Valaciclovir

{{Short description|Antiviral medication}} {{Use dmy dates|date=October 2022}} {{Infobox drug | Verifiedfields = changed | verifiedrevid = 470627698 | image = Valaciclovir structure.svg | image_class = skin-invert-image | width = | alt = | caption = | USAN = valacyclovir hydrochloride

| pronounce = | tradename = Valtrex, Zelitrex, others | Drugs.com = {{drugs.com|monograph|valacyclovir-hydrochloride}} | MedlinePlus = a695010 | DailyMedID = Valacyclovir | pregnancy_AU = B3 | pregnancy_AU_comment = | pregnancy_category = | routes_of_administration = By mouth | class = Antiviral | ATC_prefix = J05 | ATC_suffix = AB11 | ATC_supplemental =

| legal_AU = S4 | legal_AU_comment = | legal_BR =  | legal_BR_comment = | legal_CA =  | legal_CA_comment = | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK = POM | legal_UK_comment = | legal_US = Rx-only | legal_US_comment = <ref name="Valtrex FDA label">{{cite web | title=Valtrex- valacyclovir hydrochloride tablet, film coated | website=DailyMed | date=14 June 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f8e0d8f8-cb73-4206-a484-88f5c4fbd719 | access-date=22 May 2022}}</ref> | legal_EU = | legal_EU_comment = | legal_UN =  | legal_UN_comment = | legal_status = Rx-only

| index2_label = as HCl | CAS_number_Ref = {{cascite|correct|CAS}} | CAS_number = 124832-26-4 | CAS_number2 = 124832-27-5 | CAS_supplemental = | PubChem = 135398742 | PubChem2 = 135398741 | IUPHAR_ligand = 4824 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00577 | DrugBank2 = DBSALT000289 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 54770 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = MZ1IW7Q79D | UNII2 = G447S0T1VC | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D08664 | KEGG2 = D00398 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 35854 | ChEBI2 = 9919 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 1349 | ChEMBL2 = 1201110 | NIAID_ChemDB = 070982 | PDB_ligand = | synonyms = valacyclovir

| IUPAC_name = 2-[(2-Amino-6-oxo-1''H''-purin-9-yl)methoxy]ethyl (2''S'')-2-amino-3-methylbutanoate | C=13 | H=20 | N=6 | O=4 | SMILES = O=C(OCCOCn1c2N\C(=N/C(=O)c2nc1)N)[C@@H](N)C(C)C | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C13H20N6O4/c1-7(2)8(14)12(21)23-4-3-22-6-19-5-16-9-10(19)17-13(15)18-11(9)20/h5,7-8H,3-4,6,14H2,1-2H3,(H3,15,17,18,20)/t8-/m0/s1 | StdInChI_comment = | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = HDOVUKNUBWVHOX-QMMMGPOBSA-N | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}

'''Valaciclovir''', also spelled '''valacyclovir''', is an antiviral medication used to treat outbreaks of herpes simplex or herpes zoster (shingles).<ref name=AHFS2019/> It is also used to prevent cytomegalovirus following a kidney transplant in high risk cases.<ref name=AHFS2019/> It is taken by mouth.<ref name=AHFS2019/>

Common side effects include headache and vomiting.<ref name=AHFS2019>{{cite web |title=Valacyclovir Hydrochloride Monograph for Professionals |url=https://www.drugs.com/monograph/valacyclovir-hydrochloride.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |access-date=17 March 2019 }}</ref> Severe side effects may include kidney problems.<ref name=AHFS2019/> Use in pregnancy appears to be safe.<ref name=AHFS2019/> It is a prodrug, which works after being converted to aciclovir in a person's body.<ref name=AHFS2019/>

Valaciclovir was patented in 1987 and came into medical use in 1995.<ref name=":0">{{cite book | vauthors = Long SS, Pickering LK, Prober CG |title=Principles and Practice of Pediatric Infectious Disease|date=2012|publisher=Elsevier Health Sciences|isbn=978-1-4377-2702-9|page=1502|url=https://books.google.com/books?id=nQ7-o8JAH7kC&pg=PA1502}}</ref><ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=978-3-527-60749-5 |page=504 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA504 }}</ref> Valaciclovir is a therapeutic alternative on the World Health Organization's List of Essential Medicines.<ref name="WHO24th">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines, 2025: WHO Model List of Essential Medicines, 24th list | year = 2025 | hdl = 10665/382243 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | hdl-access=free }}</ref> It is available as a generic medication.<ref name=BNF76>{{cite book|title=British national formulary: BNF 76|date=2018|publisher=Pharmaceutical Press|isbn=978-0-85711-338-2|pages=625–626|edition=76}}</ref> In 2023, it was the 98th most commonly prescribed medication in the United States, with more than 7{{nbsp}}million prescriptions.<ref name="Top300Drugs">{{cite web | title=Top 300 of 2023 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=12 August 2025 | archive-date=12 August 2025 | archive-url=https://web.archive.org/web/20250812130026/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref name="ClinCalc Valacyclovir">{{cite web | title = Valacyclovir Drug Usage Statistics, United States, 2014 - 2023 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Valacyclovir | access-date = 18 August 2025 }}</ref>

==Medical uses== thumb|Valtrex brand valaciclovir 500mg tablets

Valaciclovir is used for the treatment of HSV and VZV infections, including:<ref name="AMH2006">Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. {{ISBN|0-9757919-2-3}}{{Page needed|date=September 2010}}</ref> * Oral and genital herpes simplex (treatment and prevention) * Reduction of HSV transmission from people with recurrent infection to uninfected individuals * Herpes zoster (shingles): the typical dosage for treatment of herpes is 1,000 mg orally three times a day for seven consecutive days.<ref>{{Cite book | name-list-style = vanc |chapter = Antiviral therapies of shingles in dermatology|title=Herpes zoroster: recent aspects of diagnosis and control| vauthors = Lille HM, Wassilew SW | veditors = Gross G, Doerr H |volume=26|year=2006|page=124| series = Monographs in virology|publisher=Karger Publishers|place=Basel (Switzerland)|chapter-url=https://books.google.com/books?id=3Eh51Np2w7IC&q=valacyclovir&pg=PA124|access-date=1 January 2012|isbn=978-3-8055-7982-7}}</ref> * Prevention of cytomegalovirus following organ transplantation * Prevention of herpesviruses in immunocompromised people (such as those undergoing cancer chemotherapy)<ref name="Cancer">{{cite journal | vauthors = Elad S, Zadik Y, Hewson I, Hovan A, Correa ME, Logan R, Elting LS, Spijkervet FK, Brennan MT | display-authors = 6 |title=A systematic review of viral infections associated with oral involvement in cancer patients: a spotlight on Herpesviridea |journal=Support Care Cancer |volume=18 |issue=8 |pages=993–1006 |date=August 2010 |pmid=20544224 |doi=10.1007/s00520-010-0900-3|s2cid=2969472 }}</ref> * Chickenpox in children (ages 2–18)<ref name="Valtrex FDA label" />

It has shown promise as a treatment for infectious mononucleosis<ref name=balfour2005/><ref name=simon2003>{{Cite journal| vauthors = Simon MW, Deeter RG, Shahan B |date=March 2003 |title=The Effect of Valacyclovir and Prednisolone in Reducing Symptoms of EBV Illness In Children: A Double-Blind, Placebo-Controlled Study |journal=International Pediatrics |volume=18 |issue=3 |pages=164–169 |url=https://www.researchgate.net/publication/237508616 | via=ResearchGate}}</ref><ref name="pmid17369082" /> and is preventively administered in suspected cases of herpes B virus exposure.<ref name=":3" />

Bell's palsy does not seem to benefit from using valaciclovir as its only treatment.<ref>{{Cite journal | vauthors = Baugh RF, Basura GJ, Ishii LE, Schwartz SR, Drumheller CM, Burkholder R, Deckard NA, Dawson C, Driscoll C, Gillespie MB, Gurgel RK, Halperin J, Khalid AN, Kumar KA, Micco A, Munsell D, Rosenbaum S, Vaughan W | display-authors = 6 |date=November 2013|title=Clinical practice guideline: Bell's palsy|journal=Otolaryngology–Head and Neck Surgery|volume=149|issue=3_suppl|pages=S1–S27|doi=10.1177/0194599813505967|pmid=24189771|s2cid=36915347 |doi-access=free}}</ref><ref>{{cite journal | vauthors = Gagyor I, Madhok VB, Daly F, Sullivan F | title = Antiviral treatment for Bell's palsy (idiopathic facial paralysis) | journal = Cochrane Database Syst Rev | volume = 2019 | issue = 9| article-number = CD001869 | date = September 2019 | pmid = 31486071 | pmc = 6726970 | doi = 10.1002/14651858.CD001869.pub9 }}</ref>

==Adverse effects== Common adverse drug reactions (≥1% of people) associated with valaciclovir are the same as for aciclovir, its active metabolite. They include: nausea, vomiting, diarrhea and headache. Infrequent adverse effects (0.1–1% of patients) include: agitation, vertigo, confusion, dizziness, edema, arthralgia, sore throat, constipation, abdominal pain, rash, weakness and/or renal impairment. Rare adverse effects (<0.1% of patients) include: coma, seizures, neutropenia, leukopenia, tremor, ataxia, encephalopathy, psychotic symptoms, crystalluria, anorexia, fatigue, hepatitis, Stevens–Johnson syndrome, toxic epidermal necrolysis and/or anaphylaxis.<ref name="AMH2006" />

== Pharmacology == Valaciclovir is a prodrug, an esterified version of aciclovir that has greater oral bioavailability (about 55%) than aciclovir.<ref name="Valtrex FDA label" /> It is converted by esterases to the active drug, aciclovir, and the amino acid valine via hepatic first-pass metabolism. Aciclovir is selectively converted into a monophosphate form by viral thymidine kinase, which is more effective (3000 times) in phosphorylation of aciclovir than cellular thymidine kinase. Subsequently, the monophosphate form is further phosphorylated into a disphosphate by cellular guanylate kinase and then into the active triphosphate form, aciclo-GTP, by cellular kinases.<ref name="Valtrex FDA label" />

=== Mechanism of action === Aciclo-GTP, the active triphosphate metabolite of aciclovir, is a very potent inhibitor of viral DNA replication. Aciclo-GTP competitively inhibits and inactivates the viral DNA polymerase.<ref name="Valtrex FDA label" /> Its monophosphate form also incorporates into the viral DNA, resulting in chain termination. It has also been shown that the viral enzymes cannot remove aciclo-GMP from the chain, which results in inhibition of further activity of DNA polymerase. Aciclo-GTP is fairly rapidly metabolized within the cell, possibly by cellular phosphatases.<ref>{{cite web |url=http://www.uscnk.us/protein-antibody-elisa/Valaciclovir-%28VCV%29-V511.htm |title= Valaciclovir (VCV) - USCN LIFE SCIENCE INC|website=www.uscnk.us |archive-url=https://archive.today/20141203154533/http://www.uscnk.us/protein-antibody-elisa/Valaciclovir-(VCV)-V511.htm |archive-date= 3 December 2014 |url-status=live}}</ref>

Aciclovir is active against most species in the herpesvirus family. In descending order of activity:<ref name="OBrien1989">{{Cite journal|author=O'Brien JJ, Campoli-Richards DM |title=Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy |journal=Drugs |volume=37 |issue=3 |pages=233–309 |date=March 1989 |pmid=2653790 |doi= 10.2165/00003495-198937030-00002|s2cid=240858022 |doi-access=free }}</ref> * Herpes simplex virus type I (HSV-1) * Herpes simplex virus type II (HSV-2) * Varicella zoster virus (VZV) * Epstein–Barr virus (EBV) * Cytomegalovirus (CMV)

The drug is predominantly active against HSV and, to a lesser extent, VZV. It is only of limited efficacy against EBV and CMV. However, valaciclovir has been shown to lower or eliminate the presence of the Epstein–Barr virus in subjects afflicted with acute mononucleosis, leading to a significant decrease in the severity of symptoms.<ref name=balfour2005>{{cite conference | vauthors = Balfour HH, Hokanson KM, Schacherer RM | title = A controlled trial of valacyclovir in infectious mononucleosis. | conference = 45th Interscience Conference on Antimicrobial Agents and Chemotherapy | location = Washington, DC | date = December 2005 | pages = 16–19 | id = Abstract V1392 }}</ref><ref name=simon2003 /><ref name="pmid17369082">{{Cite journal | vauthors = Balfour HH, Hokanson KM, Schacherer RM, Fietzer CM, Schmeling DO, Holman CJ, Vezina HE, Brundage RC | display-authors = 6 |title=A virologic pilot study of valacyclovir in infectious mononucleosis |journal=Journal of Clinical Virology |volume=39 |issue=1 |pages=16–21 |date=May 2007 |pmid=17369082 |doi=10.1016/j.jcv.2007.02.002 }}</ref> Valaciclovir and acyclovir act by inhibiting viral DNA replication, but as of 2016 there was little evidence that they are effective against Epstein–Barr virus.<ref name="pmid27933614">{{cite journal | vauthors=De Paor M, O'Brien K, Smith SM | title=Antiviral agents for infectious mononucleosis (glandular fever) | journal=The Cochrane Database of Systematic Reviews | volume=2016 | issue=12 | article-number=CD011487 | year=2016 | doi = 10.1002/14651858.CD011487.pub2 | pmc=6463965 | pmid=27933614}}</ref> Acyclovir therapy does prevent viral latency, but has not proven effective at eradicating latent viruses in nerve ganglia.<ref name="OBrien1989">{{Cite journal|author=O'Brien JJ, Campoli-Richards DM |title=Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy |journal=Drugs |volume=37 |issue=3 |pages=233–309 |date=March 1989 |pmid=2653790 |doi= 10.2165/00003495-198937030-00002|s2cid=240858022 |doi-access=free }}</ref>

As of 2005, resistance to valaciclovir has not been significant. Mechanisms of resistance in HSV include deficient viral thymidine kinase and mutations to viral thymidine kinase and/or DNA polymerase that alter substrate sensitivity.<ref name="Martindale34">{{Cite book| veditors = Sweetman SC |title=Martindale: the complete drug reference |edition=34th |publisher=Pharmaceutical Press |location=London |year=2005 |isbn=0-85369-550-4 |oclc=56903116}}{{Page needed|date=September 2010}}</ref>

It also is used for herpes B virus postexposure prophylaxis.<ref name=":3">{{cite web | title=Herpes B Virus: Information For Healthcare Providers | website=U.S. Centers for Disease Control and Prevention (CDC) | date=31 January 2019 | url=https://www.cdc.gov/herpesbvirus/healthcare-providers.html | access-date=22 May 2022}}</ref><ref>{{cite journal | vauthors = Cohen JI, Davenport DS, Stewart JA, Deitchman S, Hilliard JK, Chapman LE | title = Recommendations for prevention of and therapy for exposure to B virus (cercopithecine herpesvirus 1) | journal = Clin Infect Dis | volume = 35 | issue = 10 | pages = 1191–203 | date = November 2002 | pmid = 12410479 | doi = 10.1086/344754 | s2cid = 4652818 | doi-access = free }}</ref>

== Chemistry == Details of the synthesis of valaciclovir were first published by scientists from the Wellcome Foundation. :650px|class=skin-invert-image Aciclovir was esterified with a carboxybenzyl protected valine, using dicyclohexylcarbodiimide as the dehydrating agent. In the final step, the protecting group was removed by hydrogenation using a palladium on alumina catalyst.<ref>{{cite patent |country=EP |number=308065 |status=patent |pubdate=1989-03-22 |fdate=1988-08-12 |pridate=1987-08-15 |invent1=Krenitsky, Thomas Anthony |invent2=Beauchamp, Lilia Marie |title=Therapeutic nucleosides |assign1=Wellcome Foundation}}</ref><ref>{{cite book |doi=10.1016/B978-0-12-411492-0.00034-1 |doi-access=free |chapter=34: Antiviral Drugs |title=Synthesis of Best-Seller Drugs |year=2016 | vauthors = Vardanyan R, Hruby V |page=709 |isbn=978-0-12-411492-0 |s2cid=75449475 }}</ref>

== History == Valaciclovir was patented in 1987 and came into medical use in 1995.<ref name=":0" /><ref name="Fis2006" /> It is available as a generic medication.<ref name="BNF76" /> In 2022, it was the 113th most commonly prescribed medication in the United States, with more than 5{{nbsp}}million prescriptions.<ref name="Top 300">{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref name="ClinCalc Valacyclovir" />

==Society and culture== === Brand names === It is marketed by GlaxoSmithKline under the brand names Valtrex<ref name="Valtrex FDA label" /> and Zelitrex. Valaciclovir has been available as a generic drug in the US since November 2009.<ref>{{Cite news|url=https://www.wsj.com/articles/SB125931422280866181|title=Ranbaxy Launches Generic Valtrex in U.S.| vauthors = Ahmed R |date=27 November 2009|work=The Wall Street Journal|access-date=16 January 2010}}</ref>

==References== {{Reflist}}

Category:Amino acid derivatives Category:Anti-herpes virus drugs Category:Drugs developed by GSK plc Category:Carboxylate esters Category:Ethers Category:Prodrugs Category:Purines Category:Herpes Category:World Health Organization essential medicines Category:Wikipedia medicine articles ready to translate