Valaciclovir

Valaciclovir
Names
Trade namesValtrex, Zelitrex, others
IUPAC name
  • (S)-2-[(2-amino-6-oxo-6,9-dihydro-3H-purin-9-yl)methoxy]ethyl-2-amino-3-methylbutanoate
Clinical data
Pregnancy
category
  • AU: B3
  • US: B (No risk in non-human studies)
    Routes of
    use    		By mouth
    Defined daily dose3,000 mg[1]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa695010
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only)
    • UK: POM (Prescription only)
    • US: ℞-only
    • In general: ℞ (Prescription only)
    Pharmacokinetics
    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)
    Chemical and physical data
    FormulaC13H20N6O4
    Molar mass324.341 g·mol−1
    3D model (JSmol)
    SMILES
    • O=C(OCCOCn1c2N\C(=N/C(=O)c2nc1)N)[C@@H](N)C(C)C
    InChI
    • 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

    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 as an alternative to aciclovir.[5] It is available as a generic medication.[6] A month supply in the United Kingdom costs the NHS about £3 as of 2019.[6] In the United States the wholesale cost of this amount is about US$2.80.[7] In 2020, it was the 119th most commonly prescribed medication in the United States, with more than 5 million prescriptions.[8][9]

    Medical uses

    Valtrex brand valaciclovir 500mg tablets

    Valaciclovir is used for the treatment of HSV and VZV infections, including:[10]

    • 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 by mouth three times a day for seven days.[11]
    • Prevention of cytomegalovirus following organ transplantation
    • Prevention of herpesviruses in immunocompromised people (such as those undergoing cancer chemotherapy)[12]
    • Chickenpox in children (ages 2–18)[13]

    It has shown promise as a treatment for infectious mononucleosis[14][15][16] and is preventively administered in suspected cases of herpes B virus exposure.[17]

    Valaciclovir is not recommended in Bell's palsy due to lack of benefit.[18]

    Dosage

    The defined daily dose is 3,000 mg.[1] The treatment of shingles in adults is with 1,000 mg three times per day for a week.[2] For a first episode of genital herpes 1,000 mg twice per day for up to 10 days may be used while recurrent episodes may be treated with 500 mg twice per day for three days.[2] For cold sores on the lips 2,000 mg twice per day for one day may be used.[2]

    Side effects

    Common side effects (≥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.[10]

    Pharmacology

    Valaciclovir belongs to a family of molecules. Valaciclovir is a prodrug, an esterified version of aciclovir that has greater oral bioavailability (about 55%) than aciclovir.[13] It is converted by esterases to the active drug, aciclovir, and the amino acid, valine, via liver 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.[13]

    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.[13] 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.[19]

    Aciclovir is active against most species in the herpesvirus family. In descending order of activity:[20]

    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 recently 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.[14][15][16] Although it can prevent the establishment of viral latency, acyclovir therapy has not proven effective at eradicating latent viruses in nerve ganglia.[20]

    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.[17]

    History

    Valaciclovir was patented in 1987 and came into medical use in 1995.[3][4] It is available as a generic medication.[6] A month supply in the United Kingdom costs the NHS about £3 as of 2019.[6] In the United States the wholesale cost of this amount is about US$2.80.[7] In 2017, it was the 152nd most commonly prescribed medication in the United States, with more than four million prescriptions.[8][9]

    Formulations

    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.[22]

    Valtrex is offered in 500 mg and 1 gram tablets, with the active ingredient valacyclovir hydrochloride. The inactive ingredients include carnauba wax, colloidal silicon dioxide, crospovidone, FD&C Blue No. 2 Lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, and titanium dioxide.[23]

    Society and culture

    Cost

    A month supply in the United Kingdom costs the NHS about £3 as of 2019.[6] In the United States the wholesale cost of this amount is about US$2.80.[7] In 2020, it was the 119th most commonly prescribed medication in the United States, with more than 5 million prescriptions.[8][9]

    • Valacyclovir costs (US)
      Valacyclovir costs (US)
    • Valacyclovir prescriptions (US)
      Valacyclovir prescriptions (US)

    References

    1. 1 2 "Single Drug Information – International Medical Products Price Guide". Archived from the original on 6 March 2021. Retrieved 23 August 2020.
    2. 1 2 3 4 5 6 7 8 9 10 "Valacyclovir Hydrochloride Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Archived from the original on 27 March 2020. Retrieved 17 March 2019.
    3. 1 2 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. Archived from the original on 2019-12-29. Retrieved 2017-09-17.
    4. 1 2 Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 504. ISBN 9783527607495. Archived from the original on 2016-12-20. Retrieved 2019-03-02.
    5. ↑ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl:10665/371090. WHO/MHP/HPS/EML/2023.02.
    6. 1 2 3 4 5 British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 625–626. ISBN 9780857113382.
    7. 1 2 3 "NADAC as of 2019-02-27". Centers for Medicare and Medicaid Services. Archived from the original on 2019-03-06. Retrieved 3 March 2019.
    8. 1 2 3 "The Top 300 of 2020". ClinCalc. Archived from the original on 18 March 2020. Retrieved 7 October 2022.
    9. 1 2 3 "Valacyclovir - Drug Usage Statistics". ClinCalc. Archived from the original on 8 July 2020. Retrieved 7 October 2022.
    10. 1 2 Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
    11. ↑ 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.
    12. ↑ Elad S, Zadik Y, Hewson I, 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.
    13. 1 2 3 4 "VALTREX (valacyclovir hydrochloride) Caplets -GSKSource". gsksource.com. Archived from the original on 2019-08-02. Retrieved 2019-08-02.
    14. 1 2 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
    15. 1 2 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.
    16. 1 2 Balfour HH, Hokanson KM, Schacherer RM, 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.
    17. 1 2 "B Virus—First Aid and Treatment—Herpes B—CDC". Archived from the original on March 10, 2015. Retrieved June 6, 2015.
    18. ↑ Baugh, Reginald F.; Basura, Gregory J.; Ishii, Lisa E.; Schwartz, Seth R.; Drumheller, Caitlin Murray; Burkholder, Rebecca; Deckard, Nathan A.; Dawson, Cindy; Driscoll, Colin (November 2013). "Clinical Practice Guideline: Bell's Palsy". Otolaryngology–Head and Neck Surgery. 149 (3_suppl): S1–S27. doi:10.1177/0194599813505967. ISSN 0194-5998. PMID 24189771. 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.
    19. ↑ http://www.uscnk.us/protein-antibody-elisa/Valaciclovir-%28VCV%29-V511.htm%5B%5D
    20. 1 2 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.
    21. ↑ Sweetman, Sean C., ed. (2005). Martindale: the complete drug reference (34th ed.). London: Pharmaceutical Press. ISBN 0-85369-550-4. OCLC 56903116.
    22. ↑ Ahmed, Rumman (November 27, 2009). "Ranbaxy Launches Generic Valtrex in U.S." The Wall Street Journal. Archived from the original on January 17, 2016. Retrieved January 16, 2010.
    23. ↑ "Valtrex Prescribing Information" (PDF). GlaxoSmithKline. September 2008. Archived (PDF) from the original on April 13, 2009. Retrieved May 7, 2009.
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