Editing Nevirapine

{{Short description|Chemical compound}}
{{cs1 config|name-list-style=vanc}}
{{Infobox drug
| Watchedfields = changed
| verifiedrevid = 462259855
| IUPAC_name = 11-cyclopropyl-4-methyl-5,11-dihydro-6''H''- dipyrido[3,2-''b'':2′,3′-''e''][1,4]diazepin-6-one
| image = Nevirapine.svg
| image_class = skin-invert-image
| alt =
| image2 = Nevirapine 3D balls 1fkp.png
| alt2 =

<!--Clinical data-->
| tradename = Viramune
| Drugs.com = {{drugs.com|monograph|nevirapine}}
| MedlinePlus = a600035
| DailyMedID = Nevirapine
| pregnancy_AU      = B3
| pregnancy_AU_comment = 
| pregnancy_category= 
| routes_of_administration = [[Oral administration|By mouth]]
| ATC_prefix = J05
| ATC_suffix = AG01

<!-- Legal status -->
| legal_AU          = S4
| legal_AU_comment = <ref>{{cite web | title=Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/publication/publications/prescription-medicines-registration-new-generic-medicines-and-biosimilar-medicines-2017 | access-date=30 March 2024}}</ref>
| legal_BR          = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment  = 
| legal_CA          = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment  = 
| legal_DE          = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment  = 
| legal_NZ          = <!-- Class A, B, C -->
| legal_NZ_comment  = 
| legal_UK          = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_UK_comment  = 
| legal_US          = Rx-only
| legal_US_comment  = <ref name="Viramune FDA label" /><ref name="Viramune XR FDA label" />
| legal_EU          = Rx-only
| legal_EU_comment  = 
| legal_UN          = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment  = 
| legal_status      = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->
| bioavailability = 93% ± 9%
| metabolism = [[Liver]]
| elimination_half-life = 45 hours
| excretion = [[Kidney]]: <6% (Parent drug) <br /> [[Bile duct]] <5% (Parent drug)

<!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 129618-40-2
| PubChem = 4463
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00238
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4308
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 99DK7FVK1H
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00435
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 57
| NIAID_ChemDB = 001856

<!--Chemical data-->
| C=15 | H=14 | N=4 | O=1
| SMILES = O=C2Nc1c(ccnc1N(c3ncccc23)C4CC4)C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C15H14N4O/c1-9-6-8-17-14-12(9)18-15(20)11-3-2-7-16-13(11)19(14)10-4-5-10/h2-3,6-8,10H,4-5H2,1H3,(H,18,20)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = NQDJXKOVJZTUJA-UHFFFAOYSA-N
}}

<!-- Definition and medical uses -->
'''Nevirapine''' ('''NVP'''), sold under the brand name '''Viramune''' among others, is a medication used to treat and prevent [[HIV/AIDS]], specifically [[HIV-1]].<ref name=AHFS2016/> It is generally recommended for use with other [[antiretroviral medication]]s.<ref name=AHFS2016/> It may be used to prevent [[HIV and pregnancy|mother to child spread during birth]] but is not recommended following other exposures.<ref name=AHFS2016/> It is taken by mouth.<ref name=AHFS2016>{{cite web|title=Nevirapine|url=https://www.drugs.com/monograph/nevirapine.html|publisher=The American Society of Health-System Pharmacists|access-date=3 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161220121202/https://www.drugs.com/monograph/nevirapine.html|archive-date=20 December 2016}}</ref>

<!-- Side effects and mechanism -->
Common side effects include rash, headache, nausea, feeling tired, and [[liver problems]].<ref name=AHFS2016/> The liver problems and skin rash may be severe and should be checked for during the first few months of treatment.<ref name=AHFS2016/><ref name=Ric2015>{{cite book| vauthors = Hamilton R |title=Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition|date=2015|publisher=Jones & Bartlett Learning|isbn=9781284057560|page=63}}</ref> It appears to be safe for use during [[pregnancy]].<ref name=AHFS2016/> It is a non-nucleoside [[reverse transcriptase inhibitor]] (NNRTI) and works by blocking the function of [[reverse transcriptase]].<ref name=AHFS2016/>

<!-- Society and culture -->
Nevirapine was approved for medical use in the United States in 1996.<ref name=AHFS2016/> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> It is available as a [[generic medication]].<ref name=AHFS2016/>

==Medical uses==
Nevirapine is used in people six years of age and older infected with HIV-1 as part of combination antiretroviral treatment (ART or cART). Monotherapy with nevirapine is not indicated due to rapid emergence of resistance.<ref name="Viramune FDA label">{{cite web | title=Viramune- nevirapine suspension Viramune- nevirapine tablet | website=DailyMed | date=28 October 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5ec05500-6333-4bd0-ac83-464fad0d5162 | access-date=19 November 2020}}</ref><ref name="Viramune XR FDA label">{{cite web | title=Viramune- nevirapine tablet, extended release | website=DailyMed | date=25 October 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=82598cb3-a0eb-4ff2-8b8d-d8da96c25388 | access-date=19 November 2020}}</ref>

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 regimens based on a [[protease inhibitor (pharmacology)|protease inhibitor]] (PI)<ref>{{cite journal | vauthors = van Leeuwen R, Katlama C, Murphy RL, Squires K, Gatell J, Horban A, Clotet B, Staszewski S, van Eeden A, Clumeck N, Moroni M, Pavia AT, Schmidt RE, Gonzalez-Lahoz J, Montaner J, Antunes F, Gulick R, Bánhegyi D, van der Valk M, Reiss P, van Weert L, van Leth F, Johnson VA, Sommadossi JP, Lange JM | display-authors = 6 | 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 | issue = 7 | pages = 987–999 | date = May 2003 | pmid = 12700448 | doi = 10.1097/00002030-200305020-00007 | s2cid = 25420787 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Podzamczer D, Ferrer E, Consiglio E, Gatell JM, Perez P, Perez JL, Luna E, González A, Pedrol E, Lozano L, Ocaña I, Llibre JM, Casiró A, Aranda M, Barrufet P, Martínez-Lacasa J, Miró JM, Badía X, Casado A, Lupo S, Cahn P, Maños M, Estela J | display-authors = 6 | title = A randomized clinical trial comparing nelfinavir or nevirapine associated to zidovudine/lamivudine in HIV-infected naive patients (the Combine Study) | journal = Antiviral Therapy | volume = 7 | issue = 2 | pages = 81–90 | date = June 2002 | pmid = 12212928 | doi = 10.1177/135965350200700202 | s2cid = 31574879 | doi-access = free }}</ref> or [[efavirenz]].<ref name="2NN">{{cite journal | vauthors = van Leth F, Andrews S, Grinsztejn B, Wilkins E, Lazanas MK, Lange JM, Montaner J | 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 | issue = 5 | pages = 463–471 | date = March 2005 | pmid = 15764851 | doi = 10.1097/01.aids.0000162334.12815.5b | s2cid = 20933620 | doi-access = free }}</ref>

This drug is generally only to be considered for use if the CD4 cell count is very low.<ref name="Viramune FDA label" />

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 this group of people.<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 [[nucleotide reverse transcriptase inhibitor]] (NRTIs), especially in those who have not previously taken an NNRTI.

Dosing in children is based on [[body surface area]] (BSA),<ref name="Viramune FDA label" /> however, weight-based dosing algorithms have been released. These guidelines include dosing algorithms for as young as newborn babies.<ref>{{Cite web|url=http://aidsinfo.nih.gov/guidelines|title=Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children: Guidelines for the use of antiretroviral agents in pediatric HIV infection.|date=March 2016|publisher=AIDSinfo, U.S. Department of Health and Human Services (HHS).|access-date=2016-11-05|url-status=live|archive-url=https://web.archive.org/web/20161107221758/https://aidsinfo.nih.gov/guidelines|archive-date=2016-11-07}}</ref>

===Preventing mother-to-child transmission===

Although 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]] (AZT) prophylaxis, in a clinical trial in [[Uganda]],<ref>{{cite journal | vauthors = Guay LA, Musoke P, Fleming T, Bagenda D, Allen M, Nakabiito C, Sherman J, Bakaki P, Ducar C, Deseyve M, Emel L, Mirochnick M, Fowler MG, Mofenson L, Miotti P, Dransfield K, Bray D, Mmiro F, Jackson JB | display-authors = 6 | title = 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 | journal = Lancet | volume = 354 | issue = 9181 | pages = 795–802 | date = September 1999 | pmid = 10485720 | doi = 10.1016/S0140-6736(99)80008-7 | s2cid = 6740488 | doi-access = free }}</ref> that trial was found in an Associated Press investigation to be riddled with "sloppy recordkeeping" and possibly fraud.<ref>{{cite news | vauthors = Solomon J |title=Research Flawed on Key AIDS Medicine |url=https://www.washingtonpost.com/archive/politics/2004/12/14/research-flawed-on-key-aids-medicine/3a4caf23-4576-4165-ab70-83ba2976b9cf/}}</ref> A subsequent study in [[Thailand]] showed that prophylaxis with single-dose nevirapine in addition to zidovudine is more effective than zidovudine alone.<ref name="Lallemant">{{cite journal | vauthors = Lallemant M, Jourdain G, Le Coeur S, Mary JY, Ngo-Giang-Huong N, Koetsawang S, Kanshana S, McIntosh K, Thaineua V | display-authors = 6 | title = Single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of HIV-1 in Thailand | journal = The New England Journal of Medicine | volume = 351 | issue = 3 | pages = 217–228 | date = July 2004 | pmid = 15247338 | doi = 10.1056/NEJMoa033500 | doi-access = free }}</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. However, in the United States the Ugandan study was deemed flawed <ref>The HIVNET 012 Study and the Safety and Effectiveness of Nevirapine in Preventing Mother-to-Infant Transmission of HIV, {{cite web |url=http://www3.niaid.nih.gov/news/newsreleases/2004/hivnet012.htm |title=The HIVNET 012 Study and the Safety and Effectiveness of Nevirapine in Preventing Mother-to-Infant Transmission of HIV |access-date=2009-01-23 |url-status=dead |archive-url=https://web.archive.org/web/20090201162348/http://www3.niaid.nih.gov/news/newsreleases/2004/hivnet012.htm |archive-date=2009-02-01 }}</ref> and as of 2006 the FDA has not approved of such nevirapine prophylaxis.<ref>Celia Farber, "Out of Control: AIDS and the Corruption of Science" {{cite magazine |url=https://harpers.org/archive/2006/03/out-of-control/ |title=&#91;Article&#93; Out of control, by Celia Farber |magazine=Harper's Magazine |date=March 2006 |volume=March 2006 |access-date=2009-06-11 |url-status=live |archive-url=https://web.archive.org/web/20090504174126/http://www.harpers.org/archive/2006/03/0080961 |archive-date=2009-05-04 | vauthors = Farber C }}</ref> However, supporters of HIVNET 012 experiment argued that the flaws in this experiment were largely due to bureaucratic incompetence, while the findings regarding the safety and efficacy of single-dose nevirapine from this study were scientifically solid and too important to discard.<ref name="pmid21553555">{{cite journal | vauthors = Crane J | title = Adverse events and placebo effects: African scientists, HIV, and ethics in the 'global health sciences' | journal = Social Studies of Science | volume = 40 | issue = 6 | pages = 843–870 | date = December 2010 | pmid = 21553555 | doi = 10.1177/0306312710371145 | s2cid = 26027925 }}</ref> Moreover, it was argued that holding African researchers who operated under resource-poor situations to the same moral and procedural standards to their Western counterparts was unrealistic, and would further marginalize African researchers' role in the science community and impede the progress of African science.<ref>Lock, M. & Nguyen, V 2010, an Anthropology of Biomedicine, Malden, Wiley-Blackwell.</ref> Another clinical trial, ''Using Nevirapine to Prevent Mother-to-Child HIV Transmission During Breastfeeding'', was completed in September 2013.<ref>{{cite web |url=http://clinicaltrials.gov/show/NCT00074412 |title=Using Nevirapine to Prevent Mother-to-Child HIV Transmission During Breastfeeding - Full Text View - ClinicalTrials.gov |access-date=2009-01-23 |url-status=live |archive-url=https://web.archive.org/web/20081205094051/http://clinicaltrials.gov/show/NCT00074412 |archive-date=2008-12-05 }}</ref>  	

A major concern with this approach is that NNRTI resistance mutations are commonly observed in both mothers and infants after single-dose nevirapine,<ref>{{cite journal | vauthors = Johnson JA, Li JF, Morris L, Martinson N, Gray G, McIntyre J, Heneine W | title = Emergence of drug-resistant HIV-1 after intrapartum administration of single-dose nevirapine is substantially underestimated | journal = The Journal of Infectious Diseases | volume = 192 | issue = 1 | pages = 16–23 | date = July 2005 | pmid = 15942889 | doi = 10.1086/430741 | doi-access = free }}</ref> and may compromise the response to future NNRTI-containing regimens.<ref>{{cite journal | vauthors = Jourdain G, Ngo-Giang-Huong N, Le Coeur S, Bowonwatanuwong C, Kantipong P, Leechanachai P, Ariyadej S, Leenasirimakul P, Hammer S, Lallemant M | display-authors = 6 | title = Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy | journal = The New England Journal of Medicine | volume = 351 | issue = 3 | pages = 229–240 | date = July 2004 | pmid = 15247339 | doi = 10.1056/NEJMoa041305 | doi-access = free }}</ref> A short course of maternal [[Lamivudine/zidovudine]] is recommended by the U.S. Public Health Service Task Force to reduce this risk.<ref name=perinatal/>

===Nonoccupational Post-Exposure Prophylaxis===
Nevirapine is contraindicated for non-occupational post-exposure-prophylaxis including for pregnant and nonpregnant women due to severe liver toxicity.<ref>{{cite web |title=Updated guidelines for antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV—United States, 2016 |url=https://stacks.cdc.gov/view/cdc/38856 |publisher=Centers for Disease Control}}</ref>

==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 |access-date  = 2006-01-16 |url-status     = dead |archive-url  = https://web.archive.org/web/20060113014541/http://www.aegis.com/factshts/network/simple/nevi.html |archive-date = 2006-01-13 }}</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] {{webarchive|url=https://web.archive.org/web/20060506193229/http://aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=7&ClassID=1 |date=2006-05-06 }})</ref> In 2000, the U.S. [[Food and Drug Administration]] issued a [[black box warning]] on nevirapine, warning that it could cause life-threatening liver toxicity and skin reactions.<ref name="Viramune XR FDA label" /> Unacceptably high risk of serious liver symptoms in certain patient groups (women with CD4 count &gt;250 and men &gt;400)<ref name="2NN"/><ref>{{cite journal | vauthors = Stern JO, Robinson PA, Love J, Lanes S, Imperiale MS, Mayers DL | title = A comprehensive hepatic safety analysis of nevirapine in different populations of HIV infected patients | journal = Journal of Acquired Immune Deficiency Syndromes | volume = 34 | issue = Suppl 1 | pages = S21–S33 | date = September 2003 | pmid = 14562855 | doi = 10.1097/00126334-200309011-00005 | s2cid = 36971857 | doi-access = free }}</ref> has led the U.S. DHHS 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. More recent studies on the use of Nevirapine in people with higher CD4 cell counts have come to the following conclusion: Treatment-experienced patients who start NVP-based combination therapy with low pre–ART and high current CD4 cell counts and an undetectable VL have a similar likelihood for discontinuing NVP therapy because of hypersensitivity reactions (HSRs), compared with treatment-naive patients with low CD4 cell counts. This suggests that NVP-based combination therapy may be safely initiated in such patients. However, in similar patients with a detectable VL, it is prudent to continue to adhere to current CD4 cell count thresholds.<ref>{{cite journal | vauthors = Wit FW, Kesselring AM, Gras L, Richter C, van der Ende ME, Brinkman K, Lange JM, de Wolf F, Reiss P | display-authors = 6 | title = Discontinuation of nevirapine because of hypersensitivity reactions in patients with prior treatment experience, compared with treatment-naive patients: the ATHENA cohort study | journal = Clinical Infectious Diseases | volume = 46 | issue = 6 | pages = 933–940 | date = March 2008 | pmid = 18271750 | doi = 10.1086/528861 | doi-access = free }}</ref> 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">Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States. {{cite web |url=https://npin.cdc.gov/publication/recommendations-use-antiretroviral-drugs-pregnant-hiv-1-infected-women-maternal-health |title=Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States &#124; National Prevention Information Network &#124; Connecting public health professionals with trusted information and each other |access-date=2014-04-11 |url-status=live |archive-url=https://web.archive.org/web/20140412004422/http://aidsinfo.nih.gov/contentfiles/lvguidelines/perinatalgl.pdf |archive-date=2014-04-12 }}. Accessed 16 November 2016.</ref>

Cases of [[immune reconstitution syndrome]] and [[Lipodystrophy|fat redistribution]] have also been observed with this drug.<ref name="Viramune XR FDA label" />

The U.S. Food and Drug Administration recommends stopping nevirapine if a person experiences:<ref name="Viramune XR FDA label" />
* sign and symptoms of liver issues such as [[hepatitis]]
* increased [[Elevated transaminases|transaminases]] in addition to rash or systemic symptoms
* formation of rash with systemic symptoms
* severe skin or hypersensitivity reactions
Additionally, the U.S. [[Food and Drug Administration|FDA]] recommends close monitoring during the first 6 weeks of therapy for the above symptoms as there is high risk during this time. Continued monitoring is recommended for up to the first 18 weeks of treatment. If a patient experiences hepatitis plus rash or other systemic symptoms, or severe hypersensitivity or skin rash, nevirapine should not be restarted.<ref name="Viramune XR FDA label" />

==Drug interactions==
Nevirapine is a substrate for liver [[CYP3A]] and [[CYP2B6]] enzymes. Concomitant administration of drugs that are inhibitors of these enzymes may increase serum nevirapine levels significantly. Some examples of these drugs include [[ritonavir]], [[fosamprenavir]], and [[fluconazole]]. On the other hand, drugs that are [[Enzyme induction and inhibition|inducers]] of these enzymes such as [[rifampicin]] may lower serum nevirapine levels.<ref name=":02">{{Cite web|url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/201152s004lbl.pdf|title=VIRAMUNE® (nevirapine) Prescribing Information|url-status=dead|archive-url=https://web.archive.org/web/20161108141845/http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/201152s004lbl.pdf|archive-date=2016-11-08}}</ref><sup>[[Nevirapine#cite note-PInfo-18|[18]]]</sup>

In addition, concomitant use of  [[Hypericum perforatum|St. John's wort]] ''(Hypericum perforatum'', which has been shown to induce [[CYP3A4]] and [[CYP1A2]]<ref>{{cite journal | vauthors = Wenk M, Todesco L, Krähenbühl S | title = Effect of St John's wort on the activities of CYP1A2, CYP3A4, CYP2D6, N-acetyltransferase 2, and xanthine oxidase in healthy males and females | journal = British Journal of Clinical Pharmacology | volume = 57 | issue = 4 | pages = 495–499 | date = April 2004 | pmid = 15025748 | pmc = 1884478 | doi = 10.1111/j.1365-2125.2003.02049.x }}</ref>) or St. John's wort containing products may significantly lower nevirapine levels.<ref name=":02" />

Nevirapine is an inducer of [[Cytochrome P450 oxidase|cytochrome P450]] isoenzymes [[CYP3A4]] and [[CYP2B6]]. It may reduce 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/>

==Mechanism of action==
[[File:Nevirapine 3D.png|thumb|left|Nevirapine shown in ball and stick structure.]]
Nevirapine falls in the non-nucleoside reverse transcriptase inhibitor (NNRTI) class of antiretrovirals.<ref>{{cite journal |vauthors=Patel SS, Benfield P |title=New drug profile: nevirapine |journal=Clinical Immunotherapeutics |volume=6|issue=4|pages=307–317 |date=Oct 1996 |doi=10.1007/BF03259093|s2cid=260490614 }}</ref>  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 analogue|nucleoside]] RTIs, which bind at the polymerase active site, NNRTIs bind to a hydrophobic pocket in the subdomain of p66 which is about 10 angstrom away from the active site (known as the NNRTI pocket). Therefore, this NNRTI-binding pocket will inhibit reverse transcription in a way that is distinct to the NRTIs.<ref>{{cite journal | vauthors = Schauer GD, Huber KD, Leuba SH, Sluis-Cremer N | title = Mechanism of allosteric inhibition of HIV-1 reverse transcriptase revealed by single-molecule and ensemble fluorescence | journal = Nucleic Acids Research | volume = 42 | issue = 18 | pages = 11687–11696 | date = October 2014 | pmid = 25232099 | pmc = 4191400 | doi = 10.1093/nar/gku819 }}</ref>

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>{{cite journal | vauthors = Ren J, Bird LE, Chamberlain PP, Stewart-Jones GB, Stuart DI, Stammers DK | title = Structure of HIV-2 reverse transcriptase at 2.35-A resolution and the mechanism of resistance to non-nucleoside inhibitors | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 22 | pages = 14410–14415 | date = October 2002 | pmid = 12386343 | pmc = 137897 | doi = 10.1073/pnas.222366699 | doi-access = free | bibcode = 2002PNAS...9914410R }}</ref>

Resistance to nevirapine develops rapidly if viral replication is not completely suppressed.<ref name=INCAS_1998>{{cite journal | vauthors = Montaner JS, Reiss P, Cooper D, Vella S, Harris M, Conway B, Wainberg MA, Smith D, Robinson P, Hall D, Myers M, Lange JM | display-authors = 6 | title = A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients: the INCAS Trial. Italy, The Netherlands, Canada and Australia Study | journal = JAMA | volume = 279 | issue = 12 | pages = 930–937 | date = March 1998 | pmid = 9544767 | doi = 10.1001/jama.279.12.930 | doi-access = free }}</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] {{webarchive|url=https://web.archive.org/web/20061112162204/http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=%2FPrescribing+Information%2FPIs%2FViramune%2FViramune.pdf |date=2006-11-12 }}</ref><ref>{{cite journal | vauthors = Conway B, Wainberg MA, Hall D, Harris M, Reiss P, Cooper D, Vella S, Curry R, Robinson P, Lange JM, Montaner JS | display-authors = 6 | title = Development of drug resistance in patients receiving combinations of zidovudine, didanosine and nevirapine | journal = AIDS | volume = 15 | issue = 10 | pages = 1269–1274 | date = July 2001 | pmid = 11426071 | doi = 10.1097/00002030-200107060-00008 | s2cid = 24944611 | doi-access = free }}</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]]. However, second generation NNRTIs like [[rilpivirine]] and [[etravirine]] are effective in treatment for HIV strains resistant to nevirapine and other first generation drugs in that same class.

==History==
Nevirapine was discovered by Karl D. Hargrave and colleagues at Boehringer Ingelheim Pharmaceuticals, Inc., one of the [[Boehringer Ingelheim]] group of companies. It is covered by [http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=5366972.PN.&OS=PN/5366972&RS=PN/5366972 U.S. Patent 5,366,972] {{Webarchive|url=https://web.archive.org/web/20180920151929/http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=5366972.PN.&OS=PN%2F5366972&RS=PN%2F5366972 |date=2018-09-20 }} and corresponding foreign patents.  Nevirapine was the first NNRTI approved by the [[Food and Drug Administration (United States)|U.S. Food and Drug Administration]] (FDA). It was approved June 21, 1996 for adults and September 11, 1998, for children. It was also approved in Europe in 1997.

==Society and culture==
Former U.S. President [[George W. Bush]]'s [[President's Emergency Plan for AIDS Relief|PEPFAR funding]] of $500 million to help combat the African AIDS epidemic included nevirapine, among other medications and programs.

In South Africa, the [[Treatment Action Campaign]] successfully sued the government over its failure to make nevirapine widely available. In [[Minister of Health v Treatment Action Campaign]] the [[Constitutional Court of South Africa]] ordered the government to immediately "remove the restrictions that prevent Nevirapine from being made available for the purpose of reducing the risk of mother-to-child transmission of HIV at public hospitals and clinics that are not research and training sites [and] permit and facilitate the use of Nevirapine for the purpose of reducing the risk of mother-to-child transmission of HIV and to make it available for this purpose at hospitals and clinics when in the judgement of the attending medical practitioner acting in consultation with the medical superintendent of the facility concerned this is medically indicated, which shall if necessary include that the mother concerned has been appropriately tested and counselled."<ref name="atlantic">{{cite book | vauthors = Budlender S, Marcus G, Ferreira NM |title=Public interest litigation and social change in South Africa: Strategies, tactics and lessons| url=https://www.atlanticphilanthropies.org/wp-content/uploads/2015/12/Public-interest-litigation-and-social-change-in-South-Africa.pdf |publisher=The Atlantic Philanthropies |date=October 2014}}</ref><ref name="Time">{{cite web | title=Minister of Health and Others v Treatment Action Campaign and Others (No 2) (CCT8/02) &#91;2002&#93; ZACC 15; 2002 (5) SA 721; 2002 (10) BCLR 1033 (5 July 2002) | website=South African Legal Information Institute | date=5 July 2002 | url=http://www.saflii.org/za/cases/ZACC/2002/15.html | access-date=31 January 2022}}</ref>

== References ==
{{Reflist}}

{{Antiretroviral drug}}
{{Xenobiotic-sensing receptor modulators}}
{{Portal bar | Medicine | Viruses }}

[[Category:Drugs developed by Boehringer Ingelheim]]
[[Category:Cyclopropyl compounds]]
[[Category:CYP3A4 inducers]]
[[Category:Dermatoxins]]
[[Category:Hepatotoxins]]
[[Category:Lactams]]
[[Category:Non-nucleoside reverse transcriptase inhibitors]]
[[Category:Pyridodiazepines]]
[[Category:World Health Organization essential medicines]]
[[Category:Wikipedia medicine articles ready to translate]]