Metamizole sodium

from Wikipedia, the free encyclopedia
Structural formula
Structure of metamizole sodium
General
Non-proprietary name Metamizole sodium (INNv)
other names
  • [(1,5-Dimethyl-3-oxo-2-phenylpyrazol-4-yl) -methylamino] methanesulfonic acid, sodium salt
  • Noramidopyrine methanesulfonic acid sodium salt
  • Dipyrone
  • Methampyrone
  • Novaminsulfone
  • Sulpyrine
Molecular formula C 13 H 16 N 3 NaO 4 S
External identifiers / databases
CAS number
PubChem 522325
DrugBank DB04817
Wikidata Q422761
Drug information
ATC code

N02 BB02

Drug class

non-acidic non-opioid analgesic , antipyretic

Mechanism of action

Unknown

properties
Molar mass 333.34 g mol −1
Physical state

firmly

Melting point
  • 224.5–227 ° C (metamizole sodium)
  • 180 ° C (metamizole sodium monohydrate)
  • 131–132 ° C (decomposition, noramidopyrin methanesulfonic acid)
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances

Metamizole Sodium Monohydrate

08 - Dangerous to health

Caution

H and P phrases H: 361
P: 281
Toxicological data

4351 mg metamizole sodium monohydrate kg −1 ( LD 50 ,  rat ,  oral )

As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Metamizole sodium , or metamizole for short , is an analgesic and fever-lowering agent from the group of non-acidic non-opioid analgesics . Other common names of the active ingredient are Dipyrone and Novaminsulfon . Chemically, it is a pyrazolone - derivative , the name derives from Met hyl, Ami no and Pyra zol from. The actual active ingredient 4-methylaminophenazone (4-methylamino-1,5-dimethyl-2-phenyl-1,2-dihydro-3 H -pyrazol-3-one) is formed in the organism by splitting off the sulfonate and the associated methylene group .

Because of the rare, serious side effect of agranulocytosis , metamizole was not approved in many industrialized countries, especially in the English-speaking world, but also in other areas (e.g. in Scandinavia and Japan ), or an existing approval was revoked. In the German-speaking countries, on the other hand, the use of prescription drugs outside of the approved indications is still widespread, despite health and liability risks.

The active ingredient is also used in veterinary medicine as an acute pain reliever, and it is also approved for food-producing animals.

The drug was launched on the German drug market in 1922 by the Hoechst company as Metamizol-Na under the trade name Novalgin .

The sodium salt of metamizole or its water- crystallized form metamizole sodium monohydrate ( Ph. Eur. ) Is used pharmaceutically . Metamizole sodium monohydrate is a white to almost white, crystalline powder that is very easily soluble in water, soluble in ethanol 96% and practically insoluble in dichloromethane . Metamizole is not used medicinally in the acid form.

Furthermore, a calcium salt ( metamizole-calcium ) and magnesium salt ( metamizole-magnesium ) are described.

Indications

Metamizole is approved in the countries of the European Union in which it is marketed for the following indications:

  • acute severe pain after trauma or surgery,
  • painful colic,
  • Tumor pain,
  • other acute or chronic pain, if other therapeutic measures are contraindicated,
  • high fever that does not respond to other measures.

The suppliers of metamizole preparations in the European Union are obliged to publish the areas of application as well as restrictions on use in their package inserts and specialist information .

The Drugs Commission of the German Medical Association (AkdÄ) has repeatedly warned that Metamizol should only be prescribed strictly within the above indications. Apparently, however, metamizole is also often used for mild or moderate pain and (despite effective and less risky alternatives) as a first-line therapy for complaints such as back pain. With such use of metamizole, which is still not covered by the approval in Germany (" off-label use "), the risk-benefit ratio is unfavorable, about which the doctor informs the patient carefully and in accordance with the care requirements of medical liability law Check for signs of dangerous side effects. The use of metamizole is only justified if paracetamol , nonsteroidal anti-inflammatory drugs (NSAIDs) or opioids are insufficient or may not be given. Otherwise, “in the event of damage, the prescribing doctor is legally in a critical situation”.

Contraindications

Contraindications for the administration of metamizole are a known intolerance, diseases of the blood-forming cells , hepatic porphyria (congenital or acquired disorder of the production of the red blood pigment ) and a glucose-6-phosphate dehydrogenase deficiency . Metamizole did not show any teratogenic effects in animal studies , but its use during pregnancy is not recommended due to a lack of data in humans . It is contraindicated to use in the last trimester of pregnancy, during breastfeeding and in babies under three months of age.

Pharmacokinetics

Metamizole, which is itself a prodrug , is hydrolyzed to the pharmacologically active 4- N -methylaminoantipyrine (4-MAA). Metamizole preparations are administered intravenously, intramuscularly, rectally and (as tablets and drops) orally. When administered intravenously, metamizole can no longer be detected in the blood after 15 minutes. After oral administration, it does not enter the blood plasma, but is quantitatively not enzymatically hydrolyzed to 4-MAA in the gastrointestinal tract . The latter is then almost completely absorbed. The bioavailability of methylaminoantipyrine is around 90%. 4-MAA is metabolized in the liver ( hepatic ) and excreted mainly via the kidneys ( renal ). The plasma half-life and duration of action are approximately 2.5 hours. Simultaneous food consumption can lead to a slower absorption of orally administered metamizole and thus to a slightly delayed onset of action.

Mechanism of action

The exact mechanism of action of metamizole is unclear. Among other things, the involvement of 5-HT or opioid metabolism or the cGMP signaling pathway are discussed. It has been known since the 1980s that metamizole acts as a cyclooxygenase inhibitor. According to a physiological study from 2015, metamizole blocks TRPA1 - ion channels in pain receptors ( nociceptors ).

In addition to its pain-relieving and fever-lowering effects, metamizole (in high intravenous doses) may have an antispasmodic ( spasmolytic ) effect , which is explained by the opening of potassium channels and the reduced influx of calcium into the smooth muscles . Metamizole is therefore used for pain therapy in colic of the biliary and urinary tract.

Side effects

About half of the side effects recorded in the German spontaneous reporting system are skin changes, including life-threatening ones such as Stevens-Johnson syndrome (6.5%) and Lyell syndrome (7.8%). About eight percent of the side effects recorded in the German spontaneous reporting system were grouped under psychiatric disorders. In addition to confusion and drowsiness ( somnolence ), this also includes fear , delirium , depression , restlessness ( agitation ), hallucinations , poor concentration , sedation and language disorders in a few individual cases . The disturbances can persist for a few hours even with low doses.

According to an overview study from 2016, metamizole significantly increased the gastrointestinal bleeding risk in the stomach area - depending on the individual study - by a factor of 1.4 to 2.7 ( relative risk ). Isolated cases of acute renal failure with acute interstitial nephritis of a non-destructive nature have been reported. Also, nausea and vomiting, sometimes a harmless red coloration of urine by metabolites.

In principle, the side effects can be increased with parenteral administration .

Agranulocytosis

Acute agranulocytosis is a disorder in the way in which the bone marrow produces granulocytes , a subtype of white blood cells ( leukocytes ). Triggering by metamizole can occur in a very variable time interval (one day to several months) after the first administration. Since metamizole-induced agranulocytosis can be fatal, blood tests and discontinuation of the medication immediately after the first symptoms are imperative.

Symptoms local infections with a sore throat, mucosal damage (can first ulcers ), fever and chills , and later a generalization of the type infection ( sepsis ) may occur. In addition to switching off the trigger, antibiotics and possibly granulocyte transfusions or stimulation factors ( G-CSF ) are given as therapy . When the trigger is discontinued, the educational disorder is often reversible, but not or too late in a relevant number of cases. Even in countries with highly developed medical care, such as Sweden and Germany, nearly one in four (23% and 23.6%) of those who developed agranulocytosis on metamizole died. In addition to agranulocytosis, there are also cases with a blood count disorder ( neutropenia ), but without clinical symptoms.

Schematic structure of the bone marrow with precursors of white blood cells (leukocytes) and red blood cells ( erythrocytes )

In parallel to the increase in the prescriptions of Metazol in Germany since 1990, there has been an increase in spontaneous reports of agranulocytoses caused by metamizole: While an incidence of less than ten cases was reported in 1990, the average number of reports by 2010 was over 30 and in 2012 at over 50 per year. In two thirds of the cases, agranulocytosis occurred within 6 weeks of (continuous or temporary) ingestion, in 30.5% within 7 days, and in 18 cases immediately after one or two uses. 38 cases (23.6%) were fatal. In 1986, a study paid for by the German manufacturer Hoechst came to an estimate of the frequency of only 1.1 per 1 million applications per week. However, this study was heavily criticized for serious methodological errors. In fact, a Swedish study from 2002, when evaluating the systems of personal drug statistics and medical reporting requirements there, found a much higher risk of agranulocytosis of at least 1 per 1439 prescriptions. A comparable study from 2014, which was able to use the data from the largest German statutory health insurance company ( Techniker Krankenkasse ), confirmed the Swedish results from 2002 on an even larger database.

Agranulocytosis has not yet been described in animals. Only in horses was leukopenia found after repeated use of high doses .

Anaphylactic, anaphylactoid and allergic reactions

If the injection speed is too high for intravenous injection of metamizole, there is a 0.1 to 1% risk of anaphylactic shock , a life-threatening condition that can occur very quickly and carries a 25% risk of death. Anaphylactic shock can also occur after oral ingestion.

In 1980, the Federal Health Office in Germany asked the manufacturers about 260 such shock cases that were attributed to metamizole, 205 of them after injections and 54 after tablets and suppositories. According to the reports, 35 of the total number were fatal.

Because of this risk, injections with a dose of more than 1 gram have not been permitted in Italy since 1979 and in Egypt since 1983.

People who are prone to allergic reactions, asthma or chronic respiratory infections can develop a strong allergic skin reaction up to an asthma attack. If allergies to analgesics or the sweetener saccharin are present, special care should be taken.

Inhibition of platelet aggregation

A reversible inhibition of platelet aggregation and thus delayed blood clotting is known. In laboratory terms, this is comparable to the effects of other painkillers in the NSAID group . This can reduce the effectiveness of the stronger platelet aggregation inhibitor acetylsalicylic acid if taken at the same time.

Interactions

Metamizole causes a decrease in the ciclosporin serum level, which is why this must be monitored if used at the same time. Furthermore, the effect of diuretics can be weakened. Cimetidine can increase metamizole plasma concentrations by approximately 70%.

Significance in health policy ( pharmacovigilance )

2015 a research group published at Oxford University an analysis of the global responses of authorities of the Food and Drug Reports of deaths caused by medicine after the marketing authorization. For the period from 1950 to 2013, 95 drugs were found for which the approval was withdrawn due to documented deaths after the market launch. However, in 16 of the 95 cases, the revocation varied from country to country. Metamizole was analyzed in more detail as a prime example of a serious inconsistency. The first death was reported here in 1952, but the first bans did not take place until 1974 in Norway and Sweden and the last recorded ban in India in 2013, while a number of countries retained their permits. The authors of this study and another from Canada recommended improved monitoring of drugs that have already been approved, more international cooperation and more transparency of the procedures both at pharmaceutical companies and at regulatory authorities.

Approval in an international comparison

Due to the agranulocytosis risk, metamizole was withdrawn from the market or not approved in many countries, including Sweden , Norway , Denmark , Iceland , France , Greece , Ireland , Australia , Japan , Singapore , Canada , the United Kingdom , the USA , Venezuela , Morocco , Nigeria and Saudi Arabia . Metamizole was banned in India from June 2013 to February 2014.

In some countries, metamizole is still available without a prescription. B. in Russia , Poland , Bulgaria , Turkey , Egypt , Brazil , Mexico and Israel .

In the GDR metamizole was available under the brand name Analgin until 1985 and in the Federal Republic until 1987 without a prescription. The approval history in Germany since 1981 is described in a historical account by Peter Schönhöfer and Jörg Schaaber from 2015, also taking into account the interdependence of authorities, the pharmaceutical industry and researchers.

Market position in Germany

Despite the indication restrictions, the number of prescribed daily doses ( defined daily dose , for metamizole defined as three grams for adults) in Germany in the outpatient range from around ten million daily doses in 1990 to 85.8 million daily doses in 2007, more than 110 Millions in 2009 and more than 140 million in 2012. In 2013 alone, the sales value of Metamizole products that were reimbursed by the statutory health insurance in Germany was more than 214 million euros.

For private health insurances (PKV) in Germany, the metamizole product Novalgin from the manufacturer Sanofi (formerly Hoechst AG ) was ranked 16th among the drugs with the most prescriptions and 130th with a share of 0.13% among the drugs with the highest sales. In the same year, a generic product from the manufacturer ratiopharm with the generic name Novaminsulfon achieved third place among the drugs most frequently prescribed in the statutory health insurance sector.

Trade names

Metamizol is available in various dosage forms: tablets , effervescent tablets , drops , suppositories and injection solutions for intravenous or intramuscular administration .

Human medicine

  • Monopreparations : Analgin (D), Berlosin (D), Metagelan (A), Minalgin (CH), Nopain (D), Norgesic N , Novalgin (D, A, CH), Novaminsulfon (D), Nolotil (E), Optalgin (ISR)
  • Combination preparations with metamizole have not been marketable for human medical use in the Federal Republic of Germany since 1987, after the Federal Health Office classified combination medicaments containing metamizole as questionable. Combination drugs containing metamizole are also banned in the USA, Australia, Japan and most European countries. In countries like Brazil, Colombia and Costa Rica such preparations are still sold, e.g. B. Buscopan composto (BR).
  • Würzburg pain drip

Veterinary medicine

  • Monopreparations: Metapyrin (D), Novaminsulfon (D), Novacoc forte (A), Novacen (D), Novasul (A), Vetalgin (A)
  • Combination preparations with butylscopolamine bromide : Buscopan compositum (D, A), Buscosol (D), Spasmium comp. (THERE)

synthesis

Metamizole sodium ( 6 ) can be synthesized from phenazone derivative 1 and benzaldehyde ( 2 ):

Synthesis of metamizole ( 6 ).

This initially produces the imine 3 , which is methylated with dimethyl sulfate and thus forms the quaternary ammonium compound 4 . This is then hydrolyzed to 5 and then finally reacts with the addition of formaldehyde and sodium hydrogen sulfite to form metamizole sodium ( 6 ).

Individual evidence

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  13. ↑ External identifiers or database links for metamizole calcium : CAS number: 51996-59-9, EC number: 257-592-0, ECHA InfoCard: 100.052.339 , PubChem : 21117887 , ChemSpider : 19975821 , Wikidata : Q27289576 . ( Metamizole Hemicalcium ).
  14. ↑ External identifiers or database links for metamizole magnesium : CAS number: 6150-97-6, EC number: 228-161-4, ECHA InfoCard: 100.025.602 , PubChem : 80253 , ChemSpider : 72495 , Wikidata : Q10266679 . ( Metamizole hemimagnesium ).
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  63. ^ Frank Wild: Drug supply for the privately insured 2010: figures, analyzes, private health insurance comparison. WIP ( Wissenschaftliches Institut der PKV ), Cologne 2012, ISBN 978-3-9813569-1-5 , pp. 56 f., 113 and 120, PDF (accessed on June 23, 2017).
  64. ↑ Combination pain relievers . In: Deutsches Ärzteblatt . tape 84 , no. 19 . Deutscher Ärzte-Verlag, May 7, 1987, p. A-1310 ( Announcement of the drug commission of the German medical profession: sales stop for 62 metamizole-containing ).
  65. ↑ Boehringer Ingelheim wants to resell controversial drug. SWR, October 23, 2012, accessed on December 11, 2012 .
  66. ↑ Axel Kleemann , Jürgen Engel, Bernhard Kutscher, Dietmar Reichert: Pharmaceutical Substances - Syntheses, Patents and Applications of the most relevant APIs. 5th edition, Georg Thieme, Stuttgart / New York 2009, ISBN 978-3-13-558405-8 , pp. 860-861.