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1.
COX-2 Inhibitors
CPMP
advises stronger risk warnings
Europe.
The European Committee for Proprietary Medicinal Products (CPMP) has finalised a EU-wide review of the cyclooxygenase-2 (COX-2) inhibitor substances celecoxib, etoricoxib, parecoxib, rofecoxib and valdecoxib. The review was initiated by France in July 2002 due to gastrointestinal
and cardiovascular safety concerns. The CPMP
has
concluded that the benefit-risk balance for these
drugs remains positive for the target populations. However, the Committee recommends that
the product label should be strengthened with additional warnings, in particular recommending
caution in patients with underlying gastrointestinal and cardiovascular risks. The Committee also recommends
adding
(or modifying) warnings concerning the risk of severe skin and hypersensitivity reactions.
Reference:
EMEA Press Release EMEA/CPMP/5732/03/Final, 20 November 2003. Available from URL: http://www.emea.eu.int
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2.
CELECOXIB /
ROFECOXIB
Acute
temporary visual impairment
New Zealand. The Intensive Medicines
Monitoring programme (IMMP) in New Zealand has presented evidence
of acute severe temporary visual disturbance with celecoxib and
rofecoxib, two of the new selective anti-inflammatory cyclooxygenase-2
(COX-2) inhibitors. Monitoring of the two drugs was started in December
2000 and at the time this material was presented to the British
Medical Journal, the IMMP had received seven reports of visual disturbance
with these drugs; the authors report that four of the seven patients
had an onset time of one week or less. One patient regularly had
problems for a few hours after each dose. Inflammatory arthritis
in one and increased risk of vasculitis or arterial thrombosis in
another could have affected observations in two of the patients;
however, according to the authors, the rapid recovery excludes vascular
embolism or thrombosis in these patients; the ages of the patients
also suggest that the impairment was not confined to the elderly.
The authors propose inhibition of the synthesis of prostaglandins,
with an ultimate effect on retinal blood, as a likely mechanism
for the visual impairment with these drugs. Visual disturbances
have also been reported with conventional non-selective COX inhibitors.
Reports
in WHO-file: celecoxib-230; rofecoxib-244 
Reference:
British Medical Journal 327: 12141215, 22 November 2003.
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3.
NONSTEROIDAL ANTI- INFLAMMATORY DRUGS (NSAIDs)
Postpartum administration may cause hypertension
Australia. The Adverse Drug Reactions Advisory Committee (ADRAC) has recently received six reports of hypertension or hypertensive crisis in women following the postpartum administration of NSAIDs (indometacin, ibuprofen or diclofenac). Four of the women had a history of pre-eclampsia, one of whom
died of hypertensive crisis and intracranial haemorrhage after undergoing a Caesarian section. The other two women, including one who
experienced an eclamptic seizure, had no prior history of hypertension. Only two of the women were receiving antihypertensive therapy at the time of the adverse event. The committee suggests
that the severe hypertension in the reported cases may have been caused by the patients' underlying condition, but that it is plausible that NSAID administration
made a significant contribution. ADRAC advises careful monitoring of blood pressure in women (With a history of pre-eclampsia or essential hypertension) administered NSAIDs in the postpartum period.
Reference:
Reactions 980: 2, 6 December 2003.
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4.
CYCLO- OXYGENASE-2 INHIBITORS
Reports
of visual disturbances
New Zealand. The Pharmacovigilance Centre in Dunedin, New
Zealand has received nine reports
of visual changes associated with the use of cyclo-oxyg
enase- 2
(COX-2) inhibitors, celecoxib (six reports) and rofecoxib (three reports). The visual disturbances included blurred vision, abnormal VISion, scintillating scotomata, visual
field defect
and temporary blindness. In all but
one report, the duration to onset from first taking the COX-2 inhibitor was within four weeks. The eyesight changes were bilateral in eight of the cases. Blurred vision, cataract, conjunctivitis, eye pain and glaucoma are listed as adverse effects in the celecoxib (Celebrex) data sheet and
blurred vision in the rofecoxib (Vioxx) datasheet. In all of the eight reports patients recovered quickly on withdrawal of the COX-2 inhibitor. The visual disturbances did
not recur during periods of observation of up to seven months following withdrawal. Similar events have
also been reported with non-specific anti-inflammatory agents. There is evidence that the cyclo-oxygenase enzymes COX-l and COX-2 are involved in the regulation of retinal blood flow. However, other mechanisms for the observed visual disturbances with COX-inhibitors remain to
be explored. If eyesight changes occur, the anti-inflammatory medicine should be immediately withdrawn and the patient assessed for improvement of visual symptoms. Future exposure to anti-inflammatory agents should be avoided in patients with a severe
eye disturbance following first exposure.
Reference:
Prescriber
Update Artic/es,
March 2004. Available from URL: http://www.medsafe.govt.nz/profs/ PUartic/es
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5.
PARECOXIB
Associated
with renal impairment
Australia.
Parecoxib can cause renal impairment, with multiple doses associated
with a greater risk, according to a report in the Australian Adverse
Drug Reactions Bulletin. In Australia,
parecoxib is only approved for a single perioperative dose for postoperative
pain, due to concerns about the safety of multiple doses. To date,
Australia's Adverse
Drug Reactions Advisory Committee (ADRAC) has received 20 reports
of parecoxib-associated adverse reactions, 13 of which involved
renal impairment, including four cases of acute renal failure. In
six of these cases, patients had received multiple doses of parecoxib,
up to five, but the other seven had received only one dose. However,
two of these seven patients had risk factors.
Reference:
Australian Adverse Drug Reactions
Bulletin Vol. 23, No.3, June 2004. Available on the Internet at
www.tga.gov.au
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6.
CYCLO-OXYGENASE – 2
INHIBITORS
On
30 September Merck & Co., Inc. announced a voluntary withdrawal
of rofecoxib (Vioxx) from the United States
and worldwide market due to safety concerns of an increased risk
of cardiovascular events (including heart attack and stroke) in
patients on rofecoxib. Rofecoxib is a prescription cyclooxygenase2
(COX-2) selective, nonsteroidal anti-inflammatory drug (NSAID)
that was approved by the US FDA in May 1999 for the relief of the
signs and symptoms of osteoarthritis, for the management of acute
pain in adults, and for the treatment of menstrual symptoms, and
was later approved for the relief of the signs and symptoms of rheumatoid
arthritis in adults and children.
Merck
withdrew rofecoxib (Vioxx) from the market following the recommendations
of the data safety monitoring board overseeing a long-term study
in patients at risk of developing recurrent colon polypsl. This
study was halted because of an increased risk of serious cardiovascular
events, including heart attacks and strokes, among study patients
taking rofecoxib compared with patients receiving placebo.
The
rofecoxib market-withdrawal announcement has come more than five
years after the launch of the product in 1999, when more than 80
million patients have already used this medicine, with the annual
company sales topping US $ 2.5 billion.
The
first trial which showed the association of COX-2 inhibitors with
cardiovascular events came as a surprise result from the Vioxx Gastrointestinal
Outcomes Research (VIGOR) study in 2000
in which 0.4% of the rofecoxib group and 0.1
% of the naproxen group developed myocardial infarction2.
This result was extended by a between-study comparison conducted
by Mukherjee et al.3. The comparison, which included
celecoxib and rofecoxib, implicated both medicines as being associated
with a significantly higher rate of myocardial infarction than placebo.
The authors postulated that COX-2 inhibitors may have a prothrombotic
effect through inhibition of prostacyclin and concluded that 'it
is mandatory to conduct a trial specifically assessing cardiovascular
risk and benefit of these agents'.
Such
a specific trial, however, was never conducted. While the world
debates whether the rofecoxib story deserves a full congressional
review, it is important, now more than ever, to pay critical attention
to the importance of adverse drug reaction (ADR) reporting in a
post-marketing set-up and to the 'signal' generating capabilities
of the WHO global ADR database.
It
is to the credit of the WHO Programme for International Drug Monitoring
that the risk of cardiovascular adverse reactions with rofecoxib-use
was discussed (in early November 2000, well before the VIGOR study
was reported) in the session on 'Drugs of Current Interest', at
the 23rd Annual Meeting of Representatives of the National
Centres participating in the programme. It was pointed out that
within 10 months of its introduction in 2000 in the Netherlands, there
were eig ht reports of cardiovascular problems with four fatalities
associated with rofecoxib use; all four cases occurred within four
days of commencing therapy and one case occurred two hours after
taking the first tablet. It also came to light that there had been
one report of a fatality in Malaysia, three reports of cardiac failure in Australia
and a total of five reports with
various cardiovascular events in Portugal.
COX-2
inhibitors and cardiovascular events were also discussed during
the 25th and 27th Annual Meetings of the Programme.
Data from the New Zealand Intensive Medicines Monitoring Programme
(IMMP) database demonstrated a higher proportion of prothrombotic
events and a shorter time to onset of death associated with the
use of COX-2 inhibitors than with comparator drugs (that is, all
other drugs in the IMMP cohorts for the proportion of prothrombotic
events and versus omeprazole in the survival analysis). The only
identifiable difference to explain the shorter survival was the
higher rate of myocardial infarction and stroke. A cohort of 32
630 patients on celecoxib (mean age 63 years) and 26 666 on rofecoxib
(mean age 58 years) was reviewed; ischaemic heart disease was the
fourth most common type of event reported for celecoxib and rofecoxib.
Of note, there was no difference in rate between the two but celecoxib
had twice the rate of cardiac dysrhythmias. Deaths were most commonly
represented in the cardiovascular system organ classification for
celecoxib and the second most common for rofecoxib.
The
WHO Collaborating Centre for International Drug Monitoring uses
the BCPNN (Bayesian Confidence Propagation Neural Network) data
mining method, to assess disproportionality of a specific ADR-drug
combination against the ADR distribution for all drugs in the global
ADR database. Of interest is the paper by Zhao et al4
who used the BCPNN method to compare the renal-related adverse drug
reactions between rofecoxib and celecoxib, from ADR reports in the
WHO database at the end of the second quarter of 2000. They concluded
that rofecoxib had greater renal toxicity than celecoxib and other
traditional NSAIDs; and that, this negative renal impact may have
the potential to increase the risk for serious cardiac and/or cerebrovascular
events. This paper was published in 2001, nearly three years ahead
of the current company withdrawal.
A
similar analysis of the WHO global database for celecoxib has also
shown an association of myocardial infarction with celecoxib use
('Signal' 2001-09, Restricted document from the WHO Collaborating
Centre for International Drug Monitoring). At the time Pharmacia
Corporation had responded that it was likely a false-positive association.
Sulphonamide reaction terms were reported significantly more frequently
with celecoxib compared to rofecoxib in the WHO database (overall
sulphonamide relative reporting rate 1.8, 95%CI 1.6-1.9)5.
Amongst these type of reactions, fatal reactions were reported 80%
more often (relative reporting rate 1.8, 95%CI 0.94.0). These observations,
as well as the recent experience with rofecoxib should caution us
against dismissing the findings with
celecoxib, articularly amidst concerns that the cardiovascular
effects of rofecoxib may be a class effect, applicable to all COX-2
selective inhibitors6,7.
References:
- Merck
& Co Press
Release, 30 September 2004. Available on the Internet at www.merck.com
- Bombardier C, Laine L, Reicin A,
et al. Comparison
of upper gastrointestinal toxicity of rofecoxib and naproxen in
patients with rheumatoid arthritis. New Engl J Med 2000; 343: 1520-1528.
- Mukherjee
D, Nissen SE,
Topol EJ. Risk of cardiovascular events associated with selective
COX-2 inhibitors. JAMA 2001;286:954-959.
- Zhao
SZ, Reynolds MW, Lejkowith J, Whelton A, Arellano FM. A comparison of renal-related adverse drug
reactions between rofecoxib and celecoxib, based on the World
Health OrganizationjUppsala Monitoring Centre safety database.
Clin Ther 2001; 23(9): 1478-1491.
- Wiholm
BE. Identification of sulfonamide like adverse reactions to celecoxib
in the World Health Organization database. Curr Med Res Opin 2001;
17(3): 210-216
- Editorial.
Lessons from the withdrawal of rofecoxib. BMJ 2004; 329: 867-868
- Press Release. EMEA to review COX-2 inhibitors.
http://www.emea.eu.int,
22 October 2004, EMEA/117908/2004.
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7.
CELECOXIB
Withdrawn
in Turkey
Turkey. The Market Authorization Holder for celecoxib (Celebrex)
in Turkey
has voluntarily withdrawn celebrex from the Turkish market. The
Turkish Human Medicinal Products Advisory Committee had earlier
directed that the labels of celecoxib (Celebrex 100 mg and 200 mg)
capsules should state that the product may not be used by individuals
who have obstructive arterial disorder of the cardiovascular system
or the central nervous system.
Reference:
Press
Release from the Turkish Ministry of Health and Communication from
the Turkish Clinical Pharmacological Society, November 2004.
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8.
VALDECOXIB
Label
updated to warn about skin reactions
Worldwide. Pfizer is
updating the valdecoxib (Bextra) label worldwide with information
on a rare skin reaction, and has advised of an increase in cardiovascular
events in patients undergoing coronary bypass surgery who receive
either valdecoxib alone or in combination with parecoxib. Data from
spontaneous reports show that the skin reaction has been reported
at a greater rate with valdecoxib than with other cyclo-oxygenase-2
inhibitors, and that the risk mainly exists in the first two weeks
of valdecoxib therapy.
Reference:
Media Release
from Pfizer, 15 October 2004. Available on the Internet at www.pfizer.com
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9.
CYCLO-OXYGENASE-2
INHIBITORS
Plans
to review all medicines in this class
Europe.
Following the worldwide withdrawal of rofecoxib (Vioxx), the European
Medicines Agency (EMEA) has been asked by the European Commission
to conduct a review of all cyclo-oxygenase-2 (COX-2) inhibitor medicines.
The Agency's scientific committee responsible for human medicines
(CHMP) will look at newly available data on all aspects of cardiovascular
safety of the COX-2 inhibitors celecoxib, etoricoxib, lumiracoxib,
parecoxib and valdecoxib, including thrombotic
events (heart attack and stroke) and cardiorenal events (e.g. hypertension,
oedema and cardiac failure).
The objective of this review
is to assess whether there is a need to make changes to existing
marketing authorizations including labelling throughout the whole
of the European Union and whether additional studies are needed.
When completed, the outcome
of the review will be posted on the Agency's website. In the meantime
the agency reminds that the earlier warnings, issued on 6 October
2004, valid:
- Rofecoxib
(Vioxx) has been withdrawn due to serious thrombotic events. Patients
on rofecoxib should be viewed and alternative treatment considered.
When considering, treatment with other COX-2 inhibitors, prescribers
should consult the latest version of the summary of product characteristics,
particularly for cardiovascular events.
- Patients
who were on rofecoxib should consult their doctor at the next
available opportunity to discuss their treatment options.
Reference:
EMEA Press
Release, Ref. EMEA/117908/2004. Available on the Internet at www.emea.eu.int
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10.
INFLUENZA VIRUS VACCINE
Interactions
with drugs
New
Zealand. In a recent
Prescriber Update article posted on the New Zealand Medsafe website,
prescribers are advised to be alert for signs of toxicity following
influenza vaccination in patients receiving antiepileptic drugs
or warfarin. Medsafe notes that, in addition to published reports
of warfarin, phenytoin and theophylline toxicity following influenza
vaccination, a report of carbamazepine toxicity has been
received by the Australian Adverse Drug Reactions Advisory Committee,
and a report of elevated International Normalized Ratio (INR) in
a patient receiving warfarin has been received by the Centre for
Adverse Reactions Monitoring, both following influenza vaccination.
It is suggested that inhibition of cytochrome P450 3A4 may be involved
in these interactions, and prescribers are advised to watch for
toxicity in patients receiving drugs metabolized by this enzyme.
Reference:
Prescriber
Update 25(2), November 2004.
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