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Feb. 23, 2005 — The European Medicines Agency has restricted
use in the European Union of cyclooxygenase-2 (COX-2) inhibitors,
including celecoxib, valdecoxib, parecoxib, lumiracoxib, and etoricoxib,
due to the increased risk of adverse cardiovascular events associated
with their use. The U.K. Committee on Safety in Medicines is withdrawing
a paracetamol 325-mg/dextropropoxyphene 32.5-mg combination product
from the U.K. market because the risk of fatal toxicity associated
with its use outweighs the benefits of its poorly established efficacy.
Use of COX-2 Inhibitors Restricted in EU Due to Cardiovascular
Risk
On Feb. 17, the European Medicines Agency (EMA) approved revisions
to the prescribing information for cyclooxygenase-2 (COX-2) inhibitors
in the European Union (EU) to warn healthcare professionals of the
increased risk of adverse cardiovascular events, including myocardial
infarction and stroke, associated with their use.
The revisions were based on a review of available data by the Committee
on Medicinal Products for Human Use (CHMP) and are considered an
interim measure, subject to formal approval in April.
The new use restrictions apply to medications available in the
U.S. such as celecoxib and valdecoxib (Celebrex and Bextra, made
by Pfizer), as well as COX-2 inhibitors available only in the EU,
including parecoxib (Dynastat, made by Pfizer), lumiracoxib (Prexige,
made by Novartis), and etoricoxib (Arcoxia, made by Merck).
Use of COX-2 inhibitors is now contraindicated in patients with
ischemic heart disease or a history of stroke. Etoricoxib is also
contraindicated in patients with uncontrolled hypertension.
According to the EMA, the available data suggest an association
between COX-2 inhibitor exposure (dose and duration) and cardiovascular
risk. Use of these medications should therefore be restricted to
the lowest effective dose for the shortest possible duration of
treatment.
The EMA advises caution when prescribing COX-2 inhibitors for patients
with risk factors for heart disease, including hypertension, hyperlipidemia,
diabetes, peripheral arterial disease, and current smoking.
In patients who do not have heart disease but are taking low-dose
aspirin, the balance of cardiovascular and gastrointestinal risks
should be carefully considered. According to the EMA, evidence suggests
that the gastrointestinal safety advantage of COX-2 inhibitors is
substantially reduced when given with aspirin.
COX-2 inhibitors are indicated in the EU for the treatment of rheumatoid
arthritis and other painful conditions. Celecoxib is also indicated
as a treatment for familial adenomatous polyposis. Parecoxib, lumiracoxib,
and etoricoxib are currently under review by the FDA for use in
the U.S.
Co-proxamol Withdrawn From U.K. Market Due to Poorly Established
Efficacy, Risk of Toxicity
On Jan. 31, the U.K. Committee on Safety of Medicines (CSM) announced
the gradual withdrawal from market of Co-proxamol, a paracetamol/dextropropoxyphene
combination product, due to efficacy concerns and the potential
for overdose toxicity. Co-proxamol is indicated for the relief of
mild and moderate pain.
Co-proxamol contains a subtherapeutic dose of paracetamol (325
mg) and dextropropoxyphene (32.5 mg), a weak opioid analgesic that
is known to be toxic in overdose. To minimize disruption of healthcare
provision, Co-proxamol will be withdrawn from the U.K. market over
a period of six to 12 months, and interim guidelines for its use
have been established.
According to the CSM, there is evidence that fatal toxicity can
occur with a small multiple of the normal therapeutic dose; a proportion
of fatalities may be caused by inadvertent overdose. Pharmacokinetic
and pharmacodynamic interactions with alcohol or other central nervous
system depressants further reduce the threshold for fatal toxicity
and may result in fatal apnea or cardiac arrhythmia.
The CSM notes that there is "no robust evidence" for
improved efficacy of the combination product in acute or chronic
use compared with full-strength paracetamol monotherapy; the product
has been listed in the British National Formulary as "less
suitable for prescribing" since 1985.
Responses to a June 2004 inquiry did not lead to the identification
of any patient groups or indications for which objective evidence
of efficacy outweighed the risk of toxicity.
Interim prescribing information for Co-proxamol has been revised
to include contraindications for its use in acute pain, new patients,
and patients younger than 18 years. Its use is restricted to the
second-line treatment of mild to moderate pain in adults.
Use of the product is also contraindicated in patients who are
alcohol-dependent or are considered likely to consume alcohol during
therapy, and in patients who are suicidal or accident-prone.
The CSM has provided healthcare professionals with information
on alternative pain management guidelines and stepwise strategies
for implementation during medication review in normal medical care.
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