Transcript Postmarketing Surveillance

Postmarketing Surveillance
A contribution from Geneva
PMS
„Les médecins administrent des potions dont
ils ignorent tout pour soigner
des maladies dont ils ne savent rien !“
Voltaire. Dictionnaire philosophique. 1765
Overview
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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 ?
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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 :
Chronology, dechallenge and re-challenge
• Probable : Compatible sequence, positive challenge
• Possible : Compatible sequence,
but other explanation available
• Unlikely : Other than above
• Uncertain
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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 ?
• Quibus auxiliis ?
• Quid ?
• Quomodo ?
• Quis ?
• Quando ?
• Cur ?
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The „Seven Gentlemen“ quest
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• Which drug ?
• Predisposition ?
• Which event ?
• Interaction ?
• Which patient ?
• Mode of action ?
• Which indication ?
• 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
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 Na and K in serum ( osmolarity)
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 Na and K in urine ( osmolarity)
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As you like it [2]
• Dechallenge : positive
• Relation to drug : probable (80 %)
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As you like it [3]
SIADH, Antidiuresis or Schwartz-Bartter‘s syndrome1
Ætiology
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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
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Vasopressin release  water retention
Hyponatræmia (< 130 mmol/l) together with
Persistent natriuresis (> 50 mmol/l)
Urine osmolality > plasma osmolality (usually)
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Drowsiness, cramps, seizures and coma  death
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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
• Dechallenge : positive
• Relation to drug : probable (80 %)
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Much ado about nothing [2]
• 92-year old male patient with neck pain
• Celecoxib (100 mg D.U.) and tramadol (50 mg D.U.)
• Purpura on the legs
• Dechallenge : positive
• Relation to drug : probable (80 %)
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Much ado about nothing [3]
• 62-year old female patient with O.A.
• Rofecoxib (12.5 mg/d)
• Urticaria on ears and arms, then whole body
• Dechallenge : positive
• Relation to drug : probable (80 %)
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Much ado about nothing [4]
• 62-year old female patient with neck pain
• Rofecoxib (25 mg/d)
• Rash (cellulitis-like) on ears, pruritus on face
• Dechallenge : positive
• Relation to drug : probable (80 %)
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Much ado about nothing [5]
Rofecoxib
Switzerland
World
Clinical trials
Skin
Total
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16
236
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1574
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15
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[1] - % of reports
[2] - % of events
[3] - % of treated patients
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Much ado about nothing [6]
Celecoxib
Switzerland
World
Clinical trials
Skin
Total
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72
575
149
2746
48
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21
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[1] - % of reports
[2] - % of events
[3] - % of treated patients
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The Tempest [1]
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D1 :
87-year old female patient admitted :
heart failure and cognitive deficiency
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D 10 :
 Fluvoxamine (100 mg/d ) for depression
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D 14 :
 Zolpidem (10 mg/d ) for insomnia
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D 18 (a.m.) :
 Tramadol (150 mg/d ) for traumatic pain
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D 18 (p.m.) onwards : Fever, shivering  Paracetamol, antibiotic
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The Tempest [2]
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D 24 (a.m.)
Obnubilation, diarrhœa
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D 24 (p.m.)
 Fluvoxamine (150 mg/d )
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D 29-32
Tramadol is suspended, fever and diarrhœa subside
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D 33
 Tramadol (150 mg/d )
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D 34
 Fluvoxamine (200 mg/d )
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D 35
Coma, shock  therapy suspended
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D 36
Myoclonus, shacking
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D 41
Exitus
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The Tempest [3]
Serotonin syndrome1 :
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Serotoninergic agent recently introduced or increased in dosage
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Mental status change, agitation
Myoclonus, hyperreflexia, tremor, motor deficiency
Diaphoresis, fever, diarrhœa
( 3 of these signs )
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Differential diagnosis : Infection, metabolic dis., intoxication
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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
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a poison
many misses
under- and over-dosing
older polymedicated pat.
a symptom
aggravation and kill
Further objectives for the Geneva post
• 300 - 400 DE‘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
• V. Piguet 2
• P. Dayer 2
• V. Rollason 2
• J. Desmeules 2
• P. Schulz 2
• M. Gallachi 3
• R. Stoller 1
• M. Kondo 2
• J. Desmeules 2
• G. Martinek 2
• N. Vogt 2
[1] Berne
[2] Geneva
[3] Melide (TI)
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