E-drug: Withdrawing drugs: nefazodone, the start of the latest saga
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[Interesting and important commentary in last week's Lancet from the Uppsala
Monitoring Centre (for adverse drug reactions) on a) that nefazodone has not
been withdrawn in the US but in many other countries and b) how little
effect regulatory and industry warnings have on prescribing practices.
Consumer activism and mass media needed, but then we need more transparency
to enable them to communicate! KM.]
The Lancet 2003; 361: 1240-1 (12 April)
Commentary
Withdrawing drugs: nefazodone, the start of the latest saga
In 1982 the analgesic benoxaprofen was withdrawn in the UK but still
marketed in the USA. Benoxaprofen had been promoted in the USA as a harmless
drug even though the company was aware of fatal liver reactions.1 The US
Food and Drug Administration (FDA) afterwards insisted that companies submit
reports of adverse events to them--no matter from which country the report
originated. This reporting was in addition to the international reporting
system set up by WHO in the International Programme of Drug Monitoring in
1968. The Council of International Organisations of Medical Sciences
(affiliated to WHO), the International Conference on Harmonisation, and the
European Medicines Evaluation Agency within Europe have all since striven
for safety information, both case reports and analysed information and
decisions, to be exchanged.
In the USA, Public Citizen, which represents 125 000 consumers and is very
active in drug safety, is petitioning the FDA to ban nefazodone, a new
antidepressant which has been linked with serious liver toxicity.2,3 Public
Citizen quotes 53 cases of liver injury, including 21 cases of liver failure
from which 11 patients have died in the USA. There have been over 4�5
million prescriptions written for this drug, but the petition claims that
the drug has no unique advantages over existing drugs.
In other countries the petition states that liver toxicity has been studied
in Australia in 1998 as well in the USA and Spain. In Sweden, the regulatory
Medical Products Agency asked for a requirement that liver function should
be monitored in all patients on nefazodone, with the result that the company
withdrew nefazodone in January, 2003, throughout Europe, since other
European countries were thinking of the same action. In India, though, there
is a debate about the drug. Nefazodone is still available there, as are
cisapride, dipyrone, phenylbutazone, phenylpropanolamine, astemizole, and
terfenadine, which have also been withdrawn elsewhere.4 So, with all the
duplicated international safety-systems and information, are there new
lessons from the nefazodone case?
The number of patients who die or have serious adverse reactions because of
drugs is small relative to their use and their effectiveness. But what is an
acceptable risk and to whom? Regulators try to answer this question on
behalf of the public when they withdraw a drug, but it is a task with a huge
subjective component. There is even a controversy about the concept of
regulators doing comparative analyses between therapies, which would at
least add some objectivity. Often, early information on safety is based on
case reports, which are difficult to interpret for causality even when they
contain adequate information. Even with complete epidemiological
information, how can risks be compared? For instance, the greater chance of
dying from an overdose of a tricyclic antidepressant versus a drug which is
safer in overdose but sometimes causes liver damage? Such basic information
is still not easy to find, and takes a long time to assemble for a new drug
on the market. Regulatory decisions are still made in secret: there is no
scientific account of the information and logic that supports them. It is
urgent that safety regulation is made transparent, so that the arguments by
regulators in different settings can be weighed.5
Good information for prescribers about drug effectiveness and risks is a
priority, so that they can help their patients come to an informed choice
about treatment. This information should include the relative effectiveness
and risks of other treatment options, bearing in mind that none is totally
safe.
With nefazodone, a sensible recommendation from Sweden was rejected by the
company. This decision may have been on the grounds that the extra effort by
doctors to monitor liver function would make the drug unpopular as a
first-line treatment and therefore make it economically non-viable for the
company. This kind of economic thinking (including the cost of possible
legal actions) has resulted in several drug withdrawals, sometimes
selectively and not primarily because of safety. Currently, however,
regulatory or industry warnings seem to produce little effect on prescribing
practices. Liver monitoring was recommended for the antidiabetic
troglitazone, but only about 5% of patients had the full recommended
monitoring.6 After repeated warnings about contraindications to cisapride
and cerivastatin, the reduction in contraindicated use was about 2%.7
Recommendations have been made about how best to communicate new information
on safety.8,9 It is now time to consider communication seriously, and not
just to blame the recipients of communication for their laxity. Certainly,
there is no alternative to the crude withdrawal of drugs if important safety
messages are ignored.
In the past, efforts have focused on getting reports on adverse drug
reactions and pharmacoepidemiological data, and with almost no critical
evaluation of whether the new international procedures mentioned above are
helpful in improving drug safety. Systems have been replicated uncritically.
I know of neither national nor international pharmacovigilance programmes
which have built-in processes to assess their overall public-health value.
Pointing to the number of drugs withdrawn does not mean to say they were the
right drugs, nor that overall the decisions gave public or individual
health-benefits.
Consumer activism and coverage by the mass media weigh heavy with both
industry and regulators. The efforts of globally understaffed safety experts
to make consistent decisions are easily subverted by public or political
pressure, or both. Transparency would help the mass and academic media
industry to communicate issues more appropriately.
I Ralph Edwards
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Uppsala Monitoring Centre, S-753 20 Uppsala, Sweden
(e-mail:ralph.edwards@who-umc.org)
1 Biscarini L. Non-steroidal anti/inflammatory drugs. In: Dukes MNG, Aronson
JK, eds. Meyler's side effects of drugs, 14th edn. Amsterdam: Elsevier,
2000: 266-67.
2 Public Citizen. Petition to the FDA to ban the antidepressant drug
nefazadone (SERZONE) (HRG publication #1657). March 6, 2003:
http://www.citizen.org/publications/release.cfm?ID=7233 (accessed March 31,
2003).
3 Public Citizen. Public Citizen calls on FDA to ban antidepressant Serzone.
March 6, 2003: http://www.citizen.org/pressroom/release. cfm?ID=1351
(accessed March 31, 2003).
4 Sanjay AP, Lakshmi PK, Rao BC, Sahni P. Pharmaceutical companies and the
third world. Lancet 2003; 361: 1136.
5 Abraham J. The science and politics of medicines control. Drug Saf 2003;
26: 135-43. [PubMed]
6 Graham DJ, Drinkard CR, Shatin D, et al. Liver enzyme monitoring in
patients treated with troglitazone. JAMA 2001; 286: 831-33. [PubMed]
7 Smalley W, Shatin D, Wysowski DK, et al. Contraindicated use of cisapride.
JAMA 2000; 284: 3036-39. [PubMed]
8 Edwards IR, Hugman B. The challenge of effectively communicating
risk-benefit information. Drug Saf 1997; 17: 216-27. [PubMed]
9 van Grootheest ACK, Edwards IR. Labelling and 'Dear Doctor' letters: are
they noncommittal? Drug Saf 2002; 25: 1051-55. [PubMed]
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