postmarketing surveillance a contribution from geneva
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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
1.10.00 de-pres-01
Overview
• What is PMS ?• The Geneva organisation• Statistical data• Qualitative data• Real life examples• What does the future hold ?
1.10.00 de-pres-01
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
• Dechallenge : positive
• Relation to drug : probable (80 %)
[ Geneva, 6.00 ]
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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 %)
[ Geneva, 6.00 ]
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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 %)
[ Melide, 5.00 ]
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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 %)
[ Melide, 6.00 ]
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Much ado about nothing [5]
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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Much ado about nothing [6]
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)
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