Any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does

not necessarily have a causal relationship with this treatment.

any untoward medical occurrence that at any dose: 1. results in death 2. requires inpatient hospitalization 3. prolongation of existing hospitalization 4. results in persistent or significant disability/incapacity 5. is life-threatening 6. Congenital anomaly in offsprings

Excessive pharmacological action of the drug due to over dosage or prolonged usage CNS,CVS, Kidney, Liver, Lung, skin & blood forming organs common target Toxicity extension of therapeutic effect or another effect

POISON Substance which endangers life by severely affecting one or more vital functions TREATMENT OF POISONING : Termination of exposure To prevent absorption of ingested poisons Maintenance of patient airway Maintenance of blood pressure and heart beat Hastening elimination of poison

Genetically determined abnormal reactivity to a chemical Restricted to individuals having perticular genotype For eg. Barbiturate excitement and confusion

Immunologically mediated reaction producing stereotype symptoms unrelated to pharmacodynamic profile of drug DRUG HYPERSENSITIVITY

Drug induced sensitization of the skin to UV radiation Phototoxic or Photoallergic reactions Erythema, edema, hyperpigmentation, Contact dermatitis For eg. Sulfonamides, Fluoroquinolones, Chlorpromazine

Characteristic toxic effects of a drug in an individual at therapeutic doses Low threshold of an individual to drug action Eg. Single tablet of chloroquine profound vomiting and abdominal pain

Capacity of a drug to cause fetal abnormalities when administered to the pregnant mother. Effects seen are on : FERTILIZATION & IMPLANTATION : Failure of pregnancy ;goes unnoticed. ORGANOGENESIS : Deformities GROWTH & DEVELOPMENT : Developmental and functional abnormalities

Capacity of a drug to cause cancer and genetic defects respectively. Oxidation of drug reactive intermediates affect genes structural changes in chromosomes Anticancer drugs, radioisotopes, estrogens, tobacco.

I. Definition of ADR Types of ADR Mechanism of ADR Detection and Monitoring Laboratory evaluation Therapy/Management II. Collecting AE & ADR in Clinical Trial Approaches to probe AE Intensity of AE Actions taken Evaluation of AE Therapy and Management

A response to a drug that is noxious and unintended and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function

Essential features of an ADR:

There is some evidence that at least one medicine is responsible It is harmful, or potentially harmful The reaction is seen at normal doses used clinically (to distinguish ADRs from toxicity which is used to describe the symptoms of overdose or poisoning).

(1)Types-A(augmented) (2)Type-B(bizarre or idiosyncratic) (3)Type-C(chronic effect) (4)Type-D(delayed type) (5)Type-E(end of dose) (6)Type-F(failure of therapy)

1.

Type A reactions Result from an exaggeration of a medicines normal pharmacological actions when given at the usual therapeutic dose. Normally dose dependent. Response qualitatively normal but quantitatively abnormal Examples-Low blood pressure with antihypertensive Hemorrhage with warfarin Hypoglycemia with insulin. Type A reactions also include reactions that are not directly related to the desired pharmacological action of the drug (e.g. dry mouth associated with tricyclic antidepressants)

Type B reactions : Patients Reactions

Represent a novel response not expected from the known pharmacological actions of the medicine. They are not normally dose dependent. Often allergic, idiosyncratic, characteristic, occurs in minority, Unexpected & unpredictable. Characteristics: Usually serious, difficult to detect. Examples-: Anaphylaxis with penicillin Skin rashes with antibiotics Haemolytic aneamia with methyl dopa Hepatitis with isoniazid

(A) Immunologic and Non immunologic Drug Reactions Immunologic Type I reaction (IgE-mediated) e.g.Anaphylaxis from -lactam antibiotic Type II reaction (cytotoxic) e.g. Hemolytic anemia from penicillin Type III reaction e.g. Serum sickness from antithymocyte globulin complex Type IV reaction -delayed, Contact dermatitis from topical antihistamine (cell-mediated)

Nonimmunologic: (a) Predictable :e.g.Pharmacological side effect- Dry mouth from antihistamines Drug toxicity -Hepatotoxicity from methotrexate Drug-drug interactions -Seizure from theophylline while taking erythromycin Drug overdose- Seizure from excessive lidocaine (Xylocaine) (b) Unpredictable: e.g. Pseudoallergic- Anaphylactic reaction after radio contrast media Idiosyncratic- Hemolytic anemia in a patient with G6PD deficiency after primaquine therapy Intolerance- Tinnitus after a single, small dose of aspirin

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 favor adverse drug reaction.

Spontaneous reporting by doctors, pharmacists, nurses etc. ADR monitoring schemes in hospitals. Clinical trials (all phases including post marketing surveillance ). Vital statistics (Mortality, morbidity, registers, birth registers for congenital defects). Special studies (case control studies, cohort studies ).

TYPE-A PREDICTABLE COMMON RELATED TO PCOLOGICAL ACTION OF DRUG LOW MORTALITY RESPONDS TO DRUG REDUCTION

TYPE-B UNPREDICTABLE UNCOMMON NOT RELATED TO PCOLOGICAL ACTION OF DRUG HIGH MORTALITY RESPONDS TO DRUG WITH DRAWAL

Drugs with long term use- introduce new morbidity Type C-may be serious, common, affects public health Cause and incidence difficult to separate e.g. influence of oral contraceptives on incidence of breast tumors Thrombo-embolic complication with oral contraceptives

TYPE-D(Delayed type): Delayed occurrence of ADRs even after the cessation of treatment. It is uncommon , usually dose related, occur after use of drug. This effect are often difficult to reverse. Example: (1) Pulmonary peritoneal fibrosis by methyserzide. (2) Ophthalmopathy after choloroquin.

TYPE-E(End of dose): Withdrawal reaction occurs typically with the depressant drug. Examples: (1) Hypertension and restlessness in opiate abstainer. (2) Seizures on alcohol.

TYPE-F(Failure of therapy): Results from the ineffective treatment . It is common , dose related, often caused by drug interaction. Example: (1) Failure of contraception with oral contraceptive pills when used with rifampicin.

GENERAL DRUG REACTIONS :-(NON-IMMUNE) Female gender HIV infection Serious illness Herpes infection Renal insufficiency Alcoholism Liver disease Systemic lupus erythematous Poly-pharmacy

Pre marketing surveillance:-animal models carcinogenicity, teratogenicity and mutagenicity B) Safety Surveillance or ADR monitoring during clinical trials. C) Post marketing surveillance:
(A)

Pharmacovigilance is the term used for adverse event monitoring and reporting To provide signals. To improve rational decision making in adverse event monitoring Identified newer pharmacological action To ensure that medications are used-max benefits, with min. risk of treatment To monitor quality, efficacy and safety To determine long term side effect To observe drug effect in different formulation To have detailed pharmacogenetics Continuation of clinical trials Investigate drug interaction Evaluate rare but serious adverse reaction Discover new indication other than explored Assess of cost of adverse reaction

Discontinuation of the offending medication, if possible. Alternative medications with unrelated chemical structures should be substituted when available Clinical consequences of medication cessation or substitution should be closely monitored. Additional therapy for drug hypersensitivity reactions is largely supportive and symptomatic.

Adverse Event-Physical and psychological signs and symptoms of the patient that may /may not be related to trial medicine Adverse Drug Reaction- a relationship exists; predictable/unpredictable Adverse Experiences- AR + all other medical events occurring during the trial Laboratory abnormalities

1. 2. 3.

In presence of an ADR determine-intensity of symptom, time and date of onset, total duration, frequency and other medications given along to the patient. Intensity determined on investigators clinical judgment, patients report, physicians observation and experience Mild-does not interfere with patients normal func.mild annoyance Moderate-some impairment in func.-uncomfortable Severe-affects patient in terms of-Death or reduce life expectancy, life threatening event (acute but not permanent), impairment to deal with the medical problem

1.

2. 3. 4. 5.

Definite: A reaction that follows a reasonable temporal sequence from administration of medicine to attaining its levels in body fluids; follows known or expected response patternconfirmed by improvement on stoppage of medicine (dechallenge)and reappearance on re-administration of IP (rechallenge) Probable: Could not be reasonably explained by known characteristics of the patients clinical state Possible: Could have been produced by no. of other factors Unlikely: Relationship where no evaluation can be made Not related:

ADR-A response to a drug that is noxious and unintended, and occurs at doses normally used in humans Different types A,B,C. Monitoring Pre/Post marketing surveillance Evaluation by biochemical/immunological markers Therapy and management

Duration (Date of onset & resolution) Severity (Mild, Moderate, Severe) Assessment (Serious / Non serious) Relationship to study medication
(Suspected / Not suspected)

Action taken (discontinued/dose ) Outcome (Recovered, Improving, Unchanged,

Deteriorated, Permanent Disability, Death, Unknown)

INDIA : Appendix XI of Schedule Y USA : Med watch form or CIOMS form UK : Yellow card Australia : ADRAC Blue Card In clinical trials the SAE reporting form is conceptualized to cover all required aspects from regulatory point of view.