Adverse Drug Reactions

Introduction

Adverse drug reactions [ADRs] are inevitable consequence of pharmacotherapy. It is well known that all modern drugs carry the potential to produce undesirable effects, in addition to the desired ones. This is often paraphrased by saying that all drugs are poisons, the dose alone distinguishes the medicine from the poison. However, for rational drug use it is not sufficient to know only the correct dosing. No drug is absolutely safe under all circumstances of use or in all patients. ADRs can arise from many sources, even if a drug is correctly selected and dosed. If we believe that the first principle in treating patients is 'primum non nocere' i.e. above all, do no harm, it follows that we should be aware to the possibility of ADRs and the ways and means to prevent or curtail them.

Formally, an adverse drug reaction is defined as an unintended and unwanted noxious effect of a drug occurring under normal conditions of use at usual doses. This excludes effects of:

• Wrong drug
• Medication errors e.g. overdose
• Defective drug i.e. product not conforming to specifications
• Therapeutic failure

The term 'adverse event' refers to an untoward occurrence during exposure to a drug. It becomes and adverse reaction only when the causality is proven or is reasonably certain. Terminologies like 'side-effect', 'adverse (drug) experience' and 'adverse (drug) effect' are now discouraged.

Magnitude of the problem

The true incidence and prevalence of ADRs is not known, largely because formalized ADR reporting systems are in place in only a few countries. Even if a very well organized ADR reporting system does exist, it is likely that reported estimates are likely to be less than true extent because mild ADRs tend to go unreported, many drug effects are highly subjective and a large fraction of the total ADR burden in the community may not be recognized as iatrogenic events but rather attributed to the underlying or a new illness.

With these limitations in mind, it has been estimated that:

• Up to 30% of hospitalized patients suffer one or more ADRs, 3% will have an ADR of considerable severity and 0.3% may die in consequence.
• Up to 5% of hospital out-patients may require hospitalization to prevent or manage ADRs.

The development phase of a drug pays substantial attention to recognition and quantification of adverse events that may be causally attributed to the drug. Nevertheless, prior to marketing, only a fraction of all possible ADRs are detected

• During drug development, for practical reasons samples on whom trials are done, at the most, number in a few thousands. Thus uncommon ADRs are not detected.
• For technical reasons (relatively homogenous patient population studied) some ADRs go undetected.
• Some ADRs occur only after long-term exposure or only on a background of concomitant illnesses.

It must be emphasized that drug safety concerns are not confined to new chemical entities. They extend to new indications of existing products, new formulations, novel drug delivery systems and new combinations. ADR monitoring for a pharmaceutical product, thus, essentially lasts throughout its lifetime as a marketed medicine.

Classification of ADRs

ADRs may be classified in various ways. However, to understand the mechanistics of adverse reactions they have been broadly categorized into two types, A and B, as depicted in table 1.

The distinction between Type A and Type B reactions is important for multiple reasons:

• Type A reactions may be predicted from careful scrutiny of the drug's pharmacological profile. Hence they may be preventable by individualization of drug therapy,
• Type A reactions are generally more common and more readily recognized as causally related to a drug during clinical trials and post-marketing surveillance.
• Serious / persistent / recurrent Type A reactions during drug development are likely to lead to abandonment at an earlier stage.

Table 1. Salient features of the two types of adverse drug reactions

Type A [Augmented] reactions	Type B [Bizarre] reactions
Quantitative exaggeration of pharmacological / toxicological activity. Usually: More common Predictable Dose-dependent e.g. Bleeding with heparin Hypoglycemia with glibenclamide Myelosuppression with cyclophosphamide Also encompasses effects not related to drug's primary (intended) pharmacologic activity, e.g. Anticholinergic effect of TCAs Dependence liability of opioids Withdrawal reactions	Qualitatively abnormal responses with no clear-cut relation to drug's activity profile. Usually: Less common Unpredictable Dose-independent e.g. Hepatotoxicity with halothane SMON with clioquinol Aplastic anemia with chloramphenicol May have genetic / immunological basis. e.g. Anaphylaxis due to penicillin Hemolysis due to methyldopa Drug-induced lupus

SMON = Subacute myelo-optic neuropathy; TCAs = Tricyclic antidepressants

Organ specific toxicities may be Type A or Type B reactions. Some 'classic' examples are:

Bleomycin	Pulmonary fibrosis
Corticosteroids	Osteoporosis
Cyclophosphamide	Hemorrhagic cystitis
Cyclosporine	Nephrotoxicity
Didanosine	Pancreatitis
Doxorubicin	Cardiomyopathy
Ethacrynic acid	Ototoxicity
Ethambutol	Optic atrophy
Isoniazid	Hepatotoxicity
Radioiodine	Hypothyroidism
Statins	Rhabdomyolysis
Vincristine	Peripheral neuropathy

Occasionally, two other types of ADRs are recognized:

• Type C [Chronic] reactions e.g. Retinopathy with chloroquine, Oculomucocutaneous syndrome with practolol; and
• Type D [Delayed] reactions e.g. Clear cell adenocarcinoma of the vagina in mature women whose mothers have received stilbestrol during pregnancy, Other drug induced cancers

The term 'serious' adverse reactions usually refers to those that are:

• Fatal e.g. Anaphylaxis
• Life-threatening e.g. Bleeding
• Disabling e.g. Optic atrophy
• Incapacitating e.g. Jaundice
• Causing / prolonging hospitalization e.g. Stevens-Johnson syndrome

In addition teratogenic, mutagenic and carcinogenic events are also considered to be serious.

Diagnosis / Causality assessment of suspected ADRs

This is never an easy matter. There is always a difficult to bridge gap between 'clinical hunch' and 'scientific rigor'. It may be noted that both detection and causality assessment of ADRs: 

• Requires observational powers and analytical skills.
• Diagnosis specially difficult if adverse event mimics features of underlying disease.
• Despite best efforts it is frequently not possible to deduce iatrogenicity with certainty.

The following criteria may help to decide:

• Temporal relationship of event with drug exposure.
  But contrast Anaphylaxis and Carcinogenesis
• Nature of reaction.
  But contrast Stevens Johnson syndrome following co-trimoxazole, breast cancer in past OCP user and sudden deaths in asthmatics on b-agonists
• Exclusion of confounding factors specially those relating to underlying illness.
• History of similar reactions to allied drugs or reports of similar events with allied drugs.
• Specific diagnostic tests. Of limited value.
• Specific IgE antibodies in case of penicillin hypersensitivity.
• Detection of genetic polymorphism of drug metabolizing enzymes.
• Increased antinuclear antibody and serum complement levels in drug-induced lupus.
• Dechallenge - To assess resolution of ADR on withdrawal of drug.
  Not applicable to those events that cause irreparable damage e.g. ototoxicity, hepatic fibrosis and secondary malignancy.
• Rechallenge - To assess reappearance of ADR on reinstitution of drug. The gold standard for assessing causality but generally not possible for ethical reasons.

Based upon the 4 principle criteria for causality - Temporal relationship / Confounding factors excluded / Dechallenge / Rechallenge - suspected ADRs have been categorized as - a] Definite / Highly probable; b] Probable; c] Possible; and, d] Unlikely / Remote.

Table 2. Examples of marketed drug withdrawals due to causally related adverse events

Product	Therapeutic category	ADR	Type
Aclofenac	NSAID	Anaphylaxis	B
Alpidem	Anxiolytic	Hepatotoxicity	B
Amineptine	Antidepressant	Dependence liability	A
Benoxaprofen	NSAID	Photosensitivity, Hepatotoxicity	A
Bromfenac	NSAID	Hepatotoxicity	B
Chlormezanone	Anti-spasticity	Stevens-Johnson syndrome	B
Fenclofenac	NSAID	Toxic epidermal necrolysis	B
Fenfluramine	Anorectic	Pulmonary hypertension, valvular heart disease	A
Metamizole	NSAID	Agranulocytosis	B
Methysergide	Anti-migraine	Retroperitoneal fibrosis	C
Metipranolol	Anti-glaucoma	Anterior uveitis	B
Nomifensin	Antidepressant	Hemolytic anemia	B
Phenolphthalein	Laxative	Carcinogenicity	D
Proxibarbal	Sedative	Thrombocytopenia	B
Sertindole	Antipsychotic	Cardiac arrhythmias	B
Suprofen	NSAID	Nephrotoxicity	A
Terolidine	Anti-incontinence	Ventricular tachycardia	A
Tolcapone	Anti-Parkinsonism	Hepatotoxicity, Malignant neuroleptic syndrome	B
Triazolam	Hypnotic	Psychiatric reaction	A
Trovafloxacin	Antimicrobial	Hepatotoxicity	B
Zimeldine	Antidepressant	Guillain-Barre syndrome	B

Principles of ADR prevention / minimization

1. Use drugs only if specifically indicated.
2. Avoid polypharmacy and shotgun therapeutics.
3. Leave use of specialized drugs to specialists.
4. Be extra cautious with special / high-risk clinical settings and individualize drug therapy in such situations e.g.
   • Extremes of age
   • Pregnancy
   • Breast-feeding
   • Hepatic insufficiency
   • Renal insufficiency
   • QT interval prolongation
   • Immunocompromised subject
   • Critical care patient
5. Be well acquainted with the actions and the toxicity profile of the drugs intended to be used and be particularly vigilant with drugs of low therapeutic index e.g.
   • Aminoglycosides
   • Antiarrhythmics
   • Anticonvulsants
   • Cardiac glycosides
   • General anesthetics
   • Neuromuscular blockers
   • Lithium
   • Oral anticoagulants
   • Theophylline
   • Cytotoxics
   • Immunosuppressants
     
6. Take a careful drug history beforehand - exclude drug allergies and document all drugs already in use (including OTC products).
7. Instruct patients carefully on nature of drug and proper mode of use and possible alerting signs-symptoms of toxicity.
8. Unexpected deterioration of patient's condition while on drug therapy should prompt consideration of adverse drug reactions / interactions if no other cause can be found.
9. Once ADR detected consider dose modification or drug withdrawal.
10. Do not rechallenge unless there is diagnostic uncertainty or compelling clinical reason.

Pharmacovigilance strategies

There are many ways in which ADRs may be suspected and detected. These are outlined below while Table 3 lists examples of notable ADRs detected through various approaches.

1. Postmarketing surveillance [Phase IV of clinical drug development]
2. Intensive in-patient monitoring
3. Spontaneous ADR monitoring [Voluntary reporting by health professionals / manufacturers]
•  Well-established schemes are in operation in various countries.
4. Prescription event monitoring
   • Active solicitation of ADR reporting from clinical practitioners by monitoring prescriptions.
5. Case reports / Case series
   • Report of single case with an illness and an exposure.
   • Report of a series of cases with a common illness and/or a common exposure.
6. Analysis of secular trends
   • Comparison of trends in exposure with trends in events looking for coincidence.
   • Comparison over time or across geographical areas.
7. Case control studies
   • Groups selected on basis of presence (cases) and absence (controls) of illness and studied for antecedent exposure.
   • Retrospective case comparison study.
   • Individuals with disease compared to individuals without disease.
   • Generally estimates relative risk in terms of odds ratio - ratio of odds of exposure among cases to odds of exposure among controls
8. Cohort studies
   • Groups selected on basis of presence (study cohort) and absence of exposure (control cohort) and studied for subsequent illness.
   • Prospective case finding study.
   • Exposed subjects compared to unexposed subjects with respect to outcome.
   • Generally estimates relative risk in terms of ratio of disease incidence in exposed group to incidence in control group.
9. Randomized controlled trials [RCTs]
   • The 'gold standard' but difficult because of various technical, logistical and ethical factors.
   • Subjects randomly assigned to drug of interest group or control group (placebo or standard comparator drug) and followed up for a definite length of time. Incidence of adverse events compared statistically.
   • Studies may be open label or blinded to different extents.
   • Investigator has control over extraneous variables.
   • Multiple RCTs may be subjected to systematic reviews and meta-analysis.

Table 3. Examples of ADR detection through various surveillance approaches

Approach	Drug	ADR detected
Post-marketing surveillance	Felbamate	Hepatotoxicity
Intensive in-patient monitoring	Ampicillin	Skin rash
Spontaneous ADR monitoring	Zimeldine	Guillan-Barre syndrome
Prescription event monitoring	ACE inhibitors	Cough
Multipurpose database	Isotretinoin Thiazides	Birth defects Hip fracture disproven
Case reports / Case series	Thalidomide	Birth defects
Case control studies	Various drugs	Agranulocytosis, Cancers
Cohort studies	Oral contraceptives	Thromboembolism
Randomized controlled trials	SSRIs	Weight gain

ACE = Angiotensin converting enzyme; SSRI = Selective serotonin reuptake inhibitor

Ideally, in a complete ADR report, the following information should be included:

Patient information e.g. initials / age / sex / weight / attending physician / hospital

Information on suspect drug

Generic name / Brand name / Dosage form / Batch number

Therapeutic indication

Route and dosing schedule

Start and stop dates

Information on suspected reaction

• Nature and severity
• Start and stop dates
• Outcome
  

Information on concomitant and recently (within last 3 months) used medication including OTCs

• On similar lines to suspect drug

Auxiliary information

• Medical history
• Laboratory test results
• Known allergies
• In case of teratogenicity all drugs taken in pregnancy and the LMP

Spontaneous ADR monitoring

The ADR reporting strategy that is globally most successful in detecting and quantifying adverse reactions to marketed drugs is spontaneous ADR reporting. Such a system should possess the following attributes:

• Sensitivity - capability to detect rare ADRs (< 1 in 10,000) without getting overwhelmed by common reactions.
• Promptness in data acquisition and processing.
• Quantification capability.
• Risk factor identification capability.
• Ability to provide feedback to reporters.

Spontaneous ADR monitoring systems have made very important contributions to the field of pharmacovigilance, so much so that it is now regarded as the sentinel method in drug safety surveillance. These include identification of new hazards, quantification and characterization of known hazards, delineation of comparative toxicity within a therapeutic group as well as identification of drugs as epidemiologic risk factors. However, some drawbacks remain such as: 

• Under-reporting an inherent problem - estimated rates seldom > 10% of true incidence.
• Difficulty in causality assessment.
• Biased reporting - more severe reactions tend to get reported more often, frequency of reporting higher when the drug is new or when it has received media attention for some reason.
• Less successful in monitoring ADRs that mimic natural disease and in identifying delayed reactions.

Spontaneous ADR monitoring system examples

British Committee on Safety of Medicines [UK CSM] - Yellow card system

• Introduced in 1964 and is one of the most successful schemes globally.
• Doctors / Dentists / Pharmacists / HM Coroners report on prescribed yellow forms. Reporting solicited for all reactions to newly introduced products and severe / unusual reactions to existing products.
• In addition to prescription drugs, scheme applies to OTC products, herbal products, blood products, immunologicals, radiographic contrast media, dental and surgical materials, IUDs, contact lens fluids.
• Reporting is kept confidential and feedback on similar events provided to reporter on request.
• Computerization of database (ADROIT - Adverse Drug Reactions On-line Information Tracking) facilitates monitoring.

United States Food and Drugs Administration [US FDA] - ADR registry

• Manufacturers required by law to submit reports of suspected ADRs.
• 90% of reports in this database is from manufacturers contrasting to 12% with UK CSM.
• Serious suspected unlabeled reactions and increase in frequency of serious labeled reactions to be notified within 15 days.
• Other details vary depending on whether ADR originates in USA, seriousness of the reaction and length of time that the drug has been marketed.

WHO International ADR Monitoring system

• The operational responsibility for this program is vested, since 1978, with the WHO Collaborating Centre of International Drug Monitoring based in Uppsala, Sweden - the Uppsala Monitoring Centre [UMC].
• Collects and collates spontaneous ADR reports from 60 participating countries. 
• Since inception has built up a database of over 1 million records.
• Notable feature is the filtering of signals - 'information on a possible causal relationship between an adverse event and a drug, this relationship being unknown or incompletely documented previously'.
• An international volunteer panel of signal reviewers assess the clinical significance of the drug-reaction associations that are reported to the database more frequently than expected.
• UMC also develops and publishes vital pharmacovigilance literature such as the WHO Adverse Reaction Dictionary.
• Currently involved in the development of a computerized methodology - Bayesian Confidence Propagation Neural Network [BCPNN] - for the identification and analysis of new adverse reaction signals for more efficient data mining from the already huge database that continues to grow rapidly.

ADR monitoring in India

The need for ADR monitoring in India is particularly urgent in view of the woeful lack of Indian data, the genetic diversity of the Indian population and the many singular factors that influence drug use behavior in the country, including the lax implementation of prescription-only norms.
Factors making ADR monitoring in India a dire necessity

• Plethora of formulations
• Multiple systems of medicine
• Rampant self-medication and other peculiarities of drug use
• Resources cannot be wasted on managing iatrogenic illnesses
  Problems in ADR monitoring in India
• Lack of awareness - manufacturers / prescribers / dispensers / consumers
• Inadequate diagnostic capability
• Lack of patient records
• Inadequate financial and logistical resources
  

Unfortunately, to date, we do not have a nationwide ADR monitoring set-up, whether spontaneous or otherwise. With government's help some centers are functioning in different parts of the country including All India Institute of Medical Sciences, New Delhi [AIIMS]; Postgraduate Institute of Medical Research Education and Training, Chandigarh [PGIMER]; Christian Medical College, Vellore [CMC]; Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry [JIPMER]; King George's Medical College, Lucknow [KGMC] and King Edward Memorial Hospital, Mumbai [KEM]. These centers mostly cater to the patient base of their respective hospitals. This is insufficient to gather population based data and, moreover, data for the entire country. Further, there is no coordination between the centers.
To address the above lacunae, the Government of India, through the Central Drugs Control machinery has recently planned to set up a network of regional ADR monitoring centers throughout the country along with reactivation of the existing but non-functional centers. The New Delhi center, functioning from the Department of Pharmacology at AIIMS, New Delhi, has recently been designated as the National Pharmacovigilance Centre and is the Indian participating center for the WHO International Drug Monitoring Programme. These efforts are welcome and requires the cooperation of all prescribers, dispensers, as well as consumers of drugs to succeed. Meanwhile all of us can contribute in our own modest way by remaining ever alert to the possibility of ADRs, using drugs carefully and rationally to minimize and restrict them, and if they do occur reporting them to appropriate forum.

References

1. Lawrence D, Carpenter J. A dictionary of pharmacology and allied topics. 2nd ed. Amsterdam: Elsevier, 1998: 8-9.
2. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse reactions in hospitalized patients. J Am Med Assoc 1998; 279: 1200-5.
3. Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet 2000; 356: 1255-9.
4. Dukes MNG, Aronson JK, editors. Meyler's side effects of drugs: an encyclopedia of adverse drug reactions and interactions. 14th ed. Amsterdam: Elsevier, 2000.
5. Status of pharmacovigilance in India in the new millennium [Editorial] Newsletter: National Pharmacovigilance Centre [India] 2000; 2(1):1-2.

-- Avijit Hazra

Adverse drug reaction monitoring: where are we?

As per the World Health Organization (WHO) definition of adverse drug reaction [ADR], this is a response to a drug that is noxious and unintended and occurs at doses normally used in man for prophylaxis, diagnosis or therapy of disease, or for modification of physiological function. Practically speaking, no drug is absolutely safe, even when prescribed in therapeutic doses. ADR monitoring or pharmacovigilance aims to promote patient safety in relation to the use of medicines, especially with regards to prevention of unintended harm to the user. Proper pharmacovigilance also involves in provision of reliable, balanced information to avoid ADRs, and contributes to the assessment of the risk-benefit profile of medicines, thereby encouraging more effective use.

The diagnosis of an ADR is part of a broader diagnosis in a patient who is taking medicines. The differential diagnosis of a medical condition should include the possibility of an ADR. The first step is to find out what products the patient is taking, including over-the-counter formulations. The next step is to ascertain whether the observed effect could be due to any of these formulations or due to a drug-drug interaction. Problems arise when the distinction between an ADR and disease symptomatology is not clear or if the concerned patient is on several drugs concurrently. Multiple factors will have to be considered in assigning the causality of an unfortunate adverse event to the suspect drug - timing of event in relation to dosing, pattern recognition for class effects or the effects of close chemical or pharmacological congeners, and occasionally special tests such as tests for allergies or biopsies.

Rapid action in response to an ADR is important when it is of a serious nature. Emergency treatment and withdrawal of all medicines is occasionally necessary, in which case cautious reintroduction of the essential medicines should be considered. Otherwise, using clinical benefit-risk judgment, together with help from investigations, one decides which medicine should be withdrawn on trial. A problem immediately arises if one or more of such medicines is essential to the patient. A benefit-risk decision then needs to be taken considering the patient's need for the drug, the severity of reaction and the availability of appropriate treatment. If several medicines could be causative, the non-essential medicines should be withdrawn first. If the reaction is likely to be dose-related, dose reduction should be considered.

The WHO Programme for International Drug Monitoring was established in the wake of the thalidomide disaster, in 1962, when WHO was requested to study the feasibility of various measures aimed at assuring the safety of pharmaceutical products in international commerce. This resulted in the establishment of an International System for monitoring ADRs using information derived from national centers. The system started with 10 countries that had already established national systems for spontaneous ADR reporting and who agreed to contribute data. For an effective global system to become operative, a common reporting form was developed, agreed guidelines for entering information formulated, common technologies and classification prepared and compatible systems for transmitting, storing, retrieving, and disseminating the data was created. The WHO Collaborating Centre for International Drug Monitoring, the Uppsala monitoring center, holds the operational responsibility for the programme, including the maintenance of the database, which currently contains around 2 million reports of suspected ADRs. Almost 60 countries now participate in the program.

So far as India is concerned there is profound dearth of indigenous ADR data. Many factors are responsible - huge patient loads, paucity of record keeping, varying nutritional status of patients, peculiar patterns of drug usage, multiple alternative systems of medicine, inadequacy of sufficiently trained and motivated doctors and paramedical staff. These hurdles cannot be removed overnight but there is an urgent need to generate data regarding the safety profile of pharmaceutical products being marketed here. In the early 1980's, a National Programme for ADR monitoring was envisaged in the following steps; Step 1: Establishment of institution-based system where intensive monitoring would be carried out; Step 2: To be linked with class groups, such as the Central Government Health Service, Armed Forces, etc; Step 3: Involvement of general practitioners. This plan is yet to come to fruition.

Till today post-marketing surveillance of a new drug is virtually non-existent in India. It is extremely difficult to bring about withdrawal of an unsafe drug from the Indian market even after submission of serious ADR data to the Drugs Controller General of India. There is too much pressure from powerful companies not to impose ban on or stringent curbs on the sale of successful drugs, even if they are hazardous or irrational. Hardly any pharmaceutical manufacturer in India does post-marketing trials. The Union Health Ministry's recent decision to set up a network of ADR monitoring centers in the country, coordinated by the Central Drugs Standard Control Organization (CDSCO), is a step long overdue. This has to be done without expecting support from the pharmaceutical industry. To be successful the message must reach all players in the drug use cycle - the prescriber, the dispenser and the consumer - alike. All of us must participate in the educational and capacity building effort.

--Amitava Sen

Advance Drug Reactions Glossary

Adapted from the WHO publication: Safety of Medicines. A guide to detecting and reporting adverse drug reactions. Geneva: World Health Organization, 2002. [WHO/EDM/QSM/2002.2
Original: English].

Adverse drug reaction	A response to a medicine which is noxious and unintended, and which occurs at doses normally used in man. In this description it is of importance that it concerns the response of a patient, in which individual factors may play an important role, and that the phenomenon is noxious (an unexpected therapeutic response, for example, may be a side effect but not an adverse reaction).
Unexpected adverse drug reaction	An adverse reaction, the nature or severity of which is not consistent with domestic labeling or market authorization, or expected from characteristics of the drug.
Side effect	Any unintended effect of a pharmaceutical product occurring at doses normally used by a patient which is related to the pharmacological properties of the drug. Essential elements in this definition are the pharmacological nature of the effect, that the phenomenon is unintended, and that there is no deliberate overdose.
Adverse event or experience	Any untoward medical occurrence that may present during treatment with a medicine but which does not necessarily have a causal relationship with this treatment. The basic point here is the coincidence in time without any suspicion of a causal relationship.
Serious adverse event	An adverse event that is fatal, life-threatening, permanently or significantly disabling or incapacitating, requires or prolongs hospitalization or requires intervention to prevent one of the above consequences. Events that are in the nature of congenital anomalies are also regarded as serious.
Signal	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.

Other Info

Clinical Impact of Adverse Event Reporting [  download >> ]

Recognition of Drug-Induced Disease [  download >> ]

WHO - Safety of Medicines Guide [  download >> ]

Suspected ADR Reporting Form [  download>> ] or click to Fill up Online >>