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1.
CELECOXIB
Increased risk of cardiovascular events
Europe, New Zealand, USA. Pfizer has announced that the US National Cancer Institute Data Safety and Monitoring Board has stopped drug administration in the Adenoma Prevention with Celecoxib (Celebrex; APC) trial, as the risk of major cardiovascular events was significantly higher in patients receiving celecoxib than in patients receiving placebo. The US FDA and the EMEA have issued statements detailing the preliminary results, and have requested the full results for review(1-4). In the APC study, 2400 patients received celecoxib 400 mg/day, celecoxib 800 mg/day or placebo, for a mean duration of 33 months.
The relative risk (RR) of major fatal or nonfatal cardiovascular events (composite endpoint of cardiovascular death, acute myocardial infarction or stroke) was statistically significantly higher in the celecoxib 400 mg/day group (RR 2.5) and in the celecoxib 800 mg/day group (RR 3.4), compared with the placebo group. Two other celecoxib trials, the Prevention of Spontaneous Adenoma Polyps (PreSAP) trial and the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT), have also been evaluated(4). The PreSAP trial has been stopped, based on the results of the APC trial, although an increased risk of cardiovascular events with celecoxib 400 mg/day compared with placebo was not observed(3). However, the ADAPT study is still ongoing(4). The FDA has issued an Alert for Practitioners regarding the possible increased risk of cardiovascular events in patients receiving celecoxib(4). Physicians are encouraged to inform patients of the evolving information about this risk, and are advised to consider alternatives to celecoxib; when this is not appropriate, the lowest effective celecoxib dose should be used. The New Zealand Medicines Adverse Reactions Committee has issued similar advice with regard to all COX-2 inhibitors, broadly supporting the UK National Institute of Clinical Excellence guidance that was distributed to all New Zealand general practitioners(5).
References:
- FDA Statement, 17
December 2004. Available
on the Internet at www.fda.gov
- EMEA
Statement, EMEA/205831/2004, 17 December 2004. Available on the
Internet at www.emea.eu.int
- EMEA
Statement, EMEA/212271/2004, 22 December 2004. Available on the
Internet at www.emea.eu.int
- FDA
Alert for Practitioners (celecoxib),17 December 2004. Available
on the Internet at www.fda.gov
- Medsafe
Media Release, 21 December 2004. Available on the Internet at
www.medsafe.govt.nz
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2.
GLUCOSAMINE
Concerns
about hypercholesterolaemic effects
Denmark.
The Danish Medicines Agency has sent out a 'rapid alert' notification
to all European regulatory agencies, including the EMEA, requesting
any information about a potential cholesterol-raising effect of
the nutritional supplement, glucosamine. The product is marketed
for some forms of osteoarthritis and in several countries, including
Denmark,
is registered as a medicinal product. This move follows an article
in the Danish journal that reported increased cholesterol levels
in three patients, possibly as a result of glucosamine use. There
are 67 side-effect reports associated with glucosamine use in the
Danish Medicines Agency database, most of which are described in
the product summary. However, there are also reports of suspected
adverse effects that are not identified in the product summary,
including increased INR (n = 3), vision disorders (3), peripheral
oedemas (3), dyspnoea (2), pulmonary embolism (1), seizures (1),
myocardial infarction (1), increased liver enzymes (1), an increased
serum creatinine level (1), and an increased cholesterol level (1).
The agency advises that the Swedish authorities have also received
two reports of hypercholesterolaemia. The companies marketing glucosamine
are invited to
join the Danish Medicines Agency in addressing the problem, by submitting
the statutory safety updates.
References: 
- Scrip World Pharmaceutical News No 3000, 29
October 2004.
- Stenver DI. Possible interaction between glucosamine and cholesterol. Reply. Ugeskrift for Laeger 25, No. 44,
October 2004. (Danish;
summarized from a
translation.)
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3.
NAPROXEN
Long-term
study indicates cardiovascular risk
USA.
The US FDA is alerting healthcare providers to emerging information
from a long-term prevention trial/ the Alzheimer's Disease Anti-Inflammatory
Prevention Trial (ADAPT), that the risk of cardiovascular and cerebrovascular
events may increase among patients taking naproxen, a non-steroidal
anti-inflammatory drug (NSAID). The US FDA will be analysing all
available information from these studies to determine whether additional
regulatory action is needed. In the meantime, prescribers are cautioned:
to carefully weigh the benefits and risks in patients currently
on naproxen therapy, to always prescribe within the recommended
dose of 250-500 mg twice a day and, to advise patients to adhere
to the recommended daily dose indicated in over-thecounter naproxen
preparations. Several of the cyclooxygenase-2 (enzyme) specific
inhibitor drugs (rofecoxib, celecoxib etc.) are currently under
investigation for a full understanding of their adverse cardiovascular
effects (see WHO Pharmaceuticals Newsletter No.5, 2004 and section
under 'Celecoxib' in this issue). Naproxen, a nonselective over-the-counter
NSAID, is also being investigated to determine appropriate regulatory
action. The US FDA is planning an advisory committee meeting in
February 2005 to discuss the issues surrounding these drugs.
Reference:
FDA Alert for Health-care Providers
(Naproxen), 23 December 2004. Available on the Internet at www.fda.gov
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4.
Alimemazine - Paracetamol teething mixture
Contraindicated
in children below two years
UK.
The Medicines Healthcare products Regulatory Agency (MHRA) is warning
health-care professionals that a teething mixture containing alimemazine
tartrate and paracetamol, which contains dosing information for
patients over three months of age, is actually contraindicated in
children below two years. Health-care professionals are asked to
consider this product as a potential cause of adverse effects in
any presenting patients, and patients should be advised to destroy
any unused portion of the mixture.
Reference:
News & Updates, NHS, 17
February 2005. Available on the internet at www.druginfozone.nhs.uk
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5.
Cyclooxygenase (COX)-2 Inhibitors
Updated information
Australia,
Europe, India, New Zealand, USA.
Following
the withdrawal of rofecoxib in September 2004 on account of an increased
risk of myocardial infarction and stroke being demonstrated in a
clinical trial, several drug regulatory agencies worldwide have
undertaken a full review of all available data on the cardiovascular
safety of all cyclooxygenase-2 (COX-2) inhibitors. COX-2 inhibitors
belong to a relatively new class of non-steroidal anti-inflammatory
medicines used in the treatment of arthritis. In particular, celecoxib,
etoricoxib, lumiracoxib, valdecoxib and parecoxib are being investigated.
The Australian Therapeutic Goods Administration (TGA), the European
Medicines Evaluation Agency (EMEA) and the New Zealand Medicines
and Medical Devices Safety Authority (MEDSAFE) have all completed
preliminary accelerated reviews of the COX-2 inhibitors and, pending
a full review, have announced interim regulatory restrictions on
the use of these medicines. Preliminary analyses suggest a class-effect,
with an increased risk of cardiovascular adverse events for all
COX-2 inhibitors.
Australia(1):
The
Australian Drug Evaluation Committee (ADEC) made a number of recommendations
to restrict the use of these drugs in Australia.
The
TGA will immediately require manufacturers of COX-2 inhibitors to
place new highlighted explicit warnings in product information about
the increased risk of adverse cardiovascular events from this group
of drugs. The new warning statements are to be highlighted with
a black boxed margin.
The
TGA is also advising people who are taking more than 200 mg a day
of celecoxib (Celebrex) or more than 15 mg a day of meloxicam (Mobic;
Movalis) to review their treatment regime with their doctors.
The
TGA has also accepted a number of other recommendations of ADEC
and has given notice to the relevant companies.
- It
is proposed to cancel the registration of the drug parecoxib (Dynastat)
because of the risk of cardiovascular events. Dynastat is marketed
in Australia and is approved as
a single dose at the time of surgery to reduce postoperative
pa in.
- It
is proposed to withdraw the indication of management of arthritis
of the drug valdecoxib (Valdyne, Dynoral - known in some countries
as Bextra) which is converted to parecoxib in the body. Valdecoxib
has not been marketed in Australia.
Valdecoxib has been associated with an increased risk of cardiovascular
events in cardiac bypass graft patients. The use of valdecoxib
for five days as an analgesic in patients without increased cardiovascular
risk will remain.
- It
is proposed to greatly limit the approved uses of two other COX-2
inhibitors which have not yet been marketed in Australia.
They are etoricoxib and lumiracoxib. In both instances, ADEC was
not sufficiently assured of the safety of these drugs for anything
other than short term use in patients without increased cardiovascular
risk.
People
who are concerned about their use of COX-2 inhibitors should discuss
their treatment with their medical practitioner.
European
Medicines Evaluation Agency(2):
The
following urgent safety restrictions have been taken for COX-2 inhibitors
available in the European Union.
- A
contraindication is introduced for all COX-2 inhibitors in patients
with ischaemic heart disease or stroke.
- As
a further measure, a contraindication is introduced for etoricoxib
in patients with hypertension (high blood pressure) whose blood
pressure is not under control.
- A
warning is introduced for prescribers to exercise caution when
prescribing COX-2 inhibitors for patients with risk factors for
heart disease, such as hypertension, hyperlipidaemia (high cholesterol
levels), diabetes and smoking, as well as for patients with peripheral
arterial disease.
- Given
the association between cardiovascular risk and exposure to COX-2
inhibitors, doctors are advised to use the lowest effective dose
for the shortest possible duration of treatment.
These
are interim measures pending the finalization of the class review.
The Agency's Committee for Medicinal Products for Human Use (CHMP)
also concluded that more research is needed in the field to evaluate
the cardiovascular safety of COX-2 inhibitors, and that ongoing
cardiovascular trials should continue as planned.
Pfizer
Inc. has issued an updated Summary of Product Characteristics (SPCs)
for celecoxib (Celebrex), valdecoxib (Bextra) and parecoxib (Dynastat)
in light of recent EMEA guidance on COX 2 inhibitors. These agents
are now
contra-indicated in patients with:
- Ischaemic
heart disease
- Cerebrovascular
disease
- Class
II - IV congestive heart failure
The
company advises that patients with significant risk factors for
cardiovascular events (e.g., hypertension, hyperlipidaemia, diabetes
mellitus, smoking) or peripheral arterial disease should only be
treated with these drugs after careful consideration. Pareoxib and
valdecoxib should not be used in the treatment of postoperative
pain following coronary artery bypass graft (CABG). Other treatment
options should be considered in the absence of increased therapeutic
benefit from a dose increase in celecoxib and valdecoxib.
New Zealand(3):
The
Ministry of Health advises that anyone taking a COX-2 inhibitor
should follow the advice provided by the Ministry's expert committee,
released in December last year, that COX-2 agents are not recommended:
- for
routine use in patients with rheumatoid arthritis or osteoarthritis
except where the patient is at "high risk" of developing
a serious gastrointestinal adverse effect from other standard
non-steroidal anti-inflammatory agents;
- for
patients at high risk of heart attack or stroke;
- for
patients already taking aspirin;
- for
routine relief of postoperative pain.
Patients
already taking COX-2 inhibitors on a regular basis should discuss
the continuing use of these medicines with their general practitioner
or specialist. Prescribers should discuss with their patients the
available alternatives, and review the risks and benefits of these
alternatives compared with the emerging clinical concerns about
the COX-2 inhibitors, before deciding on the best course of treatment
for that individual. If the patient and prescriber decide that continued
use of a COX-2 inhibitor is appropriate, use of the lowest effective
dose is prudent.
USA(4):
- After
three days of deliberations, an advisory panel to the US FDA decided
that the Widely used COX-2 inhibitors rofecoxib, celecoxib and
valdecoxib all carry serious risks of heart attack and stroke.
The panel recommended that these products should carry strongly
worded 'black box' warnings about these risks.
A WHO Information Exchange note was issued summarizing actions/statements
from various countries.(5)
India(6):
The
Indian National Pharmacovigilance Advisory Committee has recommended
that selective COX-2 inhibitors such as celecoxib, valdecoxib, parecoxib
as well etoricoxib should carry a 'precautionary warning' on their
label saying that they should be used with caution in patients suffering
from coronary heart disease/cardiovascular disorder. The committee
had earlier recommended that the- use of all rofecoxib products
should be discontinued in India.
References:
- TGA
Media Statement, 10 February 2005. Available on the internet at
http:!/www.tga.gov.au
- EMEA
Public Statement, EMEA/62838/2005, 17 February 2005. Available
on the internet at http://www. emea. Eu. int
- MEDSAFE
Alert/Letter, 22 February 2005. Available on the internet at http://www.medsafe.govt.nz
- British
Medical Journal,26 February 2005; 333:440.
- Cyclooxygenase-2
inhibitor medicines. QSM/MC/IEA.111, WHO Information Exchange
System, 28 February 2005.
- Scrip
World Pharmaceutical News No. 3025, 2 February 2005; pg 18.
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6.
Methotrexate
Fatal
adverse effects reported
Japan. Doctors in Japan have reported
831 serious adverse effects associated with methotrexate (Rheumatrex)
to Wyeth K.K., between March 1999 and November 2004; 134 reports
were of fatal adverse effects, including interstitial pneumonia
and myelosuppression. An estimated 100 000 people are taking methotrexate
(Rheumatrex) in Japan. Wyeth K.K.
has warned doctors and patients that methotrexate (Rheumatrex) is
associated with 'life-threatening' and 'sometimes serious' adverse
effects, and has requested that the drug be used carefully. However,
pharmaceutical experts have demanded that the manufacturer and the
government clearly outline the risks associated with methotrexate.
Reference:
Japanese
Media Release, 12
February 2005. Available on the internet at www.japantimes.co.jp
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7.
Cyclo-oxygenase-2
(COX-2)
Inhibitors
To
be available under strict restrictions
New Zealand. Following the recommendations
made by New Zealand's Medicines Adverse Reactions Committee (MARC),
the country's Ministry of Health has decided that COX-2 inhibitors
will be allowed to stay on the market, but with "considerably
stronger warnings"(1). New
Zealand's Medicines and Medical
Devices Safety Authority (Medsafe) has sent a fax to doctors and
pharmacists communicating this decision, along with the following
recommendations (2):
- COX-2
inhibitors should be contraindicated in patients with previous
myocardial infarction (MI) or stroke and perioperatively for cardiac
or vascular surgery, and perioperatively for major surgery in
patients at high cardiovascular (CV) risk.
- Etoricoxib
should be contraindicated in patients with poorly controlled hypertension.
- COX-2
inhibitors should not be used if alternatives exist, and, if used,
the lowest effective dose should be used for the shortest possible
duration.
- Patients
should be reviewed after 2 weeks, with treatment discontinued
in the absence of benefit, then reviewed every 3 months.
- Prescribers
need to be aware that COX-2 inhibitors may exacerbate hypertension,
cardiac failure or oedema.
- Prophylactic
aspirin should not be discontinued.
- All
patients at high CV risk should be informed of the risks with
COX-2 inhibitors.
- Discussions
regarding perioperative use of COX-2 inhibitors should be undertaken
prior to surgery.
Medsafe
is in the process of implementing MARC's recommendations and has
asked that pharmaceutical companies continue with the voluntary
moratorium on direct-to-consumer and professional advertising of
COX-2 inhibitors.
References:
1.
Media Release. Medsafe, 29 April 2005 (http://www.medsafe.govt.nz).
2.
Alert/letter to doctors and pharmacists. Medsafe, 29 April 2005
(http://www.medsafe.govt.nz).
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8.
NSAIDs
Black
box warning for both prescription and OTC products
USA. FDA has requested that sponsors of all non-steroidal
anti-inflammatory drugs (NSAID) make labelling changes to their
products. The FDA has recommended label changes for both the prescription
and over-thecounter (OTC) NSAIDs and a medication guide for the
entire class of prescription products. All sponsors of marketed
prescription NSAIDs, including Celebrex (celecoxib), a cyclooxygenase-2
(COX-2) selective NSAID, have been asked to revise the labelling
(package insert) for their products to include a boxed warning,
highlighting the potential for increased risk of cardiovascular
(CV) events and the well described, serious, potentially life-threatening gastrointestinal (GI) bleeding associated with their use. The agency based
its advice on a review of the regulatory histories and databases
on the various NSAIDs.
Reference:
Drug
Information Page. United States Food and Drug Administration, 16 June 2005 (http://www.fda.gov).
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9.
Valdecoxib
Sales
suspended in more countries
Canada, Europe, India.
Pfizer
has voluntarily suspended the sale of valdecoxib (Bextra) in the
EU countries (1) and in Canada
(2), at the request of the respective regulatory agencies. It may
be recalled that Pfizer agreed to similar actions in the United States (WHO Pharmaceuticals
Newsletter No.2, 2005). The suspension is effective pending further
safety reviews. Health Canada
has stated that satisfactory safety evidence needs to be established
with respect to the review of cardiovascular, gastro-intestinal
and rare but potentially lifethreatening skin reactions such as
Stevens-Johnson Syndrome, toxic epidermal necrolysis and erythema
multiforme. Agencies are advising prescribers not to initiate treatment
of new patients, to monitor carefully patients being treated with
valdecoxib (1) or to switch to alternative therapy, where appropriate
(2). Ranbaxy Laboratories in India has voluntarily discontinued
sales of its valdecoxib formulations (3). Ranbaxy's decision comes
even as valdecoxib is being reviewed by India's
Drug Controller General for its benefit/risk profile. Selective
COX-2 inhibitors such as celecoxib, parecoxib, valdecoxib and etoricoxib
are required to carry a 'precautionary warning' on their labels
and promotional literature in India
(see WHO Pharmaceuticals Newsletter No.2, 2005).
References:
1.
EMEA statement, EMEA/ 121637/2005,
7 April 2005 http://www.emea.eu.int).
2.
'Dear Health-care Professional' letter from Pfizer Canada Inc.,
21 April 2005 (http://www.hc-sc.gc.ca).
3.
Scrip World Pharmaceutical News No. 3048, 22 April 2005
(
http://www.scrippharma.com
).
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10.
Meloxicam
Juvenile
rheumatoid arthritis indication: label updated
USA. The US meloxicam (Mobic) label has been
updated to include warnings about nonsteroidal anti-inflammatory
drug (NSAID)-related cardiovascular (CV) and gastrointestinal (GI)
risks following the addition of a juvenile rheumatoid arthritis
indication. The revised meloxicam (Mobic) labelling includes a black
box warning that states that NSAIDs may increase the risk of fatal
myocardial infarction, CV thrombotic events and stroke, and that
the drug is contraindicated for the treatment of peri operative
pain in the coronary bypass setting; a strengthened warning has
also been added regarding GI adverse events. The Indications section
has been updated to advise consumers to consider meloxicam's benefits
and risks and other treatment options before using meloxicam, and
to use the lowest effective dose for the shortest duration. Similar
language highlighting the CV risk has been added under the Warnings
heading, and language concerning the risk of GI ulceration, perforation
and bleeding has been updated. Warnings of stroke, hypertension
and congestive heart failure, and warnings that NSAIDs can cause
skin reactions have also been added to the label. Information concerning
toxicity and renal injury has moved to the Warnings section from
the Precautions section.
Reference:
Mobic
adds juvenile rheumatoid arthritis indication, cardiovascular black
box warnings. FDA Reports -
Pink Sheet - Prescription Pharmaceuticals and Biotechnology,
22 August 2005, 67: 15, No. 34.
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11.
Ibuprofen
Reports
of StevensJohnson syndrome
Canada. Health Canada has received four reports of
suspected ibuprofen-associated Stevens-Johnson syndrome between
1 January 1973 and 21 February 2005, according to the Canadian Adverse
Reaction Newsletter. All four reports were received after April
2001 and involved patients aged 13-34 years who had received ibuprofen
200-1200 mg/day. The time to reaction onset ranged from the day
of administration to about 15 days after ibuprofen initiation, and
carbamazepine was also identified as a suspect drug in one report.
At the time of the reports, the outcome was unknown for one patient
and three of the patients had not recovered.
Reference:
Canadian
Adverse Reaction Newsletter July 2005, NO.3.
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