Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Metamizole: Difference between pages

{{Short description|Medication}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

{{distinguish|Thiamazole{{!}}methimazole|methazolamide}}

{{Infobox drug

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 464373286

| IUPAC_name = [(2,3-Dihydro-1,5-dimethyl-3-oxo-2-phenyl-1''H''-pyrazol-4-yl)methylamino] methanesulfonic acid

| image =Metamizole2DACS.svg

| image2 =Metamizole monohydrate 3D ball-and-stick.png

| width2 = 250px

| synonyms = Dipyrone ([[British Approved Name|BAN]] {{abbr|UK|United Kingdom}}, [[United States Adopted Name|USAN]] {{abbr|US|United States}}

| JAN = Sulpyrine <!-- https://jpdb.nihs.go.jp/jan/DetailList_en.aspx?keyword=5907-38-0&submit=CAS+Search -->

| tradename = Novalgin, Algocalmin,<ref name=Brune/> Analgin, others<ref name="EMA-list"/>

| routes_of_administration = Oral, IM, IV, rectal

| pregnancy_category = None assigned; no evidence of [[Teratology|teratogenicity]] in animal studies, but use in the third trimester may cause adverse effects in the newborn or [[ductus arteriosus]] (a heart defect) due to its weak NSAID activity.<ref name="Pharmaceuticale Press-2009"/><ref name="Winthrop Arzneimittel GmbH-2013"/>

| legal_AU = Withdrawn<!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->

| legal_AU_comment =

| legal_BR = OTC

| legal_BR_comment =

| legal_CA = Veterinary only<!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_CA_comment = <ref name="Government of Canada-2022">{{Cite web |date=2022-07-18 |title=Notice of Amendment: Addition of Metamizole (Dipyrone) to the Prescription Drug List (PDL) |url=https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/prescription-drug-list/notices-changes/amendment-metamizole.html |url-status=live |archive-url=https://web.archive.org/web/20220830123117/https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/prescription-drug-list/notices-changes/amendment-metamizole.html |archive-date=2022-08-30 |access-date=2023-08-04 |website=Government of Canada}}</ref>

| legal_DE = Rx-only<!-- Anlage I, II, III or Unscheduled -->

| legal_DE_comment = <ref name="Bundesinstitut für Arzneimittel und Medizinprodukte (Federal Institute for Pharmaceuticals and Medical Products)-2009">{{Cite web |date=2009-05-28 |title=Risikoinformationen - Metamizol (Novalgin, Berlosin, Novaminsulfon, etc.): BfArM weist auf richtige Indikationsstellung und Beachtung von Vorsichtsmaßnahmen und Warnhinweisen hin |trans-title=Risk information - Metamizol (Novalgin, Berlosin, Novaminsulfon, etc.): BfArM points out the correct indication and compliance with precautionary measures and warnings |url=https://www.bfarm.de/SharedDocs/Risikoinformationen/Pharmakovigilanz/DE/RI/2009/RI-metamizol.html |url-status=live |archive-url=https://web.archive.org/web/20230518183132/https://bfarm.de/SharedDocs/Risikoinformationen/Pharmakovigilanz/DE/RI/2009/RI-metamizol.html |archive-date=2023-05-18 |access-date=2023-08-04 |website=Bundesinstitut für Arzneimittel und Medizinprodukte (Federal Institute for Pharmaceuticals and Medical Products)}}</ref>

| legal_NZ = Prescription only<!-- Class A, B, C -->

| legal_NZ_comment = <ref name="NZ-prescription">{{Cite web |date=2020-03-06 |title=Recent NZ Gazette Notices Relating to Classification |url=https://www.medsafe.govt.nz/profs/class/recent.asp |access-date=2023-08-04 |website=medsafe.govt.nz |archive-url=https://web.archive.org/web/20230429110025/https://www.medsafe.govt.nz/profs/class/recent.asp |archive-date=2023-04-29 |language=en-nz}}</ref><ref name="medsafe.govt.nz-2019">{{Cite web |date=2019-12-04 |title=Minutes of the 63rd meeting of the Medicines Classification Committee - 10 Oct 2019 |url=https://www.medsafe.govt.nz/profs/class/Minutes/2016-2020/mccMin10Oct2019.htm |url-status=live |archive-url=https://web.archive.org/web/20230610171857/https://www.medsafe.govt.nz/profs/class/Minutes/2016-2020/mccMin10Oct2019.htm |archive-date=2023-06-10 |access-date=2023-08-04 |website=medsafe.govt.nz |language=en-nz}}</ref>

| legal_UK = Withdrawn<!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->

| legal_UK_comment =

| legal_US = Veterinary only (horses)

| legal_US_comment = <ref name="FDA2019horse">{{Cite web |author=FDA's [[Center for Veterinary Medicine]] |date=November 26, 2019 |title=Zimeta (dipyrone injection) - Veterinarians |url=https://www.fda.gov/animal-veterinary/product-safety-information/zimeta-dipyrone-injection-veterinarians |url-status=dead |archive-url=https://web.archive.org/web/20220117110424/https://www.fda.gov/animal-veterinary/product-safety-information/zimeta-dipyrone-injection-veterinarians |archive-date=2022-01-17 |access-date=2023-08-04 |website=FDA}}</ref>

| legal_EU = Legally available

| legal_EU_comment = <ref name="EMA2018"/>

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| bioavailability = 100% (active metabolites)<ref name = deranaes2008/>

| protein_bound = 48–58% (active metabolites)<ref name = deranaes2008/>

| metabolism = Liver<ref name = deranaes2008/>

| elimination_half-life = 14 minutes (parent compound; parenteral);<ref name="Winthrop Arzneimittel GmbH-2013"/> metabolites: {{Val|2|-|4|u=hour}}<ref name = deranaes2008/>

| duration_of_action = {{Val|4|-|6|u=hour}}<ref name="y0"/>

| excretion = Urine (96%, IV; 85%, oral), faeces (4%, IV).<ref name="Winthrop Arzneimittel GmbH-2013"/>

| index_label =

| index2_label =

| CAS_number = 50567-35-6

| CAS_supplemental = <br />68-89-3 (sodium salt)

| PubChem = 3111

| PubChem2 = 522325 <!-- sodium salt -->

| DrugBank = DB04817 <!-- sodium salt -->

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 3000

| UNII = 934T64RMNJ

| KEGG_Ref = {{keggcite|changed|kegg}}

| KEGG = D08188

| ChEBI = 62088

| ChEMBL = 461522

| C=13 | H=17 | N=3 | O=4 | S=1

| smiles = c1ccccc1N2N(C)C(C)=C(C2=O)N(C)CS(=O)(=O)O

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI = 1S/C13H17N3O4S/c1-10-12(14(2)9-21(18,19)20)13(17)16(15(10)3)11-7-5-4-6-8-11/h4-8H,9H2,1-3H3,(H,18,19,20)

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = LVWZTYCIRDMTEY-UHFFFAOYSA-N

[[File:Dipirona PNG.png|thumb|Oral solution bottle of dypirone in its packaging (Portuguese lettering)]]

'''Metamizole''' or '''dipyrone''' is a [[Analgesic|painkiller]], [[Antispasmodic|spasm reliever]], and [[Antipyretic|fever reliever]] drug. It is most commonly given by mouth or by intravenous infusion.<ref name="Winthrop Arzneimittel GmbH-2013a">{{cite web |date=February 2013 |title=Fachinformation (Zusammenfassung der Merkmale des Arzneimittels) Novaminsulfon injekt 1000 mg Lichtenstein Novaminsulfon injekt 2500 mg Lichtenstein |url=https://www.zentiva.de/-/media/files/zentivade/produkte/novaminsulfon-lichtenstein/_de_gif_novaminsulfon_injekt_2500mg.pdf |access-date=19 April 2014 |work=Winthrop Arzneimittel GmbH |publisher=Zinteva Pharm GmbH |language=de |archive-date=16 October 2018 |archive-url=https://web.archive.org/web/20181016165140/https://www.zentiva.de/-/media/files/zentivade/produkte/novaminsulfon-lichtenstein/_de_gif_novaminsulfon_injekt_2500mg.pdf |url-status=live }}</ref><ref name="deranaes2008">{{cite journal |vauthors=Jage J, Laufenberg-Feldmann R, Heid F |date=April 2008 |title=[Medikamente zur postoperativen Schmerztherapie: Bewährtes und Neues. Teil 1: Nichtopioide] |trans-title=Drugs for postoperative analgesia: routine and new aspects. Part 1: non-opioids |journal=Der Anaesthesist |language=de |volume=57 |issue=4 |pages=382–390 |doi=10.1007/s00101-008-1326-x |pmid=18351305 |s2cid=32814418}}</ref><ref name=deranaes2004/> It belongs to the [[ampyrone]] [[sulfonate]] family of medicines and was patented in 1922. Metamizole is marketed under various trade names.<ref name="EMA-list" /><ref name="Pharmaceuticale Press-2009"/> It was first used medically in Germany under the brand name "Novalgin", <ref name="Fis20064">{{cite book |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA530 |title=Analogue-based Drug Discovery |vauthors=Fischer J, Ganellin CR |date=2006 |publisher=John Wiley & Sons |isbn=978-3-527-60749-5 |page=530 |language=en}}</ref> later becoming widely known in [[Slavs|Slavic]] nations and India under the name "Analgin".<ref name="pmid26019521"/><ref name="Business Standard India-2014"/>

Sale of Metamizole is restricted in some jurisdictions following studies in the 1970s which correlated it to severe adverse effects, including [[agranulocytosis]].<ref name="United Nations Department of Economic and Social Affairs-2005" /> Other studies have disputed this judgement, instead claiming that it is a safer drug than other painkillers.<ref name="pmid31433499-2">{{cite journal |vauthors=Lutz M |date=November 2019 |title=Metamizole (Dipyrone) and the Liver: A Review of the Literature |journal=Journal of Clinical Pharmacology |volume=59 |issue=11 |pages=1433–1442 |doi=10.1002/jcph.1512 |pmid=31433499 |s2cid=201118022 |doi-access=}}</ref><ref name="NikolovaTencheva20144">{{cite journal |vauthors=Nikolova I, Tencheva J, Voinikov J, Petkova V, Benbasat N, Danchev N |year=2014 |title=Metamizole: A Review Profile of a Well-Known "Forgotten" Drug. Part I: Pharmaceutical and Nonclinical Profile |journal=Biotechnology & Biotechnological Equipment |volume=26 |issue=6 |pages=3329–3337 |doi=10.5504/BBEQ.2012.0089 |issn=1310-2818 |s2cid=56205439|doi-access=free }}</ref> Metamizole is popular in many countries, where it is typically available as an [[Over-the-counter drug|over-the-counter]] medication. <ref name="pmid35584441">{{cite journal | vauthors = Sznejder H, Amand C, Stewart A, Salazar R, Scala WA | title = Real world evidence of the use of metamizole (dipyrone) by the Brazilian population. A retrospective cohort with over 380,000 patients | journal = Einstein | volume = 20 | pages = eAO6353 | year = 2022 | pmid = 35584441 | doi = 10.31744/einstein_journal/2022ao6353 | publisher = Sociedade Beneficente Israelita Brasileira Hospital Albert Einstein | pmc = 9060643 | doi-access = free }}</ref>

==Medical uses==

Metamizole, with its potent [[analgesic]] (pain relief), [[antipyretic]] (fever reduction), and [[Spasmolytics|spasmolytic]] (relax muscle contractions) properties, is utilized in the management of acute pain, fever, and pain caused by [[muscle spasms]].<ref name="pmid25199942">{{cite journal |vauthors=Lampl C, Likar R |title=[Metamizole (dipyrone): mode of action, drug-drug interactions, and risk of agranulocytosis] |language=German |journal=Schmerz |volume=28 |issue=6 |pages=584–90 |date=December 2014 |pmid=25199942 |doi=10.1007/s00482-014-1490-7}}</ref>

It is primarily used for [[perioperative]] pain, acute injury, [[colic]], cancer pain, other acute/chronic forms of pain and high fever unresponsive to other agents.<ref name="Winthrop Arzneimittel GmbH-2013"/> Metamizole also effectively manages biliary and intestinal colic-like pain, and reduces the spasm of the [[smooth muscle]] of the [[sphincter of Oddi]].<ref name="pmid30652827">{{cite journal |vauthors=Collares EF, Troncon LE |title=Effects of dipyrone on the digestive tract |journal=Braz J Med Biol Res |volume=52 |issue=2 |pages=e8103 |date=January 2019 |pmid=30652827 |pmc=6328969 |doi=10.1590/1414-431X20188103}}</ref>

===Special populations===

Its use in pregnancy is advised against, although animal studies are reassuring in that they show minimal risk of birth defects. Its use in the elderly and those with liver or kidney impairment is advised against, but if these groups of people must be treated, a lower dose and caution is usually advised. Its use during lactation is advised against, as it is excreted in breast milk.<ref name="Winthrop Arzneimittel GmbH-2013"/>

==Adverse effects==

While metamizole is a relatively safe medication,<ref name="pmid24724493"/> it is not entirely devoid of adverse effects.<ref name="pmid24724493"/>

Metamizole has a potential of blood-related toxicity (blood [[dyscrasia]]s), but causes less [[renal|kidney]], [[cardiovascular]], and gastrointestinal toxicity than [[non-steroidal anti-inflammatory drugs]] (NSAIDs).<ref name="deranaes2008"/> Like NSAIDs, it can trigger bronchospasm or [[anaphylaxis]], especially in those with [[asthma]].<ref name=deranaes2004>{{cite journal | vauthors = Brack A, Rittner HL, Schäfer M | title = Nichtopioidanalgetika zur perioperativen Schmerztherapie | trans-title = Non-opioid analgesics for perioperative pain therapy. Risks and rational basis for use | language = de | journal = Der Anaesthesist | volume = 53 | issue = 3 | pages = 263–280 | date = March 2004 | pmid = 15021958 | doi = 10.1007/s00101-003-0641-5 | s2cid = 8829564 }}</ref>

Serious side effects include [[agranulocytosis]], [[aplastic anaemia]], hypersensitivity reactions (like [[anaphylaxis]] and [[bronchospasm]]), [[toxic epidermal necrolysis]] and it may provoke acute attacks of [[porphyria]], as it is chemically related to the [[sulfonamide]]s.<ref name="Pharmaceuticale Press-2009">{{Cite book |title=Martindale: The complete drug reference |date=2009 |publisher=Pharmaceuticale Press |isbn=978-0-85369-840-1 | veditors = Martindale W, Sweetman SC |edition=36th |location=London; Chicago |page=49 |language=en}}</ref><ref name = deranaes2008/><ref name = deranaes2004/> The relative risk for agranulocytosis appears to greatly vary according to the country of estimates on said rate and opinion on the risk is strongly divided.<ref name="Pharmaceuticale Press-2009"/><ref name=CurrOpAnesth2014rev>{{cite journal | vauthors = Pogatzki-Zahn E, Chandrasena C, Schug SA | title = Nonopioid analgesics for postoperative pain management | journal = Current Opinion in Anesthesiology | volume = 27 | issue = 5 | pages = 513–519 | date = October 2014 | pmid = 25102238 | doi = 10.1097/ACO.0000000000000113 | s2cid = 31337982 }}</ref><ref name="Reis2022">{{Cite journal |vauthors=Reis SL, Batista AP, Assumpção J, Ramos ER, Colacite J, Souza LF |date=2022-10-09 |title=A bibliographic analysis on the use of Dipyrone and Agranulocytosis |url=https://rsdjournal.org/index.php/rsd/article/view/35570/29810 |access-date=2023-07-19 |journal=Research, Society and Development |volume=11 |issue=13 |pages=e369111335570 |doi=10.33448/rsd-v11i13.35570 |s2cid=252870061 |doi-access=free |archive-date=2023-07-19 |archive-url=https://web.archive.org/web/20230719071123/https://rsdjournal.org/index.php/rsd/article/view/35570/29810 |url-status=live }}</ref> Genetics may play a significant role in metamizole sensitivity.<ref name=PharmacogenetGenomics2015>{{cite journal | vauthors = García-Martín E, Esguevillas G, Blanca-López N, García-Menaya J, Blanca M, Amo G, Canto G, Martínez C, Cordobés C, Agúndez JA | title = Genetic determinants of metamizole metabolism modify the risk of developing anaphylaxis | journal = Pharmacogenetics and Genomics | volume = 25 | issue = 9 | pages = 462–464 | date = September 2015 | pmid = 26111152 | doi = 10.1097/FPC.0000000000000157 }}</ref> It is suggested that some populations are more prone to suffer from metamizole induced agranulocytosis than others. As an example, metamizole-related agranulocytosis seems to be an adverse effect more frequent in British population as opposed to Spaniards.<ref name=RevClinEsp2009>{{cite journal | vauthors = Mérida Rodrigo L, Faus Felipe V, Poveda Gómez F, García Alegría J | title = Agranulocitosis por metamizol: un potencial problema en la población británica |trans-title=Agranulocytosis from metamizole: a potential problem for the British population | journal = Revista Clínica Española | volume = 209 | issue = 4 | pages = 176–179 | date = April 2009 | pmid = 19457324 | doi = 10.1016/s0014-2565(09)71310-4 |language=es}}</ref> An assessment report by the European Medicines Agency remarked that "the potential to induce agranulocytosis may be associated with genetic characteristics of the population studied".<ref name="European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP)-2018">{{Cite report|url=https://www.ema.europa.eu/en/documents/referral/metamizole-article-31-referral-chmp-assessment-report_en.pdf|publisher=European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP)|date=13 December 2018|title=Assessment report: metamizole-containing medicinal products|id=EMA/143912/2019|access-date=4 August 2023|archive-date=5 February 2022|archive-url=https://web.archive.org/web/20220205033955/https://www.ema.europa.eu/en/documents/referral/metamizole-article-31-referral-chmp-assessment-report_en.pdf|url-status=live}}</ref>

A 2015 meta-analysis concluded that on the evidence available "for short-term use in the hospital setting, metamizole seems to be a safe choice when compared to other widely used analgesics", but that the "results were limited by the mediocre overall quality of the reports" analysed.<ref name="pmid25875821">{{cite journal | vauthors = Kötter T, da Costa BR, Fässler M, Blozik E, Linde K, Jüni P, Reichenbach S, Scherer M | title = Metamizole-associated adverse events: a systematic review and meta-analysis | journal = PLOS ONE | volume = 10 | issue = 4 | pages = e0122918 | date = 13 April 2015 | pmid = 25875821 | doi = 10.1371/journal.pone.0122918 | publisher = Public Library of Science (PLoS) | pmc = 4405027 | bibcode = 2015PLoSO..1022918K | doi-access = free }}</ref>

A systematic review from 2016 found that metamizole significantly increased the [[relative risk]] of upper gastrointestinal bleeding, by a factor of {{Val|1.4|-|2.7}} times.<ref name="pmid27422768">{{cite journal | vauthors = Andrade S, Bartels DB, Lange R, Sandford L, Gurwitz J | title = Safety of metamizole: a systematic review of the literature | journal = Journal of Clinical Pharmacy and Therapeutics | volume = 41 | issue = 5 | pages = 459–477 | date = October 2016 | pmid = 27422768 | doi = 10.1111/jcpt.12422 | s2cid = 24538147 | doi-access = }}</ref> A study by one of the manufacturers of the drug found the risk of agranulocytosis within the first week of treatment to be a {{Val|1.1}} in a million, versus {{Val|5.9}} in a million for [[diclofenac]].{{medical citation needed|date=April 2024}} Therapeutic effect of metamizole on intestinal colic is attributed to its analgesic properties, with no evidence of interference in small bowel or colon motility.<ref name="pmid30652827"/>

Metamizole has potential for hepatotoxicity.<ref name="pmid31433499">{{cite journal |vauthors=Lutz M |title=Metamizole (Dipyrone) and the Liver: A Review of the Literature |journal=J Clin Pharmacol |volume=59 |issue=11 |pages=1433–1442 |date=November 2019 |pmid=31433499 |doi=10.1002/jcph.1512}}</ref>

===Contraindications===

Previous hypersensitivity (such as [[agranulocytosis]] or [[anaphylaxis]]) to metamizole or any of the [[excipients]] (e.g. [[lactose]]) in the preparation used, acute [[porphyria]], impaired [[haematopoiesis]] (such as due to treatment with [[chemotherapy]] agents), third trimester of pregnancy (potential for adverse effects in the newborn), lactation, children with a body weight below 16&nbsp;kg, history of aspirin-induced asthma and other hypersensitivity reactions to analgesics.<ref name="Winthrop Arzneimittel GmbH-2013"/>

In 2018, the [[European Medicines Agency]] (EMA) reviewed the safety of metamizole and concluded it to be generally safe for the general population. However, they advised against its use in the third trimester of pregnancy or while breastfeeding due to risks of [[renal impairment]] or [[ductus arteriosus]] to the fetus or infant.<ref name="EMA2018">{{Cite web |author=[[European Medicines Agency]] |date=2018-09-17 |title=Metamizole containing medicinal products - EMA recommends aligning doses of metamizole medicines and their use during pregnancy and breastfeeding |url=https://www.ema.europa.eu/en/medicines/human/referrals/metamizole-containing-medicinal-products |url-status=live |archive-url=https://web.archive.org/web/20230201145429/https://www.ema.europa.eu/en/medicines/human/referrals/metamizole-containing-medicinal-products |archive-date=2023-02-01 |access-date=2023-08-04 |website=European Medicines Agency |language=en}}

* {{Cite web |author=[[Committee for Medicinal Products for Human Use|CHMP]] |date=2018-12-13 |publication-date=2019-03-28 |title=Metamizole - Assessment report |url=https://www.ema.europa.eu/en/documents/referral/metamizole-article-31-referral-chmp-assessment-report_en.pdf |url-status=live |archive-url=https://web.archive.org/web/20220205033955/https://www.ema.europa.eu/en/documents/referral/metamizole-article-31-referral-chmp-assessment-report_en.pdf |archive-date=2022-02-05 |access-date=2023-08-03 |website=European Medicines Agency}}

* {{Cite web |date=2019-03-28 |title=Metamizole Annex II - Scientific conclusions |url=https://www.ema.europa.eu/en/documents/referral/metamizole-article-31-referral-annex-ii_en.pdf |url-status=live |archive-url=https://web.archive.org/web/20220205034021/https://www.ema.europa.eu/en/documents/referral/metamizole-article-31-referral-annex-ii_en.pdf |archive-date=2022-02-05 |access-date=2023-08-03 |website=European Medicines Agency}}

* {{Cite web |date=2018-06-01 |title=Metamizole - Annex III - Amendments to relevant sections of the Product Information |url=https://www.ema.europa.eu/en/documents/referral/metamizole-article-31-referral-annex-iii_en.pdf |url-status=live |archive-url=https://web.archive.org/web/20220205033923/https://www.ema.europa.eu/en/documents/referral/metamizole-article-31-referral-annex-iii_en.pdf |archive-date=2022-02-05 |access-date=2023-08-03 |website=European Medicines Agency}}

</ref>

== Interactions ==

A clinically severe interaction has been identified between aspirin and metamizole for patients who regularly take aspirin to manage vascular disease: this interaction occurs due to steric hindrance at the active aspirin binding site of [[Cyclooxygenase-1|COX-1]] by metamizole; to manage this interaction, it is recommended to make a delay between the intake of each of these drugs, with aspirin being taken at least 30 minutes before metamizole.<ref name="pmid37109738">{{cite journal |vauthors=Schmelzer KP, Liebetrau D, Kämmerer W, Meisinger C, Hyhlik-Dürr A |title=Strategies for Avoiding Typical Drug-Drug Interactions and Drug-Related Problems in Patients with Vascular Diseases |journal=Medicina (Kaunas) |volume=59 |issue=4 |date=April 2023 |page=780 |pmid=37109738 |pmc=10142821 |doi=10.3390/medicina59040780 |doi-access=free}}{{Creative Commons text attribution notice|cc=by4|from this source=yes}}</ref>

{| class = wikitable

|+ Known interactions

! Drug(s) !! Interaction/reason for theoretical potential for interaction

|-

| [[Aspirin]] || Platelet aggregation inhibition (PAI) by aspirin; metamizole prevents aspirin from inhibiting COX-1.<ref name="pmid37109738"/>

|-

| [[Ciclosporin]] || Decreased serum levels of [[ciclosporin]].<ref name="Winthrop Arzneimittel GmbH-2013"/>

|-

| [[Chlorpromazine]] || Additive [[hypothermia]] (low body temperature) may result.<ref name="Winthrop Arzneimittel GmbH-2013"/>

|-

| [[Hydroxyethyl starch]] || Acute renal insufficiency. Low evidence, but discouraged simultaneous administration.<ref name="Meyler16">{{Cite book |title=Meyler's side effects of drugs: the international encyclopedia of adverse drug reactions and interactions |date=2015 |publisher=Elsevier |isbn=978-0-444-53716-4 |oclc=927102885 | veditors = Aronson JK |edition=16th |volume=4 |location=Amsterdam Boston Heidelberg |pages=859–862 |language=en}}</ref>

|-

| [[Methotrexate]] || Additive risk for haematologic (blood) toxicity.<ref name="Winthrop Arzneimittel GmbH-2013"/> More specifically, [[Aplastic anemia|bone marrow aplasia]].<ref name="Meyler16"/>

|}

Oral [[anticoagulants]] (blood thinners), [[lithium (medication)|lithium]], [[captopril]], [[triamterene]] and [[antihypertensive]]s may also interact with metamizole, as other [[pyrazolone]]s are known to interact adversely with these substances.

===Overdose===

It is considered fairly safe on overdose, but in these cases supportive measures are usually advised as well as measures to limit absorption (such as [[activated charcoal]]) and accelerate excretion (such as [[haemodialysis]]).<ref name="Winthrop Arzneimittel GmbH-2013">{{cite web|title=Fachinformation (Zusammenfassung der Merkmale des Arzneimittels) Novaminsulfon injekt 1000 mg Lichtenstein Novaminsulfon injekt 2500 mg Lichtenstein|url=https://www.zentiva.de/-/media/files/zentivade/produkte/novaminsulfon-lichtenstein/_de_gif_novaminsulfon_injekt_2500mg.pdf|language=de|date=February 2013|access-date=19 April 2014|work=Winthrop Arzneimittel GmbH|publisher=Zinteva Pharm GmbH|archive-date=16 October 2018|archive-url=https://web.archive.org/web/20181016165140/https://www.zentiva.de/-/media/files/zentivade/produkte/novaminsulfon-lichtenstein/_de_gif_novaminsulfon_injekt_2500mg.pdf|url-status=live}}</ref>

==Physicochemistry==

Metamizole is a sulfonic acid and comes in [[calcium]], [[sodium]] and [[magnesium]] salt forms.<ref name="Pharmaceuticale Press-2009"/> Its sodium salt [[monohydrate]] form is a white/almost crystalline powder that is unstable in the presence of light, highly soluble in water and [[ethanol]] but practically insoluble in [[dichloromethane]].<ref name="Council Of Europe: European Directorate for the Quality of Medicines and Healthcare-2013">{{cite encyclopedia|encyclopedia=European pharmacopoeia|title=Metamizole|pages=3791|date=2013|publisher=Council Of Europe: European Directorate for the Quality of Medicines and Healthcare|edition=English 8.1|url=https://archive.org/details/europeanpharmaco0000unse/page/3790/mode/2up?q=metamizole|isbn=978-92-871-7527-4}}</ref>

==Pharmacology==

Its precise mechanism of action of metamizole is unknown, although it is believed that metamizole generally exerts its action by inhibiting the [[Cyclooxygenase-3|COX-3]] enzyme which is responsible for the biosynthesis of [[prostaglandin]]s in the [[central nervous system]] (CNS)—in the brain and spinal cord. Prostaglandins are lipid compounds that play a role in inflammation, pain, and fever. By inhibiting the COX-3 enzyme in the CNS, metamizole reduces the production of prostaglandins, thereby alleviating pain, reducing fever, and potentially lessening inflammation.<ref name = deranaes2004/><ref name="pmid31519356"/> Activation of the [[Endocannabinoid system|endocannabinoid]] and [[Opioid peptide|opioidergic]] systems is also thought to play a role in analgesic effects of metamizole.<ref>{{Cite journal | vauthors = Himcheva I, Stavreva GT, Naydenova E, Bocheva A |date=2022-10-06 |title=Involvement of the opioidergic and nociceptinergic systems in the analgesic effects of novel nociceptin analogues after acute and chronic immobilization stress |journal=Pharmacia |volume=69 |issue=4 |pages=935–942 |doi=10.3897/pharmacia.69.e89379 |doi-access=free |issn=2603-557X}}</ref><ref name="NikolovaTencheva20144" /> Metamizole is classified as an atypical [[nonsteroidal anti-inflammatory drug]] (NSAID). Unlike typical NSAIDs, metamizole exhibits weak or no anti-inflammatory properties (at least in therapeutic doses),<ref name="pmid25199942"/><ref name="pmid31519356"/> but possesses potent analgesic effects via its action in the CNS: this central action distinguishes it from other NSAIDs, which generally exert their effects peripherally.<ref name="pmid31519356">{{cite journal | vauthors = Monteiro B, Steagall PV | title = Antiinflammatory Drugs | journal = The Veterinary Clinics of North America. Small Animal Practice | volume = 49 | issue = 6 | pages = 993–1011 | date = November 2019 | pmid = 31519356 | doi = 10.1016/j.cvsm.2019.07.009 | quote = Metamizole (dipyrone) is considered an atypical NSAID with weak antiinflammatory properties, but potent analgesic effects that are thought to be related mainly via central inhibition of COX-3 enzyme | doi-access = }}</ref> The inhibition by metamizole of [[Cyclooxygenase-1|COX-1]] and [[Cyclooxygenase-2|COX-2]] is less potent than the inhibition of these enzymes by traditional NSAIDs.<ref name="y0">{{cite journal|doi=10.52778/efsm.22.0153 |title=Metamizole: A comprehensive approach to its benefit-risk profile |date=2022 |journal=Evidence for Self-Medication |volume=2 | vauthors = Stromer W, Palladini M }}</ref>

Metamizole is metabolized in the liver, where it is converted into active metabolites through the process of N-demethylation.<ref name="pmid29746911">{{cite journal | vauthors = Bachmann F, Duthaler U, Rudin D, Krähenbühl S, Haschke M | title = N-demethylation of N-methyl-4-aminoantipyrine, the main metabolite of metamizole | journal = European Journal of Pharmaceutical Sciences | volume = 120 | issue = | pages = 172–180 | date = July 2018 | pmid = 29746911 | doi = 10.1016/j.ejps.2018.05.003 | doi-access = free }}</ref> The mechanism of action of metamizole is believed to be exerted via its active metabolites, specifically, [[arachidonoyl-4-methylaminoantipyrine]] (ARA-4-MAA) and [[arachidonoyl-4-aminoantipyrine]] (ARA-4-AA).<ref name="pmid36364259">{{cite journal | vauthors = Lupu G, Bel L, Andrei S | title = Pain Management and Analgesics Used in Small Mammals during Post-Operative Period with an Emphasis on Metamizole (Dipyrone) as an Alternative Medication | journal = Molecules | volume = 27 | issue = 21 | page = 7434 | date = November 2022 | pmid = 36364259 | pmc = 9657641 | doi = 10.3390/molecules27217434 | doi-access = free }}</ref><ref name="pmid31433499-2"/><ref name="pmid24724493">{{cite journal | vauthors = Jasiecka A, Maślanka T, Jaroszewski JJ | title = Pharmacological characteristics of metamizole | journal = Polish Journal of Veterinary Sciences | volume = 17 | issue = 1 | pages = 207–214 | date = 2014 | pmid = 24724493 | doi = 10.2478/pjvs-2014-0030 | doi-access = free }}</ref> This mechanism of action has been compared to [[paracetamol]] and its active arachidonic acid metabolite [[AM404]]. The CB1 receptor inverse agonist AM-251 was able to reduce the cataleptic response and thermal analgesia of metamizole.<ref>{{cite journal | vauthors = Crunfli F, Vilela FC, Giusti-Paiva A | title = Cannabinoid CB1 receptors mediate the effects of dipyrone | journal = Clinical and Experimental Pharmacology & Physiology | volume = 42 | issue = 3 | pages = 246–255 | date = March 2015 | pmid = 25430877 | doi = 10.1111/1440-1681.12347 | s2cid = 13598808 }}</ref> Another study found its antihyperalgesic effect reversed by the CB2 inverse agonist AM-630<ref name="pmid32057719">{{cite journal | vauthors = Gonçalves Dos Santos G, Vieira WF, Vendramini PH, Bassani da Silva B, Fernandes Magalhães S, Tambeli CH, Parada CA | title = Dipyrone is locally hydrolyzed to 4-methylaminoantipyrine and its antihyperalgesic effect depends on CB₂ and kappa-opioid receptors activation | journal = European Journal of Pharmacology | volume = 874 | pages = 173005 | date = May 2020 | pmid = 32057719 | doi = 10.1016/j.ejphar.2020.173005 | s2cid = 211112059 | doi-access = free }}</ref> Although it seems to inhibit fevers caused by prostaglandins, especially [[prostaglandin E2]],<ref name="pmid24712707">{{cite journal | vauthors = Malvar D, Aguiar FA, Vaz A, Assis DC, de Melo MC, Jabor VA, Kalapothakis E, Ferreira SH, Clososki GC, de Souza GE | title = Dipyrone metabolite 4-MAA induces hypothermia and inhibits PGE2 -dependent and -independent fever while 4-AA only blocks PGE2 -dependent fever | journal = British Journal of Pharmacology | volume = 171 | issue = 15 | pages = 3666–3679 | date = August 2014 | pmid = 24712707 | pmc = 4128064 | doi = 10.1111/bph.12717 }}</ref> metamizole appears to produce its therapeutic effects by means of its metabolites, especially ''N''-methyl-4-aminoantipyrine (MAA) and [[ampyrone|4-aminoantipyrine]] (AA) which form through the FAAH enzyme to create arachidonoyl-4-methylaminoantipyrine (ARA-4-MAA) and arachidonoyl-4-aminoantipyrine (ARA-4-AA).<ref name="Winthrop Arzneimittel GmbH-2013"/>

Metamizole likely induces the CYP2B6 and CYP3A4 enzymes.<ref name="pmid25199942"/>

{| class = wikitable

|+ Pharmacokinetics of metamizole's major metabolites<ref name="Winthrop Arzneimittel GmbH-2013"/>

! Metabolite !! Acronym !! Biologically active? !! Pharmacokinetic properties

|-

| {{center|[[File:N-methyl-4-aminoantipyrine2DACS.svg|200px]]<br />''N''-methyl-4-aminoantipyrine}} || MAA || Yes || Bioavailability≈90%. Plasma protein binding: 58%. Excreted in the urine as 3±1% of the initial (oral) dose

|-

| {{center|[[File:4-aminoantipyrine2DACS.svg|200px]]<br />4-aminoantipyrine}} || AA || Yes || Bioavailability≈22.5%. Plasma protein binding: 48%. Excreted in the urine as 6±3% of the initial (oral) dose

|-

| {{center|[[File:N-formyl-4-aminoantipyrine2DACS.svg|200px]]<br />''N''-formyl-4-aminoantipyrine}} || FAA || No || Plasma protein binding: 18%. Excretion in the urine as 23±4% of the initial oral dose

|-

| {{center|[[File:N-acetyl-4-aminoantipyrine.svg|200px]]<br />''N''-acetyl-4-aminoantipyrine}} || AAA || No || Plasma protein binding: 14%. Excretion in the urine as 26±8% of the initial oral dose

|}

==History==

[[Ludwig Knorr]] was a student of [[Hermann Emil Fischer|Emil Fischer]] who won the Nobel Prize for his work on purines and sugars, which included the discovery of [[phenylhydrazine]].<ref name=Brune>{{Cite journal | doi = 10.1016/S1366-0071(97)80033-2 | title = The early history of non-opioid analgesics | date = December 1997 | vauthors = Brune K | journal = Acute Pain | volume = 1 | pages = 33–40 }}</ref><ref name="Nobel Committee">{{cite web | work = Nobel Committee | url = https://www.nobelprize.org/nobel_prizes/chemistry/laureates/1902/fischer-bio.html | title = Emil Fischer – Biographical | access-date = 2017-06-14 | archive-date = 2017-06-06 | archive-url = https://web.archive.org/web/20170606075707/http://www.nobelprize.org/nobel_prizes/chemistry/laureates/1902/fischer-bio.html | url-status = live }}</ref> In the 1880s, Knorr was trying to make [[quinine]] derivatives from phenylhydrazine, and instead made a [[pyrazole]] derivative, which after a methylation, he made into [[phenazone]], also called antipyrine, which has been called "the 'mother' of all modern antipyretic analgesics."<ref name=Brune/><ref name="Raviña Rubira-2011">{{cite book | vauthors = Raviña Rubira E |title=The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs |date=2011 |publisher=Wiley-VCH |location=Weinheim |isbn=978-3-527-32669-3}}</ref>{{rp|26–27}} Sales of that drug exploded, and in the 1890s chemists at Teerfarbenfabrik Meister, Lucius & Co. (a precursor of [[Hoechst AG]] which is now [[Sanofi]]), made another derivative called [[pyramidon]] which was three times more active than antipyrine.<ref name=Brune/>

In 1893, a derivative of antipyrine, [[aminopyrine]], was made by [[Friedrich Stolz]] at Hoechst.<ref name="Raviña Rubira-2011"/>{{rp|26–27}} Yet later, chemists at Hoechst made a derivative, melubrine (sodium antipyrine aminomethanesulfonate), which was introduced in 1913;<ref name="JAMA-1913">{{cite journal | url = https://books.google.com/books?id=xZw1AQAAMAAJ&pg=PA869 | title = New and Nonofficial Remedies: Melubrine | journal = JAMA | volume = 61 | issue = 11 | pages = 869 | date = 1913 }}</ref> finally in 1920, metamizole was synthesized.<ref name="NikolovaTencheva20144" /> Metamizole is a methyl derivative of melubrine and is also a more soluble prodrug of pyramidon.<ref name=Brune/><ref name="Raviña Rubira-2011"/>{{rp|26–27}} Metamizole was first marketed in Germany as "Novalgin" in 1922.<ref name=Brune/><ref name="NikolovaTencheva20144" />

==Society and culture==

===Legal status===

[[File:Metamizole (Dipyrone) Availability World Map.svg|thumb|200px|alt=World map of availability of Metamizole|

{{legend-table|lang=en|style=|title=World map of availability of Metamizole (Dipyrone)

|#40D0FF| Over-the-counter with limited restrictions.

|#4080FF| Available, but no data on the requirement of prescriptions.

|#3465A4| Prescription-only, with fairly limited restrictions on its use.

|#f57900| Prescription-only, with extensive restrictions on its use.

|#cc0000| Banned for human use. It may still be used by veterinary cases in some countries.

|#b9b9b9| No data.

}}|right]]

Metamizole is banned in several countries, available by prescription in others (sometimes with strong warnings, sometimes without), and available [[over the counter]] in yet others.<ref name="United Nations Department of Economic and Social Affairs-2005">{{cite book |author=United Nations Department of Economic and Social Affairs |url=https://www.un.org/esa/coordination/CL12.pdf |title=Consolidated List of Products Whose Consumption and/or Sale Have Been Banned, Withdrawn, Severely Restricted of Not Approved by Governments |publisher=United Nations |year=2005 |edition=12th |location=New York |pages=171–5 |author-link=United Nations Department of Economic and Social Affairs |access-date=3 April 2013 |archive-date=21 April 2021 |archive-url=https://web.archive.org/web/20210421024234/https://www.un.org/esa/coordination/CL12.pdf |url-status=live }}</ref><ref name=UNList2>Department of Economic and Social Affairs of the United Nations Secretariat [https://www.un.org/esa/coordination/CL-14-Final.for.Printing.pdf Consolidated List of Products Whose Consumption and/or Sale Have Been Banned, Withdrawn, Severely Restricted or not Approved by Governments Fourteenth Issue (New data only) (January 2005 – October 2008): Pharmaceuticals] {{Webarchive|url=https://web.archive.org/web/20170309125944/http://www.un.org/esa/coordination/CL-14-Final.for.Printing.pdf |date=2017-03-09 }} United Nations – New York, 2009</ref><ref name=NR12>{{cite journal | vauthors = Rogosch T, Sinning C, Podlewski A, Watzer B, Schlosburg J, Lichtman AH, Cascio MG, Bisogno T, Di Marzo V, Nüsing R, Imming P | title = Novel bioactive metabolites of dipyrone (metamizol) | journal = Bioorganic & Medicinal Chemistry | volume = 20 | issue = 1 | pages = 101–107 | date = January 2012 | pmid = 22172309 | pmc = 3248997 | doi = 10.1016/j.bmc.2011.11.028 }}</ref> For example, approval was withdrawn in Sweden (1974), the US (1977),<ref name="FR1977">{{Cite report |url=https://www.govinfo.gov/app/details/FR-1977-06-17 |title=Drug products containing dipyrone - Withdrawal of Approval of New Drug Applications | vauthors = Gardner S |date=1977-06-07 |publisher=Federal Register |issue=117 |publication-date=1977-06-17 |volume=42 |pages=30893–4 |language=en |issn=0097-6326 |quote=This notice withdraws approval of the new drug applications (NDA's) for drug products containing dipyrone. The drug products have been used to reduce fever, but they are not shown to be safe for use. On the basis of new evidence, not contained in the applications or not available until after the applications were approved, evaluated together with the evidence available when the applications were approved, the Commissioner of Food and Drugs finds that such drugs have not been shown to be safe for use upon the basis of which the applications were approved. (...) approval of the NDA's providing for the drug products named above, and all amendments and supplements applying thereto, is withdrawn effective June 27,1977. Shipment in interstate commerce of the above-listed products or of any identical, related, or similar product, not the subject of an approved NDA, will then be unlawful. |access-date=2023-08-04 |archive-url=https://web.archive.org/web/20200929015340/https://www.govinfo.gov/app/details/FR-1977-06-17 |archive-date=2020-09-29 |url-status=live}}<!-- direct PDF URL in case of link rot: https://www.govinfo.gov/content/pkg/FR-1977-06-17/pdf/FR-1977-06-17.pdf --></ref> and India (2013, ban lifted in 2014).<ref name="pmid23833116">{{cite journal | vauthors = Bhaumik S | title = India's health ministry bans pioglitazone, metamizole, and flupentixol-melitracen | journal = BMJ | volume = 347 | pages = f4366 | date = July 2013 | pmid = 23833116 | doi = 10.1136/bmj.f4366 | s2cid = 45107003 }}</ref><ref name="Business Standard India-2014">{{cite news|title=Govt lifts ban on painkiller Analgin|url=http://www.business-standard.com/article/companies/govt-lifts-ban-on-painkiller-analgin-114031900803_1.html|work=Business Standard India|date=19 March 2014|access-date=7 January 2018|archive-date=7 January 2018|archive-url=https://web.archive.org/web/20180107175220/http://www.business-standard.com/article/companies/govt-lifts-ban-on-painkiller-analgin-114031900803_1.html|url-status=live}}</ref><ref name="Panda-2014">{{Cite report |url=https://cdsco.gov.in/opencms/resources/UploadCDSCOWeb/2022/drug_rules/DR_G.S.R.%2086(E)%20dt_13.02.2014_Revoke%20GSR378(E)_Reg.%20Suspension%20of%20Analgin.pdf |title=Drugs Rules - G.S.R. 86(E) 13.02.2014 Revoke GSR378(E) Reg. Suspension of Analgin | vauthors = Panda AK |date=2014-02-13 |publisher=[[The Gazette of India]] |location=New Delhi |language=en |access-date=2023-08-11 |archive-url=https://web.archive.org/web/20230811174806/https://cdsco.gov.in/opencms/resources/UploadCDSCOWeb/2022/drug_rules/DR_G.S.R.%2086(E)%20dt_13.02.2014_Revoke%20GSR378(E)_Reg.%20Suspension%20of%20Analgin.pdf |archive-date=2023-08-11 |url-status=live}}</ref>

Although metamizole is banned in the US because of its risk of [[agranulocytosis]],<ref name="pmid12042592">{{cite journal | vauthors = Bonkowsky JL, Frazer JK, Buchi KF, Byington CL | title = Metamizole use by Latino immigrants: a common and potentially harmful home remedy | journal = Pediatrics | volume = 109 | issue = 6 | pages = e98 | date = June 2002 | pmid = 12042592 | doi = 10.1542/peds.109.6.e98 | url = https://publications.aap.org/pediatrics/article-pdf/109/6/e98/996066/pe0602000e98.pdf | access-date = 2024-03-15 | url-status = | archive-url = | archive-date = }}</ref> it was reported by small surveys that 28% of Hispanics in Miami have possession of it,<ref name="pmid17004525">{{cite journal | vauthors = Garcia S, Canoniero M, Lopes G, Soriano AO | title = Metamizole use among Hispanics in Miami: report of a survey conducted in a primary care setting | journal = Southern Medical Journal | volume = 99 | issue = 9 | pages = 924–926 | date = September 2006 | pmid = 17004525 | doi = 10.1097/01.smj.0000233020.68212.8f | s2cid = 41638378 }}</ref> and 38% of Hispanics in [[San Diego]] reported some usage.<ref name="pmid11527837">{{cite journal | vauthors = Taylor L, Abarca S, Henry B, Friedman L | title = Use of Neo-melubrina, a banned antipyretic drug, in San Diego, California: a survey of patients and providers | journal = The Western Journal of Medicine | volume = 175 | issue = 3 | pages = 159–163 | date = September 2001 | pmid = 11527837 | pmc = 1071527 | doi = 10.1136/ewjm.175.3.159 }}</ref>

There were unauthorized sales and use of metamizole in horses in the US. After reviewing trial data on its safety, the FDA approved it for treating fever in equines.<ref name="FDA2019horse"/>

Amid the [[Opioid epidemic|opioid crisis]], a study pointed out that the legal status of metamizole has a relation to the consumption of [[oxycodone]], showing the use of those drugs were inversely correlated. Its use could be beneficial when adjusted for the addictive risk of opioids, especially on limited and controlled use of metamizole.<ref name="cdrr1">{{cite journal | vauthors = Preissner S, Siramshetty VB, Dunkel M, Steinborn P, Luft FC, Preissner R | title = Pain-Prescription Differences - An Analysis of 500,000 Discharge Summaries | journal = Current Drug Research Reviews | year = 2019 | volume = 11 | issue = 1 | pages = 58–66 | pmid = 30207223 | doi = 10.2174/1874473711666180911091846 | s2cid = 52192130 }}</ref> A 2019 Israeli conference also justified the approved status as a preventive to opioid dependence, and metamizole being safer than most analgesics for renal impaired patients.<ref name="pmid31721040">{{cite journal | vauthors = Dinavitser N |title=Dipyrone – a Good Medication with a Bad Reputation | journal = Journal of Medical Toxicology | volume = 16 | issue = 1 | pages = 75–86 | date = January 2020 <!-- |url=https://www.acmt.net/_Library/2019_Israeli_Conference/Dipyrone_-_Dinavitser.pdf |url-status=dead --> <!-- the URL pointed to the presentation file that is not included in the DOI nor anywhere else, link rot, not in webarchive, its lost -->| pmid = 31721040 | pmc = 6942089 | doi = 10.1007/s13181-019-00743-w | quote = ACMT/IST 2019 American-Israeli Medical Toxicology Conference | publisher = American College of Medical Toxicology | publication-place = Rambam Health Care Campus, Haifa, Israel }}</ref>

Metamizole is the most sold medication in [[São Paulo]], Brazil, accounting for 488 tons in 2016.<ref name="pmid33237204">{{Cite journal | vauthors = Aragão RB, Semensatto D, Calixto LA, Labuto G |date=2020 |title=Pharmaceutical market, environmental public policies and water quality: the case of the São Paulo Metropolitan Region, Brazil |journal=Cadernos de Saúde Pública |volume=36 |issue=11 |pages=e00192319 |doi=10.1590/0102-311x00192319 |issn=1678-4464 |pmid=33237204|s2cid=227168554 |doi-access=free }}</ref> Given this contrasting consumption compared to other countries, the [[Brazilian Health Regulatory Agency|Brazilian Health Regulatory Agency (ANVISA)]] convened an international panel for evaluating its safety in 2001, and the conclusion was that the benefits substantially outweighed the risks, and imposing restrictions would lead to significant negative consequences to the population.<ref name="ANVISA2001">{{Cite report |vauthors=(([[Brazilian Health Regulatory Agency|Brazilian Health Regulatory Agency (ANVISA)]])) |url=https://www.anvisa.gov.br/divulga/informes/relatoriodipirona2.pdf |title=Painel Internacional de Avaliação da Segurança da Dipirona | trans-title=International Panel for the Evaluation of Dipyrone Safety |date=24 July 2001 |location=Brasília |language=pt |archive-url=https://web.archive.org/web/20090121175932/https://www.anvisa.gov.br/divulga/informes/relatoriodipirona2.pdf |archive-date=2009-01-21 |url-status=dead}}</ref><ref name="Reis2022"/> It is also highly popular in Latin America overall. In 2022 in Brazil alone over 215 million doses were administered.<ref name="Biernath-2023">{{Cite web |vauthors=Biernath A |date=2023-08-17 |title=Dipirona: por que é vendida no Brasil, mas proibida nos EUA e em parte da Europa? |url=https://www.bbc.com/portuguese/articles/crgrky6rmlyo |access-date=2023-09-21 |website=BBC News Brasil |language=pt-br |archive-date=2023-10-14 |archive-url=https://web.archive.org/web/20231014010311/https://www.bbc.com/portuguese/articles/crgrky6rmlyo |url-status=live }}</ref>

The Bulgarian pharmaceutical [[Sopharma]] produces it under the brand Analgin, which as of 2014, has been the top-selling analgesic in Bulgaria for over a decade.<ref name="pmid26019521">{{cite journal | vauthors = Petkova V, Valchanova V, Ibrahim A, Nikolova I, Benbasat N, Dimitrov M | title = Marketing approaches for OTC analgesics in Bulgaria | journal = Biotechnology, Biotechnological Equipment | volume = 28 | issue = 2 | pages = 360–365 | date = March 2014 | pmid = 26019521 | pmc = 4433822 | doi = 10.1080/13102818.2014.911477 | doi-access = free }}</ref>

In Germany, the drug is the most commonly prescribed painreliever.<ref name="cdrr1"/>

In 2012, headache accounts for 70% of its use in Indonesia.<ref name="Kurniawati-2012">{{Cite journal |vauthors=Kurniawati M, Ikawati Z, Raharjo B |title=The evaluation of metamizole use in some places of pharmacy service in Cilacap county |journal=Jurnal Manajemen Dan Pelayanan Farmasi (Journal of Management and Pharmacy Practice) |year=2012 |volume=2 |issue=1 |pages=50–55 |language=indonesian |url=https://jurnal.ugm.ac.id/jmpf/article/view/29379 |access-date=15 March 2022 |archive-date=7 April 2023 |archive-url=https://web.archive.org/web/20230407143206/https://jurnal.ugm.ac.id/jmpf/article/view/29379 |url-status=live }}</ref>

In 2018, investigators in Spain looked into Nolotil (as metamizole is known in Spain) after the death of several British people in Spain. A possible factor in these deaths might have been a side effect of metamizole that can cause agranulocytosis (a lowering of [[white blood cell]] count).<ref name="Exclusive-2018">{{cite web

| url = http://www.theolivepress.es/spain-news/2018/04/23/exclusive-southern-spain-hospitals-in-british-expat-hotspot-issue-warning-for-lethal-painkiller-nolotil/

| title = Exclusive: southern spain hospitals in british expat hotspot issue warning for 'lethal' painkiller nolotil

| date = 23 April 2018

| access-date = 27 April 2018

| archive-date = 28 April 2018

| archive-url = https://web.archive.org/web/20180428011844/http://www.theolivepress.es/spain-news/2018/04/23/exclusive-southern-spain-hospitals-in-british-expat-hotspot-issue-warning-for-lethal-painkiller-nolotil/

| url-status = live

}}</ref>

===Brand names===

Metamizole is the [[international nonproprietary name]], and in countries where it is marketed, it is available under many brand names.<ref name="EMA-list">{{Cite web |date=2018-06-01 |title=Metamizole Annex I - List of nationally authorised medicinal products |url=https://www.ema.europa.eu/en/documents/referral/metamizole-article-31-referral-annex-i_en.pdf |url-status=live |archive-url=https://web.archive.org/web/20220205033956/https://www.ema.europa.eu/en/documents/referral/metamizole-article-31-referral-annex-i_en.pdf |archive-date=2022-02-05 |access-date=2023-08-14 |website=European Medicines Agency}}</ref>

In Romania metamizole is available as the original marketed pharmaceutical product by Zentiva as Algocalmin, as 500&nbsp;mg immediate release tablets. It's also available as an injection with 1&nbsp;g of metamizole sodium dissolved in 2&nbsp;ml of solvent.

In Israel it is sold under the brand name "Optalgin" ({{langx|he|אופטלגין}}), manufactured by [[Teva Pharmaceuticals|Teva]].

It is known as Sulpyrin and Sulpyrine in South Korea ({{lang|ko|설피린}}) and Japan. ({{lang|ja|スルピリン}})<ref name="Kim-2004">{{Cite web |date=2004-08-26 |vauthors=Kim CH|title=해열진통제 '설피린' 국내사용 논란 |trans-title=Controversy over domestic use of antipyretic analgesic Sulpyrin |url=http://www.kgnews.co.kr/news/article.html?no=66244 |url-status=live |archive-url=https://web.archive.org/web/20230814051807/https://www.kgnews.co.kr/news/article.html?no=66244 |archive-date=2023-08-14 |access-date=2023-08-14 |website=경기신문 [kgnews] |language=ko}}</ref><ref name="Pharmaceutical and Medical Device Regulatory Science Society of Japan-2022">{{Cite book | author = Pharmaceutical and Medical Device Regulatory Science Society of Japan |url=https://jpdb.nihs.go.jp/kyokuhou/files/000904449.pdf |title=The Japanese Pharmacopoeia |publisher=Yakuji Nippo-sha |year=2022 |isbn=978-4-8408-1589-5 |edition=18th English |pages=1760 |language=en |access-date=2023-08-14 |archive-url=https://web.archive.org/web/20230120063124/https://jpdb.nihs.go.jp/kyokuhou/files/000904449.pdf |archive-date=2023-01-20 |url-status=live}}</ref>

====Analgin====

Analgin ({{Langx|ru|link=no|Анальгин}}) is a [[generic term|generic name]] used in the former [[Soviet Union|USSR]] [[pharmacopeia]],<ref name="Ministry of Health of the USSR-1968">{{Cite book |title=Государственная Фармакопея Союза Советских Социалистических Республик |year=1968 |edition=10th |location=Moscow |publisher=Медицина [Medicine] | author = Ministry of Health of the USSR |pages=94 |language=ru |trans-title=State Pharmacopoeia of the Union of Soviet Socialist Republics}}</ref> continuing in use in [[Slavs|Slavic]] nations. A firm in Russia tried unsuccessfully in 2011 to claim the name as their trademark.<ref name="Ovchinnikov-2011">{{Cite web |date=2011-12-22 |vauthors=Ovchinnikov R |title=Анальгин хотят отпустить в одни руки |trans-title=Analgin want to let go in one hand |url=https://iz.ru/news/510490 |url-status=live |archive-url=https://web.archive.org/web/20230812060914/https://iz.ru/news/510490 |archive-date=2023-08-12|website=Известия |language=ru}}</ref><ref name="EPAM Law-2012">{{Cite web |date=2012-02-22 |title=Pavel Sadovsky comments on trademarks registering for RIA Novosti - Insights |url=https://epam.ru/en/media/view/pavel-sadovsky-comments-on-trademarks-registering-for-ria-novosti |url-status=live |archive-url=https://web.archive.org/web/20210225185525/https://epam.ru/en/media/view/pavel-sadovsky-comments-on-trademarks-registering-for-ria-novosti |archive-date=2021-02-25 |access-date=2023-08-14 |website=EPAM Law |language=en}}</ref> In Bulgaria, [[Sopharma]] succeeded in registering Analgin as a trademark in 2004.<ref name="FFBH-2004">{{Cite web |date=2004-08-05 |title=Sopharma wins TM battle over analgesic drug Analgin |url=https://www.ffbh.bg/en/post/sopharma-wins-tm-battle-over-analgesic-drug-analgin-x000d--158997700025989 |url-status=live |archive-url=https://web.archive.org/web/20230814025944/https://www.ffbh.bg/en/post/sopharma-wins-tm-battle-over-analgesic-drug-analgin-x000d--158997700025989 |archive-date=2023-08-14 |access-date=2023-08-14 |website=FFBH}}</ref>

Analgin is also the common term used in the Indian pharmacopeia.<ref name="Ministry of Health and Family Welfare-2007">{{Cite book |url=https://www.planetayurveda.com/ayurveda-ebooks/indian-pharmacopoea.pdf | author = Ministry of Health and Family Welfare |title=Indian Pharmacopeia |year=2007 |volume=2 |publisher=Indian Pharmacopoeia Commission |location=Ghaziabad, India |pages=117 |language=en |access-date=2023-08-13 |archive-url=https://web.archive.org/web/20230728083229/https://www.planetayurveda.com/ayurveda-ebooks/indian-pharmacopoea.pdf |archive-date=2023-07-28 |url-status=live}}</ref>

== References ==

{{Reflist}}

{{Anti-inflammatory and antirheumatic products}}

{{Analgesics}}

{{Authority control}}

[[Category:Analgesics]]

[[Category:Antipyretics]]

[[Category:CYP3A4 inducers]]

[[Category:Drugs with unknown mechanisms of action]]

[[Category:Pyrazolones]]

[[Category:Sulfonates]]

[[Category:Withdrawn drugs]]