prescription event monitoring - who · prescription-event monitoring -recent progress and future...

27 March 2003 Lusaka 1

Prescription Event Monitoring

David CoulterNZ Intensive Medicines Monitoring Programme


PEM worldwide

• NZ Intensive Medicines Monitoring Programme (IMMP), Dunedin, 1977

• Drug Safety Research Unit, Southampton, UK, 1980

• J-PEM, Tokyo, Japan

27 March 2003 Lusaka 3David Coulter


A method of pro-active safety surveillance


The Reason• Post-marketing surveillance is essential because the safety

database on newly licensed drugs is limited by both the number and characteristics of the patients involved. In the UK for example, successful applications for product licenses for medicines containing new active substances include, as a safety database, information on a median number of 1480 patients. Most of these patients will have been carefully chosen to have only one disease being treated with one drug. Few, if any of them, will be typical of the patients likely to receive the drugonce it has been marketed. The identification of uncommon, even if serious or lethal, reactions from such a small number ofhighly selected patients is unlikely.

• Mann RD. Prescription-event monitoring -recent progress and future horizons. Br J Clin Pharmacol 1998;

46: 195-201.


Randomised clinical trialsCannot provide adequate safety profile

• Study cohort is highly selected to exclude confounders in study of efficacy -excludes:– comorbidity– co-prescription– pregnant– elderly or young– self medication


Randomised clinical trialsCannot provide adequate safety profile

• Short term– delayed reactions– withdrawal effects– changes in death rates

• Dose variations• Women• Unlabelled use


Spontaneous ReportingThe advantages

• Easy to implement• Cheap• Covers all medicines• Rare reactions identifiable


Spontaneous ReportingThe disadvantages

• Incomplete (<3%)• No denominator• Markedly subject to biases• Delayed effects unnoticed• Common clinical problems not linked to

drug


Practolol the ModelThe oculomucocutaneous syndrome

• Early symptoms delayed until 2 years– dry eyes– popping ears

• Caused blindness, retroperitoneal fibrosis, death

• Syndrome unrecognised for 4 years with spontaneous reporting even though symptoms common


Monitoring requirements

• Adverse events - the numerator– as complete as possible

• Patients exposed (cohort) - the denominator– as complete as possible


Events definition

The term event designates a desirable or undesirable manifestation, without presuming that it is or not related to the use of a drug


EventsReporting requirements

• All new events even if common & minor• Change in a pre-existing condition• Abnormal changes in laboratory tests• Accidents• All deaths with date & cause• Possible interactions

– NB alcohol, OCs, CAMs


Basic methodology 1

• Observational cohort studies on selected new drugs– prospective– longitudinal– non-interventional– inceptional– dynamic– descriptive


Basic methodology 2

• Cohorts established from prescription data– supplied by community & hospital

pharmacisits on request– 93% compliance rate

• Events data obtained by– Prescription event monitoring (PEM) &– Spontaneous reporting


Basic methodology 3Event collection

• Spontaneous reporting• Questionnaires (PEM)

– computer generated– patient & drug data entered– minimal recording - events since date given– return envelope– compliance 80% +

• Reasons for cessation of therapy


Data elements - patient•Name

•Title

•Gender

•Address

•National Patient Number

•Date of Birth


Data elements - doctor•Name

•Type

•Specific worksite address

•Doctor database

•(Pharmacy)


Data elements - drug

• Name & formulation• Dose• Date of dispensing• Quantity dispensed


How many patients?

• The magic figure is 10,000

• IMMP mean 10,964


Events = reactions + incidents

• Reactions–definite–probable–possible

• Incidents (background noise)–unlikely


COULTER F 65432

Celecoxib

400mg OA

MelenaHypotensionMyocardial infarctionURTI

1122

2224

3m

3m3m

3m

H

ALI CIR RES

1 2, 3 4


Incidents

• Should represent background morbidity• May contain unrecognised signals

– unexpected profiles• Useful for assessing reporting bias

– as within-drug controls– as between-drug controls

• Unmasking

24

Profile of Incidents3.

2

4.9

21.8

2.8

1.8

7.7

3.9

3.2

2.1

7.7

4.9

2.83.

4

3.4

13.2

4

1.7

5.2

2.3

9.2

1.2

9.8

6.8

3.4

0

5

10

15

20

25

Acci Alim Card Emd/Met Hepa Musc Neop Neur Psyc Resp Skin Urog

Rates/1000

BezGem


Angina with bezafibrate

• Bezafibrate• Gemfibrozil• Odds Ratio

21 / 24732 / 1598

10.9 (2.17-54.41)


Angina & bezafibrateEvaluation

• Detailed survey of cohort• Excess angina confirmed• Diabetes mellitus 25% (gem 7%)• Hypertension 60% (gem 47%)

• Confounding by indication


Incidents: within-drug control

Gender DifferencesRelative Risk F:M (95%

C.I.)Reactions Incidents

Moclobemide 1.7 (1.4-2.0) 1.0 (0.8-1.2)

Fluoxetine 1.7 (1.3-2.2) 1.0 (0.7-1.4)


The purpose• Signal identification• Measurement of risk (rates)• Characterisation of reactions

– features, onset, outcome, seriousness• Identifying risk factors

– M/F, age, dose, kidney, morbidity, other drugs

• Validation of signals


Signal definition

Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously.

WHO


Development of a signal

Omeprazole and polymyositis


OmeprazolePolymyositis

• Increase in expected incidence• No reports with other monitored drugs• Increase in expected rate of falls• Compared with ranitidine (WHO)

– more muscle weakness– more CPK elevation


Other adverse events possibly relatedFALLS

No CohortOmeprazole 7 (3.5) 2014

Other drugs * 9(1.5) 5390Figures are numbers (rates per 1000 > 60 yrs)

Relative Risk for omeprazole 2.3 (CI 0.9-6.5)

* moclobemide, fluoxetine, bezafibrate, gemfibrozil, simvastatin


WHO data

omeprazole ranitidineCPK increased 19 (0.15) 16 (0.08)

RR 1.9 (95% CI 1.0 - 3.7)

Muscle weakness 26 (0.21) 18 (0.09)RR 2.3 (1.3 - 4.2)


Sumatriptan

An example of a monitoring study and demonstration of

methodology


Use

• Acute treatment of migraine and cluster headache

• Injections (pre-filled) 6mg; tablets 100mg (& 50mg)

• Usage restrictions– maximum of 6 doses prescribed– maximum of 2 doses dispensed


Basic data

Patients 14,964Prescriptions 107,654Questionnaires 26,309Spontaneous events 348PEM events 3631Total events 3979


Questionnaires

• Completed by:– doctor from records (35%)– nurse by telephone interview (50%)– patient (15%)

• 83% return (n=21,836)


Sumatriptan Signals 1

Event No. 1st alert PublAngioedema 4 Yes 0Chest pain 296 Yes >2Depression 19 Yes 2Panic 17 Yes 2Rebound 93 No 2


Sumatriptan Signals 2

Event No. 1st Alert Publ

Sensorydisturbance

254 Yes 1

Tolerance 50 Yes 1

Throattightness

119 Yes 1

Painactivation

22 Yes 2


Sumatriptan signals 3

Event No. 1st Alert PublAmnesia 9 Yes 1Anxiety 25 Yes 1Apnoea 5 Yes 1Confusion 15 Yes 1

Deperson-alisation

103 Yes 1



Event No. 1st alert PublDry mouth 30 Yes 1Hallucinations 5 Yes 1Weakness 30 Yes 1Myalgia/arthralgia

31 Yes 1



Event No. 1st Alert PublRigors 41 Yes 1Sweating 26 Yes 1Tachycardia 146 Yes 1


Sumatriptan & autonomic response

‘Fight or flight’ reaction• Tachycardia• Cold sweat• Dry mouth• Anxiety / panic• Pallor• Paraesthesia• Piloerection


SumatriptanPain activation syndrome

• Pain trauma activated– skin scratches– sunburn– bruising– recent surgery

• Pain inflammation activated– rheumatoid arthritis– colitis– sinus pain– toothache– backache


Sumatriptan & tolerance 1

• 50 reports from PEM of– increased number of doses required per

attack– treatment becoming ineffective– ‘Doesn’t work as well as it used to’


Tolerance to SumatriptanMean number of items dispensed per patient per 6 month

period (tablets and/or injections)

Interval Patients TotalDispensed

Mean noper patient

1st 8253 35911 4.42nd 1846 11929 6.53rd 1398 10326 7.44th 1083 8097 7.55th 786 6513 8.36th 565 5124 9.17th 370 3675 9.98th 169 1742 10.3


Sumatriptan Injections Only: mean numbers of items dispensed per patient per six month intervals of

treatment

Injections OnlyInterval Patients Mean

2 1765 5.233 1372 5.874 1031 6.675 750 8.766 494 10.347 300 13.498 135 18.61


SumatriptanPregnancy & lactation

• 31 pregnancy exposures

• 25 pregnancy outcomes

• 11% of world-wide experience

(Glaxo)

• 29 lactation exposures


Sumatriptan & chest pain (n=295)

• Analysis of – age & gender– duration of event– other possibly related events eg

tachycardia– control events


Sumatriptan and chest painSuggested mechanisms

Coronary artery spasmOesophageal dysfunctionMuscle pain chest wallBronchospasm


Sumatriptan & chest pain

• Analyses showed – no relationship with

• cardiovascular events• oesophageal problems• musculoskeletal events• bronchospasm

– strong relationship with• throat tightness


Sumatriptan & chest pain

Acute changes in pulmonary circulation

Increase in pressure

Pulmonary systolic 40-50%

Pulmonary diastolic 40-50%

Capillary wedge 90%


Media scare

• Sudden death of woman in 40’s from ?cardiac arryhthmia

• Legal proceedings• 80 deaths linked to sumatriptan (USA)• Media interest in NZ


Reassurance

• No deaths in NZ (cohort 7,500)• No reports of MI• Cardiac dysrythmias

– tachycardia 23– palpitations 35– bradycardia 2– multiple VPBs with Cafergot


Multiple dosing

• Multiple dosing within a short period of time, but within the recommended guidelines, is a risk factor for arterial occlusion

• This may affect cerebral or peripheral arteries• It may occur well after the normal

pharmacological action• The mechanism is likely to be due to receptor

changes


Standard reports 1Monitoring summary

• Reporting rates by gender– total, reactions, incidents

• Age & sex distribution of cohort• Regional distribution• Indications for use• (Historical morbidity)• Dose distribution


Standard reports 2Monitoring summary

• Duration of therapy• Frequency of events by SOC (profile)• Most frequent events with rates• Reasons for withdrawal of therapy• Listing of events in clinically related

groupings with sex, age, dose, duration to onset, relationship

• Reports listing


Doctors’ role

• Privacy requirements– leaflets

• Event reporting– spontaneous– questionnaires– duplicate prescriptions

• events yes/no, dob, (record event)


Pharmacists’ role

• Privacy Code requirement– leaflets

• Provision of prescription data– include duplicates

• Provision of events data– annotate printout– spontaneous reports– duplicates

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