Adverse drug reactions identification and management

Robin Ferner City Hospital Birmingham

West Midlands Centre for ADRs

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Identifying ADRs: What done it? 1.

West Midlands Centre for ADRs
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Diagnosis: oral candida

Topical corticosteroid Oral antibiotics Cytotoxics..

Identifying ADRs: What done it? 2.

Diagnosis: gingival hypertrophy
Infiltration e.g. myelomonocytic leukaemia Drug causes
Phenytoin Calcium channel antagonists Calcineurin inhibitors (ciclosporin)
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Identifying ADRs: What done it? 3.

Diagnosis: marrow aplasia
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Antiepileptics: carbamazepine, phenytoin Anti-inflammatory drugs: penicillamine, sulfasalazine

Antimalarials: pyrimethamine, chloroquine

Antimicrobials: co-trimoxazole, chloramphenicol, Antipsychotics: phenothiazines, clozapine, Antithyroid drugs: carbimazole, propylthiouracil

Cumulative Incidence of Agranulocytosis among 11,555 Patients Taking Clozapine

West Midlands Centre for ADRs
Alvir J et al. N Engl J Med 1993;329:162-167

Alvir et al NEJM 1993; 329: 162167

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Identifying ADRs: What done it? 4.

Diagnosis: pulmonary fibrosis
Cytotoxics
methotrexate, bleomycin, busulphan
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Amiodarone Ergot derivatives

methysergide, pergolide

Antibacterials
nitrofurantoin

Identifying ADRs: What done it? 5.

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Diagnosis: torsade de pointes

Antiarrhythmics: amiodarone, disopyramide, sotalol
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Antiemetics: cisapride, domperidone, ondansetron Antiinfectives: chloroquine, macrolides, some quinolones

Antipsychotics: chlorpromazine, thioridazine, pimozide

Addicts: levomethadyl, methadone

Not all adverse reactions are to conventional medicine

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Identifying ADRs: takes patience

Stilbestrol
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Dodds 1938

Smith Dieckmann 1949 1953

Herbst 1970

Identifying ADRs: takes patience

Stilbestrol and clear cell c/a vagina
Annual incidence per 10 million
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Age at diagnosis (years) Herbst AL. Am J Obstet Gynecol 1977;28:43-50.

ADRs can be odd (2)

A deaf 88-year-old woman Rx pentoxifylline for tinnitus > auditory hallucinations Male voice singing in her right ear Favourite song "Amazing Grace", but he often sang "Rock of Ages" and "Sweet By and By"!
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Diagnosis:
Strategies
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th st 20 21

century

1.Gestalt = pattern recognition 2.Algorithmic 3.Exhaustive 4.Hypothetico-deductive

Sackett Clinical Epidemiology 1991

Diagnosis: 1. pattern recognition

The recognition of classical patterns of disease Related to designated medical events (TEN, bone marrow aplasia)
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Diagnosis: 1. pattern recognition

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Goya 1828 Sur la feuille E. 23 du Louvre, la lgende efface et illisible s'intitulerait Cosa rara (Chose rare ), d'aprs le titre de la vente de 1877. L'enfant difforme ...

Diagnosis: 1. pattern recognition

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Nine children born of members of the group Thalidomide UK have thalidomide-like deformities. Dr Claus Newman: ...Their parents are not thalidomide, although for obvious reasons, they were mistaken for thalidomide people. It's all genetic... Independent October 1, 2002

Diagnosis: 1. pattern recognition

intra-ocular traumatic impact Berkson
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Definitive anecdotes 1a: Extracellular deposition of drug or metabolite 1b: Intracellular deposition of drug or metabolite 2: Specific location or pattern of injury 3: Physicochemical dysfunction or tissue damage 4: Infection related Aronson & Hauben BMJ 2006; 333:12679

Diagnosis: 1. pattern recognition

Definitive anecdotes
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Diagnosis: 2. by algorithm Naranjo

Clin Pharmacol Ther. 1981; 30 (2): 23945. Challenge Dechallenge Rechallenge Timing Alternative aetiology at least sufficient exposure resolves after withdrawal recurs after readministration consistent considered

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Diagnosis: 2. by algorithm
Causality term Assessment criteria WHO-UMC

Certain
Event or laboratory test abnormality with plausible time relation to exposure
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Cannot be explained by diseases or other drugs

Response to withdrawal plausible (pharmacologically, pathologically) Event definitive pharmacologically or phenomenologically

Rechallenge causes definite recurrence

Algorithms
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Karch

Naranjo

Benichou

Kramer

Stricker

Diagnosis: 2. by algorithm
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Consensual Expert Judgement

Doubtful (74%) Possible (16%) Probable (10%) Probabilistic Algorithmic

Diagnosis: 2. by algorithm
Final assessment produced by a given algorithm depends highly on the relative weight of each criterion, which is fixed more or less arbitrarily by the author...
Theophile Drug Safety 2010; 33: 104554
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No evidence of validity, that is, consistent and reproducible approximation to the truth.
Meyboom Drug Safety 1997; 16: 355-65

Diagnosis: 2. by algorithm
Final assessment produced by a given algorithm depends highly on the relative weight of each criterion, which is fixed more or less arbitrarily by the author...
Theophile Drug Safety 2010; 33: 104554
West Midlands Centre for ADRs
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No evidence of validity, that is, consistent and reproducible approximation to the truth.
Meyboom Drug Safety 1997; 16: 355-65

Diagnosis: 3. exhuastive
Generally impossible Anyway, without a prior hypothesis, noise obscures signal
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Diagnosis: 4. hypotheticodeductive
Set out a hypothesis Seek information to confirm it Doctors almost invariably fail to seek information to refute their hypotheses (cf. Karl Poppers view of scientific method)
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So: identification in an individual

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Explore the diagnostic space Consider the prior probabilities Adjust them according to DoTS

Treatment in an individual
Consider specific therapy Consider prevention