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1st QUARTER 2004
Arthritis Rheum. 2001 Jun;45(3):209-15.
Editor’s Notes • Watson DJ, Harper SE, Zhao PL, Quan H, Bolognese JA, Simon TJ. Gastroin-
testinal tolerability of the selective cyclooxygenase-2 (COX-2) inhibitor rofe-
coxib compared with nonselective COX-1 and COX-2 inhibitors in
The summaries of two studies of general interest conducted by osteoarthritis. Arch Intern Med. 2000 Oct 23;160(19):2998-3003.
the INFARMED Pharmacovigilance Department Adverse Drug
Reactions Sector are included in this issue. Finally, the association between pulmonary interstitial disease
and leflunomide, as well as between prolonged QT interval
The first paper gives a glimpse into the initially shy but rapidly and quinolones, are briefly discussed. In both cases, one is
growing dynamics of ADR reporting by both community and dealing with serious but apparently very rare ADRs.
hospital pharmacists. It was presented at the 32nd European
Symposium on Clinical Pharmacy (Valencia, October, 2003).
Rui Pombal
The second paper is a descriptive study on reported adverse
What do they stand for?!
reactions to cox-2 inhibitors, and was awarded a prize for best
poster presentation in the field of Pharmaceutical Records and ADR Adverse Drug Reaction
Regulations at the National Pharmacists’ Congress (Lisbon, CPMP European Committee of Proprietary Medicinal Products
November 2003). Although interestingly raising the issue of EMEA European Medicines Evaluation Agency
adverse reaction patterns of COXIBs and of NSAIDs in general, IL Information Leaflet
its methodological design does not allow for any assumptions MA Marketing Authorization
to be made on possible differences in safety profiles. For the SPC Summary of the Product’s Characteristics
sake of example, amongst other sources of bias, one has only
to remind oneself that the proportion of reported ADRs to a
recently marketed product with potential for widespread use
will probably be much higher than that for long established
How can I report an
medicines whose well-known ADRs are not surprising anymore,
adverse reaction?
thus tending to be underreported. Keeping up with the litera-
ture on the subject is essential for an opinion on this complex yellow (physicians), purple (pharmacists) or white (nurses) postage paid
subject. Below a few interesting references can be found for an card
initial approach and reflection: INFARMED’s Pharmacovigilance Department
Tel: 217 987 140 - Fax: 217 987 155
E-mail: [email protected]
• Brune K, Hinz B. Selective cyclooxygenase-2 inhibitors: similarities and dif-
ferences. Scand J Rheumatol. 2004;33(1):1-6. Northern Regional Pharmacovigilance Unit
Tel: 225 573 990 - Fax: 225 573 971
• Deeks JJ, Smith LA, Bradley MD. Efficacy, tolerability, and upper gastroin- E-mail: [email protected]
testinal safety of celecoxib for treatment of osteoarthritis and rheumatoid
arthritis: systematic review of randomised controlled trials. BMJ. 2002 Sep Centre Regional Pharmacovigilance Unit
21;325(7365):619. OR Tel: 239 851 830 - Fax: 239 851 839
E-mail: [email protected]
• Garner S, Fidan D, Frankish R, Judd M, Shea B, Towheed T, Wells G, Tugwell
Lisbon and Tagus Valley Regional
P. Celecoxib for rheumatoid arthritis (Cochrane Review). In: The Cochrane Pharmacovigilance Unit
Library, Issue 2, 2004. Chichester, UK: John Wiley & Sons, Ltd Tel: 217 802 120 - Fax: 217 802 129
E-mail: [email protected]
• Garner S, Fidan D, Frankish R, Judd M, Towheed T, Wells G, Tugwell P. Rofe-
coxib for rheumatoid arthritis (Cochrane Review). In: The Cochrane Library, Southern Regional Pharmacovigilance Unit
Issue 2, 2004. Chichester, UK: John Wiley & Sons, Ltd. Tel: 217 971 340 - Fax: 217 971 339
E-mail: [email protected]
• Simon LS. COX-2 inhibition: an advance or only pharmaceutical “hype”?
INDEX CARD • Director: Dr.ª Regina Carmona Editor: Dr. Rui Pombal Editorial Assistance: Dr.ª Paula Roque Contributors:
Dr.ª Alexandra Pêgo, Dr.ª Ana Araújo, Prof.ª Doutora Cristina Sampaio, Dr. Eugénio Teófilo, Dr.ª Fátima Bragança, Dr.ª Isabel
Afonso, Prof. Doutor Jorge Polónia, Dr. Luís Pinheiro, Dr.ª Paula Roque, Dr.ª M. Rosário Pereira Rosa, Dr. Pedro Marques da
Silva, Dr.ª Regina Carmona, Dr.ª Susana Prisca, Prof. Doutor Vasco Maria; Advisory Board: Dr. A. Faria Vaz, Dr.ª Ana Corrêa
Nunes, Prof. Doutor J.M.G. Toscano Rico; Prof. Doutor Frederico José Teixeira; Prof. Doutor Jorge Gonçalves; Prof. Doutor J.M.
de Sousa Pinto; Dr. J.C.F. Marinho Falcão; Prof.ª Dr.ª Rosário Brito Correia Lobato; Publisher: INFARMED-Instituto Nacional da
Farmácia e do Medicamento, Parque de Saúde de Lisboa, Av. Brasil, N.º 53, 1749-004 Lisboa, Tel. 21 798 71 00, Fax. 21 798
73 16, e-mail: [email protected] Design and Production: PROS - Promoções e Serviços Publicitários; Printing: Gráfica
Maiadouro; Legal Deposit: 00.000; ISSN: 0873-7118; Print run: 200
farmacovigilancia8(ing) 04/07/28 15:05 Page 2
Pharmacists and Pharmacovigilance 150
- What Role? 150
The National Pharmacovigilance System (NPS) was created in
1992. As any other system based on spontaneous reporting of General disorders
ADRs, it depends on the active contributions from every 104
health professional. The role of pharmacists in this system has Skin
Central and Peripheral Nervous S.
been taking on growing relevance, especially since 1997. We Psychiatric
characterised the cases of ADRs reported by pharmacists to Respiratory
the NPS between the 1st of January 1997 and the 31st of Musculoskeletal
December 2002. Autonomous Nervous S.
Within the above mentioned period of time (Fig. 1), there was 36
a significant increase in the number of reports (from only one 28
in 1997 to 144 in 2002), in a cumulative total of 413 individ- 23 21 20
ual cases. They corresponded to 17% of all direct reports
from health professionals, and 9% of the total number
of cases reported to the NPS. Female patients predomi- 0
nated in every age group. They corresponded to sixty percent
Figure 3. ADR reports from community and hospital pharmacists (1997-2002): distribution by SOC.
of the total, with a peak in the seventh decade. Serious cases
made up for 42% of total (Fig. 2) SOC (System Organ Classes)
more frequently involved were: general disorders (22%),
gastrointestinal (19%), and skin (15%) (Fig. 3). The groups These results illustrate ADR underreporting, which is well-
of medicines with the greater number of reports did overlap known and common worldwide. Considering that community
with the more frequently prescribed pharmacological groups. pharmacists dispense 85% of all medicines, a higher number
of ADRs from these group of professionals could be expected.
Given their proximity to the general population, and consider-
ing on the other hand, that hospital pharmacists are part of a
multidisciplinary team, there is room for growth in both cases,
in spite of their already relevant overall role in pharmacovigi-
lance (Fig. 4).
15 17%
1 9
1997 1998 1999 2000 2001 2002
Figure 1. Evolution of the distribution of ADRs reported annually by pharmacists to the NPS (1997-2002).
Non Serious
60% 57,9% Other (serious)
Hospital Adm.
Life Threatening
Death Figure 4. ADR reports from community and hospital pharmacists (1997-2002).
It is necessary and urgent that the institutions in charge of
20% pharmacovigilance motivate pharmacists for ADR reporting,
8,2% namely by investing in specific training.
0,2% Susana Prisca, Ana Araújo, Fátima Bragança,
Figure 2. ADR reports from community and hospital pharmacists (1997-2002): seriousness.
Luís Pinheiro, Regina Carmona
farmacovigilancia8(ing) 04/07/28 15:05 Page 3
Quinolone Associated Adverse Reactions to Selective
Cardiotoxicity COX-2 Inhibitors Reported to the
National Pharmacovigilance System
In October 1999, grepafloxacin was withdrawn from the
market by its MA holder following reports of fatal cases of
serious cardiac rhythm disorders. Grepafloxacin seemed to ADR reports are extremely relevant for the definition of the
cause QT interval prolongation by blocking cardiac K+ safety profile of medicines, especially for the more recent
channels. Also for more recent quinolones, cases of drugs, given the natural limitations of sampling in pre-market-
prolonged QT interval and cardiac arrhythmia have been ing clinical trials. Characterising ADRs ascribed to selective
reported. The European Pharmacovigilance Working Party has cox-2 inhibitors (COXIBs) is also relevant due to their being
agreed on the following changes to the SPCs of quinolones: part of the broad group of non-steroidal anti-inflammatory
drugs (NSAIDs), some of the most extensively used medicines
• CIPROFLOXACIN worldwide. We characterised the ADR reports to COXIBs, and
No text to be included in the SPC. compared them to the total of ADRs to NSAIDs reported to
the National Pharmacovigilance System (NPS) between Janu-
• LEVOFLOXACIN ary 1993 and December 2002 (the cases reported from clini-
Section 4.8 (under cardiovascular effects) cal trials were excluded).
Very rarely: QT interval prolongation (see section 4.9)
Section 4.9 The total number of reports of COXIB ADRs was 155. The
According to toxicity studies in animals, or to clinical pharma- number of cases for celecoxib (52%) was similar to that for
cology studies with supratherapeutic doses, the most impor- rofecoxib (48%). Most reports (81%) were sent in directly by
tant expected signs following an acute overdose with health professionals, and 19% through the MA holders.
levofloxacin tablets are central nervous system symptoms such Reports concerning COXIBs accounted for 39% of the total
as delirium, dizziness, loss of consciousness and seizures, pro- 401 reports of ADRs to NSAIDs. The latter corresponded to
longed QT interval, as well as gastrointestinal reactions such around 11% of the total number of reports received by the
as nausea and mucosal erosions. In case of overdose, sympto- NPS within that period of time (Fig. 1). Reports concerning
matic treatment is indicated, together with ECG monitoring, either COXIBs specifically or NSAIDs in general peaked in
due to the possible occurrence of QT interval prolongation. 2001. This was however, a year of high overall ADR reporting
Antacids for gastric mucosal protection may be administered. to the NPS, during which a great number of pharmacovigi-
Haemodialysis, including peritoneal dialysis and CAPD, are not lance training sessions took place. It was also the year that fol-
effective for the removal of levofloxacin from the body. There lowed the first year of COXIBs in the market.
is no specific antidote.
Warning or contraindication in patients with risk factors such COXIBs (n=155)
as congenital QT syndrome, hypokalaemia, or taking medica- Total NSAIDs (n=401)
tions which may prolong the QT interval. 92
Section 4.8 (under cardiovascular effects) 49
Very rarely: QT interval prolongation. 38
12 14
• OFLOXACIN 10 5 6
No text to be included in the SPC.
There is currently no evidence of increased risk of QT interval
prolongation for either enoxacin, fleroxacin, perfloxacin, Figure 1. Annual number of reports of ADRs to COXIBs and NSAID total.
or rufloxacin.
Females accounted for the majority of cases in all age groups
(74% for COXIBs, and 72% for other NSAIDs). Males are rep-
resented in all age groups as well for other NSAIDs, but for
COXIBs reports in this gender were only received concerning
patients 30 years or older.
Serious cases of ADRs to COXIBs (55%) and NSAIDs (59%)
prompted hospital admission in 31% and 37% of cases,
The System Organ Classes (SOC) most commonly involved
in association with COXIBs and NSAIDs concerned: the body
as a whole, gastrointestinal, skin, central and peripheral nerv-
ous system, cardiovascular, vascular, respiratory, urinary, liver
farmacovigilancia8(ing) 04/07/28 15:05 Page 4
and billiary, platelets and coagulation (Fig. 2). For the gastroin-
testinal SOC, the most prevalent ADR was abdominal pain, Leflunomide an Pulmonary
whereas rashes and oedema were the most prevalent under Interstitial Disease
the skin and whole body SOC.
AravaTM (leflunomide) is indicated for the treatment of adult
3% patients with active rheumatoid arthritis as a disease-modifying
2% antirheumatic drug (DMARD). January last, the Japanese branch
of the MA holder gave a set of new precautions exclusively for
Plaquetas e
Japan, following detection of serious respiratory reactions (pul-
monary interstitial disease).
Fígado e 3%
vias biliares 7%
In Portugal, as well as all over Europe, AravaTM was granted MA
in 1999. Since then, no respiratory ADR associated to it has been
4% reported to the National Pharmacovigilance System.
5% Pulmonary interstitial disease is a well-known adverse reaction to
leflunomide which is mentioned in the SPC* as a very rare unde-
Vascular (n=244)
sirable effect (0.01% of patients, or less). However, given those
recent cases in Japan, INFARMED, in articulation with all the
NSAID Total other European medicines agencies, has been following up on
5% (n=602)
Cárdiovascular this safety issue very closely.
*The SPC can be accessed at:
periféricos 5%
Online details (Portuguese):
Pele http://www.infarmed.pt/pt/noticias_eventos/noticias/nt_28_01_200
Organismo 23%
todo 20%
Figure 2. Distribution of ADRs to COXIBs and other NSAIDs by SOC (1993-2002). More than one SOC
described may correspond to each report.
In summary, COXIB cases seem to be relevant within the over-
all context of ADRs to NSAIDs. These results might suggest
some similarity between ADRs to COXIBs and to other
NSAIDs, in terms of severity, need for hospital admission and
most frequently involved SOC, namely allergic and gastroin-
testinal reactions.
Corresponding to an increased number of reports, the reporting
rate for the years of 2001 and 2002 was about 130, still below
the desirable ratio of 250 reports per 106 reports per year. Phar-
macovigilance systems are crucial for the safety evaluation of
medicines. Every time a health professional reports an ADR, he
or she is making an active contribution towards safer use of
Fátima Bragança, Susana Prisca, Ana Araújo,
Luís Pinheiro, Regina Carmona
ADR Report Form (Physicians)

Use: 0.1305