Identification

Summary

Metamizole is an antipyretic and analgesic drug used to relieve severe and persistent fever and pain.

Generic Name
Metamizole
DrugBank Accession Number
DB04817
Background

Metamizole (dipyrone) is a pyrazolone derivative that belongs to the group of nonacid nonopioids. It is considered a potent analgesic and antipyretic with favourable gastrointestinal tolerability.2 Metamizole was formerly marketed in the US as Dimethone tablets and injection, Protemp oral liquid, and other drug products, and was withdrawn due to its association with potentially fatal agranulocytosis. Approvals of the NDA's for metamizole drug products were withdrawn on June 27, 1977 (see the Federal Register of June 17, 1977, 42 FR 30893).9 In 1963, metamizole was withdrawn from the Canadian market and banned in the UK, France, Sweden, Norway and Australia.1 Metamizole is still used in certain countries in Europe, Asia and South America.1

Type
Small Molecule
Groups
Approved, Investigational, Withdrawn
Structure
Weight
Average: 311.36
Monoisotopic: 311.093977213
Chemical Formula
C13H17N3O4S
Synonyms
  • Dipyrone
  • Metamizol

Pharmacology

Indication

Metamizole is banned in several countries, where it was previously used as a powerful analgesic and fever reducer. In countries where it is still available, metamizole is indicated for acute severe pain after injuries or surgeries, colic, tumor pain, and acute or severe pain symptoms, as well as high fever if other treatments are unsuccessful.1

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Metamizole is a strong analgesic and antipyretic with spasmolytic properties. It has weak anti-inflammatory or antithrombotic properties and does not follow the same mechanism of action as conventional non-steroidal anti-inflammatory drugs (NSAIDs).1 Metamizole can lead to agranulocytosis, a life-threatening side effect where a patient’s neutrophil count falls below 500 cells per microliter.1 It has been shown that metamizole-induced agranulocytosis is caused by the development of drug-dependent anti-neutrophil antibodies requiring covalent binding of neutrophils to metamizole and its metabolites.2

Mechanism of action

The mechanism of action of metamizole is not fully understood. Its active metabolites, 4-methyl-amino-antipyrine (MAA) and 4-amino-antipyrine (AA), inhibit prostaglandin E2 (PGE2)-induced hyperalgesia.7 It has been suggested that the anti-hyperalgesic effect of MAA is mediated by guanosine 3',5'-cyclic monophosphate (cGMP) activation and ATP-sensitive potassium channel opening, while the effects of AA are associated with the activation of cannabinoid receptor type 1 (CB1).7 Metamizole is classified in some sources as a weak non-steroidal anti-inflammatory drug (NSAID);2 however, evidence suggests that its analgesic effects do not depend on its anti-inflammatory properties.7 Although the inhibition of cyclooxygenase (COX) 2 may play a role in the central nervous system effects of metamizole,7 reports suggest that metamizole inhibits COX-3 with a higher affinity compared to COX-1 or COX-2.6,8

TargetActionsOrganism
UProstaglandin G/H synthase 1Not AvailableHumans
Absorption

Metamizole is hydrolyzed to 4-methyl-amino-antipyrine (MAA) in gastric juice and is mostly absorbed in this form. MAA bioavailability differs based on the administration route. In patients given metamizole tablets, the bioavailability of MAA is 85%, in patients given drops, 89%, in patients given suppositories, 54%, and in patients given an intramuscular injection, 87%.3 There is a linear relationship between metamizole oral dose and MAA Cmax. After oral doses ranging between 0.75 and 3 g, the tmax is reached at 1.4-2.0 hours.3

Volume of distribution

Metamizole is quickly metabolized into 4-methyl-amino-antipyrine (MAA), its active metabolite. MAA has a volume of distribution of 1.15 L/kg.3

Protein binding

The protein binding of metamizole and its metabolites is low, with an average of 60% for the metabolites 4-methyl-amino-antipyrine, 4-formyl-amino-antipyrine, 4-amino-antipyrine and 4-acetyl-amino-antipyrine.3,4

Metabolism

Metamizole undergoes rapid hydrolysis to the active moiety 4-methyl-amino-antipyrine (MAA). MAA is then metabolized to 4-formyl-amino-antipyrine (FAA) via c-oxidation and 4-amino-antipyrine (AA) via N-demethylation. The N-demethylation of MAA is mainly mediated by CYP3A4, although CYP2B6, CYP2C8 and CYP2C9 may also be involved.2 FAA is an end metabolite, while AA is acetylated by N-acetyl-transferase to form 4-acetyl-amino-antipyrine (AAA).3 The unchanged drug may be present in plasma following the intravenous administration of metamizole; however, following oral administration, it cannot be detected in plasma or urine.3

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Route of elimination

After intravenous or oral administration, 90% of metamizole is recovered in urine, while 10% is recovered in feces.3 Approximately 60% of four metamizole metabolites (4-methyl-amino-antipyrine, 4-formyl-amino-antipyrine, 4-amino-antipyrine and 4-acetyl-amino-antipyrine) are excreted through urine.3

Half-life

In vitro, the half-life of metamizole is 16 minutes. The half-life of 4-methyl-amino-antipyrine (MAA), its active metabolite, ranges from 2.6 to 3.5 hours.3

Clearance

The clearance of 4-methyl-amino-antipyrine (MAA), the active metabolite of metamizole, ranges from 110 mL/min to 180 mL/min after oral administration.3

Adverse Effects
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Toxicity

A metamizole overdose (7.5 g) may lead to gastrointestinal toxicity. If less than an hour has passed since metamizole ingestion, gastrointestinal decontamination and supportive measures are suggested as overdose treatment.5 Metamizole can also cause myelotoxicity, leading to drug-induced agranulocytosis.2,6

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirMetamizole may decrease the excretion rate of Abacavir which could result in a higher serum level.
AcebutololMetamizole may decrease the antihypertensive activities of Acebutolol.
AceclofenacThe risk or severity of nephrotoxicity can be increased when Metamizole is combined with Aceclofenac.
AcemetacinThe risk or severity of nephrotoxicity can be increased when Metamizole is combined with Acemetacin.
AcetaminophenMetamizole may decrease the excretion rate of Acetaminophen which could result in a higher serum level.
Acetylsalicylic acidThe risk or severity of nephrotoxicity can be increased when Acetylsalicylic acid is combined with Metamizole.
AclidiniumMetamizole may decrease the excretion rate of Aclidinium which could result in a higher serum level.
AcrivastineMetamizole may decrease the excretion rate of Acrivastine which could result in a higher serum level.
AcyclovirThe risk or severity of nephrotoxicity can be increased when Acyclovir is combined with Metamizole.
Adefovir dipivoxilThe risk or severity of nephrotoxicity can be increased when Adefovir dipivoxil is combined with Metamizole.
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Food Interactions
Not Available

Products

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Product Ingredients
IngredientUNIICASInChI Key
Metamizole magnesiumMS156427256150-97-6NHMUJYOBLYTIKO-UHFFFAOYSA-L
Metamizole sodiumVSU62Z74ON68-89-3DJGAAPFSPWAYTJ-UHFFFAOYSA-M
Metamizole sodium monohydrate6429L0L52Y5907-38-0UNZIDPIPYUMVPA-UHFFFAOYSA-M
International/Other Brands
Algocalmin / Algozone / Analgin / Dimethone / Dipirona / Neo-Melubrina / Novalgin / Optalgin / Protemp / Pyralgin
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
ANTIALGINA®Metamizole sodium (300 mg) + Caffeine (30 mg) + Isometheptene mucate (30 mg)Tablet, film coatedOralTECNOQUIMICAS S.A.2007-04-24Not applicableColombia flag
ANTIALGINA®Metamizole sodium (300 mg) + Caffeine (30 mg) + Isometheptene (50 mg)SolutionOralTECNOFAR TQ S.A.S2007-03-062015-02-27Colombia flag
BUSCAPINA® COMPOSITUM AMPOLLASMetamizole sodium (2.5 g) + Butylscopolamine bromide (0.02 g)SolutionIntramuscular; IntravenousBOEHRINGER INGELHEIM ESPAŃA S.A.2006-11-102020-06-01Colombia flag
CAFETRIN ®Metamizole (300 mg) + Caffeine (30 mg) + Isometheptene mucate (30 mg)Tablet, coatedOralLABORATORIOS RICH MONDS S.A.S2018-05-11Not applicableColombia flag
DIPIRONA 300 MG + ISOMETEPTENO 50 MG + CAFEINA 30 MG GOTASMetamizole sodium monohydrate (300 mg) + Caffeine (30 mg) + Isometheptene (50 mg)SolutionOralSANOFI-AVENTIS DE COLOMBIA S.A.2018-07-062019-04-22Colombia flag
DIPIRONA 300 MG + ISOMETEPTENO MUCATO 30 MG + CAFEINA 30 MGMetamizole sodium monohydrate (300 mg) + Caffeine (30 mg) + Isometheptene mucate (30 mg)Tablet, coatedOralSANOFI - AVENTIS DE COLOMBIA S.A.2006-11-102020-10-20Colombia flag
DIPIRONA SODICA / ISOMETEPTENO MUCATO/CAFEINA 300 MG / 30 MG/30MG TABLETA RECUBIERTAMetamizole sodium (300 mg) + Caffeine (30 mg) + Isometheptene mucate (30 mg)Tablet, coatedOralLABORATORIO FRANCO COLOMBIANO - LAFRANCOL S.A.S.2013-07-09Not applicableColombia flag
DIPIRONA SODICA 300 MG/ ISOMETEPTENO CLORHIDRATO 50 MG / CAFEINA 30 MG GOTASMetamizole sodium (300 mg) + Caffeine (30 mg) + Isometheptene (50 mg)SolutionOralLABORATORIO FRANCO COLOMBIANO - LAFRANCOL S.A.S.2013-08-30Not applicableColombia flag
ESPASMOBIL®SOLUCION INYECTABLEMetamizole sodium (2.5 g) + Butylscopolamine bromide (20 mg)SolutionIntramuscular; IntravenousLABORATORIOS RYAN DE COLOMBIA S. EN C.2006-11-102019-08-05Colombia flag
ESPASMOBILGRAGEASMetamizole (300 mg) + Butylscopolamine bromide (10 mg)Tablet, coatedOralFARMACOL CHINOIN S.A.S..2008-11-05Not applicableColombia flag
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
NOVOPYRINE 1 GR/2 ML 10 AMPULMetamizole sodium (1 g/2ml)InjectionIntramuscular; IntravenousOSEL İLAÇ SAN. VE TİC. A.Ş.2020-08-14Not applicableTurkey flag

Categories

ATC Codes
N02BB72 — Metamizole sodium, combinations with psycholepticsN02BB02 — Metamizole sodiumN02BB52 — Metamizole sodium, combinations excl. psycholeptics
Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
934T64RMNJ
CAS number
50567-35-6
InChI Key
LVWZTYCIRDMTEY-UHFFFAOYSA-N
InChI
InChI=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)
IUPAC Name
[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)(methyl)amino]methanesulfonic acid
SMILES
CN(CS(O)(=O)=O)C1=C(C)N(C)N(C1=O)C1=CC=CC=C1

References

General References
  1. Cascorbi I: The Uncertainties of Metamizole Use. Clin Pharmacol Ther. 2021 Jun;109(6):1373-1375. doi: 10.1002/cpt.2258. [Article]
  2. Lutz M: Metamizole (Dipyrone) and the Liver: A Review of the Literature. J Clin Pharmacol. 2019 Nov;59(11):1433-1442. doi: 10.1002/jcph.1512. Epub 2019 Aug 21. [Article]
  3. Levy M, Zylber-Katz E, Rosenkranz B: Clinical pharmacokinetics of dipyrone and its metabolites. Clin Pharmacokinet. 1995 Mar;28(3):216-34. doi: 10.2165/00003088-199528030-00004. [Article]
  4. Zylber-Katz E, Granit L, Levy M: Plasma protein binding of dipyrone metabolites in man. Eur J Clin Pharmacol. 1985;29(1):67-71. doi: 10.1007/BF00547371. [Article]
  5. Bentur Y, Cohen O: Dipyrone overdose. J Toxicol Clin Toxicol. 2004;42(3):261-5. doi: 10.1081/clt-120037425. [Article]
  6. Jasiecka A, Maslanka T, Jaroszewski JJ: Pharmacological characteristics of metamizole. Pol J Vet Sci. 2014;17(1):207-14. doi: 10.2478/pjvs-2014-0030. [Article]
  7. dos Santos GG, Dias EV, Teixeira JM, Athie MC, Bonet IJ, Tambeli CH, Parada CA: The analgesic effect of dipyrone in peripheral tissue involves two different mechanisms: neuronal K(ATP) channel opening and CB(1) receptor activation. Eur J Pharmacol. 2014 Oct 15;741:124-31. doi: 10.1016/j.ejphar.2014.07.019. Epub 2014 Jul 21. [Article]
  8. Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, Simmons DL: COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13926-31. Epub 2002 Sep 19. [Article]
  9. FDA Federal Register: List of Drug Products That Have Been Withdrawn or Removed From the Market for Reasons of Safety or Effectiveness [Link]
KEGG Drug
D08188
PubChem Compound
522325
PubChem Substance
46509035
ChemSpider
3000
BindingDB
235671
RxNav
3523
ChEBI
62088
ChEMBL
CHEMBL461522
ZINC
ZINC000001782155
Therapeutic Targets Database
DNC000568
PharmGKB
PA166128206
Wikipedia
Metamizole

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedSupportive CareBeta-endorphin / Dipyrone / Hernia Surgery / Pain1
4CompletedTreatmentCesarean Sections / Neuropathic Pain / Postoperative pain1
4CompletedTreatmentChronic Lower Back Pain (CLBP)2
4CompletedTreatmentFever1
4CompletedTreatmentInadequate or Impaired Respiratory Function / Pain1
4CompletedTreatmentPain1
4CompletedTreatmentPostoperative pain1
4CompletedTreatmentSub-acute Back Pain1
4Not Yet RecruitingTreatmentProphylaxis of preeclampsia1
4RecruitingPreventionAnesthesia therapy / Hip Fracture1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Zhejiang Haisen Pharmaceutical Co. Ltd.
Dosage Forms
FormRouteStrength
Injection, solution
Injection, solutionParenteral1000 mg
TabletOral500 mg/1
SuppositoryRectal1000 MG
SolutionParenteral2 g
SuppositoryRectal
SolutionIntramuscular; Intravenous
SyrupOral3 g
Injection, solutionIntramuscular; Intravenous
SolutionIntramuscular; Intravenous
SolutionParenteral2.5 g
InjectionParenteral1 g
SolutionIntramuscular1 g
Tablet, coatedOral30 mg
SolutionOral500 mg
SolutionParenteral2000 mg
InjectionIntramuscular; Intravenous2 g
SolutionIntramuscular; Intravenous2 g
SolutionParenteral
SolutionParenteral1 g
SolutionIntramuscular; Intravenous; Subcutaneous2.5 g
InjectionIntramuscular; Intravenous2500 mg
TabletOral0.5 g
SolutionIntramuscular; Intravenous1 g
TabletOral
TabletOral30 mg
InjectionParenteral
Capsule, coatedOral
SolutionOral
Tablet, coatedOral
Tablet, coatedOral300 mg
InjectionIntravenous
SolutionOral0.5 g
SolutionIntramuscular2.5 g
SolutionIntravenous; Parenteral2.5 g
Tablet, coatedOral500 mg
Injection, solutionParenteral
TabletOral
Solution / dropsOral
SolutionOral500 MG/ML
Injection, solutionParenteral7.5 mg
Injection
TabletOral5 mg
SolutionOral300 mg
SolutionOral96 mg
Tablet
Tablet; tablet, film coatedOral
InjectionIntramuscular; Intravenous
Solution / drops; suspension / drops
Ointment
SyrupOral
Injection, solutionIntramuscular; Intravenous500 mg/ml
Injection, solutionParenteral2.5 G
Tablet, film coatedOral500 mg
Injection, solutionIntramuscular; Intravenous1 G/2ML
Solution / dropsOral500 MG/ML
SuppositoryRectal1 G
SuppositoryRectal300 mg
TabletOral500 MG
SolutionIntramuscular; Intravenous2.5 g
Injection, solutionParenteral1 G/2ML
Injection500 mg/ml
Tablet, coatedOral850 mg
Tablet, film coatedOral
Tablet, sugar coatedOral
SolutionIntravenous
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility2.53 mg/mLALOGPS
logP-0.4ALOGPS
logP-0.82Chemaxon
logS-2.1ALOGPS
pKa (Strongest Acidic)-1.4Chemaxon
pKa (Strongest Basic)-0.54Chemaxon
Physiological Charge-1Chemaxon
Hydrogen Acceptor Count6Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area81.16 Å2Chemaxon
Rotatable Bond Count4Chemaxon
Refractivity80.04 m3·mol-1Chemaxon
Polarizability31.41 Å3Chemaxon
Number of Rings2Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.7868
Blood Brain Barrier+0.8896
Caco-2 permeable-0.5869
P-glycoprotein substrateNon-substrate0.8148
P-glycoprotein inhibitor INon-inhibitor0.828
P-glycoprotein inhibitor IINon-inhibitor0.8107
Renal organic cation transporterNon-inhibitor0.921
CYP450 2C9 substrateNon-substrate0.8588
CYP450 2D6 substrateNon-substrate0.7959
CYP450 3A4 substrateSubstrate0.6035
CYP450 1A2 substrateNon-inhibitor0.7153
CYP450 2C9 inhibitorNon-inhibitor0.7064
CYP450 2D6 inhibitorNon-inhibitor0.8562
CYP450 2C19 inhibitorNon-inhibitor0.6768
CYP450 3A4 inhibitorNon-inhibitor0.9297
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8506
Ames testAMES toxic0.7763
CarcinogenicityCarcinogens 0.8197
BiodegradationReady biodegradable0.7192
Rat acute toxicity2.6224 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8411
hERG inhibition (predictor II)Non-inhibitor0.6724
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Prostaglandin-endoperoxide synthase activity
Specific Function
Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Involved in the constitutive production of prostanoids in particular in the stomach and platelets. In gas...
Gene Name
PTGS1
Uniprot ID
P23219
Uniprot Name
Prostaglandin G/H synthase 1
Molecular Weight
68685.82 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. Saussele T, Burk O, Blievernicht JK, Klein K, Nussler A, Nussler N, Hengstler JG, Eichelbaum M, Schwab M, Zanger UM: Selective induction of human hepatic cytochromes P450 2B6 and 3A4 by metamizole. Clin Pharmacol Ther. 2007 Sep;82(3):265-74. doi: 10.1038/sj.clpt.6100138. Epub 2007 Mar 7. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Saussele T, Burk O, Blievernicht JK, Klein K, Nussler A, Nussler N, Hengstler JG, Eichelbaum M, Schwab M, Zanger UM: Selective induction of human hepatic cytochromes P450 2B6 and 3A4 by metamizole. Clin Pharmacol Ther. 2007 Sep;82(3):265-74. doi: 10.1038/sj.clpt.6100138. Epub 2007 Mar 7. [Article]

Drug created at September 11, 2007 20:09 / Updated at December 01, 2022 22:37