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{{short description|HIV treatment}}
{{Drugbox
{{Infobox drug
| IUPAC_name = 4-{-2,6-dimethylphenyl}amino)pyrimidin-2-yl]amino}benzonitrile
| Verifiedfields = changed
| image = Rilpivirine.svg
| Watchedfields = changed
| image2 = Rilpivirine3D.PNG
| verifiedrevid = 417509820
| CAS_number = 500287-72-9
| image = Rilpivirine.svg
| ATC_prefix = none
| width = 180px
| ATC_suffix =
| alt =
| PubChem = 6451164
| image2 = Rilpivirine 3D 2zd1.png
| DrugBank =
| alt2 =
| C=22|H=18|N=6

| molecular_weight = 366.42 g/mol
<!--Clinical data-->
| bioavailability =
| tradename = Edurant, Rekambys
| protein_bound =
| Drugs.com = {{drugs.com|monograph|rilpivirine}}
| metabolism =
| MedlinePlus = a611037
| elimination_half-life = 38 hours
| DailyMedID = Rilpivirine
| excretion =
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> | pregnancy_AU = B1
| pregnancy_category =
| pregnancy_US = <!-- A / B / C / D / X -->
| licence_EU = yes
| pregnancy_category=
| legal_AU = S4
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII --> | legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = POM
| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->
| legal_UK_comment = <ref>{{cite web | title=Edurant 25 mg tablets - Summary of Product Characteristics (SmPC) | website=(emc) | date=21 January 2020 | url=https://www.medicines.org.uk/emc/product/4968 | access-date=4 January 2021}}</ref>
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_US = Rx-only
| legal_status =
| legal_US_comment = <ref>{{cite web | title=Edurant- rilpivirine hydrochloride tablet, film coated | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=03880372-2c68-45c6-a53a-f420c49541d6 | access-date=4 January 2021}}</ref>
| routes_of_administration = Oral
| legal_EU = Rx-only
| legal_EU_comment = <ref>{{cite web | title=Edurant EPAR | website=] (EMA) | date=12 December 2011 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/edurant | access-date=4 January 2021}}</ref><ref name="Rekambys EPAR" />
| legal_status =
| routes_of_administration = ], ]
| ATC_prefix = J05
| ATC_suffix = AG05
| ATC_supplemental = <br />combinations:<br />{{ATC|J05|AR19}}<br />{{ATC|J05|AR21}}<br />{{ATC|J05|AR08}}

<!--Pharmacokinetic data-->
| bioavailability =
| protein_bound = 99.7%
| metabolism = ]
| elimination_half-life = tablets: 45 hours<br />injection: 13–28 weeks
| excretion = 85% via faeces, 6% via urine

<!--Identifiers-->
| index2_label = as HCl
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 500287-72-9
| CAS_number2 = 700361-47-3
| PubChem = 6451164
| PubChem2 = 11711114
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB08864
| DrugBank2 = DBSALT000152
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 4953643
| ChemSpiderID2 = 9885836
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII = FI96A8X663
| UNII2 = 212WAX8KDD
| KEGG = D09720
| KEGG2 = D09958
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 68606
| ChEBI2 = 68602
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 175691
| ChEMBL2 = 1628504
| NIAID_ChemDB = 169030
| PDB_ligand = T27
| synonyms = TMC278

<!--Chemical data-->
| IUPAC_name = 4-<nowiki/>{-2,6-dimethylphenyl}amino)pyrimidin-2-yl]amino}benzonitrile
| C=22 | H=18 | N=6
| smiles = Cc1cc(cc(c1Nc2ccnc(n2)Nc3ccc(cc3)C#N)C)/C=C/C#N
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 1S/C22H18N6/c1-15-12-18(4-3-10-23)13-16(2)21(15)27-20-9-11-25-22(28-20)26-19-7-5-17(14-24)6-8-19/h3-9,11-13H,1-2H3,(H2,25,26,27,28)/b4-3+
| StdInChI2 = 1S/C22H18N6.ClH/c1-15-12-18(4-3-10-23)13-16(2)21(15)27-20-9-11-25-22(28-20)26-19-7-5-17(14-24)6-8-19;/h3-9,11-13H,1-2H3,(H2,25,26,27,28);1H/b4-3+;
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = YIBOMRUWOWDFLG-ONEGZZNKSA-N
| StdInChIKey2 = KZVVGZKAVZUACK-BJILWQEISA-N
}} }}
'''Rilpivirine''' (TMC278) is an ], developed by ], for the treatment of ] infection.<ref>{{cite web |publisher=Tibotec |url=http://www.tibotec.com/bgdisplay.jhtml?itemname=HIV_tmc278 |title=TMC278 - A new NNRTI |retrieved=2010-03-07}}</ref><ref name="pmid17933730">{{cite journal |author=Stellbrink HJ |title=Antiviral drugs in the treatment of AIDS: what is in the pipeline ? |journal=Eur. J. Med. Res. |volume=12 |issue=9 |pages=483–95 |year=2007 |pmid=17933730 |doi=}}</ref> It is a second-generation ] (NNRTI) with higher ], longer ] and reduced ] compared with older NNRTIs, such as ].<ref>{{cite journal |author=Goebel F, Yakovlev A, Pozniak AL, Vinogradova E, Boogaerts G, Hoetelmans R, de Béthune MP, Peeters M, Woodfall B |title=Short-term antiviral activity of TMC278--a novel NNRTI--in treatment-naive HIV-1-infected subjects |journal=AIDS |volume=20 |issue=13 |pages=1721–6 |year=2006 |pmid=16931936 |doi=10.1097/01.aids.0000242818.65215.bd |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?an=00002030-200608220-00005}}</ref><ref>Pozniak A, Morales-Ramirez J, Mohap L et al. Oral abstract 144LB.
</ref> It entered ] in April 2008, with an estimated study completion date in January 2011.<ref>ClinicalTrials.gov </ref><ref>ClinicalTrials.gov </ref> Like ], a second-generation NNRTI approved in 2008, rilpivirine is a ] (DAPY).


'''Rilpivirine''', sold under the brand names '''Edurant''' and '''Rekambys''', is a ], developed by ], used for the treatment of ].<ref>{{cite web |publisher=Tibotec |url=http://www.tibotec.com/bgdisplay.jhtml?itemname=HIV_tmc278 |title=TMC278 — A new NNRTI |access-date=2010-03-07 |url-status=dead |archive-url=https://web.archive.org/web/20081220203841/http://www.tibotec.com/bgdisplay.jhtml?itemname=HIV_tmc278 |archive-date=2008-12-20 }}</ref><ref name="pmid17933730">{{cite journal | vauthors = Stellbrink HJ | title = Antiviral drugs in the treatment of AIDS: what is in the pipeline ? | journal = European Journal of Medical Research | volume = 12 | issue = 9 | pages = 483–495 | date = October 2007 | pmid = 17933730 }}</ref> It is a second-generation ] (NNRTI) with higher ], longer ] and reduced ] compared with older NNRTIs such as ].<ref>{{cite journal | vauthors = Goebel F, Yakovlev A, Pozniak AL, Vinogradova E, Boogaerts G, Hoetelmans R, de Béthune MP, Peeters M, Woodfall B | display-authors = 6 | title = Short-term antiviral activity of TMC278--a novel NNRTI--in treatment-naive HIV-1-infected subjects | journal = AIDS | volume = 20 | issue = 13 | pages = 1721–1726 | date = August 2006 | pmid = 16931936 | doi = 10.1097/01.aids.0000242818.65215.bd | s2cid = 26078073 | doi-access = free }}</ref><ref>{{cite web |vauthors=Pozniak A, Morales-Ramirez J, Mohap L, etal |url=http://www.retroconference.org/2007/Abstracts/30659.htm |title=48-Week Primary Analysis of Trial TMC278-C204: TMC278 Demonstrates Potent and Sustained Efficacy in ART-naïve Patients. Oral abstract 144LB. |publisher=14th Conference on Retroviruses and Opportunistic Infections |archive-date=October 19, 2007 |archive-url=https://web.archive.org/web/20071019211215/http://www.retroconference.org/2007/Abstracts/30659.htm }}</ref>
==References==
{{reflist}}


==Medical uses==
{{HIVpharm}}
In the US, rilpivirine is approved for treatment-naive patients with a ] of 100,000 copies/mL or less at therapy initiation. It has to be combined with other drugs against HIV.<ref name="drugs.com">Rilpivirine {{drugs.com|monograph|rilpivirine}}. Accessed 2021-02-23.</ref>


In the European Union, rilpivirine is approved in combination with ] for maintenance treatment of adults who have undetectable HIV levels in the blood (viral load less than 50 copies/ml) with their current ], and when the virus has not developed resistance to certain class of anti-HIV medicines called ] (NNRTIs) and integrase strand transfer inhibitors (INIs).<ref name="Rekambys EPAR" /><ref name="EMA PR" />
]
]
]


===Available forms===
The drug is available as tablets (brand name ''Edurant'') and as a long-acting ] to be given once every month or every two months (''Rekambys''). Before using the injection, the tablets are given for about four weeks to assess tolerability.<ref name="drugs.com" /><ref name="EPAR Rekambys" />


==Contraindications and interactions==
{{antiinfective-drug-stub}}
The drug is contraindicated for use with drugs that ] the liver enzyme ], such as ], ], ], and ]. Such drugs can accelerate the breaking down of rilpivirine, substantially decreasing its plasma concentrations and potentially resulting in loss of effectiveness and possible ].<ref name="drugs.com" /> Some of these drugs also induce the enzyme ] and thus reduce blood plasma concentrations of cabotegravir, further compromising the effectiveness of this combination therapy.<ref>{{cite web|url=https://www.ema.europa.eu/en/documents/product-information/vocabria-epar-product-information_en.pdf|publisher=]|title=Vocabria: EPAR – Product information|date=2021-01-05}}</ref>


It is also contraindicated in combination with ]s because the increased gastric pH causes decreased rilpivirine absorption from the gut, with similar consequences as with CYP3A4 inducers.<ref name="drugs.com" />
]

]
==Adverse effects==
The most common side effects of the injectable formulation are reactions at the injection site (in up to 84% of patients) such as pain and swelling, as well as headache (up to 12%) and fever or feeling hot (in 10%). Less common (under 10%) are ]s, ], and ].<ref name="drugs.com" /><ref name="EPAR Rekambys">{{cite web|title=Rekambys: EPAR – public assessment report|publisher=]|date=2021-02-22|url=https://www.ema.europa.eu/en/documents/product-information/rekambys-epar-product-information_en.pdf}}</ref> The most common side effects of the tablets are also depressive disorders (4.1%), headache (3.5%), insomnia (3.5%) and rashes (2.3%).<ref name="EPAR Edurant">{{cite web|title=Edurant: EPAR – public assessment report|publisher=]|date=2021-01-04|url=https://www.ema.europa.eu/en/documents/product-information/edurant-epar-product-information_en.pdf}}</ref> All of these side effects occurred under combination therapies of rilpivirine with one or more other drugs against HIV.

] of the heart rhythm has been observed at very high doses, but is not clinically relevant at standard doses of the drug.<ref name="EPAR Edurant" />

==Pharmacology==
===Mechanism of action===
{{see|Reverse-transcriptase inhibitor#Mechanism of action}}
Rilpivirine is a non-] reverse transcriptase inhibitor (NNRTI).<ref name="EPAR Edurant" />

===Pharmacokinetics===
When taken by mouth, rilpivirine reaches highest levels in the ] after about four to five hours. Taking the drug without food lowers its plasma levels by 40% as compared to taking it with food, which is considered to be clinically relevant. Therefore, patients are advised to take the medication together with a meal.<ref name="EPAR Edurant" /> After injection into the muscle, the substance reaches highest plasma levels after three to four days.<ref name="EPAR Rekambys" />

Independently of the mode of application, rilpivirine is almost completely bound to ]s (99.7%), mostly to ]. It is metabolised mainly by the liver enzyme ]. ]s include several ] products, ]s, and glucuronides of oxidized metabolites. The ] is approximately 45 hours for the tablets and 13 to 28 weeks for the injection.<ref name="EPAR Rekambys" /><ref name="EPAR Edurant" />

Elimination has only been studied for oral administration: Most of the drug is excreted via the faeces (85%), partly in unchanged form (25%), partly in form of its metabolites (60%). A minor amount is excreted via the urine (6%), almost exclusively as metabolites.<ref name="EPAR Rekambys" /><ref name="EPAR Edurant" />

] enzyme ] (and ]) and the ] enzyme ].<ref>{{cite journal | vauthors = Lade JM, Avery LB, Bumpus NN | title = Human biotransformation of the nonnucleoside reverse transcriptase inhibitor rilpivirine and a cross-species metabolism comparison | journal = Antimicrobial Agents and Chemotherapy | volume = 57 | issue = 10 | pages = 5067–5079 | date = October 2013 | pmid = 23917319 | pmc = 3811466 | doi = 10.1128/AAC.01401-13 }}</ref>]]

==Fixed-dose combinations==
A ] medication combining rilpivirine with ] and ] (TDF) was approved by the U.S. ] (FDA) in August 2011 under the brand name ],<ref>{{cite web |title=Approval of Complera: emtricitabine/rilpivirine/tenofovir DF fixed dose combination |url=https://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm267592.htm |publisher=U.S. ] (FDA) |date=August 10, 2011 }}</ref> and was approved for use in the European Union with the brand name Eviplera in November 2011.<ref>{{cite web |url=http://www.aidsmap.com/resources/treatmentsdirectory/drugs/iEviplerai/page/2188046/ |title=Eviplera |date=March 2011 |publisher=] |access-date=September 1, 2014 }}</ref> This combination has been shown to have higher rates of virologic failure than ] in people with baseline HIV viral loads greater than 100,000 copies/mm<sup>3</sup>.<ref>{{cite book|title=Austria-Codex| veditors = Haberfeld H |at=Eviplera Filmtabletten|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2021|language=German}}</ref><ref>{{cite journal | vauthors = Molina JM, Cahn P, Grinsztejn B, Lazzarin A, Mills A, Saag M, Supparatpinyo K, Walmsley S, Crauwels H, Rimsky LT, Vanveggel S, Boven K | display-authors = 6 | title = Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial | journal = Lancet | volume = 378 | issue = 9787 | pages = 238–246 | date = July 2011 | pmid = 21763936 | doi = 10.1016/S0140-6736(11)60936-7 | s2cid = 7313885 | author13 = ECHO study group }}</ref>

A fixed-dose medication combining rilpivirine with emtricitabine and ] (TAF) was approved for use in the US in March 2016 with the brand name ].<ref>{{cite web | title=Odefsey (emtricitabine, rilpivirine, and tenofovir alafenamide) Tablets | website=U.S. ] (FDA) | date=29 November 2016 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208351Orig1s000TOC.cfm | access-date=23 January 2021}}</ref>

], sold under the brand name Juluca, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. It was approved for use in the United States in November 2017 and for use in the European Union in May 2018.

In January 2021, the U.S. ] (FDA) approved ] (brand name Cabenuva) for the treatment of HIV-1 infections in adults to replace a current antiretroviral regimen in those who are virologically suppressed on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine.<ref name="FDA PR">{{cite press release | title=FDA Approves First Extended-Release, Injectable Drug Regimen for Adults Living with HIV | website=U.S. ] (FDA) | date=21 January 2021 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-extended-release-injectable-drug-regimen-adults-living-hiv | access-date=21 January 2021}} {{PD-notice}}</ref><ref name="FDA Cabenuva/Vocabria">{{cite web | title=Cabenuva and Vocabria approved for HIV infection | website=U.S. ] (FDA) | date=27 January 2021 | url=https://www.fda.gov/drugs/human-immunodeficiency-virus-hiv/fda-approves-cabenuva-and-vocabria-treatment-hiv-1-infection | access-date=27 January 2021}} {{PD-notice}}</ref> This is the first FDA-approved injectable, complete regimen for HIV-infected adults that is administered once a month.<ref name="FDA PR" /><ref name="FDA Cabenuva/Vocabria" /> The label for rilpivirine tablets was revised to reflect the oral lead-in recommendations for use with ].<ref name="FDA Cabenuva/Vocabria" />

==Chemistry==
Like ], a second-generation NNRTI approved in 2008, rilpivirine is a ] (DAPY).<ref name="EPAR Edurant" />

The tablets contain rilpivirine ],<ref name="EPAR Edurant" /> while the injection contains free rilpivirine.<ref name="EPAR Rekambys" />

==History==
Rilpivirine entered ] in April 2008,<ref>{{cite web |work=ClinicalTrials.gov |publisher=] |url=http://clinicaltrials.gov/ct2/show/NCT00540449 |title=A Clinical Trial in Treatment naïve HIV-1 Patients Comparing TMC278 to Efavirenz in Combination With Tenofovir + Emtricitabine |date=October 25, 2012 |access-date=January 1, 2014 }}</ref><ref>{{cite web |work=ClinicalTrials.gov |publisher=] |url=http://clinicaltrials.gov/ct2/show/NCT00543725 |title=A Clinical Trial in Treatment naïve HIV-Subjects Patients Comparing TMC278 to Efavirenz in Combination With 2 Nucleoside/Nucleotide Reverse Transcriptase Inhibitors |date=May 14, 2012 |access-date=January 1, 2014 }}</ref> and was approved for use in the United States in May 2011 under the brand name Edurant.<ref>{{cite web | title=Drug Approval Package: Edurant (rilpivirine) NDA #202022# | website=U.S. ] (FDA) | date=20 August 2013 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202022Orig1s000TOC.cfm | access-date=23 January 2021 }}</ref><ref>{{cite press release |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm256087.htm |title=FDA approves new HIV treatment |publisher=U.S. ] (FDA) |access-date=2011-05-20 |archive-date=2017-01-18 |archive-url=https://web.archive.org/web/20170118091142/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm256087.htm |url-status=dead }}</ref>

On 15 October 2020, the ] (CHMP) of the ] (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for rilpivirine under the trade name Rekambys, intended for the treatment of ] (HIV-1) infection in combination with ] injection.<ref>{{cite web | title=Rekambys: Pending EC decision | website=] (EMA) | date=16 October 2020 | url=https://www.ema.europa.eu/en/medicines/human/summaries-opinion/rekambys | access-date=16 October 2020}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> It was approved for medical use in the European Union in December 2020.<ref name="Rekambys EPAR">{{cite web | title=Rekambys EPAR | website=] (EMA) | date=13 October 2020 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/rekambys | access-date=4 January 2021}}</ref> The two medicines are the first antiretrovirals that come in a long-acting injectable formulation.<ref name="EMA PR">{{cite press release | title=First long-acting injectable antiretroviral therapy for HIV recommended approval | website=] (EMA) | date=16 October 2020 | url=https://www.ema.europa.eu/en/news/first-long-acting-injectable-antiretroviral-therapy-hiv-recommended-approval | access-date=16 October 2020}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref>

== References ==
{{Reflist}}

== External links ==
* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/rilpivirine | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Rilpivirine }}
* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/rilpivirine%20hydrochloride | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Rilpivirine hydrochloride }}

{{Antiretroviral drug}}
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Rilpivirine: Difference between revisions Add topic