, nonimmunologic effects. The remaining 20 to 25% of adverse drug events are caused by unpredictable effects that may or may not be immune mediated. Immune-mediated reactions account for 5 to 105 of all drug reactions and constitute true drug hypersensitivity, with IgE-mediated drug allergies falling into this category.

TYPE EXAMPLE
Immunologic
Type I reaction (IgE-mediated) Anaphylaxis from β-lactam antibiotic
Type II reaction (cytotoxic) Hemolytic anemia from penicillin
Type III reaction (immune complex) Serum sickness from anti-thymocyte globulin
Type IV reaction (delayed, cell-mediated) Contact dermatitis from topical antihistamine
Specific T-cell activation Morbilliform rash from sulfonamides
Fas/Fas ligand-induced apoptosis Stevens-Johnson syndrome
Toxic epidermal necrolysis
Other Drug-induced, lupus-like syndrome
Anticonvulsant hypersensitivity syndrome
Nonimmunologic
Predictable
Pharmacologic side effect Dry mouth from antihistamines
Secondary pharmacologic side effect Thrush while taking antibiotics
Drug toxicity Hepatotoxicity from methotrexate
Drug-drug interactions Seizure from theophylline while taking erythromycin
Drug overdose Seizure from excessive lidocaine (Xylocaine)
Unpredictable
Pseudoallergic Anaphylactoid reaction after radiocontrast media
Idiosyncratic Hemolytic anemia in a patient with G6PD deficiency after primaquine therapy
Intolerance Tinnitus after a single, small dose of aspirin

Other Reportable Events

The EU regulatory network and its governance structure have developed specific guidance to support stakeholders, including the pharmaceutical industry and regulatory authorities in Member States involved in the reporting, evaluation and prevention of medication errors. This guide is complementary to the guideline on GVP and other existing guidelines published by the Agency.

The Heads of Medicines Agencies (HMA) endorsed the final two-part guide in November 2015, taking into account comments from a two-month public consultation.

The first part of the guide clarifies specific aspects related to recording, coding, reporting and assessment of medication errors in the context of EU pharmacovigilance activities with the objective of improving reporting and learning from medication errors for the benefit of public health:

Event Description
Overdose Administration of a quantity of a medicinal product given per administration or per day which is above the maximum recommended dose according to the authorized product information.(e.g.: Core Data Sheet (CDS), European Union Summary of Product Characteristics (SPC), country-specific local label, investigator brochure or trial protocol) This also takes into account cumulative effects due to overdose.This includes overdoses due to either accidental or intentional prescriptions by a physician. Clinical judgment should always be applied. [86]
Medication Error A medication error is "Any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professional, patient, or consumer. Such events may be related to professional practice, health care products, procedures, and systems, including prescribing; order communication; product labeling, packaging, and nomenclature; compounding; dispensing; distribution; administration; education; monitoring; and use." [87] A potential medication error is the recognition of circumstances that could lead to a medication error, and may or may not involve a patient.[88]

The national coordinating council for medication error reporting and prevention (NCC MERP) defines a medication error as any potential event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professionals, patient or consumer. Such events may be related to professionals, heath care products, procedure and systems, including prescribing, order communication, product labeling, dispensing, distribution, administration, education, monitoring and use. [89][90]

Use of outdated drugs is common for patients. Outdated drugs may be ineffective, and some (eg, aspirin, tetracycline) can be harmful if used when outdated.

Abuse Persistent or sporadic,intentional excessive use of a medicinal product, which is accompanied by harmful physical or psychological effects .[91] Psychoactive substance abuse' is defined as a 'mal-adaptive pattern of use indicated by continued use despite knowledge of having a persistent or recurrent social, occupational, psychological or physical problem that is caused or exacerbated by the use [or by] recurrent use in situations in which it is physically hazardous'. It is a residual category, with dependence taking precendence when applicable. The term 'abuse' is sometimes used disapprovingly to refer to any use at all, particularly of illicit drugs. In other contexts, abuse has referred to non-medical or unsanctioned patterns of use, irrespective of consequences. [92]. Abused drugs include
  • Methamphetamine
  • Anabolic steroids
  • Club drugs
  • Cocaine
  • Heroin
  • Inhalants
  • Marijuana
  • Prescription drugs, including opioids [93].
Misuse Misuse is related to situations where the medicinal product is intentionally and inappropriately used not in accordance with the prescribed or authorized dose, route of administration, and/or the indication(s) or within the legal status of its supply (e.g. without prescription for medicinal products subjects to medical prescription). The focus is on the intention of the patient or consumer to use a product outside the authorized conditions. For cases where a patient has misunderstood the instructions for how to use the medicine correctly, this should be considered an error. [94]

To misuse a drug is to use a drug for purposes it is not intended for. Using Vicodin for a headache, Xanax for nausea, or any other example of people believing a drug can make them ‘feel better.’ Misuse involves not following medical instructions, but the person may not necessarily be looking to ‘get high’ from their use. For example, if a person isn’t able to fall asleep after taking a single sleeping pill, he or she may take another pill an hour later, thinking, “That will do the job.” [95]

Lack of therapeutic efficacy It is indicated by the reporter that the drug is not effective or its therapeutic response is decreased. In other words, it means the drug did not work for the patient. Reports of lack of therapeutic efficacy should be recorded and followed-up if incomplete. They should not normally be reported but should be discussed in periodic safety update reports as applicable. Clinical judgment should be used when considering if other cases of lack of therapeutic efficacy qualify for reporting. For example, an antibiotic used in a life-threatening situation where the medicinal product was not in fact appropriate for the infective agent should not be reported. Another examples, a life-threatening infection, where the lack of therapeutic efficacy appears to be due to the development of a newly resistant strain of a bacterium previously regarded as susceptible, should be reported within 15 days. [96]
Pregnancy/ Breastfeeding/Paternal exposure/Transmammary exposure Pregnancy, breastfeeding or paternal exposure has occurred at the time when the patient is taking the drug. (Paternal exposure in this context may affect the fetus through transmission of a medicinal product via semen). Reports of exposure to medicinal products during pregnancy should contain as many detailed elements as possible in order to assess the causal relationships between any reported adverse events and the exposure to the suspected medicinal product. A transmammary exposure is exposure to the medical product or drug through breast milk. Transmammary exposure happens when the mother breast feeds the child. [97]
Suspected transmission of an infectious agent Microbial contamination of the medicinal product occurring at any step in the manufacturing, packaging, storage or distribution of the product, or contamination through other means (e.g. after dispensing the medication).[98]
Off-label Refers to situations where the medicinal product is intentionally used for a medical purpose, not in accordance with the authorized product information, or using a medical device outside the scope of the approved label. Healthcare providers may prescribe a drug for an unapproved use when they judge that it is medically appropriate for their patient. Unapproved use of an approved drug is often called “off-label” use.Off-label use is the use of pharmaceutical drugs for an unapproved indication or in an unapproved age group, dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) can be used in off-label ways, although most studies of off-label use focus on prescription drugs. [99]

Some examples of unapproved use of a drug:

  • Use of a drug for a disease or medical condition that it is not approved to treat, such as when a chemotherapy is approved to treat one type of cancer, but healthcare providers use it to treat a different type of cancer.
  • Given in a different way, such as when a drug is approved as a capsule, but it is given instead in an oral solution.
  • Given in a different dose, such as when a drug is approved at a dose of one tablet every day, but a patient is told by their healthcare provider to take two tablets every day.[100]

Example of off-label use of medical device:

  • Coronary stents are constantly used in off-label indications and studies have been performed to show safety of such use.[101]
Occupational exposure This refers to the exposure to a medicinal product as a result of one’s professional or non-professional occupation.
For example, nurse accidentally pricked the needle while injecting the patient.
[102]

It does not include the exposure to one of the  ingredients during the manufacturing process before the release as finished product.

Falsified medicinal product This relates to any medicinal product with a false representation of:

 • Its identity, including its packaging and labelling, its name or its composition as regards any of the ingredients including excipients and the strength of those ingredients;

 • Its source, including its manufacturer, its country of manufacturing, its country of origin or its marketing authorisation holder; or

 • Its history, including the records and documents relating to the distribution channels used.  

 When a report of suspected adverse reactions is associated with a suspected or confirmed falsified  medicinal product or quality defect of a medicinal product, a valid ICSR should be reported. The seriousness of the ICSR is linked to the seriousness of the reported suspected adverse reactions in  accordance with the definitions provided in VI.A.2.4.. Electronic reporting recommendations provided  in VI.C.6.2.3.5. should be followed. In addition in order to protect public health, it may become necessary to implement urgent measures such as the recall of one or more defective batches of a medicinal product from the market. Therefore, marketing authorisation holders should have a system in place to ensure that reports of suspected adverse reactions related to falsified medicinal products or to quality defects of a medicinal  products are investigated in a timely fashion and that confirmed quality defects are notified separately to the manufacturer and to competent authorities in accordance with the provisions described in Article 13 of Directive 2003/94/EC. 1247 VI.C.2.2.5. [103]

Frequency of ADRs

When a drug is suspected of producing an adverse reaction, this will have implications for patients, doctors, drug regulatory authorities and pharmaceutical companies. Several factors will need to be addressed, the first of which is whether or not the drug was truly responsible for the observed effect. If this seems probable, the next question is whether or not such a reaction is acceptable in the context of the expected benefits of the drug. The severity and seriousness (actual and potential) of the reaction will be important factors in this assessment. Severity refers to the intensity of the event and it is expressed in ‘grades’ of severity. This can be used with any event, without regard to whether or not it meets the federal criteria for ‘serious’. [104] A further piece of information that will be required is the frequency of the reaction or more specifically the risk of it occurring in a given population. [105] The frequency of an adverse reaction may be expressed in various ways and which is used will be dependent on the method of measurement. [106] In giving an estimate of the frequency of ADRs, the following standard categories are recommended by the Council for International Organizations of Medical Sciences (CIOMS): [107]
ADR frequency Categories
Very common (frequent) ≥10%
Common (infrequent) ≥1% and <10%
Uncommon ≥0.1% and <1%
Rare ≥0.01% and <0.1
Very Rare <0.01%

Barriers to Reporting

In the United States and many other countries, the reporting of ADRs is voluntary. The underreporting of ADRs remains the largest barrier to health care system. The most prevalent reasons for not reporting suspected ADRs are consistently stated to be inadequate staffing and the time-consuming nature of evaluating and submitting the reports. The time needed to collect the necessary information, document the findings, and submit the report can be considerable, and other staffing demands often take precedence. Many healthcare facilities lack dedicated staff for these tasks, so ADR reporting fails to occur. Another barrier to ADR reporting involves information systems some still rely on paper charts and not using electronic medical reporting. Many facilities have internal reporting methods for ADRs and medication errors, but often these reports are not submitted to the FDA or other reporting agencies, staff view this additional reporting step as duplication of effort.

Standardizing internal reporting forms to align with those of national reporting systems, such as the MedWatch form, or providing interfaces between internal and external reporting systems can assist staff in collecting appropriate data and reporting ADRs at the institution. Taking the extra step of informing the FDA of the ADR can help improve patient safety on a national or global level by identifying signals that might otherwise go undetected at an individual facility.A ‘signal’ consists of reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously. Usually more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information.

Additional reasons cited for not reporting an ADR have included lack of information and available resources, unawareness of the importance of reporting, unavailability of training programs for healthcare professionals on ADR detection, and fear of the ramifications of reporting. Still, other reasons include difficulties in diagnosing the ADR, the assumption that the ADR is unimportant or minor, and uncertainty about how and to whom to report it.

The absence of a formal pharmacovigilance system is an additional barrier to the reporting of ADRs in health care facilities, and developing such a system is strongly encouraged. Although patients can also report the ADRs, many see this as not their concern or their responsibility. Educating patients on the importance of reporting ADRs and encouraging them to report, as well as instructing them on where and how to complete the forms, can overcome this barrier; however, relying solely on patient reporting may be unrealistic.

By working to overcome perceived barriers to reporting, the number of reported ADRs may be increased, which can help patients throughout the world. Reporting leads to increased awareness and detection of ADRs and can prevent their occurrence in both inpatient and outpatient settings, which in turn can help prevent hospital admissions or readmissions. Spurred by a controversial report from the Institute of Medicine on the prevalence of medical error, To Err Is Human,the medical profession has seen an increase in event reporting systems at the international, national, and institutional levels. Studies have shown that many physicians are reluctant to participate in programs to report medical errors and that underreporting of adverse events may be as high as 96 percent. These findings suggest that the success of a reporting system is determined by the attitudes and perceptions of frontline care providers. Therefore, prior to implementing an event reporting system, an assessment of the opinions of care providers should be conducted to identify critical barriers to reporting. The University of Texas Human Factors Research Project has developed a survey instrument designed to assess a wide array of attitudes deemed relevant to the implementation of reporting systems. This paper summarizes preliminary survey findings and recommendations for successful implementation of an event reporting system.

A recent study aimed to identify the barriers to ADR reporting among community pharmacists practising in the UK [108]:

How to recognize ADRs?

Since ADRs may act through the same physiological and pathological pathways as different diseases, they are difficult and sometimes impossible to distinguish. However, the following step-wise approach may be helpful in assessing possible drug-related ADRs:

  1. Identify the actual nature of ADRs received from the reporter, using Medical Dictionary for Regulatory Activities - MedDRA before proceeding the case investigation.
  2. Ensure that the medicine ordered is the medicine received and actually taken by the patient at the dose advised;
  3. Verify that the onset of the suspected ADR was after the drug was taken, not before and discuss carefully the observation made by the patient;
  4. Determine the time interval between the beginning of drug treatment and the onset of the event;
  5. Evaluate the suspected ADR after discontinuing the drugs or reducing the dose and monitor the patient's status (Dechallenge). If appropriate, restart the drug treatment and monitor recurrence of any adverse events (Rechallenge).
  6. Analyse the alternative causes (other than the drug) that could on their own have caused the reaction. Verify that the ADRs was not occurred due to DRUG & DRUG interaction or FOOD & DRUG interaction by removing the drug or food for a couple of days if possible.
  7. Use relevant, up-to-date literature and personal experience as a health professional on drugs and their ADRs and verify if there are previous conclusive reports on this reaction. The National Pharmacovigilance Center and Drug Information Centers are very important resources for obtaining information on ADR. The manufacturer of the drug can also be a resource to consult;
  8. Data base provided by Upsala monitoring center called "VigiAccess" can also be used for searching the previously reported ADRs of the same category.
  9. Report any suspected ADR to the person nominated for ADR reporting in the hospital or directly to the National ADR Center. [109]

Causality Assessment could be performed using the following WHO definitions:[110]

Causality assessment of ADRs is a method used for estimating the strength of relationship between drug(s) exposure and occurrence of adverse reaction(s). ... These elements of assessing strength of relationship between exposure (drugs) and outcome (adverse reaction) are used widely in ADR CATs.

Certain:

• Clinical event, lab test abnormality with plausible time relationship to drug intake

• Cannot be explained by concurrent disease or other drugs /chemicals

• Response to dechallenge- plausible

• Event must be definitive pharmacologically / immunologically

• Positive rechallenges (if performed).

Probable/ Likely:

• Clinical event, lab test abnormality with reasonable time relationship to drug intake

• Unlikely to be to concurrent disease, drugs / chemicals

• Clinically reasonable response to withdrawal (dechallenge)

• Rechallenge not required.

Possible:

• Clinical event lab test abnormality with reasonable time relationship to drug intake.

• Could also be explained by concurrent disease or other drugs or chemicals.

• Information on drug withdrawal may be lacking or unclear.

Unlikely:

• Clinical event , lab test with improbable time relationship to drug intake.

• Other drugs , chemicals or underlying disease provide plausible explanations.

Inaccessible /unclassifiable:

• Insufficient /contradictory evidence which cannot be supplemented or verified.

Conditional / unclassified

• More data is essential for proper assessment or additional data are under

examination

In most cases there is some level of uncertainty as to whether the drug is directly responsible for the reaction. Many of the questions above may remain unanswered or may be contradictory, however this should not dissuade from reporting the reaction to the {National Pharmacovigilance Programme}. A well-documented report which includes information about all the above-mentioned questions can provide the first signal of a previously unknown problem.

Examples of reportable drug reactions

The following are examples of reportable drug adverse reactions. [111]

Type Comment Type
Patient Comment "I've been using Drug X for seizures for almost 3 weeks now. At first it made me dizzy, but it definitely stopped my fits and I felt it was working. But since last week it hasn't been helping at all, and I have a terrible headache . Disappointed." Adverse Event, Lack of Efficacy
Patient Comment "After surgery my uvula was SO swollen, so my surgeon prescribed drug X. It didn't help much though, as it took 3 days to get my uvula back to a normal size. Just my personal experience." Adverse Event, Lack of efficacy
Patient Comment "I did not like it that much because it made me sick. However it seemed to help when I was on it. My face puffed up a bit which I did not like." Adverse Event
Physician Comment Drug B was planned to be prescribed, but continuing with Drug A due to lack of efficacy in Drug B Adverse Event
Physician Comment "I have prescribed drug C, for cough and cold to a patient. but he was admitted to the ER for a hypersensitivity reaction in the next day. The symptoms were so bad, he was itching all over the body and having breathing problems too." Serious Adverse Event
Reporter Comment Drug C did not work for my disease as per the claim Lack of efficacy
Physician Comment Patient died due to the progression of cancer. Not related to Drug A. Serious Adverse Event
Clinical Investigator Comment Hemorrhaging and internal bleeding with the rapid drop in blood pressure leading to hospitalization in 50% of the patients Serious Adverse Event
Clinical Investigator Comment Loss of consciousness from increase in pressure on the brain Serious Adverse Event
Nurse Comment Routine Blood test shows decreased haemoglobin for patient after started Drug B, as consequence patient discontinue the drug. Adverse Event
Patient

Comment

Drug A worked great for my severe pain so I took 3 more tablets immediately, to feel better faster. Drug

Overdose

Patient

Comment

I forgot to take drug Z for past 3 days.So today I took 4 tablets instead of one to cover it. Drug Overdose

History

  • January 29, 1848 - One of the most famous examples recorded of the ADR happened in the UK. A young girl called Hannah Greener was given an anesthetic before treatment for an in-growing toenail. The anesthetic was chloroform which had only been introduced a year earlier. Hannah died during the anesthetic from what was thought to be an episode of ventricular fibrillation.
  • 1893 - The incident received wide publicity and as a result of continuing public and professional concern over anesthetic safety The Lancet journal set up a commission which invited doctors throughout Britain and its colonies to report anesthesia-related deaths. This was the forerunner of a spontaneous reporting system for suspected ADRs. Unfortunately, the system was neither retained for the reporting of anesthesia-related deaths nor extended to the adverse effects of other drugs. [112]
  • 1961 - The second catastrophe that influenced the development of medicines regulation far more than any event in history was the thalidomide disaster. Thalidomide was a sedative and hypnotic that first went on sale in Western Germany in 1956. Between 1958 and 1960 it was introduced in 46 different countries worldwide resulting in an estimated 10,000 babies being born with phocomelia and other deformities. [113]
  • 1963-1964 - the UK government set up a committee to advise it on what measures were needed to ensure adequate safety testing and clinical trials of new drugs before general use, to ensure the early detection of adverse effects, and to keep doctors informed of issues. One of its recommendations was to establish a Committee on the Safety of Drugs (CSD). This was to be a voluntary scheme, working closely with the pharmaceutical industry to look at toxicity tests, clinical trials, efficacy, and adverse reactions during general use. [114]
  • 1962 - In the United States, The Drug Amendments Act was passed by Congress requiring the FDA to approve all new drug applications (NDA) and, for the first time, demanded that a new drug should be proven to be effective and safe. Of equal importance, the FDA was also given the authority to require compliance with current Good Manufacturing Practices (GMP), to officially register drug establishments and implement other requirements. [115]
  • 1968 - During the 16th WHO World Assembly, the 16.36 resolution called for “A systematic collection of information on serious adverse drug reactions during the development and particularly after medicines have been made available for public use”. This led to the formation of the WHO Programme for International Drug Monitoring (PIDM).[116]
  • January 26, 1965 - Induced by thalidomide disaster, Europe adopted the EEC Directive 65/65/EEC, which was the first European pharmaceutical directive. [117]
  • 1975 - To improve the rate of reporting of adverse reactions a “Black triangle” symbol was launched into highlight to prescribers recently-introduced products for at least two years after marketing. This mark applied to new medicines, new combinations of existing medicines, medicines with a new route of administration, medicines with a significant new indication, and new types of formulation for that medicine. [118]
  • 1975 - It took almost ten years for the European Community (EC), since Council Directive 65/65/EEC was introduced, to further develop harmonization in the Community. Two Council Directives were introduced, the first on approximation of the laws of Member States relating to analytical, pharmaco- toxicological and clinical standards and protocols in respect of the testing of proprietary medicinal products (75/318/EEC), and the second on the approximation of provisions laid down by law, regulation and administrative action relating to medicinal products (75/319/EEC). The latter established an ‘old’ Committee on Proprietary Medicinal Products (CPMP) as an advisory committee to the EC and introduced the multi state procedure known now as the mutual recognition procedure.
  • December 22, 1986 - Directive 87/22/EEC introduced the concentration procedure which is now known as the centralized procedure. These directives, and following council regulation, were the landmarks for starting harmonization inside the European Union with the final longstanding aim of creating a ‘common market’ for medicines. [119][120]
  • 1990 - Because of the need for wider harmonization, officials from Japan, EU, and US established the International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH), a collaborative initiative between these countries with observers from WHO, EFTA, and Canada. the Topics selected for harmonization were divided into Safety, Quality and Efficacy to reflect the three criteria which are the basis for approving and authorizing new medicinal products. [121][122]
  • August 24, 1993 - The Council Regulation EEC/2309/93 established the European Medicines Evaluation Agency (EMEA) in 1993 and re-established the CPMP as a ‘new’ CPMP to formulate the opinion of the Agency on questions relating to the submission of applications and granting marketing authorizations in accordance with the centralized procedure. ICH harmonization focused primarily on technical requirements for new, innovative medicines. However, countries with limited resources are mostly generic markets had difficulties of implementing numerous sophisticated ICH standards.[123][124]
  • 1995 - The European Medicines Agency (EMA) was set up to ensure the safe and effective use of Centrally Authorized medicines, that is, those medicines which are authorized throughout the European Union.
  • December 2001 - EudraVigilance, a data processing network, and management system was launched to facilitate the collection of information about ADRs. Requirements were set out in Council Regulation (EEC) 2309/93 and Commission Directive 2000/38/EC. [125]

The story of Uppsala Monitoring Centre (UMC) and the WHO Programme

Uppsala Monitoring Centre (UMC) started by WHO as a pilot project which was collaborated with a small group of countries as a global response to the thalidomide tragedy. Major determination of UMC was to gather information about the adverse events of medicines from as many sources as possible across the world, to ensure that the first signs of the potential threat from medicines would not be neglected or missed.

Awareness of the need for pharmacovigilance has spread to a majority of the world’s countries from 1960’s. Most of the countries have active and well-established systems for the monitoring of the safety and use of medicines. UMC plays a major role in establishing and developing these systems and supporting them. UMC contributes to the drive to protect patients from harm and to help patients and health professionals make wise therapeutic decisions.

According to WHO,

  • The Centre is an independent, self-funded, non-profit organisation.
  • The UMC holds and maintains the largest global database of Individual Case Safety Reports (ICSRs), known as VigiBaseTM, on behalf of WHO and its Member States.
  • The UMC provides technical support and guidance to national centres in pharmacovigilance practice.
  • The UMC develops and supports countries with reporting and data management tools such as VigiFlow, a web-based system that integrates international standards to record and manage ICSRs at many national centres.
  • The UMC conducts training sessions and publishes scientific articles, books, newsletters and periodicals in pharmacovigilance and risk communication. [126]

Regulatory Deadlines

In the United States

For post-marketing reporting of adverse drug experiences: "The applicant must report each adverse drug experience that is both serious and unexpected, whether foreign or domestic, as soon as possible but no later than 15 calendar days from initial receipt of the information by the applicant." [127]

In the EU

Serious valid Individual Case Safety Reports (ICSRs) should be reported by competent authorities in the Member States or by marketing authorization holders within 15 days from the date of receipt of the reports. Non-serious valid ICSRs should be reported by competent authorities in the Member States or by marketing authorization holders within 90 days from the date of receipt of the reports. [128]

In the Canada

Consumers/patients and health professionals can report adverse reactions (also known as side effects) to health products, including prescription and non-prescription medications, biologics, (includes biotechnology products, vaccines, fractionated blood products, human blood and blood components, as well as human cells, tissues and organs), natural health products and radiopharmaceuticals, to the Canada Vigilance Program. [129]

Individual Case Safety Reports (ICSRs)

This refers to the format and content for the reporting of one or several suspected adverse reactions in relation to a medicinal product that occur in a single patient at a specific point of time. A valid ICSR should include at least one identifiable reporter, one single identifiable patient, at least one suspect adverse reaction and at least one suspect medicinal product.[130] [131] [132]


1. An identifiable reporter.

An identifiable reporter who may be identified by name or initials, address or qualification (e.g. physician, pharmacist, other health professional, lawyer, patient or consumer or other non-healthcare professional). For the reporter to be considered identifiable, contact details need to be available in order to confirm or follow-up the case if necessary. However, if the reporter does not wish to provide contact details, the ICSR should still be considered as valid providing the organization who was informed of the case was able to confirm it directly with the reporter. All parties providing case information or approached for case information should be identifiable, not only the initial reporter.

There are several types of reporters:

– A healthcare professional is defined as a medically-qualified person such as a physician, dentist, pharmacist, nurse, coroner or as otherwise specified by local regulations.

– A consumer is defined as a person who is not a healthcare professional such as a patient,lawyer, friend, a relative of a patient or carer. (If a consumer provides medical documentations that support the occurrence of the suspected adverse reaction, or which indicate that an identifiable healthcare professional suspects a reasonable possibility of causal relationship between a medicinal product and the reported adverse event, then the report is considered as confirmed by a healthcare professional. Also, if a consumer initially reports more than one reaction and at least one receives medical confirmation, then the whole report should be documented as confirmed by a healthcare professional). [133]


2. An identifiable patient.

An identifiable patient who may be characterized by initials, patient identification number, date of birth, age, age group or gender. The information should be as complete as possible.

Reasonable attempts should, therefore, be made to obtain and submit the age or age group of the patient when a case is reported by a healthcare professional, or consumer in order to be able to identify potential safety signals specific to a particular population.

When collecting reports of suspected ARs via the internet or digital media, the term “identifiable” refers to the possibility of verification of the existence of a reporter and a patient via verifiable contact details (e.g. an email address under a valid format).


3. A suspected medicine.

One or more suspected substances/medicinal products.

Biological medicinal products, the definite identification of the concerned product with regard to its manufacturing is of particular importance. Therefore, all appropriate measures should be taken to clearly identify the name of the product and the batch number. Marketing Authorization Holder (MAH) responsibilities apply to reports related to medicinal products for which ownership cannot be excluded on the basis of one the following criteria: medicinal product name, active substance name, pharmaceutical form, batch number or route of administration.


4. At least one suspected adverse reaction.

One or more suspected ADRs.

The report does not also qualify as a valid ICSR if it is reported that the patient experienced an unspecified ADR, and there is no information provided on the type of ADR experienced. Reports, for which the minimum information is incomplete, should nevertheless be recorded within the pharmacovigilance system for use in on-going safety evaluation activities.


The lack of any of these four elements means that the case is considered incomplete and does not qualify for reporting. Competent authorities and marketing authorization holders are expected to exercise due diligence in following up the case to collect the missing data elements. Reports, for which the minimum information is incomplete, should nevertheless be recorded within the pharmacovigilance system for use in on-going safety evaluation activities.

Periodic Safety Update report (PSUR)

A Periodic Safety Update Report is a pharmacovigilance document intended to provide an evaluation of the risk-benefit balance of a medicinal product at defined time points post-authorisation. The objective of the PSUR is to present a comprehensive and critical analysis of the risk-benefit balance of the product taking into account new or emerging safety information in the context of cumulative information on risk and benefits. Marketing authorization holder shall be responsible for submitting PSUR for its own products. PSUR is providing an evaluation of the risk-benefit balance of a medicinal product for submission by the marketing authorization holder at defined time points during the post-authorization phase. It is necessary to continue evaluating the risks and benefits of a medicine in everyday medical practice and long term use in the post-authorization phase. Because clinical development of a medicinal product frequently continues following marketing authorization, relevant information from post-authorization studies or clinical trials in unauthorized indications or populations should also be included in the PSUR

Click here for details : https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM346564.pdf

https://www.fda.gov/downloads/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/vaccines/ucm092257.pdf

port (PSUR). The report is produced by the marketing authorization holder (the individual or business that is granted authorization to market a medicine) at defined time points after a medicine has been given marketing authorization.

The purpose of the report is to provide comprehensive and up-to-date information about the safety of a medicine. The report should summarize any new evidence on safety, efficacy and effectiveness that might affect the balance of risks and benefits. The PSUR communicates risk to regulatory authorities and identifies where risk management initiatives may be required.

Safety reports of suspected adverse reactions

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Competent authorities and marketing authorisation holders should take appropriate measures to collect and collate all reports of suspected adverse reactions associated with medicinal products for human use originating from unsolicited or solicited sources.

We can distinguish two types of safety reports in the post-authorisation phase; reports originating from unsolicited sources and those reported as solicited.

I. Unsolicited reports

1. Spontaneous reports

Systematic spontaneous reporting of possible drug caused adverse effects began with the ‘Yellow card system’ in the UK in 1964[134]A spontaneous report is an unsolicited communication by a healthcare professional, patient or consumer to a competent authority, marketing authorization holder or other organization (e.g. Regional Center, Poison Control Center) that describes one or more suspected adverse reactions in an patient who was given one or more medicinal products and that does not derive from a study or any organized data collection schemes. Stimulated reporting that occur consequent to a “Direct Healthcare Professional Communication”, publication in the press, questioning of healthcare professionals by company representatives, or class action lawsuits should be considered spontaneous reports. Unsolicited consumer adverse reactions reports should be handled as spontaneous reports irrespective of any subsequent “medical confirmation”. [135]

2. Literature reports

Scientific and medical literature is a significant source of information for the monitoring of the safety profile and the risk-benefit balance of medicinal products, particularly in relation to the detection of new safety signals or emerging safety issues. A 'signal' consists of reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously. Early identification of the hazards associated with drugs is the main goal of those involved in pharmacovigilance ‘Signal detection’, ‘signal generation’ or ‘signalling’ refers to a process that aims to find, as soon as possible, any indication of an unexpected drug safety problem which may be either new ADRs or a change of the frequency of ADRs that are already known to be associated with the drugs involved. The results of this surveillance exercise tend to arouse suspicions and should always be followed up by in-depth investigations. Spontaneous reporting systems for suspected adverse drug reactions (ADRs) remain a cornerstone of pharmacovigilance. Marketing authorization holders are therefore expected to maintain awareness of possible publications through a systematic literature review of widely used reference databases (e.g. Medline, Excerpta Medica or Embase) no less frequently than once a week. The marketing authorization holder should ensure that the literature review includes the use of reference databases that contain the largest reference of articles in relation to the medicinal product properties.

In addition, marketing authorization holders should have procedures in place to monitor scientific and medical publications in local journals in countries where medicinal products have a marketing authorization, and to bring them to the attention of the company safety department as appropriate. Reports of suspected adverse reactions from the scientific and medical literature, including relevant published abstracts from meetings and draft manuscripts, should be reviewed and assessed by marketing authorization holders to identify and record ICSRs originating from spontaneous reports or non-interventional post-authorization studies. If multiple medicinal products are mentioned in the publication, only those who are identified by the publication's author(s) as having, at least, a possible causal relationship with the suspected adverse reaction should be considered by the concerned marketing authorization holder(s). [136]

3. Reports from other sources

If a marketing authorization holder becomes aware of a report of suspected adverse reactions originating from a non-medical source, for example the lay press or other media, it should be handled as a spontaneous report. Every attempt should be made to follow-up the case to obtain the minimum information that constitutes a valid ICSR. The same reporting time frames should be applied as for other spontaneous reports.

4. Information on suspected adverse reactions from the social media

Marketing authorization holders should regularly screen the internet or digital media under their management or responsibility, for potential reports of suspected adverse reactions. [137]There has been a rise in the monitoring of social media (such as Twitter, Facebook and/or personal blogs) to fill in the gaps on unreported ADRs by researchers.The under-reporting of ADRs through traditional reporting channels is a limitation in the efficiency of the current pharmacovigilance system. Patients’ experiences with drugs that they report on social media represent a new source of data that may have some value in post-marketing safety surveillance. Social media constitutes a new data source for post-marketing drug safety surveillance and may be of interest in identifying signals because of their high volume and availability.

The use of Internet discussions as an additional data source relies on methods to parse, extract, structure, collect, and organize relevant information from the Web pages for analysis. The use of many sources, the large amount of data, and the heterogeneity of data require multiple steps to obtain analyzable corpora. Methods derived from big data and natural language processing (NLP) need to be considered. In addition, questions remain about the quality of information available in users’ Web discussions. Whereas electronic health records and health professionals’ ADR reports are structured and well documented, there are no requirements regarding writing and structuring descriptions of pharmacovigilance related events on social media, and information may be scarce or incomplete.

More than the quality of the information shared in social media, issues can be raised about the reliability of this information. Indeed, social media users adopt pseudonyms, which may allow malicious persons to spread false rumors using multiple pseudonyms with limited risk of being identified as the origin of the rumor. Furthermore, a user can post the same message twice or more on the same forum or different forums using the same or different pseudonyms with no malevolent intent simply to maximize their chances of obtaining an answer. However, there is a sufficient volume of data on pharmacovigilance in social media to work with and that quantity may eventually support the pharmacovigilance process despite the variable quality. [138]

Why Adverse Event Reporting and Social Media Matters

  • Data from clinical trials provides a limited, incomplete picture
  • Sample sizes in clinical trials are relatively modest
  • Patients in clinical trials are rarely over 65 or 70 years old
  • Adverse Event Reporting can provide information about what happens when people are not healthy or are taking other medications
  • Early warning system about unexpected side effects
  • Drug taken by wide range of patients hailing from different ethnicity, various co-morbid medical conditions and various regions across the world

Limitations of Adverse Event Reporting and Social media

  • System reportedly captures only 10% of adverse events
  • No certainty that the reported event was actually due to the product
  • No clear guidelines on reporting criteria and timelines for social media
  • Because FDA does not require a causal relationship between a product and event to be proven before reporting
  • Reports often do not contain enough detail to properly evaluate
  • Data cannot be used to calculate incidence of AE [139]

II. Solicited reports

As defined in ICH-E2D guideline, solicited reports of suspected adverse reactions are those derived from organized data collection systems, which include clinical trials, non-interventional studies, registries, post-approval named patient use programs, other patient support and disease management programs, surveys of patients or healthcare providers, or information gathering on efficacy or patients compliance. Adverse reactions reports obtained from any of these data collection systems should not be considered spontaneous. [140][141]

For the purpose of safety reporting, solicited reports should be classified as study reports, and should have an appropriate causality assessment, to consider whether they meet the criteria for expedited reporting. For all solicited reports, marketing authorization holders should have mechanisms in place to record and document complete and comprehensive case information and to evaluate that information, in order to allow meaningful assessment of individual cases and reporting of valid ICSRs. [142][143]

Country-level Information

Within India, Adverse drug Reactions (ADRs) are reported to NCC-PvPI (National Coordination Center- The Pharmacovigilance Program of India), which work in collaboration with the WHO-UMC to contribute in the global ADRs data base. [144] The ADR reporting rate (ADRs reported per million population) in India has almost doubled in the last three years to 40, but it is lower than 130, the average ADR reporting rate for high-income countries, and clearly disproportionate to the country's population and medicine consumption.

Sri Lanka is now a full time member of the WHO collaboration centre for ADR Monitoring and Reporting, and the Department of Pharmacology, Faculty of Medicine, Kynsey Road, Colombo 8, is the national collaborationg centre. Yet the number of ADR reports received is far below what is expected. The Cosmetic Devices and Drugs Authority should initiate the statutory and logistical processes necessary to improve ADR reporting [145]

In Egypt, the Egyptian Pharmacovigilance Centre (EPVC) has been established by the Egyptian Drug Authority (EDA) and Ministry of Health to be responsible for the collection and evaluation of information on pharmaceutical products marketed in Egypt with particular concern to adverse reactions. EPVC is taking all appropriate measures to encourage physicians and other healthcare professionals to report the suspected adverse reactions to EPVC and oblige marketing authorization holders to systematically collect information on risks related to their medical products and to transmit them to EPVC, in addition, providing information to end-users through adverse drug reaction news bulletins, drug alerts and seminars.

The objectives of EPVC are:

  • Enhance patient care and patient safety in relation to the use of medicines, especially with regard to the prevention of unintended harm from the use of drugs.
  • Improve public health and safety in relation to the use of medicines by the provision of reliable, balanced information resulting in more rational use of drugs.
  • Contribute to the assessment of the risk-benefit profile of medicines, thus encouraging safer and more effective use of medicines and a resolution of the sometimes apparently conflicting interests of public health and individual patient welfare.[146]

In the Philippines, the Philippine Food Drug Administration have created an advisory to report suspected adverse drug reaction using a prescribed ADR form. [147]

While in Russia, adverse events/adverse reactions and follow-ups for ongoing clinical trials must be reported to the RZN but sponsors of international multi-center clinical trials must report these in parallel to the Council on Ethics and ensure reporting by the local investigator to the local ethics committees. After evaluation of the reports by the RZN, reports are forwarded to the “Department of State Regulation of Drug Circulation” in the Ministry of Health and Social Development ("MHSD"), which decides on possible actions in order to safeguard public health. The MHSD’s decision on possible actions is posted on the official MHSD website. [148]

Detection, Prevention and Treatment

Early detection is very important and critical as it open doors for proper management and sheds light on the best measures for prevention. Hospital systems can be changed so that ADEs are more readily detected and prevented. Research funded by Agency for Healthcare Research and Quality (AHRQ) shows that computerized systems can reduce medication errors and prevent ADEs. These studies indicate that anywhere from 28 to 95 percent of ADEs can be prevented.
For example, at least, two studies attribute 42-60 percent of ADEs to excessive drug dosage for the patient's age, weight, underlying condition, and renal function. Yet systems are available that prompt doctors to take these factors into consideration when ordering medications. Even if an ADE is not preventable, computerized systems can detect ADEs early so that health care providers can initiate interventions to mitigate the effects and lessen the severity of the reaction eg, pre-medications that are administered before the Endoxan dose. Hospitals usually rely on hospital staff to complete manual, written incident reports in order to track adverse events, improve quality, and assess risk. However, only a very few (6 percent) of ADEs are reported by this method. Automatic systems can improve detection considerably. Computerized systems currently in use at hospitals perform many different functions. AHRQ has funded research on at least two functions essential to preventing and identifying ADEs — prevention and identification of ADEs and prescription order entry — to determine their effectiveness.

Other Systems Can Prevent and Reduce Adverse Drug Events

Computer systems are only part of the solution in preventing and reducing ADEs. Research studies (some funded in part by AHRQ) on medication errors support other methods that improve the medication delivery system. These methods include:

1. Using the FDA's MedWatch program to report serious ADRs. Reporting would allow the FDA to pass safety information on to other providers, require labelling, or even withdraw a drug from the market.

2. Improving incident reporting systems by streamlining the process of incident reporting to accommodate the health care provider's busy schedule which can offer feedback indicating that reported information is being used. Health care workers sometimes do not recognize that a change in a patient's condition is due to pharmaceutical treatment. Therefore, workers should be educated to identify signs and symptoms that might indicate an ADE and thus increase reporting of ADEs.

3. Creating a better atmosphere for health care providers to report ADEs where the person reporting the error does not fear repercussions or punishment. As the aviation industry has discovered, punishment is a deterrent to reporting an error; if an error is not reported, nothing can be done to correct the situation that created the potential for error. Health care personnel can find it difficult to acknowledge that they make mistakes.

4. Relying more on pharmacists to advise physicians in prescribing medications, and promoting health care provider education on medications. Brigham and Women's Hospital reduced the ADE rate in its Intensive Care Unit (ICU) from 33.0 per 1,000 patient days to 11.6 per 1,000 patient days by having a pharmacist participate in patient rounds with the ICU team. As a result, the hospital estimated it could reduce its costs by $270,000 per year simply by using the pharmacist's time in a different manner.

5. Improving the nursing medication administration and monitoring systems. These changes might include bar coding medications, along with additional warnings on medications with higher potential for harm, such as insulin, opiates, narcotics, potassium chloride, and anticoagulants. [149]

6. Training the healthcare professional and healthcare providers. Training nurses and other healthcare providers in hospitals and healthcare facilities on how important it is to report ADRs and ADEs and how to properly manage them will serve as the first line defense against ADRs as this will raise the awareness and make those professionals more prone to reporting rather than neglecting to report.

7. Avoiding Polypharmacy. Polypharmacy is the use of four or more medications, that generally occurs in patient 65 years old and above. The more medications being used by a patient, the greater the risk of having ADRs.

8. Medication Therapy Management (MTM). MTM is a service or group of services that optimize therapeutic outcomes for individual patients. Medication therapy management services include medication therapy reviews, pharmacotherapy consults, anticoagulation management, immunizations, health and wellness programs and many other clinical services. Pharmacists provide medication therapy management to help patients get the best benefits from their medications by actively managing drug therapy and by identifying, preventing and resolving medication-related problems. [150]

Treatment of any adverse drug reaction would involve dose modifications, change in the dosage regimen or discontinuation of the drug and switch to an alternative drug.[151] All drugs can cause ADRs to a greater or lesser extent. • Knowledge of the mode of action of drugs integrated with an understanding of physiology in health and disease is necessary to maximise safe prescribing • Individual patient factors must always be taken into account before prescribing drugs to minimise the risk of ADRs. [152]

Postmarket Drug and Biologic safety evaluations - preventive approach for safer medicinal products

The postmarket safety evaluations of adverse experience reports made to FDA for New Drug Applications (NDAs) and Biologics License Applications (BLAs) approved since September 27, 2007. The evaluations are done to determine if there are any new serious adverse events not previously identified during product development, known side effects reported in unusual number, or potential new safety concerns now that the products are being used in the general population. In accordance with Title IX, section 915 of the Food and Drug Administration Amendments Act of 2007 (FDAAA) which created a new section 505(r) of the Federal Food, Drug, and Cosmetic Act (FDCA) (21 U.S.C. 355(r)), these postmarket evaluations are performed 18 months after approval of the drug or after its use by 10,000 individuals, whichever is later.

FDA analyses right from the pre approval safety profile to current FDA approval label,Manufacturer-submitted periodic safety reports, Medical literature for the product to post approval clinical trials data . Beginning not later than 18 months after approval, scientists from the Office of Surveillance and Epidemiology and Office of New Drugs in the Center for Drug Evaluation and Research (CDER) jointly review the relevant data, summarize findings and, when necessary, develop a plan to further investigate potential new safety issues for products regulated by CDER. For medical products regulated by the Center for Biologics Evaluation and Research, this safety review and evaluation is conducted by scientists from CBER's Office of Biostatistics and Epidemiology and the relevant product office (Office of Blood Research and Review, Office of Vaccine Research and Review, or Office of Cellular, Tissue and Gene Therapies). FDA compiles the postmarket safety evaluations and periodically posts the summary reports on the website. list is usually displayed on the website.

A new report is usually made available each quarter beginning with the period from January 2013 to March 2013 

https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/ucm204091.htm

Top 5 Latest Tweets

DateAuthorComment
September 18, 2018bengoldacreThis adverse drug reaction to MDMA is a tragedy, but blaming the bereaved friend who handed it over is like blaming… https://t.co/qxvGOfIhbp
September 21, 2018FlorinDanPopescDrug reaction with eosinophilia and systemic symptoms #DRESS is a severe adverse drug reaction that often starts wi… https://t.co/uBBv6smnbN
September 22, 2018bewareblackdogExample 3 Significant mistakes but excellent cultural values &amp; accountability immediately demonstrated by clinici… https://t.co/Gq0wcuzsM3
September 20, 2018DrugApprovalBioThe class imbalance problem detecting adverse drug reactions in electronic health records.: This work focuses on ad… https://t.co/lS18dEhlye
September 22, 2018mattbc@cynthiaLdarnell to be fair to the proposal, if you can prove that you have an adverse reaction because of antibodi… https://t.co/Solp4TPQrz

Top 5 Lifetime Tweets

Date Name Comment
May 23, 2017 McdOrgHealth  #Research suggests 10K-22K Canadians die per year due to adverse #drug reactions (via @amani_saini) http://globalnews.ca/news/3141824/b-c-woman-advocates-for-genetic-testing-after-sister-nearly-dies-of-adverse-drug-reaction/ …
May 20, 2017 Oxyconmdamu CYP Testing to Help Prevent Dangerous Adverse Drug Reactions

https://www.madinamerica.com/2017/01/cyp-testing-prevent-dangerous-adverse-drug-reactions/

May 19, 2017 g_orl Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): evaluation and management of adverse drug reactions

https://cancersfakianakis.wordpress.com/2017/05/19/combined-immune-checkpoint-blockade-anti-pd-1anti-ctla-4-evaluation-and-management-of-adverse-drug-reactions-2/

May 19, 2017 PVpapers Cost-effectiveness Analysis Genotyping before #Allopurinol Treatment Prevent Severe Cutaneous #AdverseDrugReactions

http://www.jrheum.org/content/jrheum/early/2017/04/03/jrheum.151476.full.pdf

May 19, 2017 mlazqui Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): evaluation and management of adverse drug reactions

http://www.cancertreatmentreviews.com/article/S0305-7372(17)30070-1/fulltext?rss=yes

May 18, 2017 ClinicalInnTech A study conducted at @BrighamWomens found that safety testing could prevent adverse drug reactions & reduce costs

http://www.clinical-innovation.com/topics/analytics-quality/drug-safety-testing-could-prevent-adverse-drug-effects-save-medical-costs

Latest News Stories

  1. German pharmaceutical giant Bayer is due in court over claims that a birth control pill from its Yasmin range caused a woman to have a double pulmonary embolism. The firm has paid out billions in similar cases in the US. [153]
  2. One man is brain-dead and another five people are in the hospital after an experimental painkiller was administered to 90 people in a French clinical trial in 2016. The trial was conducted by Biotrial, a French-based company with an international reputation which has carried out thousands of trials since it was set up in 1989. The side effects may be due to the administration of the experimental drug at higher or multiple doses. In a message on its website, the company said that "Serious adverse events related to the test drug" had occurred. [154]
  3. In December 2015, the China Food and Drug Administration (CFDA) proposed a number of revisions that would modify existing rules regarding medical device adverse event reporting. While the rules have yet to be implemented, the proposals represent significant changes to existing laws. [155]
  4. In 2015, CARM received a total of 4206 suspected adverse reaction reports. Of these, 64.6% were associated with medicines, 34.8% were associated with vaccines, and 0.6% were associated with complementary or alternative medicines (CAMs). [156]
  5. (PRAC) has recommended that the marketing authorization for fusafungine-containing medicines be revoked, so the medicines can no longer be marketed in the EU. This follows a review by the PRAC which concluded that the benefits of fusafungine did not outweigh its risks, particularly the risk of serious allergic reactions. Fusafungine is an antibiotic and anti-inflammatory nose and mouth spray used to treat upper airway infections such as rhino-pharyngitis (common cold). [157]
  6. The Health Ministry of India has banned 344 fixed drug combinations through a gazette notification. These include several common cough syrup solutions, analgesics, and antibiotic combinations, many of which are sold over the counter. [158]
  7. The New Clinical Trial Directive, (EU 536/2014) is applicable since May 2016 with a transition period of three years (May 2019) for CT applications submitted before that date, with impact on low-risk intervention clinical trials and pharmacovigilance reporting adjustments. [159]
  8. In March 2017 FDA warned about increased risk of serious pancreatitis with irritable bowel drug Viberzi (eluxadoline) in patients without a gallbladder. The agency review revealed that patients without a gallbladder treated with Viberzi (eluxadoline) present an increased risk of developing serious pancreatitis that could lead to hospitalization or death. FDA is currently working with the Viberzi manufacturer, Allergan, to address these safety concerns. [160]
  9. A new study covering all 222 prescription drugs approved by the U.S. Food and Drug Administration from 2001 through 2010 which is almost one-third of new drugs approved by U.S. regulators over a decade ended up years later with warnings about unexpected, sometimes life-threatening side effects or complications, this new information is suggested by an analysis published Tuesday, May 9, 2017 by the Journal of the American Medical Association; for example the painkiller Bextra (Valdecoxib, a COX-2 Inhibitor) was taken off the market in 2005 because of an increased risk of heart problems. [161]
  10. A recent pilot study investigated whether direct-acting antiviral regimens for chronic hepatitis C virus infections have neuropsychiatric adverse drug reactions. The aim was to assess the development of psychiatric effects related to DAA regimens based on sofosbuvir in the real-life setting. Results indicate that the occurrence of the psychiatric effects seems to be more frequent than previously reported in the registration trials or the summary of product characteristics, which is likely due to different characteristics between the patients enrolled in the registration trials and the patients in daily clinical practice.[162]

Severity is a point on an arbitrary scale of intensity of the adverse event in question. The terms "severe" and "serious" when applied to adverse events are technically very different. They are easily confused but can not be used interchangeably, requiring care in usage.A headache is severe, if it causes intense pain. There are scales like "visual analog scale" that help clinicians assess the severity. On the other hand, a headache is not usually serious (but may be in case of subarachnoid haemorrhage, subdural bleed, even a migraine may temporally fit criteria), unless it also satisfies the criteria for seriousness

[163]


Epidemiology

A study by the Agency for Healthcare Research and Quality (AHRQ) found that in 2011, sedatives and hypnotics were a leading source for adverse drug events seen in the hospital setting. Approximately 2.8% of all ADEs present on admission and 4.4% of ADEs that originated during a hospital stay were caused by a sedative or hypnotic drug.[20] A second study by AHRQ found that in 2011, the most common specifically identified causes of adverse drug events that originated during hospital stays in the U.S. were steroids, antibiotics, opiates/narcotics, and anticoagulants. Patients treated in urban teaching hospitals had higher rates of ADEs involving antibiotics and opiates/narcotics compared to those treated in urban nonteaching hospitals. Those treated in private, nonprofit hospitals had higher rates of most ADE causes compared to patients treated in public or private, for-profit hospitals.

In the U.S., females had a higher rate of ADEs involving opiates and narcotics than males in 2011, while male patients had a higher rate of anticoagulant ADEs. Nearly 8 in 1,000 adults aged 65 years or older experienced one of the four most common ADEs (steroids, antibiotics, opiates/narcotics, and anticoagulants) during hospitalization. A study showed that 48% of patients had an adverse drug reaction to at least one drug, and pharmacist involvement helps to pick up adverse drug reactions.

In 2012 McKinsey &Co. concluded that the cost of the 35 million preventable adverse drug events would be as high as US$115 billion.

The reviews of all epidemiological studies quantifying ADRs in a European setting that were published between 1 January 2000 and 3 September 2014 included studies assessed the number of patients who were admitted to hospital due to an ADR, studies that assessed the number of patients who developed an ADR during hospitalization, and studies that measured ADRs in the outpatient setting. In total, 47 articles were included in the final review. The median percentage of hospital admissions due to an ADR was 3.5 %, based on 22 studies, and the median percentage of patients who experienced an ADR during hospitalization was 10.1 %, based on 13 studies. Only five studies were found that assessed ADRs occurring in the outpatient setting. These results indicate that the occurrence of ADRs in the European hospital setting—both ADRs that result in hospitalization and ADRs that occur during the hospital stay—is significant. Furthermore, the limited number of studies that were performed in the outpatient setting identify a lack of information regarding the epidemiology of ADRs in this setting. [164]

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    113. mhttp://apps.who.int/medicinedocs/documents/s17088e/s17088e.pdf

118. http://www.aafp.org/afp/2003/1101/p1781.html Adverse drug reactions can be considered a form of toxicity; however, toxicity is most commonly applied to effects of overingestion (accidental or intentional) or to elevated blood levels or enhanced drug effects that occur during appropriate use (eg, when drug metabolism is temporarily inhibited by a disorder or another drug).[1]

  1. https://www.merckmanuals.com/professional/clinical-pharmacology/adverse-drug-reactions/adverse-drug-reactions/

Adverse drug reactions are classified into six types (with mnemonics): dose-related (Augmented), non-dose-related (Bizarre), dose-related and time-related (Chronic), time-related (Delayed), withdrawal (End of use), and failure of therapy (Failure).[1]

  1. https://www.ncbi.nlm.nih.gov/pubmed/11072960

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