postmarketing surveillance a contribution from geneva

Postmarketing Surveillance

A contribution from Geneva

P M S

„Les médecins administrent des potions dont ils ignorent tout pour soigner des maladies dont ils ne savent rien !“

Voltaire. Dictionnaire philosophique.

1765

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Overview

• What is PMS ?• The Geneva organisation• Statistical data• Qualitative data• Real life examples• What does the future hold ?

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What is PMS ?

• Thalidomide, clioquinol, DES • Life-cycle of drugs (pre-/post-marketing)• Industry-driven databases (e.g. PSUR)• WHO co-ordination (e.g. CIOMS)• Regulatory „watch-dogs“ (e.g. FDA, IKS)

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The IKS „Pharmacovigilance Centre“

• DE reports „from the field“

• Data processing and analysis

• International network

• Feed-back to Industry and Regulators

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The Geneva organisation

• A Clinical Pharmacology Dpt. in a Teaching Hospital

• A 3-fold mission : Pain Unit, Clin. Pharm., PMS

• Clinical Pharmacology Unit : 1‘000 consultations p.a. - ca. 20 % should lead to DE reports

• Psychiatry Pharmacology Unit : 1‘500 cons. p.a. - ca. 20 % should lead to DE reports

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Statistical data

• ca. 200‘000 DE‘s worldwide

• ca. 2‘000 DE‘s in Switzerland

• ca. 200 DE‘s in Geneva

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Qualitative data

• „Serious“ : death, hospitalisation, injury or disability, vital risk, malformation,

overdosage

• Drug „newly marketed“ : < 5 years

• Event not mentioned in the P.I.

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„Causality“ assessment

• Certain :

• Probable :

• Possible :

• Unlikely :

• Uncertain

Chronology, dechallenge and re-challenge

Compatible sequence, positive challenge

Compatible sequence, but other explanation available

Other than above

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Physiopathology

• Pharmacological by nature [ Type A ] - 80 %

– primary : Neuroleptic sedation

– secondary : Neuroleptic malignant syndrome

• Idiosyncratic [ Type B ] - 20 %

– allergic reaction, etc.

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The „Seven Gentlemen“ quest

• Qui ?

• Quid ?

• Quis ?

• Cur ?

• Quibus auxiliis ?

• Quomodo ?

• Quando ?

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The „Seven Gentlemen“ quest

• Which drug ?

• Which event ?

• Which patient ?

• Which indication ?

• Predisposition ?

• Interaction ?

• Mode of action ?

• When ?

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As you like it [1]

• 80-year old female patient with depression

Citalopram (20 mg/d) for 30 days

• Peripheral œdema (moderate)

• Confusion

• Na and K in serum ( osmolarity)

• Na and K in urine ( osmolarity)

[ Geneva, 5.00 ]

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As you like it [2]

• Dechallenge : positive

• Relation to drug : probable (80 %)

[ Geneva, 5.00 ]

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As you like it [3]

SIADH, Antidiuresis or Schwartz-Bartter‘s syndrome1

Ætiology

• Cancer : carcinoma, lymphoma

• Chest disorder : pneumonia, φθ, asthma

• CNS disorder : meningitis, encephalitis, Guillain-Barré‘s syndrome

• Drug : diuretics, oxytocin, psychotropics - notably SSRI‘s

[1] - Gill G et al. Hyponatræmia : Biochemical and clinical perspectives. Postgrad Med J 1998 ; 74 (875) : 516-23

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As you like it [4]

SIADH, Antidiuresis or Schwartz-Bartter‘s syndrome1 :

Pathophysiology

• Vasopressin release water retention

• Hyponatræmia (< 130 mmol/l) together with

• Persistent natriuresis (> 50 mmol/l)

• Urine osmolality > plasma osmolality (usually)

• Drowsiness, cramps, seizures and coma death

• When drug-related, recedes promptly upon withdrawal

[1] - Gill G et al. Hyponatræmia : Biochemical and clinical perspectives. Postgrad Med J 1998 ; 74 (875) : 516-23

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Much ado about nothing [1]

• 85-year old female patient with back pain

• Celecoxib (400 mg/d)

• Rash on face, arms and body within 2 days



[ Geneva, 6.00 ]

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• 92-year old male patient with neck pain

• Celecoxib (100 mg D.U.) and tramadol (50 mg D.U.)

• Purpura on the legs



[ Geneva, 6.00 ]

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• 62-year old female patient with O.A.

• Rofecoxib (12.5 mg/d)

• Urticaria on ears and arms, then whole body



[ Melide, 5.00 ]

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• 62-year old female patient with neck pain

• Rofecoxib (25 mg/d)

• Rash (cellulitis-like) on ears, pruritus on face



[ Melide, 6.00 ]

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Rofecoxib

Skin Total [ % ]Switzerland 16 70 23 1

World 236 1574 15 2

Clinical trials .1 – 1.9 3

[1] - % of reports[2] - % of events[3] - % of treated patients

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Celecoxib

Skin Total [ % ]Switzerland 72 149 48 1

World 575 2746 21 2

Clinical trials .1 – 1.9 3

[1] - % of reports[2] - % of events[3] - % of treated patients

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The Tempest [1]

• D 1 :

• D 10 :

• D 14 :

• D 18 (a.m.) :

• D 18 (p.m.) onwards :

87-year old female patient admitted :heart failure and cognitive deficiency

Fluvoxamine (100 mg/d ) for depression

Zolpidem (10 mg/d ) for insomnia

Tramadol (150 mg/d ) for traumatic pain

Fever, shivering Paracetamol, antibiotic

[ Geneva, 4.00 ]

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The Tempest [2]

• D 24 (a.m.)

• D 24 (p.m.)

• D 29-32

• D 33

• D 34

• D 35

• D 36

• D 41

Obnubilation, diarrhœa

Fluvoxamine (150 mg/d )

Tramadol is suspended, fever and diarrhœa subside

Tramadol (150 mg/d )

Fluvoxamine (200 mg/d )

Coma, shock therapy suspended

Myoclonus, shacking

Exitus

[ Geneva, 4.00 ]

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The Tempest [3]

Serotonin syndrome1 :

• Serotoninergic agent recently introduced or increased in dosage

• Mental status change, agitation

• Myoclonus, hyperreflexia, tremor, motor deficiency

• Diaphoresis, fever, diarrhœa( 3 of these signs )

• Differential diagnosis : Infection, metabolic dis., intoxication

• No antipsychotic started or increased (# NMS)

[1] - Sternbach H. The serotonin syndrome. Am J Psychiatr 1991 ; 148 : 705

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Dr. Jekyll and Mr. Hyde

a medicine

a target

a therapeutic „window“

healthy volunteers

a textbook disorder

mitigation and cure

a poison

many misses

under- and over-dosing

older polymedicated pat.

a symptom

aggravation and kill

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Further objectives for the Geneva post

• 300 - 400 D E‘s p.a.

• Five papers p.a.

• Training ground for junior staff

• Networking into Pædiatrics, Geriatry, Psychiatry, Surgery

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The way forward

• Dedicated staff

• PMS desk and facilities

• On-line connexion with Bern and Upsaala

• „Cookies“ for the contributors

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Aknowledgements

• Ch. Boyle 1

• P. Dayer 2

• J. Desmeules 2

• M. Gallachi 3

• M. Kondo 2

• G. Martinek 2

• V. Piguet 2

• V. Rollason 2

• P. Schulz 2

• R. Stoller 1

• J. Desmeules 2

• N. Vogt 2

[1] Berne

[2] Geneva

[3] Melide (TI)

postmarketing surveillance a contribution from geneva

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