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ADVERSE DRUG REACTIONS_LASUCOM LECTURE.ppt
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- 2. WHO – responseto a drug that is noxious and unintended and that occurs at doses used in humans for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiologic function – Excludes: • therapeutic failures, • overdose, • drug abuse, • noncompliance, • medication errors Definition
- 3. Adapted from Bateset al. Adverse Drug Events Medication Errors (preventable) Adverse Drug Event: preventable or unpredicted medication event---with harm to patient Adverse Drug Events (ME & ADR)
- 4. The first Appearanceof Thalidomide 'Thalidomide Babies'
- 6. First appearedin Germany on 1st October 1957. As a sedative with apparently remarkably few side effects. Prescribing to pregnant women to help combat morning sickness. The tests were conducted on rodents which metabolise the drug in a different way to humans. Later tests on rabbits and monkeys produced the same horrific side effects as in humans. Thalidomide
- 7. Towards theend of the fifties, children began to be born with shocking disabilities. Probably the most renowned is Phocomelia, the name given to the flipper-like limbs which appeared on the children of women who took thalidomide. Babies effected by this tragedy were given the name Thalidomide Babies.
- 8. Why drugs cancause tragedy?
- 9. Compound Success RatesBy Stages 0 2 4 6 8 10 12 14 16 Years Discovery (2-10 Years) Preclinical Testing Laboratory and animal testing Phase I 20-80 healthy volunteers used to determine safety and dosage Phase II 100-300 patient volunteers to look for efficacy and side effects Phase III 1,000-5,000 patient volunteers used to monitor adverse reactions to long-term use FDA Review/Approval Additional post-marketing testing Compound Success Rates by Stage 5,000-10,000 screened 250 Enter preclinical testing 5 Enter clinical testing 1 Approved by the FDA Postmarketing survillence
- 10. Limitations of PremarketingClinical Trials • Short duration – Effects develop with chronic use – Some effects have long latency period • Narrow Population – Generally do not include special populations like children, pregnant women, elderly – Not always representative of the population that may be exposed to the drug after approval • Narrow set of indications – Actual evolving use not usually covered • Small size(3,000 -4,0000 – Effects that occur rarely are difficult to detect
- 11. Substantial morbidityand mortality Estimates of incidence vary with study methods, population, and ADR definition 6.7% incidence of serious ADRs* 0.3% to 7% of all hospital admissions 30% to 60% are preventable 1 in 1000 deaths on medical wards *JAMA. 1998;279:1200-1205. Epidemiology of ADRs
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- 13. • Onset ofEvent – Acute • Within 60 mins – Sub acute • 1 to 24 hours – Latent • > 2 days
- 14. • Severity ofReaction – Mild • Bothersome but requires no change in therapy – Moderate • Requires change in therapy, additional therapy or hospitalization – Severe • Disabling or life threatening
- 15. • Serious AdverseDrug Reactions (FDA) – Results in death – Life threatening – Requires hospitalization – Prolong hospitalization – Cause disability – Cause congenital anomaly – Requires intervention to prevent permanent injury
- 16. Type A( Augmented/Predictable) •Extension of pharmacologic effect • Often predictable and dose dependent • Responsible for at least 2/3rd of ADRs • Rarely life threatening, though could produce significant disability • Examples include: – Propranolol and bradycardia – Anticholinergics and dry mouth – Hemorrhage due to anticoagulants
- 17. Type B( Bizarre/Unpredictable) •Idiosyncratic or immunologic/allergic reactions • Rare and unpredictable • Constitutes the most serious and potentially life threatening ADRs • A major cause of important drug induced disease • Example: – Chloramphenicol and Aplastic anemia – Acute hepatic necrosis due to halothane – Anaphylaxis due to penicillin
- 18. Type C (Chronic) • Associated with long term use • Involves dose accumulation • Examples: – Phenacetin and Interstitial nephritis – Antimalaria and ocular toxicity – Iatrogenic cushion's syndrome due to prednisolone – Colonic dysfunction due to laxatives
- 19. Type D (Delayed) •Delayed effect (dose independent) • Occurs remotely from treatment either in children of treated patients or in the patients years after treatment • Examples: – Second cancers in those treated with alkylating agents for Hodgkin's lymphoma – Craniofacial malformations in children whose mothers had taken isotretinoin – Clear cell carcinoma of vagina in daughter of whose mother took diethylstibesterol in pregnancy – Teratogenicity (Fetal Hydantoin syndrome)
- 20. Type E (Endof Treatment Effects) • Effects occurring when a drug is stopped especially when stopped suddenly • So called ‘withdrawal effects’ • Example – Unstable angina after beta adrenoceptor antagonist is stopped suddenly – Adrenocortical insufficiency after glucocorticoid e.g prednisolone is stopped suddenly – Withdrawal seizures following stoppage of anticonvulsants like phenytoin and phenobarbital
- 21. Common causes ofADR • Anitibiotics • Antineoplastics • Anticoagulants • Cardiovascular drugs • Hypoglycemics • Antihypertensives • NSAIDs/ Anagesics • Diagnostics • CNS drugs
- 22. ADR Risk factors •Age: Children and Elderly • Multiple medications • Multiple co morbid conditions • Inappropriate medication prescribing, use or monitoring • End organ dysfunction • Altered physiology • Prior history of ADR • Extent (dose) and duration of exposure • Genetic predisposition
- 23. ADR Frequency byDrug Use 0 10 20 30 40 50 60 0-5 6-10 11-1516-20 Number of Medications Frequency (%) May FE. Clin Pharmacol Ther 1977;22:322-8
- 24. Detection of ADRs •Subjective Reports – Patient’s complaints • Objective Reports – Direct observation of events – Abnormal findings • Physical examinations • Laboratory tests • Diagnostic procedures
- 25. ADR Detection • Medicationorder screening – Abrupt medication discontinuation – Abrupt dosage reduction – Orders for special tests or serum drug concentration – Orders for ‘triggers’ or ‘tracer’ substances • Spontaneous reporting • Medication utilization review – Computerized screening – Chart review and concurrent audit
- 26. Preliminary Assessments • Preliminarydescription of events – Who is involved? – What is the most likely causative agent? • Is it an exacerbation of a pre existing condition? • Alternative explanations/Differential diagnosis – When did the event take place? – Where did the event occur? – How has the event been managed thus far?
- 27. • Determination ofurgency – What is the patient’s current clinical status? – How severe is the reaction? • Appropriate triage – Acute (ER, ICU, Poision control)
- 28. Important Patient/Disease factors •Demography – Age ,Race, Ethnicity, Gender, Height, Weight • Medical History – Concurrent conditions or special circumstances • E.g dehydration, autoimmune condition, HIV infection, pregnancy, breast feeding – Recent procedures or surgeries and any resultant complications • E.g. contrast materials, radiation treatment, hypotension, shock, renal insufficiency
- 29. Important Patient/Disease factors •End organ function • Review of systems • Laboratory tests and diagnostics • Social History – Tobacco, Alcohol, Substance abuse, Physical activity, Environmental or Occupational hazards or exposures. • Pertinent family history • Nutritional status – Special diets, Malnutrition, Weight loss
- 30. Medication Factors • MedicationHistory – Prescription medication – Non Prescription medication – Alternatives and Investigational therapies – Medication use within past 6 months – Allergies or intolerance – History of medication reactions – Adherence to prescribed regimen – Cumulative medication dosages
- 31. Medication Factors • Medication –Indication, Dose, Diluents, Volume • Administration – Route, Method, Site , Schedule, Rate, Duration • Formulation – Pharmaceutical excipients • Colorings, flavorings, preservatives – Other products • DEHP, latex
- 32. Medication Factors • Pharmacology •Pharmacokinetics • Pharmacodynamics • Adverse effects profiles • Interactions – Drug-drug – Drug-nutrient – Drug-lab test interference • Cross-allegenicity or Cross reactivity
- 33. ADR Information • Incidenceand Prevalence • Mechanism and Pathogenesis • Clinical presentation and diagnosis • Time course • Dose relationship • Reversibility • Cross reactivity/Cross allegenicity • Treatment and Prognosis
- 34. ADR Information Resources •Primary – Spontaneous reports or unpublished data – Anecdotal and descriptive reports – Observational studies – Experimental and other studies (Meta analysis, Clinical Trials) • Secondary – MEDLAR data bases( e.g. Medline) – International Pharmaceutical abstracts
- 35. • Tertiary – Referencebooks – Review articles
- 36. Causality Assessment • Priorreport of reaction • Temporal relationship • De-challenge • Re-challenge • Dose response relationship • Alternative etiologies • Objective confirmation • Past history of reaction to same or similar medication
- 37. Causality Assessment • Standardizedcase causality assessment has become a routine at pharmacovigilance centre around the world. • Decrease the ambiguity of the data and prevention of erroneous conclusion • It neither eliminates nor quantifies uncertainty but, at best, categorizes it in a semi quantitative way
- 38. • What itcan do? - Decrease disagreement between accessor. - Classify uncertainty - Mark individual case reports - Improve the scientific basis of assessment
- 39. What it cannot do - Give and accurate quantitative measurement of the likelihood of a relationship. - Distinguish valid form invalid cases - Quantify the contribution of a drug to the development of an adverse event - Change uncertainty to certainty
- 40. Methods There were severalmethod that can be use to make a causality assessment of ADRs reports. • The literature (9 points of consideration – Morges, Switzerland , 1981) • Probability calculation (Bayes’ Theorem) • Aetiological – Diagnostic Systems (Bénchiou’s group method) • French imputation systems
- 41. Methods contd • TheEuropean ABO Systems • The US Reasonable Possibility Systems • The Naranjo ADR Probability Scale • Kramer Probability scale • WHO Causality Categories
- 42. Naranjo ADR ProbabilityScale Questions Yes No Don’t Know 1) Are there previous conclusive reports on this reaction? +1 0 0 2) Did the ADR appear after the suspected drug was administered? +2 -1 0 3) Did the ADR improve when the drug was discontinued? +1 0 0 4) Did the ADR appear with re-challenge? +2 -1 0 5) Are there alternative causes for the ADR? -1 +2 0 6) Did the reaction appear when placebo was given? -1 +1 0 7) Was the drug detected in blood at toxic levels? +1 0 0 8) Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? +1 0 0 9) Did the patient have a similar reaction to the same or similar drug in any previous exposure? +1 0 0 10) Was the ADR confirmed by any objective evidence? +1 0 0
- 43. The score :- >8 = Highly probable 5-8 = probable 1-4 = possible 0 = doubtful
- 44. WHO Causality Categories •C3 – Possible • C1 – Certain • C4 – Unlikely • C5 – Unclassifiable • C2 – Probable
- 45. • C1: Plausibletime, not related to underlying condition, concurrent disease, other drugs or chemicals, related pharmacologically, +ve dechallenge, +ve rechallenge • C2: Reasonable time, unlikely to be related to concurrent disease, other drugs, +ve de- challenge, no re-challenge • C3: Reasonable time, may be due to concurrent disease, other drugs, no information on dechallenge
- 46. • C4: Improbabletemporal relationship, other confounding factors such as drugs, chemicals, underlying disease • C5: Insufficient information to analyse the report
- 47. Definitions • Dechallenge –withdrawing the drug (s) and recording the outcome – improved or not improved • Rechallenge – giving one drug again under the same conditions as before and recording the outcome – recurrence or no recurrence.
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- 50. Discontinue the offendingagent if: • it can be safely stopped • the event is life-threatening or intolerable • there is a reasonable alternative • continuing the medication will further exacerbate the patient’s condition –Continue the medication (modified as needed) if: • it is medically necessary • there is no reasonable alternative • the problem is mild and will resolve with time Management Options
- 51. –Discontinue non-essential medications –Administerappropriate treatment • e.g., atropine, benztropine, dextrose, antihistamines, epinephrine, naloxone, phenytoin, phytonadione, protamine, sodium polystyrene sulfonate, digibind, flumazenil, corticosteroids, glucagon –Provide supportive or palliative care • e.g., hydration, glucocorticoids, warm / cold compresses, analgesics or antipruritics –Consider rechallenge or desensitization Management Options
- 52. • Patient’s progress •Course of event • Delayed reactions • Response to treatment • Specific monitoring parameters Follow-up and Re-evaluation
- 53. Medical record •Description • Management • Outcome Reporting responsibility • Food and Drug Administration (NAFDAC) • post-marketing surveillance • particular interest in serious reactions involving new chemical entities • Pharmaceutical manufacturers • Publishing in the medical literature Documentation and Reporting
- 54. Product nameand manufacturer Patient demographics Description of adverse event and outcome Date of onset Drug start and stop dates/times Dose, frequency, and method Relevant lab test results or other objective evidence De-challenge and re-challenge information Confounding variables Components of an ADR Report
- 55. Prevention of ADR •Never use any drug unless there is good indication. If the patient is pregnant do not use the drug unless the need is imperative. • Allergy and idiosyncrasy are important causes of ADRs. Ask if the patient had previous reactions. • Ask if the patient is already taking other drugs including self medication
- 56. Prevention of ADR •Age, hepatic and renal disease may impair clearance of drugs so smaller doses may be needed. Genetic factors may also predispose to certain ADRs • Prescribe as few drugs as possible and give clear instructions
- 57. Prevention of ADR •Where possible use familiar drugs. With new drugs be particularly alert for ADRs and unexpected event. • If serious ADRs are liable to occur warn the patient
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- 59. Classification Type I- immediate, anaphylactic type (IgE) • e.g., anaphylaxis with penicillins, insulin urticaria Type II – cytotoxic type (IgG, IgM) • e.g., methyldopa and hemolytic anemia Type III - Immune complex type i.e serum sickness like drug reactions (IgG, IgM) • antigen-antibody complex • e.g., procainamide-induced lupus Type IV - Cell mediated or delayed hypersensitivity (T cell) • e.g., contact dermatitis (neomycin)
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- 64. Pharmacovigilance What isPharmacovigilance? Proactive monitoring and reporting on the quality, safety and efficacy of drugs Assessment of the risks and benefits of marketed medicines Monitoring the impact of any corrective actions taken Providing information to consumers, practitioners and regulators on the effective use of drugs Designing programmes and procedures for collecting and analyzing reports from patients and clinicians
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