ADR Identification and Management

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Adverse drug reactions

identification andmanagement

Robin Ferner

City Hospital Birmingham


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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

Antiepileptics: carbamazepine, phenytoin

Anti-inflammatory drugs: penicillamine, sulfasalazine

Antimalarials: pyrimethamine, chloroquine

Antimicrobials: co-trimoxazole, chloramphenicol,

Antipsychotics: phenothiazines, clozapine,

Antithyroid drugs: carbimazole, propylthiouracil


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Alvir J et al. N Engl J Med 1993;329:162-167

Cumulative Incidence of Agranulocytosis among 11,555 Patients

Taking Clozapine

Alvir et al NEJM 1993; 329: 162 167


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Identifying ADRs: What done it?4.

Diagnosis: pulmonary fibrosis Cytotoxics

methotrexate, bleomycin, busulphan Amiodarone Ergot derivatives

methysergide, pergolide Antibacterials

nitrofurantoin


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Identifying ADRs: What done it?

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Diagnosis: torsade de pointes

Antiarrhythmics : amiodarone, disopyramide, sotalol

Antiemetics : cisapride, domperidone, ondansetron

Antiinfectives : chloroquine, macrolides, some quinolones

Antipsychotics : chlorpromazine, thioridazine, pimozide

Addicts : levomethadyl, methadone


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Not all adverse reactions areto conventional medicine


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Dodds1938

Smith1949

Dieckmann1953

Identifying ADRs: takes patienceStilbestrol

Herbst1970


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Identifying ADRs: takes patienceStilbestrol and clear cell c/a vagina

Age at diagnosis (years ) A n n u a

l i n c i

d e n c e p e r 1

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i l l i o n

Herbst AL. Am J Obstet G necol 1977 28:43-50.


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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: 20 th 21 st century

Strategies1.Gestalt = pattern recognition2.Algorithmic3.Exhaustive4.Hypothetico-deductive

Sackett Clinical

Epidemiology 1991


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Diagnosis: 1. pattern recognition

The recognition of classicalpatterns of disease

Related to designated medicalevents (TEN, bone marrowaplasia)


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


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Nine children born of members of the group Thalidomide UKhave thalidomide-like deformities.

Dr Claus Newman: ...Their parents are not thalidomide,although for obvious reasons, they were mistaken forthalidomide people. It's all genetic...

Independent October 1, 2002


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Diagnosis: 1. pattern recognitionintra -ocular traumatic impact Berkson

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; 333:1267 9


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Definitive anecdotesDiagnosis: 1. pattern recognition


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Diagnosis: 2. by algorithm NaranjoClin Pharmacol Ther. 1981; 30 (2): 239 45.

Challenge Dechallenge Rechallenge

Timing

Alternative aetiology

at least sufficient exposureresolves after withdrawalrecurs after readministrationconsistent

considered


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Diagnosis: 2. by algorithmCausality term Assessment criteria WHO-UMC

Certain Event or laboratory test abnormality with plausible

time relation to exposure

Cannot be explained by diseases or other drugs

Response to withdrawal plausible (pharmacologically,pathologically)

Event definitive pharmacologically or

phenomenologically Rechallenge causes definite recurrence


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AlgorithmsKarch Naranjo Benichou Kramer Stricker


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Diagnosis: 2. by algorithm

Algorithmic

Consensual Expert Judgement

Probabilistic

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


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No evidence of validity, that is, consistent and reproducible approximation to the truth. Meyboom Drug Safety 1997; 16: 355-65

Final assessment produced by a givenalgorithm depends highly on the relative weightof each criterion, which is fixed more or lessarbitrarily by the author...

Theophile Drug Safety 2010; 33: 1045 54


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No evidence of validity, that is, consistent and reproducible approximation to the truth. Meyboom Drug Safety 1997; 16: 355-65

Final assessment produced by a givenalgorithm depends highly on the relative weightof each criterion, which is fixed more or lessarbitrarily by the author...

Theophile Drug Safety 2010; 33: 1045 54


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Diagnosis: 3. exhuastive

Generally impossible Anyway, without a prior hypothesis,

noise obscures signal


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Diagnosis: 4. hypothetico-deductive

Set out a hypothesis Seek information to confirm it

Doctors almost invariably fail to seekinformation to refute their hypotheses (cf.Karl Poppers view of scientific method)


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So: identification in anindividual

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

Treatment in an individual Consider specific therapy

Consider prevention

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ADR Identification and Management