|
|
| Line 1: |
Line 1: |
| {{drugbox | | | __NOTOC__ |
| |image= Nevirapine.svg
| | {{Nevirapine}} |
| |IUPAC_name = 1-cyclopropyl-5,11-dihydro-4-methyl<br>-6H-dipyrido [3,2-b:2',3'-e][1,4] diazepin-6-one
| | '''''For patient information, click <u>[[Nevirapine (patient information)|here]]</u>'''''. |
| |CAS_number = 129618-40-2
| |
| | ATC_prefix=J05
| |
| | ATC_suffix=AG01
| |
| | PubChem=4463
| |
| | DrugBank=APRD00705
| |
| | C=15 | H=14 | N=4 | O=1
| |
| |molecular_weight = 266.298 [[gram|g]]/[[Mole (unit)|mol]]
| |
| |bioavailability = 93% ± 9%
| |
| |metabolism = [[Liver|Hepatic]]
| |
| |elimination_half-life = 45 [[hour]]s
| |
| |excretion = [[Kidney|Renal]]: <6% (Parent drug) <br> [[Bile|Biliary]] <5% (Parent drug)
| |
| |pregnancy_category = C: ([[United states of America|USA]])
| |
| |legal_status =
| |
| |routes_of_administration = [[Mouth|Oral]]
| |
| }}
| |
| '''Nevirapine''', also marketed under the trade name '''Viramune'''® ([[Boehringer Ingelheim]]), is a non-nucleoside [[reverse transcriptase inhibitor]] (NNRTI) used to treat [[HIV|HIV-1]] infection and [[AIDS]]. | |
|
| |
|
| As with other [[antiretroviral drug]]s, HIV rapidly develops resistance if nevirapine is used alone, so recommended therapy consists of combinations of three or more antiretrovirals.
| | {{CMG}} |
|
| |
|
| ==History== | | ==Overview== |
| Nevirapine was discovered by Hargrave et al. at Boehringer Ingelheim Pharmaceuticals, Inc., one of the [[Boehringer Ingelheim]] group of companies. It is covered by [http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=US5366972&F=0 U.S. Patent 5,366,972] and corresponding foreign patents. Nevirapine was the first NNRTI approved by the [[Food and Drug Administration]] (FDA) of the United States. It was approved [[Jun 21]], [[1996]] for adults and [[Sep 11]], [[1998]] for children. It was also approved in Europe in 1997.
| |
|
| |
|
| It was twice rejected by [[Canada]], in [[1996]] and again in [[1998]], due to its high toxicity and lack of evidence of its effectiveness,<ref name="farber">[http://www.mindfully.org/Health/2006/AIDS-Medical-Corruption1mar06.htm Out of Control] – [[Celia Farber]]'s article in ''[[Harper's Magazine]]'' on nevirapine drug trials in [[Uganda]]</ref> though it was later approved in that country. The drug is currently recalled by Roche because of the presence of [[ethyl methanesulfonate]] as a byproduct from the manufacturing process.<ref>http://aidsinfo.nih.gov/contentfiles/AdultNFVNotice.pdf</ref>
| | ==Category== |
| | Antiretroviral |
| | ==US Brand Names== |
| | VIRAMUNE<sup>®</sup> |
| | ==FDA Package Insert== |
|
| |
|
| ==Mode of action==
| | ''' [[Nevirapine description|Description]]''' |
| Nevirapine falls in the non-nucleoside reverse transcriptase inhibitor (NNRTI) class of antiretrovirals. Both nucleoside and non-nucleoside RTIs inhibit the same target, the [[reverse transcriptase]] enzyme, an essential viral enzyme which transcribes viral RNA into DNA. Unlike nucleoside RTIs, which bind at the enzyme's active site, NNRTIs bind within a pocket termed the NNRTI pocket. | | '''| [[Nevirapine clinical pharmacology|Clinical Pharmacology]]''' |
| | '''| [[Nevirapine microbiology|Microbiology]]''' |
| | '''| [[Nevirapine indications and usage|Indications and Usage]]''' |
| | '''| [[Nevirapine contraindications|Contraindications]]''' |
| | '''| [[Nevirapine warnings and precautions|Warnings and Precautions]]''' |
| | '''| [[Nevirapine adverse reactions|Adverse Reactions]]''' |
| | '''| [[Nevirapine drug interactions|Drug Interactions]]''' |
| | '''| [[Nevirapine overdosage|Overdosage]]''' |
| | '''| [[Nevirapine clinical studies|Clinical Studies]]''' |
| | '''| [[Nevirapine dosage and administration|Dosage and Administration]]''' |
| | '''| [[Nevirapine how supplied|How Supplied]]''' |
| | '''| [[Nevirapine labels and packages|Labels and Packages]]''' |
|
| |
|
| Nevirapine is not effective against HIV-2, as the pocket of the HIV-2 reverse transcriptase has a different structure, which confers intrinsic resistance to the NNRTI class.<ref>[http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=12386343 Ren J, Bird LE, Chamberlain PP, ''et al.'' (2002) Structure of HIV-2 reverse transcriptase at 2.35-A resolution and the mechanism of resistance to non-nucleoside inhibitors. ''Proc Natl Acad Sci USA'' 99: 14410–15]</ref>
| | ==Mechanism of Action== |
|
| |
|
| Resistance to nevirapine develops rapidly if viral replication is not completely suppressed.<ref name="INCAS_1998">[http://jama.ama-assn.org/cgi/reprint/279/12/930 Montaner JSG, Reiss P, Cooper D, ''et al''. (1998) A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients: the INCAS trial. ''JAMA'' 279: 930–937]</ref> The most common mutations observed after nevirapine treatment are Y181C and K103N, which are also observed with other NNRTIs.<ref name="PInfo">[http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing+Information/PIs/Viramune/Viramune.pdf Viramune® (nevirapine) tablets; Viramune® (nevirapine) oral suspension prescribing information]</ref><ref>Conway B, Wainberg MA, Hall D, ''et al.'' (2001) Development of drug resistance in patients receiving combinations of zidovudine, didanosine and nevirapine. ''AIDS'' 15:1269-74</ref> As all NNRTIs bind within the same pocket, viral strains which are resistant to nevirapine are usually also resistant to the other NNRTIs, [[efavirenz]] and [[delavirdine]].
| | ==References== |
| | {{Reflist|2}} |
|
| |
|
| ==Clinical efficacy==
| | [[Category:Antiretroviral]] |
| | | [[Category:Wikinfect]] |
| Nevirapine in triple combination therapy has been shown to suppress [[viral load]] effectively when used as initial antiretroviral therapy (''i.e.'', in antiretroviral-naive patients).<ref name="INCAS_1998" /> Some clinical trials have demonstrated comparable HIV suppression with nevirapine-based regimens to that achieved with [[protease inhibitor (pharmacology)|protease inhibitors]] (PIs)<ref>{{cite journal | author=van Leeuwen R, Katlama C, Murphy RL, ''et al.'' | year=2003 | title=A randomized trial to study first-line combination therapy with or without a protease inhibitor in HIV-1-infected patients | journal=AIDS | volume=17 | pages=987–99 }}</ref><ref>{{cite journal | author=Podzamczer D, Ferrer E, Consiglio E, ''et al.'' | title=A randomized clinical trial comparing nelfinavir or nevirapine associated to zidovudine/lamivudine in HIV-infected naive patients (the Combine Study)
| |
| | journal=Antiviral Ther | volume=7 | pages=81–90 }}</ref> or [[efavirenz]].<ref name="2NN">{{cite journal | author=van Leth F, Andrews S, Grinsztejn B, ''et al.'' | year=2005 | title=The effect of baseline CD4 cell count and HIV-1 viral load on the efficacy and safety of nevirapine or efavirenz-based first-line HAART | journal=AIDS | volume=19 | pages=463–71 }}</ref> Although concerns have been raised about nevirapine-based regimens in those starting therapy with high viral load or low CD4 count, some analyses suggest that nevirapine may be effective in these patients.<ref name="2NN" />
| |
| | |
| Nevirapine may also form a useful component of salvage regimens after virological failure, usually in combination with one or more PIs as well as nRTIs, especially in those who have not previously taken an NNRTI.
| |
| | |
| ==Adverse effects==
| |
| | |
| The most common adverse effect of nevirapine is the development of mild or moderate rash (13%).<ref name="PInfo" /><ref name="ATDN">{{cite web
| |
| | url=http://www.aegis.com/factshts/network/simple/nevi.html
| |
| | title=Facts sheet from the AIDS Treatment Data Network
| |
| | accessdate=2006-01-16}}</ref> Severe or life-threatening skin reactions have been observed in 1.5% of patients, including [[Stevens-Johnson syndrome]], [[toxic epidermal necrolysis]] and [[hypersensitivity]].<ref name="PInfo" />
| |
| | |
| Nevirapine may cause severe or life-threatening liver toxicity, usually emerging in the first six weeks of treatment.<ref name="PInfo" /><ref name="dhhs"> DHHS panel. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (May 4, 2006). (Available for download from [http://www.aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=7&ClassID=1 AIDSInfo])</ref> In 2000, the U.S. [[Food and Drug Administration]] issued a [[black box warning|black box label]] on nevirapine, warning that it could cause severe liver damage, including liver failure.<ref>[http://www.fda.gov/medwatch/safety/2000/viramune.htm Viramune (nevirapine) letter (November 2000)]</ref> Unacceptably high risk of serious liver symptoms in certain patient groups (women with CD4 count >250 and men >400)<ref name="2NN"/> has led the U.S. DHSS to recommend the restriction of nevirapine use to those at lower risk, unless the benefit to the patient clearly outweighs the risk;<ref name="dhhs" /> although in the 2NN study which found these CD4 limits, the effect was seen only in patients recruited from Thailand. The U.S. Public Health Service Task Force advocates caution in the use of nevirapine in pregnancy due to toxicity issues, which may be exacerbated during pregnancy.<ref name="perinatal">Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States. Public Health Service Task Force. (November 17, 2005) (Available for download from [http://www.aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=9&ClassID=2 AIDSInfo)</ref>
| |
| | |
| ==Drug interactions==
| |
| Significant lowering of nevirapine levels occurs with the anti-tuberculosis drug, [[rifampicin]], and the drugs should not be administered together.<ref name="PInfo" />
| |
| | |
| Nevirapine is an inducer of [[Cytochrome P450 oxidase|cytochrome P450]] isoenzymes [[CYP3A4]] and [[CYP2B6]]. It reduces the levels of several co-administered drugs including the antiretrovirals [[efavirenz]], [[indinavir]], [[lopinavir]], [[nelfinavir]] and [[saquinavir]], as well as [[clarithromycin]], [[ketoconazole]], forms of [[hormonal contraception]], and [[methadone]].<ref name="PInfo" />
| |
| | |
| ==Preventing mother-to-child transmission==
| |
| | |
| A single dose of nevirapine given to both mother and child reduced the rate of HIV transmission by almost 50% compared with a very short course of [[zidovudine|zidovudine (AZT)]] prophylaxis, in a clinical trial in [[Uganda]].<ref>Guay LA, Musoke P, Fleming T, et al. (1999) Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. ''Lancet'' 354: 795-802 [http://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=10485720&ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum PMID:10485720]</ref> A subsequent study in [[Thailand]] showed that prophylaxis with single-dose nevirapine in addition to zidovudine is more effective than zidovudine alone.<ref>[http://content.nejm.org/cgi/content/full/351/3/217 Lallemant M, Gonzague Jourdain G, Sophie Le Coeur S, ''et al.'' (2004) Single-Dose Perinatal Nevirapine plus Standard Zidovudine to Prevent Mother-to-Child Transmission of HIV-1 in Thailand. ''N Engl J Med'' 351: 217-28]</ref> These and other trials have led the [[World Health Organization]] to endorse the use of single-dose nevirapine prophylaxis in many developing world settings as a cost-effective way of reducing mother-to-child transmission.
| |
| | |
| A major concern with this approach is that NNRTI resistance mutations are commonly observed in both mothers and infants after single-dose nevirapine,<ref>Johnson JA, Li JF, Morris L, ''et al.'' (2005) Emergence of drug-resistant HIV-1 after intrapartum administration of single-dose nevirapine is substantially underestimated. ''J Infect Dis'' 192: 16-23</ref> and may compromise the response to future NNRTI-containing regimens.<ref>[http://content.nejm.org/cgi/content/full/351/3/229 Jourdain G, Ngo-Giang-Huong N, Le Coeur S, ''et al.'' (2004) Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. ''N Engl J Med'' 351: 229-40]</ref> A short course of maternal zidovudine/lamivudine is recommended by the U.S. Public Health Service Task Force to reduce this risk.<ref name="perinatal" />
| |
| | |
| Further concerns are raised in the following section.
| |
| | |
| ==Controversy in Africa==
| |
| U.S. President [[George W. Bush]]'s $500 million plan to help combat the African AIDS epidemic includes nevirapine, among other medications and programs. Nevirapine has also been tested in trials in Africa, some of which have been highly controversial.
| |
| | |
| [[Jonathan Fishbein|Jonathan M Fishbein, MD]] (former director of the Office for Policy in Clinical Research Operations at the [[National Institutes of Health|NIH]] [[Division of Acquired Immunodeficiency Syndrome|Division of AIDS]] [DAIDS]) has alleged that the Ugandan mother-to-child transmission trial (HIVNET 012) -- which was pivotal to establishing single-dose nevirapine prophylaxis in [[Africa]] and other countries -- was not conducted in accordance with good clinical practice.<ref name="farber" /><ref name="Fishbein">[http://honestdoctor.org/allegations.html Allegations Of Waste, Fraud and Abuse] at [[Jonathan Fishbein]]'s website</ref><ref>{{cite web
| |
| | url=http://www.usatoday.com/news/washington/2005-01-04-nih-aids_x.htm
| |
| | accessdate=2006-01-16
| |
| | title=Whistleblower says government bungled AIDS study
| |
| | year=[[2006-01-04]]
| |
| | publisher=USA Today
| |
| | author=[[Associated Press]]}}</ref> Fishbein claims that DAIDS has "Implement[ed] a double standard regarding the quality of clinical trial practices – one standard for Africa and a higher standard for the U.S."<ref name="Fishbein" /> An independent review of that study by the Institute of Medicine determined "...the Ugandan drug trial's findings that the AIDS medication nevirapine is effective and safe in preventing HIV transmission from mother to unborn child during birth were well-supported." <ref> {{cite web
| |
| | url=http://www.iom.edu/CMS/3793/22182/26287.aspx
| |
| | title=IOM Review of Ugandan HIVNET 012 Clinical Trial
| |
| | accessdate=2007-29-07}}</ref> Fishbein has called the value of that review into question, however, alleging that the authors of the review refused to consider certain testimony and evidence that would have vitiated the drug trial, and also that six of the nine authors were, at the time of the review, receiving grants from DAIDS, the very body whose conduct they were reviewing. Fishbein has argued that this conflict of interest must also undermine confidence in the review.<ref> {{cite web
| |
| | url=http://honestdoctor.org/images/media/IOMpressRelease1.pdf
| |
| | title=Press release on Fishbein's response to Institute of Medicine Report
| |
| | accessdate=2007-13-11}}</ref>
| |
|
| |
| Recently, [[South African]] [[President]] [[Thabo Mbeki]] accused the [[United States]] of using Africans as "guinea pigs".<ref> {{cite web
| |
| | url=http://www.gnn.tv/articles/article.php?id=1011
| |
| | title=Nevirapine Controversy
| |
| | accessdate=2006-01-16}}</ref> Questions regarding the efficacy of the [[antiretroviral]] nevirapine when compared with its side effects were the main stated reason for President Mbeki's concern. Until recently, however, Mbeki endorsed claims by some scientists that HIV is not the cause of AIDS--findings which are considered well outside the realm of reasonable scientific thought by the vast majority of the scientific community.<ref> {{cite web
| |
| | url = http://www.aegis.com/news/dmg/2000/MG000411.html
| |
| | title = AEGiS-M&G: Mbeki's Aids Letter Defies Belief
| |
| | accessdate = 2006-04-12}}</ref>
| |
| | |
| ==References==
| |
| | |
| {{reflist|2}}
| |
| | |
| {{HIVpharm}}
| |
| | |
| [[Category:Non-nucleoside reverse transcriptase inhibitors]] | |
| | |
| [[de:Nevirapin]]
| |
| [[th:นีวิราปีน]]
| |
| {{WikiDoc Sources}}
| |