Nimesulide

{{Short description|Anti-inflammatory drug}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Drugbox | Verifiedfields = changed | verifiedrevid = 413700508 | IUPAC_name = ''N''-(4-Nitro-2-phenoxyphenyl)methanesulfonamide | image = nimesulide.svg | image_class = skin-invert-image | width = 200  | tradename = | Drugs.com = {{drugs.com|international|nimesulide}} | legal_AU = S4 | legal_status = prescription only | routes_of_administration = By mouth, rectal, topical  | protein_bound = >97.5% | metabolism = Hepatic (via CYP2C9) | elimination_half-life = 1.8–4.7h | excretion = Renal (50%), fecal (29%)  | IUPHAR_ligand = 7401 | CAS_number_Ref = {{cascite|correct|CAS}} | CAS_number = 51803-78-2 | ATC_prefix = M01 | ATC_suffix = AX17 | ATC_supplemental = {{ATC|M02|AA26}} | PubChem = 4495 | DrugBank_Ref = {{drugbankcite|changed|drugbank}} | DrugBank = DB04743 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 4339 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = V4TKW1454M | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D01049 | ChEBI_Ref = {{ebicite|changed|EBI}} | ChEBI = 44445 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 56367  | C=13 | H=12 | N=2 | O=5 | S=1 | smiles = [O-][N+](=O)c2cc(Oc1ccccc1)c(cc2)NS(=O)(=O)C | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C13H12N2O5S/c1-21(18,19)14-12-8-7-10(15(16)17)9-13(12)20-11-5-3-2-4-6-11/h2-9,14H,1H3 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = HYWYRSMBCFDLJT-UHFFFAOYSA-N }}  '''Nimesulide''' is a nonsteroidal anti-inflammatory drug (NSAID) with pain medication and fever reducing properties. Its approved indications are the treatment of acute pain, the symptomatic treatment of osteoarthritis, and primary dysmenorrhoea in adolescents and adults above 12 years old.

Side effects may include liver problems.<ref name=Liv2017>{{cite journal|title=Nimesulide|url=https://livertox.nih.gov/Nimesulide.htm|website=livertox.nih.gov|date=2012 |pmid=31643176 |access-date=22 December 2017|archive-url=https://web.archive.org/web/20171223043951/https://livertox.nih.gov/Nimesulide.htm|archive-date=23 December 2017}}</ref> It has a multifactorial mode of action and is characterized by a fast onset of action. It works by blocking the production of prostaglandins (a chemical associated with pain), thereby relieving pain and inflammation.

==Medical uses== It may be used for pain, including period pains. Nimesulide is not recommended long-term, as for chronic conditions such as arthritis. This is due to its association with an increased risk of liver toxicity, including liver failure.<ref>{{cite web|title=Current status: European Commission final decision|url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Nimesulide/human_referral_000275.jsp&mid=WC0b01ac0580024e9a|access-date=12 November 2014|url-status=live|archive-url=https://web.archive.org/web/20141019113817/http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fmedicines%2Fhuman%2Freferrals%2FNimesulide%2Fhuman_referral_000275.jsp&mid=WC0b01ac0580024e9a|archive-date=19 October 2014}}</ref> Despite its risk of hepatotoxicity, a 2012 evaluation by the European Medicines Agency (EMA) concluded that the overall benefit/risk profile of nimesulide is favourable and in line with that of the other NSAIDs such as diclofenac, ibuprofen, and naproxen provided that the duration of use is limited to 15 days and the dose does not exceed 200 mg/day.<ref name="pmid30689999" />

===Children=== Less than 10 days of nimesulide does not appear to increase the risk of hypothermia, gastrointestinal bleeding, epigastric pain, vomiting, diarrhea, or transient, asymptomatic elevation of liver enzymes compared to ketoprofen, paracetamol, mefenamic acid, aspirin, or ibuprofen in children. However, data does not speak to populations less than 6 months old.<ref name="Gupta and Sachdev">{{cite journal | vauthors = Gupta P, Sachdev HP | title = Safety of oral use of nimesulide in children: systematic review of randomized controlled trials | journal = Indian Pediatrics | volume = 40 | issue = 6 | pages = 518–531 | date = June 2003 | pmid = 12824661 }}</ref>

===Pregnancy and lactation=== Women should use the drug with caution during lactation and nimesulide is contraindicated during pregnancy, and research suggest that it is also contraindicated in lactating women.<ref>{{cite web|url=http://www.pharmaceutical-drug-manufacturers.com/pharmaceutical-drugs/nimesulide.html|title=Nimesulide, Nimesulide Tablets, Ainex Nimesulide, Nimesulide Manufacturers|website=www.pharmaceutical-drug-manufacturers.com|url-status=live|archive-url=https://web.archive.org/web/20160303202009/http://www.pharmaceutical-drug-manufacturers.com/pharmaceutical-drugs/nimesulide.html|archive-date=2016-03-03}}</ref>

===Available forms=== left|thumb|100mg Nimesulide pills

Nimesulide is available in a variety of forms: tablets, powder for dissolution in water, suppositories, mouth dissolving tablets, and topical gel.

==Contraindications== It should be avoided by children under 12 and people with liver problems.

==Side effects== Due to concerns about the risk of liver toxicity, nimesulide has been withdrawn from market in several countries (Mexico,<ref>{{cite web |title=Aviso sobre los riesgos del consumo y uso de los medicamentos que contengan en su formulación Nimesulida |url=https://www.gob.mx/cofepris/articulos/aviso-sobre-los-riesgos-del-consumo-y-uso-de-los-medicamentos-que-contengan-en-su-formulacion-nimesulida?idiom=es |publisher=Cofepris |access-date=1 July 2023 |language=es |date=30 May 2019}}</ref> Spain, Finland, Belgium, and Ireland).<ref>{{cite journal | vauthors = McNaughton R, Huet G, Shakir S | title = An investigation into drug products withdrawn from the EU market between 2002 and 2011 for safety reasons and the evidence used to support the decision-making | journal = BMJ Open | volume = 4 | issue = 1 | article-number = e004221 | date = January 2014 | pmid = 24435895 | pmc = 3902466 | doi = 10.1136/bmjopen-2013-004221 | doi-access = free}} {{open access}}</ref> Liver problems have resulted in both deaths and the need for transplantation.<ref name=Liv2017/> The frequency of nimesulide-induced liver injury is estimated at around 1 in 50,000 patients, severe injury has occurred in as little as three days after starting the medication.<ref name=Liv2017/><ref>{{cite web | url=https://www.ncbi.nlm.nih.gov/books/NBK547948/ | pmid=31643281 | date=2012 | title=Nimesulide | publisher=National Institute of Diabetes and Digestive and Kidney Diseases }}</ref> Shorter (≤ 15 days) duration of therapy does not prevent serious nimesulide hepatotoxicity.<ref>{{cite journal | vauthors = Bessone F, Hernandez N, Mendizabal M, Ridruejo E, Gualano G, Fassio E, Peralta M, Fainboim H, Anders M, Tanno H, Tanno F, Parana R, Medina-Caliz I, Robles-Diaz M, Alvarez-Alvarez I, Niu H, Stephens C, Colombato L, Arrese M, Reggiardo MV, Ono SK, Carrilho F, Lucena MI, Andrade RJ | title = Serious liver injury induced by Nimesulide: an international collaborative study | journal = Archives of Toxicology | volume = 95 | issue = 4 | pages = 1475–1487 | date = April 2021 | pmid = 33759010 | doi = 10.1007/s00204-021-03000-8 | bibcode = 2021ArTox..95.1475B | hdl = 10630/23626 | hdl-access = free }}</ref>

Continuous use of nimesulide (more than 15 days) may cause the following side effects:{{Medcn|date=June 2014}}

* Diarrhea * Vomiting * Skin rash * Itchiness * Dizziness * Bitterness in mouth

==Pharmacology==

===Pharmacodynamics=== Nimesulide is a nonsteroidal anti-inflammatory drug (NSAID), acting specifically as a relatively selective cyclooxygenase-2 inhibitor.<ref name="pmid30689999">{{cite journal | vauthors = Caiazzo E, Ialenti A, Cicala C | title = The relatively selective cyclooxygenase-2 inhibitor nimesulide: What's going on? | journal = European Journal of Pharmacology | volume = 848 | issue = | pages = 105–111 | date = April 2019 | pmid = 30689999 | doi = 10.1016/j.ejphar.2019.01.044 | s2cid = 59339842 }}</ref><ref name="pmid18333314">{{cite journal | vauthors = Suleyman H, Cadirci E, Albayrak A, Halici Z | title = Nimesulide is a selective COX-2 inhibitory, atypical non-steroidal anti-inflammatory drug | journal = Current Medicinal Chemistry | volume = 15 | issue = 3 | pages = 278–283 | date = 2008 | pmid = 18333314 | doi = 10.2174/092986708783497247 }}</ref> However, the pharmacological profile of nimesulide is peculiar, and additional, unknown/yet-to-be-identified mechanisms appear to also be involved.<ref name="pmid30689999" /><ref name="pmid18333314" /> One pathway that has been implicated in its actions is the ecto-5'-nucleotidase (e-5′NT/CD73)/adenosine A<sub>2A</sub> receptor pathway.<ref name="pmid30689999" />

===Pharmacokinetics=== Nimesulide is absorbed rapidly following oral administration.<ref name="clinpharmacokinet">{{cite journal | vauthors = Bernareggi A | title = Clinical pharmacokinetics of nimesulide | journal = Clinical Pharmacokinetics | volume = 35 | issue = 4 | pages = 247–274 | date = October 1998 | pmid = 9812177 | doi = 10.2165/00003088-199835040-00001 | s2cid = 26895870 }}</ref>

Nimesulide undergoes extensive biotransformation, mainly to 4-hydroxynimesulide (which also appears to be biologically active).<ref name="clinpharmacokinet"/>

Food, sex, and advanced age have negligible effects on nimesulide pharmacokinetics.<ref name="clinpharmacokinet"/>

Moderate chronic kidney disease does not necessitate dosage adjustment, while in patients with severe chronic kidney disease or liver disease, nimesulide is contraindicated.<ref>{{cite web | url = http://www.emea.europa.eu/pdfs/human/referral/nimesulide/308603en.pdf | title = Nimesulide Tablets: Summary of Product Characteristics | work = Europeans Medicines Agency | date = 2004 | archive-url = https://web.archive.org/web/20070611052514/http://www.emea.europa.eu/pdfs/human/referral/nimesulide/308603en.pdf | archive-date = 11 June 2007 }}</ref>

Nimesulide has a relatively rapid onset of action, with meaningful reductions in pain and inflammation observed within 15 minutes from drug intake.<ref name="currmedresopin">{{cite journal | vauthors = Rainsford KD | title = Nimesulide -- a multifactorial approach to inflammation and pain: scientific and clinical consensus | journal = Current Medical Research and Opinion | volume = 22 | issue = 6 | pages = 1161–1170 | date = June 2006 | pmid = 16846549 | doi = 10.1185/030079906X104849 | s2cid = 23004446 }}</ref><ref>{{cite journal | vauthors = Bianchi M, Broggini M | title = A randomised, double-blind, clinical trial comparing the efficacy of nimesulide, celecoxib and rofecoxib in osteoarthritis of the knee | journal = Drugs | volume = 63 | issue = Suppl 1 | pages = 37–46 | date = 2003 | pmid = 14506910 | doi = 10.2165/00003495-200363001-00006 | s2cid = 19826636 }}</ref>

The therapeutic effects of nimesulide are the result of its complex mode of action, which targets a number of key mediators of the inflammatory process such as: COX-2 mediated prostaglandins, free radicals, proteolytic enzymes, and histamine.<ref name="currmedresopin"/> Clinical evidence is available to support a particularly good profile in terms of gastrointestinal tolerability.<ref>{{cite journal | vauthors = Laporte JR, Ibáñez L, Vidal X, Vendrell L, Leone R | title = Upper gastrointestinal bleeding associated with the use of NSAIDs: newer versus older agents | journal = Drug Safety | volume = 27 | issue = 6 | pages = 411–420 | year = 2004 | pmid = 15144234 | doi = 10.2165/00002018-200427060-00005 | s2cid = 1786767 }}</ref>

==History== Nimesulide was launched in Italy for the first time as Aulin and Mesulid in 1985 and is available in more than 50 countries worldwide, including among others Portugal, Greece, Russia, Thailand, and Brazil.<ref>{{cite book | vauthors = Rainsford KD |title= Nimesulide – Actions and Uses|location= Bazylea, Boston, Berlin|publisher= Birkhäuser Verlag|page= 7|date=2005|isbn= 978-3-7643-7068-8}}</ref> Nimesulide has never been filed for Food and Drug Administration (FDA) evaluation in the United States, where it is not marketed.

==Society and culture==

===Brand names=== Nimesulide is available throughout the world as original product with the following trademarks: Sulide, Nimalox, Mesulid (Novartis, Brazil, Boehringer Ingelheim, Greece, Italy, Hungary), Coxtal (Sanofi, China, Bulgaria), Sintalgin (Abbott, Brazil), Eskaflam (GSK, Brazil, Mexico), Octaprin, Nimside (Teva, Pakistan), Nise (Russia, Venezuela, Vietnam, Ukraine), Nilsid (Egypt); Aulin (Bulgaria, Czech Republic, Italy, Romania, Poland), Ainex, Drexel, Donulide, Edrigyl, Enetra, Heugan, Mesulid, Minapon, NeRelid, Nexen, Nidolon, Nilden (Mexico); Emsulide, Nimed, Nimedex, Nimesil (Czech Republic, Moldova, Latvia, Lithuania, Kazakhstan, Georgia, Poland, Russia, Ukraine), Nimulid (Trinidad & Tobago), Nimutab, Nimdase, Nimopen-MP Nise, Nimuwin, Nisulid, Nodard Plus, Nicip, Nimcap, Nic-P, Nic-Spas, Nimupain (India); Mesulid, Novolid, Relmex (Ecuador); Remisid (Ukraine); Coxulid, Emulid, Frenag, Fuzo, Motival, Nimeksil, Nimelid, Nîmes, Nimesdin, Romasulid, Sulidin, Suljel, Thermo Sulidin (Turkey), Xilox (Hungary); Modact-IR (Pakistan); and ad Sulidene and Zolan for veterinary use. Many generic and copy-products also exist (Lusemin, Medicox, Nidol, Nimalox, Nimesil, Nimotas, Nimulid, Nizer, Sorini, Ventor, Vionim, Neolide, Willgo among others), new-aid, Nexulide (Syria), Nims, Nice, Nimulide (Nepal)

===India=== Several reports have been made of nimesulide's adverse drug reactions in India.<ref>Safety of nimesulide. CD ROM, Appropriate Use of Antipyretics / Analgesics in Children, Health Informatics, New Delhi, 2004.</ref><ref>{{cite journal |vauthors=Rahman SZ, Khan RA |title=Is nimesulide safe in a cardiovascular-Compromised patient? |journal=Indian Journal of Pharmacology |volume=36 |pages=252–3 |year=2004 | url = https://journals.lww.com/iphr/fulltext/2004/36040/is_nimesulide_safe_in_a_cardiovascular_compromised.15.aspx }}</ref><ref>{{cite journal |vauthors=Khan RA, Rahman SZ |title=A Case Report on Nimesulide and its Relation with Angina |journal=J Pharmacovigilance Drug Safety |volume=1 |pages=19–21 |year=2004 }}</ref><ref>{{cite journal |vauthors=Khan RA, Rahman SZ |title=Nimesulide Induced Coronary Artery Insufficiency – A Case Report |journal=J Pharmacovigilance Drug Safety |volume=1 |pages=11–3 |year=2004 }}</ref> On 12 February 2011, ''The Indian Express'' reported that the Union Ministry of Health and Family Welfare had finally decided to suspend the pediatric use of the analgesic suspension.<ref>{{cite news| vauthors = Thacker T |title=Nimesulide for kids to be banned, finally|url=http://indianexpress.com/article/news-archive/web/nimesulide-for-kids-to-be-banned-finally/|access-date=2018-05-19|work=The Indian Express|date=12 February 2011}}</ref> From 10 March 2011 onward, nimesulide formulations are not indicated for human use in children below 12 years of age.<ref>{{cite web | url = https://cdsco.gov.in/opencms/opencms/system/modules/CDSCO.WEB/elements/download_file_division.jsp?num_id=MTE5NA== | work = CDSCO | title = Gazette notification GSR 82(E) | date = 10 March 2011 }}</ref>

On 13 September 2011, the Madras High Court revoked a suspension on manufacture and sale of paediatric drugs nimesulide and phenylpropanolamine (PPA).<ref>{{cite web|url=https://www.scribd.com/doc/64907025/Madras-High-Court-Revokes-Ban-on-Manufacture-and-Sale-PPA|title=Madras High Court Revokes Ban on Manufacture and Sale PPA - Adverse Effect - Medical Treatments|website=Scribd|url-status=live|archive-url=https://web.archive.org/web/20140107193045/http://www.scribd.com/doc/64907025/Madras-High-Court-Revokes-Ban-on-Manufacture-and-Sale-PPA|archive-date=2014-01-07}}</ref>

On 30 December 2024, the Central government banned the manufacture, sale and distribution of nimesulide and its formulations for animal use.<ref>{{Cite web |date=30 December 2024 |title=The Gazette of India - Notification regarding Banning Nimesulide for animal use |url=https://cdsco.gov.in/opencms/opencms/system/modules/CDSCO.WEB/elements/download_file_division.jsp?num_id=MTIzMjM= |access-date=26 January 2025 |website=Central Drugs Standard Control Organisation |format=PDF |publication-place=New Delhi}}</ref> This was in response to studies conducted at the Indian Veterinary Research Institute (IVRI) at Izatnagar, Bareilly, showing nimesulide causing lethal kidney problems in wild vultures, especially Himalayan griffon vultures, which consume the drug through carcasses of treated livestock.<ref>{{Cite news |last=Singh |first=Kanwardeep |date=3 January 2025 |title=Popular painkiller banned for animal use after vultures die |url=https://timesofindia.indiatimes.com/city/bareilly/centre-bans-nimesulide-for-animal-use-after-vultures-die-in-experiment/articleshow/116892014.cms |access-date=26 January 2025 |work=The Times of India}}</ref><ref>{{Cite web |last=Choudhary |first=Vikas |date=7 January 2025 |title=Painkiller nimesulide finally banned after research confirms lethality for vultures |url=https://www.downtoearth.org.in/wildlife-biodiversity/painkiller-nimesulide-finally-banned-after-research-confirms-lethality-for-vultures |access-date=26 January 2025 |website=Down to Earth}}</ref>

===EMA confirms the positive benefit/risk ratio=== On September 21, 2007 the EMA released a press release on their review on the liver-related safety of nimesulide. The EMA has concluded that the benefits of these medicines outweigh their risks, but that there is a need to limit the duration of use to ensure that the risk of patients developing liver problems is kept to a minimum. Therefore, the EMA has limited the use of systemic formulations (tablets, solutions, suppositories) of nimesulide to 15 days.<ref>{{cite web | url = http://www.emea.europa.eu/pdfs/general/direct/pr/43260407en.pdf | title = EMA press release on nimesulide | date = September 2007 | archive-url = http://arquivo.pt/wayback/20090718094456/http://www.emea.europa.eu/pdfs/general/direct/pr/43260407en.pdf | archive-date = 2009-07-18 | work = European Medicines Agency | access-date = 2007-09-21 | url-status = live }}</ref>

===Irish Medicines Board=== The Irish Medicines Board has decided to suspend Nimesulide from the Irish market and refer it to the EU Committee for Human Medicinal Products (CHMP) for a review of its benefit/risk profile. The decision is due to the reporting of six cases of potentially-related liver failures to the IMB by the National Liver Transplant Unit, St. Vincent's University Hospital. These cases occurred in the period from 1999 to 2006.<ref>{{cite web|url=https://www.irishtimes.com/news/irish-agency-rejects-european-ruling-on-safety-of-painkiller-1.964481|title=The Irish Times|website=www.irishtimes.com}}</ref>

===Bribes=== In May 2008, Italy's leading daily paper ''Corriere della Sera'' and other media outlets{{citation needed|date=June 2014}} reported that a top-ranking official at Italy's medicines agency AIFA had been filmed by police while accepting bribes from employees of pharmaceutical companies.<ref>{{cite web | url = http://www.corriere.it/cronache/08_maggio_23/aulin_mazzette_controlli_torino_2eed67d6-288a-11dd-97ea-00144f02aabc.shtml | title = Mazzette per evitare i controlli sull'Aulin | vauthors = Pappagallo M | work = Corriere della Sera | date = 23 May 2008 | archive-url = https://web.archive.org/web/20080525221510/http://www.corriere.it/cronache/08_maggio_23/aulin_mazzette_controlli_torino_2eed67d6-288a-11dd-97ea-00144f02aabc.shtml | archive-date = 25 May 2008 }}</ref><ref>{{cite web|title=Italian medicines agency officials arrested in corruption probe|url=https://www.manufacturingchemist.com/news/article_page/Italian_medicines_agency_officials_arrested_in_corruption_probe/40712|publisher=Manufacturing Chemist|access-date=2018-05-19|date=22 May 2008}}</ref> The money allegedly was being paid to ensure that certain drugs would be spared scrutiny from the drugs watchdog. The investigation had started in 2005 following suspicions that some AIFA drug tests had been faked. Eight arrests were made. Nimesulide can be bought carrying a prescription from a physician that is kept as a receipt at the chemist shop, nominally allowing strong control over selling.

The original manufacturer of nimesulide is Helsinn Healthcare SA, Switzerland, which acquired the rights for the drug in 1976. After the patent protection terminated in 2015,<ref>{{Cite web|url=https://patents.google.com/patent/EP0782855B1/en|title=Nimesulide for external use}}</ref> a number of other companies started production and marketing of Nimesulide.

== References == {{Reflist}}

Category:Antipyretics Category:Diphenyl ethers Category:Drugs with unknown mechanisms of action Category:Hepatotoxins Category:N-phenylmethanesulfonamide derivatives Category:Nitrobenzene derivatives Category:Nonsteroidal anti-inflammatory drugs Category:Withdrawn drugs