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Revision as of 10:51, 26 October 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'ChEMBL', 'CAS_number').← Previous edit Latest revision as of 14:56, 19 July 2024 edit undoWikiCleanerBot (talk | contribs)Bots928,066 editsm v2.05b - Bot T20 CW#61 - Fix errors for CW project (Reference before punctuation)Tag: WPCleaner 
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{{Short description|Medication}}
{{Drugbox
{{Use dmy dates|date=July 2024}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug
| Verifiedfields = changed | Verifiedfields = changed
| Watchedfields = changed | Watchedfields = changed
| verifiedrevid = 401043706 | verifiedrevid = 464383196
| image = Roflumilast structure.svg
| IUPAC_name = 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide
| image = Roflumilast.png
| width = 240 | width = 240
| alt =
| image2 = Roflumilast ball-and-stick model.png
| width2 = 240
| alt2 =
| caption =


<!--Clinical data--> <!-- Clinical data -->
| tradename = | pronounce =
| tradename = Daxas, Daliresp, Zoryve, others
| Drugs.com = {{drugs.com|CDI|roflumilast}}
| Drugs.com = {{drugs.com|monograph|roflumilast}}
| MedlinePlus = a611034 | MedlinePlus = a611034
| DailyMedID = Roflumilast
| licence_EU = Daxas
| pregnancy_AU = B3
| licence_US = Roflumilast
| pregnancy_AU_comment =
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = C | pregnancy_category =
| routes_of_administration = ], ]
| pregnancy_category =
| class = ]
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| ATC_prefix = R03
| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->
| ATC_suffix = DX07
| ATC_supplemental = {{ATC|D05|AX06}}

<!-- Legal status -->
| legal_AU = S4
| legal_AU_comment =
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment =
| legal_CA = Rx-only
| legal_CA_comment = <ref name="Daxas CA PI" /><ref>{{cite web | title=Zoryve Product information | website=] | date=7 November 2023 | url=https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=102624 | access-date=13 July 2024}}</ref>
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = POM | legal_UK = POM
| legal_UK_comment = <ref name="Daxas SmPC" />
| legal_US = Rx-only | legal_US = Rx-only
| legal_US_comment = <ref name="Daliresp FDA label" /><ref name="Zoryve cream FDA label" /><ref name="Zoryve foam FDA label" />
| legal_status =
| legal_EU = Rx-only
| routes_of_administration = Oral
| legal_EU_comment = <ref name="Daxas EPAR" />
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_status = <!-- For countries not listed above -->


<!--Pharmacokinetic data--> <!-- Pharmacokinetic data -->
| bioavailability = 79%<ref name="Daliresp FDA label"/><ref name="Daxas SmPC"/><ref name=EMA/><ref name=MSR/>
| bioavailability =
| protein_bound = 99%<ref name="Daliresp FDA label"/><ref name="Daxas SmPC"/><ref name=EMA/><ref name=MSR/>
| protein_bound =
| metabolism = ] via ] & ]<ref name="Daliresp FDA label"/><ref name="Daxas SmPC"/><ref name=EMA/><ref name=MSR/>
| metabolism =
| metabolites =
| elimination_half-life =
| excretion = | onset =
| elimination_half-life = 17 hours (30 hours )<ref name="Daliresp FDA label"/><ref name="Daxas SmPC"/><ref name=EMA/><ref name=MSR/>
| duration_of_action =
| excretion = Urine (70%)<ref name="Daliresp FDA label"/><ref name="Daxas SmPC"/><ref name=EMA/><ref name=MSR/>


<!--Identifiers--> <!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|??}} | CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = <!-- blanked - oldvalue: 162401-32-3 --> | CAS_number = 162401-32-3
| ATC_prefix = R03 | CAS_supplemental =
| ATC_suffix = DX07 | PubChem = 449193
| PubChem = 158787 | IUPHAR_ligand = 6962
| DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = | DrugBank = DB01656
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 139677 | ChemSpiderID = 395793
| UNII_Ref = {{fdacite|changed|FDA}} | UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 0P6C6ZOP5U | UNII = 0P6C6ZOP5U
| KEGG_Ref =
| KEGG = D05744
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 47657
| ChEMBL_Ref = {{ebicite|changed|EBI}} | ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = <!-- blanked - oldvalue: 193240 --> | ChEMBL = 193240
| NIAID_ChemDB =
| PDB_ligand = ROF
| synonyms =

<!-- Chemical and physical data -->
| IUPAC_name = 3-(Cyclopropylmethoxy)-''N''-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide
| C=17 | H=14 | Cl=2 | F=2 | N=2 | O=3 | C=17 | H=14 | Cl=2 | F=2 | N=2 | O=3
| SMILES = C1CC1COC2=C(C=CC(=C2)C(=O)NC3=C(C=NC=C3Cl)Cl)OC(F)F
| molecular_weight = 403.207 g/mol
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| smiles = Clc3c(N(OCC1CC1)C(=O)c2ccc(OC(F)F)cc2)c(Cl)cnc3
| InChI = 1/C17H14Cl2F2N2O3/c18-13-7-22-8-14(19)15(13)23(25-9-10-1-2-10)16(24)11-3-5-12(6-4-11)26-17(20)21/h3-8,10,17H,1-2,9H2 | StdInChI = 1S/C17H14Cl2F2N2O3/c18-11-6-22-7-12(19)15(11)23-16(24)10-3-4-13(26-17(20)21)14(5-10)25-8-9-1-2-9/h3-7,9,17H,1-2,8H2,(H,22,23,24)
| StdInChI_comment =
| InChIKey = IWONQDOIPBAXGV-UHFFFAOYAH
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = MNDBXUUTURYVHR-UHFFFAOYSA-N
| StdInChI = 1S/C17H14Cl2F2N2O3/c18-13-7-22-8-14(19)15(13)23(25-9-10-1-2-10)16(24)11-3-5-12(6-4-11)26-17(20)21/h3-8,10,17H,1-2,9H2
| density =
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| density_notes =
| StdInChIKey = IWONQDOIPBAXGV-UHFFFAOYSA-N
| melting_point =
| melting_high =
| melting_notes =
| boiling_point =
| boiling_notes =
| solubility =
| sol_units =
| specific_rotation =
}} }}


'''Roflumilast''', sold under the brand name '''Daxas''' among others, is a medication used for the treatment of ],<ref name="Daliresp FDA label" /> ],<ref name="Zoryve cream FDA label" /> ],<ref name="Zoryve foam FDA label" /> and ].<ref name="Zoryve cream FDA label" /> It acts as a selective, long-acting ] (PDE-4).<ref name="pmid18044684" /> It has ] effects.<ref name="pmid18044684">{{cite journal | vauthors = Boswell-Smith V, Spina D | title = PDE4 inhibitors as potential therapeutic agents in the treatment of COPD-focus on roflumilast | journal = International Journal of Chronic Obstructive Pulmonary Disease | volume = 2 | issue = 2 | pages = 121–9 | year = 2007 | pmid = 18044684 | pmc = 2695611 | url = }}</ref><ref name="pmid18307529">{{cite journal | vauthors = Herbert C, Hettiaratchi A, Webb DC, Thomas PS, Foster PS, Kumar RK | title = Suppression of cytokine expression by roflumilast and dexamethasone in a model of chronic asthma | journal = Clinical and Experimental Allergy | volume = 38 | issue = 5 | pages = 847–56 | date = May 2008 | pmid = 18307529 | doi = 10.1111/j.1365-2222.2008.02950.x | s2cid = 19050454 }}</ref><ref name="pmid18447606">{{cite journal | vauthors = Field SK | title = Roflumilast: an oral, once-daily selective PDE-4 inhibitor for the management of COPD and asthma | journal = Expert Opinion on Investigational Drugs | volume = 17 | issue = 5 | pages = 811–8 | date = May 2008 | pmid = 18447606 | doi = 10.1517/13543784.17.5.811 | s2cid = 73241684 }}</ref>
'''Roflumilast''' (trade names '''Daxas''', '''Daliresp''') is a drug which acts as a selective, long-acting ]. It has ] effects and is under development as an orally administered drug for the treatment of inflammatory conditions of the lungs such as ], and ] (COPD).<ref name="pmid18044684">{{cite journal
| last1 = Boswell-Smith | first1 = V
| last2 = Spina | first2 = D
| title = PDE4 inhibitors as potential therapeutic agents in the treatment of COPD-focus on roflumilast
| journal = ]
| volume = 2
| issue = 2
| pages = 121–9
| year = 2007
| pmid = 18044684
| pmc = 2695611
| url = http://www.dovepress.com/getfile.php?fileID=971
| issn = 1178-2005
}}</ref><ref name="pmid18307529">{{cite journal
| last1 = Herbert | first1 = C
| last2 = Hettiaratchi | first2 = A
| last3 = Webb | first3 = DC
| last4 = Thomas | first4 = PS
| last5 = Foster | first5 = PS
| last6 = Kumar | first6 = RK
| title = Suppression of cytokine expression by roflumilast and dexamethasone in a model of chronic asthma
| journal = ]
| volume = 38
| issue = 5
| pages = 847–56
| year = 2008
| month = May
| pmid = 18307529
| doi = 10.1111/j.1365-2222.2008.02950.x
| issn = 1365-2222
}}</ref><ref name="pmid18374614">{{cite journal
| last1 = Hohlfeld | first1 = JM
| last2 = Schoenfeld | first2 = K
| last3 = Lavae-Mokhtari | first3 = M
| last4 = Schaumann | first4 = F
| last5 = Mueller | first5 = M
| last6 = Bredenbroeker | first6 = D
| last7 = Krug | first7 = N
| last8 = Hermann | first8 = R
| title = Roflumilast attenuates pulmonary inflammation upon segmental endotoxin challenge in healthy subjects: a randomized placebo-controlled trial
| journal = ]
| volume = 21
| issue = 4
| pages = 616–23
| year = 2008
| month = August
| pmid = 18374614
| doi = 10.1016/j.pupt.2008.02.002
| issn = 1094-5539
}}</ref><ref name="pmid18447606">{{cite journal
| last1 = Field | first1 = SK
| title = Roflumilast: an oral, once-daily selective PDE-4 inhibitor for the management of COPD and asthma
| journal = ]
| volume = 17
| issue = 5
| pages = 811–8
| year = 2008
| month = May
| pmid = 18447606
| doi = 10.1517/13543784.17.5.811
| issn = 1354-3784
}}</ref> While roflumilast was found to be effective in clinical trials, it produced several dose-limiting side effects including ], ] and ], and development is continuing in an attempt to minimise the incidence of side effects while retaining clinical efficacy.<ref name="pmid18660825">{{cite journal
| last1 = Spina | first1 = D
| title = PDE4 inhibitors: current status
| journal = ]
| volume = 155
| issue = 3
| pages = 308–15
| year = 2008
| month = October
| pmid = 18660825
| pmc = 2567892
| doi = 10.1038/bjp.2008.307
| issn = 1476-5381
}}</ref>


It was approved for medical use in the European Union in 2010,<ref name="Daxas EPAR">{{cite web | title=Daxas EPAR | website=] | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/daxas | access-date=28 September 2020 | archive-date=12 August 2020 | archive-url=https://web.archive.org/web/20200812193907/https://www.ema.europa.eu/en/medicines/human/EPAR/daxas | url-status=live }}</ref> in the United States in 2011,<ref name="Daliresp FDA label">{{cite web | title=Daliresp- roflumilast tablet | website=DailyMed | date=12 March 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c9a1d0a8-581f-4f91-a2b8-f419192d0ebf | access-date=28 September 2020 | archive-date=25 March 2021 | archive-url=https://web.archive.org/web/20210325081719/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c9a1d0a8-581f-4f91-a2b8-f419192d0ebf | url-status=live }}</ref> and in Canada in 2017.<ref name="Daxas CA PI">{{cite web | title=Daxas Product information | website=] | date=20 July 2017 | url=https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=84447 | access-date=13 July 2024}}</ref> It is available as a ].<ref>{{cite web | title=2022 First Generic Drug Approvals | website=U.S. ] (FDA) | date=3 March 2023 | url=https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/2022-first-generic-drug-approvals | archive-url=https://web.archive.org/web/20230630003602/https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/2022-first-generic-drug-approvals | archive-date=30 June 2023 | url-status=live | access-date=30 June 2023}}</ref>
In June 2010, Daxas was approved in the ] for severe ] associated with chronic bronchitis.<ref></ref> In March 2011, Daliresp gained FDA approval in the ] for reducing COPD exacerbations.<ref>{{cite press release
| url = http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm244989.htm
| title = FDA approves new drug to treat chronic obstructive pulmonary disease
| date = March 1, 2011
| publisher = ] (FDA)
}}</ref>


==Chemical synthesis== ==Medical uses==
Roflumilast is ] for the treatment of severe chronic obstructive pulmonary disease (COPD),<ref name="Daliresp FDA label" /> plaque ],<ref name="Zoryve cream FDA label">{{cite web | title=Zoryve- roflumilast cream | website=DailyMed | date=16 August 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ec1bb0d1-f38a-4080-831a-68791d1d1fdb | access-date=21 January 2023 | archive-date=21 January 2023 | archive-url=https://web.archive.org/web/20230121062229/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ec1bb0d1-f38a-4080-831a-68791d1d1fdb | url-status=live }}</ref><ref>{{cite press release | title=FDA Approves Arcutis' Zoryve (Roflumilast) Cream 0.3% For the Treatment of Plaque Psoriasis in Individuals Age 12 and Older | publisher=Arcutis Biotherapeutics | via=GlobeNewswire | date=29 July 2022 | url=https://www.globenewswire.com/news-release/2022/07/29/2488966/0/en/FDA-Approves-Arcutis-ZORYVE-Roflumilast-Cream-0-3-For-the-Treatment-of-Plaque-Psoriasis-in-Individuals-Age-12-and-Older.html | access-date=1 August 2022 | archive-date=1 August 2022 | archive-url=https://web.archive.org/web/20220801114445/https://www.globenewswire.com/news-release/2022/07/29/2488966/0/en/FDA-Approves-Arcutis-ZORYVE-Roflumilast-Cream-0-3-For-the-Treatment-of-Plaque-Psoriasis-in-Individuals-Age-12-and-Older.html | url-status=live }}</ref> seborrheic dermatitis,<ref name="Zoryve foam FDA label">{{cite web | title=Zoryve- roflumilast aerosol, foam | website=DailyMed | date=20 December 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f9e0b4a9-a227-4947-b00c-41fb18d16589 | access-date=13 July 2024}}</ref> and atopic dermatitis,<ref name="Zoryve cream FDA label" /><ref>{{cite web |title=FDA Approves Atopic Dermatitis Label Expansion for Arcutis' Zoryve Cream |url=https://www.biospace.com/article/fda-approves-atopic-dermatitis-label-expansion-for-arcutis-zoryve-topical-cream-/ |access-date=13 July 2024 |website=BioSpace }}</ref>
Chemical synthesis:<ref>Amschler, H.; 1998, {{US Patent|5712298}}.</ref>


It is used in the prevention of exacerbations (lung attacks) in severe chronic obstructive pulmonary disease (COPD).<ref name="Daxas SmPC">{{cite web | title=Daxas 250 micrograms tablets - Summary of Product Characteristics (SmPC) | website=(emc) | date=11 June 2020 | url=https://www.medicines.org.uk/emc/product/9162/smpc | access-date=28 September 2020 | archive-date=19 September 2020 | archive-url=https://web.archive.org/web/20200919164902/https://www.medicines.org.uk/emc/product/9162/smpc | url-status=live }}</ref><ref name="Daliresp FDA label" /><ref name="Daxas EPAR" /><ref name=EMA>{{cite web|title=Daliresp : EPAR - Product Information|work=European Medicines Agency|publisher=Takeda GmbH|date=26 September 2013|access-date=18 November 2013|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002398/WC500103078.pdf|archive-date=26 June 2016|archive-url=https://web.archive.org/web/20160626155812/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002398/WC500103078.pdf|url-status=live}}</ref><ref name=MSR>{{cite web|title=roflumilast (Rx) - Daliresp|work=Medscape Reference|publisher=WebMD|access-date=18 November 2013|url=http://reference.medscape.com/drug/daliresp-roflumilast-999626|archive-date=12 September 2017|archive-url=https://web.archive.org/web/20170912145935/http://reference.medscape.com/drug/daliresp-roflumilast-999626|url-status=live}}</ref>
]


==See also== ==Adverse effects==
*]


Common (1–10% incidence) adverse effects include diarrhea, weight loss, nausea, headache, insomnia, decreased appetite, abdominal pain, rhinitis, sinusitis, urinary tract infection, and depression.<ref name="Daliresp FDA label"/><ref name="Daxas SmPC"/><ref name=EMA/><ref name=MSR/><ref name="pmid18660825">{{cite journal | vauthors = Spina D | title = PDE4 inhibitors: current status | journal = British Journal of Pharmacology | volume = 155 | issue = 3 | pages = 308–15 | date = October 2008 | pmid = 18660825 | pmc = 2567892 | doi = 10.1038/bjp.2008.307 }}</ref>
==References==

== Society and culture ==
=== Legal status ===
In June 2010, it was approved in the European Union for severe COPD associated with chronic bronchitis.<ref name="Daxas EPAR" /><ref>{{Cite web |url=http://www.genengnews.com/gen-news-highlights/nycomed-s-anti-inflammatory-gains-approval-in-eu-for-copd/81243622/ |title="Nycomed's Anti-Inflammatory Gains Approval in EU for COPD" |access-date=10 July 2010 |archive-date=24 August 2017 |archive-url=https://web.archive.org/web/20170824222207/http://www.genengnews.com/gen-news-highlights/nycomed-s-anti-inflammatory-gains-approval-in-eu-for-copd/81243622 |url-status=live }}</ref> In February 2011, it gained FDA approval in the United States for reducing COPD exacerbations.<ref>{{cite web | title=Drug Approval Package: Daliresp Tablets (roflumilast) NDA #022522 | website=U.S. ] (FDA) | date=24 December 1999 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000TOC.cfm | access-date=28 September 2020 | archive-date=27 October 2020 | archive-url=https://web.archive.org/web/20201027013611/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000TOC.cfm | url-status=live }}</ref><ref>{{cite press release | url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm244989.htm | title = FDA approves new drug to treat chronic obstructive pulmonary disease | date = 1 March 2011 | publisher = U.S. ] (FDA) | access-date = 16 December 2019 | archive-date = 18 January 2017 | archive-url = https://web.archive.org/web/20170118091136/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm244989.htm | url-status = dead }}</ref>

== References ==
{{Reflist}} {{Reflist}}


== Further reading ==
{{Phosphodiesterase inhibitors}}
* {{cite journal | vauthors = Hohlfeld JM, Schoenfeld K, Lavae-Mokhtari M, Schaumann F, Mueller M, Bredenbroeker D, Krug N, Hermann R | title = Roflumilast attenuates pulmonary inflammation upon segmental endotoxin challenge in healthy subjects: a randomized placebo-controlled trial | journal = Pulmonary Pharmacology & Therapeutics | volume = 21 | issue = 4 | pages = 616–23 | date = August 2008 | pmid = 18374614 | doi = 10.1016/j.pupt.2008.02.002 | url = https://hal.archives-ouvertes.fr/hal-00499153/file/PEER_stage2_10.1016%252Fj.pupt.2008.02.002.pdf | access-date = 24 June 2019 | archive-date = 28 August 2019 | archive-url = https://web.archive.org/web/20190828080728/https://hal.archives-ouvertes.fr/hal-00499153/file/PEER_stage2_10.1016%25252Fj.pupt.2008.02.002.pdf | url-status = live }}

{{Drugs for obstructive airway diseases}} {{Drugs for obstructive airway diseases}}
{{Phosphodiesterase inhibitors}}
{{AstraZeneca}}
{{Portal bar | Medicine}}
{{Authority control}}


]
==External links==
]
* {{Official website|http://www.daliresp.com/}}
* European Public Assessment Report (EPAR)

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