E-drug: Banning metamisole in Moldova (5)
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Dear Natalia,
This is a remark from Dr.Herxheimer, had been sent more then a two years
ago. But it is still relevant to this question.
Prof. Vladimir S. Shoukhov, M.D., D.Sci (Med)
+7 (095) 930 4105
shoukhov@yahoo.com
April 1999
The following question and answer will interest e-druggers.
Andrew Herxheimer
Andrew_Herxheimer@compuserve.com
DIPYRONE (METAMIZOL): RESTORED TO GOOD REPUTE ?
translated from:
P.S. Schonhofer: Internistische Praxis 1999; 39: 184-185
Question:
Dipyrone (NOVALGIN etc.) has been re-licensed without restrictions
in Sweden. What implications does this have in Germany?
Answer:
1. The licensed indications for dipyrone in Germany have not
changed since 1986. There is no recent new scientific evidence
affecting the state of knowledge. The licensed indications are:
a) acute severe pain due to trauma or surgery,
b) colic pain,
c) cancer pain or other severe acute or chronic pain, but only if
other therapeutic interventions have failed or are contra-indicated,
d) severe hyperpyrexia, when other measures have failed.
Therefore, dipyrone is not licensed for pain such as migraine
headache, since other non-opioid analgesics (acetylsalicylic acid,
paracetamol or naproxen) are equally effective and other drugs are
even superior, such as sumatriptan or ergotamine. Dipyrone is also
not to be considered a substitute for acetylsalicylic acid,
paracetamol or diclofenac in the WHO-guideline for control of pain,
since it poses a higher risk to the patient than the other drugs at
equieffective doses.
The regulations of the German drug law are not invalidated by
claims of 'therapeutic freedom' made by the medical profession.
The attending physician who has used dipyrone outside the
approved indications is legally liable in cases of suspected drug-
induced damage. The onus is on the physician, not the patient, to
prove that the therapeutic choice was appropriate. This is difficult to
achieve, especially since few data appear to exist to show that
dipyrone is more effective or safer than other non-opioid analgesics.
2. The producer of dipyrone and some scientific advisers have
repeatedly stated that the risk of developing agranulocytosis due to
dipyrone is as low as 1:1 million. This is misleading and false. The
results from the IAAAS (International Agranulocytosis and Aplastic
Anemia Study) (5) give as dimension of the denominator "1 week of
use", while the incidence of agranulocytosis is usually given as
cases per year. So one has to multiply the incidence of dipyrone-
induced agranulocytosis in the IAAAS (1:1 million) by 52 (weeks) in
order to obtain the correct units (year). This gives the figure of 1
case of agranulocytosis in 20,000 users of dipyrone per year
(1:20,000), a realistic value.
In 1985 the IAAAS documented about 100 cases of dipyrone-
Induced agranulocytosis in the Federal Republic of Germany. The
use of dipyrone was close to 10 million packages prescribed for
about 3 million patients in the same year. This gives 1 case of
agranulocytosis in 30,000 users (1:30,000). This value is in
agreement with data calculated from the international literature by
the Federal Health Office in 1982 (1). Both calculations show that
the risk of dipyrone-induced agranulocytosis is in fact about 50-fold
higher than the "weekly" risk dimension of 1: 1 million described by
the IAAAS (5) and widely propagated by the producer.
3. Dipyrone is a highly immunogenic compound. It not only causes
allergic reactions in the bone marrow but also the whole spectrum of
severe immunogenic diseases including interstitial nephritis,
hepatitis, alveolitis, and pneumonitis as well as severe skin
diseases such as Lyell or Stevens-Johnson syndrome (2). Dipyrone
often causes vasculitis which clinically presents as shock-syndrome
of acute or delayed onset. Data from our hospital-based adverse
drug reactions monitoring system suggest that dipyrone-induced
shock reactions of the vasculitis type occur about 10 times more
often than agranulocytosis. The mortality of this reaction appears to
be about 30-50 % in our patients: both substitution of volume and
vasoconstrictor measures fail to raise blood pressure due to the
destruction of the vascular endothelial cells by the dipyrone-induced
hypersensitivity vasculitis.
This dimension of the risks induced by dipyrone is neither published
nor discussed by producers or users (4), even though information is
available on the high risks for many immunogenic diseases in
addition to agranulocytosis (2).
4. It cannot be argued that dipyrone was re-licensed in Sweden,
since the Swedish authorities wanted to revise a false evaluation of
the risks of the drug in 1973 (3). The clinician who described the
special risk of agranulocytosis by dipyrone in Sweden is no longer
professionally active. On the other hand, the head of the
department of drug safety in the Swedish drug agency appears to
be close to the interests of the main dipyrone producer Hoechst
which can be inferred from his participation in the IAAAS.
It appears strange that a responsible official of a drug regulatory
office is allowed to participate in projects sponsored by the
pharmaceutical industry and to profit in his scientific career from
such support. Suspected similar activities caused the resignation
even of the president of the German Federal Health Office (BGA) in
the mid-eighties.
References:
1. Anonymous. Dipyrone Hearing of the German Drug Authority.
Lancet 1986;II: 737.
2. A.T.I. Arzneimittelinformation: Vom Verdacht zur Diagnose,
2. Aufl., S. 5-14. Berlin 1998.
3. Boettiger LE, Westerholm B. Drug-induced blood dyscrasia in
Sweden. Br.med. J. 1973;III:339-343.
4. Gericke D. Editorial: Eindrucksvolles Comeback.
Munch.med.Wschr. 1997; 139:110.
5. Kaufmann DW et al. The Drug Epidemiology of Agranulocytosis
and Aplastic Anemia. Monographs in Epidemiology and Statistics,
Vol.18. Oxford University Press 1991.
Prof Dr. P.S. Schonhofer
Institute of Clinical Pharmacology
ZKH Sankt-Jorgen-Strasse
D-28205 Bremen, GERMANY
e-mail: klin.pharm@zkhstjuergen.bremen.de
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