Reporting Adverse Drug Reactions: A guide for healthcare professionals


May 2006

Appendices Appendix A Clinical trials process for drugs
Clinical trials for pharmaceutical products are carried out in four phases, only moving from one phase to the next if the previous phase has shown promising results. The four ‘ideal’ phases are as follows:
  • Phase I – the drug is tested on a small number of healthy volunteers to test how it is metabolised, whether it is safe for humans and to find the best way of administering the treatment.
  • Phase II – a small number of patients are given the drug to test for side effects, activity and optimum dose, and to start comparing it to the current treatment or a placebo.
  • Phase III – the drug is given to a larger group of patients for continued testing of safety and efficacy and to compare it with the current treatment or a placebo. These trials are nearly always randomised.
  • Phase IV – this phase occurs once the drug has been licensed and checks for possible long-term side effects of the drug. It is also known as post-marketing surveillance.
The extract above is taken from the BMA clinical trials internet resource which can be found at www.bma.org.uk/ap.nsf/Content/Hubclinicaltrials

Appendix B: Some major safety issues identified through the Yellow Card Scheme

Year Medicine Adverse reaction Resulting action
1995 Tramadol (Zydol *)
 Psychiatric reactions Warnings
1995 Cyproterone acetate (Cyprostat, Androcur) Dose-related hepatotoxicity Restricted indications, requirement for monitoring of liver function
1995 Quinolone antibiotics Tendinitis, tendon rupture Improved warnings
1995 Tacrolimus (Prograf *)
 Hypertrophic cardiomyopathy Warnings, dose reduction and monitoring requirements
1996
Alendronate (Fosamax *) Severe oesophageal reactions Warnings and revised dosing instructions
1997 Clozapine (Clozaril) GI obstruction Improved warnings
1997 HIV protease inhibitors Hyperlipidaemia and fat redistribution Improved warnings and monitoring recommendations
1998 Isotretinoin (Roaccutane) Psychiatric reactions Improved warnings
1998 Sertindole (Serdolect *)
 Sudden cardiac death Drug withdrawn**
1999 Human clottable protein concentrate (Quixil *) Fatal neurotoxic reactions following unlicensed use in neurosurgery Improved warnings
1999 Aristolochia in Chinese herbal remedies Renal failure Aristolochia banned
2000 Cisapride (Prepulsid, Alimix) Serious cardiovascular reactions Use of Cisapride suspended in the UK***
2001 Bupropion (Zyban *)
 Seizures Improved warnings and revised dosing instructions
2003 Kava-kava Hepatotoxicity Supply of Kava-kava prohibited in the UK


* Black Triangle ( *) drug at the time the major safety issue was identified
** Sertindole was reinstated in 2002 with increased warnings
*** Cisapride licences have been cancelled

Source: MHRA (2004) Report of an Independent Review of Access to the Yellow Card Scheme.

Appendix C: Examples of serious ADRs

Blood

 Gastrointestinal

Musculoskeletal

Bone marrow dyscrasias
 Colitis

Arthropathy
Coagulopathies
 Haemorrhage

Aseptic bone necrosis

Haemolytic anaemias Hepatic cirrhosis

Osteomalacia
  Hepatic dysfunction

Pathological fracture
Central nervous system
 Hepatic fibrosis
  
Anorexia nervosa
 Ileus

Renal
Catatonia
 Pancreatitis

Renal dysfunction
Cerebrovascular accident
 Perforation

Urinary retention
Coma
 Peritonitis (inc fibrosing)
  
Confusional state
 Pseudo-obstruction

Reproduction
Dependence
 

Spontaneous abortion
Depression
 Immunological

Antepartum haemorrhage
Epilepsy (inc exacerbations)
 Anaphylaxis

Congenital abnormalities
Extrapyramidal reactions
 Arteritis

Eclampsia, pre-eclampsia
Hallucinations
 Drug fever

Infertility
Hyperpyrexia
 Lupus syndrome

Uterine haemorrhage, perforation
Intracranial pressure
 Graft rejection
  
Myasthenia
 Polyarteritis nodosa

Respiratory
Neuroleptic malignant Vasculitis

Alveolitis (allergic, fibrosing)
   

Bronchospasm (inc exacerbation)
Cardiovascular
 Malignancy

Pneumonitis
Arrhythmias
 Any

Respiratory failure
Cardiac arrest
  

Thromboembolism
Cardiac failure
 Metabolic
  
Cardiomyopathy
 Acidosis
 Skin
Circulatory failure
 Adrenal dysfunction
 Angioedema
Hypertension
 Diabetes
 Bullous eruptions
Hypotension
 Hypercalcaemia
 Epidermal necrolysis
Myocardial
 Hyperkalaemia
 Exfoliation (generalised)
Ischaemia/infarction
 Hyponatraemia
  
Sudden death Hypokalaemia Special senses
    Cataract


Appendix D: Information held by the General Practice Research Database which can be used for pharmacovigilance

Illustration - Information held by the General Practice Research Database






























Source: GPRD, Pharmacovigilance information sheet. www.gprd.com

Appendix E: Number of suspected adverse drug reactions reports on the ADROIT database received from 01/07/91 to 31/07/05

Received year Reports with serious adverse reactions Reports associated with black triangle drugs Reports associated with herbal products Reports where patient age is specified as 65 and over (elderly) Reports where patient age is specified as less than 18 years Total number of reports
1991*
5,076 41 20 2,680 713 10,351
1992
9,865 158 43 4,630 1,772 20,136
1993
9,156 240 31 3,834 2,447 18,035
1994
9,256 123 25 3,801 2,522 17,522
1995
9,830 210 28 3,909 1,818 17,640
1996
9,530 359 36 3,914 1,583 17,107
1997
9,659 418 46 4,204 1,436 16,627
1998
10,463 512 41 4,657 1,470 18,053
1999
10,574 803 66 4,541 2,675 18,483
2000
15,112 4,082 143 5,528 12,332 33,152
2001
12,693 5,433 80 5,082 1,712 21,461
2002
11,549 2,535 72 4,828 1,634 17,619
2003
12,742 3,965 77 5,233 2,500 19,246
2004
13,665 5,214 92 5,419 2,198 20,021
2005* 8,758 4,150 54 3,206 1,571 12,924


Source of reports - who reported

Received Year Reports from pharmacists Reports from general practitioners Reports from hospital doctors Reports from nurses Reports from other healthcare professionals Reports from patients Total number of reports
1991*
23 6,526 2,678   1,124   10,351
1992
149 13,205 4,846   1,936   20,136
1993
179 9,992 4,944   2,920   18,035
1994
68 9,614 4,632   3,208   17,522
1995
100 10,304 4,755   2,481   17,640
1996
101 9,831 4,743 21 2,411   17,107
1997
901 9,254 5,195 193 1,084   16,627
1998
1,285 9,465 5,412 195 1,696   18,053
1999
1,513 9,604 5,270 388 1,708   18,483
2000
2,431 15,254 6,179 6,171 3,117   33,152
2001
2,534 10,378 5,144 1,227 2,178   21,461
2002
2,907 6,687 4,596 1,232 2,197   17,619
2003
3,515 6,142 4,700 2,365 2,524   19,246
2004
3,421 6,265 4,941 2,388 3,006   20,021
2005* 2,021 3,238 3,173 1,742 2,319 431 12,924

Source: Data supplied by MHRA
* Note: data provided for 1991 and 2005 are not for the complete years.

© British Medical Association 2008

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