Increasing the range of OTC medicines: issues for patient safety and pharmacovigilance Professor...

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


Traditional area of careNewly deregulated medicine

dyspepsia treated with H2 blockeror PPI






New area of careMedicine already OTC

hydrocortisone for eczema



Self care and medicines availability 1





New area of careNewly deregulated medicine

simvastatin for hyperlipidaemia



1 After S. Kilby RPSGB, UK

A cultural leap (1983-2005)





New area of careNewly deregulated medicine

simvastatin for hyperlipidaemia



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

Increasing the range of OTC medicines: issues for patient safety and pharmacovigilance Professor...

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