Author: Netherlands Pharmacovigilance Centre Lareb Version date: 14 Nov 2017 Content: This lecture describes Drug allergy, by R. van Eekeren, PharmD, The Netherlands. This lecture can be used for teaching key aspect 2,3,4: preventing, recognizing, managing ADRs.

Drug allergy Pharmacovigilance course 2017 University of Groningen, The Netherlands Drs R. (Rike) van Eekeren Pharmacist

Hypersensitivity? Intolerance? Allergy? Idiosyncrasy? Side effect?

Learning objectives Knowing the meaning of terms like allergy, hypersensitivity and intolerance Explain differences in immunological reaction according to the Gell and Coombs classification and give some examples Be able to discuss if a drug should be considered as contra- indicated and what consultation with other health care providers is necessary

Content ∙ Terminology Various types of hypersensitivity Some diagnostics Recordings and actions Exam question examples

Terminology Classification of ADR Mechanism Side effect / primary and secundary (type A) Pharmacological Hypersensitivity (type B) - Allergic Immunological - Non-allergic Pseudo-allergic Various mechanisms, mimicking allergy Idiosyncrasy Genetic susceptibility for side effect or hypersensitivity Intolerance (avoid this term) Sensitivity (poorly defined) Unusually how treshold for type A reactions Atypical or unknown reactions

Examples Enalapril Mechanism? Cough (dry) Hypotension Rash Angio-edema (mouth, tongue, throat) Diarrhoea Side-effect (collateral Unknown mechanism Pseudo-allergy Intolerance Allergy Idiosyncrasy Hypersensitivity

Examples Enalapril Mechanism? Cough (dry) Side-effect / Collateral Hypotension Rash Allergy / hypersensitivity Angio-edema (mouth, tongue, throat) Pseudo-allergy (true allergy is also possible) Diarrhoea Unknown mechanism Side-effect (collateral) Unknown mechanism Pseudo-allergy Intolerance Allergy Idiosyncrasy Hypersensitivity

Content Terminology Various types of hypersensitivity Some diagnostics Recording and actions Exam question examples

Allergic hypersensitivity A specific unwanted immune-mediated allergic reaction, resulting in tissue damage As a rule, previous contact with the allergy inducing substance (allergen) is necessary (sensitization) Risk of recurrence on repeated exposure with a risk of an increasing severity of the reaction Cross-reaction based on drug structure may occur

Naissbitt et al. Drug Saf 2000; 23 (6):483-507

Classification according to Gell & Coombs Four different type of allergic reactions: Type I: Immediate hypersensitivity, IgE mediated. e.g. urticaria (hives), anaphylactic reaction Type II: Antibody-dependent cytotoxic hypersensitivity. e.g. disorder of production of blood Type III: Immune complex disease, e.g. serum sickness Type IV: Delayed T-cell mediated hypersensitivity, e.g. cutaneous reactions

Type I allergy Naisbitt et al. Drug Saf 2000; 23 (6):483-507

Urticaria (hives, galbulten) Wheal flare Van den Bemt et al. Pharm Weekbl 1998; 133(32):1183-92

Case report type I Female, 56 years Hypertension for a couple years, causing abnormalities of the retinal vessels (retinophaty) Medication - Betahistine - Furosemide, Felodipine, Metoprolol Because of decreased vision, consultation of an ophthalmologist - Decision to fluorescence angiography - IV administration fluorescein 100mg / ml;

Case report After administration fluorescein i.v. suddenly unwell - Flushing - Low blood pressure - Treatment with epinephrine, clemastine and dexamethasone, Died within minutes after administration of fluorescein A known but very rare side effect fluorescein - Previous exposure to fluorescein - Influence of metoprolol?

Anaphylaxis (2)

Anaphylactic reaction and - shock Anaphylactic reaction - At least two “organ systems” involved - Symptoms can vary considerably Anaphylactic shock - Anaphylactic reaction in combination with very low blood pressure - Immediate treatment is required - High risk of death Anaphylactic reaction may precede an anaphylactic shock

Type II allergy Naisbitt et al. Drug Saf 2000; 23 (6):483-507

Type II reactions Blood dyscrasias Involved drugs Hemolytic anaemia Penicillins, cephalosporins, NSAIDs, kinidine, … Thrombocytopenia Sulfonamides, beta-lactam antibiotics, NSAIDs, carbamazepine, heparin, … Neutropenia Propylthyuracil, flecainide, … Timing : > 5-8 days to weeks after exposure (sometimes asymptomatic at first)

Type III allergy Naisbitt et al. Drug Saf 2000; 23 (6):483-507

Case report type III Male, 35 years Bupropion 150 mg for smoking cessation One week after starting bupropion complaints - Fever, Fatigue - Rash on forearms - Lymph node swelling - Upper abdominal pain - Arthralgia Increased markers for inflammation, decrease in renal and liver function Referred to an internist; diagnosis “serum sickness like reaction”

Serum sickness like Reaction Type III reaction - Formation of immune complexes between antibodies and drug - Precipitation of antibodies in various organs Inflammation - Usually within 2-3 weeks after starting - Upon re-exposure occur within a week Rare, serious side effect, which should be recongnized in time and treated. Drugs: antibiotics, bupropion

Type IV allergy Naisbitt et al. Drug Saf 2000; 23 (6):483-507

Example of contact dermatitis after ingestion of a herbal drug Van den Bemt et al. Pharm Weekbl 1998; 133(32):1183-92

Case report type IV Female 88 years, amputation of lower leg in the past Medication - Carbamazepine - Oxazepam - Lactulose - Nitrofurantion Eczema of - Hands and feet - Head

Case Eczema Carbamazepine is replaced by oxcarbazepine Complaints are gradually worse After discontinuation only gradual improvement Treatment with tropical steriods Note: cross hypersensitivity Carbamazepine Oxcarbazepine

Clinical presentations type IV Contact dermatitis Maculopapular eruptions Drug fever Acute generalized exanthematous pustolosis (AGEP) Stevens-Johnsom syndrome and toxic epidermal necrolysis (SJS / TEN) Drug-induced hypersensitivity syndrome (DRESS) Interstitial pneumonitis Granulomatous hepatitis

Non-allergic hypersensitivity Pseudo-allergy - Signs and symptoms that mimic immunologic drug allergies - No immunological mechanism Idiosyncrasy - Unknown mechanism - Genetic predisposition

Pseudo-allergy Direct mastcell stimulation - Opiates  pruritus, urticaria - Vancomycin  flushing during infusion (red man synd) - Ciprofloxacin  urticaria Alteration in immunological mediators - Aspirin, NSAIDs  exacerbation asthma, rhinitis  urticaria, angioedema - ACE inhibitors  angioedema Direct complement activation - Radio contrast media  anaphylaxis, shock

Idiosyncrasy (example) Hemolytic anaemia caused by nitrofurantion, sulfasalzine, hydroxychloroquine, glibenclamide, ..., in patients with G6PD deficiency

Idiosyncrasy / Risk factors

Content Terminology Various types of hypersensitivity Some diagnostics Recording and actions Exam question examples

Diagnosis Correct anamnese - Symptoms - Time relationship - Changes in the use of drugs - Prior exposure to drugs Physical examination - Additional diagnostics (lab, skin testing) - Specific IgE to penicillin allergy (RAST) - Skin prick - Proofs (oral challenge; patch in type IV) - Specific parameters - histamine and tryptase in type I, - complement in type III - eosinophils in type IV

Afbeelding: website LUMC

Content Terminology Various types of hypersensitivity Some diagnostics Recording and actions Exam question examples

Which information should be recorded?

Which information should be recorded?

To avoid, or? Should a drug that has caused a true immunologic reaction always be avoided in future? Should a drug that has caused a pseudo allergic reaction always be avoided in future?

Learning objectives Knowing the meaning of terms like allergy, hypersensitivity and intolerance Explain differences in immunological reaction according to the Gell and Coombs classification and give some excamples Be able to discuss if a drug should be considered as contra- indicated and what consultation with other health care providers is necessary

Exam question (1) a. Type I, immediate type Urticaria (hives) is a sign of a specific type of allergic reaction. Do you know which one? a. Type I, immediate type b. Type II, cytotoxic reaction c. Type III, immune complex reaction d. Type IV, delayed type

Exam question (2) a. Postural hypotension b. Dry cough c. Angioedema Give an example of a non-allergic hypersensitivity reaction of enalapril (ACE-inhibitor) a. Postural hypotension b. Dry cough c. Angioedema d. Rash