increasing the range of otc medicines: issues for patient safety and pharmacovigilance professor...
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Increasing the range of OTC medicines: issues for patient safety
and pharmacovigilance
Professor Christine Bond
Department of General Practice and Primary Care
University of Aberdeen
Today• Overview of medicines classifications
• Describe the OTC market
• Update on deregulation and evidence of emerging safety issues
• Discuss some issues for pharmacovigilance
• Identify challenges and make recommendations
UK medicines classificationsPOM Prescription only
medicinePrescribed by specified Health Care Professional
P Pharmacist supervised Sold by or under supervision of pharmacist
GSL General Sales List Available from any sales outlet-includes petrol stations!
Herbal New regulations Available any sales outlet-some specialist shops
CD Misuse of Drugs Act schedules
Special regulations apply
UK medicines classificationsPOM Prescribed by specified
Health Care Professional. Record kept.
Most professional control-
least patient control
hard to access
P Sold by or under supervision of pharmacist. Record rarely kept.
GSL Available from any sales outlet-includes petrol stations! Record not kept.
Easy to access
most patient control-
least professional control
OTC drugs (P and GSL) £2b OTC market
20% of global market in pharmaceuticals by value 27% in Europe
Approaching equal proportion in volume In the UK 45% of adults have used an OTC product in
past two weeks1
Analgesics most commonly used OTC drug (59%) 61% paracetamol; 23% ibuprofen
Headache, migraine, cold, flu, back pain, joint pain 50% purchased from pharmacy
1 Porteous, T., Bond, C.M., Hannaford, P., Sinclair, H. How and why are non-prescription
analgesics used in Scotland? Family Practice 2005 In press
OTC drugs £2b OTC market
20% of global market in pharmaceuticals by value 27% in Europe
Approaching equal in volume In the UK 45% of adults have used an OTC product in past
two weeks Analgesics most commonly used OTC Headache, migraine, cold, flu, back pain, joint pain
Safety? OTCs cause 600 deaths each year in the UK
(Pharmaceutical Journal 2000; 264:530)
• The drug is:– A danger to health if used without medical
supervision (ADRs likely, misdiagnosis a problem)
– Frequently used incorrectly i.e. misused– Has activity or side effects which require
further investigation– Parenterally administered
• 1European Parliament and Council of the European Communities (2001) Directive 2001/83/EEC of 6 November 2001 on the Community code relating to medicinal products for human use
EU criteria for retaining as a POM1
European trends in deregulation• Government policies to increase self care
– Patient empowerment– Patient convenience– Savings in national drugs budget
• Commercial need to extend the life of products beyond their patent
• Professional benefits– Pharmacists can deliver roles more effectively– GPs have reduced workload (service redesign)
Key UK switches since 1983
1983 loperamide, ibuprofen 2001 levonorgestrel EHC
1992 clotrimazole 2004 simvastatin
1994 cimetidine, beclametasone nasal
2005 chloramphenicol opthalmic
1995 fluconazole 2006 ?trimethoprim
European variation in OTC availability
Belgium Portugal UK
Chloramphenicol
Codeine
Fluconazole
Levonorgestrel
Naproxen
Simvastatin
Self care and medicines availability
Traditional area of careMedicine already OTC
dyspepsia treated with antacids
Self care and medicines availability
Traditional area of careNewly deregulated medicine
dyspepsia treated with H2 blockeror PPI
Traditional area of careMedicine already OTC
dyspepsia treated with antacids
Self care and medicines availability
Traditional area of careNewly deregulated medicine
dyspepsia treated with H2 blockeror PPI
New area of careMedicine already OTC
hydrocortisone for eczema
Traditional area of careMedicine already OTC
dyspepsia treated with antacids
Self care and medicines availability 1
Traditional area of careNewly deregulated medicine
dyspepsia treated with H2 blockeror PPI
New area of careMedicine already OTC
hydrocortisone for eczema
New area of careNewly deregulated medicine
simvastatin for hyperlipidaemia
Traditional area of careMedicine already OTC
dyspepsia treated with antacids
1 After S. Kilby RPSGB, UK
A cultural leap (1983-2005)
Traditional area of careNewly deregulated medicine
dyspepsia treated with H2 blockeror PPI
New area of careMedicine already OTC
hydrocortisone for eczema
New area of careNewly deregulated medicine
simvastatin for hyperlipidaemia
Traditional area of careMedicine already OTC
dyspepsia treated with antacids
Minor self limiting conditions
Chronic conditions
Drug safety
• Appropriate use– appropriate dosage– indications/contraindications
• Adverse event profile of the drug
• Interactions
• Problems may not be understood at launch
• OTC drugs no different from POMs
Appropriate use? Ibuprofen1
Correct dosage (1.2g per day 7 days)
• 62% already taking; 11% daily
• 38% use for chronic conditions (>13 weeks)
• 23% used ibuprofen for total of >8 weeks• 8% exceeded the maximum daily OTC dose
(>8,400mg -16,800mg weekly; 5 exceeded Rx dose of 2,400mg daily)
1 Sinclair, H.K., Bond, C.M. , Hannaford, P.C. Over the counter ibuprofen: how and
why is it used? IJPP 2000; 8;121-7
Appropriate use? IbuprofenCorrect indication
back pain 25%
joint pain 19%
headache 18%
toothache 9%
women's problems 7%
keep for future use 7%
cold/flu 6%
injury 5%
other 4%
Appropriate use? IbuprofenNo contra indication!
• 4% had a history of stomach ulcer; 7% history of asthma
• 4% sought advice about GI symptoms during the week after purchase
Adverse events and OTCs• All therapeutically active substances have intended and
unintended effects• Need to balance these (benefit-risk)• OTC medicines no exception• Predictable ‘side effects’
– Eg antihistamines and drowsiness– NSAIDs and GI
• Unpredictable/idiosyncratic– Need large numbers of users to identify– Deregulation increases user population– eg terfenadine
Re-regulation• Terfenadine
– Deregulated 1984; reregulated 1994– Severe cardiac arrhythmias with grapefruit juice and ketoconazole
(Cytochrome P450 isoenzymes)
• Carbaryl– Reregulated 1995– Carcinogenicity
• St John’s Wort– UK warning 2000 for wide range of drug interactions
• Central pharmacodynamic effects SSRI• CYT P 450 inducer reduces efficacy of e.g. OCP, antivirals
– Ireland made a POM
Potential for DI: OTC ibuprofen 38% used other medicines while taking ibuprofen
• 27% with another analgesic
• 11% with an antihypertensive• 8% with a diuretic
• 7% with a GI medicine • 4% with an asthma medicine
So should we assume OTCs are safe?
• Probably most are
• We do need to respect them
• We do need to monitor in use
• We need systems of pharmacovigilance
Methods of Pharmacovigilance • Signal generation
– UK Yellow card system– Said to report minority of events (?20%)– Reporters include doctors, pharmacists, nurses
• Most recently patients– Includes OTCs but proportionally less reports– Depends on links being made
• Retrospective studies– Case control or cohort– Depend on routine records– Not suitable for OTCs due to lack of systematic records
Methods of Pharmacovigilance • Prospective studies
– Dedicated studies possible for OTC– Recruit through pharmacy point of sale eg ibuprofen,
hayfever treatments, paediatric medicines• Sinclair, H.K., Bond, C.M. , Hannaford, P.C. Over the counter ibuprofen: how and why is
it used? IJPP 2000; 8;121-7 • Sinclair, H., Bond, C., Largue, G., Price, D., Hannaford, P Community pharmacy
provision of allergic rhinitis treatments: a longitudinal study of patient reported outcome IJPP 2005 In press
• Stewart, D., Helms, P., McCaig, D., Bond, C., McLay, J. Monitoring Adverse Drug reactions in children using community pharmacies: a pilot study British Journal of Clinical Pharmacology 2005 59: 677-83
– Recruit through surveys• Porteous, T., Bond, C.M., Hannaford, P., Sinclair, H. How and why are non-prescription
analgesics used in Scotland? Family Practice 2005 In press
• Gastro intestinal symptoms
Six month pharmacovigilance data for ibuprofen
User type No symptom Symptom
Ever users(279)
189 (64%) 108 (36%)
Neverusers (70)
53 (76%) 17 (24%)
X 2 3.68 d.f. 1 p=0.055
Symptoms experienced prior and post purchase1
Category of adverse event
Proportion with symptom
McNemars Chi2 test (1df)
p-value
Prior to purchase
Post purchase
Gastro-intestinal system
0.058 0.080 3.52 0.061
Central nervous system
0.058 0.080 3.24 0.072
Hypersensitivity 0.035 0.050 3.60 0.058
1Layton, D.,Sinclair, H.K., Bond, C., Hannaford, P., Shakir, S. Pharmacovigilance of over-the-counter products based in Community Pharmacy: methodological issues from pilot work conducted in Hampshire and Grampian, UK. 2002 .Pharmacoepidemiology and Drug Safety 11; 503-13
Case study 1
Ibuprofen used by 15 (4%) with peptic ulcere.g. Informed by doctor in last five years that she had an
ulcer. Consulted a doctor in six months after purchase because of ‘low blood count (on iron tablets) due to a bleeding ulcer (on Zantac)’. She had used ibuprofen daily for two years for back and joint pain, took 400 mg on each of the seven days after the index purchase and continued to use the preparation
(54 year old female)
Case study II
Ibuprofen used by 30 (7%) with asthmae.g. Took ibuprofen for ‘arthritis’ every day for ‘many
years’ concurrently with ‘cimetidine, Dyazide, salbutamol inhaler and Becloforte inhaler for several years’. Consulted doctor during six months after purchase because of ‘asthmatic attacks’ and during the seven days after the index purchase because of ‘severe attack of asthma allergy’, yet continued using the preparation afterwards.
(76 year old male)
Challenges in OTC use and recommendations Risks must be quantified and understood Systems of OTC pharmacovigilance must be improved Consider need for routine records to be kept
Pharmacies possible but other outlets? Integrated single record Links to other HCP
Educate professionals and patients about possible risks as well as benefits Doctors should always ask and patients should volunteer concurrent OTC medicines Customer must seek pharmacist’s advice, and expect to be asked questions Customer must read and follow instructions
Consider P-to-GSL moves very carefully
In conclusion
• The risk is small but the potential effect could be widespread
• We must identify any problem at the earliest opportunity
• Only if we put systems in place should we make more potent medicines, for chronic use, available without a prescription, to the benefit of the public, and increased efficiency of health care