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Adverse drug reaction monitoring

16. Dec 2017
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Adverse drug reaction monitoring

  1. ADVERSE DRUG REACTION MONITORING DR. KHUSHBOO BHOJWANI BDS, MSC CLINICAL RESEARCH
  2. CONTENT Terminologies What is ADR? Classification of ADR Objective of ADR monitoring Why ADR is important? Adverse drug reaction reporting form. Reporting of adverse drug reaction. Haemovigilance Adverse event following immunization Causality Assessment of Adverse Event
  3. ADVERSE DRUG REACTION In the pre-approval clinical experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be established: all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. The phrase responses to a medicinal product means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out
  4. ADVERSE EVENT 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.
  5. SERIOUS ADR 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, • Is a congenital anomaly/birth defect.
  6. AN ADVERSE DRUG REACTION (ADR) CASE REPORT A case report in ADR monitoring programme is a notification relating to a patient with an adverse effect or laboratory test abnormality suspected to be induced by a medicinal product
  7. INTRODUCTION • According to WHO, adverse drug reaction is defined as “any response to a drug that is noxious and unintended and that occurs at doses used in man for prophylaxis, diagnosis or therapy.” • All drugs are capable of producing adverse effects and whenever a drug is given a risk is taken. • Adverse effect may develop promptly or only after prolonged medication or even after stoppage of the drug.
  8. CLASSIFICATION OF ADVERSE DRUG REACTION
  9. TYPE A OR EXPECTED UNDESIRABLE EFFECTS • Type a adverse effects are called augmented effects. • These are largely predictable and dose dependent. • There incidence rate is high but mortality is rare or very low • Reduction in dose can minimize these adverse effects.
  10. SIDE EFFECTS • Undesirable effects which are observed even with the therapeutic doses of the drug • Usually mild and manageable • Example: dicyclomine (an anticholinergic drug) • Desirable effect- antispasmodic action • Side effect- dryness of mouth Promethazine ( an antihistaminic drug) • Desirable effect- antiallergic action • Side effect- sedation Atropine (preanaesthetic medication) • Desirable effect- antisecretory action • Side effect- dryness of mouth
  11. SECONDARY EFFECTS These are the indirect consequences of a primary action of the drug. Example: • Development of superinfection after suspension of bacterial flora by antibiotics
  12. TOXIC EFFECTS • These are the result of excessive pharmacological action of the drug due to the over dosage or prolonged use. • Over dosage may be absolute or relative • Toxic effects are predictable and dose related • Toxicity may result from extension of the therapeutic effect itself • Example: • Bleeding due to high doses of heparin. • Hallucination, delirium with overdoses of atropine causes atropine poisoning. • Hypoglycaemia due to insulin
  13. UNEXPECTED UNDESIRABLE EFFECTS (TYPE B ADR OR BIZARRE EFFECTS • These arise unexpectedly, even when the drug is used in therapeutic doses. • These are grouped as unpredictable responses because there is no linear relationship with drug doses. • These are relatively uncommon but, if occur mortality rates are high. • Reduction in the dose does not reduce the risk for type B adr.
  14. DRUG ALLERGY • Allergic responses to drug occur when there has been previous exposure to drug and when this sensitised individual is re exposed to the same drug again. • During the first uneventful exposure, the drug acts as a hapten, which after combing with the host protein become antigenic, specific antibodies are formed against this antigen. • On reexposure, there is then antigen antibody response which results in the release of the chemical mediators of allergy(histamine, leukotriene) causing effects like urticaria, rhinitis, pruritis, asthma.
  15. TYPE 1 OR IMMEDIATE TYPE • Allergy develops within minutes and lasts for 2-3 hour. • The drug causes formation of tissue sensitizing IgE antibodies that are fixed to mast cell or leucocyte. • The subsequent exposure to drug activates the release of chemical mediators of allergy. • Results into itching, asthma, rhinitis, urticaria or anaphylactic shock.
  16. TYPE 2 OR ACCELERATED ALLERGY OR ANTIBODY DEPENDENT CYTOTOXIC HYPERSENSITIVITY • It results when a drug(antigen) binds to RBC and is recognized by IgG antibody. • The antigen-antibody reaction then triggers the lysis of RBC either by activating complement system or by the action of cytotoxic T cell or by phagocytosis by macrophages. • Example: • Thrombocytopenia, agranulocytosis, fever and systemic lupus erythematous after the use of quinidine, penicillin G. • It results within 72 hours of drug administration.
  17. TYPE 3 OR SERUM SICKNESS TYPE • It occurs after 72 hrs. but within 1-2 weeks of drug administration. • Soluble antigen-antibody form complexes which are deposited on vascular endothelium and active complement. • It is characterized by allergic inflammatory reactions in tissue, glomerular nephritis and serum sickness(fever, urticaria, lymphadenopathy
  18. TYPE 4 OR DELAYED OR CELL MEDIATED HYPERSENSITIVITY • These reaction are mediated by sensitised T cells following contact with an antigen. • The activation of sensitised T cell results in the release of cytokines which activate macrophages, granulocytes and natural killer cells to generate an inflammatory response • Example: • Photosensitivity and rashes with fever • Contact dermatitis
  19. IDIOSYNCRATIC DRUG RESPONSE • It is genetically determined abnormal reactivity to a chemical • Certain adverse effects of some drugs are largely restricted to individuals with a particular genotype • These are harmful and sometimes fatal reactions that occur in a small minority of individuals, for which the cause is yet poorly understood • Examples: • Barbiturates causes excitement and mental confusion in some individual • Occurrence of aplastic anaemia with a single dose or either low doses of chloramphenicol is in approximately 1:50000 patients.
  20. TYPE C (CHRONIC EFFECTS) DRUG • These are the adverse effects that are associated with prolonged use of drug. • Drug dependence: • Drugs are capable of altering mood and feelings are liable to repetitive use to derive euphoria, withdrawal from reality, social adjustment etc • Physiological dependence: • It is said to have developed when the individual believes that optimal state of wellbeing is achieved only through the actions of the drug. • Physical dependence: • It is an altered physiological state produced by repeat administration of drug which necessitates the continued presence of the drug to maintain physiological equilibrium. • Discontinuation of the drug results in a characteristic withdrawal syndrome. • Drug producing physical dependence are- • Barbiturates • benzodiazepines
  21. • Drug abuse: • refers to use of a drug by self medication in a manner and amount that deviates from the approved medical and social pattern in a given culture at a given time. • Drug addiction: • it is a pattern of compulsive drug use characterized by overwhelming involvement with the use of drug even after withdrawal most addicts tend to relapse. • Drug habituation: • it denotes less intensive involvement with the drug, so that its withdrawal produces only mild discomfort. • Consumption of tea, coffee, tobacco, social drinking are regarded as habituating, not dependence.
  22. TYPE D(DELAYED EFFECT) DRUGS • These are the adverse effects that occur remotely from the treatment i.e., delayed adverse effect in patients years after the treatment, or effects appearing in their children who did not receive that treatment. • Teratogenic effects are also type D ADR • Drugs can affect the foetus at three stages: • Fertilization and implantation • Organogenesis: 18 to 55 days of gestation, most vulnerable period, deformities are produced • Growth and development: 56 days onwards, development and functional abnormalities can occur • Ace inhibitors can cause hypoplasia of lungs
  23. TYPE E (END OF TREATMENT EFFECTS) DRUG • These ADRs occur when a drug is suddenly discontinued. • It mostly result in the worsening of clinical condition for which the drug was being used. • Examples: • Withdrawal seizures after suddenly stopping phenytoin(antiepileptic) • Withdrawal symptoms of barbiturates include anxiety, nausea, hallucination, seizures • Worsening of angina pectoris or myocardial infarction may result from stoppage of beta blockers
  24. OBJECTIVE OFADR MONITORING • To detect the nature and frequency of ADRs including periodic reevaluation of the benefit-risk ratio of medicinal products in order to assist the drug regulatory authority, public health programs, scientists and consumer society take appropriate action to minimise risks of ADR • Providing updated drug safety information to health care professionals • Upgrading package insert, design appropriate package insert information and dissemination of information which may constitute withdrawal of the product in the market or restrictions for marketing
  25. • Initiation of further studies for education value. For example benefit of the drug especially in long term for prevention of relapse or study of new indication, overuse, possible mechanism underlying the adverse reaction observed or misuse • To identify risk factors that may predispose, induce or influence the development, severity and incidence of adverse reactions in the population examples; • i. Patient factors: genetics, racial differences, diets, diseases, prescribing practices, culture of drug use and traditions of the people e.g. high carbohydrate, fat diet etc. • ii. Drug interactions, drug distribution, storage and use including indications, dose, availability and other underlying conditions
  26. WHYADVERSE DRUG REACTION IS IMPORTANT???
  27. ADR REPORTING FORM
  28. HOW TO FILL THE ADR REPORTING FORM????
  29. PATIENT INFORMATION 1. Patient initials: A reporter should only mention the initials of a patient instead of the full name. For e.g.: Madhu Gupta should be written as MG. 2. Age at time of event or date of birth: A reporter must report either the date of birth or age of the patient at the time the event or reaction occurred. 3. Sex: A reporter must mention the gender of the patient. 4. Weight: The weight of the patient should be in kilograms.
  30. SUSPECTED ADVERSE REACTION 5. Date of reaction started: A reporter must report the date on which the reaction was first observed. 6. Date of recovery: If the reaction recovered, the date on which the reaction recovered should be reported. 7. Describe reaction: A reporter must briefly describe the event in terms of nature, localization etc.
  31. SUSPECTED MEDICATION 8. The details of suspected medication(s) such as the drug name (brand or generic name), manufacturer, batch no/lot no, expiry date, dose used, route used, frequency, dates of therapy started and stopped, and indication of use must be provided by the reporter
  32. 9. De-challenge details: A reporter must report the status of de-challenge as: A) ‘Yes’- if reaction abated or reduced after de-challenge B)‘No’- if reaction did not abated after de-challenge C) ‘Unknown’- if information on de-challenge is not confirmed or not known D) ‘Not Applicable’ or ‘NA’- if de-challenge is not possible as in case of anaphylaxis, life threatening events, anaesthetic drugs or where a single dose is given. E) ‘Reduced dose’- If dose at which the reaction occurred is reduced Note: Also mention the reduced dose
  33. 10. Re-challenge details: A reporter must report the status of re-challenge as: ‘Yes’- if reaction reappeared after re-challenge ‘No’- if reaction did not reappear after re-challenge ‘Unknown’- if information on re-challenge is not confirmed or not known ‘Not Applicable’ or ‘NA’- if re-challenge is not applicable as in the case of injections. ‘Re-introduced dose’- If the drug is reintroduced is it a reduced dose or is it the same dose at which adverse event occurred initially.
  34. 11. Concomitant drugs: A reporter should include all the details of concomitant drugs including self medication, OTC medication, herbal remedies with therapy dates (start and stop date.) 12. Relevant tests/ laboratory data: A reporter must mention any laboratory data (if available) relevant to the adverse event that occurred. 13. Other relevant history: A reporter must mention any relevant history pertaining to the patient including pre-existing medical conditions (e.g. allergies, pregnancy, smoking, alcohol use, hepatic/renal dysfunction).
  35. 14. Seriousness of the reaction: If any event is serious in nature, a reporter must select the appropriate reason for seriousness : ‘Death’- if the patient died due to the adverse event ‘Life-threatening’- if patient was at substantial risk of dying because of the adverse event ‘Hospitalisation/prolonged’- if the adverse event led to hospitalization or increased the hospital stay of the patient Disability’- if the adverse event resulted in a substantial disruption of a person's ability to conduct normal life functions ‘Congenital anomaly’- if exposure of drug prior to conception or during pregnancy may have resulted in an adverse outcome in the child. ‘Required intervention to prevent permanent impairment/damage’- if medical or surgical intervention was necessary to preclude permanent impairment of a body function, or prevent permanent damage to a body structure ‘Other’ -when the event does not fit the other outcomes, but the event may put the patient at risk and may require medical or surgical intervention to prevent one of the other outcomes. Examples include serious blood dyscrasias (blood disorders) or seizures/convulsions that do not result in hospitalization, development of drug dependence or drug abuse
  36. 15. Outcomes: The reporter must tick the outcome of the event as: ‘Fatal’- if the patient dies due to the adverse event ‘Continuing’- if the patient is continuing to have the symptoms of the adverse event which occurred ‘Recovering’- if the patient is recovering from the existing adverse event ‘Recovered’- if the patient has recovered from the event ‘Unknown’- if the outcome is not known
  37. REPORTER 16. Name and Professional address: A reporter must mention his/her name and professional address on the form. The identity of the reporter will be maintained confidential 17. Causality assessment: The reporter (if trained) must perform the causality assessment. 18. Date of report: Mention the date on which he/she reported the adverse event
  38. WHO CAN REPORT? All healthcare professionals (clinicians, dentists, pharmacists, nurses etc) and non- healthcare professionals including consumers can report suspected adverse drug reaction.
  39. WHY TO REPORT? As a healthcare professional, it is a moral responsibility to report adverse reactions associated with use of medicines and safeguard the health of public. The safety of more than 1.2 billion population is a concern and occurrence of ADR constitute a significant economic burden on the patient and government. India has a vast genetic and ethnic variability with different disease prevalence. Use of multi-modal practices, poor patient compliance are the other factors requires ADR reporting.
  40. WHAT TO REPORT • In order to foster the culture of reporting, PvPI encourages reporting of all types of suspected ADRs- irrespective of whether they are • known or unknown, • serious or non-serious, • frequent or rare and regardless of a established causal relationship. • Although pharmacovigilance is primarily concerned with pharmaceutical medicines and vaccines, adverse reactions associated with drugs used in traditional medicine (e.g. herbal remedies) • special field of interest associated with the drug use in pregnancy, lactation, paediatric and geriatric.
  41. HOWAND WHOM TO REPORT? Use the “suspected adverse drug reaction reporting form” which is available on the official website of IPC (www.ipc.gov.in) as well as CDSCO (www.cdsco.nic.in) to report any ADR.
  42. HAEMOVIGILANCE • Haemovigilance programme in India is a process of data collection and analysis of transfusion related adverse reactions in order to investigate their causes and outcomes and prevent their occurrence and recurrence. • Haemovigilance was launched across the country under the following term of references: • To track adverse reactions/events and incidence associated with blood transfusion and blood product administration.(Haemovigilance) • To help in identifying trends, recommend best practises and interventions required to improve patient care and safety, while reducing overall cost of the healthcare system.
  43. GUIDANCE FOR REPORTING ADVERSE EVENT FOLLOWING IMMUNIZATION • AEFI is defined as a medical event that takes place after immunization, causes concern and is believed to be caused by immunization. The AEFI should be handled effectively in order to maintain/restore public faith in immunization programme. • AEFIs may occur due to intrinsic property of vaccines and constituents like stabilizers, adjuvant, antibiotics, diluents,etc added to vaccines or hypersensitivity of some individuals to vaccine component. • AEFI may also result as a result of inappropriate storage, improper handling, preparation and administeration,etc. of vaccines.
  44. • AEFI surveillance monitors immunization safety, detects and respond to adverse event, corrects unsafe immunization practises, reduces the negative impact of the event on health and contributes to the quality of immunization activities.
  45. CAUSALITYASSESSMENT • Causality assessment is defined as the evaluation of the likelihood that a medicine was the causative agent of an observed adverse event. • Whether or not an adverse drug reaction is attributable to the drug can be established by causality assessment using the following parameters: • Timing(between administration of a drug and development of an ADR) • Dose-response relationship • Nature of reaction • Absence of alternative etiologies • Past history of reaction to same or related medication.
  46. NARANJOALGORITHM FORASSESSING PROBABILITY OFAN ADR The Naranjo algorithm, Naranjo Scale, or Naranjo Nomogram is a questionnaire designed for determining the likelihood of whether an ADR is actually due to the drug rather than the result of other factors.
  47. SCORING ≥ 9 = definite ADR 5-8 = probable ADR 1-4 = possible ADR 0 = doubtful ADR
  48. WHO-UMC CAUSALITY ASSESSMENT SCALE Causality term Assessment criteria Certain • Event or laboratory test abnormality, with plausible time relationship to drug intake. • Cannot be explained by disease or other drugs • Response to withdrawal possible(pharmacologically, pathologically) • Rechallenge satisfactory, if necessary. Probable/likely • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drug • Response to withdrawal clinically reasonable • Rechallenge not required Possible • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be explained by disease or other drug • Information on drug withdrawal may be lacking or unclear
  49. Causality term Assessment criteria Unlikely • Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable(but not impossible) • Disease or other drugs provide plausible explanation Conditional/ unclassified • Event or laboratory test abnormality • More data for proper assessment needed or • Additional data under examination Unassessable/ unclassifiable • Report suggesting an adverse reaction • Cannot be judged because information is insufficient or contradictory • Data cannot be supplemented or verified
  50. COMMON ADVERSE DRUG REACTIONS
  51. Thank you
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