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Läkemedelsverkets Farmakovigilansdag 2018-05-29
Observera att bilderna är presentatörens tolkning och avspeglar den information som fanns tillgänglig vid presentationstillfället. 1
PRAC : Pharmacovigilance Risk Assessment Committee
Kommittén för säkerhetsövervakning & riskbedömning av läkemedel
Farmakovigilansdagen maj 2018Ulla Wändel Liminga, PhD
Ämnesområdesansvarig farmakologi/toxikologi; PRAC‐ delegat 1
2
The PRACStructure, responsibilities & tasksSome figures
Transparency Public hearing
Recent referral proceduresExamples
PRAC Workplan 2018
Summary of presentation
Läkemedelsverkets Farmakovigilansdag 2018-05-29
Observera att bilderna är presentatörens tolkning och avspeglar den information som fanns tillgänglig vid presentationstillfället. 3
Agenda items 2012‐2017
5
Signals at PRAC 2012‐2017
400 signals– 700 discussions
Outcomes – update of Product information 50%
– routine PhV / monitor within PSUR 36%
– ongoing end 2017 7%
– referral 4%
– update RMP 2%
– PASS < 1%
Läkemedelsverkets Farmakovigilansdag 2018-05-29
Observera att bilderna är presentatörens tolkning och avspeglar den information som fanns tillgänglig vid presentationstillfället. 5
9
View of risks of using valproate during pregnancy, incl child?Agreement risks undeniable, well characterised. Seriousness & impact on those affected powerfully & movingly conveyed
Views on current risk minimisation measures? Improved information resources developed after PRAC review 2014; BUT not reaching right people at right timeHoped‐for strengthening of risk minimisation not seen
Other measures to reduce valproate risks during pregnancy? Many proposals e.g. Visual reminder on package Always dispensed in appropriate package + adequate risk info Alert in prescribing / dispensing software Regular reviews for all women on long‐term valproate Record women appropriately counselled Development of professional education More coordinated care services at national level Public awareness (tools for campaigns)
10
Valproate – referral 2017‐18 outcome
• Contraindicated in girls / women of child bearing potential unless pregnancy prevention programme followed
– assessment of each patient’s potential for becoming pregnant
– pregnancy tests before starting & during treatment as needed,
– counselling risks & need for effective contraception whole treatment
– at least annual review of ongoing treatment by specialist
– new risk acknowledgement form
• Not used unless alternative treatments not suitable
• Visual warning on package (boxed text / pictogram)
• Educational materials for patients & prescribers
• MAHs undertake further studies
Läkemedelsverkets Farmakovigilansdag 2018-05-29
Observera att bilderna är presentatörens tolkning och avspeglar den information som fanns tillgänglig vid presentationstillfället. 7
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Ongoing referrals
• Hydroxyethyl starch (HES)• low adherence to restrictions aimed at reducing risks of kidney injury and
death (Art 107i), SE PRAC CoRapp , triggered by SE
• Ulipristal acetat (Esmya) • risk of rare, serious liver injury (Art 20), SE PRAC Rapp; PRAC Rec May ‐18
• Quinolone and fluoroquinolone • long‐lasting effects mainly affecting musculoskeletal and nervous systems
(Art 31)
• Radium (223Ra) dichloride (Xofigo) • increased risk of death and fractures reported in an ongoing clinical trial
(Art 20)
• Methotrexate • risk of dosing errors (Art 31)
14
Paracetamol modified release 2016‐2018
• Review B/R of modified & prolonged‐release paracetamol [MR] triggered by Sweden July 2016
• Paracetamol + tramadol combo included in review; not IR
• Case reports & retrospective PK & clinical analysis* indicate
– recommended risk assessment of suspected poisonings inadequate
– standard treatment protocol with antidote NAC insufficient to manage overdoses with Alvedon 665 mg MR
– Overdoses w. Alvedon 665 mg MR causing hepatic injury, despite timely treatment, reported
• PRAC review
– Several rounds of questions, incl . re‐examination. Two ad hoc expert meetings
– BE PRAC Rapp, SE PRAC CoRapp, Re‐examination PRAC Rapp HR, CoR PL
* Salmonson H, et al. Clin Toxicol 2016;54:424 (Abstract 124)
Läkemedelsverkets Farmakovigilansdag 2018-05-29
Observera att bilderna är presentatörens tolkning och avspeglar den information som fanns tillgänglig vid presentationstillfället. 8
15
Paracetamol modified release 2016‐2018
Review of all data submitted – PRAC concluded Benefit/risk balance negative:
• Highly variable PK‐profile of overdoses with MR paracetamol formulations, uncertainties related to quantity & formulation that patient has ingested increase challenges in effective RMM for paracetamol toxicity
• Tramadol safety profile additional challenges for RMM
• Proposed RMM to reduce risk for
– overdose (education, communication, restricting availability) insufficient to minimise intentional / accidental overdoses
– hepatic injury following MR overdose not sufficiently effective/ reliable
• Majority recommendation in PRAC and CMDh Sept / Dec 2017
• EC decision February 2018
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HES (hydroxyethyl starch) 2017‐ 2018
• HES: synthetic colloids used for plasma volume expansion
• 2012/2013: PRAC referrals due to large RCTs showing increased mortality, renal impairment in patients with sepsis, or being critically ill
• Contraindicate e.g. sepsis, critically ill etc
• Conditions : Studies in approved indication; drug utilisation studies (DUSs)
• Autumn 2017: DUSs show continued use in contraindicated patients
• SE trigger 107i referral (urgent safety review) in October 2017
• Non‐adherence to revised product information e.g. 20 – 34 % non‐adherence to contraindications (9 % of patients exposed to HES critically ill, 5‐8% of patients renal impairment, 3‐4 % sepsis)
• Use in CI patient populations associated with scientifically well‐established risk for serious harm including mortality.
• Estimations in EU ‐ approx 750 000 – 1.5 million patients exposed yearly
Sweden seriously questioned if benefit/risk balance of these medicinal products remains favourable