18 Adverse Drug Reaction Reporting

Question 1

What is an ADR?

Answer 1

A response to a medicinal product which is noxious and unintended

Question 2

Are they important?

Answer 2

• Major cause of hospital admissions ~6.5%
• Affect quality of life
• Cost to the NHS in £ hundreds of millions
• Many are preventable
• Several hundred deaths per year

Question 3

Classifications

Answer 3

• Rawlins and Thompson

* DoTS

Question 4

Rawlins and Thompson – Type A

Answer 4

• Dose related
• Common, predictable
• Related to the pharmacology
• Low mortality
• e.g. Digoxin toxicity, constipation from morphine, or sedation from a hypnotic

Question 5

Rawlins and Thompson - Type B

Answer 5

• Not dose related
• Uncommon, unpredictable
• Not related to pharmacology
• High mortality
• e.g. Penicillin hypersensitivity, malignant hyperthermia, hepatitis

Question 6

ACE-inhibitor induced

angioedema

Answer 6

• Life threatening
• Rare
• Unlikely to be picked up in clinical trials
• Biggest cause of angioedema presenting to A&E
• 0.2%incidence

Question 7

Rawlins and Thompson - Type C, D, E and F

Answer 7

Classification became complicated 
• Type C – long term
• Type D – delayed
• Type E – end of use (withdrawal) 
• Type F – failure of treatment

New simplified classification DoTS

Question 8

DoTS stands for

Answer 8

Dose, Time and Susceptibility

Question 9

DoTS

Dose (response)

Answer 9

The ADR can occur
– at doses below therapeutic doses 
• anaphylaxis with penicillin
– in the therapeutic dose range 
• nausea with morphine
– at high doses
• liver failure with paracetamol

Question 10

DoTS
Time (course) can be
characteristic

Answer 10

– with the first dose
– early, or after a time, or with long-term treatment – on stopping treatment (withdrawal)
– delayed

Question 11

DoTS

Time (course)

Answer 11

• Easily observed in the patient
• Relevant to monitoring and prevention in a patient
• Relevant to pharmacovigilance and drug development

Question 12

DoTS

Time – independent

Answer 12

• E.g. Increased risk of haemorrhage with change in effective dose of warfarin
  • NSAID-induced GI bleeding
  • so monitor closely throughout

Question 13

DoTS

Time - immediate

Answer 13

• Immediate, due to rapid administration
• e.g. red man syndrome from vancomycin
• So infuse slowly

Question 14

DoTS

Time – first dose

Answer 14

• After the first-dose
• e.g. Hypotension from ACE inhibitors
• Anaphylaxis (type I hypersensitivity)
• So take special precautions for first dose

Question 15

DoTS

Time – early

Answer 15

• Early (risk falls with time)
• e.g. Nitrate-induced headache
• so advise and monitor

Question 16

DoTS

Time – intermediate

Answer 16

-Intermediate - risk maximal after a few
days or weeks
– e.g. Ampicillin rash, delayed hypersensitivity
– Quinine and thrombocytopenia (type II)
– Pencillin and interstitial nephritis (type III)
– Cutaneous reactions to antihistamines (type IV)

Question 17

DoTS

Time – late

Answer 17

• Late (risk increases with time)
• e.g. Osteoporosis (corticosteroids)
• Withdrawal reactions
• So prevent; monitor those on long term treatment

Question 18

DoTS

Time – delayed

Answer 18

– e.g. Carcinogenesis (ciclosporin, diethylstilbestrol)

– Teratogenesis (thalidomide phocomelia) • so avoid

Question 19

DoTS

Time – after withdrawal

Answer 19

• e.g. Withdrawal syndromes (e.g. opiates, benzodiazepines)
• Myocardial infarction (beta-blockers)
• so withdraw slowly

Question 20

DoTS

Susceptibility

Answer 20

• Increased risk can be due to: 
– genetic variation,
– age,
– sex,
– physiological variation, 
– exogenous factors,  
– disease

• More than one factor can be present

Question 21

Susceptibility examples

Answer 21

Genetic - Porphyria, Malignant hyperthermia

Age - Neonates (chloramphenicol), Elderly (hypnotics)

Sex - Mefloquine and psychiatric effects

Exogenous factors - Drug interactions
Interactions with food

Disease - Renal insufficiency (e.g. lithium)

Question 22

Examples of DoTS

Osteoporosis

Answer 22

Osteoporosis due to corticosteroids

Dose—collateral effect
Time—late
Susceptibility—older people; women

Question 23

Examples of DoTS

Anaphylaxis

Answer 23

Anaphylaxis due to penicillin

Dose—hypersusceptibility Time—first dose of a course Susceptibility—not understood;
needs previous sensitisation

Question 24

Examples of DoTS

Hepatotoxicity

Answer 24

Hepatotoxicity due to isoniazid:

Dose—collateral effect
Time—intermediate
Susceptibility—genetics (drug metabolism),age,
exogenous (alcohol), disease (malnutrition)

Question 25

Yellow Card scheme

Answer 25

MHRA-run ADR reporting scheme

Complete a yellow card online, telephone, by paper, app

Question 26

Black triangle drugs

Answer 26

means ‘intensive monitoring’

Question 27

Who may report?

Answer 27

1964 Doctors, dentists, coroners
1997 Hospital pharmacists
1999 Community pharmacists
2002 Nurses, midwives and health visitors (2005 Pilot patient scheme)
2008 Patients
Pharmaceutical companies must report