Valaciclovir: Difference between revisions

From Wikipedia, the free encyclopedia
Browse history interactively
← Previous editNext edit →
Content deleted Content added
VisualWikitext
m remove square brackets from bare URL inline refs. The URL is much more helpful than a random number
update infobox, refs, links; ce
Line 1: Line 1:
{{Infobox drug
{{Drugbox
| Verifiedfields = changed
| Verifiedfields = changed
| verifiedrevid = 470627698
| verifiedrevid = 470627698
| type = <!-- empty -->
⚫
| IUPAC_name = 2-[(2-Amino-6-oxo-1''H''-purin-9-yl)methoxy]ethyl (2''S'')-2-amino-3-methylbutanoate
| image = Valaciclovir structure.svg
| image = Valaciclovir structure.svg
| width =
| alt =
| caption =
| USAN = valacyclovir hydrochloride


<!--Clinical data-->
<!-- Clinical data -->
| pronounce =
| tradename = Valtrex, Zelitrex, others
| tradename = Valtrex, Zelitrex, others
| Drugs.com = {{drugs.com|monograph|valacyclovir-hydrochloride}}
| Drugs.com = {{drugs.com|monograph|valacyclovir-hydrochloride}}
| MedlinePlus = a695010
| MedlinePlus = a695010
⚫
| licence_EU =
| DailyMedID = Valacyclovir
| DailyMedID = Valacyclovir
⚫
| licence_EU =
| licence_US = Valacyclovir
| licence_US = Valacyclovir
| pregnancy_AU = B3
| pregnancy_AU = B3
| pregnancy_AU_comment =
| pregnancy_category =
| pregnancy_category =
| routes_of_administration = [[Oral administration|By mouth]]
| routes_of_administration = [[Oral administration|By mouth]]
| class =
| ATC_prefix = J05
| ATC_prefix = J05
| ATC_suffix = AB11
| ATC_suffix = AB11
| ATC_supplemental =


<!-- Legal status -->
| legal_AU = S4
| 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 = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| 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 = POM
| legal_UK = POM
| legal_UK_comment =
| legal_US = Rx-only
| 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 = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_status = Rx-only
| legal_status = Rx-only


<!--Pharmacokinetic data-->
<!-- Pharmacokinetic data -->
| bioavailability = 55%
| bioavailability = 55%
| protein_bound = 13–18%
| protein_bound = 13–18%
| metabolism = Liver (to [[aciclovir]])
| metabolism = [[Liver]] (to [[aciclovir]])
| metabolites =
| onset =
| elimination_half-life = <30 minutes (valaciclovir);<br />2.5–3.6 hours (aciclovir)
| elimination_half-life = <30 minutes (valaciclovir);<br />2.5–3.6 hours (aciclovir)
| duration_of_action =
| excretion = Kidney 40–50% (aciclovir),<br />faecal 47% (aciclovir)
| excretion = [[Kidney]] 40–50% (aciclovir),<br />faecal 47% (aciclovir)


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


<!--Chemical data-->
<!-- Chemical and physical data -->
⚫
| 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
| C=13 | H=20 | N=6 | O=4
| smiles = O=C(OCCOCn1c2N\C(=N/C(=O)c2nc1)N)[C@@H](N)C(C)C
| SMILES = O=C(OCCOCn1c2N\C(=N/C(=O)c2nc1)N)[C@@H](N)C(C)C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| 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 = 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_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = HDOVUKNUBWVHOX-QMMMGPOBSA-N
| StdInChIKey = HDOVUKNUBWVHOX-QMMMGPOBSA-N
| density =
| density_notes =
| melting_point =
| melting_high =
| melting_notes =
| boiling_point =
| boiling_notes =
| solubility =
| sol_units =
| specific_rotation =
}}
}}


Line 76: Line 125:
* [[Herpes zoster]] (shingles): the typical dosage for treatment of herpes is 1,000&nbsp;mg orally three times a day for seven consecutive days.<ref>{{Cite book|title=Herpes zoroster: recent aspects of diagnosis and control|last1=Lille|first1=H. Martina|last2=Wassilew|first2=Sawko W.|chapter = Antiviral therapies of shingles in dermatology|editor-last=Gross|editor-first=Gerd| editor2-last = Doerr| editor2-first = H.W.|volume=26|year=2006|page=124| series = Monographs in virology|publisher=[[Karger|Karger Publishers]]|place=Basel (Switzerland)|chapter-url=https://books.google.com/books?id=3Eh51Np2w7IC&q=valacyclovir&pg=PA124|access-date=January 1, 2012|isbn=978-3-8055-7982-7}}</ref>
* [[Herpes zoster]] (shingles): the typical dosage for treatment of herpes is 1,000&nbsp;mg orally three times a day for seven consecutive days.<ref>{{Cite book|title=Herpes zoroster: recent aspects of diagnosis and control|last1=Lille|first1=H. Martina|last2=Wassilew|first2=Sawko W.|chapter = Antiviral therapies of shingles in dermatology|editor-last=Gross|editor-first=Gerd| editor2-last = Doerr| editor2-first = H.W.|volume=26|year=2006|page=124| series = Monographs in virology|publisher=[[Karger|Karger Publishers]]|place=Basel (Switzerland)|chapter-url=https://books.google.com/books?id=3Eh51Np2w7IC&q=valacyclovir&pg=PA124|access-date=January 1, 2012|isbn=978-3-8055-7982-7}}</ref>
* Prevention of [[cytomegalovirus]] following [[organ transplantation]]
* 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, etal |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>
* 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=":2">{{Cite web|url=https://gsksource.com/pharma/content/gsk/source/us/en/brands/valtrex.html|title=VALTREX (valacyclovir hydrochloride) Caplets -GSKSource|website=gsksource.com|access-date=2019-08-02}}</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|first=Michael W. |last=Simon |author2=Robert G. Deeter |author3=Britt Shahan |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=http://int-pediatrics.com/PDF/Volume_18/18-3/164_169_ip1803.pdf }}{{dead link|date=May 2012}}</ref><ref name="pmid17369082" /> and is preventively administered in suspected cases of herpes B virus exposure.<ref name=":3" />
It has shown promise as a treatment for [[infectious mononucleosis]]<ref name=balfour2005/><ref name=simon2003>{{Cite journal|first=Michael W. |last=Simon |author2=Robert G. Deeter |author3=Britt Shahan |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=http://int-pediatrics.com/PDF/Volume_18/18-3/164_169_ip1803.pdf }}{{dead link|date=May 2012}}</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 Valaciclovir.<ref>{{Cite journal|last1=Baugh|first1=Reginald F.|last2=Basura|first2=Gregory J.|last3=Ishii|first3=Lisa E.|last4=Schwartz|first4=Seth R.|last5=Drumheller|first5=Caitlin Murray|last6=Burkholder|first6=Rebecca|last7=Deckard|first7=Nathan A.|last8=Dawson|first8=Cindy|last9=Driscoll|first9=Colin|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|issn=0194-5998|quote = In summary, antiviral therapy alone (acyclovir or valacyclovir) is not recommended in the treatment of Bell’s palsy due to lack of effectiveness of currently available drugs, unnecessary cost, and the potential for drug-related complications.}}</ref>
[[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 }}</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 = 9 | issue = | pages = CD001869 | date = September 2019 | pmid = 31486071 | pmc = 6726970 | doi = 10.1002/14651858.CD001869.pub9 }}</ref>


==Adverse effects==
==Adverse effects==
Line 87: Line 136:


== Pharmacology ==
== Pharmacology ==
Valaciclovir is a prodrug, an [[ester]]ified version of [[aciclovir]] that has greater oral bioavailability (about 55%) than aciclovir.<ref name=":2" /> It is converted by [[esterase]]s 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-[[Guanosine triphosphate|GTP]], by cellular [[kinase]]s.<ref name=":2" />
Valaciclovir is a prodrug, an [[ester]]ified version of [[aciclovir]] that has greater oral bioavailability (about 55%) than aciclovir.<ref name="Valtrex FDA label" /> It is converted by [[esterase]]s 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-[[Guanosine triphosphate|GTP]], by cellular [[kinase]]s.<ref name="Valtrex FDA label" />


=== Mechanism of action ===
=== Mechanism of action ===
Aciclo-GTP, the active triphosphate metabolite of aciclovir, is a very potent inhibitor of [[Viral disease|viral]] [[DNA replication]]. Aciclo-GTP competitively inhibits and inactivates the [[Virus|viral]] [[DNA polymerase]].<ref name=":2" /> Its monophosphate form also incorporates into the viral DNA, resulting in [[protein biosynthesis|chain termination]]. It has also been shown that the viral enzymes cannot remove aciclo-[[GMP synthase (glutamine—hydrolysing)|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 [[phosphatase]]s.<ref>https://web.archive.org/web/20180914060811/http://www.uscnk.us/protein-antibody-elisa/Valaciclovir-%28VCV%29-V511.htm</ref>
Aciclo-GTP, the active triphosphate metabolite of aciclovir, is a very potent inhibitor of [[Viral disease|viral]] [[DNA replication]]. Aciclo-GTP competitively inhibits and inactivates the [[Virus|viral]] [[DNA polymerase]].<ref name="Valtrex FDA label" /> Its monophosphate form also incorporates into the viral DNA, resulting in [[protein biosynthesis|chain termination]]. It has also been shown that the viral enzymes cannot remove aciclo-[[GMP synthase (glutamine—hydrolysing)|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 [[phosphatase]]s.<ref>https://web.archive.org/web/20180914060811/http://www.uscnk.us/protein-antibody-elisa/Valaciclovir-%28VCV%29-V511.htm</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}}</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}}</ref>
Line 100: Line 149:
*[[Cytomegalovirus]] (CMV)
*[[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, valacyclovir 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>Balfour ''et al.'' (December 2005) A controlled trial of valacyclovir in infectious mononucleosis. Presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC., December 18, 2005. Abstract V1392</ref><ref name=simon2003>{{Cite journal|first=Michael W. |last=Simon |author2=Robert G. Deeter |author3=Britt Shahan |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=http://int-pediatrics.com/PDF/Volume_18/18-3/164_169_ip1803.pdf }}{{dead link|date=May 2012}}</ref><ref name="pmid17369082">{{Cite journal |vauthors=Balfour HH, Hokanson KM, Schacherer RM, etal |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, they are expensive, they risk causing resistance to [[Antiviral drug|antiviral agents]],{{Citation needed|date=March 2022}} and (in 1% to 10% of cases) can cause unpleasant [[side effect]]s.<ref name="pmid27933614">{{cite journal | vauthors=De Paor M, O'Brien K, Smith SM | title=Antiviral agents for infectious mononucleosis (glandular fever) | journal=[[Cochrane Library#The Cochrane Database of Systematic Reviews|The Cochrane Database of Systematic Reviews]] | volume=2016 | issue=12 | pages=CD011487 | year=2016 | doi = 10.1002/14651858.CD011487.pub2 | pmc=6463965 | pmid=27933614}}</ref> Acyclovir therapy does prevent [[Virus latency|viral latency]], but has not proven effective at eradicating latent viruses in [[ganglion|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}}</ref>
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>Balfour ''et al.'' (December 2005) A controlled trial of valaciclovir in infectious mononucleosis. Presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC., December 18, 2005. Abstract V1392</ref><ref name=simon2003>{{Cite journal|first=Michael W. |last=Simon |author2=Robert G. Deeter |author3=Britt Shahan |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=http://int-pediatrics.com/PDF/Volume_18/18-3/164_169_ip1803.pdf }}{{dead link|date=May 2012}}</ref><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, they are expensive, they risk causing resistance to [[Antiviral drug|antiviral agents]],{{Citation needed|date=March 2022}} and (in 1% to 10% of cases) can cause unpleasant [[side effect]]s.<ref name="pmid27933614">{{cite journal | vauthors=De Paor M, O'Brien K, Smith SM | title=Antiviral agents for infectious mononucleosis (glandular fever) | journal=[[Cochrane Library#The Cochrane Database of Systematic Reviews|The Cochrane Database of Systematic Reviews]] | volume=2016 | issue=12 | pages=CD011487 | year=2016 | doi = 10.1002/14651858.CD011487.pub2 | pmc=6463965 | pmid=27933614}}</ref> Acyclovir therapy does prevent [[Virus latency|viral latency]], but has not proven effective at eradicating latent viruses in [[ganglion|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}}</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|editor-first=Sean C. |editor-last=Sweetman |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>
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|editor-first=Sean C. |editor-last=Sweetman |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|url=https://www.cdc.gov/herpesBvirus/firstaid-treatment.html|title=B Virus—First Aid and Treatment—Herpes B—CDC|access-date=June 6, 2015}}</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 }}</ref>


== Chemistry ==
== Chemistry ==
Line 114: Line 163:
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 2019, it was the 110th most commonly prescribed medication in the United States, with more than 5{{nbsp}}million prescriptions.<ref name="Top 300" /><ref name="ClinCalc Valacyclovir" />
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 2019, it was the 110th most commonly prescribed medication in the United States, with more than 5{{nbsp}}million prescriptions.<ref name="Top 300" /><ref name="ClinCalc Valacyclovir" />


==Society and culture ==
==Formulations==
=== Brand names ===
It is marketed by [[GlaxoSmithKline]] under the trade names Valtrex and Zelitrex. Valaciclovir has been available as a generic drug in the U.S. since November 25, 2009.<ref>{{Cite news|url=https://www.wsj.com/articles/SB125931422280866181|title=Ranbaxy Launches Generic Valtrex in U.S.|last=Ahmed|first=Rumman|date=November 27, 2009|work=[[The Wall Street Journal]]|access-date=January 16, 2010}}</ref>
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 U.S. since November 2009.<ref>{{Cite news|url=https://www.wsj.com/articles/SB125931422280866181|title=Ranbaxy Launches Generic Valtrex in U.S.|last=Ahmed|first=Rumman|date=November 27, 2009|work=[[The Wall Street Journal]]|access-date=January 16, 2010}}</ref>

Valtrex is offered in 500&nbsp;mg and 1&nbsp;gram tablets, with the active ingredient valacyclovir hydrochloride. The inactive ingredients include [[carnauba wax]], colloidal silicon dioxide, [[crospovidone]], [[Indigo carmine|FD&C Blue No. 2]] [[Lake pigment|Lake]], [[hypromellose]], [[magnesium stearate]], [[microcrystalline cellulose]], [[polyethylene glycol]], [[polysorbate 80]], [[povidone]], and [[titanium dioxide]].<ref>{{cite web|url=http://us.gsk.com/products/assets/us_valtrex.pdf|title=Valtrex Prescribing Information|date=September 2008|publisher=[[GlaxoSmithKline]]|access-date=May 7, 2009}}</ref>


==References==
==References==
Line 124: Line 172:
==External links==
==External links==
* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/valaciclovir | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Valaciclovir }}
* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/valaciclovir | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Valaciclovir }}
* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/valacyclovir%20hydrochloride | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Valacyclovir hydrochloride }}


{{Antivirals}}
{{Antivirals}}

Revision as of 19:07, 22 May 2022

Valaciclovir
Clinical data
Trade namesValtrex, Zelitrex, others
Other namesvalacyclovir, valacyclovir hydrochloride (USAN US)
AHFS/Drugs.comMonograph
MedlinePlusa695010
License data
Pregnancy
category
  • AU: B3
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only[1]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability55%
Protein binding13–18%
MetabolismLiver (to aciclovir)
Elimination half-life<30 minutes (valaciclovir);
2.5–3.6 hours (aciclovir)
ExcretionKidney 40–50% (aciclovir),
faecal 47% (aciclovir)
Identifiers
  • 2-[(2-Amino-6-oxo-1H-purin-9-yl)methoxy]ethyl (2S)-2-amino-3-methylbutanoate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard100.114.479 Edit this at Wikidata
Chemical and physical data
FormulaC13H20N6O4
Molar mass324.341 g·mol−1
3D model (JSmol)
  • O=C(OCCOCn1c2N\C(=N/C(=O)c2nc1)N)[C@@H](N)C(C)C
  • InChI=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 checkY
  • Key:HDOVUKNUBWVHOX-QMMMGPOBSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Valaciclovir, also spelled valacyclovir, is an antiviral medication used to treat outbreaks of herpes simplex or herpes zoster (shingles).[2] It is also used to prevent cytomegalovirus following a kidney transplant in high risk cases.[2] It is taken by mouth.[2]

Common side effects include headache and vomiting.[2] Severe side effects may include kidney problems.[2] Use in pregnancy appears to be safe.[2] It is a prodrug, which works after being converted to aciclovir in a person's body.[2]

Valaciclovir was patented in 1987 and came into medical use in 1995.[3][4] It is on the World Health Organization's List of Essential Medicines.[5] It is available as a generic medication.[6] In 2019, it was the 110th most commonly prescribed medication in the United States, with more than 5 million prescriptions.[7][8]

Medical uses

Valtrex brand valaciclovir 500mg tablets

Valaciclovir is used for the treatment of HSV and VZV infections, including:[9]

  • 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.[10]
  • Prevention of cytomegalovirus following organ transplantation
  • Prevention of herpesviruses in immunocompromised people (such as those undergoing cancer chemotherapy)[11]
  • Chickenpox in children (ages 2–18)[1]

It has shown promise as a treatment for infectious mononucleosis[12][13][14] and is preventively administered in suspected cases of herpes B virus exposure.[15]

Bell's palsy does not seem to benefit from using valaciclovir as its only treatment.[16][17]

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.[9]

Pharmacology

Valaciclovir is a prodrug, an esterified version of aciclovir that has greater oral bioavailability (about 55%) than aciclovir.[1] 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.[1]

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.[1] 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.[18]

Aciclovir is active against most species in the herpesvirus family. In descending order of activity:[19]

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.[12][13][14] 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, they are expensive, they risk causing resistance to antiviral agents,[citation needed] and (in 1% to 10% of cases) can cause unpleasant side effects.[20] Acyclovir therapy does prevent viral latency, but has not proven effective at eradicating latent viruses in nerve ganglia.[19]

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.[21]

It also is used for herpes B virus postexposure prophylaxis.[15][22]

Chemistry

Details of the synthesis of valaciclovir were first published by scientists from the Wellcome Foundation.

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.[23][24]

History

Valaciclovir was patented in 1987 and came into medical use in 1995.[3][4] It is available as a generic medication.[6] In 2019, it was the 110th most commonly prescribed medication in the United States, with more than 5 million prescriptions.[7][8]

Society and culture

Brand names

It is marketed by GlaxoSmithKline under the brand names Valtrex[1] and Zelitrex. Valaciclovir has been available as a generic drug in the U.S. since November 2009.[25]

References

  1. ^ a b c d e f "Valtrex- valacyclovir hydrochloride tablet, film coated". DailyMed. 14 June 2021. Retrieved 22 May 2022.
  2. ^ a b c d e f g "Valacyclovir Hydrochloride Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 17 March 2019.
  3. ^ a b Long, Sarah S.; Pickering, Larry K.; Prober, Charles G. (2012). Principles and Practice of Pediatric Infectious Disease. Elsevier Health Sciences. p. 1502. ISBN 978-1437727029.
  4. ^ a b Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 504. ISBN 9783527607495.
  5. ^ World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
  6. ^ a b British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 625–626. ISBN 9780857113382.
  7. ^ a b "The Top 300 of 2019". ClinCalc. Retrieved 16 October 2021.
  8. ^ a b "Valacyclovir - Drug Usage Statistics". ClinCalc. Retrieved 16 October 2021.
  9. ^ a b Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3[page needed]
  10. ^ Lille, H. Martina; Wassilew, Sawko W. (2006). "Antiviral therapies of shingles in dermatology". In Gross, Gerd; Doerr, H.W. (eds.). Herpes zoroster: recent aspects of diagnosis and control. Monographs in virology. Vol. 26. Basel (Switzerland): Karger Publishers. p. 124. ISBN 978-3-8055-7982-7. Retrieved January 1, 2012.
  11. ^ Elad S, Zadik Y, Hewson I, Hovan A, Correa ME, Logan R, et al. (August 2010). "A systematic review of viral infections associated with oral involvement in cancer patients: a spotlight on Herpesviridea". Support Care Cancer. 18 (8): 993–1006. doi:10.1007/s00520-010-0900-3. PMID 20544224. S2CID 2969472.
  12. ^ a b Balfour et al. (December 2005) A controlled trial of valaciclovir in infectious mononucleosis. Presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC., December 18, 2005. Abstract V1392
  13. ^ a b Simon, Michael W.; Robert G. Deeter; Britt Shahan (March 2003). "The Effect of Valacyclovir and Prednisolone in Reducing Symptoms of EBV Illness In Children: A Double-Blind, Placebo-Controlled Study" (PDF). International Pediatrics. 18 (3): 164–169.[dead link]
  14. ^ a b Balfour HH, Hokanson KM, Schacherer RM, Fietzer CM, Schmeling DO, Holman CJ, et al. (May 2007). "A virologic pilot study of valacyclovir in infectious mononucleosis". Journal of Clinical Virology. 39 (1): 16–21. doi:10.1016/j.jcv.2007.02.002. PMID 17369082.
  15. ^ a b "Herpes B Virus: Information For Healthcare Providers". U.S. Centers for Disease Control and Prevention (CDC). 31 January 2019. Retrieved 22 May 2022.
  16. ^ Baugh RF, Basura GJ, Ishii LE, Schwartz SR, Drumheller CM, Burkholder R, et al. (November 2013). "Clinical practice guideline: Bell's palsy". Otolaryngology–Head and Neck Surgery. 149 (3_suppl): S1–S27. doi:10.1177/0194599813505967. PMID 24189771. S2CID 36915347.
  17. ^ Gagyor I, Madhok VB, Daly F, Sullivan F (September 2019). "Antiviral treatment for Bell's palsy (idiopathic facial paralysis)". Cochrane Database Syst Rev. 9: CD001869. doi:10.1002/14651858.CD001869.pub9. PMC 6726970. PMID 31486071.
  18. ^ https://web.archive.org/web/20180914060811/http://www.uscnk.us/protein-antibody-elisa/Valaciclovir-%28VCV%29-V511.htm
  19. ^ a b O'Brien JJ, Campoli-Richards DM (March 1989). "Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy". Drugs. 37 (3): 233–309. doi:10.2165/00003495-198937030-00002. PMID 2653790.
  20. ^ De Paor M, O'Brien K, Smith SM (2016). "Antiviral agents for infectious mononucleosis (glandular fever)". The Cochrane Database of Systematic Reviews. 2016 (12): CD011487. doi:10.1002/14651858.CD011487.pub2. PMC 6463965. PMID 27933614.
  21. ^ Sweetman, Sean C., ed. (2005). Martindale: the complete drug reference (34th ed.). London: Pharmaceutical Press. ISBN 0-85369-550-4. OCLC 56903116.[page needed]
  22. ^ Cohen JI, Davenport DS, Stewart JA, Deitchman S, Hilliard JK, Chapman LE (November 2002). "Recommendations for prevention of and therapy for exposure to B virus (cercopithecine herpesvirus 1)". Clin Infect Dis. 35 (10): 1191–203. doi:10.1086/344754. PMID 12410479.
  23. ^ EP patent 308065, Krenitsky, Thomas Anthony & Beauchamp, Lilia Marie, "Therapeutic nucleosides", published 1989-03-22, assigned to Wellcome Foundation 
  24. ^ Vardanyan, Ruben; Hruby, Victor (2016). "34: Antiviral Drugs". Synthesis of Best-Seller Drugs. p. 709. doi:10.1016/B978-0-12-411492-0.00034-1. ISBN 9780124114920. S2CID 75449475.
  25. ^ Ahmed, Rumman (November 27, 2009). "Ranbaxy Launches Generic Valtrex in U.S." The Wall Street Journal. Retrieved January 16, 2010.

External links

Retrieved from "https://en.wikipedia.org/w/index.php?title=Valaciclovir&oldid=1089252311"