An 'adverse drug reaction (ADR)' can be defined as a response to a drug which is noxious and unintended. Simply ADR can be defined as any unexpected effect arising after administration of medications. Adverse reactions can arise from use of the product within or outside the terms of the marketing authorization or from occupational exposure. Use outside marketing authorization includes off-label use, overdose, misuse, abuse and medication errors. ^[1] Generally the cause of adverse drug reactions is uncertain, therefore it is more accurate to call it ‘suspected ADRs’. However, not all unwanted clinical phenomena encountered in practice are related to use of drugs and it is 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]

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 "Is any 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". 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 world health organisation 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 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]

The objective of adverse event reporting during pre-market clinical investigations is to improve protection of the health and safety of patients, users and others by identifying safety issues early in the human use of medical devices so that these can be addressed. These safety issues can, therefore, be addressed as soon as possible by modification of the device, revision of the instructions for use, modification of the clinical investigation plan or withdrawal of the device from use.^[7]

If an unexpected reaction is observed in a patient it may be difficult to establish its causality and thus if it has resulted from the administration of a drug or combination of drugs. Guidance on factors that should be considered when trying to establish causality of a reaction is provided by the MHRA on their website at www.mhra.gov.uk.6, b The resource notes that it is important to consider the nature of the reaction, the timing of the reaction in relation to drug administration, the relationship to the dose administered and other possible causes of the reaction including concomitant medications and the patient’s underlying disease. Further information on the different types of ADRs that occur and on the identification of ADRs can be found in guidance for healthcare professionals produced jointly by the Department of Health (DH) and the NHS on their PRODIGY guidance website at www.prodigy.nhs.uk.7 For information about allergic reactions to medications, an important type of ADR, refer to the British Society of Allergy and Clinical Immunology which works to improve the management of allergic and related disease, at www.bsaci.org. A clinical review published in the BMJ offers a good summary of the importance and types of ADRs that can be experienced.^[8]

Serious Adverse Event (SAE)

A serious adverse event (SAE) in human drug trials is defined as any untoward medical occurrence that at any dose. results in death are life-threatening. requires inpatient hospitalization or causes prolongation of existing hospitalization. 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 a rapid drop in blood pressure, loss of consciousness from an 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). ^[9]
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. ^[10]^[11]^[12]
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. ^[13].....

A serious adverse event (experience) or reaction is any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.

Adverse effect(AE)

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. ^[14]

Many commonly employed quality improvement mechanisms, such as incident reporting, occurrence screening, significant event auditing, processes for dealing with complaints, and (in the UK) the national confidential enquiries into various areas of clinical care are essentially focused on such adverse events. Even traditional medical quality improvement mechanisms such as mortality and morbidity conferences or death and complications meetings are predicated on the idea that by identifying and examining adverse events, we can learn lessons and change practice in ways that will make such events less likely in future and hence improve the quality of health care

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.” ^[15]

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’. ^[16]

Dose-related adverse drug reactions represent an exaggeration of the drug's therapeutic effects. For example, a person taking a drug to reduce high blood pressure may feel dizzy or light-headed if the drug reduces blood pressure too much. A person with diabetes may develop weakness, sweating, nausea, and palpitations if insulin or an oral antidiabetic drug reduces the blood sugar level too much. This type of adverse drug reaction is usually predictable but sometimes unavoidable. It may occur if a drug dose is too high (overdose reaction), if the person is unusually sensitive to the drug, or if another drug slows the metabolism of the first drug and thus increases its level in the blood (see Drug Interactions). Dose-related reactions are usually not serious but are relatively common.

Allergic drug reactions are not dose-related but require prior exposure to a drug. Allergic reactions develop when the body's immune system develops an inappropriate reaction to a drug (sometimes referred to as sensitization). After a person is sensitized, later exposures to the drug produce one of several different types of allergic reaction. Sometimes doctors do skin tests to help predict allergic drug reactions.

Idiosyncratic adverse drug reactions result from mechanisms that are not currently understood. This type of adverse drug reaction is largely unpredictable. Examples of such adverse drug reactions include rashes, jaundice, anaemia, a decrease in the white blood cell count, kidney damage, and nerve injury that may impair vision or hearing. These reactions tend to be more serious but typically occur in a very small number of people. Affected people may have genetic differences in the way their body metabolizes or responds to drugs.

Some adverse drug reactions are not related to the drug's therapeutic effect but are usually predictable, because the mechanisms involved are largely understood. For example, stomach irritation and bleeding often occur in people who regularly use aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs). The reason is that these drugs reduce the production of prostaglandins, which help protect the digestive tract from stomach acid.

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. ^[17]
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 a mix of various medications.
ADR is also defined as any noxious and unintended responses to the medicinal product related to any dose. ^[18]

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. ^[19]

How does an ADR different from a side effect or allergy?

An allergy is an adverse drug reaction mediated by an immune response (e.g., rash, hives). A side effect is an expected and known effect of a drug that is not the intended therapeutic outcome. The term “side effect” tends to normalize the concept of injury from drugs. It has been recommended that this term should generally be avoided in favour of an adverse drug reaction.

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 inefficiencies 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 user error or intentional misuse. In an instance if a patient is using a blood glucose monitoring meter and the strip used to monitor the blood glucose is giving an 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 the current pharmaceutical market, many hormonal implants were used as a long-term contraceptive. If the implant is broken inside the body and causes blood clotting then it is identified as an Adverse Event. In the worst case, implants were moved from the implanted location to another location and a surgery needed to remove it from the body. This is called as serious device adverse reaction. ^[20] ^[21]

Definition of Serious Adverse Device Effect:

Adverse device effect 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. NOTE 1: This includes device deficiencies that might have led to a serious adverse event if: a) suitable action had not been taken or b) intervention had not been made or c) if circumstances had been less fortunate. These are handled under the SAE reporting system. NOTE 2: 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. Definition of Unanticipated Serious

Adverse Device Effect (USADE):

A serious adverse device the effect which by its nature, incidence, severity or outcome has not been identified in the current version of the risk analysis report. Anticipated: an effect which by its nature, incidence, severity or outcome has been previously identified in the risk analysis report.

Adverse Device Effects (ADE)

Definition of ‘Adverse Device Effect (ADE)’: adverse event related to the use of an investigational medical device. - This includes any adverse event resulting from inefficiencies 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 user error or intentional misuse.

Legend for severity of ADE:

- Mild: Minor discomfort noticed but does not interfere with normal daily activity - Moderate: Discomfort reducing or affecting normal daily activity - Severe: Incapacitating with inability to work or perform normal daily activity Any Serious Adverse Device Effect (SADE) must ALSO be reported on a Serious Adverse Events Log Form (see ISF) and e-mailed within 24 hours of becoming aware of the event to the Sponsor.

Definition of Serious Adverse Device Effect:

Adverse device effect 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. NOTE 1: This includes device deficiencies that might have led to a serious adverse event if: a) suitable action had not been taken or b) intervention had not been made or c) if circumstances had been less fortunate. These are handled under the SAE reporting system. NOTE 2: 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.

Term	Definition
Application Integrity Policy (AIP)	Application Integrity Policy (AIP) is FDA's policy for the integrity of data or information submitted in an application. If it is suspected that an applicant has submitted false or misleading information, the data are thoroughly investigated. Submitting false or misleading information may result in FDA refusal to review submissions until certain requirements are met
Early Feasibility Study (EFS)	An early feasibility study (EFS) is a limited clinical investigation of a device early in development. It typically: enrolls a small number of subjects; is used to evaluate the device design concept with respect to initial clinical safety and device functionality; and may guide device modifications.
Implant	Implant is a device that is placed into a surgically or naturally formed cavity of the human body and is intended to remain there for a period of 30 days or more. In order to protect public health, FDA may determine that devices placed in subjects for shorter periods are also implants.
Institutional Review Board (IRB)	Institutional Review Board (IRB) is a board, committee, or other group formally designated by an institution to review, to approve the initiation of, and to conduct periodic review of biomedical research involving human subjects. The primary purpose of such review is to assure the protection of the rights, safety, and welfare of human subjects. The IRB should be established, operated, and function in conformance with 21 CFR 56. The term has the same meaning as "institutional review committee" in section 520(g) of the FD&C Act.
Investigation	Investigation is a clinical investigation or research involving one or more subjects to determine the safety and/or effectiveness of a device.
Investigational device	Investigational device is a device, including a transitional device, that is the object of an investigation.
Investigational device exemption (IDE)	IDE refers to the regulations under 21 CFR 812. An approved IDE means that the IRB (and FDA for significant risk devices) has approved the sponsor’s study application and all the requirements under 21 CFR 812 are met.
Investigator	Investigator is an individual who actually conducts a clinical investigation, i.e., under whose immediate direction the investigational device is administered, dispensed to, or used involving a subject. In the event of an investigation being conducted by a team of individuals, "investigator" refers to the responsible leader of that team.
Monitor	When used as a noun, monitor is an individual designated by a sponsor or contract research organization to oversee the progress of an investigation. The monitor may be an employee of a sponsor, or a consultant to the sponsor, or an employee of or consultant to a contract research organization. When used as a verb "monitor" means to oversee an investigation.
Premarket Approval (PMA)	A premarket approval means any premarket approval application for a Class III medical device, including all information submitted with or incorporated by reference therein. (21 CFR 814.3)
Premarket Notification [PMN or 510(k)]	510(k) refers to the type of submission to FDA described under 21 CFR 807 Subpart E in which the applicant must establish that their device is substantially equivalent to a legally marketed device. This type of submission is used for most Class II devices and some Class I devices.
Significant risk device (SR device)	Significant risk device is an investigational device that: (1) is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject; (2) is for use in supporting or sustaining human life and represents a potential for serious risk to the health, safety, or welfare of a subject; (3) is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a subject; or (4) otherwise presents a potential for serious risk to a subject.
Sponsor	Sponsor is a person or other entity that initiates but does not actually conduct the investigation. An entity other than an individual (e.g., a corporation or an agency) which uses one or more of its own employees to conduct an investigation that it has initiated is considered to be a sponsor, not a sponsor-investigator, and the employees are considered to be investigators. The sponsor of an IDE must be located in the United States (see 21 CFR 812.18).
Sponsor-investigator	Sponsor-investigator is an individual who both initiates and actually conducts, alone or with others, a clinical investigation, i.e., under whose immediate direction the investigational device is administered, dispensed, or used. The term does not, for example, include a corporation or agency. The obligations of a sponsor-investigator include those of an investigator and those of a sponsor.
Subject	Subject is a human who participates in an investigation, either as an individual on whom or on whose specimen an investigational device is used or who participates as a control. A subject may be in normal health or may have a medical condition or disease.
Transitional device	Transitional device is a device subject to section 520(l) of the FD&C Act and which FDA previously regulated as a new drug or an antibiotic drug before May 28, 1976.
Unanticipated adverse device effect	Unanticipated adverse device effect is any serious adverse effect on health or safety, any life-threatening problem or death caused by, or associated with a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the application; or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects.

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
Required in-patient hospitalization or prolongation of existing hospitalization or
Resulted in a permanent impairment of a body structure or a body function 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:

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

Product Quality Complaint (PQC)

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, labelling, inserts, etc. Examples include:

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

Product quality issues, particularly for marketed drugs, is an area that many in drug safety do not pay too much attention to. This is unfortunate in many regards: FDA and other regulators expect companies to be aware of and act immediately on any product quality issues and this includes safety reporting if there is an adverse event (AE) involved.

Product Quality Issues

As is expected, even in the best and most careful of companies, sometimes products are released to the market that has problems. This is expected in any human endeavour, particularly those involving complex manufacturing processes. In the US pharma industry, manufacturing must normally be done under Good Manufacturing Practices (GMP). Similar requirements exist in many countries and regions including the EU. The WHO has also put out GMP. In the US these date back to the 1938 Food, Drug and Cosmetic Act. The expectation and requirements of these laws, regulations and directives are that manufacturing will be done using clearly defined, controlled and consistent practices. The end product must meet predetermined specifications concerning content, quality, appearance, etc. There must be written procedures that are followed with detailed and meticulous record keeping which will allow a root cause analysis (“failure analysis”) to be done in case of problems.

Suspected ADR

The suspected ADR is any AE for which there is a reasonable possibility that the drug caused the adverse event. ^[23]. For the purposes of IND safety reporting, ―reasonable possibility‖ means there is evidence to suggest a causal relationship between the drug and the adverse event. Suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug. ^[24]

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. ^[25]^[26]

An adverse reaction to a drug, the nature, severity, specificity or outcome of which is unanticipated based on the applicable product information.^[27]

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. ^[28]

Medication Error

Main article: Medication Error

A medical error is a preventable adverse effect of care, whether or not it is evident or harmful to the patient. This might include an inaccurate or incomplete diagnosis or treatment of a disease, injury, syndrome, behavior, infection, or other ailments. They are Potential mediation error and Intercepted medication error. Potential medication error refers to the recognition of circumstances that could lead to a medication error and may or may not involve a patient. It refers to all possible mistakes by all persons who are involved in the medication process. Intercepted medication error refers to situations where a medication error occurred, and an intervention caused a break in the chain of events in the treatment process before reaching the patient. The intervention prevented actual harm being caused to the patient.

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, healthcare products, procedures, and systems, including prescribing, order communication, product labeling, packaging, and nomenclature, compounding, dispensing, distribution, administration, education, monitoring, and use. ^[29]

Medication Errors can occur in:

Choosing a medicine—irrational, inappropriate, and ineffective prescribing, under-prescribing and over-prescribing
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 ^[30]

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 labelling, packaging, and nomenclature, compounding, dispensing, distribution, administration, education, monitoring, and use." ^[31]

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. ^[32]

The European Union (EU) pharmacovigilance legislation has introduced a number of changes related to medication errors which affect the operation of pharmacovigilance systems in the EU Member States. To support implementation of the new legal provisions amongst the stakeholders involved in the reporting, evaluation and prevention of medication errors the European Medicines Agency (EMA) was mandated to develop in collaboration with the EU regulatory network specific guidance for medication errors, taking into account the recommendations of a stakeholder workshop held in London in 2013. This good practice guide is a key deliverable of the EU regulatory network’s medication error initiative to improve reporting and learning from medication errors for the benefit of public health.

WHO Definitions for Causality Assessment

Certain: • The clinical event, lab test abnormality with plausible time relationship to drug intake • Cannot be explained by concurrent disease or other drugs /chemicals • Response to de-challenge- plausible • The event must be definitive pharmacologically / immunologically • Positive re-challenges (if performed).

Probable/ Likely: • The clinical event, lab test abnormality with reasonable time relationship to drug intake • Unlikely to be to concurrent disease, drugs/chemicals • The 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: • The clinical event, lab test with an improbable time relationship to drug intake • Other drugs, chemicals or underlying disease provide plausible explanations Inaccessible /unclassified: • 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 maybe contradictory, however, this should not dissuade you, from reporting the reaction to the {National Pharmacovigilance Programme}. A well-documented the report which includes information about all the above-mentioned questions can provide us with the first signal of a previously unknown problem.

ADVERSE DRUG REACTION NEWS AND RESEARCH

	[1]
Adverse Drug Reaction
Related Certifications	Certificate in Current Pharmacovigilance Regulatory Landscape

1. SLU researcher seeks to find solutions for 'chemo brain' symptoms and side effects of opioids

With a pair of RO1 grants from the National Institutes of Health, pain researcher Daniela Salvemini, Ph.D., will embark on two new research projects, studying chemotherapy-induced cognitive impairment, or "chemo brain," symptoms and unwanted side effects of opioids.

Salvemini, who is professor of pharmacology and physiology at Saint Louis University, has spent her career attempting to understand how pain happens in the body, including chronic pain, cancer pain and chemotherapy-induced pain. She studies pain pathways, the series of interactions between molecular-level components, to understand how pain occurs in order to develop new treatments.

With these awards, Salvemini will expand her work to seek answers to urgent questions surrounding pain and cancer drugs.

Chemotherapy-induced cognitive impairment, or "chemo-brain"

A $2,814,902 grant will allow Salvemini to study a common, debilitating side-effect of chemotherapy called chemotherapy-induced cognitive impairment. She is joined by co-investigators Timothy Doyle, Ph.D., Grant R. Kolar, Ph.D., and Susan Farr, Ph.D. from SLU as well as Jacoba (Cobi) Heijnen, Ph.D., and her team at MD Anderson Cancer Center.

Advances in cancer treatment have led to a sharp increase in the number of cancer survivors, reaching nearly 15 million people in the United States alone. However, in many cases, cancer treatment is associated with severe neurotoxic side effects that not only can disrupt social, educational and occupational functioning, but also decrease survival by interfering with adherence to medication and healthy behavior.

Chemotherapy-induced cognitive impairment (CICI), sometimes called "chemo-brain," is a major neurotoxic side effect of platinum-based (such as cisplatin) and anthracyclins (such as doxorubicin) chemotherapy drugs that are widely used as part of standard treatment for numerous cancers, including head and neck, testicular, colon, breast, ovarian and non-small cell lung cancers.

CICI is characterized by subtle to moderate cognitive deficits that include decreases in processing speed, memory, executive functioning and attention - side effects which can dramatically impact quality of life for patients, with symptoms persisting well after exposure. With nearly 40 percent of adults projected to be diagnosed with cancer in their lifetime and with CICI rates that are greater 50 percent in cancer patients and survivors, CICI represents a growing public health concern.

Little is known about the mechanisms underlying CICI, and there are no FDA-approved drugs to prevent or cure the condition.

"It is imperative that we understand the underlying causes of this serious adverse drug reaction and identify novel therapeutic approaches with the potential for rapid translation to the clinic," Salvemini said.

In previous work, Salvemini and her team found that chemotherapy dysregulates endogenous adenosine signaling at one of its receptors, A3AR, leading to neuroinflammatory processes and mitochondrial dysfunction in the central nervous system that contribute to the development and continuation of cognitive impairment.

This grant will explore the use of highly selective A3AR agonists - chemicals that activate the nuclear receptor - as a therapeutic approach to mitigate chemo-brain, providing new molecular insights that will advance our understanding of how chemo-brain occurs.

Opioids and Pain, Tolerance and Dependence

A $1,722,666 NIH grant will allow Salvemini to study another alarming problem: opioid pain killers that are capable of quelling terrible pain also carry debilitating side effects and significant risk of addiction. She is joined by co-investigators who include Timothy Doyle, Ph.D. and Grant R. Kolar, Ph.D., from SLU as well as Todd Vanderah, Ph.D., and his team at the University of Arizona.

This pain problem sets up a discouraging dilemma for patients and doctors. Opioid pain killers, like hydrocodone and morphine, can ease unbearable pain for those who are suffering. The price, however, can be side effects like nausea, vomiting, drowsiness or sedation, and psychological effects like euphoria, hallucinations or delirium. They also can lead to addiction and cause withdrawal symptoms once halted.

As she searches for new ways to mitigate the side effects of these drugs while preserving their pain killing ability, Salvemini will build on previous work that studied alterations in sphingolipid signaling in the brain.

Salvemini found that these alterations cause the development of several opioid side effects, including pain caused by the chronic use of opioids, called opioid-induced hyperalgesia (OIH), and tolerance, which happens when opioids lose their effects over time, called antinociceptive tolerance, which can lead to increased doses which in turn can contribute to dependence.

Salvemini and her team have identified the molecular cause that drives these unwanted opioid effects. With this grant, they will explore the mechanisms at the cellular and molecular levels that cause OIH, tolerance and dependence.

Salvemini hopes this work will lead to a drug that could be taken together with opioids.

"The idea is to combine a drug that blocks sphingolipid signaling with opioids in order to preserve opioids' pain-killing properties, but minus their side effects," Salvemini said."

Researchers develop a new tool to help avoid adverse reactions to drugs

Researchers at the University of Liverpool, Alder Hey, University of Central Lancashire and University College London have developed a new tool to help avoid adverse reactions to medicines.

Medicines are an important part of treating and preventing disease in adults and children. The ideal medicine would have no side effects or adverse drug reactions (ADRs) as they are also called, but the reality is all medicines can cause unwanted effects, in some people.

Medicines can have different effects on different people. The effects in children can vary due to changes that take place as they grow and develop. When healthcare professionals prescribe medicine, they weigh up the benefits of medicine against the risk of an ADR.

Avoidable

Previous research at Alder Hey found that three out of every 100 children admitted to hospital experience an ADR due to medicine taken at home. 22% of these ADRs might have been avoidable. Examples of ADRs which were avoidably included: diarrhoea with antibiotics, and constipation with medicines given to relieve pain and vomiting related to chemotherapy.

The team also found that around 1 in 6 children experienced at least one ADR whilst in hospital, which is similar to findings in adults. More than half of the ADRs seen in children in hospital were due to medicines used in general anaesthesia and for the treatment of pain after surgery.

Most of the ADRs were not severe and resolved soon after the medicine was stopped. The five most common ADRs seen were nausea and/or vomiting, itching, constipation, diarrhoea and sleepiness.

Personalized medicine

Dr Louise Bracken is a Research Pharmacist from the University's Department of Women's and Children's Health. She is based at the Pediatric Medicines Research Unit at Alder Hey Children's Hospital.

Of the research, Dr Bracken said: "Assessing the avoidability of ADRs is a complex process which requires consideration of a number of factors.

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. ^[33] 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. ^[34]

Study highlights the need for additional systems to report adverse drug reactions in infants

A new study reveals that adverse drug reactions in newborns and infants may be under-reported.

For the study, investigators analyzed 2001-2010 information from the UK Medicines and Healthcare products Regulatory Agency, which runs a national spontaneous reporting system to collect suspected adverse drug reaction data.

The researchers found that spontaneous reports alone are not currently generating required data, and important safety messages from the regulator do not match reporting patterns. Additional reporting strategies will be required to improve the quantity and quality of information on suspected adverse drug reactions in young children.

"The UK set up the first system in the world to report adverse drug reactions, the Yellow Card Scheme, over 50 years ago. It has helped improve the safety of drugs immensely by identifying adverse drug reactions, and continues to be valuable today," said Dr Daniel Hawcutt, lead author British Journal of Clinical Pharmacology study. "This research shows that for newborn babies and infants, the spontaneous reporting of adverse drug reactions may not be enough, and additional systems to seek out and report adverse drug reactions are required."

Targeted Medical Events (TME)

Also known as Medical Events of Special Interest (MESI), are adverse events that are thought to be (potentially) associated with a particular product, group of products (class), or patient population. These events are identified and the list is developed by the Sponsor, in conjunction with external agencies and/or experts in the therapeutic area in which the investigational product is being developed.

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.^[35]

The FDA Adverse Event Reporting System In the United States, the primary adverse event reporting system is MedWatch, the FDA Safety Information and Adverse Event Reporting Program. Health care professionals and consumers voluntarily report ADRs, ADEs, and medication errors for entry into the FDA Adverse Event Reporting System (FAERS) database. The events are evaluated by clinical reviewers in the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). This evaluation may lead to regulatory action by the FDA, including labelling changes, communicating new safety information to the public, restricting the use of the drug, or removing the drug from the market.

The FDA may also require Risk Evaluation and Mitigation Strategies (REMS), which are plans that use risk minimization strategies beyond professional labelling to ensure that the benefits of the drug outweigh the risks. Drug sponsors develop REMS programs and submit them to the FDA, where they are reviewed and approved. This requirement can be mandated either before or after a drug is approved for marketing, and can be required for a single drug or a class of drugs. Proposed REMS may include one or more of the following: a medication guide to be distributed to patients when filling a prescription for the drug; a communication plan to educate health care professionals on the safe and appropriate use of the drug; Elements to Assure Safe Use (ETASU) such as physician certification requirements to prescribe the drug or patient enrollment in a central registry; an implementation plan of how ETASUs will be implemented; and a timetable for submitting assessments on performance with respect to meeting the goals and objectives of the REMS. The timetable requires assessments by 18 months, 3 years, and in the seventh year after the REMS is approved. Assessment results may be used to modify the REMS or to eliminate it after 3 years if the REMS has met its goals.

The FDA can also require a boxed warning on product information inserts and other drug literature. A boxed warning is indicated when drug use presents potential serious risks that may outweigh the intended benefits. Boxed warnings are often based on serious adverse reactions reported by health care practitioners and patients. Boxed warnings inform the prescriber of appropriate use of the drug, such as patient selection, monitoring, concomitant therapies to avoid, adjunctive therapies to administer, or specific clinical situations in which to avoid the drug. The presence of a boxed warning in the drug literature should alert the health care provider to examine the risks and benefits of the therapy and to consider the consequences that potential ADRs can inflict. It is still important to report an observation of a known ADR because the severity or prevalence may lead to further FDA action including, but not limited to, removal of the drug product from the market.

The online MedWatch reporting form is used to submit suspected ADRs, ADEs, or medication errors to the FDA. The form may also be printed and mailed to FAERS. Health care professionals and consumers may alternatively choose to report adverse events and/or medication errors to the product manufacturer, which is then required to send a report to the FDA. These reports are also entered into FAERS for review.

The data contained in FAERS are not without limitations. There is no certainty that the reported event was caused by the drug or product. The FDA does not require that a causal relationship is proved in order to submit a report. Many reports do not contain enough details about the event to properly evaluate the occurrence. Because reporting is voluntary, there is not an FDA report for every event that occurs in the United States; therefore, the FAERS data cannot be used to calculate the true incidence of any given adverse reaction or event. The information contained in FAERS is available to the public through FAERS statistics, FAERS data files FOIA, and individual case safety reports from the FAERS database. You can get a summary FAERS report for a product by submitting a Freedom of Information Act (FOIA) request. You can request individual case reports by submitting a FOIA request. Your request must include the FAERS case numbers.

The FAERS statistics provide the number of reports the FDA has received for drug and biologic products during the past 10 years. The FAERS data files provide raw data from individual case safety reports within the FAERS database. Individual case safety reports can be obtained by sending a Freedom of Information request to the FDA. Quarterly reports on potential serious adverse effects identified by FAERS are published and can be found on the FDA Web site.

Identification of ADRs

In both the inpatient and outpatient section, 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 over sedation, 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. ^[36]

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). ^[37] 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.^[38]

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.^[37] 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). ^[39]

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. ^[40]
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. ^[41]^[42]

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. ^[43]

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.

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.
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.
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.
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.
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. ^[44]

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. ^[45]

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.^[46] 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.^[47]

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. ^[48] 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). ^[49]

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.^[50]

How to Report to FDA MedWatch

Consumers can continue to ask their health care professional to file a MedWatch report or to report a suspected problem directly to a drug manufacturer. By law, companies are required to report to FDA certain serious problems that may have been caused by their products, including in cases where consumers report suspected problems to the company. Currently, the clear majority of more than 900,000 MedWatch reports a year are funneled to FDA through companies.

Consumers are not expected to provide proof that the problem was caused by the product. Fritsch adds that consumers should send the report even if they don’t have all the information requested. Questions are answered at MedWatch’s toll-free line, 1-800-332-1088, between 8 a.m. and 4:30 p.m. ET.

MedWatch forms for both consumers and health care professionals must be faxed or mailed. Online submission capability will be available in coming months. According to the Form FDA 3500B.

What's New

Programmable CSF Shunts and Magnetic Field Interference with Implanted Hearing Devices: Letter to Health Care Providers - Due to Potential Unintended Changes intended for Patient, Health Professional, Pediatrics, Neurology, Otolaryngology, Surgery, Risk Manager. [07/16/2019]
Giraffe Infant Warmers and Panda i-Res Infant Warmers by GE Healthcare: Recall - Due to Bedside Panels and Latch Areas Cracking or Breaking intended for Nursing, Health Professional, Risk Manager. [07/12/2019]
Hamilton-G5 Ventilator by Hamilton Medical AG: Recall - Due to Potential for Sporadic Error Message Resulting in the Ventilator to Cease Ventilation and Enter Ambient State intended for Health Professional, Risk Manager, Pulmonology. [07/12/2019]
Multiple Ophthalmic Products by Altaire Pharmaceuticals Sold at CVS Health: Recall - Due to Potential for Non-sterility intended for Consumer, Health Professional, Risk Manager, Pharmacy. [07/10/2019]
Multiple Ophthalmic Products by Altaire Pharmaceuticals: Recall - Due to Potential for Nonsterility intended for Consumer, Patient, Health Professional, Pharmacy. [07/03/2019]
Multiple Ophthalmic Products by Altaire Pharmaceuticals Sold at Walgreens Stores: Recall - Due to Potential for Non-sterility intended for Consumer, Health Professional, Risk Manager, Pharmacy. [07/03/2019]
Fluorouracil Injection by Fresenius Kabi USA: Recall - Due to the Potential for Glass Particulate intended for Pharmacy, Oncology, Health Professional, Risk Manager. [07/02/2019]
SmartSite Syringe Administration Set by Becton Dickinson & Company: Class I Recall - Due to Risk of Leaks intended for Health Professional, Nursing, Risk Manager, Critical Care Medicine. [07/01/2019]
IntraClude Intra-Aortic Occlusion Device by Edwards Lifesciences: Class I Recall - Due to Risk of Balloon Rupture intended for Cardiology, Surgery, Risk Manager, Health Professional. [07/01/2019]

How to Report - General

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:

Complete and submit the report Online: www.fda.gov/MedWatch/report.htm
Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

How to Report - Dear Healthcare Professional Letters, Recall Notices or other communications targeted to healthcare professionals:

Adverse events, product quality problems, product use errors, or reports of therapeutic inequivalence/failure should be reported to FDA's MedWatch Safety Information and Adverse Event Reporting Program:

Complete and submit the report Online: www.fda.gov/MedWatch/report.htm
Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178^[51]

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. ^[52]

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. ^[53]

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 an increasing number of patients and by the end of full pre-marketing the 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 the 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 a new formulation which has no clinical trial, f2 comparison or even incomplete understanding about impurities profile. So the chance of ADRs inpatient 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:^[54]

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 the clinic.

Examples of therapeutic side effects

Bevacizumab (Avastin), ^[55]used to slow the growth of blood vessels, has been used against wet age-related macular degeneration, as well as macular oedema from diseases such as diabetic retinopathy and central retinal vein occlusion. mainly used as a cancer medicine.
Buprenorphine ^[56]has been shown experimentally to be effective against severe, refractory depression.
Bupropion^[57] an anti-depressant, is also used as a smoking cessation aid; this indication was later approved, and the name of the smoking cessation product is Zyban. In Ontario, Canada, smoking cessation drugs are not covered by provincial drug plans; elsewhere, Zyban is priced higher than Wellbutrin, despite being the same drug. Therefore, some physicians prescribe Wellbutrin for both indications.
Carbamazepine 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.
Dexamethasone and Betamethasone^[58] in premature labour, to enhance pulmonary maturation of the fetus.
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.
Hydroxyzine^[60], an antihistamine, is also used as a sedative to treat anxiety and tension.
Magnesium sulfate^[61] in obstetrics for premature labor and preeclampsia.
Methotrexate (MTX)^[62], approved for the treatment of choriocarcinoma, is frequently used for the medical treatment of an unruptured ectopic pregnancy.
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.
Pregabalin l^[63] Pregabalin is used with other medicines to help control partial seizures (convulsions) in the treatment of epilepsy also used for postherpetic neuralgia (pain that occurs after shingles) and pain caused by nerve damage from diabetes or a spinal cord injury.
Sildenafil^[64] was originally intended for pulmonary hypertension; subsequently, it was discovered that it also produces erections, for which it was later marketed.
Terazosin^[65], 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 ^[66]– 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.
.

5 Dangerous Food-Drug Interactions: 1. Calcium-Rich Foods + Antibiotics Dairy products such as milk, yoghurt, and cheese can interfere with certain medications, including antibiotics such as tetracycline, doxycycline, and ciprofloxacin.

These antibiotics may bind to the calcium in milk, forming an insoluble substance in the stomach and upper small intestine that the body is unable to absorb.^[67] 2. Pickled, Cured, and Fermented Foods + MAIOs This food category contains tyramine, which has been associated with a dangerous increase in blood pressure among patients taking monoamine oxidase inhibitors (MAIOs) and certain medications for Parkinson’s disease.^[68] 3. Vitamin K-Rich Foods + Warfarin Pharmacists should counsel patients taking warfarin to maintain a consistent intake of vitamin K and avoid introducing kale, spinach, and other leafy greens to their diets.

Vitamin K is vital for the production of clotting factors that help prevent bleeding, but anticoagulants like warfarin exert their effect by inhibiting vitamin K. Therefore, an increased intake of the nutrient can antagonize the anticoagulant effect and prevent the drug from working.^[69] 4. Alcohol + Prescription Stimulants Patients should always be wary of mixing any medication with alcohol, but some interactions are more serious than others.

For instance, ingesting alcohol while taking a prescription stimulant could cause the patient to not fully realize how intoxicated they are. This is especially true when the stimulant is being abused, but it can also happen when the patient takes the drug as prescribed.^[70] 5. Grapefruit and Grapefruit Juice + Statins Patients should avoid eating grapefruit or drinking grapefruit juice while taking some medications, in particular, statins. Monitoring is a process of checking a system that changes with time, in order to guide changes to the system that will maintain it or improve it. A recent article discussing the monitoring of disease in medicine has drawn attention to the more general problem of monitoring the health of patients suffering from chronic disease [1]. Monitoring has three components: proactive, targeted observation; analysis; and action. There are some obvious requirements for monitoring to achieve its aims. It should be clear from the outset of the process which observations are to be monitored. The observations have to reflect important characteristics of the system’s variation relative to the goal of monitoring and be made with sufficient frequency and accuracy to capture important changes. The analysis of the observations has to define the changes that need to be made to the system to return it to a desirable state or improve the chances of a desirable outcome. The actions should bring about those changes.

The oxygen saturation monitor, which sounds an alarm if the patient’s oxygen saturation drops below some threshold value, illustrates the process. The monitoring, in this case, is designed to improve the safety of the system by warning of a need to increase the concentration of oxygen in inspired air, so that the patient does not suffer from the consequences of hypoxia. The observations of oxygen saturation are made continuously and are reasonably accurate. The analysis, which consists of comparing the measured oxygen saturation with some preset warning value, is based on clinical experience. If the analysis is correct, then it is safe to maintain the current inspired oxygen concentration. If the alarm sounds, then the action is required to improve oxygenation.

Compounds in grapefruit called furanocoumarin chemicals cause an increase in medication potency by interacting with enzymes in the small intestine and liver. This interaction partially inactivates a number of medications under normal circumstances.^[71]

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.
In clinical routine, adverse drug reactions (ADR) are common, and they should be included in the differential diagnosis in all patients undergoing drug treatment. Only part of those ADR are immune-mediated hypersensitivity reactions and thus true drug allergies. Far more common are non-immune-mediated ADR, e.g. due to the pharmacological properties of the drug or to the individual predisposition of the patient (enzymopathies, cytokine dysbalance, mast cell hyperreactivity). In true drug allergiesT cell- and immunoglobulin E (lgE)-mediated reactions dominate the clinical presentation. T cell-mediated ADR usually have a delayed appearance and include skin eruptions in most cases. Nevertheless, it should not be forgotten that they may involve systemic T cell activation and thus take a severe, sometimes lethal turn. Clinical danger signs are involvement of mucosal surfaces, blistering within the exanthematous skin areas and systemic symptoms, e.g. fever or malaise. Drug presentation via antigen-presenting cells to T cells can either involve the classical pathway of haptenization of endogenous proteins or be directly mediated via noncovalent binding to immune receptors (MHC molecules or T cell receptors), the so-called p-i concept. Flare-up reactions during the acute phase of T cell-mediated ADR should not be mistaken for true drug allergies, as they only occur in the setting of a highly activated T cell pool. IgE-mediated ADR are less frequent and involve mast cells and/or basophils as peripheral effector cells. Recent data suggest that certain patients with drug allergy have a preexistent sensitization although they have never been exposed to the culprit drug, probably due to cross-reactivity. Thus, allergic drug reactions on first encounter are possible. In general, the extent of cross-reactivity is higher in IgE-compared to T cell-mediated ADR. Based on a specific ethnic background and only for severe T cell-mediated ADR to certain drugs, a strong HLA association has been established recently.

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.^[72].

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. ^[73]

^[74]

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. ^[75]

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 ^[76]

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.^[77]

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. ^[78]

(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. ^[79]

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 ^[80]
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
Age	Elderly people (hypnotics)	Adjust doses according to age
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
Exogenous factors	Interactions with food (eg grapefruit juice with drugs cleared by CYP3A4)	Alter dose or avoid co-administration
Disease	Renal insufficiency (eg lithium)	Screen for abnormalities; avoid specific drugs; use reduced doses
Disease	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).^[81]

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. ^[82]

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)	Mild
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	Moderate
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.

^[83]

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:

use of a medicinal product within the terms of the marketing authorisation;
use outside the terms of the marketing authorisation, including overdose, misuse, abuse and medication errors;
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) ^[84]

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. ^[85]^[86]

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 ^[87]
Reports of overdose, abuse, off-label use, misuse, medication error, occupational exposure, or falsified medicinal product ^[88]

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. ^[89]

Immunologic and Nonimmunologic Drug Reactions^[90]

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 guidelines to support stakeholders, including the pharmaceutical industry and regulatory authorities in the 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
Adverse event of special interest (AESI)	A noteworthy event for the particular product or class of products that a sponsor may wish to monitor carefully. It could be serious or non-serious (e.g. hair loss, loss of taste, impotence), and could include events that might be potential precursors or prodromes for more serious medical conditions in susceptible individuals. Such events should be described in protocols or protocol amendments, and instructions provided for investigators as to how and when they should be reported to the sponsor
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. ^[91]
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 labelling, packaging, and nomenclature; compounding; dispensing; distribution; administration; education; monitoring; and use." ^[92] A potential medication error is the recognition of circumstances that could lead to a medication error, and may or may not involve a patient.^[93] 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, health care products, procedure and systems, including prescribing, order communication, product labelling, dispensing, distribution, administration, education, monitoring and use. ^[94]^[95] 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 .^[96] 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. ^[97]. Abused drugs include Methamphetamine Anabolic steroids Club drugs Cocaine Heroin Inhalants Marijuana Prescription drugs, including opioids ^[98].
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. ^[99] 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.” ^[100]
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. Other 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. ^[101]
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 an exposure to the medical product or drug through breast milk. Transmammary exposure happens when the mother breastfeeds the child. ^[102]
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).^[103]
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. ^[104] 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.^[105] Example of off-label use of the medical device: Coronary stents are constantly used in off-label indications and studies have been performed to show the safety of such use.^[106]
Occupational exposure	This refers to the exposure to a medicinal product as a result of one’s professional or non-professional occupation. For example, a nurse accidentally pricked the needle while injecting the patient ^[107] It does not include the exposure to one of the ingredients during the manufacturing process before the release as a 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 medical 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. ^[108]

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’. ^[109] 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. ^[110] The frequency of an adverse reaction may be expressed in various ways and which is used will be dependent on the method of measurement. ^[111] 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): ^[112]

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 ^[113]:

Overcoming Barriers in reporting AE:

Serious adverse drug events (ADEs) may emerge after a new drug is brought to market; in fact, a median of 7 years elapses before such incidents are described by pharmaceutical companies or the US Food and Drug Administration (FDA). An important factor underlying this delay is low reporting of ADEs, with only 1% to 10% of all such incidents reported.

In an effort to improve detection of serious ADEs, the FDA is forming partnerships with large health insurers and is planning to monitor insurance claims, electronic medical records, and laboratory test results for persons who are covered by these health insurers. However, recent studies highlight the importance of clinicians reporting even small numbers of clinical events that may be involved in serious and potentially fatal ADEs.

For instance, clinician involvement was key in identifying problems with natalizumab- and rituximab-associated progressive multifocal leukoencephalopathy, epoetin-associated pure red blood cell aplasia, ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura, zolendronate-associated osteonecrosis of the jaw, and gadolinium-associated nephrogenic systemic fibrosis. These toxicities were elucidated based on comprehensive reporting of just 3 to a few hundred individual events to the FDA. These cases provide important lessons for clinicians and policy makers who are interested in improving the safety of pharmaceutical agents and devices.

In general, an important barrier to identifying and reporting ADEs is that the toxicity profiles of many agents are not well characterized at the time of FDA approval. In addition, increasing numbers of novel targeted agents are receiving approval for the treatment of serious diseases, especially cancer. The unique molecular pathways of these agents often increase efficacy while minimizing the side effects of older, more conventional therapies. However, several serious ADEs have been associated with these newer agents that were not associated with conventional therapies, and they have not yet been fully characterized.

Accelerated approval regulations were established in 1992 to enable patients with life-threatening diseases to have rapid access to therapeutics. The accelerated process allows for drug marketing based on surrogate outcomes that show meaningful therapeutic benefit. Drug sponsors are still required to conduct confirmatory phase III studies to verify clinical benefit. However, this requirement has not been met for many drugs that received accelerated approval, suggesting that the safety profiles of these agents may not be adequately described.

A recent study in The New England Journal of Medicine found that drug review deadlines imposed by the Prescription Drug User Fee Act lead to rushed approvals and unanticipated safety problems following FDA approval. The study found that drugs approved in the 2 months before that deadline were more likely to be later withdrawn from the market for safety reasons, and more likely to receive a black box warning compared with drugs approved at other times.

In light of these findings, clinicians must be cognizant that some new drugs may not have undergone extensive safety reviews. If a novel agent receives accelerated FDA approval, the safety database may be as small as a few hundred carefully screened individuals. If an unexpected clinical event occurs with a novel agent, you can be fairly certain that neither the manufacturer nor the FDA has seen such an event before. This is especially true for novel agents that are used in off-label clinical settings or by individuals with complex medical histories.

For example, gemtuzumab ozogamicin, the first FDA-approved immunoconjugate, received its initial approval based on monotherapy findings from 3 phase II trials of older patients with acute myeloid leukemia. Immediately thereafter, clinicians at MD Anderson Cancer Center in Houston, Texas, evaluated the drug as an off-label treatment with combination chemotherapeutic regimens for younger persons with AML. Between 10% and 40% of these individuals unexpectedly developed ascites and hepatic dysfunction. In addition, a new syndrome termed sinusoidal obstructive syndrome was identified by a single astute leukemia clinician.

Unfortunately, many clinicians are unaware of how to file ADE reports, or they feel that such efforts would be too costly or time-consuming, seeing little benefit in their voluntary actions. Fortunately, regulatory guidance offers some assistance. An astute clinician who identifies a potential serious ADE but does not have the time or resources to report comprehensive details of the case still has some options.

In the inpatient setting, hospital pharmacy personnel are usually willing to assist the clinician in filing a report with the FDA's ADE reporting system, MedWatch. These individuals generally are not paid specifically for this service, but hospital quality improvement regulations allow for them to review medical records and report the clinical details, laboratory findings, and outcomes of an ADE.

In the outpatient setting, such assistance may not be identified quite as easily. However, the clinician can summarize the relevant findings in a memo (without disclosing personal identification) and forward this information to the sales representative from the relevant pharmaceutical company. By law, this individual must forward the clinical information to MedWatch. In fact, the clinician should ask the sales representative to provide a copy of the MedWatch report after it is submitted.

Clinicians who identify an unexpected, serious ADE should also consider sharing de-identified information on the case with academic investigators who have expressed an interest in the subject area or in pharmacovigilance. These individuals are highly motivated to develop concise case summaries and to submit this information for review at scientific conferences and in peer-reviewed medical journals.

For example, the Research on Adverse Drug Events and Reports (RADAR) project of Northwestern University is very interested in reporting small case series of rare but serious ADEs. The RADAR team has identified and evaluated 38 reports of serious drug reactions over the last decade, with most of these toxicities identified in the oncology setting. The RADAR methodology has relied on initial recognition of sentinel cases that then prompt hypothesis-driven inquiries as to whether an unrecognized ADE signal is present in the population exposed to that drug. A clinician may contact collaborators with the RADAR project who, in turn, develop reports describing the case series. In our paper on clopidogrel-associated thrombocytopenic purpura, 4 clinicians who submitted case reports of individuals with this unexpected toxicity were co-authors on The New England Journal of Medicine report. Their help in this investigation was indispensable.

Lawyers can also join the safety team. An observant attorney submitted to the RADAR group clinical information on a healthy volunteer in a phase I clinical trial of megakaryocyte growth and development factor who subsequently developed severe thrombocytopenia as well as a lymphoproliferative disorder. This report was followed by other clinicians submitting information on 12 healthy volunteers who also developed severe thrombocytopenia and 2 other volunteers who developed lymphoproliferative disorders.

Patients are aware of the time and financial crunch that clinicians face. When a patient experiences a potential ADE, the immediate goal is getting through the complication and moving on. Subsequently, anger arises as they wonder why the FDA or the manufacturer did not warn them in advance about such a possibility.

If a clinician reports the event to the FDA (or to the pharmacist or sales representative), then a MedWatch report is generated. Patients generally are appreciative if they receive a copy of the MedWatch report and understand that the clinician took the extra step to report the clinical details to the proper authorities. If the FDA or drug manufacturer subsequently issues a report about this drug, the patient is likely to appreciate the previous notice even more.

With the increasing focus on pharmacovigilance, academic organizations have evolved with focused interests in specific toxicities. The Arizona Center for Education and Research on Therapeutics (CERT) has developed a novel Web site for reporting unexpected drug-associated Q-T prolongation events. The RADAR project focuses primarily on adverse drug reactions involving the disciplines of hematology and oncology.

The National Registry of Drug Induced Ocular Side-Effects focuses on drugs that unexpectedly result in blindness or severe vision changes. Several other toxicity-specific centers have developed around the country at academic centers (Table). These centers focus on liver failure, muscular-skeletal disorders, cardiovascular disorders, and many other toxicities. Contacting any 1 of these sites would help the pharmacovigilance investigators assist the busy clinician by summarizing relevant case information.

Table. Academic Organizations With Focused Interests in Specific Drug Toxicities

Organization	Location	Area of focus	Website/ Contact information
Research on Adverse Drug events And Reports (RADAR)	Chicago, Ill	Hematology/Oncology	https://www.secure.cancer. northwestern.edu/redesign/ radar/index.cfm
Surveillance Epidemiology and Risk Factors for Thrombotic Thrombocytopenic Purpura (SERF-TTP)	Chicago, Ill	Thrombotic thrombocytopenic purpura	Charles Bennett, MD, PhD, Principal Investigation, cbenne@northwestern.edu
Clinical Center for Liver Disease at University of Texas Southwestern	Dallas, Tex	Acute liver failure	http://www8.utsouthwestern. edu/utsw/home/research/ liver/index.html
University of Alabama Center for Education & Research on Therapeutics (CERT)	Birmingham, Ala	Therapies for musculoskeletal disorders	http://www.certs.cme.uab. edu/default.html
University of North Carolina CERT	Chapel Hill, NC	Therapeutics in the pediatric population	http://www.certs.unc.edu/
Duke University CERT	Durham, NC	Therapies in cardiovascular medicine	Robert Califf, MD, Principal Investigator, Phone 919-668-8820
National Registry of Drug-Induced Ocular Side Effects	Portland, Ore	Blindness and severe vision changes	http://piodr.sterling.net/
Arizona CERT	Tucson, Ariz	QT Cardiac Arrhythmia	http://www.qtdrugs.org/
Vanderbilt CERT	Nashville, Tenn	Prescription drug use in the Medicaid and veteran populations	http://www.vucert.org/ mission.html
Cleveland Clinic	Cleveland, OH	Cox-2 inhibitors	Steven Nissen, MD Phone 216-445-6852
University of Pennsylvania CERT	Philadelphia, Penn	Therapies for infection, antibiotic drug resistance	http://www.cceb.upenn.edu/ pages/cert/

Source for CERT information: Centers for Education and Research on Therapeutics. Fact sheet. Agency for Healthcare Research and Quality. AHRQ Pub. No. 00-P048, Revised September 2000. Available athttp://www.cceb.upenn.edu/pages/cert/Materials/00-P048_CERTs_.pdf Accessed May 29, 2008

In addition, a number of Web sites offer social networking opportunities for clinicians, facilitating a discussion of suspected ADEs. Clinicians use sites such as Medscape and Sermo to share patient case details, observations, and comments. In fact, Sermo was originally conceptualized as an ADE reporting system. Other Web sites, such as PatientsLikeMe.com, also can facilitate adverse event reporting. This site collects patient information and provides forums where members share advice and provide feedback on particular drugs or treatment issues.

In conclusion, most clinicians experience serious ADEs first-hand, yet fewer than 0.01% of them ever report this information to the FDA, the manufacturer, or a pharmacovigilance program. Reporting these incidents is crucial to improving drug safety. The objective is for fairly complete case descriptions to be added to the MedWatch database. Novel strategies exist by which a busy clinician can facilitate the timely and accurate reporting of ADEs to the appropriate authorities.

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:

Pharmacovigilance is like a sunshade to describe the processes for monitoring and evaluating ADRs and it is a key component of effective drug regulation systems, clinical practice and public health programmes. The number of Adverse Drug Reactions (ADRs) reported resulted in an increase in the volume of data handled, and to understand the pharmacovigilance, a high level of expertise is required to rapidly detect drug risks as well as to defend the product against an inappropriate removal. The current global network of pharmacovigilance centers, coordinated by the Uppsala Monitoring Centre, would be strengthened by an independent system of review. This would consider litigious and important drug safety issues that have the potential to affect public health adversely beyond national boundaries. Recently, pharmacovigilance has been confined, mainly to detect adverse drug events that were previously either unknown or poorly understood. Pharmacovigilance is an important and integral part of clinical research and these days it is growing in many countries. Today many pharmacovigilance centers are working for drug safety monitoring in this global pitch, however, at the turn of the millennium pharmacovigilance faces major challenges in aspect of better safety and monitoring of drugs. In this review we will discuss about drug safety, worldwide pharmacovigilance centers and their role, benefits and challenges of pharmacovigilance and its future consideration in healthcare sectors.

Identify the actual nature of ADRs received from the reporter, using Medical Dictionary for Regulatory Activities - MedDRA before proceeding the case investigation.
Ensure that the medicine ordered is the medicine received and actually taken by the patient at the dose advised;
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;
Determine the time interval between the beginning of drug treatment and the onset of the event;
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).
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.
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;
Data base provided by Upsala monitoring center called "VigiAccess" can also be used for searching the previously reported ADRs of the same category.
Report any suspected ADR to the person nominated for ADR reporting in the hospital or directly to the National ADR Center. ^[114]

Causality Assessment could be performed using the following WHO definitions:^[115]

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.

Naranjo ADR probability scale—items and score

Question	Yes	No
Are there previous conclusion reports on this reaction?	+1	0
Did the adverse event appear after the suspect drug was administered?	+2	–1
Did the AR improve when the drug was discontinued or a specific antagonist was administered?	+1	0
Did the AR reappear when drug was re-administered?	+2	–1
Are there alternate causes [other than the drug] that could solely have caused the reaction?	–1	+2
Did the reaction reappear when a placebo was given?	–1	+1
Was the drug detected in the blood [or other fluids] in a concentration known to be toxic?	+1	0
Was the reaction more severe when the dose was increased or less severe when the dose was decreased?	+1	0
Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	+1	0
Was the adverse event confirmed by objective evidence?	+1	0

Scoring for Naranjo algorithm: >9 = definite ADR; 5–8 = probable ADR; 1–4 = possible ADR; 0 = doubtful ADR.

Examples of reportable drug reactions

The following are examples of reportable drug adverse reactions. ^[116]

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. ^[117]
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. ^[118]
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. ^[119]
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. ^[120]
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).^[121]
January 26, 1965 - Induced by thalidomide disaster, Europe adopted the EEC Directive 65/65/EEC, which was the first European pharmaceutical directive. ^[122]
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. ^[123]
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. ^[124]^[125]
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. ^[126]^[127]
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.^[128]^[129]
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. ^[130]

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. ^[131]

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." ^[132]

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. ^[133]

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. ^[134]

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.^[135] ^[136] ^[137]

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). ^[138]

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

A periodic safety update report must include:

a list of the adverse reactions known to the company
an estimate of the number of humans or animals exposed to the medicinal product
an overall safety evaluation of the medicinal product
proposals for new safety measures, if relevant
an overall evaluation of the benefits of the medicinal product
a scientific evaluation of the benefit-risk ratio of the medicinal product based on information from primarily clinical trials, scientific literature and adverse reaction reports.

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. 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. The legal requirements for submission of PSURs are established in Regulation (EU) No 1235/2010, Directive 2010/84/EU and in Commission Implementing Regulation (EU) No 520/2012. The format of PSURs follows the structure described in the Implementing Regulation Article 35 and Module VII of the Guidelines on Good Pharmacovigilance Practices (GVP) provides guidance on the preparation, submission and assessment of PSURs. This format is a legal requirement for both Nationally Authorised Products (NAPs) and Centrally Authorised Products (CAPs).

Who should submit PSURs? The 2010 legislation introduces the principle of EU single assessment where a substance is authorised in more than one Member State. The European Medicines Agency maintains a list of EU reference dates and frequency of submission of PSURs (EURD list) for active substances contained in medicines in the EU and is updated on an ongoing basis.

Marketing Authorisation Holders (MAHs) are required to submit PSURs according to the data lock points published in the EURD list. The legislation introduces derogation for routine PSUR reporting for certain products. Unless there is a specific condition in the authorisation, or it is indicated otherwise in the EURD list, routine PSUR reporting is not required for medicinal products authorised under the following articles of Directive 2001/83/EC:

• Article 10.1 generics • Article 10.a well-established use • Article 14 homeopathic medicines • Article 16a traditional herbal medicines

Further information on GVP and the EURD list may be found on the European Medicines Agency website. Please note that the EURD list is a living document which will be amended whenever considered necessary by the PRAC, the CHMP or CMDh in response to the emergence of relevant new safety information, newly authorised substances and requests received from MAHs. Substances can be added or removed as appropriate. MAHs should therefore maintain an awareness of the current status of the list which is reviewed on a monthly basis.

Guidance on PSUR Submission Mandatory submission of PSURs via the EU PSUR Repository As of 13th June 2016, it is mandatory for all MAHs to submit PSURs for human medicines authorised in the EU directly to the PSUR repository. The repository will act as the single point for all submissions (including responses and supplementary information). This is mandatory for both centrally authorised and nationally authorised medicinal products whether they follow the EU single assessment or a purely national assessment procedure. As a consequence, no further PSUR submissions should be made to the HPRA from this date onwards and the CMDh document “Requirements on Submissions for Periodic safety update reports (PSUR) to National Competent Authorities (NCAs) for products authorised via National Procedures, MRP and DCP (NAPs)” is no longer applicable. PSURs not sent to the PSUR repository are considered as not submitted and will not fulfil the MAH’s legal obligation to submit PSURs.

All PSURs should be submitted to the PSUR repository using the eSubmission Gateway/Web Client: http://esubmission.ema.europa.eu/esubmission.html

Information on the repository, guidance on how to register and multimedia tutorials for MAHs on how to submit a PSUR, as well as on the correct structured electronic formats, can be found on EMA’s PSUR repository web pages here: http://esubmission.ema.europa.eu/psur/psur_repository.html

Further information for MAHs on changes to submission of PSURs for human medicines is available here: PSUR repository mandatory use: Q&A

Users of the repository should direct any questions on use of the EMA PSUR repository and/or the eSubmission Gateway/Web Client to the EMA Service Desk portal: https://servicedesk.ema.europa.eu.

For further information on submission dates, PSUSA procedure number and requirements for submission of products referred to in articles 10(1), 10a, 14, 16a of Directive 2001/83/EC as amended please refer to the EURD list.

Detailed guidance on procedural aspects of the EU single assessment is available on the EMA website: PSURs: questions and answers

Safety reports of suspected adverse reactions

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^[139]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”. ^[140]

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). ^[141]

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. ^[142]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. ^[143]

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 ^[144]

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. ^[145]^[146]

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. ^[147]^[148]

III. Contractual Agreements The marketing of many medicines increasingly takes place through contractual agreements between two or more companies, which may market same product in the same or different countries/region. Arrangements vary considerably with respect to inter-company communication and regulatory responsibilities. Overall, this can be a complex issue.

In such relationships, it is very important that explicit licensing/contractual agreements specify the processes for exchange of safety information, including timelines and regulatory reporting responsibilities. Safety personnel should be involved in development of any agreements from the beginning. Processes should be in place to avoid duplicate reporting to the regulatory authority, e.g. assigning responsibility to one company for literature screening.

Whatever the nature of the arrangement, the MAH is ultimately responsible for regulatory reporting. Therefore, every reasonable effort should be made between the contracting partners to minimize the data exchange period so as to promote compliance with MAH responsibilities.

IV. Regulatory Authority Sources Individual serious unexpected adverse drug reaction reports originating from foreign regulatory authorities are subject to expedited reporting to other authorities by each MAH. Re-submission of serious ADR cases without new information to the originating regulatory authority is not usually necessary, unless otherwise specified by local regulation.

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. ^[149] 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 ^[150]

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.^[151]

In the Philippines, the Philippine Food Drug Administration have created an advisory to report suspected adverse drug reaction using a prescribed ADR form. ^[152]

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. ^[153]

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 the 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 per cent of ADEs can be prevented.

For example, at least, two studies attribute 42-60 per cent 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 per cent) 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.

Events and Effects When we compare the good clinical practice requirements for medical devices and pharmaceuticals, adverse event reporting is among the top three causes of confusion.

In the device world not all adverse events are reportable, instead the investigator makes the decision as to whether a given adverse event is device related or not. If so it is called an adverse device effect (think of cause and effect) and only adverse device effects are recordable and reportable.

As with drugs, an adverse event is any unwanted medical occurrence in a subject. And an adverse device effect is any device related adverse event. ISO/DIS 14155--Clinical investigations of medical devices in humans, good clinical practices, 2008, defines a serious adverse device effect as one that, just like any serious adverse event, results in hospitalization, permanent impairment, death, or other sequelae.

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. ^[154]

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 defence 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. ^[155]

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.^[156] 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. ^[157]

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. FDA is posting this information in accordance with section 505(r) of the FDCA. This section of the statute directs FDA to improve the transparency of information about drugs and to provide patients and health care providers better access to information about drugs by developing a website with specified types of drug safety information. The table in each quarterly report lists the names of drug and biological products, application number, approval date, approved indication, summary of evaluation findings, actions taken, and ongoing surveillance activities. Beginning with the period from July 2012 to December 2012, drugs with an active moiety that has not been previously approved or legally marketed in the United States in any form (also known as New Molecular Entities) appear in the table and are marked as “NME.” The table also includes all biological products, including biosimilar products. Postmarket safety evaluation findings include potential new safety concerns that are first identified during the evaluation and should not be viewed as a summary of all safety issues addressed since the product's approval.

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

Postmarket Drug and Biologic Safety Evaluations

What is FDA posting?

This website provides summary information about ongoing and completed 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.

Why is FDA posting this summary information?

FDA is posting this information in accordance with section 505(r) of the FDCA. This section of the statute directs FDA to improve the transparency of information about drugs and to provide patients and health care providers better access to information about drugs by developing a website with specified types of drug safety information.

In response to the statutory requirement, FDA developed the Postmarket Drug Safety Information for Patients and Providers website, which has links to a wide variety of drug safety information, including this web page.

What information is provided on this website?

The table in each quarterly report lists the names of drug and biological products, application number, approval date, approved indication, summary of evaluation findings, actions taken, and ongoing surveillance activities. Beginning with the period from July 2012 to December 2012, drugs with an active moiety that has not been previously approved or legally marketed in the United States in any form (also known as New Molecular Entities) appear in the table and are marked as “NME.” The table also includes all biological products, including biosimilar products. Postmarket safety evaluation findings include potential new safety concerns that are first identified during the evaluation and should not be viewed as a summary of all safety issues addressed since the product's approval.

A new report will be made available each quarter beginning with the period from January 2013 to March 2013.

What information does FDA consider for these postmarket safety evaluations?

FDA assesses several data sources including:

The product's pre-approval safety profile
The product's current FDA-approved label
Reports made to the FDA Adverse Event Reporting System (FAERS), previously known as AERS
Reports made to the Vaccine Adverse Event Reporting System (VAERS)
Manufacturer-submitted periodic safety reports
Medical literature
Drug utilization databases
Data from post-approval clinical trials and other studies, when applicable

Please see the Drug and Biologics Safety Surveillance Best Practice Statement (PDF 79KB) for more information.

How is the information analyzed?

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 this website.

For additional information about postmarket drug and biologic safety issues, including FDA Safety Communications and web postings of Potential Signals of Serious Risks Identified from the FDA Adverse Event Reporting System (FAERS), please refer to FDA's website on Postmarket Drug Safety Information for Patients and Providers or Safety and Availability (Biologics).

Postmarket Drug and Biologic Safety Evaluation Summaries

(previous Postmarket Drug and Biologic Safety Evaluations)

Drug Safety Evaluations Completed From April 1, 2017 to June 30, 2017

Product Name: Trade (active ingredient) with Dosage form NDA/BLA Number ("NME" indicates New Molecular Entity) Approval Date	Major Indications	Summary of Findings from Evaluation	Actions taken and Ongoing Surveillance Activities
Aptensio XR (methylphenidate hydrochloride) extended-release capsules, for oral use NDA 205831 April 17, 2015	For treating attention deficit hyperactivity disorder	The potential safety issue of dystonia was identified from postmarketing adverse event reports.	FDA continues to evaluate adverse event reports of dystonia to determine if regulatory action is required.
Aptiom (eslicarbazepine acetate) tablets, for oral use NDA 022416 (NME) November 8, 2013	For treating partial-onset seizures as monotherapy or adjunctive therapy	Three potential safety issues were identified from postmarketing adverse event reports: Hematologic events Syndrome of inappropriate ntidiuretic hormone secretion (SIADH) Atrioventricular block	On September 13, 2017, an efficacy supplement for Aptiom was approved and included the addition of SIADH to the existing “Warnings and Precautions” subsection describing the risk for hyponatremia, and the addition of a new “Warnings and Precautions” subsection describing the risk for hematologic adverse reactions. It was determined that no regulatory actions related to atrioventricular block are required at this time.
Bexsero (Meningococcal Group B Vaccine) BLA 125546 January, 23, 2015	For active immunization to prevent invasive disease caused by Neisseria meningitidis serogroup B in individuals 10 through 25 years of age	No new safety issues were identified.	No regulatory actions required at this time.
Corlanor (ivabradine) tablets, for oral use NDA 206143 (NME) April 15, 2015	For reducing the risk of hospitalization for worsening heart failure in patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction less than or equal to 35 percent, who are in sinus rhythm with resting heart rate greater than or equal to 70 beats per minute and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use	No new safety issues were identified.	No regulatory actions required at this time.
Epiduo Forte (adapalene and benzoyl peroxide) gel, 0.3%/2.5% is for topical use NDA 207917 July 15, 2015	For the topical treatment of acne vulgaris	No new safety issues were identified.	No regulatory actions required at this time.
Gardasil 9 (Human Papillomavirus 9-valent Vaccine, Recombinant) BLA 125508 December 10, 2014	Prevention of cervical, vulvar, vaginal, and anal cancer caused by HPV types 16 and 18, 31, 33, 45, 52, and 58 and genital warts (condyloma acuminata) caused by HPV types 6 and 11	No new safety issues were identified.	No regulatory action required at this time.
Injectafer (ferric carboxymaltose) injection, for intravenous use NDA 203565 July 25, 2013	An iron replacement product for treating iron deficiency anemia in adult patients: who have intolerance to oral iron or have had unsatisfactory response to oral iron; who have non-dialysis dependent chronic kidney disease	No new safety issues were identified.	No regulatory actions required at this time.
Jevtana (cabazitaxel) injection, for intravenous use NDA 201023 (NME) June 17, 2010	For treating hormone-refractory metastatic prostate cancer	The potential safety issue of tumor lysis syndrome was identified from postmarketing adverse event reports.	FDA continues to evaluate adverse event reports of tumor lysis syndrome to determine if regulatory action is required.
Noxafil (posaconazole) delayed-release tablets, for oral use NDA 205053 November 25, 2013	For use as a prophylaxis of invasive Aspergillus and Candida infections in patients (13 years of age and older) who are at high risk of developing these infections	No new safety issues were identified.	No regulatory actions required at this time.
Opdivo (nivolumab), solution for injection BLA 125527, 125554 (NME) December 22, 2014	For treating: BRAF V600 wild-type unresectable or metastatic melanoma, as a single agent BRAF V600 mutation-positive unresectable or metastatic melanoma, as a single agent Unresectable or metastatic melanoma, in combination with ipilimumab Metastatic non-small cell lung cancer and progression on or after platinum based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Opdivo Advanced renal cell carcinoma in patients who have received prior anti-angiogenic therapy Classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and posttransplantation brentuximab vedotin Recurrent or metastatic squamous cell carcinoma of the head and neck with disease progression on or after a platinum-based therapy Locally advanced or metastatic urothelial carcinoma who: have disease progression during or following platinum-containing chemotherapy; have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.	Three potential safety issues were identified from postmarketing adverse event reports: Retinal detachment Severe vision loss Tumor lysis syndrome	FDA continues to evaluate adverse event reports of retinal detachment, severe vision loss, and tumor lysis syndrome to determine if regulatory action is required.
Otrexup (methotrexate) injection, for subcutaneous use only NDA 204824 October 11, 2013	For managing severe, active rheumatoid arthritis in selected adults or children with active polyarticular juvenile idiopathic arthritis, who have had insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents For controlling symptoms of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after dermatologic consultation	Potential device-related safety issues were identified from postmarketing adverse event reports.	No regulatory action required at this time.
ProAir RespiClick (albuterol sulfate) inhalation powder, for oral inhalation use NDA 205636 March 31, 2015	For treating or preventing bronchospasm in patients 4 years of age and older with reversible obstructive airway disease For preventing exercise-induced bronchospasm in patients 4 years of age and older	No new safety issues were identified.	No regulatory actions required at this time.
Tuzistra XR (codeine polistirex and chlorpheniramine polistirex) extended-release oral suspension, CIII NDA 207768 April 30, 2015	For relief of cough symptoms associated with upper respiratory allergies or a common cold	No new safety issues were identified.	No regulatory actions required at this time.
Velphoro (sucroferric oxyhydroxide) chewable tablets, for oral use NDA 205109 November 27, 2013	For the control of serum phosphorus levels in patients with chronic kidney disease on dialysis	Two potential safety issues were identified from postmarketing adverse event reports: Tooth discoloration Rash	On August 3, 2017, a labeling supplement was approved that included the addition of information in the “Adverse Reactions; Postmarketing Experience” section of labeling pertaining to reports of tooth discoloration and rash.
Zarxio (filgrastim-sndz) injection, for subcutaneous or intravenous use BLA 125553 March 6, 2015	For decreasing the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever For reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML) For reducing the duration of neutropenia and neutropenia-related clinical sequelae, e.g., febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation For mobilizing autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis For reducing the incidence and duration of sequelae of severe neutropenia (e.g. fever, infections, orophyaryngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia	No new safety issues were identified.	No regulatory actions required at this time.
Zortress (everolimus) tablets, for oral use NDA 021560 April 20, 2010	For the prophylaxis of organ rejection in adult patients	No new safety issues were identified.	No regulatory actions required at this time.

Drug Safety Evaluations Completed July 1, 2017 to September 30, 2017

Product Name: Trade (active ingredient) with Dosage form NDA/BLA Number ("NME" indicates New Molecular Entity) Approval Date	Major Indications	Summary of Findings from Evaluation	Actions taken and Ongoing Surveillance Activities
Finacea (azelaic acid) foam, 15% for topical use NDA 207071 July 29, 2015	For the topical treatment of the inflammatory papules and pustules of mild to moderate rosacea	No new safety issues were identified.	No regulatory actions required at this time.
Humalog (insulin lispro) injection, for subcutaneous or intravenous use NDA 205747 May 26, 2015	A concentrated (200 units/ml) rapid acting human insulin analog for improving glycemic control in adults and children with diabetes mellitus	No new safety issues were identified.	No regulatory actions required at this time.
Ibrance (palbociclib) capsules, for oral use NDA 207103 (NME) February 3, 2015	For treating hormone receptor (HR)-positive, human epidermal growth receptor 2 (HER-2)-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine based therapy in postmenopausal women; or fulvestrant in women with disease progression following endocrine therapy	No new safety issues were identified.	No regulatory actions required at this time.
Prezcobix (darunavir and cobicistat) tablets, for oral use NDA 205395 January 29, 2015	For use in combination with other antiretroviral agents for treating HIV-1 infection in treatment-naïve and treatment-experienced adults with no darunavir resistance-associated substitutions	No new safety issues were identified.	No regulatory actions required at this time.
Stiolto Respimat (tiotropium bromide and olodaterol) inhalation spray, for oral inhalation use NDA 206756 May 21, 2015	For long-term, once-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease	No new safety issues were identified.	No regulatory actions required at this time.
Triumeq (abacavir, dolutegravir, and lamivudine) tablets, for oral use NDA 205551 August 22, 2014	For treating human immunodeficiency virus (HIV-1) infection	The potential safety issue of anxiety was identified from postmarketing adverse event reports.	FDA continues to evaluate adverse event reports of anxiety to determine if regulatory action is required.
Viberzi (eluxadoline) tablets, for oral use NDA 206940 (NME) May 27, 2015	For treating irritable bowel syndrome with diarrhea in adults	The potential safety issue of hypersensitivity reactions, including anaphylaxis, was identified from postmarketing adverse event reports.	FDA continues to evaluate adverse event reports of hypersensitivity reactions, including anaphylaxis, to determine if regulatory action is required.

2007-2014 reports are in the FDA Archive

Previous Postmarket Drug and Biologic Safety Evaluation Summaries

January 2017 â March 2017
October 2016 â December 2016
July 2016 â September 2016
April 2016 â June 2016
January 2016 â March 2016
October 2015 â December 2015
July 2015 â September 2015
Previous Postmarket Drug and Biologic Safety Evaluation Summaries: April 2015 â June 2015
January 2015 - March 2015
October 2014 - December 2014
July 2014 â September 2014
April 2014 â June 2014
January 2014 â March 2014
October 2013 â December 2013
July 2013 â September 2013
April 2013 â June 2013
January 2013 - March 2013
July 2012 â December 2012
January 2012 â June 2012
July 2011 â December 2011
January 2011 â June 2011
October 2010 â December 2010 (updated 11/2012)
January 2010 â September 2010 (updated 5/2011)
September 2007 â December 2009

Related Information

Information on the 21st Century Cures Act
Questions and Answers on FDAâs Postmarketing Safety Summaries of Recently Approved Drugs and Biologics
FDA to Communicate Safety Monitoring Activities to Consumers and Health Care Professionals
FDA Fact Sheet: FDAAA 2007 Section 915 - Enhancing FDAâs Safety Reporting on Recently Approved Therapies
Postmarketing Safety Evaluation of New Molecular Entities: Final Report
Test Table (Clean Code)

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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/ …
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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

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. ^[158]
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. ^[159]
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. ^[160]
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). ^[161]
(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). ^[162]
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. ^[163]
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. ^[164]
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. ^[165]
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. ^[166]
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.^[167]

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

^[168]

Epidemiology

Epidemiology is the study of the distribution and determinants of health-related states or events (including disease), and the application of this study to the control of diseases and other health problems. Various methods can be used to carry out epidemiological investigations: surveillance and descriptive studies can be used to study distribution; analytical studies are used to study determinants.

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. ^[169]

REFERENCES

↑ https://medical-dictionary.thefreedictionary.com/unexpected+adverse+drug+reaction<ref>

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 of 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." <ref>http://apps.who.int/medicinedocs/en/d/Js4893e/9.html

112. https://www.who-umc.org/global-pharmacovigilance/specialist-centres/

117. http://www.fda.gov.ph/advisories-2/pharmaceutical-2/306166-fda-advisory-no-2016-026

    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]

↑ 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]

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

[1] ttp://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2017/08/WC500232767.pdf

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[3] ttps://www.who-umc.org/global-pharmacovigilance/global-pharmacovigilance/glossary/

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[5] ttps://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__Step_4_2016_1109.pdf

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[12] ttps://hub.ucsf.edu/sites/hub.ucsf.edu/files/6.%20Adverse%20Eventsd%20Definitions.pdf

[13] ttp://www.ema.europa.eu/docs/en_GB/document_library/Other/2016/08/WC500212100.pdf

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[20] :///C:/Users/TMohanadas/Downloads/electronics-02-00001.pdf

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[26] ttps://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2A/Step4/E2A_Guideline.pdf

[27] ttps://medical-dictionary.thefreedictionary.com/unexpected+adverse+drug+reaction<ref>
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 of 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." <ref>http://apps.who.int/medicinedocs/en/d/Js4893e/9.html

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