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E-DRUG: Dipyrone/metamizol


  • From: Andrew Herxheimer <Andrew_Herxheimer@compuserve.com>
  • Date: Fri, 9 Apr 1999 15:45:53 -0400 (EDT)

E-drug: Dipyrone/metamizol
----------------------------------------------------------

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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