INTENSIVE MONITORING OF ADVERSE DRUG REACTIONS STATE OF THE ART J.J. Joaquim1,2 L. Härmark3 C.A. Fontes Ribeiro4 R. Mateos-Campos5 1. Faculty of Pharmacy, University of Salamanca, Spain 2. Research Group in Applied Pharmacy - Instituto Politécnico de Coimbra, Coimbra Health School – ESTESC, Farmácia, Coimbra, Portugal 3. Netherlands Pharmacovigilance Centre Lareb, ‘s-Hertogenbosch, the Netherlands; 4. Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, Portugal 5. Department of Preventive Medicine and Public Health, Faculty of Medicine. University of Salamanca, Spain
INTRODUCTION It is well known that information on medicines safety, gathered in clinical trials, is insufficient when the medicine enters the market. Since the early sixties the scientific community has searched for the best practices in pharmacovigilance. The goal is to collect useful information of Adverse Drug Reactions (ADRs) as early as possible. Risk minimization measures are interventions intended to prevent or reduce the occurrence of ADRs and to reduce their severity or impact on the patient. Active pharmacovigilance, like intensive monitoring, has been performed by different organizations and prove validity to generate signals in an early stage.
AIM
Table 1 – Studies perfiormed per Centre/Year
Centres
LIM
IMMP
PEM
To highlight the scientific research on intensive monitoring of ADR and to review the reasons to include active substances in the list under additional monitoring of European Medicines Agency. Other
METHODS
Drugs
Year
Varenicline Duloxetine Pregabalin Pregabalin Influenza A (H1N1) vaccine
2014 2013 2011 2011 2011
Varenicline Varenicline Dapoxetine Celecoxib vs Rofecoxib (Thrombotic Cardiovascular Events) Levonorgestrel-releasing intrauterine device
2012 2011 2011 2005 2003
Varenicline Orlistat and Sibutramine
2008 2007
Antibiotics (Saudi Arabia) Liraglutide (Denmark) Artemisinin-Based Combination Therapies (Nigeria) ADR’s in Pediatric patients (Saudi Arabia) Antiretroviral therapy (Italy) Hepatitis C Treatment (Mexico) ADR’s in Internal Medicine (Uruguay) Meningococcal serogroup C vaccination (France) Antibiotics (Italy)
2014 2013 2013 2013 2008 2008 2008 2005 2004
A systematic review based on peer-reviewed articles, published between 2000 and 2014, was performed in PubMed and for primary search were used mesh terms as (methods in pharmacovigilance OR pharmacovigilance strategies) AND (intensive monitoring of adverse drug reaction) AND (educational tool in pharmacovigilance) AND (patient reporting). The list of medicinal products under additional monitoring (May 2015) and the Guideline on good pharmacovigilance practices (modules VI and XVI) were included in this review.
Reasons for Additional Monitoring PASS
New biological, authorised under exceptional circumstances
RESULTS Were retrieved, from the search, 32 articles. Were identified the origin of the studies, see Table 1, and found 3 centre’s worldwide where intensive monitoring studies are performed namely the LIM - Lareb Intensive Monitoring (The Netherlands), the PEM - Prescription Event Monitoring (UK) and the IMMP - Intensive Medicines Monitoring Programme (New Zealand). The IMMP has stopped in 2013 and PEM moved to Modified Prescription-Event Monitoring (MPEM). The reason to include an active substance was checked in the list of of medicinal products under additional monitoring (graphic 1) and each active substance was grouped per reason. Were identified 98 pharmacotherapeutic groups of active substances included in the list and 242 active substances. Graphic 2 highlights the top 5 pharmacotherapeutic groups.
New biological
New active substance, PASS
New active substance, conditional authorisation
New active substance, authorised under exceptional circumstances
New active substance
Conditional authorisation
Authorised under exceptional circumstances 0 May
20
40
60
80
100
120
140
Sep
Graphic 1 – Number of active substances included in the list of medicines under additional monitoring of EMA. Comparison beetwen May (Rev. 23) and September (Rev. 26) of 2015.
DISCUSSION In opposition to spontaneous reporting, intensive monitoring programs usually focus on one medicine and unlike clinical trials in an intensive monitoring study it is possible to include all patients, without the exclusion criteria that limit the coverage of real individual characteristics of medicines users in clinical trials.
Pharmacotherapeutic Group
12%
CONCLUSION Intensive Monitoring confirmed to be a potential important method in post-marketing medicines surveillance. It can anticipate information about severe or unexpected ADR’s. It gives real information temporally linked with the adverse reaction and allows an early identification of adverse events of medicines. In the future intensive monitoring should be considered to be used as an educational tool for patient reporting.
REFERENCES 1. L. Härmark; E. van Puijenbroek - Intensive monitoring of duloxetine: results of a web-based intensive monitoring study. Eur J Clin Pharmacol (2013) 69:209–215 - DOI 10.1007/s00228-012-1313-7 2. L. Härmark; E. van Puijenbroek; S. Straus; K. van Grootheest - Intensive Monitoring of Pregabalin - Results from an Observational, Web-Based, Prospective Cohort Study in the Netherlands Using Patients as a Source of Information - Drug Saf 2011; 34 (3): 221-231 0114-5916/11/0003-0221/$49.95/0 3. M. Harrison-Woolrych; J. Ashton - Psychiatric Adverse Events Associated with Varenicline - An Intensive Postmarketing Prospective Cohort Study in New Zealand - Drug Saf 2011; 34 (9): 763-772 01145916/11/0009-0763/$49.95/0 4. Mira Harrison-Woolrych, Simran Maggo, Ming Tan, Ruth Savage, Janelle Ashton1,3 - Cardiovascular Events in Patients taking Varenicline - A Case Series from Intensive Postmarketing Surveillance in New Zealand - Drug Saf 2012; 35 (1): 33-43 0114-5916/12/0001-0033/$49.95/0 5. Michael J. Perrio,* Lynda V. Wilton,*† and Saad A. W. Shakir*† - The Safety Profiles of Orlistat and Sibutramine: Results of Prescription-Event Monitoring Studies in England - OBESITY Vol. 15 No. 11 November 2007 6. G Niklas Norén,I Ralph Edwards - Modern methods of pharmacovigilance: detecting adverse effects of drugs - Clinical Medicine 2009, Vol 9, No 5: 486–9
Correspondence to:
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40%
19%
16% 13%
Antineoplastic agents
Antivirals for systemic use
Drugs for obstructive airway diseases
Drugs used in diabetes
Immunosuppressants
Graphic 2 – Top 5 of pharmaceotherapeutic groups of active substances included in the list of medicines under additional monitoring.
